摘要:

1 Introduction By JOHN A. JOULEaAND JOHN P. RICHARDb aDepartment of Chemistry The University of Manchester Manchester UK M13 9PL bDepartment of Chemistry State University of New York at Buffalo Buffalo NY 14260–3000 USA Annual Reports B aims to provide an overview of the most important advances and achievements in Organic Chemistry and related fields described in the literature of a calendar year. It is not comprehensive and is not intended to be comprehensive. The reviewers comment and emphasise the significance and usefulness–of new synthetic methods of newNMRtechniques of new chromatographic methods etc.–so that the non-specialist can use the volume as an easy access to recent significant developments. It aims to be a short-cut to useful recent material. It is the only publication which provides this global year-by-year coverage.It is di¶cult to define subjects for chapters to prevent overlap–perhaps this is not a fault for topics can be usefully discussed from more than one viewpoint. This year sees material subdivided in a somewhat di§erent way to that employed in previous volumes in this series. The Scientific Editors would welcome comments on this new format and suggestions for its improvement. Reviews of Biosynthesis (dealt with this year) will be biennial covering a two-year period and will alternate with two-year reviews of Natural Products. The interests of organic synthesis will we hope be better served by new subdivisions chapters on Pericyclic Methods Heteroatom Methods Free-radical Reactions Enzyme Chemistry and Protecting Groups will focus attention.Organometallic chemistry formerly covered as a single non-focused chapter has been subdivided into discussions of Stoichiometric Methods and Palladium and Nickel Catalysed Methods. Discussions of Aromatic Chemistry and of Heterocyclic Chemistry follow the pattern of previous Volumes. The chemistry of organic polymers will be covered on a biennial basis–Synthesis of Man-made Polymers (dealt with this year) alternating with Natural Polymers. Finally a chapter on Synthesis Highlights–the year’s tours de force–will concentrate on the strategic aspects of such achievements. This volume features several chapters on topics which have been neglected in recent years. The chapter on Free-radical Reactions provides coverage of thermochemical and theoretical studies on neutral free-radical and radical ions.The characterization of novel pathways for the generation of these species is reported and studies of the mechanisms for their rearrangement elimination and addition reactions are summarized. The chapter on Bioorganic Chemistry presents an overview of recent advances in our understanding of the chemical mechanism for enzyme catalysis of simple 1 organic reactions and on the role and mechanism of action of coenzymes in these reactions. The chapter on NMR Spectroscopy describes recent advances in the application of NMR to monitoring the progress of organic reactions to the determination of the chemical structure and conformation of complex organic molecules and to the development of structure–activity relationships for drug discovery. In addition advances in NMR methodology of specific interest to the organic chemist are reviewed. Many of these chapters provide evidence for the increasing reliance placed on modern computational methods in rationalizing the results of studies on organic reaction mechanisms. The chapter on Theoretical Organic Chemistry provides an indepth description of recent advances in computational chemistry which allow for calculation of the structure and energy of stable organic molecules and of unstable reaction intermediates and transition states with an ever-increasing degree of accuracy. 2 John A. Joule and John P. Richard

ISSN:0069-3030    

DOI:10.1039/oc094001

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

2 Synthetic methods Part (i) Free-radical reactions By S. CADDICK N. J. PARR and S. SHANMUGATHASAN The Chemistry Laboratory School of Chemistry Physics and Environmental Science University of Sussex Falmer Brighton UK BN1 9QJ 1 Introduction It is with great regret that at the time of writing this report we note the recent death of Professor Sir Derek H. R. Barton. Professor Barton’s numerous pioneering contributions to the area of free-radical research are well-known and his contributions to chemistry will be sorely missed. Most notably in recent times his desire to clarify and develop the mechanistically complex and synthetically valuable GIF chemistry has been impressive and once again over the last year he sought to add to1 and clarify the state-of-play2 with regard to the involvement of free-radicals in these systems.The e§ect of radicals in biology is of fundamental importance and chemists continue to provide important mechanistic detail on which new developments can be based. Recent model studies on 4@-DNA radicals have shown a radical cation as an intermediate in strand cleavage.3 Moreover double-stranded 4@-DNA radicals are pyramidalised have half-lives of milliseconds and undergo highly stereoselective H-abstraction with suitable donors to give natural DNA double strands.4 2 Initiators promoters and reagents One of the di¶culties with using tin-based systems to initiate free-radical reactions is the isolation of products with high purity. In the last year there have been a number of reports on the use of fluorous tin reagents.5 The main benefit of these procedures is in their simplified purification achieved by partitioning into a triphasic mixture of organic aqueous and perfluoroalkane allowing the tin species and the product to be separated and isolated.6 The ability to conduct these reactions in fluorinated or supercritical fluids7 is also significant and it is likely that these protocols will gain widespread application in synthesis.The understanding of relative rates of radical reactions is critical for the development of synthetic procedures and in particular the strategic introduction of additional propagation steps can improve levels of synthetic e¶ciency. Recent reports have detailed the use of (PhSe) 2 to improve the rate of H-donation in the fragmentation of b-lactones as highlighted in the transformation of 1 to 2 and 3 which is poor in the absence of (PhSe) 2 (Scheme 1).8 3 O Ph Ph Ph Br (PhSe)2 AlBN TBTH 1 2 3 Yield 84% (2:3 � 95:5) O Scheme 1 Br O S OEt CN S Br O CN Dilauroyl peroxide (1 equiv.) DCE 4 5 Yield 56% Scheme 2 It is now accepted that methods for initiation need to be carefully considered when carrying out radical reactions.A nice example of the use of a stoichiometric quantity of a conventional initiator has been recently reported in the synthesis of a-tetralones.9 Thus treatment of a substrate such as 4 (itself synthesised via an intermolecular radical addition process) with stoichiometric dilauroyl peroxide generates the product 5 (Scheme 2).It is assumed that the presumed intermediate cyclohexadienyl radical cannot propagate the chain and eventually undergoes aromatisation hence the requirement for stoichiometric peroxide.This protocol is particularly noteworthy because it avoids the use of an organotin reagent. The employment of the more conventional initiator AIBN in conjunction with TBTH needs to be carefully studied in order to avoid the generation of undesirable products. In a recent report it has been shown that the cyanoisopropyl radical undergoes addition reactions with certain substituted alkynes (TMS Ph CO 2 R) but not with others (alkyl) and that unusual cyclisations onto the cyano triple bond can take place.10 Deoxygenation has long been recognised as important in organic synthesis. In an exciting piece of synthetic method development a new deoxygenation protocol for primary and secondary alcohols has been described.11 A single-step Mitsunobu procedure is employed to prepare a monoalkyl diazene which has been detected spectroscopically.This then undergoes a concerted sigmatropic elimination of dinitrogen generating an alkyl radical. The involvement of a free-radical is likely in view of the transformations of 6 and 8 to 7 and 9 respectively and the isolation of hex-1-ene from cyclisation of 8 when the reaction was carried out at room temperature. The procedure has been found to be sensitive to steric hindrance as is evident by the selective deoxygenation of 10 to give 11. Elimination can in some cases intervene as is illustrated in the preparation of interesting polyene systems e.g. 13 from 12 (Scheme 3). 4 S. Caddick N. J. Parr and S. Shanmugathasan OH N O N O OH PPh3 DEAD NBSH O2 THF 6 7 Yield 84% OH PPh3 DEAD NBSH NMM 8 9 Yield 66% H H OH H HO H H H HO H PPh3 DEAD NBSH THF 10 11 Yield 84% CH2OH CH2 PPh3 DEAD NBSH NMM 12 13 Yield 65% Scheme 3 3 Intramolecular reactions Cyclisation reactions continue to dominate the field of radical chemistry and in a very elegant atom-transfer process Nicholas and co-workers have devised highly regio- and stereo-selective annulation processes;12 irradiation of bromides 14 15 and 16 leads to products 17–20 (Scheme 4).The regio- and stereo-selectivity of the transformations are rationalised by a late product-like transition state. In the formation of bromosulfonyl dienes 24–26 by radical cyclisation of their precursor diynes 21–23 the authors rely on the use of electrophilic tosyl radicals to promote these cyclisations successfully (Scheme 5).13 Isolation of good yields of cyclic bis-sulfonyl dienes such as 28 from 27 was achieved when an excess of p-toluenesulfonyl bromide was used (Scheme 6).The formation of medium and larger rings continues to attract considerable atten- 5 Synthetic methods Part (i) Free-radical reactions Br Ph Co2(CO)6 R Ph Co2(CO)6 Ph Co2(CO)6 Ph Co2(CO)6 Ph R Br Br Br Br 14–16 18 19 17 20 Yield 73% Yield 60% (18:19 1:1) Yield 56% hn hn hn (R = Me) (R = CO2Me) (R = H) Scheme 4 X R X R Br Ts TsBr AIBN C6H6 21–23 R = H X = N 24 R = H X = O 25 R = Me X = C(CO2Me)2 26 Yields 40–91% Scheme 5 EtO2CCO2Et Ts Ts EtO2CCO2Et TsBr AIBN C6H6 27 28 Yield 91% Scheme 6 tion from synthetic chemists. A recent study demonstrates that six to nine membered cyclic amino acid derivatives can be prepared by a tin mediated radical cyclisation as illustrated in the transformation of 29 to 30 (Scheme 7).14 In a similar fashion Beckwith and co-workers have shown that macrocyclic polyethers can be synthesised 6 S.Caddick N. J. Parr and S. Shanmugathasan Boc N CO2 Me I ( ) n NBoc ( ) n CO2Me AIBN TBTH DBU 29 30 n = 0–3 Yields 52–73% Scheme 7 R O O O I O O O O R O n TBTH AIBN C6H6 31 n = 1–4 R = H CO2Et CO2But 32 Yields 29–78% n Scheme 8 I O O H O O H TBTH AIBN 33 34 Yields 45–60% Scheme 9 O I O O O TBTH AIBN 35 36 Yield 40% Scheme 10 e¶ciently by radical cyclisation (e.g. 31 to 32 Scheme 8).15 The presence of oxygen is known to accelerate the rate of small ring radical cyclisation and extensions to macrocycle formation are preparatively useful and mechanistically interesting. In studies toward the taxane skeleton Pattenden and co-workers have exploited a radical cascade of compound 33 which involves a 12-endo-dig macrocyclisation followed by a 6-exo-8-endo cyclisation a§ording 34 in good yield (45–60%) (Scheme 9).16 Success with these demanding types of cyclisation are dependent upon a number of features perhaps the most obvious appears to be related to the presence of the alkyne and indeed in related work the same group have exploited ynones in cascade processes exemplified in the transformation of 35 to 36 (Scheme 10).17 Vinyl cyclopropanes have 7 Synthetic methods Part (i) Free-radical reactions I O H H H H H H O O H H TTMSS AIBN C6H6 37 38 39 Yield 65% (38:39 2:1) R1 R2 R3 O SePh O R1 R2 R3 TBTH AIBN 40 41 Yields 40–66% R1 = H alkyl Ph R2 = H alkyl Scheme 11 O I Ph O Ph O Ph BEt3 TBTH PhCH3 O Pr I O Pr 42 43 53% ATPH 44 16% ( E/ Z = 54:46) 99% ( E/ Z = 19:81) Et3B TBTH PhCH3 45 46 95% ( cis/ trans = 3:97) ATPH 99% ( cis/ trans = 92:8) Sche 12 also been utilised as electrophores in macrocyclisation processes (37 to 38 39)18 and in a novel cyclisation approach to cyclohexenones (40 to 41 Scheme 11).19 Stereocontrol This is an attractive aspect of many synthetically important cyclisation reactions and understanding of the features associated with stereoselectivity has been enhanced again this year.The use of Lewis acids is well documented and in some impressive examples aluminium tris(2,6-diphenyl)phenoxide (ATPH) has been shown to improve the stereochemical outcome (e.g. 42–44 and 45–46 Scheme 12).20 The experimental procedures involve pre-coordination of reagent and substrate followed by a Et 3 B–TBTH mediated cyclisation.The use of covalently bound stereoinducing elements is also an attractive strategy and Curran and collaborators have extended the principles of Unimolecular Chain Transfer (UMCT) to control the stereochemical outcome of cyclisation reactions. Although the governing factors have yet to be fully 8 S. Caddick N. J. Parr and S. Shanmugathasan I OSi H Ph Ph H O Si H I (Bu3Sn)2 hn C6H6 47 48 Yield 53% I OSi Ph Ph H O Si TBTH AIBN C6H6 49 50 Z/ E 95:5 Scheme 13 I OH BnO BnO BnO BnO BnO BnO OH NaOEt NaBH4 Co(Salen) air 51 52 53 Yield 57% (52:53 4:1) Scheme 14 delineated some highly stereoselective procedures have been developed as illustrated in the isolation of 48 and 50 from 47 and 49 using TBTH (Scheme 13).21,22 The control of stereochemistry by employing radical-based transformations in carbohydrate chemistry has been the subject of intensive investigations and the synthesis of carbocycles from carbohydrates has been an important part of this area.23 A cobalt-mediated oxidative cyclisation protocol is illustrated in the transformation of 51 to 52; in order to be successful the cyclisation rate must be faster than oxidation of the initially formed radical as highlighted by the formation of 53 (Scheme 14).24 The synthesis and utility of a-amin‘o acids in radical-based synthesis has also seen considerable activity.Bowman and co-workers have attempted to use the chirality of amino acids to induce stereocontrol in cyclisations for the preparation of unusual cyclic amino acids.The reactions proceed as expected but with moderate selectivities and yields exemplified in the synthesis of the proline derivative 55 from 54 (Scheme 15).25 Aryl radicals The generation of highly reactive aryl radicals from arenediazonium salts has been cleverly exploited in a novel indole synthesis involving ipso substitution of vinyl bromides (56 to 57) (Scheme 16).26 In many cases tetrathiafulvalene (TTF) is used to promote the decomposition of diazonium salts and recent studies have discounted a purely ionic mechanism for a range of established synthetic reactions.27 This ability to generate aryl radicals from arenediazonium salts has also been used to form acyl radicals by intramolecular acyl substitution. The involvement of acyl rad- 9 Synthetic methods Part (i) Free-radical reactions N N SPh H CO2 R2 R1 H CO2 R2 R1 TBTH AMBN PhMe 54 55 R1 R2 = alkyl Yields 20–48% de 20–48 Scheme 15 N NR2 R1 R2 R1 N2 Br SO2Me SO2Me BF4 – NaI Acetone 56 57 R1 = H Me Ph; R2 = H Me Yields 44–83% Scheme 16 S N2 + O S O O O NaI Acetone 58 59 60 Yields 81% 90% BF4 – Scheme 17 icals is suggested as they can be trapped in conventional addition processes e.g.58 to 59 and 60 (Scheme 7).28 Aryl radical cyclisations have provided a useful vehicle for demonstrating the feasibility of intramolecular solid-phase radical reactions. In addition to the obvious applications of such approaches in the combinatorial chemistry area a particularly attractive benefit is their ease of purification. Appropriate resin choice has been shown to be important for example the use of TentaGel resin enables the transformation of 61 to 62 using 5–6mol% AIBN and a large excess of TBTH,29 and a related samarium mediated cyclisation of 63 to 64 used Rink resins (Scheme 18).30 It is clear that radical cyclisations can be carried out on solid support and it is likely that a wide range of related reports will be forthcoming in the near future.The intramolecular addition of aryl radicals to aromatic rings to generate biaryl systems can be e§ected via ipso substitution of sulfonamides. This method compares favourably with the majority of ionic methodologies which are commonly employed particularly as the conditions would be expected to tolerate a wide range of functional groups including electron-withdrawing or -donating substituents on the aromatic ring as illustrated in the formation of 66 from 65 (Scheme 19).31 However as the authors note the scope of the procedure is not easily predicted due to the many subtle features which have a profound e§ect on the feasibility of a particular variant.32 10 S.Caddick N. J. Parr and S. Shanmugathasan O Br O O O O O H2N H2N O I NH Ph O NH Ph OMe O O OMe TBTH AlBN PhCH3 THF SmI2 HMPH 61 62 63 64 Yield >90% Yield 63% Scheme 18 I X O2 S XH S S TBTH AlBN 65 66 X = O NMe Yields 50–69% Scheme 19 N N N N Ts Ts Ts Ts ( ) n ( ) n ( ) n 67 68 69 70 n = 0,1 Yields 84–89% n = 0,1 Yields 64–73% TsSePh AlBN C6H6 TsSePh AlBN C6H6 Scheme 20 Ipso substitution of aromatic sulfones has also been used in the preparation of fused indoles as depicted in the formation of 68 and 70 from 67 and 69 respectively (Scheme 20).33 The main feature of this approach which is related to previous work from the same authors is that the reactions employ sub-stoichiometric amounts of the sulfonyl radical precursor as an alternative to stoichiometric tin reagents.Similar ipso substitu- 11 Synthetic methods Part (i) Free-radical reactions N N N N SePh Ts ( ) n ( ) n TBTH AlBN PhMe 71 72 n = 1–3 Yields 48–63% N N N N SPh SePh TBTH AlBN PhMe ( ) n ( ) n 73 74 n = 1–3 Yields 17–59% N N N N OHC OHC PhSe ( ) n ( ) n TBTH AlBN MeCN 75 76 n = 1,2 Yields 14–49% N N Br ( ) n ( ) n TBTH AlBN PhMe 77 78 n = 1–3 Yields 45–54% COMe COMe N N R1 R1 R2 SO2 R2 BsNa Cu(OAc)2 H+ 79 80 Yields 45–94% R1 = COMe CN CO2Me R2 = CO2Et SO2Ph H Scheme 21 tion of phenylsulfonyl- and phenylsulfanyl-substituted imidazoles 71 to 72 and benzimidazoles 73 to 74 have also been described as have related oxidative cyclisations of 75 77 and 79 to 76 78 and 80 respectively (Scheme 21).34–36 The majority of these reactions involve ipso substitution followed by re-aromatisation but a recent report shows that aromatisation does not have to be implicit.12 S. Caddick N. J. Parr and S. Shanmugathasan N R O CCl3 N R O Cl Cl Cl Ni CH3CO2H 81 82 R = alkyl Bn Yields 30–65% Scheme 22 O R1 O Br R2 O R1 O R2 AlBN AllylSnBu3 C6H6 83 84 R1 = H Me; R2 = Alkyl Ph Yields 58–76% Scheme 23 Reactions which involve addition of a radical to an aromatic ring can also lead to the formation of spirocyclic products e.g. 82 from 81 (Scheme 22).37 4 Intermolecular reactions As previously noted the application of solid-phase conditions to radical reactions was inevitable and in an important development Sibi and co-workers describe preliminary work for intermolecular radical reactions using a-halo esters 83.38 The precursors were supported on Wang resin and were found to undergo high yielding substitution with allylstannanes to give products 84 (Scheme 23).Unlike previously described intramolecular examples these reactions rely on the use of a large excess (3 equiv.) of initiator. Carbohydrates The preparation of stable C-glycosides is an important goal given their numerous potential applications in biological chemistry. Motherwell and coworkers have developed a procedure for the synthesis of carbohydrate-bound difluoromethylene- phosphates and -phosphonothionates 87 via addition of phosphonyl or thiophosphonyl radicals generated from 85 to carbohydrate gem-difluoroenol ether precursors 86.39 The same group have developed two useful protocols for the preparation of novel glycopeptides one involves the addition of either the iodoalanine reagent 89 to 88 or bromo-oxazolidinone 92 to 91 to give 90 and 93 respectively (Scheme 24).The second approach which appears to be of greater synthetic potential provides 96 in good yield from the addition of 94 to 95 (Scheme 25).40 The control of glycoside stereochemistry at the C1 position has been the subject of a recent investigation by Kita and co-workers. They have found that 2,2@-azobis(2,4- dimethyl-4-methoxyvaleronitrile) (V70) can act as a radical generator at room temperature. Application of this initiator to TBTH mediated C-glycoside formation (101 to 102) has led to much improved levels of stereoselectivity as is demonstrated in the comparison with the AIBN mediated procedure (97 gives 98–100) (Scheme 26).41 13 Synthetic methods Part (i) Free-radical reactions O O O O O F F O O O O O P OEt F F X OEt X (RO)2P H + AlBN TBTH C6H6 or (Bu tO)2 86 87 85 X = O S; R = Et Bn Yields 14–73% O O O O O O O O O O AlBN TBTH C6H6 88 90 Yield 14% BocN H CO2Me I F F 89 CO2Me F F NHBoc O O O 91 F F O O O AlBN TBTH C6H6 93 F F HN O O R2 R1 F3C CF3 R2 R1 O HN Br O F3C F3C 92 O O R1 = H CH2OMe; R2 = H Yields 20–41% Scheme 24 O O O 94 O O O AlBN TBTH 96 N O O R2 R1 R2 R1 O O R1 = H CH2OTBS; R2 = H Yields 71–91% SePh F F H N O O Bz 95 C6H6 Bz H Scheme 25 14 S.Caddick N. J. Parr and S. Shanmugathasan O AcO AcO OAc OAc Br O AcO AcO OAc OAc CN O AcO AcO OAc OAc CN O AcO AcO OAc OAc 97 98 99 2% 100 18% Yields 32% TBTH AlBN C6H6 Æ O AcO AcO OAc OAc Br O AcO AcO OAc OAc CN 101 102 Yield 68% TBTH V-70 Et2O RT Scheme 26 O N OH O• O N OH O NHNH2 PbO2 PhMe 103 104 Yield 80% (92:8 ds) Scheme 27 Stereocontrol The control of stereoselectivity in acyclic systems is still one of the compelling problems to be addressed in free-radical chemistry.An interesting recent development has been reported in which chiral aminoxyls have been used to e§ect diastereoselective radical reactions. Treatment of the steroidal aminoxyl 103 with a prochiral radical derived unusually from an oxidative method using lead dioxide and alkyl hydrazines led to the isolation of product 104 with a high level of diastereoselectivity (Scheme 27).42 Another stoichiometric approach utilises a covalently bound chiral auxiliary and recent developments in this area have been promising.Addition of isopropyl radicals to electron-deficient alkenes (e.g. 105 to 106) in the presence of lanthanide-based Lewis acids is found to be highly regio- and stereo-selective and a similar process involving haloalkyl radical addition has been exploited in the synthesis of nephrosteranic and rocellaric acids 109 (from 107 via 108) (Scheme 28).43 Although stoichiometric auxiliaries o§er a practical procedure for asymmetric synthesis via radical-based technology extending the principles to an achiral auxiliary with a chiral Lewis acid catalyst is another potential benefit of pursuing such 15 Synthetic methods Part (i) Free-radical reactions N O CO2 Et O O Ph Ph N O CO2 Et O O Ph Ph Er(OTf)3 Pri-I TBTH Et3B O2 105 106 Yield 91% (ds 71:1) N O CO2 Et O O N O CO2 Et O O Ph Ph Cl Sm(OTf)3 TBTH AlBN ClCH2I Et3B O2 107 108 Yield 91% (ds > 100:1) Ph Ph steps HO O 109 R = C11H23 C13H27 O O R Scheme 28 N O Ph O O N O Ph O O TBTH Et3B O2 Ligand 110 111 88% [93% ee ( R)] MgI2 PriI N O N O Ligand = 112 (4 S 5 R) Scheme 29 16 S.Caddick N. J. Parr and S. Shanmugathasan approaches. Sibi and co-workers have been actively involved in developing catalytic asymmetric conjugate radical addition reactions. They have discovered that addition of isopropyl radicals to oxazolidinone derivatives 110 e.g. to give 111 gives very high levels of enantioselectivity in the presence of sub-stoichiometric quantities of bisoxazoline ligands such as 112 (Scheme 29).44 Further work on pyrazole derivatives demonstrates that these can also serve as templates for similar reactions albeit with modest levels of selectivity.45 References 1 D.H.R.Barton F. Launay V. N. Le Gloahec L. Tingsheng and F. Smith Tetrahedron Lett. 1997 38 8491. 2 D.H.R. Barton Synlett 1997 229. 3 A. Gugger R. Batra P. Rzadek G. Rist and B. Giese J. Am. Chem. Soc. 1997 119 8740. 4 B. Giese A. Dussy E. Meggers M. Petretta U. Schesitter J. Am. Chem. Soc. 1997 119 11 130. 5 H. J. Horner N. F. Martinez M. Newcomb S. Hadida and D. P. Curran Tetrahedron Lett. 1997 38 2783. 6 I. Ryu T. Nignma S. Minakata and M. Komatsu Tetrahedron Lett. 1997 38 7883. 7 D.P. Curran S. Hadida S. M. Super and E. J. Beckman J. Am. Chem. Soc. 1997 119 7406. 8 D. Crich and X. Mo J. Org. Chem.1997 62 8624. 9 A. Laird B. Quiclet-Sire R. N. Saicic and S. Z. Zard Tetrahedron Lett. 1997 38 1759. 10 P. C. Montevecchi M. L. Navacchia and P. Spagnolo Tetrahedron 1997 53 7929. 11 A. G. Myers M. Movassaghi and B. Zheng J. Am. Chem. Soc. 1997 119 8572. 12 K. L. Salazaar M. A. Khan and K. M. Nicholas J. Am. Chem. Soc. 1997 119 9053. 13 S. Caddick C. L. Shering and S. N. Wadman Chem. Commun. 1997 171. 14 S. E. Gibson N. Guillo and M. J. Tozer Chem. Commun. 1997 637. 15 A. L. J. Beckwith K. Drok B. Maillard M. D. Castaing and A. Philippon Chem. Commun. 1997 499. 16 S. J. Houldsworth G. Pattenden D. C. Pryde and N. M. Thomson J. Chem. Soc. Perkin Trans. 1 1997 1091. 17 P. Jones W.S. Li G. Pattenden and N. M. Thomson Tetrahedron Lett. 1997 38 9069. 18 G. Pattenden and P. Wiedenan Tetrahedron Lett.1997 38 3647. 19 G. Pattenden and N. Herbert Synlett 1997 69. 20 T. Ooi Y. Hokke and K. Maruoka Angew. Chem. Int. Ed. Engl. 1997 36 1181. 21 D. P. Curran and J. Xu Synlett 1997 1103. 22 D. P. Curran and A. Martinez-Grau Tetrahedron 1997 53 5679. 23 J. C. Lopez and B. Fraser-Reid Chem. Commun. 1997 2251. 24 J. Desire and J. Prandi Tetrahedron Lett. 1997 38 6189. 25 W.R. Bowman M. J. Broadhurst D. R. Coghlan and K. A. Lewis Tetrahedron Lett. 1997 38 6301. 26 J. A. Murphy K. A. Scott R. S. Sinclair and N. Lewis Tetrahedron Lett. 1997 38 7295. 27 N. Bashir O. Callaghan J. A. Murphy T. Ravishanker and S. J. Roome Tetrahedron Lett. 1997 38 6255. 28 D. Crich and H. Xiaolin J. Org. Chem. 1997 62 5982. 29 A. Routledge C. Abell and S. Balasubramanian Synlett 1997 61. 30 X. Du and R.W. Armstrong J. Org. Chem. 1997 62 5678. 31 M.L. E. N. Da Mata W. B. Motherwell and F. Ujjainwalla Tetrahedron Lett. 1997 38 137. 32 M.L. E. N. Da Mata W. B. Motherwell and F. Ujjainwalla Tetrahedron Lett. 1997 38 141. 33 S. Caddick C. L. Shering and S. N. Wadman Tetrahedron Lett. 1997 38 6249. 34 W.R. Bowman and F. Aldabbagh Tetrahedron Lett. 1997 38 3793. 35 W.R. Bowman E. Mann and F. Aldabbagh Tetrahedron Lett. 1997 38 7937. 36 S. F. Wang and C. P. Chuang Tetrahedron Lett. 1997 38 7597. 37 J. Boivin M. Yousfi and S. Z. Zard Tetrahedron Lett. 1997 38 5985. 38 M.P. Sibi and V. S. Chandeamauli Tetrahedron Lett. 1997 38 8929. 39 T. F. Herpin W. B. Motherwell B. P. Roberts S. Roland and J. M. Weibel Tetrahedron 1997 53 15 085. 40 T. F. Herpin W. B. Motherwell and J. M. Weibel Chem. Commun. 1997 923. 41 Y. Kita K. Gotanda A. Sano M. Oka K. Murata M. Suemura and M. Matsugi Tetrahedron Lett. 1997 38 8345. 42 R. Braslau L. C. Burrill II L. K. Mahal and T. Wedeking Angew. Chem. Int. Ed. Engl. 1997 36 237. 43 M.P. Sibi and J. Ji Angew. Chem. Int. Ed. Engl. 1997 36 274. 44 M.P. Sibi and J. Ji J. Org. Chem. 1997 62 3800. 45 M.P. Sibi and J. Ji Tetrahedron Lett. 1997 38 5955. 17 Synthetic methods Part (i) Free-radical reactions mmmm

ISSN:0069-3030    

DOI:10.1039/oc094003

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

2 Synthetic methods Part (ii) Pericyclic methods By PAUL J. STEVENSON School of Chemistry The Queen’s University of Belfast Belfast Northern Ireland BT9 5AG 1 Diels–Alder reaction Catalysis Cationic chiral C 27 symmetric bis(oxazoline) copper complex 1 is finding application as a Lewis acid catalyst in a number of natural product syntheses which involve both inter- and intra-molecular Diels–Alder reactions of a,b-unsaturated imides as the key step (Scheme 1). The nature of the anion is important with hexafluoroantimonate giving both higher reactivity and better ee values. Chelation of both carbonyl groups of the imide to the metal prior to cycloaddition is an important feature of this chemistry. Hence a one molar solution of triene 2 in methylene chloride underwent intramolecular Diels–Alder reaction at 0 °C over 24 h in the presence of 5mol% catalyst 1 and gave cycloadduct 3 in 81% yield without any competition from intermolecular reactions.1 The endo/exo diastereoselection was greater than 99 1 and the ee of adduct 3 was 96%.Adduct 3 has both the correct relative and absolute stereochemistry at the four newly generated chiral centres for elaboration to isopulo’upone. Intermolecular Diels–Alder reaction of furan with a,b-unsaturated imide 4 using 5mol% of copper catalyst 1 in methylene chloride as solvent at[78 °C for 42 h gave the endo adduct 5 with 97% ee.2 The endo exo ratio was a disappointing 4 1 but the major isomer was isolated in 67% yield by a single crystallisation. A major drawback with this procedure is maintaining a low temperature for a very long reaction time.Although the reaction is complete after 2.5 h at [20 °C the endo exo ratio drops to 2 1 and the ee to 59%. Interestingly the exo-isomer is racemic. Adduct 5 was converted to ent-shikimic acid in six additional steps. 1-Acetoxy-3-methylbuta- 1,3-diene undergoes Diels–Alder reaction with imide 4 at [20 °C in methylene chloride in the presence of 2mol% of copper catalyst 1 and gave a 73 27 mixture of exo endo isomers with 97% ee for the exo-isomer 6.3 The additional methyl group in the 3-position in the diene is interacting with the ligand and this is reversing the endo selectivity usually observed for these reactions. The exo-isomer crystallises and can be isolated in 57% yield. This was converted to ent-tetrahydrocannabinol in four additional steps. All manipulations of copper catalyst 1 were carried out in a dry box.Only the S,S-bis(oxazoline) ligand was used in these studies even though in two cases it gave the opposite enantiomer of the natural product. This suggests that the S,S-enantiomer of the bis(oxazoline) ligand is much more readily available than the R,R-enantiomer. 19 O N O N But But Cu N O O O O O H N O O O H H TBSO O N O O TBSO O N O O OAc O O N O AcO 6 (iii) (ii) (i) 4 5 3 2 1 2 SbF6 – 2+ Scheme 1 Reagents (i) 5mol% 1 0 °C; (ii) 5mol% 1 [78 °C; (iii) 2mol% 1[20 °C Bis(oxazoline) magnesium complex 7a 10 mol% catalyses the Diels–Alder reaction of cyclopentadiene with a,b-unsaturated imide 4 in methylene chloride at[80 °C. The products of this reaction have an endo exo ratio of 96 4 and a 73% ee in favour of the S-enantiomer for the endo isomer (Scheme 2).4 Incredibly the ee reverses to give predominantly the oppositeR-enantiomer with an ee of 73% when water or alcohol is added to the reaction medium.These results can be rationalised by invoking chelation of the hydroxy group of the additive to magnesium with a change in geometry from tetrahedral to octahedral when the imide binds. This is the first example of an achiral auxiliary reversing the ee of a bis(oxazoline) catalyst. With catalyst 7b the endo exo ratio increases to 99.5 0.5 with 97% ee S for the endo adduct representing the best stereocontrol reported to date in these systems. Water and ethanol with this catalyst decrease the ee to 78% S and 76% S respectively. From a general practical viewpoint it is worrying that adventitious water or small amounts of alcohol added to stabilise 20 P.J. Stevenson O N O N Mg Ph R Ph R O O N O N O O O 4 2ClO4 – 7a R = H 7b R = Ph 2+ + Scheme 2 O O O (ii) (i) 10 9 8 Scheme 3 Reagents (i) ZnCl 2 ; (ii) 6]BF 3 chlorinated solvents can catalytically produce the undesired enantiomer hence lowering the overall ee in reactions of intrinsically high ee. Methylrhenium trioxide (abbreviation MTO) 1 mol% catalyses Diels–Alder reactions of a,b-unsaturated aldehydes and ketones with dienes in chloroform or water at room temperature.5MTOis acting as a Lewis acid and has the big advantage that it is neither air nor water sensitive and does not produce protonic acid on hydrolysis. Hence reaction of isoprene with methyl vinyl ketone in chloroform proceeds at room temperature in the presence of 1mol%MTOand gave the Diels–Alder adduct in 90% yield after 2.5 h with the expected regiochemistry.In the absence of added dienophile MTO catalyses self Diels–Alder reaction of the dienes over one week. A recent approach to the Taxol™ A,B,C-ring system is based on coupling a bis-diene 8 to a bis-dienophile penta-1,4-dien-3-one in two consecutive Diels–Alder reactions (Scheme 3).6 The chemoselectivity of the initial intermolecular Diels–Alder reaction is controlled by the substitution pattern on the dienes with the least substituted diene participating in the intermolecular Diels–Alder reaction. This proceeded in methylene chloride at 25 °C in the presence of a catalytic amount of zinc chloride and gave exclusively the endo adduct 9 in 63% yield. The second step involved intramolecular Diels–Alder reaction between the more highly substituted diene 9 and the pendant dienophile.This proceeded in toluene at[78 °C and warming to 0 °C in the presence of six equivalents of boron trifluoride. The tricyclic compound 10 was isolated in 82% yield as a single diastereoisomer (albeit the wrong one for Taxol™). Although it looks as though these two steps should be achievable in a single operation neither Lewis acid was capable of catalysing both the inter- and the intra-molecular Diels–Alder reactions. Z-Penta-2,4-diene is a notoriously di¶cult diene to get to participate in Diels–Alder reactions. With Lewis acid catalysts it readily polymerises even at low temperatures. It 21 Synthetic methods Part (ii) Pericyclic methods O O O NO2 O O NO2 O AcO CHO R2 R3 R1 R1 CHO R3 R2 OAc (ii) (i) + 11a R1 = H R2 = Me R3 = CH2OTBS 12a,b 11b R1 = R2 = R3 = Me 13 11b Scheme 4 Reagents (i) Me 2 AlCl; (ii) BCl 3 2,6-di-tert-butylpyridine is generally accepted that all Z-dienes will be poor partners for Diels–Alder chemistry.This myth has now been challenged and it is reported that Z-dienes with additional alkyl groups are excellent partners for Lewis acid catalysed Diels–Alder reactions (Scheme 4).7 Hence diene 11a reacted with acetoxyacrolein in methylene chloride at [80 °C in the presence of dimethylaluminium chloride and gave 12a in 75% yield ratio endo exo 96 4. For diene 11b the regiochemistry was excellent and gave a workable 60% yield of 12b with a tertiary centre adjacent to a geminal dimethyl group. Presumably the additional alkyl groups attached to these dienes gave them extra stability.2,6-Di-tert-butylpyridine 25 mol% in combination with boron trichloride 110 mol% has also been used to promote reactions of diene 11b with dienophiles in methylene chloride at 25 °C to give Taxol™ ring A precursors 13 in 99% yield.8 It is believed that 2,6-di-tert-butylpyridine is acting as a proton scavenger hence protecting the diene from decomposition but that it is bulky enough not to react with the Lewis acid. Dienes with Lewis acidic appendages 14 undergo rapid intermolecular Diels–Alder reactions with fumarate esters in tetrahydrofuran at 25 °C and gave cycloadduct 15 in 51% yield endo exo ratio 4 1 (Scheme 5).9 Chelation of the ester carbonyl group to the aluminium makes the cycloaddition pseudo intramolecular and hence allows the mild reaction conditions.On the same theme titanium enolates of a,b-unsaturated aldehydes reacted with N-benzylmaleimide in toluene–isopropan-2-ol at [15 °C and gave exclusively the endo adducts 16a and 16b ratio 9 1 in 90% overall yield.10 The acetate 16b is the ‘normal’ Diels–Alder product whereas the alcohol 16a is derived from the titanium enolate. When 1.2 equivalents of NpTADDOL were added to the reaction the alcohol 16a was produced with an ee of 90%. Interest continues in metallated dienes which give allyl metal derivatives on cycloaddition (Scheme 6). Boronate 17 reacts with ethyl acrylate in methylene chloride at 25 °C in the presence of ethylaluminium dichloride and gave a cycloadduct with an endo exo ratio greater than 95 5.11 The isolated allyl boronate could be reacted further with propanal and gave a 1,4-disubstituted cyclohexene 18 in 67% overall yield for the two steps.In a similar fashion silicon-substituted diene 19 reacted with ethyl acrylate in methylene chloride at[60 °C with titanium tetrachloride one equivalent 22 P. J. Stevenson OH CO2Me CO2Me O O OMe MeO O AlMe2 OR N O O Ph N O O Ph O Ac (ii) (i) 16a R = OH 16b R = OAc 15 14 Scheme 5 Reagents (i) 25 °C; (ii) Ti(OPr*) 4 CO2Et HO CO2Et B O O CO2Et B O O CO2Et Ph2MeSi CO2Et CO2Et OH OH (iii) (ii) (i) 21 20 19 18 17 Scheme 6 Reagents (i) EtAlCl 2 20 °C; (ii) EtCHO; (iii) TiCl 4 ,Me 2 AlCl 2 ,[60 °C then EtCHO and 20mol% dimethylaluminium chloride as Lewis acids and gave an intermediate allylsilane product.12 Propanal was added to the reaction mixture at [60 °C and the stereoisomeric adducts 21 and 22 were isolated as a 4 1 mixture in 60% overall yield.The Lewis acids are catalysing both the Diels–Alder and the allylation reactions. Anthracenebisresorcinol in the solid state forms a hydrogen bonded network with cavities in which small polar molecules can be bound; 1.7mol% of this solid catalyses the Diels–Alder reaction of neat cyclohexa-1,3-diene with acryloin at 25 °C.13 The catalyst is insoluble in the reaction medium and the endo Diels–Alder adduct was obtained in unspecified yield. 23 Synthetic methods Part (ii) Pericyclic methods N N M O Ph N N M Ph N N O O Ph O 22a M = Cr(CO)4 22b M = W(CO)4 23 24 (i) (ii) Scheme 7 Reagents (i) 45 °C CH 2 Cl 2 ; (ii) (NH 4 ) 2 Ce(NO 3 ) 6 O NMe2 TSBO NMe2 CHO TSBO Me2N CHO (i) (ii) 25 26 27 Scheme 8 Reagents (i) KN(SiMe 3 ) 2 Bu 3 SiCl; (ii) PhMe 20 °C Intermolecular Diels–Alder reaction A major current problem in Diels–Alder chemistry is the production of exo-cycloadducts with high ee.The use of chiral chromium 22a and tungsten 22b carbene complexes as dienophile goes some distance to solving this problem (Scheme 7).14 Hence complex 22a reacted with penta-2,4-diene in methylene chloride at 45 °C for 60 h and gave 23a in 48% yield ratio 84 16 exo endo products. The de for the exo product was greater than 99%. With the more reactive Danishefsky diene the Diels–Alder adduct was isolated in 80% yield ratio exo endo 96 4 de greater than 99%. Finally the metal can be oxidatively removed with ceric ammonium nitrate and gave the formal exo products 24 from an a,b-unsaturated imide. An aza analogue of the Danishefsky diene has recently been reported (Scheme 8).15 The vinylogous amide precursor 25 was readily prepared from dimethylamine and commercially available 4-methoxybut-4-en-2-one.Treatment of 25 with potassium hexamethyldisilazide at low temperature followed by tributylsilyl chloride gave the diene 26 in quantitative yield. It appears that this diene is more reactive than Danishefsky’s diene and it reacts with methacrolein at 20 °C in toluene to give cycloadduct 27 in 87% yield as a single regioisomer endo exo ratio 25 1. A chiral version of this reaction has also been reported in which the dimethylamino group is substituted for 2,5-diphenylpyrrolidine.16 In this case the same reaction proceeded at 0 °C to give a product with a de of 85%. Cyclohexenes are usually poor dienophiles even when activated with electron withdrawing groups.Boryl groups are emerging as powerful neutral activating groups for dienophiles. The reactivity can be tuned by the choice of the other groups attached to boron. Stock solutions of the dibromoboryl alkenes are readily available by treating the corresponding vinyl stannanes with boron tribromide. The dibromoboryl group activates cyclohexene to undergo Diels–Alder reaction with isoprene in hexane at 25 °C for 8 h (Scheme 9).17 Oxidative workup gave the cis-decalin 28 in 66% overall yield. 24 P. J. Stevenson Br2B H OH 28 (i) (ii) Scheme 9 Reagents (i) 25 °C hexane; (ii) Et 3 N then H 2 O 2 NaOH O CO2Et OEt O H CO2Et OEt (i) 29 30 Scheme 10 Reagents (i) 90 °C in a sealed tube Inverse electron demand Diels–Alder reaction with dienes containing two electron withdrawing groups working in synergy with electron rich alkenes has been investigated (Scheme 10).18 Hence reaction of 29 with a tenfold excess of ethyl vinyl ether 90 °C in a sealed tube for 24 h gave exclusively the endo cycloadduct 30 in quantitative yield.A new ketene equivalent a-cyano-2,4-dinitrophenylcarboxylate has being reported. 19 This is readily prepared in 62% yield by reaction of acyl nitriles with 2,4-dinitrobenzoyl chloride. It is 5–6 times more reactive than acetoxyacrylonitrile and reacts with cyclopentadiene in acetonitrile at room temperature to give the Diels–Alder adduct in 95% yield. Hydrolysis of the ester with one molar aqueous sodium hydroxide generates the cyanohydrin which collapses to a ketone. Control of exo/endo-selectivity can be di¶cult in Diels–Alder reactions of 1-oxgenated- 1,3-dienes with 2-nitroacrylates.However the choice of the substituent on oxygen has been shown to have a dramatic e§ect on controlling the exo/endoselectivity. 20 Acyl was found to be better than alkyl or silyl and 1-acetoxybuta-1,3- diene reacted with methyl 2-nitroacrylate in dichloromethane at room temperature and gave a 71% yield of cycloadduct with endo exo ratio greater than 95 5. Hetero Diels–Alder reactions Indium trichloride 20 mol% catalyses the imino Diels–Alder reaction of cyclohexenone with aromatic imines 31 at 25 °C in acetonitrile and gave the regioisomeric products 32 33 ratio 2.2 1 in 65% overall yield (Scheme 11).21 With cyclopentadiene as dienophile product 34 was isolated in 75% yield after 30 min.The reaction of Danishefsky type dienes with aldehydes continues to attract attention. In reactions with chiral aromatic aldehydes it has been shown that the de of the cycloadduct can be controlled to some extent by the size of the lanthanide metal catalyst. Lanthanides of greater ionic radii gave the best des.22 Chiral tris-1,1@-binaphthyl- 2,2@-diylphosphate ytterium 10mol% catalyses the hetero Diels–Alder reaction of aromatic aldehydes with Danishefsky’s diene in methylene chloride at room temperature and gave cycloadducts in both high yield 86% and ee 93% (in the case of 25 Synthetic methods Part (ii) Pericyclic methods NH O O N Ph NH Ph O NH Ph Ph 31 32 33 34 (i) (ii) Scheme 11 Reagents (i) InCl 3 ; (ii) cyclopentadiene N O Et N N Et O Ph O N H Ph (i) 36 35 Scheme 12 Reagents (i) PhNCO CH 2 Cl 2 25°C 4-methoxybenzaldehyde).23 To date all other catalysts required low temperatures to achieve good ees for this reaction.One disadvantage is that each mole of catalyst requires three moles of 1,1@-bi-2-napthol and a heavy loading 10 mol% of catalyst is required. Chiral 1-azadiene 35 reacts with two equivalents of phenyl isocyanate in methylene chloride at 25 °C over 48 h and gave the 2 1 cycloadduct 36 in 58% yield as a single diastereoisomer (Scheme 12).24 This is a rare example of e¶cient 1,5-asymmetric induction. Intramolecular Diels–Alder reactions In model studies directed towards the synthesis of squalene synthase inhibitor CP225 917 the Lewis acid catalysed intramolecular Diels–Alder reaction of triene 37 was investigated (Scheme 13).25 This reaction proceeded in methylene chloride at[10 °C in the presence of 0.5 equivalents of dimethylaluminium chloride and gave the cycloadduct 38 in 86% yield as a 3 1 mixture of stereoisomers.The most significant aspect of this reaction is that the intramolecular reaction competes favourably with the intermolecular one even though the product of the former reaction contains a double bond at a bridgehead. The rings in this bridged bicyclic system are obviously large enough to 26 P. J. Stevenson O OBn MeO O Et Et BnO MeO (i) 38 37 Scheme 13 Reagents (i) Me 2 AlCl O NH N TfO N NC N NC H N NC H (iii) (ii) (i) 41 40 39 Scheme 14 Reagents (i) Tf 2 O; (ii) LiCN 12-crown-4; (iii) 110 °C PhH accommodate this allowing rapid entry to this novel ring system. 1-Aza-1,3-dienes are potentially useful dienes for intramolecular Diels–Alder cycloadditions.However in general yields are low due to the formation of side products and the instability of the adducts. The introduction of a 2-cyano-substituent into 1-aza-1,3-dienes gave much cleaner Diels–Alder reactions.26,27 a,b-Unsaturated amides are readily converted to 1-aza-2-cyano-1,3-dienes by treating the corresponding imidoyl triflate in tetrahydrofuran with lithium cyanide in the presence of 12-crown-4 (Scheme 14). Although the overall yield for the two step process is not very high 42% the starting materials are readily available. The 1-aza-2-cyano-1,3-diene 39 is stable enough to be isolated and undergoes intramolecular Diels–Alder reactions when heated in benzene at 110 °C in a sealed tube and gave the bicyclic products 40 41 in 94% combined yield ratio 4 1.An e¶cient synthesis of xestoquinone is based on an interesting intramolecular Diels–Alder reaction (Scheme 15).28 Treatment of 2-methoxy-4-methylphenol with a fourfold excess of penta-2,3-dien-1-ol and bis(trifluoroacetoxy)iodobenzene as oxidant in tetrahydrofuran gave an intermediate 42 which contains two diene moieties. The major product from the Diels–Alder reaction 43 61% yield is the one in 27 Synthetic methods Part (ii) Pericyclic methods OH OMe O O O Me HO O H H O H (iii) (ii) (i) 42 44 O O OMe 43 + Scheme 15 Reagents (i) PhI(OCOCF 3 ) 2 ; (ii) 60 °C; (iii) trimethylbenzene 175 °C EtO2C EtO2C OH H EtO2C EtO2C H 45 (i) (ii) Scheme 16 Reagents (i) (c-C 6 H 11 ) 2 BH; (ii) trimethylamine N-oxide which the cyclic diene behaves as the diene and one of the double bonds of the acyclic diene behaves as the dienophile.The required product 44 in which the acyclic diene behaves as the diene and the cyclic diene behaves as the dienophile is formed in a miserable8% yield. However if 43 is heated in boiling trimethylbenzene it undergoes a [3,3]-sigmatropic rearrangement and gave the required adduct 44 in 81% yield. Therefore it is possible to obtain 44 in 56% overall yield from 2-methoxy-4-methylphenol by this route. Others have independently published very similar chemistry.29 A thermal intramolecular Diels–Alder reaction which gave endo-selectivity has been reported (Scheme 16).30 This was achieved by the introduction of boron into the dienophile by chemoselective hydroboration of an alkyne in the presence of the diene using dicyclohexylborane.The boron substituent activates the alkene and the intramolecular Diels–Alder reaction proceeds in refluxing benzene overnight and gave after oxidative workup the endo trans ring junction product 45 in 44% isolated yield. 28 P. J. Stevenson O R R O O H H O N2 O H O R R C O+ O H 48 46a R = H 46b R = Me 47 46 – (i) Scheme 17 Reagents (i) Rh(OAc) 2 CH 2 Cl 2 25°C 2 1,3-Dipolar cycloadditions Dipolar cycloaddition of transient oxonium ylides followed by cleavage of the carbon –oxygen bond is emerging as a powerful method in the synthesis of fused ring carbocycles. The oxonium ylides are invariably generated by reaction of transition metal carbene complexes with carbonyl compounds. In turn the carbene complex is generated by reaction of a carbonyl stabilised diazo compound with a transition metal complex usually of rhodium.Two groups have independently used this approach to synthesise the indane ring skeleton common to the anti-tumour illudalanes sesquiterpenes (Scheme 17).31–33 Oxonium ylide 47 generated from the diazo compound reacted with cyclopentenones 46a,b in methylene chloride at room temperature and gave the adducts 48a,b in 52% and 40% yields respectively. A major feature of this chemistry is the highly regioselective nature of the 1,3-dipolar cycloadditions and the mild reaction conditions to which the cyclopropyl groups are stable. Unactivated alkenes undergo intramolecular dipolar cycloaddition with oxonium ylides in boiling benzene at 50 °C for 4 h producing multiple fused ring systems from simple precursors (Scheme 18).Hence for substrates 49 and 51 carbene reaction with the imide carbonyl generates one ring and the intramolecular cycloaddition generates another two rings and gave 5034 and 5235,36 in 95% yields and 97% yields respectively. Adducts 50 and 52 are interesting in that they are precursors to N-acyl iminium ions. This chemistry was exploited in the conversion of 52 to lycopodine. The scope of this strategy was considerably widened when chiral rhodium carboxylate complexes 1 mol% were used to generate the oxonium ylide in hexane from achiral precursors. In this case the products of the intramolecular cycloaddition were formed in 76% yield and 53% ee,37 strongly suggesting that the metal is still bound to the substrate during the cycloaddition. Nitrone cycloaddition remains a popular synthetic method.New versatile methods for nitrone generation have substantially broadened the scope of this procedure. Nitrones can be generated in high yield by IntermolecularN-alkylation of the sodium salt of an oxime with a chiral epoxide in ethanol.38 IntramolecularN-alkylation of an oxime with a chiral epoxide with ring formation in ethanol at 80 °C.38 Intramolecular addition of an oxime to an unactivated alkene either catalysed by palladium chloride bis-acetonitrile 10 mol% in benzene,39 or mediated by phenylselenyl chloride.40 The nitrones generated by these new methods underwent the normal range of 29 Synthetic methods Part (ii) Pericyclic methods N O CO2Et O O CO2Et H N O CO2Et O CO2Et O N2 N C– O CO2Et O O+ CO2Et N OMe O Bn N2 EtO2C O N O EtO2C O Bn OMe (ii) (i) 52 50 51 49 Oxonium ylide Scheme 18 Reagents (i) Rh(OAc) 2 ; (ii) Rh(O 2 CC 3 F 7 ) 2 N O – R2 R3 N – O R2 R3 N R1 R2 R3 (i) or (ii) 53a R1 = H R2 = CO2Me R3 = H + + 53b R1 = OH R2 = H R3 = OCOPh 54a 55b Scheme 19 Reagents (i) dimethyl dioxirane; (ii) HgO 1,3-dipolar cycloaddition reactions.Dimethyl dioxirane oxidation of proline methyl ester 53a in acetone gave a mixture of cyclic nitrones from which 54a could be easily isolated in 30% yield (Scheme 19).41 Although the yield is poor and the other regio-isomeric nitrone 55a is also produced purification is easy and this method is more attractive than the alternative multistep literature procedure for making this versatile intermediate. Regioselective oxidation of chiral hydroxylamines 53b to nitrone 55b using mercury oxide in methylene chloride was complete within 2 h at room temperature.42 1,3-Dipolar cycloaddition of 55b with dimethyl fumarate in benzene gave after three days at room temperature a 91% yield of cycloadducts as a 4 1 mixture of stereoisomers.The major diastereoisomer was converted to the pyrrolizidine alkaloid ([)-hastanecine. Azomethine ylide cycloadditions remain popular and new innovative methods for generating these species have been forthcoming (Scheme 20). Hence heating homochiral 56 in acetonitrile at 80 °C in the presence of a large range of 30 P. J. Stevenson N+ O CO2PNB CO2H N+ CH– O CO2PNB N S O CO2PNB H Ph Ph N O O O CO2PNB H (ii) (i) 56 57 58 – 59 Scheme 20 Reagents (i) 80 °C MeCN; (ii) Ph 2 CS N SnBu3 Cl N+ CH2 N Ph H (ii) – (i) 62 61 60 Scheme 21 Reagents (i) 110 °C PhMe; (ii) PhCH––CH 2 dipolarophiles in the case shown a thioketone gave racemic cycloaddition products 59 51% yield as a single diastereroisomer.43 Although product 59 is formally derived from the azomethine ylide 57 mechanistic studies suggests that cycloaddition precedes decarboxylation and that azomethine ylide 58 is the true intermediate.44 Azomethine ylide 61 generated by loss of tributyltin chloride from substrate 60 by heating in toluene can be trapped with styrene and gave a 31% yield of cycloadduct 62 as a single stereoisomer (Scheme 21).45 With other dipolarophiles mixtures of stereoisomers resulted.The generality of this procedure is doubtful as all substrates investigated contained a geminal dimethyl group adjacent to the azomethine ylide thus preventing enamine formation.Commercially available trimethylsilyldiazomethane undergoes regioselective 1,3- dipolar cycloaddition with electron deficient chiral disubstituted alkenes in hexane –methylene chloride and gave product 63 containing three new chiral centres as a mixture of diastereoisomers in quantitative yield (Scheme 22).46,47 Removal of the trimethylsilyl group gave 64 exclusively trans in 84% de (with respect to the chirality on the sultam auxiliary) from which 64 could be isolated pure in 71% overall yield for the two steps. Compound 64 is a key intermediate in the synthesis of alkaloid ent-stellettamide. Intramolecular 1,3-dipolar cycloaddition of a thiosemicarbazone 66 was used to construct two rings of the antibiotic palau’amine (Scheme 23).48 Hence condensation of thiosemicarbazide with 65 in acetic acid at 80 °C gave an initial cycloadduct which further condensed and gave the thioimide 67 87–95% yield under the reaction conditions.The reaction is completely regioselective and stereoselective with one chiral centre in the substrate directing the relative stereochemistry of three other centres two of which are tertiary in the product. Tandem [4]2][3]2]-cycloadditions of vinyl nitronates has emerged as a useful protocol for the construction of carbocyclic and heterocyclic compounds (Scheme 24). This reaction sequence is very powerful in that it allows the generation of up to six new chiral centres with control both over the relative and absolute stereochemistry. Permutations of both the [4]2] and [3]2] reactions being inter- or intra-molecular increase the diverse range of structures that can be obtained.Hence intermolecular 31 Synthetic methods Part (ii) Pericyclic methods X OBn O N N SiMe3 X SiMe3 O N N OBn X O N N OBn CO2Et (i) (ii) 63 64 X = Camphor sultam + – Scheme 22 Reagents (i) 25 °C; (ii) ClCO 2 Et AgOTf N N N CO2Me O S H CBz MeO2C N CBz CO2Me N + N – H S H2N MeO2C N CBz CO2Me O (i) 67 66 65 N H Scheme 23 Reagents (i) H 2 NCSNHNH 2 AcOH reflux O N O Me2Si O MeO2C N O O Ph GO O N Ph OG O O N Ph OG O O N Ph OG O O N O OG Ph Ph H2N OH HO O G O N O Me2Si O O MeO2C G Ph (ii) (iv) (iii) (i) or (ii) 75 74 72 71 70 69 68 73 G = detoxinine – – – – – + + + + + Scheme 24 Reagents (i) SnCl 4 ; (ii) methylaluminium bis(2,6-diphenylphenoxide) MAPh; (iii) PhH reflux; (iii) NaBH 4 NiCl 2 [4]2]-cycloaddition of 68 with a chiral enol ether derived from 2-phenylcyclohexan- 1-ol proceeded in methylene chloride at[78 °C in the presence of tin tetrachloride and gave diastereoisomers 69 70 71 in 93% combined yield in the ratio 32 2 1.49 Heating 69 in boiling benzene gave cycloadduct 72 in quantitative yield as a single diastereoisomer.Finally cleavage of the NO bonds followed by reduction gave the tet- 32 P. J. Stevenson N O O Bn O TBSO TBSO N O O Bn O O BnO OBn BnO BnO BnO OBn O OPMB OPMB TEOS TEOS (iii) (ii) (i) 81 80 79 78 77 76 Scheme 25 Reagents (i) 180 °C; (ii) 165 °C; (iii) 45 °C rasubstituted cyclopentane 73 in 82% yield and 94% recovery of the auxiliary. On changing the Lewis acid from tin tetrachloride to MAPh in the initial Diels–Alder reaction the isomer ratio 69 70 71 changed to 1 15 1.8.After intramolecular cycloaddition and ring cleavage of the major diastereoisomer the product is now the enantiomer of 73 i.e. changing the Lewis acid reverses the enantioselectivity for this sequence. Intermolecular [4]2] reaction of chiral vinyl ether with 74 followed by spontaneous intramolecular [3]2] cycloaddition in methylene chloride at [85 °C for 18 h using MAPh as catalyst gave 75 in 59% yield with a de [25 1.50 This was a key intermediate in the synthesis of detoxinine. A similar approach intermolecular [4]2] intramolecular [3]2] was used in the synthesis of mesembrine51 and crotanecine.52 3 Sigmatropic rearrangements Asymmetric aldol reaction of chiral b,c-unsaturated imides with a,b-unsaturated aldehydes gave syn 1,5-dienes 76 in both high de and yield. Protection of the alcohol as a tributylsilyl ether followed by heating in toluene at 180 °C in a sealed tube gave the Cope rearrangement product 77 in 87% yield de [97 3 (Scheme 25).53 As expected the stereochemistry of the two new chiral centres can be controlled by choice of the stereochemistry of the original alkene.Both ends of 77 are suitably di§erentiated to allow further chain extension in either direction. Enol ether 78 derived from glucose undergoes Claisen rearrangement when heated in boiling xylene and gave the eight membered ring product 79 in 60% yield.54 This is the first example of a b-vinyl group on a carbohydrate template undergoing Claisen 33 Synthetic methods Part (ii) Pericyclic methods N N B Ph Ph Br SO2Ar ArO2S R OH R O (i) 84a,b 83 82 a R = OH b R = CO2H Scheme 26 Reagents (i) 1.5 equivalents 83 Et 3 N O OPri O O H2N O OPri O N O OPri N C O O OPri N H O 87 86 85 (ii) (i) Scheme 27 Reagents (i) Bu 3 P CBr 4 Et 3 N[20 °C; (ii) Me 3 Al ring expansion and isomerisation problems of exo going to endo enol ethers were not encountered.Divinylcyclopropane rearrangement of 80 proceeded in tetrahydrofuran at 45 °C for 4 h and gave 81 95% yield with two double bonds at bridgehead positions.55 The first example of an asymmetric aromatic Claisen rearrangement has been reported (Scheme 26).56 Hence 82a rearranges to 84a in 89% yield 94% ee when treated with 1.5 equivalents of chiral boron reagent 83 in methylene chloride at [45 °C containing 1.5 equivalents of triethylamine. The presence of the ortho-hydroxy is important and the ee drops to 57% when this is substituted for a carboxy group 82b.Allyl cyanate to isocyanate rearrangement has been used to introduce stereoselectively nitrogen functionality into a pyran ring (Scheme 27).57 Mild dehydration of primary carbamate 85 to the cyanate proceeded in methylene chloride at[20 °C. On warming to room temperature for one hour the cyanate undergoes [3,3]-sigmatropic rearrangement to isocyanate 86. This was converted in situ to the N-acyl amide 87 by reaction with trimethylaluminium. This one pot sequence produced only the diastereoisomer shown and the overall yield of 87 from 85 was 55%. Deprotonation of chiral amidate 88 in tetrahydrofuran at[78 °C gave keteneN@O acetal 89 which underwent [3,3]-sigmatropic rearrangement on warming to 0 °C and gave 90 in 78% yield 94% de (Scheme 28).58 The valuable auxiliary was easily recovered by hydrolysis of the amide.A catalytic asymmetric allyl imidate to allylic amide [3,3]-sigmatropic rearrangement has been achieved (Scheme 29).59,60 Imidate 91 rearranges to amide 93 in 68% yield 55% ee when heated in methylene chloride at 40 °C containing 5mol% of the chiral cationic palladium catalyst 92. Although the ees in this reaction are still too low for it to be a practical it is a major advance in the search to find a catalytic asymmetric synthesis of acyclic amines. 34 P. J. Stevenson N H Ar O O N Li Ar O ArN MeO (ii) (i) 90 89 88 Ar = Scheme 28 Reagents (i) LDA THF,[78 °C; (ii) 5 h 0 °C then NH 4 Cl N N Cl Pd N N Pd Cl N O Ph p-CF3C6H4 O Ph N p-CF3C6H4 (i) 2+ 91 92 93 2BF4 – Scheme 29 Reagents (i) 5mol% 92 PriO PriO O O PriO PriO O – O – – O PriO PriO O O PriO PriO O – PriO PriO O OH O PriO PriO PriO PriO O OH PriO PriO O OH (iii) (ii) (i) 95 96 94 – – O– Scheme 30 Reagents (i) CH 2 ––CHLi[78 °C; (ii) 0 °C; (iii) NH 4 Cl 0 °C 4 Electrocyclic reactions Diisopropyl squarate reacts with vinyllithiums in tetrahydrofuran at [78 °C to give bicyclo[3.3.0]octane derivative 94 in 45% yield after work up with aqueous ammonium chloride at room temperature (Scheme 30).61 Although the exact details of what is happening are still unclear 94 is formally derived via a 4p-cyclobutene ring opening followed by 8p-electrocyclisation to the eight membered ring followed by an intramolecular aldol condensation on quenching with ammonium chloride.These 35 Synthetic methods Part (ii) Pericyclic methods N OBn OTBS Ar H H N OBn OTBS Ar H Me2PhSi C H SiMe2Ph OTBS N OBn Ar H (ii) 98 97 (i) Scheme 31 Reagents (i) 162 °C; (ii) TBAF SO2Ph H C SO2Ph H O (i) (i) 100 99 S Ph O Scheme 32 Reagents (i) 130 °C pericyclic reactions are clearly accelerated due to the anionic nature of the intermediates.When two moles of cyclopentenyllithium were employed then 96 and 95 containing four fused five membered rings with five contiguous chiral centres were obtained in 40 and 26% yields respectively. The two vinyllithiums need not be the same and when a chiral cyclopentenyllithium was employed as one component then a product containing six contiguous chiral centres was isolated in 49% yield as a single diastereoisomer. 62,63 The complexity of the products derived from such simple starting materials makes this chemistry truly remarkable.5 Ene reactions Intramolecular ene reaction of imine to chiral allene 97 in mesitylene at 162 °C for 2 h gave after removal of the dimethylphenylsilyl group the acetylenic product 98 as a single diastereoisomer in greater than 63% yield (Scheme 31). This intermediate was further elaborated to the alkaloids pancracine64 and coccinine.65 Cyclopentene 100 was formed in 90% yield by heating 99 in o-dichlorobenzene (Scheme 32).66 Tandem [2,3] sulphinate to sulphone rearrangement followed by an intramolecular ene reaction rationalises the formation of 100. Yb(FOD) 3 and acetic acid in the ratio 1 1 0.5 mol% catalyses the ene reaction of methoxypropene (as reagent and solvent) with unactivated aldehydes at 25 °C to give the protected alcohols 101 (Scheme 33).67 For aliphatic and aromatic aldehydes the yields are high and these compounds can be easily hydrolysed to the b-hydroxy ketone.In essence what has been developed is a clean catalytic cross aldol condensation. This chemistry was used as a key step in the synthesis of mitomycinoids68 and phyllanthocin.69 36 P. J. Stevenson R O MeO OMe OMe R O H (i) 101 Scheme 33 Reagents (i) Yb(FOD) 3 References 1 D.A. Evans and J. S. Johnson J. Org. Chem. 1997 62 786. 2 D.A. Evans and D. M. Barnes Tetrahedron Lett. 1997 38 57. 3 D.A. Evans E. A. Shaughnessy and D. M. Barnes Tetrahedron Lett. 1997 38 3193. 4 G. Desimoni G. Faita A. G. Invernizzi and P. Righettil Tetrahedron 1997 53 7671. 5 Z. Zhu and J. H. Espenson J. Am. Chem. Soc. 1997 119 3507. 6 J.D. Winkler H. S. Kim S. Kim K. Ando and K.N. Houk J. Org. Chem. 1997 62 2957. 7 W.R. Roush and D. A. Barda J. Am. Chem. Soc. 1997 119 7402. 8 J.D. Dudones and P. Sampson J. Org. Chem. 1997 62 7508. 9 H. Bienayme and A. Longeau Tetrahedron 1997 53 9637. 10 H. Bienayme Angew. Chem. Int. Ed. Eng. 1997 36 2670. 11 P. Y. Renard Y. Six and J. Y. Lallemand Tetrahedron Lett. 1997 38 6589. 12 M.G. Organ D. D. Winkle and J. Hu§mann J. Org. Chem. 1997 62 5254. 13 K. Endo T. Koike T. Sawaki O. Hayashida H. Masuda and Y. Aoyama J. Am. Chem. Soc. 1997 119 4117. 14 T. S. Powers W. Jiang J. Su W.D. Wul§ B. E. Waltermire and A. L. Rheingold J. Am. Chem. Soc. 1997 119 6438. 15 S. A. Kozmin and V. H. Rawal J. Org. Chem. 1997 62 5252. 16 S. A. Kozmin and V. H. Rawal J. Am. Chem. Soc. 1997 119 7165. 17 D. A. Singleton and Y. K. Lee J. Org. Chem.1997 62 2255. 18 G. J. Bodwell and Z. L. Pi Tetrahedron Lett. 1997 38 309. 19 D. I. MaGee and M. L. Lee Synlett 1997 786. 20 R. J. Stoodley and W. H. Yuen Chem. Commun. 1997 1371. 21 P. T. Perumal and G. Babu Tetrahedron Lett. 1997 38 5025. 22 R. P. C. Cousins W. C. Ding R. G. Pritchard and R. J. Stooley Chem. Commun. 1997 2171. 23 T. Hanamoto H. Furuno Y. Sugimot and J. Inanaga Synlett 1997 79. 24 M.C. Elliot and E. Kruishwijk Chem. Commun. 1997 2311. 25 K. C. Nicolaou M.W. Harter L. Boulton and B. Jandeleit Angew. Chem. Int. Ed. Eng. 1997 36 1194. 26 N. J. Sisti E. Zeller D. S. Grierson and F. W. Fowler J. Org. Chem. 1997 62 2093. 27 I. A. Motorina D. S. Grierson and F. W. Fowler J. Org. Chem. 1997 62 2098. 28 R. Carlini K. Higgs C. Older S. Randhawa and R. Rodrigo J. Org. Chem.1997 62 2330. 29 P. Hsiu and C. C. Liao Chem. Commun. 1997 1085. 30 R. A. Batey D. Lin A. Wong and C. L. S. Hayhoe Tetrahedron Lett. 1997 38 3699. 31 A. Padwa E. A. Curtis and V. P. Sandanayaka J. Org. Chem. 1997 62 1317. 32 T. C. McMorris J. Yu Y. Hu L. A. Estes and M. J. Kelner J. Org. Chem. 1997 62 3015. 33 T. C. McMorris Y. Hu J. Yu and M. J. Kelner Chem. Commun. 1997 315. 34 M.D. Weingarten M. Prein A. T. Price J. P. Snyder and A. Padwa J. Org. Chem. 1997 62 2001. 35 A. Padwa M. A. Brodney J. P. Marino and S. M. Sheehan J. Org. Chem. 1997 62 78. 36 A. Padwa M. A. Brodney J. P. Marino M.H. Osterhout and A. T. Price J. Org. Chem. 1997 62 67. 37 D.M. Hodgson F. Chiappelli N. S. Morrow and A. N. Taylor Tetrahedron Lett. 1997 38 6471. 38 H. A. Dondas M. Frederickson R. Grigg J. Markandu and M.ThorntonPett Tetrahedron 1997 53 14 339. 39 M. Frederickson R. Grigg J. Markandu M. ThorntonPett and R. Redpath Tetrahedron 1997 53 15 051. 40 H. A. Dondas R. Grigg and C. S. Frampton Tetrahedron Lett. 1997 38 5719. 41 M. Closa P. deMarch M. Figuered and J. Font Tetrahedron Asymmetry 1997 8 1031. 42 A. Goti V. Fedi L. Nannelli F. DeSarlo and A. Brandi Synlett 1997 577. 43 D. Planchenault R. Wisedale T. Gallagher and N. J. Hales J. Org. Chem. 1997 62 3438. 44 S. R. Martell P. Planchenault R. Wisedale and T. Gallagher Chem. Commun. 1997 1897. 45 W.H. Pearson and Y. Mi Tetrahedron Lett. 1997 38 5441. 46 G. A. Whitlock and E. M. Carreira J. Org. Chem. 1997 62 7916. 47 M.R. Mish F. M. Guerra and E. M. Carreira J. Am. Chem. Soc. 1997 119 8379. 37 Synthetic methods Part (ii) Pericyclic methods 48 L.E. Overman B. N. Rogers J. E. Tellew and W. C. Trenkle J. Am. Chem. Soc. 1997 119 7159. 49 S. E. Denmark and J. A. Dixon J. Org. Chem. 1997 62 7086. 50 S. E. Denmark A. R. Hurd and H. J. Sacha J. Org. Chem. 1997 62 1668. 51 S. E. Denmark and L. R. Marcin J. Org. Chem. 1997 62 1675. 52 S. E. Denmark and A. Thorarensen J. Am. Chem. Soc. 1997 119 125. 53 M. Rehfeuter and C. Schneider Tetrahedron 1997 53 133. 54 J. Thiem and B. Werschkun Angew. Chem. Int. Ed. Eng. 1997 53 2793. 55 K. C. Nicolaou M.H. D. Postema N. D. Miller and G. Yang Angew. Chem. Int. Ed. Eng. 1997 36 2821. 56 H. Ito A. Sato and T. Taguchi Tetrahedon Lett. 1997 38 4815. 57 Y. Ichikawa M. Osada I. I. Ohtani and M. Isobe J. Chem. Soc. Perkin Trans 1 1997 1449. 58 B. Hungerho§ and P. Metz J.Org. Chem. 1997 62 4442. 59 M. Calter T. K. Hollis L. E. Overman J. Ziller and G. G. Zipp J. Org. Chem. 1997 62 1449. 60 L. E. Overman and T. K. Hollis Tetrahedron Lett. 1997 38 8837. 61 L. A. Paquette and T. M. Morwich J. Am. Chem. Soc. 1997 119 1230. 62 L. A. Paquette A. T. Hamme L. H. Kuo J. Doyon and R. Krenaholz J. Am. Chem. Soc. 1997 119 1242. 63 L. A. Paquette and J. S. Tae Tetrahedron Lett. 1997 38 3151. 64 J. Jin and S. M. Weinreb J. Am. Chem. Soc. 1997 119 2050. 65 J. Jin and S. M. Weinreb J. Am. Chem. Soc. 1997 119 5773. 66 C. Bintzgiudicelli and D. Uguen Tetrahedron Lett. 1997 38 2973. 67 M.A. Ciufolini M. V. Deaton S. R. Zhu and M. Y. Chen Tetrahedron 1997 53 16 299. 68 M.A. Ciufolini M. Y. Chen D. P. Lovett and M.V. Deaton Tetrahedron Lett. 1997 38 4355. 69 M.A. Ciufolini S. Zhu and M.V. Deaton J. Org. Chem. 1997 62 7808. 38 P. J. Stevenson

ISSN:0069-3030    

DOI:10.1039/oc094019

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

2 Synthetic methods Part (iii) Enzyme chemistry By A. J. CARNELL Department of Chemistry Robert Robinson Laboratories University of Liverpool Liverpool UK L69 7ZD 1 Introduction The use of enzymes in synthetic chemistry continues to capture the imagination of organic chemists interested in using highly selective catalysts under mild conditions. The range and scope of biotransformations is being extended by the increasing availability of the enzymes and in particular the ability of gene technology to provide the catalysts in larger quantities through overexpression of the proteins in recombinant strains. Several general reviews have appeared in the last year1,2 as well as reviews on specific classes of reaction. The microbial hydrolysis of nitriles and amides3 and the use of epoxide hydrolases from mammalian microbial and other sources has been reviewed.4 Holland has summarized recent advances in predictive active site modelling with an emphasis on cubic space models developed for sulfoxidations aromatic and aliphatic hydroxylation and Baeyer–Villiger oxidation.5 Asymmetric epoxidations using enzymes have been extensively reviewed6 and several reviews summarizing recent advances in the use of aldolases and transketolase in the synthesis of polyfunctional oligosaccharides have appeared.7–9 2 Hydrolytic enzymes Several groups have used hydrolytic enzymes for the desymmmetrization or resolution of enol esters.Duhamel used Candida cylindracea lipase to hydrolyse prochiral dienol diacetates 1 in aqueous or biphasic conditions to a§ord the ketone acetates (S)-2 in good yields (62–80%) and enantiomeric purity ([98%ee).10 Replacement of the methyl group with an allyl group in the substrate where R\CH 2 Ph gave diminished selectivity.Carnell has resolved the racemic enol acetate 3 derived from 4-cyano-4- phenylcyclohexanone 4 with Pseudomonas fluorescens lipase in tetrahydrofuran–nbutanol. 11 Chemical recycling of the prochiral ketone the hydrolysis product allowed isolation of enantiomerically pure (S)-enol ester 3 in 55% yield. Again the selectivity obtained appeared to be dependent on a large di§erence in steric requirement of the two groups attached to the quaternary centre (Scheme 1). The cheap and readily available sugar dulcitol was desymmetrized by first making the diacetonide in order to make the substrate rigid and more hydrophobic and then 39 OAc AcO R Me O AcO R Me OAc Ph CN O Ph CN OAc Ph CN R = CH2CH=CH2 CH2CH=CHCH3 ( E) CH2CH=C(Cl)CH3( E) CH2C=CCH3 CH2Ph 1 ( S)-2 (±)-3 + ( S)-3 100% ee 4 P.fluorescens lipase THF–Bu nOH recycle C. cylindracea lipase Scheme 1 O O R O O Me O O Pri OH Pri CO2Bn OH Me CO2Bn CAL-B MTBE BnOH R = Pri + CAL-B MTBE BnOH R = Me + (±)-5 or 6 ( R)-6 ( S)-5 ( R)-7 ( S)-8 Scheme 2 acylating one terminal hydroxy group with a lipase in vinyl acetate–diethyl ether.12 Enantiocomplementary selectivity was obtained with lipase PS a§ording the (])- acetate and Pseudomonas fluorescens lipase the ([)-product. In another example of reversal of selectivity the a-methylene-b-lactones 5 and 6 were resolved using Candida antartica lipase (fraction B) in methyl tert-butyl ether–BunOH.13 The reversal of enantioselectivity was rationalized by substituent size di§erence i.e.for lactone 6 a-methylene is large and methyl is small and for lactone 5 a-methylene is small and isopropyl is large (Scheme 2). An e¶cient synthesis of 1a,25-(OH) 2 -vitamin D 3 A-ring carbamate derivatives 10 was developed using a two-step chemoenzymatic approach involving enzymatic synthesis of C-5 carbonates followed by reaction with amino derivatives.14 Candida antartica lipase (CAL SP435L Novo Nordisk) in toluene was found to be the best enzyme for di§erentiating the C-3 and C-5 positions of compound 9 catalysing the formation of the 5-vinyloxycarbonyl derivatives in quantitative yield. The best alkoxycarbonyl donor was the oxime (R2\Me 2 C––N). Enzyme-catalysed Cbz-protection was acheived in 85% yield under the same conditions a potentially useful mild method of introduction (Scheme 3).Waldemann has reported an extremely mild and e¶cient way to remove phenylacetyl amino protecting groups used in oligodeoxyribonucleotide synthesis using Penicillin G acylase either in solution or on solid support.15 Chemists from Lonza have resolved piperazine 2-carboxamide to give the (S)-acid a key intermediate in the synthesis of the Merk HIV protease inhibitor Crixivan in 41% yield 99.4% ee using Klebsiella DSM 9174. The organism can grow on the substrate with a substrate concentration of 22 g l~1 on a large scale.16 40 A. J. Carnell HO OH O OH NH O R3 1. R1OCO2R2 enzyme solvent R3NH2 = ammonia amines amino alcohols diamines and amino acids 9 10 5 5 R1 = Me CH2 CH Ph; R2 = Me2C N CH2 CH 2.R3NH2 Scheme 3 R C N C N X M M hydration hydration Scheme 4 3 Nitrile and epoxide hydrolysis A series of papers by Meth-Cohn reported a detailed and systematic study of the synthetic potential for selective hydrolysis and possible mechanism of a nitrile hydratase system present in Rhodococcus rhodochrous AJ270.17–19 Aliphatic dinitriles NC(CH 2 )nCN such as succinonitrile and glutaronitrile were hydrolysed selectively giving moderate yields of the monoacids. Generally dinitriles with n\4 gave selective hydrolysis however upon extended reaction times the monoacids are metabolized resulting in low yields. Adiponitrile (n\4) gave the monacid in 40% yield if the reaction was stopped after 3 h. Dinitriles with n[4 generally gave no selectivity a§ording diacids and in good yield (ca.90%) for longer chains (n\7 or 8). A series of a,x-dinitriles NC(CH 2 )nX(CH 2 )nCN (X\O S NR) were examined for regioselective hydrolysis. For X\O the chain length n\4 was optimal giving 72% yield of the monoacid after 2 h. A b or c-oxygen (n\2 or 3) was also e§ective whereas five methylene groups between X and the nitrile gave no selectivity. For X\S a c-sulfur allowed optimal control the b-analogue showed selectivity but not the d-analogue. Good selectivity was found for a b or c-nitrogen although the precise dependence on chain length was not defined. The observed selectivity was explained by invoking bidentate complexation to an active site metal ion (iron or cobalt) by the nitrile and the heteroatom (X or CO 2 ~) which deactivates hydrolysis of the coordinated nitrile by the pyrroloquinone quinone cofactor (Scheme 4).In a parallel study on dintriles separated by an aromatic or aliphatic ring the latter were found to undergo hydrolysis preferentially. cis,cis-Mucononitrile and fumaronitrile were regioselectively hydrolysed to monoacids as were m- and p-diacetonitriles. However o-phenylene-diacetonitrile gave the diamide in 65% yield. In contrast to suberonitrile NC(CH 2 ) 6 CN which gives the diacid trans-cyclohexane-1,4-diyldiacetonitrile in which the CN groups are separated by six carbons a§orded only the 41 Synthetic methods Part (iii) Enzyme chemistry O R O R OH R OH O R O R H H O H OH R OH S R S R d– d+ + S Nocardia EH1 epoxide hydrolase yields 94–98% ee 92–99% 11 12 12 buffer pH 8.0 retention R = (CH2)4CH3 (CH2)3CH CH2 CH2Ph Scheme 5 monoacid suggesting the importance of a more constrained substrate.A variety of aliphatic aromatic and heterocyclic mono nitriles were also hydrolysed to acids with this organism. Substrates bearing an adjacent substituent such as an ortho-substituent on an aromatic nitrile an adjacent heteroatom in a heterocyclic ring or a geminal substituent in an a,b-unsaturated nitrile undergo slow hydrolysis of the intermediate amides allowing them to be isolated in good yield. A substrate size of [7Å and the presence of functional groups near to the nitrile capable of metal complexation inhibit nitrile hydrolysis. E§enburger et al. have used polyurethane immobilized resting cells of Rhodococcus erythropolis MP50 for the resolution of naproxen amide to give (S)-naproxen in [99%ee.20 The free cells were inactive in organic solvents.Optimized conditions involved use of immobilized cells in butyl acetate containing 3 vol% DMSO and residual water. Recent contributions in the area of epoxide hydrolysis focus on the use of microbial sources of hydrolase enzymes. Faber et al. have identified six novel bacterial strains for the enantioselective hydrolysis of 2-methyl-2-alkyl and 2-methyl-2-aryl oxiranes.21 The best results (E[200) were obtained for the resolution of 2-methyl-2-pentyl oxirane with a Nocardia sp. which gave optically pure ([99%ee) (R)-epoxide and (S)-diol at 50% conversion. The microorganisms used in the study were identified by a search for strains known to catalyse the asymmetric epoxidation of alkenes. The author noted that the chance of finding selective epoxide hydrolases from a random screen would be low due to both epoxide enantiomers being equally toxic to the living cell.The same group has used a chemoenzymatic approach for the deracemization of 2,2-disubstituted epoxides via enantioconvergent hydrolysis using Nocardia EH1 epoxide hydrolase (Scheme 5).22 Racemic epoxides 11 were resolved with the enzyme to give (S)-diols 12 and unreacted (R)-epoxides. After slightly beyond 50% conversion treatment of the crude product mixture with concentrated sulfuric acid in dioxane –water gave near quantitative yields of the (S)-diol product 12. The two steps proceed with complementary selectivity. The enzyme hydrolysis occurs by attack at the less substituted carbon leading to retention of configuration whereas the acidcatalysed opening occurs with inversion at the more substituted centre.A lyophilized preparation of Aspergillus niger has been used to enantioselectively (E\41) hydrolyse p-nitrostyrene oxide,23 and a series of para-substituted styrene oxides have been resolved with the fungus Beauvaria densa CMC 3240 with stereoinversion of the hydrolysed enantiomer. However for o- and p-methyl- and chloro-styrene oxides the enantioselectivity is compromised and negligible activity was observed with p-nitrostyrene oxide.24 42 A. J. Carnell R1 R2 OH OH R1 R2 E. coli 13,14 R1 = H R2 = MeO (2.5 g l–1) 15,16 R1 = MeO R2 = MeO (0.8 g l–1) JM 109 (pDTG 601) Scheme 6 X O O O HO OH OH F OH O OH O O F OH X = Cl 8 steps X = Br 4 steps 18 19 17 1 6 4 5 Scheme 7 4 Oxidations Biooxidations continue to attract much interest transformations often being carried out with whole-cell systems due to the instability of the isolated enzymes or the need for cofactor recycling.Escherichia coli JM109 (pDTG601) is a recombinant organism which overexpresses the enzyme toluene dioxygenase. This strain has been used to convert substituted biphenyls 13 and 15 into the corresponding 3-aryl (1S,2R)-cyclohexadienediols 14 and 16 (Scheme 6).25 The absolute configurations of the diol products were determined by chemical correlation with (1S,2R)-3-iodocyclohexa-3,5- diene-1,2-diol. There have been further elegant examples of the use of bromocyclohexadiene cis-diol 17 (X\Br) obtained from the microbial oxidation of bromotoluene including the synthesis of two fluorinated inositols26 and a multigram synthesis of allo-inositol. 27 A versatile approach to deoxyfluorosugars allowed synthesis of the fluorinated lactol 18 and 2-deoxy-2-fluoroglucose 19 (Scheme 7).28 The key feature of this approach is ozonolysis of the C-1–C-6 double bond after substitution at C-4 and C-5 as a fluorohydrin was established.The naphthalene dioxygenase gene and its regulatory region from Pseudomonas fluorescens N3 has also been cloned in Escherichia coli JM109 giving an e¶cient bacterial system inducible by salicylic acid. The recombinant organism showed fairly broad substrate specificity for a range of naphthalenes with alpha or beta subtituents in the aromatic ring giving dihydrodiols in 50–94% yields.29 Continuing the work of Fonshen and Furstoss on remote hydroxylation of cyclic and bicyclic alkanes by Beauvaria bassiana ATCC 7159 Pietz et al.have proposed a key distance of 5.5Å from the oxygen of an N-phenyl carbamate ‘anchoring group’ and the position which is hydroxylated.30,31 Filamentous fungi such as Absidia coerula 43 Synthetic methods Part (iii) Enzyme chemistry OAc AcO H AcO OAc H OAc OAc AcO R1 AcO OAc H OAc R2 14 1 Absidia coerula 21 R1 = OH R2 = H (39%) 22 R1 = H R2 = OH (26%) 20 Scheme 8 O Cl O Cl O H2N OH O Cl H H HCl. Cunninghamella 4 steps ( R)-baclofen 25 23 ( R)-24 echinulata NRLL 3655 Scheme 9 have been used to hydroxylate the taxane skeleton in compound 20 giving novel C-1 and C-14 hydroxylated derivatives 21 and 22 (Scheme 8).32 The substrate for these biotransformations can be isolated from Taxomyces baccata T. mairei and related strains. Two new luciferase enzymes are able to catalyse the model Baeyer–Villiger reaction of bicyclohept-2-en-7-one.33 The synthetic application of the enzymatic Baeyer–Villiger reaction has been further demonstrated.In the synthesis of the GABA B agonist (R)-([)-baclofen 2534 asymmetric Baeyer–Villiger oxidation of the prochiral cyclobutanone 23 with Cunninghamella echinulata NRLL 3655 gave the enantiomerically pure (R)-chlorobenzyl lactone 24 in 30% yield (Scheme 9). Use of the better known biocatalyst Acinetobacter calcoaceticus NCIMB 9871 a§orded the (S)-lactone 24 with complementary selectivity but in lower enantiopurity (85% ee). The enzyme from the latter organism cyclohexanone monooxygenase (CHMO) is also able to catalyse asymmetric sulfoxidation reactions and a recent review by Willetts35 discusses synthetic applications and predictive active site models for this and related Baeyer–Villiger monooxygenase enzymes.It is interesting to compare a recently discovered enantioselective metal-catalysed Baeyer–Villiger reaction with the enzymatic results.36 Colonna has carried out highly selective asymmetric sulfoxidation of dialkyl sulfides with CHMO and chloroperoxidase (CPO) from Caldariomyces fumago.37 The CPO enzyme which requires hydrogen peroxide as the oxidant gave (R)-configured sulfoxides with generally high ee ([98%) and conversion (75–98%) for alkyl (cyclopentyl allyl pentyl isopropyl) methyl sulfides. Increasing the ring size (cyclohexyl) chain length ([C5) increased branching or replacement of methyl with ethyl gave lower selectivities. CHMO also exhibited high selectivity for alkyl methyl sulfides for substrates with limited steric requirements giving in most cases (R)-configured sulfoxides.Octyl and pentyl methyl 44 A. J. Carnell sulfoxides were (S)-configured in lower ee (50 and 60%). For the non-specialist the chloroperoxidase is a more convenient enzyme since it uses hydrogen peroxide and does not require regeneration of a redox cofactor. CPO can also be used in ButOH–water (1 1) and enhancements in enantioselectivity have been observed.38 Rabbit lung flavin monooxygenase (FMO2) has been used for the sulfoxidation of 2-naphthyl- and p-tolyl alkyl sulfides.39 For the p-tolyl series the enantioselectivity switched from giving (R)- to (S)-sulfoxides on changing the chain length from methyl to heptyl. Only short alkyl chains were tolerated for the 2-naphthyl series giving (R)- sulfoxides.Whole cells of the fungus Mortierella isabellina ATCC 42613 also gave (R)-configured sulfoxides from methyl aryl sulfides.40 Gallagher et al. have isolated a multicomponent alkene monooxygenase from Nocardia corallina B276 which catalyses the epoxidation of propene to (R)-propene oxide in 83%ee. Use of the whole cell system gave lower ee (69%) due to the presence of an (R)-selective epoxide hydrolase.41 5 Reductions Bakers’ yeast reductions continue to be widely used with the range of substrate types undergoing selective transformation expanding rapidly. Reduction of aromatic azides to amines has been reported in the chemoenzymatic synthesis of a benzodiazepine42 and a 4-aminopodophyllotoxin.43 Reports on the e§ects of organic solvents44 additives such as methyl vinyl ketone or chloroacetone45 and heat treatment46 enable selection of appropriate reaction conditions for a given b-keto ester or b-diketone.Reduction of 3-substituted cyclohexanones 28 with Baker’s yeast gave Prelog selectivity for both enantiomers of the substrate (38–46% yields,[90%ee) where the C-3 side chain possesses a sulfone or nitro function (Scheme 10).47 Evidently axial versus equatorial hydride delivery by NADH does not determine the selectivity as would be assumed for a reduction by a metal hydride (L-selectride gives predominantly the trans-isomer for R\Bun). 1-Methylsulfonylalkan-2-ones have been reduced to the corresponding b-hydroxy sulfones with Baker’s yeast under ‘dilute’ (A) and ‘concentrated’ (B) conditions in terms of the amount of yeast and sucrose used in the biotransformation.48 The reduction proceeded with good enantioselectivity (up to 87%ee) using conditions B (though isolated yields were moderate).These results are an improvement on those previously obtained with phenylsulfonyl derivatives. trans-2-Phenylsulfonyl-3-ethylcyclopentanone underwent a near perfect resolution to give the corresponding (1S,2R,3S)-alcohol product which could be oxidized to the (2R,3S)-ketone after separation. Treatment of either ketone with aqueous sodium hydroxide a§orded the corresponding enantiomer of 4-(phenylsulfonylmethyl)hexanoic acid through a retro-Claisen type process.49 Adam and co-workers have extended the scope of the horseradish peroxidase (HRP)-catalysed asymmetric reduction to that of erythro or threo hydroperoxyhomoallylic alcohols resulting in the (R,R)- or (R,S)-enantiomers being enantioselectively reduced to the allylic diols leaving unreacted peroxides in high ee.50 45 Synthetic methods Part (iii) Enzyme chemistry OH R R OH R O + Bakers' yeast H2O 30 °C (±)-26 (1 S 3 S)-27 (1 S 3 R)-28 R = CH2NO2 SPh SO2Ph CH2SO2Ph Scheme 10 6 Carbon–carbon bond formation The synthesis of N-acetyl-D-neuraminic acid (Neu5Ac) 30 (R\CH 3 ) using the corresponding aldolase to catalyse the reaction between N-acetyl-D-mannosamine (MannNAc) 29 (R\CH 3 ) and pyruvic acid has been scaled up by the Glaxo Wellcome group.51 Base-catalysed epimerization of N-acetylglucosamine (GlcNAc) gave a GlcNAc–MannNAc mixture (4 1) which could be used directly for the aldolase reaction.However GlcNAc is an inhibitor of the enzyme and therefore a high concentration of pyruvate was required to drive the equilibrium towards Neu5Ac.The excess pyruvate could then be removed as a bisulfate adduct. A second approach was developed to enrich the GlcNAc–MannNAc mixtures for MannNAc. This mixture could then be used in much higher concentration obviating the need to use a large excess of pyruvate. Neu5Ac aldolase is specific for pyruvic acid but is known to tolerate substitutions at C-4 C-5 or C-6 of ManNAc and configurations at C-4 and C-5 can be di§erent. The configuration at C-2 is essential but Wong has recently shown that a range of C-2 mannosamines 29 are accepted by the enzyme to produce the corresponding C-5 modified sialic acids 30 in good yields (55–72%) (Scheme 11).52 This will be a useful alternative to the use of the 5-deoxy-5-azide derivative in cases where synthetic elaboration proves di¶cult.Rabbit muscle aldolase (RAMA) catalyses the stereoselectiveC–C coupling between dihydroxyacetone phosphate (DHAP) and a broad range of aldehydes. An improved route for the preparation of DHAP on a large scale has been reported starting from 1,3-dibromoacetone.53 Wong has recently shown that remote dialdehydes with an aliphatic linkage lead to formation of multifunctional monoaldehydes.54 RAMA appeared to have no diastereopreference (R,R S,S and meso all reacted). The same group have used recombinant D- and L-threonine aldolases for the enzymatic synthesis of a range of b-hydroxy-a-amino acids (Scheme 12).55 L-Threonine aldolase (LTA) from E. coli and D-threonine aldolase (DTA) from Xanthomonas oryzae were cloned and overexpressed in E.coli. The enzymes are pyridoxal-5-phosphate dependent and LTA requires Mg2` as a cofactor. Both enzymes tolerate up to 40% DMSO as cosolvent and DMSO-induced rate enhancement of the LTA reactions was observed. LTA gave erythro b-hydroxy-a-L-amino acids with aliphatic aldehydes and the threo isomer with aromatic aldehydes as kinetically controlled products. DTA formed threo b-hydroxy-a-D-amino acids with aliphatic and aromatic aldehydes but the diastereoselectivity was lower than that of LTA. Although yields in many cases were low several b-hydroxy-a-amino acids such as hydroxyleucines c-benzyloxythreonines c-benzyloxymethyl threonines and polyoxamic acids were synthesized stereoselectively on a preparative scale. 46 A. J. Carnell HN O HO HO OH O R HO O OH CO2H HO N HO OH HO R O CO2H O H Neu5Mann 29 30 R = amino acyl peptidyl dansyl biotin aldolase Scheme 11 R OH O OH NH2 R OH O OH NH2 R OH O OH NH2 R OH O OH NH2 R H O OH O NH2 + DTA LTA D- threo D- erythro L- threo L- erythro + + Scheme 12 Some novel sources of (R)-oxynitrilases from apple apricot cherry and plum meal have been compared with the commercially available almond meal for the synthesis of aliphatic and aromatic cyanohydrins.Apple meal gave best results accepting sterically hindered substrates such as pivaldehyde to give (R)-cyanohydrins with high enantiopurity. 56 Optically active (S)-cyanohydrins have also been obtained by enantioselective cleavage of racemic cyanohydrins with (R)-hydroxynitrile lyase. Optimum conditions used a biphasic system (citrate bu§er–Pr*OH and capture of the aldehyde as a semicarbazone.57 7 C–O and C–N bond formation Modified sialic acids are present at the termini of many biologically important oligosaccharides and are among the most important residues for interactions with receptors.Halcomb and Chappell have demonstrated that a-2,3-sialyl transferase will accept variation in the 5-substituent on the activated CMP sialyl donor for glycosylation reactions with allyl b-lactoside (Scheme 13).58 The R\NHC(O)CH 2 OH and NH 2 (easily formed from NHCbz) features are found in a number of gangliosides. The sialyl transferase reaction can be used in vivo and therefore has the potential for modification of antigenic properties of intact cells. 3-Methyl aspartase isolated from a recombinant E. coli strain has been used to catalyse the enantioselective conjugate addition of a range of N-nucleophiles to the si-face of substituted fumaric acids in good yields (Scheme 14).59 The size of the substituents (R2) on theN-nucleophile tolerated by the enzyme displayed a profound dependence on the 47 Synthetic methods Part (iii) Enzyme chemistry O OCMP CO2 – HO R HO OH HO O CO2H O HO R HO OH HO O OH OH OH O O HO OH O OH allyl b-lactoside a-2,3-sialyl transfrase R = NHAc (Sialic acid) OH NHC(O)CH2OH NHCbz 5 Scheme 13 HO2C R1 H CO2 H R2 N R3 H HO2C R1 H CO2H H R2 N R3 2 3 + Mg2+ K+ 3-methyl aspartase R1 = H Me hal Et Pr Pri R2 = NH2 Me Et OH OMe R3 = H Me 12–61% yield (2 S 3 S) Scheme 14 size of R1 on the Michael acceptor in a mutually exclusive manner indicating that R1 and R2 are able to access similar regions of space in the enzyme active site.References 1 S.M. Roberts and N.M. Williamson Curr. Org. Chem. 1997 1 1. 2 N. J. Turner Curr. Org. Chem. 1997 1 21. 3 T. Sugai T. Yamazaki M. Yokoyama and H. Ohta Biosci. Biotechnol. Biochem. 1997 61 1419. 4 I.V. J. Archer Tetrahedron 1997 53 15 617. 5 H.L. Holland Adv. App. Microbiol. 1997 44 125. 6 A. Archelas and R. Furstoss Ann. Rev. Microbiol. 1997 51 491. 7 W.D. Fessner and C. Walter Top. Curr. Chem. 1997 184 97. 8 M. Petersen M.T. Zaetti and W. D. Fessner Top. Curr. Chem. 1997 186 87. 9 M. J. Kim I. T. Lim H. J. Kim and C. H. Wong Tetrahedron Asymmetry 1997 8 1507. 10 P. Renouf J.-M. Poirere and P. Duhamel J. Chem. Soc. Perkin Trans 1 1997 1739. 11 A. J. Carnell J. Barkley and A. Singh Tetrahedron Lett. 1997 38 7781.12 C. Bonini R. Ragoppi and L. Viggiani Tetrahedron Asymmetry 1997 8 353. 13 W. Adam P. Groer and G. R. Saha-Mo� ller Tetrahedron Asymmetry 1997 8 833. 14 M. Ferrero S. Fernandez and V. Gotor J. Org. Chem. 1997 62 4358. 15 H. Waldemann and A. Reidel Angew. Chem. Int. Ed. Engl. 1997 36 647. 16 F. E§enberger B. W. Graef and S. Oßwald Tetrahedron Asymmetry 1997 8 27. 17 O. Meth-Cohn and M.-X. Wang Chem. Commun. 1997 1041. 18 O. Meth-Cohn and M.-X. Wang J. Chem. Soc. Perkin Trans. 1 1997 3197. 19 O. Meth-Cohn and M.-X. Wang J. Chem. Soc. Perkin Trans. 1 1997 1099. 20 F. E§enberger B. W. Graef and S. Oßwald Tetrahedron Asymmetry 1997 8 2749. 48 A. J. Carnell 21 I. Osprian W. Kroutil M. Mischitz and K. Faber Tetrahedron Asymmetry 1997 8 65. 22 R. V. A. Orru W. Kroutil and K.Faber Tetrahedron Lett. 1997 38 1753; see also I. V. J. Archer D. J. Leak and D. A. Widdowson Tetrahedron Lett. 1996 37 8819. 23 C. Morisseau H. Nellaiah A. Archelas R. Furstoss and J. C. Baratti Enzyme Microb. Technol. 1997 20 446. 24 G. Grogan C. Rippe and A. Willetts J. Mol. Catal. B-Enzymatic 1997 3 253. 25 D. Gonzalez V. Schapiro G. Seoane and T. Hudlicky Tetrahedron Asymmetry 1997 8 975. 26 B. V. Nguyen C. York and T. Hudlicky Tetrahedron 1997 53 8807. 27 M. Desjardins L. E. Brammer and T. Hudlicky Carbohydr. Res. 1997 304 39. 28 F. Y. Yan B. V. Nguyen C. York and T. Hudlicky Tetrahedron 1997 53 11 541. 29 P. DiGennaro E. Galli G. Albini F. Pelizzoni G. Sello and G. Bestetti Res. Microbiol. 1997 148 355. 30 S. Pietz D. Wolker and G. Haufe Tetrahedron 1997 53 17 067. 31 S. Pietz R.Frohlich and G. Haufe Tetrahedron 1997 53 17 055. 32 S. H. Hu D. A. Sun X. F. Tian and Q. C. Fan Tetrahedron Lett. 1997 38 2721. 33 R. Villa and A. Willetts J. Mol. Catal. B-Enzymatic 1997 2 193. 34 C. Mazzini J. Lebreton V. Alphand and R. Furstoss Tetrahedron Lett. 1997 38 1195. 35 A. Willetts TIBTECH 1997 15 55. 36 C. Bolm T. K. K. Luong and G. Schlingho§ Synlett 1997 1151 and references therein. 37 S. Colonna N. Gaggero G. Carrea and P. Pasta Chem. Commun. 1997 439. 38 M.P. J. vanDeurzen I. J. Remkes F. vanRantwijk and R. A. Sheldon J. Mol. Catal. A-Chemical 1997 117 329. 39 M.B. Fisher and A. E. Rettie Tetrahedron Asymmetry 1997 8 613. 40 H. L. Holland L. J. Allen M.J. Chernishenko M. Diez A. Kohl J. Ozog and J. X. Gu J. Mol. Catal. B-Enzymatic 1997 3 311. 41 S. C. Gallagher R.Cammack and H. Dalton Eur. J. Biochem. 1997 247 635. 42 A. Kamal Y. Damayanthi B. S. Narayan Reddy B. Lakminarayana and B. S. Praveen Reddy Chem. Commun. 1997 1015. 43 A. Kamal B. Laxminarayana N. L. Gayatri Tetrahedron Lett. 1997 38 6871. 44 O. Rotthaus D. Kruger M. Demuth and K. Scha§ner Tetrahedron 1997 52 935. 45 Y. Kawai K. Takanobe and A. Ohno Bull. Chem. Soc. Jpn. 1997 70 1683. 46 J.-N. Cui R. Teraoka T. Ema S. Takashi and U. Masanori Tetrahedron Lett. 1997 38 3021. 47 R. Tanikaga Y. Obata and K.-i. Kawamoto Tetrahedron Asymmetry 1997 8 3101. 48 A. R. Maguire and D. G. Lowney J. Chem. Soc. Perkin Trans. 1 1997 235. 49 A. R. Maguire and L. L. Kelleher Tetrahedron Lett. 1997 38 7459. 50 W. Adam U. Hoch H. U. Humpf C. R. SahaMoller and P. Schreier Chem. Commun. 1997 2701.51 M. Mahmoudian D. Noble C. S. Drake R. F. Middleton D. S. Montgomery J. E. Piercey D. Ramlakhan M. Todd and M.J. Dawson Enzyme Microb. Technol. 1997 20 393. 52 C. C. Lin C. H. Lin and C. H. Wong Tetrahedron Lett. 1997 38 2649. 53 T. Geßaut M. Lemaire M. L. Valentin and J. Bolte J. Org. Chem. 1997 62 5920. 54 M.J. Kim I. T. Lim H. J. Kim and C. H. Wong Tetrahedron Asymmetry 1997 8 1507. 55 T. Kimura V. P. Vassilev G. J. Shen and C. H. Wong J. Am. Chem. Soc. 1997 119 11 734. 56 E. Kiljanen and L. T. Kanera Tetrahedron Asymmetry 1997 8 1225. 57 F. E§enberger and A. Schwaemmle Biocatal. Biotransform. 1997 14 167. 58 M.D. Chappell and R. L. Halcomb J. Am. Chem. Soc. 1997 119 3393. 59 M.S. Gulzar M. Akhtar and D. Gani J. Chem. Soc. Perkin Trans. 1 1997 649. 49 Synthetic methods Part (iii) Enzyme chemistry mmmm

ISSN:0069-3030    

DOI:10.1039/oc094039

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

OEt O O R OEt O R PPh3Br + – 62–90% (7 examples) 1 i Scheme 1 Reagents i BuLi Et 2 O 0 °C 2 Synthetic methods Part (iv) Heteroatom methods By PATRICK J. MURPHY Department of Chemistry University of Wales Bangor Gwynedd UK LL57 2UW 1 Introduction This report focuses on the organic chemistry of phosphorus arsenic sulfur silicon selenium and tellurium. The heterocyclic free radical and transition metal chemistry of these areas has been largely ignored as this will be covered in other reports. 2 Organophosphorus and organoarsenic chemistry In this the centenary year1 of the birth of Georg Wittig the reaction that bears his name is still of considerable interest to synthetic chemists and continues to find application in many synthetic procedures. Indeed a review by Nicolaou et al. on the applications of the Wittig and related reactions in natural product synthesis has appeared highlighting many landmark achievements of this reaction.2 Several applications of tandem processes involving Wittig reactions have appeared for example the use of a tandem Michael–Wittig reaction for the formation of substituted cyclohexadienes 1 which are potential A-ring precursors for taxol3 (Scheme 1).The conjugate addition of crotonate arsonium ylide to a,b-unsaturated carbonyl compounds has also been reported.4 In general the reactivity of arsonium ylides was found to be higher than in the corresponding phosphorus ylide which also forms the tandem product however considerable quantities of direct Wittig condensation byproducts were also isolated. The first example of cyclopropane formation by ylides of this type was also reported in the same paper.The same worker also reported the synthesis of highly functionalised cyclohex-2-enonedicarboxylates from a novel Michael–Wittig reaction of methyl 3-oxo-4-(triphenylarsoranylidene)butanoate 2 and substituted 2H-pyran-5-carboxylates.5 Reaction of two equivalents of 2 with al- 51 O COSEt Ph3As CO2R O O COSEt CO2Me HO HO CO2R R¢ CO2R + R = Me 2 i 48% Scheme 2 Reagents i 0.5 equiv. R@CHO; R@\aryl alkyl R\Pr* Et Me P Ph Ph R OEt O P+ O– EtO Ph Ph R EtO R PPh2 O 3 5 examples 37–73% R = alkyl aryl 4 Scheme 3 Reagents i reflux 16 h dehydes has been shown to give cyclohepta-1,2,5-trienes in moderate yields (6 examples 8–53%) (Scheme 2).6 The reaction of the cyclic phosphonium ylide 3 with a,b-unsaturated esters leads to the formation of the seven-membered cyclic enol ether derivatives 4 via a tandem Michael–intramolecular Wittig reaction with the ester group (Scheme 3).7 A tandem Michael–HWE (Horner–Wittig–Emmons) procedure for the one-pot synthesis of d-substituted a,b-unsaturated esters has been reported in which the HWE reagent is deprotonated in situ by the enolate formed from a conjugate addition of a cuprate or organolithium species to an enone; yields of 15–92% were quoted (23 examples) with E:Z ratios of 1 1\4 1 being typical.8 In a series of papers9–11 Akiba has reported the use of the pentacoordinate spirophosphorane unit 5 in Wittig style reactions; for example reaction of the phosphorane (R\CH 2 CO 2 Et) under Wittig conditions with a range of aldehydes gave excellent Z-selective olefin formation (7 examples 73–83% yield[96 4 Z:E) (Scheme 4).9 High Z-selectivity has been observed in the olefination of base-sensitive chiral b-hydroxy-a-amino aldehydes using the HWE reaction; this was achieved under mild conditions using bis(trifluoroethyl)phosphonates and LiCl–DBU in THF.12 Nishizawa et al.have reported an indirect Wittig reaction which proceeds via the low temperature isolation of the intermediate 1,2-hydroxyphosphonium salts; elimination of water from these to give the required alkene was achieved by treatment with DBU. The reaction displayed identical stereoselectivity to the corresponding direct 52 P. J. Murphy R1 CO2Et P R O O F3C CF3 CF3 F3C i 5 Scheme 4 Reagents i R1CHO KOBut 3h N Ph2(O)P CHO H 7 (racemic) (RO)2P O O O 6 N CO2R* Ph2(O)P H N CO2R* Ph2(O)P H N Ph2(O)P H N Ph2(O)P H CO2R* CO2R* + Scheme 5 Wittig reaction for aliphatic aldehydes and unstabilised ylides.13 Microwave heating has been shown to accelerate the rate of the Wittig reaction of stabilised phosphoranes with ketones under solvent-free conditions; reasonable yields (36–85%) were obtained with a range of ketones over reaction times of 15–20 min however E:Z ratios were generally poor.14 Nagao has reported a Sn(OSO 2 CF 3 ) 2 and N-ethylpiperidine catalysed variant of the HWE reaction that is thought to proceed via a tin enolate species; high levels of Z or E selectivity have been observed using aryl ketones or aldehydes respectively.These observations are explained using a tin-chelated 6-membered transition state for the addition of the carbonyl species to the enolate.15 Phosphonates 6 have been used in the kinetic resolution of the diphenylphosphinylprotected a-amino aldehyde 7 and it was found that by using di§erent bases and phosphonate ester groups any of the four possible diastereomeric products can be obtained.16 Geometric selectivities from 66 34 to 98 2 and diastereomeric ratios between 93 7 and 99 1 were reported (Scheme 5).A similar kinetic resolution has been employed in the synthesis of the C1–C11 subunit of the macrocyclic marine meta- 53 Synthetic methods Part (iv) Heteroatom methods But O + EtO2P CN O 9 RNH Me Ph OLi i 8 77–96% But CN 17–52% e.e. Scheme 6 Reagents i PhMe [78 °C 3 h; R\H Me Pr* CH 2 But CH 2 CHPh 2 CH 2 -(1-adamantyl) O Ph3As O Ph 10 O R1 11 R1 R O O Ph + i Scheme 7 Reagents i [78 °C THF; R1\Ph Me Et But bolites the iejimalides.17 Chiral lithium 2-amino alkoxides 8 were applied as chiral bases for the enantioselective HWE reaction between the achiral phosphonates 9 and 4-tert-butylcyclohexanone; ees of up to 52% were obtained.18 It was demonstrated that the formation of the lithium aldolate intermediate is reversible and it is not this step that is responsible for the asymmetric induction (Scheme 6).An asymmetric Wittig-type olefination of 4-substituted cyclohexanones 11 with the 8-phenylmenthol-derived chiral arsonium ylide 10 gave the alkene product in 58–69% yield and 47–80% de which is an improvement on results reported previously for the corresponding chiral phosphonate (Scheme 7).19 An alternative to traditional Wittig procedures has been reported by Ledford and Carreira who used a combination of N 2 CHCO 2 Et a catalytic (1%) amount of ReOCl 3 (PPh 3 ) 2 and (EtO) 3 P in the olefination of a range of aldehydes.Yields of 70–95% (11 examples) and E/Z selectivities of 3 1 to 20 1 were observed.20 The olefination of dialkyl squarates by Wittig and HWE reactions has also been reported; limited and generally E-stereoselectivity was observed with stabilised phosphoranes whereas high levels of Z-selectivity (2 1 to 19 1) were observed under HWE conditions. 21 The formation of N-styrylformamides by the reaction of N,N-diformylamines with arylmethylenephosphoranes under mild conditions has been detailed.22 The transformation of one or both of the methoxycarbonyl groups of a substituted porphyrin into isopropenyl groups was e§ected by treatment with excess methylenetriphenylphosphorane.23 In an elegant new approach to the synthesis of aristolactams 24 Couture and co-workers have e§ected the conversion of the phosphine oxide 12 into the enamine product 13 via an intermediate benzyne intermediate (Scheme 8). Warren and co-workers have investigated the configurational stability of lithiated phosphine oxides by studying their addition to phenylalanine-derived aldehydes (the Ho§mann test); they concluded that lithiated diphenylphosphine oxides are not con- figurationally stable in THF at [78 °C.25 Warren has also reported a range of 54 P. J. Murphy R1 R2 N Br P O R3 O Ph Ph 12 R1 R2 N P O R3 O Ph Ph R1 R2 N O R3 K P O Ph Ph K R1 R2 N O R3 I 13 ii i 71–81% R1 H H CH2—O—CH2 OMe R2 H H OMe R3 Me Bn 4-MeOC6H4CH2 4-MeOC6H4CH2 Scheme 8 Reagents i KHDMS,[78 °C to[30 °C THF; ii o-iodobenzaldehyde Ph2P R O OH 14 Ph2P R O OH Me anti syn 2:1–4:1 i Ph2P R1 O OP 15 Ph2P R1 O OP SiPhMe2 anti syn 70:30–95:5 ii Scheme 9 Reagents i methylcuprates; ii (PhMe 2 Si) 2 CuLi 2 diastereoselective reactions of optically active c-substituted vinyl phosphine oxides;26 addition of dimethylcuprate to substrates 14 (R\Me Bun Ph) proceeds with 2 1 to 4 1 anti syn stereoselectivity whilst the addition of (TBDMS) 2 CuLi 2 to substrates 15 (R\Bun Ph P\TBS MOM) proceeds with 70 30 to 95 05 anti syn stereoselectivity (Scheme 9).The factors governing the e¶ciency of the asymmetric dihydroxylation of allylic phosphine oxides under Sharpless conditions have also been investigated by Warren; the use of the monomeric DHQD-CLB ligand was found to give the best results (42–68%ee).27 The direct conversion of easily prepared and air-stable phosphine–borane complexes directly into phosphonium salts (some chiral) by reaction with an alkyl (or aryl) halide in the presence of an alkene has been reported; the reaction proceeds in reasonable yields (50–92% 11 examples) and sometimes requires the use of high pressure.28 An interesting route to vinyl phosphonium iodides 16 by treatment of a,b-epoxysilanes sequentially with LiPPh 2 and methyl iodide has also been reported (Scheme 10).29 55 Synthetic methods Part (iv) Heteroatom methods O R SiPhR1R2 PPh2MeI– R + i ii 16 Scheme 10 Reagents i LiPPh 2 ; ii MeI; R\Bu Ph; R1\Me But; R2\Me Ph OM P RO RO O S p-Tol N Ar H •• + OM P RO RO N S Tol- p H Ar O •• i 17 Scheme 11 Reagents i THF,[78 °C; R\Et Pr*; M\Li Na p-Tol S N Ph O H 18 i p-Tol S N O Ph P(OMe)2 O H Scheme 12 Reagents i (MeO) 2 P(O)CH 2 Li Several addition reactions to sulfinimines have been reported for example the asymmetric synthesis of a-amino phosphoric acids via the addition of phosphites to enantiopure sulfinimine 17 has been reported to give the addition products in de of 84–97% (Scheme 11).30 Similarly addition of the a-phosphonate carbanions to (S)- sulfinimines 18 gives N-sulfinyl-b-aminophosphonates with diastereoselectivity of up to 10 1 (Scheme 12).31 In a similar but enantiodivergent approach Mikolajczyk has reported that the addition of either dialkyl phosphite or diamido phosphite anions to 18 leads to either the R- 19 or S-isomer 20 at the carbon centre predominating; hydrolysis of these adducts o§ers a new convenient synthesis of a-aminophosphonic acids (Scheme 13).32 The addition of diethylaluminum cyanide and the lithium enolate of methyl a-bromoacetate to enantiopure sulfinimines leads to the formation of a-amino nitriles and N-sulfinylaziridines respectively.33 A TMSOTf-promoted 1,4- addition of silyl phosphites prepared in situ from dialkyl phosphites and N,Obis( trimethylsilyl)acetamide to cyclic enones leading to b-keto phosphonates in 20–98% has also been reported.34 Several organophosphorus-related reviews have appeared in 1997 including a volume of the Journal of Organometallic Chemistry devoted to current trends in organophosphorus chemistry.35 An account detailing several synthetic strategies for the preparation of chiral hydroxy phosphine ligands,36 and reviews on the synthetic methods available for the synthesis of non-racemic phosphonates37 and dialkyl a- halogenated methylphosphonates38 have also appeared.3 Organosulfur chemistry A comprehensive review on the preparation and reactions of chiral sulfonium ylides and related species has appeared which includes details of their use in asymmetric 56 P. J. Murphy p-Tol S NH C P(OMe)2 O H Ph O p-Tol S NH C P(NEt2)2 O H Ph O p-Tol S N Ph O H i ii 18 19 20 94:6 90:10 Scheme 13 Reagents i (MeO) 2 POLi; ii (Et 2 N) 2 POLi Me 2-Py +S p-Tol –O Me 2-Py +S p-Tol –O 2-Py S ButMe2SiO Me p-Tol OSiMe2But OMe ( S) ( S) ( R) ( S) 21 22 or 23 24 Scheme 14 epoxidation cyclopropanation aziridination olefination and rearrangement.39 The Pummerer reaction has been the topic of several reports indeed a detailed review highlighting the applications of the Pummerer reaction to the preparation of complex carbocyclic and heterocyclic ring systems has been published by Padwa et al.40 Kita et al.have reported an enantioselective Pummerer-type rearrangement of enantiopure a-substituted sulfoxides with O-silylated ketene acetals. For example diastereomeric sulfoxides 21 or 22 both undergo rearrangement to sulfide 23 in [99%ee on treatment with the O-silyl ketene acetal 24 (Scheme 14).41,42 Similarly Shibata has reported that Pummerer-type reactions induced by ethoxyvinyl esters are an alternative to the generally used acid anhydrides and that high levels of asymmetric induction are possible with ees as high as 84%.43 The chemistry of sulfoxides continues to be of interest for example chiral b-hydroxy sulfoxides (e.g.25) have been shown to be excellent proton sources for the enantiofacial protonation of prochiral lithium enolates with ees as high as 97% being observed for the reaction with lithium enolates of cyclohexanone derivatives.44 This methodology was used for the protonation of enolate 26 in 82%ee yielding ketone 27 a synthetic precursor of ([)-epibatidine (Scheme 15).45 c-Hydroxy sulfoxides have been prepared by a highly stereoselective sulfoxide-directed reduction of c-keto sulfoxides 28 using 57 Synthetic methods Part (iv) Heteroatom methods O O OLi N Cl O O O N Cl S O F3C OH 25 i 2.5 26 27 Scheme 15 Reagents i [90 °C to [60 °C R¢ S O p-Tol R¢ S O p-Tol R¢ S O p-Tol O OTBS OTBS OH OTBS OH 28 29 30 Syn-6 yield > 90% de > 90% Anti-6 yield > 90% de > 93% i ii Scheme 16 Reagents i DIBAL THF [78 °C; ii DIBAL ZnI 2 THF [78 °C; R\Me Ph allyl vinyl DIBAL or DIBAL–ZnI 2 leading to the syn- 29 or anti-products 30 respectively (Scheme 16).46 A short stereocontrolled synthesis of 31 an unusual amino acid component of ustiloxins A and B has been achieved; the key step being the RBINOL –Ti(OPr*) 4 –ButOOH mediated oxidation of sulfide 32 with [50 1 6Sstereoselectivity.The use of S-BINOL gave the 6R-sulfoxide with 16 1 stereoselectivity (Scheme 17).47 TheN-sulfinylsultam 33 has been utilised as a new sulfinyl transfer agent; reaction of this conveniently prepared reagent with Grignard reagents led to the formation of the corresponding sulfoxide 34 in 91–98% yield and 99–99%ee.48 In addition reaction with LiHMDS led to the formation of the intermediate 35 which can be converted into the corresponding sulfinimine ([98%ee) via a modification of the Davis procedure (Scheme 18).Davis et al. have reported full details of this method for the asymmetric synthesis of sulfinimines together with two other less e¶cient methods for their synthesis by either the asymmetric oxidation of sulfenimines (Ar–SN––CR 2 ) with chiral oxaziridines or by the reaction of metal aldimines (RCH––NM) prepared from nitriles with (R)- or (S)-menthyl toluene-p-sulfinate were also reported.49 The asymmetric sulfimidation of sulfides to sulfimides (R 2 S––NTs) using TsN–– IPh in the presence of a catalytic amount of CuOTf and a chiral bis-oxazoline ligand has been reported to proceed with a wide range of sulfides in yields of 50–83% with ees of up to 71%.58 P. J. Murphy O O CO2H S Ph O OH H2N O BocHN BocHN O S Ph O i steps 32 31 SPh 75% Scheme 17 Reagents i But OOH Ti(OPr*) 4 (R)-BINOL S R O S N SiMe3 SiMe3 O S N R¢ O S N SO2 33 34 35 O iii 65–84% i ii •• •• •• •• Scheme 18 Reagents i RM THF [78 °C 1 h; ii LiHMDS; ii R@CHO; R\alkyl allyl vinyl aryl thienyl furyl pentynyl; M\MgBr ZnBr; R@\allyl aryl a,b- unsaturated Sulfonamides are produced via a [2,3]-sigmatropic rearrangement when the reaction is applied to allylic sulfides; ees of up to 58% are obtained.50 The reaction of lithiated chiral non-racemic methyl p-tolyl sulfoxide with imidoyl chlorides [RC(––NR)Cl] has been reported as a general synthetic method for the synthesis of N-substituted fluorinated b-imino sulfoxides.51 The first example of a Claisen rearrangement stereocontrolled by a sulfinyl group has been reported; the thermal rearrangement of ketene dithioacetals 36 occurs over 5–45 hours at room temp.giving product 37 in 40–65% yield as 93 7 to 99 1 mixtures of diastereoisomers (Scheme 19).52 The ability of sulfur-containing functional groups to mediate carbanion formation continues to generate new synthetic methodology. The 1,4-dithiin 38 is easily deprotonated leading to the lithiated species 39 which can be reacted with a range of electrophiles including alkyl halides epoxides and aldehydes. Desulfurisation of the products obtained leads to the formation of substituted cis-allylic alcohols e§ectively illustrating the use of 38 as an allylic alcohol anion equivalent (Scheme 20).53 Simpkins has reported the enantioselective rearrangement of three-membered ring sulfoxides (episulfoxides) into alkenyl sulfoxides using chiral lithium amide bases.For example the episulfoxide 40 was converted (over two steps) to the sulfone 41 in 59 Synthetic methods Part (iv) Heteroatom methods S SMe R2 R1 S O 36 SMe S S R1 O R2 37 [3.3] CH2Cl2 ca 20 °C •• Scheme 19 R1\Me But Pr* c-C 6 H 11 ; R2\Me H S S H MPMO S S MPMO – Li+ 39 S S OH OBn MPMO MPMO OBn OH 70% iii HO – 38 º i ii 88% O OBn Scheme 20 Reagents i BuLi THF; ii Ti(OPr*) 4 ; iii Raney Ni N N Ph Ph Ph Ph H H OBn S+ O– i 65% OBn H SOMe OBn H SO2 Me 4 R ii 87% 40 41 Li Li 42 4 R Scheme 21 Reagents i THF,[78 °C MeI; ii Oxone' MeOH H 2 O 85–88%ee using the base 42 (Scheme 21).54 Full details of the synthesis anionic substitution conversion to alkenes and ring-opening rearrangement of cyclic three membered sulfones (episulfones) have also been described by the same group55 as well as the conjugate addition reaction of a metallated 2-methoxypyridine to an azabicyclic alkenyl sulfone as the key step in the synthesis of racemic epibatidine.56 Magnus has reported that only two out of a possible four diastereomers are formed from the reaction of the dilithiated sulfone 43 with benzaldehyde.It is felt that the aggregate 43 (n\1–4) is responsible for this long range asymmetric induction the highest level being observed when n\2 where the erythro threo ratio was 2.75 1 (Scheme 22).57 A novel tandem conjugate addition–Ramberg–Ba� cklund rearrangement process has been reported by Taylor and Evans.58 This involved the conjugate 60 P.J. Murphy PhO2S NH N Me Me O Ph H ( ) n ( n = 1,2,3,4) i 43 Me N Li PhO2S N OLi Me Ph ( ) n 44 ii PhO2S NH N Me Me O Ph H ( )n Ph OH H H Scheme 22 Reagents i BuLi THF,[70 °C; ii PhCHO,[100 °C S O2 Br 45 SO2 Ph Br BnS SO2 Ph Bn BnS H – – i BnS Ph 46 77% E Z 93:7 Scheme 23 Reagents i BnSH KOBut But OOH DCM 15 h rt addition of a range of oxygen nitrogen sulfur and carbon nucleophiles to the brominated vinyl sulfone 45 which after proton exchange rearranges and eliminates under the conditions of the reaction to give the Ramberg–Ba� cklund product for example the allyl sulfide 46 (Scheme 23). The Jacobsen epoxidation of dienyl sulfones has been investigated and it has been observed that symchiral (salen)Mn(III)CI complexes catalyse the epoxidation of 2- sulfonyl-cyclic-1,3-dienes with high enantioselectivity (68–99%) and that the incorporation of the sulfone moiety increases the enantioselectivity by up to 30% when compared with the unsubstituted cyclic-1,3-diene.59 The preparation and reactions of trithiocarbonate oxides (sulfines) has been reported.60 These interesting intermediates undergo addition of alkyllithium species to form trithioorthoesters which are unstable and undergo rearrangement to give a disulfide and a thioester as illustrated in the intramolecular example leading to 47. The intermediate lithiated trithioorthoesters can be used in conjugate addition reactions to enones and enals to give 48 which rearrange over a few hours to the ketene thioacetals 49 which are hydrolysed to give thioesters 50 in reasonable overall yield (37–55%) (Scheme 24).Several organosulfur related reviews have appeared in 1997 including a Tetrahedron 61 Synthetic methods Part (iv) Heteroatom methods S S S O S S S O Me i ii S S O SMe Me S S S H O 47 R1S SR1 S O R1S SR1 S O Me – Li+ i R2 R3 O R1S S O Me R3 O R2 R1S 48 R1S R3 O R2 R1S 49 O R3 O R2 R1S 50 then ii –MeSOH ii Scheme 24 Reagents i MeLi THF [78 °C; ii H 2 O; R1\Me Et But Bn; R2\Me Et; R3\H Me specialist periodical report on ‘Recent aspects of S Se and Te chemistry’.61 Others include those on synthetic applications of N-sulfonyl imines,62 xanthates,63 chiral acetylenic sulfoxides,64 and on the chemistry of thioacylsilanes;65 the preparation and asymmetric reactions of chiral sulfinyl-1,3-dienes has also been reviewed.66 4 Organoselenium and organotellurium chemistry There has been continued interest in the asymmetric oxyselenylation of alkenes indeed the area has been reviewed67 and several new reagents have been reported during 1997.A range of chiral ferrocenylselenium reagents were applied to asymmetric methoxyselenylation of alkenes and the amine-derived reagent 51 was found to be the most e§ective with ees in the range of 15–96% being reported.68 This reagent was also applied in the selenation of silyl enol ethers with modest success. A similar series of optically active selenium reagents having a pendant chiral tertiary amino group have been reported.69 Reagent 52 was found to give the best asymmetric induction in the methoxyselenylation of (E)-phenylpropene where a de of 97% was obtained; the presence of a strong Se–N interaction was inferred to explain the results.The C 2 - symmetric reagent 53 has also been reported to give excellent diastereoselectivities sometimes as high as 98% in the selenoalkoxylation reactions of alkenes (Scheme 25).70 In a new twist to selenoxide eliminations it has been reported that antibodies have been elicited that catalyse the selenoxide elimination of several racemic benzylic selenoxides at a k#!5/k6/#!5 of up to 2200; chiral discrimination between individual 62 P. J. Murphy NMe2 Me H SeOTf Fe N O O O O Ph SePF6 Ph 51 52 53 O O SeOTf Scheme 25 OAc C3H7 i Se Ar OH O ii O C3H7 54 Scheme 26 Reagents i MeLi ZnBr Et 2 O 0 °C to RT; ii,[100 °C enantiomers of the substrate selenoxide was also observed.71 The enantiofacial protonation of cyclic enol acetates with chiral c-hydroxyselenoxides 54 (and analogous sulfoxides) in the presence of MeLi and zinc bromide has also been described; ees as high as 88% have been reported when Ar\4-MeOC 6 H 4 (Scheme 26).72 The application of the Sharpless AD-mix oxidation to allyl selenides has been reported; chemoselectivity for dihydroxylation of the double bond was only observed when o-nitrophenylallylselenides were employed and selectivity of 93 7 was observed for both a-ADmix and b-ADmix.73 The synthesis characterisation and stability of selenothioic acid S-esters 55 has been reported; a general method involving the treatment of a terminal alkyne with BuLi and selenium followed by addition of an alkyl thiol results in their formation in 23–83% yield (Scheme 27).74 Treatment of selenocyanates (RSeCN) with either one molar equivalent of LiH NaH or lithium triethylborohydride or 0.25 equivalents of lithium or sodium borohydrides led to the formation of diselenides in good yields (52–96% 14 examples); the reaction proceeds via the intermediate selenol or selenolate.75,76 Sodium phenylseleno(triethyl)borate complex M[NaPhSeB(OEt) 3 ] prepared by reduction of (PhSe) 2 with NaBH 4 in EtOHN and benzeneselenol (PhSeH) generated in situ from this complex by addition of acetic acid have been demonstrated to serve as excellent reducing agents for a,b-epoxy ketones and esters yielding b-hydroxy carbonyl compounds in good to excellent yields.77 An e¶cient stereocontrolled strategy for the cyclopropanation of a,b-unsaturated ketones with semi-stabilized telluronium ylides has been reported which a§ords cis-2- vinyl-trans-3-substituted cyclopropyl ketones 56 with hitereoselectivity (generally [95 5) and in good yield.Conversely the same enones gave trans-2-vinyl-trans-3- substituted cyclopropyl ketones 57 when the corresponding arsonium ylides were employed (Scheme 28).78 63 Synthetic methods Part (iv) Heteroatom methods RC CH i-iii R SR¢ Se 55 Scheme 27 Reagents i BunLi Et 2 O; ii Se; iii R@SH; R\Me 3 Si Ph 3 Si Me n-C 4 H 9 Ph; R@\allyl aryl Bui 2Te+ R1 Br– R R2 O ii i COR2 H R R1 H H > 95:5 Ph3As+ R1 R R2 O ii iii COR2 H R H R1 H > 87:13 56 57 Scheme 28 Reagents i KHMDS THF; ii chalcone; iii LiBr KOBut or i; R\Ph aryl; R1\Ph vinyl CH––CHTMS CH––CHMe CH–– CHPh; R2\Ph But The preparation reactivity and synthetic applications of vinylic selenides and tellurides has been reviewed covering the literature from 1983 to 199679 as has the synthesis and asymmetric applications of optically active selenium and tellurium compounds.80 5 Organosilicon chemistry Fleming Barbero and Walter have co-authored a review entitled ‘Stereochemical control in organic synthesis using silicon-containing compounds’.81 This significant piece of work covers all aspects of stereocontrol involving silicon and will no doubt become an essential reference work for all researchers interested in the organic chemistry of silicon.Other reviews of interest include one focusing on the temporary silicon-connection tethering strategy in synthesis particularly applications involving radical cyclisations cycloadditions nucleophilic delivery and hydrosilation.82 Per- fluoroalkylation with organosilicon reagents83 and the application of fluorotitanium compounds to the addition of allylsilanes to aldehydes84 have also been reviewed.The chemistry of allylsilanes continues to be of considerable interest. Some new computational and experimental evidence for the mechanism of the Sakurai–Hosami reaction the BF 3 catalysed addition of allyltrimethylsilane to an aldehyde has suggested that the reaction proceeds through an eight-membered cyclic transition state deriving from C–C and Si–F bond formation and synclinal (gauche) disposition of the reacting double bonds.85 Several examples of the Sakurai–Hosami reaction in which allylsilanes with chiral non-racemic silyl substituents are utilised have been reported. Barrett et al. have reported the enantioselective synthesis of homoallylic alcohols using (E)-but-2-enyl- 64 P.J. Murphy SiCl3 + ArCHO + N N O Ar OH Me i 58 Scheme 29 Reagents i DCM,[78 °C 4 h N P N N O H O O Si O O OBn O O Si R¢ CO2Pri CO2Pri 59 60 61 Scheme 30 R@\Me Ph Pr* Cl OBut trichlorosilane in the presence of chiral pyridinyloxazolines 58; excellent anti-diastereoselectivity ([99%) and good enantioselectivity (36–74%) were observed (Scheme 29).86 A similar asymmetric allylation or crotylation of aromatic aldehydes catalyzed by chiral phosphoramides e.g. 59 prepared from (S)-proline has been shown to proceed in ees as high as 88%.87 The enantioselective allylation of aldehydes using tartrate ester-modified allylsilanes 60 gave homoallylic alcohols in 63–93% and ees of up to 80%,88 whereas allysilanes containing arabinose-derived chiral substituents for example 61 gave alcohols in 36–45%ee and 54–72% yield (5 examples) (Scheme 30).89 Panek has continued to investigate the applications of chiral-non-racemic crotylsilanes in synthesis reporting a stereodi§erentiating crotylation reaction of a-amino aldehydes 62 where reaction with the R E-crotylsilane 63 leads to predominantly anti-stereoselectivity (2 1 to 30 1) whereas the S E-crotylsilane 64 leads to the synproduct (1 1 to 5 1) (Scheme 31).90 Other work from this group includes the Lewis acid-promoted C-glycosidation reactions of activated glycals with crotylsilanes for example 65 (R\CH 2 CO 2 Me) the reaction being highly a-selective and highly diastereoselective; a factor which was dependent on the chirality of the silane.91 The asymmetric synthesis of (E)-olefin dipeptide isosteres from 65 can also be achieved either by reaction with nitronium tetrafluoroborate (R\CH 2 CO 2 Me) to give eventually 66 or by CuOTf enantioselective aziridination (R\CH 2 CH 2 OH).92 Furthermore Lewis acid-mediated carbocyclization can also be e§ected with excellent stereoselectivity (Scheme 32).93 Panek has also reported a synthesis of the C1–C17 polypropionate fragment and the C19–C34 spiroketal fragment of the macrocycle rutamycin B via a series of syn-selective additions of E-crotylsilanes to aldehydes.94,95 Akiyama et al.have demonstrated that it is possible to modify the outcome of the Sakurai–Hosami reaction by changing its stoichiometry. Reaction of allyl-tert-butyldimethylsilane with an aldehyde in a 2 1 ratio in the presence of SnCl 4 led to the 65 Synthetic methods Part (iv) Heteroatom methods R H NHBoc O R BocHN OH R¢ CO2Me Me anti syn 2:1–30:1 R BocHN OH R¢ CO2Me Me syn anti 1:1–5:1 Me R¢ CO2Me PhSiMe2 Me R¢ CO2Me PhSiMe2 63 64 i i Scheme 31 Reagents i BF3 ·OEt 2 ; R\Bn TBDPSOCH 2 CH3 Me2 CHCH 2 ; R@\H Me O OAc OAc H MeO2C Me CbzNH Me OMe O 41% >30:1 80% >13:1 Me 65 R SiPhMe2 O OAc OAc OAc R = CH2CO2Me R = CH2CO2Me i ii–iv TsNH Me OH 65% >30:1 Me TBDPSO 90% >30:1 v R = CH2CH2OH R = CH2CHO vi vii 66 Scheme 32 Reagents i 2BF 3 ·OEt 2 CH 3 CN [30 °C; ii NO 2 BF 4 ; iii HCl Zn dust; iv CBzCl; v PhI–– NTs Cu(I)OTf CH 3 CN rt; vi TiCl 4 DCM,[78 °C; vii imidazole DMF TBDPSCl 66 P.J. Murphy O R H Si Ph SiMe2But O SiMe2But O O R R SiMe2But + 67 68 i ii 1:2 2:1 64% 13–73% Scheme 33 Reagents i SnCl 4 CH2 Cl 2 8 min [78 °C; R\PhCH 2 CH 2 ; ii BF 3 ·OEt 2 CH 2 Cl 2 15 min,[78 °C; R\alkyl O O SiMe3 Me CO2Me H H Me 69 (80% 2 steps) 10:1 trans cis 70 i ii Scheme 34 Reagents i 2.0 equiv.SnCl 4 ,[78 °C to[45 °C CH 2 Cl 2 12 h; ii CH 2 N 2 ketone 67 in 64% yield whereas when the aldehyde was in excess and BF 3 ·OEt 2 was employed the acetal 68 was formed in 13–73% yield (Scheme 33).96 The formation of [2]2]- and [2]3]-cycloadducts has been reported to be an alternative outcome of the Sakurai reaction of allylsilanes with quinones catalysed by Me 2 AlCl.97 The Yb(OTf) 3 catalysed allylation of the hydrates of a-keto aldehydes and glyoxylates with allylsilanes in yields of 65–83% has been reported; examples employing chiral substrates and an allylsilane containing a menthoxy substituent gave low de in the final product.98 Bismuth bromide has also been reported to be an e¶cient and versatile catalyst for the cyanation and allylation of aldehydes ketones and acetals with organosilicon reagents leading to good yields of alcohols and cyanohydrins or ethers in the case of acetals.99 The Lewis acid-promoted intramolecular addition of allylsilanes to b-lactones has been shown to proceed smoothly to give variously substituted cyclopentanes.For example allylsilane 69 was converted to cyclopentane 70 in 80% yield on treatment with tin tetrachloride (Scheme 34).100 The intermolecular trialkylsilylallylation of an iminium species generated from 71 led to the formation of oxazinones via trapping of the incipient b-silyl carbocation by the N-Boc-protecting group; several other examples were reported (Scheme 35).101 The trans-allylsilylation of unactivated alkynes is catalysed by Lewis acids with HfCl 4 giving the best results.The reaction leads to silylated 1,4-dienes in a regio- and stereo-selective manner in yields of 10–97% (18 examples) (Scheme 36).102 Yamaguchi has described the allylation of alkynes with allyltrimethylsilanes in the presence of 67 Synthetic methods Part (iv) Heteroatom methods N O O OMe N O O N O O SiMe3 SiMe3 + SiMe3 64% i 71 Scheme 35 Reagents i TiCl 4 DCM,[78 °C R2 R1 R5 R3 R4 SiMe3 R2 SiMe3 R1 R3 R5 R4 + i Scheme 36 Reagents i HfCl 4 CH 2 Cl 2 0 °C; R1\allyl aryl H R2\H Me Et TMSi R3,R4,R5\H Me Si O OH OH But But 73 O Si But But 72 O Si But But O O iii 62% 74 i ii Scheme 37 Reagents i Oxone' NaHCO 3 acetone,H 2 O; ii SiO 2 ; iii NBS acetone H 2 O,[23 °C to 0 °C GaCl 3 (allylgallation) leading to the formation of 1,4-dienes after treatment with methylmagnesium bromide.103 In an interesting application of allylsilanes 72 was found to undergo ring expansion on sequential treatment with oxone and silica gel to give the six-membered silyl ether 73 or on NBS–acetone–water treatment the seven-membered silyl ether 74 (Scheme 37).104 The chemistry of silanols has attracted attention in 1997 for example the reaction of the dimetallated allyldiphenylsilanol 75 with a range of electrophiles (E\aldehydes ketones alkyl iodides TMSCl ethylene oxide D 2 O) has been shown to be E-c- regioselective ([97 3 E:Z and [90 10 c a) the best results being obtained when a potassium allylsilanolate is deprotonated with butyllithium (Scheme 38).105 A basepromoted preparation of alkenylsilanols from allylsilanes has been reported for example treatment of allyl-tert-butyldiphenylsilane with ButOK and 18-crown-6 in DMSO at room temperature led to isomerization of the olefinic double bond and subsequent substitution of a phenyl group by a hydroxy group.Eight further examples of this reaction were reported with yields between 52–97% (Scheme 39).106 In two communications107,108 the group of Bruckner has reported an interesting application of the retro-[1,4]-Brook rearrangement. For example treatment of a 68 P. J. Murphy SiPh2 O–K+ SiPh2 O–K+ – Li+ 75 SiPh2 OH E i ii Scheme 38 Reagents i BunLi THF HMPA,[45 °C; ii electrophile (E) SiPh2But SiPh2ButOH i Scheme 39 Reagents i But OK DMSO 18-crown-6 15 min Ph OTBDPS SPh 76 Ph OH SiPh2But 77 i 98% 96:4 Scheme 40 Reagents i 2.2 equiv.K naphthalenide THF,[78 °C 50 min S S TBS (2.6 equiv.) 78 BnO O i ii iii BnO S S OTBS – Li+ Cl O (1 equiv.) (2.6 equiv.) 79 OBn BnO TBSO OH OTBS S S S S 80 iv Scheme 41 Reagents i 2.6 equiv. ButLi [78 °C to [45 °C Et 2 O 1 h; ii [78 °C to [25 °C 1 h; iii 0.3 equiv. HMPA,[78 °C 5 min syn-anti-mixture of sulfide 76 with potassium naphthalenide led to the formation of allylsilane 77 as a 96 4 mixture of the anti-trans syn-trans isomers (Scheme 40). In all the examples quoted there was a strong preference for anti-selectivity and in the majority the formation of the trans-alkene predominated. In a demonstration of the synthetic potential of the [1,4]-Brook rearrangement the reaction of lithiated silyl dithianes 78 with epoxides leads to the formation of the intermediate 79 via a solventcontrolled Brook rearrangement; when an excess (2.6 equiv.) of this intermediate was treated with ([)-epichlorohydrin the highly functionalised product 80 was isolated in 69 Synthetic methods Part (iv) Heteroatom methods Br O Al O Br Me O SiPri 3 OSiPri 3 SiPri 3 CHO 81 i ii 74% 93% Scheme 42 Reagents i 0.2 equiv.81 DCM rt 30 min; ii 2 equiv. 81 DCM,[40 °C 30 min O Ph OH Ph SiMe2Ph SiMe2Ph Ph i ii 90% Ph iii 95% Scheme 43 Reagents i PhMe 2 SiLi PhMe [78 °C 2 h; ii SOCl 2 Py rt 4 h; iii BF 3 ·2AcOH DCM 1–5h rt an impressive 66% overall yield (Scheme 41).109 Two diverse rearrangement pathways to give either a-silyl aldehydes or silyl enol ethers have been described using the bulky Lewis acid 81 by using either 2 equivalents of the reagent or a catalytic amount respectively.It was found that bulky silyl groups were essential for high yields to be obtained (Scheme 42).110 Fleming has reported a new method for the overall reductive conversion of esters and ketones into alkenes. Treatment of ketones with PhMe 2 SiLi followed by dehydration and protodesilylation of the resultant vinylsilanes gives alkenes in good overall yields (Scheme 43).111 A similar process utilising 2 equivalents of PhMe 2 SiLi can be used to convert esters and lactones into terminal alkenes. Singer et al. have studied the conjugate addition of Me 2 PhSiLi to a,b-unsaturated carbonyl compounds mediated by sub-stoichiometric quantities of dimethylzinc (as low as 10 mol%) and have found that good to excellent yields of b-silylated products are obtained.112 The catalytic behaviour is most prevalent when the Me 2 Zn employed is generated in situ from the addition of methyllithium to ZnI 2 .Yamamoto and Fleming have reported a novel route to allylsilanes via a conjugate 1,6-addition of PhMe 2 SiLi to aromatic carbonyl complexes of bulky Lewis acid aluminium tris(2,6-diphenylphenoxide).113 Shimizu has reported that the reaction of bromo(tert-butyldimethylsilyl)fluoromethyllithium (ButMe 2 SiCBrFLi) with aldehydes and ketones yields 1-fluoro-1-silyl oxiranes in good yields (73–98% yield 6 examples); the reagent can also be alkylated with a range of alkyl halides alkyl triflates and TMSCl in good yield (71–90% 9 examples).114 Woerpel has reported115,116 the stereo- and regio-selectivity of reactions of siliranes with aldehydes ketones and imines for example the reaction of cis-82 with aldehydes leads to the formation of cyclic silyl ethers 83a,b which are potential precursors of 1,3-diols.A similar reaction occurs with formamides for example trans-82 reacts with formamide 84 to give 85 as a single isomer which after conversion to the acetate derivative 86 reacts with silyl enol ethers in high yield and with high levels of stereoselectivity (Scheme 44). 70 P. J. Murphy cis – 82 Si But But Me Me O Si But But Ph Me Me i + O Si But But Ph Me Me 83a 83b 69 30 Si But But Me Me trans – 82 ii N H O / 93% 84 O Si But But N Me Me O Si But But OAc Me Me 85 iii,iv 100% 86 Me OSiMe3 Me v O Si Me O But But Me H Me Me 100% > 92 8 selectivity Scheme 44 Reagents i PhCHO 18-crown-6 0.1 equiv.KOBut; ii hexanes 120 °C; iii HOAc H 2 O THF; iv Ac 2 O Py; v CH 2 Cl 2 [78 °C SnBr 4 OSiMe2But 87 + 2 O CO2Me OH OH 0.1 equiv. / Cl2Ti(OPri)2 i MeO2C CO2 Me OH OSiMe2But OH MeO2C CO2 Me O OH HO 89 88 ii Scheme 45 Reagents i CH 2 Cl 2 0 °C 3 h; ii HCl MeOH Mikami has reported the first example of a tandem two-directional asymmetric Mukaiyama aldol reaction; addition of 2 equivalents of methyl glyoxylate to silyl enol ether 87 in the presence of a binaphthol-derived chiral titanium complex gave the silyl enol ether 88 in 77% yield; subsequent hydrolysis gave the diol 89 in 99%ee and 99%de (Scheme 45).117 The isolation of a,a-difluoroketene silyl acetal 90 and its application in asymmetric aldol reactions has been reported; addition of 90 to aldehydes in the presence of Masamune’s catalyst 91 or the analogous Kiyooka’s 71 Synthetic methods Part (iv) Heteroatom methods RCHO + F F OTMS OEt i R OEt OH O F F 90 Me O B N O Ts H Pri N B O H p-NO2C6H4SO2 O But 91 92 Scheme 46 Reagents i 20 mol%91 or 92 EtNO 2 [78 °C or[45 °C catalyst 92 gave the aldol products (8 examples) in good yields (85–99%) and ees (81–98%) (Scheme 46).118,119 Similar results were reported for an analogous bromo- fluoroketene silyl acetal with catalyst 91.120 Kiyooka has applied catalysts similar to 92 to the synthesis of either syn- or anti-1,3-diols from b-silyloxy aldehydes with complete stereoselection controlled by the choice of the absolute stereochemistry of the catalyst.121 Organotin perchlorates have been found to be e§ective and mild catalysts for the Mukaiyama reaction of ketene silyl acetals; they also appear to be chemoselective in competition reactions between aldehydes and acetals.Similarly enals react with ketene silyl acetals in preference to the corresponding alkanal in the presence of organotin perchlorates whilst the presence of an electron-donating group will increase the reactivity of an aldehyde in aldehyde–aldehyde competition reactions. An additional factor is that silyl enol ethers derived from ketones are not activated by organotin perchlorates.122 Kobayashi and Nagayama have studied the competition reaction between aldimines and aldehydes towards nucleophilic addition and have reported that an unprecedented change in their normally assumed reactivity is observed. Preferential reaction of aldimines over aldehydes in nucleophilic additions using lanthanide salts [Yb(OTf) 3 in particular] as catalysts for the addition of silyl enol ethers ketene silyl acetals allyltributylstannane or cyanotrimethylsilane was observed with selectivity as high as 99 1.123,124 The high pressure induced Mukaiyamatype aldol reaction of bis-trimethylsilyl ketene acetals with benzaldehyde has been reported to give an overall syn-selectivity (ca.2 1 to 4 1) for the formation of silylated aldol products.125 A study on the indium trichloride catalysed Mukaiyama-aldol reaction in water has been reported a rationale for reaction rate and stereoselectivity based on the internal pressure e§ect of water is described.126 The Sc(OTf) 3 catalysed aqueous aldol reactions of silyl enol ethers with aldehydes has been successfully carried out in the presence of a small quantity of a surfactant; the reactions are organic solvent free and were found to be sluggish if the surfactant is omitted.127 72 P.J. Murphy References 1 J. Emsley Chem. Brit. 1997 33 43. 2 K.C. Nicolaou M.W. Harter J. L. Gunzner and A. Nadin Liebigs Ann. Chem. 1997 1283. 3 J. S. Yadav and D. Srinivas Tetrahedron Lett. 1997 38 7789. 4 C.M. Moorho§ Synlett 1997 126. 5 C.M. Moorho§ Tetrahedron 1997 53 2241. 6 C.M. Moorho§ Tetrahedron Lett. 1997 38 4157. 7 T. Fujimoto Y. Kodama I. Yamamoto and A. Kakehi J. Org. Chem. 1997 62 6627. 8 O. Piva and S. Comesse Tetrahedron Lett. 1997 38 7191. 9 S. Kojima R. Takagi and K. Akiba J. Am. Chem Soc. 1997 119 5970. 10 S. Kojima K. Kawaguchi and K. Akiba Tetrahedron Lett. 1997 38 7753. 11 S. Kojima and K.Akiba Tetrahedron Lett. 1997 38 547. 12 F. Rubsam A. M. Evers C. Michel and A. Giannis Tetrahedron 1997 53 1707. 13 M. Nishizawa Y. Komatsu D. M. Garcia Y. Noguchi H. Imagawa and H. Yamada Tetrahedron Lett. 1997 38 1215. 14 A. Spinella T. Fortunati and A. Soriente Synlett 1997 93. 15 S. Sano K. Yokoyama M. Fukushima T. Yagi and Y. Nagao Chem. Commun. 1997 559. 16 R. Kreuder T. Rein and O. Reiser Tetrahedron Lett. 1997 38 9035. 17 M.T. Mendlik M. Cottard T. Rein and P. Helquist Tetrahedron Lett. 1997 38 6375. 18 T. Kumamoto and K. Koga Chem. Pharm. Bull. 1997 45 753. 19 W.M. Dai J. L. Wu and X. Huang Tetrahedron Asymmetry 1997 8 1979. 20 B. E. Ledford and E. M. Carreira Tetrahedron Lett. 1997 38 8125. 21 K. Hayashi T. Shinada K. Sakaguchi M. Horikawa and Y. Ohfune Tetrahedron Lett.1997 38 7091. 22 M.C. A. vanVliet G. J. Meuzelaar J. Bras L. Maat and R. A. Sheldon Liebigs Ann. Chem. 1997 1989. 23 P. K. Malinen A. Y. Tauber P. H. Hynninen and F. P. Montforts Tetrahedron Lett. 1997 38 3381. 24 A. Couture E. Deniau P. Grandclaudon and S. Lebrun Synlett 1997 1475. 25 P. O’Brien H. R. Powell P. R. Raithby and S. Warren J. Chem. Soc. Perkin Trans. 1 1997 1031. 26 J. Clayden A. Nelson and S. Warren Tetrahedron Lett. 1997 38 3471. 27 A. Nelson and S. Warren J. Chem. Soc. Perkin Trans. 1 1997 2645. 28 J. Uziel N. L. Riegel B. Aka P. Figuiere and S. Juge Tetrahedron Lett. 1997 38 3405. 29 P. Cuadrado and A. M. Gonzalez-Nogal Tetrahedron Lett. 1997 38 8117. 30 I. M. Lefebvre and S. A. Evans Jr. J. Org. Chem. 1997 62 7532. 31 M. Mikolajczyk P. Lyzwa and J. Drabowicz Phosphorus Sulfur Silicon Relat.Elem. 1997 120 357. 32 M. Mikolajczyk P. Lyzwa and J. Drabowicz Tetrahedron Asymmetry 1997 8 3991. 33 F. A. Davis P. S. Portonovo R. E. Reddy G. V. Reddy and P. Zhou Phosphorus Sulfur Silicon Relat. Elem. 1997 120 291. 34 I. Mori Y. Kimura T. Nakano S. Matsunaga G. Iwasaki A. Ogawa and K. Hayakawa Tetrahedron Lett. 1997 38 3543. 35 F. Mathey J. Org. Chem. 1997 529 1. 36 J. Holz M. Quirmbach and A. Borner Synthesis 1997 983. 37 D. F. Weimer Tetrahedron 1997 53 16 609. 38 R. Waschbusch J. Carran A. Marinetti and P. Savignac Synthesis 1997 727. 39 A. H. Li L. X. Dai and V. K. Aggarwal Chem. Rev. 1997 97 2341. 40 A. Padwa D. E. Gunn and M.H. Osterhout Synthesis 1997 1353. 41 Y. Kita N. Shibata S. Fukui M. Bando and S. Fujita J. Chem. Soc. Perkin Trans. 1 1997 1763.42 Y. Kita Phosphorus Sulfur Silicon Relat. Elem. 1997 120 145. 43 N. Shibata M. Matsugi N. Kawano S. Fukui C. Fujimori K. Gotanda K. Murata and Y. Kita Tetrahedron Asymmetry 1997 8 303. 44 H. Kosugi K. Hoshino and H. Uda Tetrahedron Lett. 1997 38 6861. 45 H. Kosugi M. Abe R. Hatsuda H. Uda and M. Kato Chem. Commun. 1997 1857. 46 G. Solladie G. Hanquet and C. Rolland Tetrahedron Lett. 1997 38 5847. 47 C. A. Hutton and J. M. White Tetrahedron Lett. 1997 38 1643. 48 W. Oppolzer O. Froelich C. Wiaux-Zamar and G. Bernardinelli Tetrahedron Lett. 1997 38 2825. 49 F. A. Davis R. E. Reddy J. M. Szewczyk V. G. Reddy P. S. Portonovo H. M. Zhang D. Fanelli R. T. Reddy P. Zhou and P. J. Carroll J. Org. Chem. 1997 62 2555. 50 H. Takada Y. Nishibayashi K. Ohe S. Uemura C. P. Baird T. J. Sparey and P.C. Taylor J. Org. Chem. 1997 62 6512. 51 S. Fustero A. Navarro and A. Asensio Tetrahedron Lett. 1997 38 4891. 52 C. Alayrac L. C. Fromont L. P. Metzner and N. T. Anh Angew. Chem. Int. Ed. Engl. 1997 36 371. 53 R. Caputo A. Guaragna G. Palumbo and S. Padatella J. Org. Chem. 1997 62 9369. 54 A. J. Blake S. M. Westaway and N. S. Simpkins Synlett 1997 919. 55 A. P. Dishington R. E. Douthwaite A. Mortlock A. B. Muccioli and N. S. Simpkins J. Chem. Soc. Perkin 73 Synthetic methods Part (iv) Heteroatom methods Trans. 1 1997 323. 56 G.M. P. Giblin C. D. Jones and N. S. Simpkins Synlett 1997 589. 57 N. Magnus and P. Magnus Tetrahedron Lett. 1997 38 3491. 58 P. Evans and R. J. K. Taylor Synlett 1997 1043. 59 M. F. Hentemann and P. L. Fuchs Tetrahedron Lett. 1997 38 5615. 60 C.Leriverend P. Metzner A. Capperucci and A. DeglInnocenti Tetrahedron 1997 53 1323. 61 R. S. Glass and R. Okazaki Tetrahedron 1997 53 12 067. 62 S. M. Weinreb Top. Curr. Chem. 1997 190 131. 63 S. Z. Zard Angew. Chem. Int. Ed. Engl. 1997 36 673. 64 L. W. M. Lee and H. Chan Top. Curr. Chem. 1997 190 103. 65 B. F. Bonini and M. Fochi Rev. Heteroat. Chemistry 1997 16 47. 66 M. C. Aversa A. Barattucci P. Bonaccorsi and P. Giannetto Tetrahedron Asymmetry 1997 8 1339. 67 K. Fujita Rev. Heteroat. Chemistry 1997 16 101. 68 S. Fukuzawa K. Takahashi H. Kato and H. Yamazaki J. Org. Chem. 1997 62 7711. 69 K. Fujita K. Murata M. Iwaoka and S. Tomoda Tetrahedron 1997 53 2029. 70 R. Deziel L. E. Malenfant C. Thibault S. Frechette and M. Gravel Tetrahedron Lett. 1997 38 4753. 71 Z. S. Zhou N. Jiang and D.Hilvert J. Am. Chem. Soc. 1997 119 3623. 72 T. Takahashi N. Nakao and T. Koizumi Tetrahedron Asymmetry 1997 8 3293. 73 A. Krief C. Colaux and W. Dumont Tetrahedron Lett. 1997 38 3315. 74 T. Murai K. Kakami A. Hayashi T. Komuro H. Takada M. Fujii T. Kanda and S. Kato J. Am. Chem. Soc. 1997 119 8592. 75 A. Krief C. Delmotte and W. Dumont Tetrahedron Lett. 1997 38 3079. 76 A. Krief C. Delmotte and W. Dumont Tetrahedron 1997 53 12 147. 77 M. Miyashita T. Suzuki M. Hoshino and A. Yoshikoshi Tetrahedron 1997 53 12 469. 78 Y. Tang Z. Y. Huang L. X. Dai J. Sun and W. Xia J. Org. Chem 1997 62 954. 79 J. V. Comasseto L. W. Ling N. Petragnani and H. A. Stefani Synthesis 1997 373. 80 T. Shimizu and N. Kamigata Org. Prep. Proced. Int. 1997 29 603. 81 I. Fleming A. Barbero and D. Walter Chem.Rev. 1997 97 2063. 82 L. Fensterbank M. Malacria and S.McN. Sieburth Synthesis 1997 813. 83 G. K. S. Prakash and A. K. Yudin Chem. Rev. 1997 97 757. 84 R. O. Duthaler and A. Hafner Angew. Chem. Int. Ed. Engl. 1997 36 43. 85 A. Bottoni A. L. Costa D. DiTommaso I. Rossi and E. Tagliavini J. Am. Chem. Soc. 1997 119 12 131. 86 R.M. Angell A. G.M. Barrett D. C. Braddock S. Swallow and B. D. Vickery Chem. Commun. 1997 919. 87 K. Iseki Y. Kuroki M. Takahashi S. Kishimoto and Y. Kobayashi Tetrahedron 1997 53 3513. 88 L. C. Zhang H. Sakurai and M. Kira Chem. Lett. 1997 129. 89 T. K. M. Shing and L. H. Li J. Org. Chem. 1997 62 1230. 90 J. S. Panek and P. Liu Tetrahedron Lett. 1997 38 5127. 91 J. S. Panek and J. V. Schaus Tetrahedron 1997 53 10 971. 92 C. E. Masse B. S. Knight P. Stavropoulos and J.S. Panek J. Am. Chem. Soc. 1997 119 6040. 93 C. E. Masse L. A. Dakin B. S. Knight and J. S. Panek J. Org. Chem. 1997 62 9335. 94 N. F. Jain and J. S. Panek Tetrahedron Lett. 1997 38 1345. 95 N. F. Jain and J. S. Panek Tetrahedron Lett. 1997 38 1349. 96 T. Akiyama M. Nakano J. Y. Kanatani and S. Ozaki Chem. Lett. 1997 385. 97 W. S. Murphy and D. Neville Tetrahedron Lett. 1997 38 7933. 98 Y. Yang M. W. Wang and D. Wang Chem. Commun. 1997 1651. 99 N. Komatsu M. Uda H. Suzuki T. Takahashi T. Domae and M. Wada,Tetrahedron Lett. 1997 38 7215. 100 C. X. Zhao and D. Romo Tetrahedron Lett. 1997 38 6537. 101 S. Brocherieux-Lanoy H. Dhimane J. C. Poupon C. Vanucci and G. Lhommet J. Chem. Soc. Perkin Trans. 1 1997 2163. 102 E. Yoshikawa V. Gevorgyan N. Asao and Y. Yamamoto J. Am.Chem. Soc. 1997 119 6781. 103 M. Yamaguchi T. Sotokawa and H. Hirama Chem. Commun. 1997 743. 104 K. Tanino N. Yoshitani F. Moriyama and I. Kuwajima J. Org. Chem. 1997 62 4206. 105 K. Takaku H. Shinokubo and K. Oshima Tetrahedron Lett. 1997 38 5189. 106 T. Akiyama and S. Imazeki Chem. Lett. 1997 1077. 107 C. Gibson T. Buck M. Noltemeyer and R. Bruckner Tetrahedron Lett. 1997 38 2933. 108 D. Goeppel and R. Bruckner Tetrahedron Lett. 1997 38 2937. 109 A. B. Smith and A.M. Boldi J. Am. Chem. Soc. 1997 119 6925. 110 T. Ooi T. Kiba and K. Maruoka Chem. Lett. 1997 519. 111 A. Chenede N. Abj.Rahman and I. Fleming Tetrahedron Lett. 1997 38 2381. 112 B. L. MacLean K. A. Hennigar K. W. Kells and R. D. Singer Tetrahedron Lett. 1997 38 7313. 113 S. Saito K. Shimada H. Yamamoto E. M. deMarigorta and I.Fleming Chem. Commun. 1997 1299. 114 M. Shimizu T. Hata and T. Hiyama Tetrahedron Lett.,1997 38 4591. 115 P. M. Bodnar W.S. Palmer B. H. Ridgway J. T. Shaw J. H. Smitrovich and K. A. Woerpel J. Org. Chem. 1997 62 4737. 74 P. J. Murphy 116 J. T. Shaw and K. A. Woerpel Tetrahedron 1997 53 16 597. 117 K. Mikami S. Matsukawa M. Nagashima H. Funabashi and H. Morishima Tetrahedron Lett. 1997 38 579. 118 K. Iseki Y. Kuroki D. Asada and Y. Kobayashi Tetrahedron Lett. 1997 38 1447. 119 K. Iseki Y. Kuroki D. Asada M. Takahashi S. Kishimoto and Y. Kobayashi Tetrahedron 1997 53 10 271. 120 K. Iseki Y. Kuroki and Y. Kobayashi Tetrahedron Lett. 1997 38 7209. 121 S. Kiyooka T. Yamaguchi H. Maeda H. Kira M.A. Hena and M. Horiike Tetrahedron Lett. 1997 38 3553. 122 J. X. Chen and J.Otera Tetrahedron 1997 53 14 275. 123 S. Kobayashi and S. Nagayama J. Am. Chem. Soc. 1997 119 10 049. 124 S. Kobayashi and S. Nagayama J. Org. Chem. 1997 62 232. 125 M. Bellassoued E. Reboul and F. Dumas Tetrahedron Lett. 1997 38 5631. 126 T. P. Loh J. Pei K. S. V. Koh G. Q. Cao and X. R. Li Tetrahedron Lett. 1997 38 3465. 127 S. Kobayashi T. Wakabayashi S. Nagayama and H. Oyamada Tetrahedron Lett. 1997 38 4559. 75 Synthetic methods Part (iv) Heteroatom methods mmmm

ISSN:0069-3030    

DOI:10.1039/oc094051

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

2 Synthetic methods Part (v) Protecting groups By ALAN C. SPIVEY and STEVEN J. WOODHEAD Department of Chemistry Brook Hill University of Sheffield Sheffield S3 7HF UK Another excellent and comprehensive ‘update’ review of protecting group strategies in organic synthesis has appeared this year.1 1 Hydroxy protecting groups The use of allylic protection of alcohols in the context of complex synthesis (mainly of oligosaccharides) has been reviewed.2 Sodium borohydride–iodine (THF at 0 °C) appears to be an attractive method for the reductive cleavage of both aryl and alkyl allyl ethers.3 An alternative reductive cleavage of allyl ethers employs naphthalene catalysed lithiation.4 This method uses an excess of lithium powder in the presence of catalytic naphthalene at low temperature and generally gives higher yields for the removal of benzyl ethers and is also e§ective for the de-sulfonylation of primary tosyl amides and tosyl or mesyl carboxamides.Deprotection of allyl ethers is also frequently achieved by a two step procedure involving base or transition metal complex mediated isomerisation to the corresponding vinyl ether followed by acid mercury(II) chloride or iodine assisted hydrolysis. Wacker type oxidation o§ers a mild alternative for this second step.5 Such oxidation is compatible with acid sensitive benzylidene acetals and proceeds with retention of configuration for anomeric vinyl ethers. Benzyltriethylammonium tetrathiomolybdate in acetonitrile e§ects selective deprotection of propargyl ethers in the presence of allyl and benzyl ethers and other easily reducible functionalities such as nitro aldehyde and keto groups under essentially neutral conditions.6 Two very similar new methods for the selective removal of p-methoxybenzyl ethers are ethanethiol–aluminium trichloride [or tin(II) chloride] and dimethylsulfide–magnesium bromide.7,8 The former method employs 0.2 equiv.of Lewis acid at ambient temperature and is tolerant of methyl and benzyl ethers p-nitrobenzoyl esters tertbutyldiphenylsilyl ethers (TBDPS) and isopropylidene acetals whilst the latter employs 3 equiv. of Lewis acid at ambient temperature and is tolerant of 1,3-dienes tert-butyldimethylsilyl (TBDMS) and benzyl ethers benzoyl esters and isopropylidene acetals. Commercially available and reusable HSZ zeolites o§er a useful and environmentally benign method for the large scale preparation of both alkyl and aryl tetrahydropyranyl ethers (THP) in neat dihydropyran (DHP).9 Selectivity for the former over the latter is also possible.The same zeolite catalyst can also be employed to e§ect 77 NC O O NaN(SiMe3)2 or LiN(Pri)2 (2.5 equiv.) THF–DMEU 185 °C sealed tube 95% NC OH OH Scheme 1 O OR OX O O Me PACH X = PACM X = PACLev X = OMe ROH O O H2–Pd(OH)2 (PACH and PACM) or NH2NH2–AcOH–pyridine (PACLev) + Scheme 2 quantitative deprotection in methanol as can anhydrous tin(II) chloride.10 An interesting method for the deprotection of methyl and benzyl aryl ethers in good to excellent yields employs sodium hexamethyldisilazide (NaHMDS) or lithium diisopropylamide (LDA) in THF–1,3-dimethyl-2-imidazolidinone (DMEU) at 185 °C in a sealed tube.11 NaHMDS is slightly less reactive than LDA and this can be exploited for the mono deprotection of o-dimethoxybenzenes.Of particular note is that either base can also be employed for the almost quantitative deprotection of the methylenedioxy functionality (Scheme 1). Partial resolution (39–97% ee) of the enantiomers of selected simple cis-diols has been achieved by acetal formation with a polymer-supported 7-keto-steroid followed by hydrolysis.12 In the area of ester protection of alcohols there has been exciting progress in the area of non-enzymatic kinetic resolution of secondary alcohols via acylation using a number of ‘synthetic’ chiral catalysts and this area has been briefly reviewed.13 The use of magnesium methoxide in methanol at ambient temperature has been advocated for the deprotection of alkyl acetates.14 Of note is the sensitivity of the procedure to steric hindrance thereby allowing the selective removal of primary acetates in the presence of secondary and tertiary acetates in complex substrates.Three 2-(2-oxyethyl)benzoate protecting groups PAC H PAC M and PAC L%7 have been introduced and their utility demonstrated for the preparation of phosphorylated inositol derivatives.15 These esters are generally introduced using DCC–DMAP and have cleavage properties dependent on the 2-oxyethyl ether substituent e.g. H 2 –Pd(OH) 2 or H 2 –PdCl 2 for the 2-benzyloxy- and 2-(4-methoxybenzyloxy)ethylbenzoyl groups (PAC H and PAC M ) and NH 2 NH 2 –AcOH–pyridine for the 2-(2-levulinoyloxy)ethylbenzoyl group (PAC L%7). PAC is an abbreviation for ‘proximately assisted cleavable group’ as the ester hydrolysis is facilitated by 6-exo-trig lactonisation (Scheme 2).A protecting group closely related to PAC L%7 is the 2-(levulinyloxymethyl)nitrobenzoyl group (LMNBz) which has been employed successfully as a 5@-hydroxy protecting group which suppresses depurination [cf. dimethoxytrityl (DMTr)] during automated ribonucleoside and 2@-deoxyribonucleoside 3@-phosphoramidite synthesis.16 Cleavage is via 5-exo-trig lactonisation using 0.5M imidazole in acetonitrile following ether cleavage using 0.5M NH 2 NH 2 in 1 4 AcOH–pyridine. 78 A. C. Spivey and S. J. Woodhead Two new carbonate type 5@-hydroxy protecting groups for ribonucleoside synthesis have been developed the 2-(2-nitrophenyl)ethoxycarbonyl group (NPEoc) is removed by photolysis (365 nm) and displays a ca.3-fold rate enhancement for cleavage relative to the 2-nitrobenzyloxycarbonyl group (NBoc).17 The (2-cyano-1-phenyl)ethoxycarbonyl group (CPEoc) is base labile (0.1M DBU in acetonitrile) and works e¶ciently in conjunction with 4-ethoxytetrahydropyran-4-yl 2@-hydroxy protection.18 Carbonate protection of the phenol of tyrosine as a 2,4-dimethyl-3-pentyloxycarbonyl group (Doc) has been proposed as an alternative to the 2-bromobenzyloxycarbonyl group (2-BrZ) during tert-butoxycarbonyl (Boc) solid phase synthesis.19 However although this group displays superior resistance to nucleophilic cleavage it is more acid sensitive and much less rapidly cleaved using 20% piperidine–DMF. The tris(trimethylsilyl)silyl group (Sisyl) has been introduced as a new fluoride resistant photolabile (medium pressure Hg lamp MeOH ca.30 min) protecting group for primary and secondary alcohols.20 These ethers are prepared from the corresponding chlorosilane using CH 2 Cl 2 –DMAP (1.2 equiv.). They are not stable towards certain nucleophiles (TBAF BuLi LiAlH 4 ) but are stable towards other fluoride sources (CsF KF–18-crown-6) Grignard and Wittig reagents (MeMgBr Ph 3 P––CH 2 ) oxidation (Jones’ reagent) and are more acid stable than TBDMS TBDPS and triisopropysilyl (TIPS) groups [p-TSA (1 equiv.) 0.2M HCl–acetone (1 1)]. These latter silyl ethers are photostable under the conditions which remove the Sisyl group. Primary TBDMS ethers can be selectively removed in the presence of secondary TBDMS ethers using LiBr–18-crown-6 in acetone at elevated temperatures.21 Additionally quinolinium fluorochromate has been shown to e§ect concomitant cleavage and oxidation of primary TBDMS ethers (including allyl and benzyl) to aldehydes in the presence of secondary TBDMS ethers (including allyl and benzyl).Primary methoxymethyl(MOM) THPand TBDPS ethers are stable to these conditions.22 The e¶cient one-pot deprotection–oxidation of primary and secondary trimethylsilyl ethers (TMS) using 3-carboxypyridinium chlorochromate in refluxing acetonitrile or dichloromethane to give aldehydes and ketones respectively has also been described.23 THP ethers also undergo this oxidation but more slowly. The susceptibility to cleavage by LiAlH 4 of TBDMS ethers 1,3- or 1,4-disposed to an unprotected hydroxy group has been demonstrated and is proposed to result from intramolecular hydride delivery from the alcohol-derived alkoxyaluminium hydride.24 2 Carboxy protecting groups Just 5mol% of potassium tert-butoxide believed to form highly reactive caged tetramers e§ects almost quantitative ester metathesis between methyl benzoate and tert-butyl acetate to give tert-butyl benzoate provided the volatile by-product (methyl acetate) is removed by application of an aspirator vacuum.25 The full scope of this procedure has yet to be established (Scheme 3).The p-acid tetracyanoethylene (TCNE) is an e§ective catalyst (20 mol%) for the esterification of lauric acid with a wide variety of alcohols (1° 2° benzyl allyl propargyl 2-trimethylsilylethyl) for the esterification of a-hydroxy- and N-benzyloxycarbonyl- (Cbz) or N-Boc-a-amino acids with methanol to give methyl esters and also for the transesterification of methyl laurate with a variety of alcohols (1° 2° 79 Synthetic methods Part (v) Protecting groups Ph O O Me Me O O But Ph O O But Me O O Me + + 5 mol% KOBu t neat 45 °C 30 min 98% Scheme 3 N S OH O H S O O S O 4.6 mol% Pd(PPh3)4 TolSO2Na (1.1equiv.) THF–MeOH 25 min 87% N S OH O H S OH O S O Scheme 4 benzyl allyl propargyl).26 These reactions are driven towards products by using the appropriate alcohol as solvent.Magnesium bromide etherate has been previously shown to cleave b-(trimethylsilyl)ethoxymethyl esters (SEM) and this methodology has now been extended to amino acid and peptide derivatives in the presence of protecting groups typically encountered in peptide chemistry [Boc Cbz fluoren-9- ylmethoxycarbonyl (Fmoc) and 2,2,2-trichloroethoxycarbonyl (Troc) carbonates and benzyl (Bn) But TBDMS ethers].27 Other fluoride sensitive protecting groups are stable to magnesium bromide.An extensive survey of allyl scavengers has been undertaken for the tetrakistriphenylphosphine catalysed deprotection of allyl esters.28 Toluenesulfinic acid was identified as the most e¶cient scavenger (better than carboxylic acids morpholine dimedone etc.) allowing e¶cient deprotection on sensitive penem substrates (Scheme 4). Salts of toluenesulfinic acid can also be employed and this allows the use of other palladium catalysts such as palladium acetate dichlorobis(acetonitrile)palladium triethylphosphite although these reactions are substantially slower. 2-Chloroallyl 2-methylallyl crotyl and cinnamyl esters are similarly e¶ciently scavenged and the process can also be extended to the deprotection of allyl carbonates allyl ethers allylamines and O-allyl oximes.3 Phosphate and sulfate protecting groups Non-hydrolytic deprotection of phosphite and phosphate alkyl esters is often accomplished using TMS iodide or TMS chloride. The reactive inorganic polymer silica chloride is an attractive alternative.29 tert-Butyl and benzyl esters are cleaved almost quantitatively at ambient temperature in chlorinated hydrocarbon solvents (CCl 4 CHCl 3 CH 2 Cl 2 ) in under an hour as are the corresponding sulfite esters. Isopropyl and phenyl esters however do not react and the reaction was shown to produce racemic 1-phenethyl chloride when using bis(S)-1-phenethylphosphite as substrate. The use of ammonia gas under pressure o§ers an e¶cient alternative to hot aqueous ammonium hydroxide for the deprotection and cleavage steps during the large scale synthesis of oligonucleotides and their phosphorothioate (PS) analogues prepared using N-pent-4-enoyl (PNT) protected nucleoside phosphoramidites (O-2-cyanoethyl 80 A.C. Spivey and S. J. Woodhead O MeO OMe O O montmorillonite K10 CH2Cl2 D 4 h 82% O O O O Scheme 5 N,N-diisopropyl) and H-phosphonates.30 Methylamine with or without added ammonium hydroxide has also been advocated for the same purpose when employing N-acetyl protected nucleoside phosphoramidites (O-2-cyanoethyl N,N-diisopropyl) and H-phosphonates.31 Use of N4-acetyldeoxycytidine (dCA#) was noted to suppress transamination relative to use of dCB; during this procedure. O-4-Cyanobut-2-enyl protection (CB) has been reported as an alternative to the ubiquitous O-2-cyanoethyl phosphoramidite protecting group.32 Deprotection by d-elimination is e§ected using aqueous ammonium hydroxide under identical conditions as the O-2-cyanoethyl analogues but the method is purported to be ca.60% less costly on a kilogram scale. Eight new S-protecting groups have been investigated for the synthesis of dithymidine phosphorothioates by the solution phase phosphotriester method.33 The best of these was the 4-chloro-2-nitrobenzyl group which allowed e¶cient coupling using 4-nitro-6- trifluoromethylbenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyFNOP 96% 15 min) and could be removed with a minimum of side reactions using thiophenolate. The trifluoroethyl ester has been demonstrated to be a useful protecting group for sulfate monoesters in carbohydrates.34 These esters are readily formed from the appropriate sulfate using trifluoroethyldiazoethane are stable to TFA but cleaved with mineral acids (dil.H 2 SO 4 ) stable to TBAF sodium methoxide in methanol and hydrogenation but selectively cleaved using potassium tert-butoxide in refluxing tert-butyl alcohol. 4 Carbonyl protecting groups Monomorillonite K10 in dichloromethne at ambient temperature has been found to be an extremely convenient mild and e¶cient method for the deprotection of acetals and ketals.35 Its utility has been demonstrated in the first synthesis of syn-4,8- dioxatricyclo[5.1.0.03,5]octane-2,6-dione and is e§ective not only for dimethyl acetals but also 1,3-dioxolanes and 5,5-dimethyl-1,3-dioxanes (Scheme 5).Monomorillonite K10 in refluxing dichloromethane is also e¶cient for the deprotection of 1,1-diacetates.36 Ferric chloride hexahydrate is a mild promoter of hydrolytic deprotection of acetals in dichloromethane at ambient temperature which appears to be more selective for this process (particularly with 1,3-dioxolanes) over interaction with other acid sensitive functionalities than alternative Lewis acids.37 Hydrogenolytic deprotection of 4-phenyl-1,3-dioxolane protected ketones and aldehydes simply using Pd-C–H 2 has been shown to be a very clean and e¶cient alternative to electrolytic deprotection.38 Cyclo-SEM has been introduced as a new 81 Synthetic methods Part (v) Protecting groups O O O O Me3Si H Me O O H Me O LiBF4 THF 66 °C 3 h >80% Scheme 6 fluoride labile acetal protecting group for carbonyl groups.39 Protection is accomplished at ambient temperature using a slight excess of 2-trimethylsilylpropane-1,3- diol in dry dichloromethane with activated powdered 3 or 4Å MS and catalytic camphorsulfonic acid (0.25 equiv.) and deprotection using LiBF 4 in THF (conditions which do not a§ect 1,3-dioxolanes Scheme 6).A rapid and e¶cient deprotection of a series of simple aryl aldehyde 1,1-diacetates catalysed by ‘expansive graphite’ in refluxing dichloromethane or benzene has been reported preceded by details of the synthesis of the catalyst.40 5 Amine protecting groups Amides are rarely used for amine protection in peptide synthesis due to their proclivity towards racemisation (via azalactones) and resistance to hydrolysis.The hydrolysis of N-trifluoroacetyl-a-amino acid tert-butyl esters to the corresponding tert-butyl ester hydrochlorides using liquid–liquid phase transfer catalysis [20% KOH triethylbenzylammonium chloride (10 mol%) H 2 O–CH 2 Cl 2 25–35 °C] followed by precipitation (HCl Et 2 O) has been reported but is accompanied by partial racemisation in the case of phenylalanine (23%) and complete racemisation for phenylglycine.41 The corresponding N-trifluoroacetyl-a-amino acids can be obtained using TFA (probably without racemisation although this was not verified). A more e§ective approach to amide deprotection employs enzymatic amide hydrolysis. The exquisite selectivity of N-phenylacetyl deprotection using immobilised penicillin G acylase (SeparaseG') under extremely mild neutral conditions allowed cleavage of an N-phenylacetyl ethanolamine phosphate heptosyl disaccharide42 (Scheme 7).Soluble penicillin G acylase has also been found to be e§ective for the deprotection of a controlled pore glass (CPG) bound TGGGG-pentanucleotide containing Nphenylacetyl protected bases.43 The synthetic scope of recombinant phthaloyl amidase for the mild unmasking of N-phthaloyl imides (Phth) following partial hydrolysis to their mono acids has also been further delineated.44 A range of primary amines can be deprotected and the enzyme exhibits modest chiral selectivity between diastereomeric dipeptides. An alternative solution to mild phthalimide deprotection is to employ a tetrachlorophthalyl group (TCP).45 Installation can be accomplished in two steps by treating the free base with commercially available TCP anhydride followed by ring closure with Ac 2 O–pyridine and the group is stable under conditions ranging from mildly basic to harshly acidic.Cleavage is e§ected by 2–4 equiv. of ethylenediamine at 60 °C in MeCN–THF–EtOH(2 1 ) conditions under which glycopeptides containing standard N-Phth and ester groups retain their constitutional and stereochemical integrity. trans-2-Hydroxycinnamic acid has been investigated as a photolabile protecting group for amines.46 Photolysis (low intensity 4W lamp 365 nm) of derived amides results in quantitative cleavage via trans to cis isomerisation and 6-exo-trig 82 A. C. Spivey and S. J. Woodhead O HO O OH O O HO HO O(CH2)3NH2 HO HO HO HO O HO O OH O O HO HO O(CH2)3NH2 HO HO HO HO P O NH PhAc O –O P O NH3 O –O SeparaseG® pH 7.5 1.5 h 93% Scheme 7 lactonisation.Secondary amides are cleaved more slowly than primary amides and in both cases the addition of a trace of acid to the organic solvent (e.g. MeOH–AcOH 70 1) is essential to assist lactonisation. The free phenol present in this protecting group was noted as a limitation but presumably this could be orthogonally protected if necessary. Allyl based protection strategies for the synthesis of peptides are attractive alternatives to Boc and Fmoc strategies for both solid and solution phase peptide synthesis particularly of sensitive glyco- nucleo- and sulfopeptides due to the extremely mild nature of the palladium catalysed deprotection conditions. This strategy has now been further refined for large-scale solution phase synthesis exploiting the chemoselective deprotection of N-allyloxycarbonyl-O-dimethylallyl-a-amino esters with a water soluble Pd0 catalyst generated in situ from Pd(OAc) 2 and triphenylphosphinotrisulfonate sodium salt (TPPS) with diethylamine as allyl scavenger.47 Care however needs to be taken to avoid N-terminal diketopiperazine (DKP) formation.This problem has been addressed in the context of allyl based solid phase protection strategies by employing phenyltrihydrosilane (PhSiH 3 ) as a neutral non-nucleophilic allyl scavenger.48 The allyloxycarbonyl group (Alloc) has also been shown to be a useful orthogonal protection group for the indolic nitrogen of tryptophan (preventing oxidation during global phosphorylation) during Fmoc–But solid phase synthesis providing the Fmoc groups are removed using DBU.49 C-terminal incorporation of a-trifluoromethyl substituted amino acids into Fmoc peptide acyl fluorides via in situ deprotection of N-(trimethylsilyl) ethoxycarbonyl (Teoc) derivatives using tetraethylammonium fluoride in acetonitrile at 50 °C has been described.50 a-Trifluoromethyl amino acids are notoriously non-nucleophilic at the a-nitrogen and this coupling is proposed to proceed via the ‘mixed anhydride’ of the Fmoc protected peptide and the Teoc derived carbamic acid.This subsequently extrudes CO 2 (Scheme 8). 83 Synthetic methods Part (v) Protecting groups TeocHN CO2Me CF3 –O O NH CO2Me CF3 TBAF 50 °C Fmoc-Xaa-F FmocHN O O O NH H R CO2Me CF3 –CO2 FmocHN O NH H R CO2Me CF3 Scheme 8 Since all the a-trifluoromethyl amino acids used in this study were racemic the configurational integrity of the a-trifluoromethyl residue during coupling could not be ascertained.The p-nitrobenzyloxycarbonyl group (PNZ) has been utilised in syntheses of b-GlcNAc terminating glycosides as an e¶cient participating group in the stereoselective formation of the 2-amino-b-glucosidic linkage and as an N-protecting group which can be removed either by hydrogenolysis or by reaction with dithionite under neutral conditions.51 Lewis acid mediated deprotection of Boc groups is well established but improved methods for their clean removal using boron trifluoride etherate in dichloromethane and for the deprotection of N,N@-bis(tert-butoxycarbonyl) protected guanidino groups using tin(IV) chloride have been reported.52,53 Interestingly,N-silated carbamates (e.g.N-Boc-N-TMS aliphatic benzyl and amino acids) are readily formed from the corresponding primary carbamates using silyl triflates are generally stable to silica chromatogrphy and provide a useful method for the temporary protection of the carbamate NH.54 Base sensitive carbamates such as Fmoc owe their reactivity to facile b-elimination.The b-elimination side-product dibenzofulvene is usually trapped out but occasionally this proves problematic. A new type of urethane protecting group the 1,1-dioxobenzo[b]thiophen-2-ylmethyloxycarbonyl group (Bsmoc) has been introduced as an alternative protecting group for solution and solid phase peptide segment synthesis which circumvents this limitation. 55 this group owes its base sensitivity to an ingenious Michael-type addition process whereby the deblocking event is simultaneously a scavenging event (Scheme 9).A variety of nucleophiles were investigated piperidine was preferred for solid phase synthesis whilst tris(2-aminoethyl)amine (TAEA) gave a water soluble side product making this the nucleophile of choice for solution phase work. The Bsmoc group was compatible with acyl fluoride and in situ ammonium or phosphonium salt based coupling methods and being UV active allows for accurate tracking and quantitation. The Bsmoc group is more sensitive to piperidine than Fmoc is stable to tertiary amines [pyridine diisopropylethylamine (DIEA) hydroxybenzotriazole (HOBt)–DIEA] stable to neat TFA or saturated HCl in EtOAc (but not HBr in AcOH) but is rapidly cleaved by thiols. Sulfonamide protection of amines has traditionally been plagued by their problematic deprotection in highly functionalised sensitive substrates.However in recent 84 A. C. Spivey and S. J. Woodhead NH-(Xaa) n- O O S O2 H2N-(Xaa) n- S O2 2–5% piperidine CH2 N + CO2 + S O2 N Scheme 9 years a number of sulfonamide protecting groups which are amenable to mild deprotection have been developed. Samarium iodide (SmI 2 ) has become widely used for selective arylsulfonamide deprotection particularly of amino sugars.56 2,4-Dinitrobenzenesulfonamides are readily deprotected using excess n-propylamine (20 equiv.) in dichloromethane at ambient temperature or more conveniently using HSCH 2 CO 2 H (1.3 equiv.) and triethylamine (2 equiv.) whereby the side-product 2,4-dinitrophenylthioacetic acid can be easily removed by washing with aqueous NaHCO 3 .57 This year a new sulfonamide analogue of the Boc group tert-butylsulfonyl (Bus) has been introduced which is stable to strong metallation conditions but readily cleaved using 0.1M triflic acid in dichloromethane.58 Introduction of this group requires a two step procedure employing tert-butylsulfinyl chloride followed by oxidation (m-CPBA or RuCl 3 –NaIO 4 ) since tert-butylsulfonyl chloride is unreactive and unstable.The group is stable towards BusLi–TMEDA 0.1M HCl–MeOH 0.1M TFA–CH 2 Cl 2 and pyrolysis neat at 180 °C for 3 h. Selective deprotection of Bus groups from secondary amines in the presence of primary amines (using triflic acid) is possible although the origin of this selectivity is unclear. The vinyl group has been reported to be an e¶cient and economical group for the protection of azole nitrogens in simple heterocyclic systems (e.g.imidazole).59 Protection is a one-pot two step process involving heating first with 1,2-dibromoethane –Et 3 N then aqueous NaOH to e§ect elimination and removal involves treatment with ozone in MeOH at [78 °C in the presence of dimethylsulfide. A methylene ‘bridge’ between the N-1 nitrogens of two 1,2,4-triazoles has also been advocated as a simple but e§ective protecting group during selective 4-alkylation.60 The 2-adamantyloxymethyl group (2-Adom) has been utilised for imidazole protection of histidine during peptide synthesis.61 Boc-His(Nn-2-Adom)-OH is prepared from Boc-His(Nn-2-Boc)-OMe by treatment with 2-adamantyloxymethyl chloride followed by saponification (NaOH). The group is stable to TFA 1M NaOH and 20% piperidine–DMF and easily removed by 1M trifluoromethanesulfonic acid–thioanisole or anhydrous HF.The o-nitrobenzyl group has been shown to function as a reasonably e¶cient photocleavable protecting group for indoles ben- 85 Synthetic methods Part (v) Protecting groups zimidazoles and 6-chlorouracil.62 The 1-thiophenylbenzyl group has been introduced as a b-lactam protecting group during the synthesis of N-unsubstituted b-lactams by [2]2] cycloaddition.63 Deprotection is via oxidation using potassium persulfate. The monomethoxytrityl group (MMTr) is frequently employed for alcohol protection in nucleoside chemistry but its utility as an amino protecting group is often overlooked. A rare instance of this group’s utility in this capacity is its application for the protection of a lysine side chain during the synthesis of complex cathespin B-sensitive maleimidocaproyl-Phe-Lys linked prodrugs.The favourable solubilising properties conferred by the lipophilic MMTr unit were noted.64 References 1 K. Jarowicki and P. Kocienski Contemp. Org. Synth. 1997 454. 2 F. Guibe Tetrahedron 1997 53 13 509. 3 R.M. Thomas G. H. Mohan and D. S. Iyengar Tetrahedron Lett. 1997 38 4721. 4 E. Alonso D. J. Ramon and M. Yus Tetrahedron 1997 53 14 355. 5 H.B. Mereyala and S. R. Lingannagaru Tetrahedron 1997 53 17 501. 6 V.M. Swamy P. Ilankumaran and S. Chandrasekaran Synlett 1997 513. 7 A. Bouzide and G. Sauve Synlett 1997 1153. 8 T. Onoda R. Shirai and S. Iwasaki Tetrahedron Lett. 1997 38 1443. 9 R. Ballini F. Bigi S. Carloni R. Maggi and G. Sartori Tetrahedron Lett.1997 38 4169. 10 K. J. Davis U. T. Bhalerao and B. V. Rao Indian J. Chem. Sect. B-Org. Chem. Med. Chem. 1997 36 211. 11 J. R. Hwu F. F. Wong J. J. Huang and S. C. Tsay J. Organomet. Chem. 1997 62 4097. 12 I. D. Clarke and P. Hodge Chem. Commun. 1997 1395. 13 P. Somfai Angew. Chem. Int. Ed. Engl. 1997 36 2731. 14 Y. C. Xu A. Bizuneh and C. Walker J. Org. Chem. 1996 61 9086. 15 Y. Watanabe and T.Nakamura Nat. Prod. Lett. 1997 10 275. 16 K. Kamaike K. Takahashi T. Kakinuma K. Morohoshi and Y. Ishido Tetrahedron Lett. 1997 38 6857. 17 A. Hasan K.-P. Stengele H. Giegrich P. Cornwell K. R. Isham R. A. Sachleben W. Pfleiderer and R. S. Foote Tetrahedron 1997 53 4247. 18 U. Mu� nch and W. Pfleiderer Nucleosides Nucleotides 1997 16 801. 19 K. Rosenthal A. Karlstrom and A. Unden Tetrahedron Lett.1997 38 1075. 20 M.A. Brook C. Gottardo S. Balduzzi and M. Mohamed Tetrahedron Lett. 1997 38 6997. 21 M. Tandon and T. P. Begley Synth. Commun. 1997 27 2953. 22 S. Chandrasekhar P. K. Mohanty and M. Takhi J. Org. Chem. 1997 62 2628. 23 I. Mohammadpoor-Baltork and S. Pouranshirvani Synthesis 1997 756. 24 P. Saravanan S. Gupta A. DattaGupta S. Gupta and V. K. Singh Synth. Commun. 1997 27 2695. 25 M.G. Stanton and M. R. Gange J. Am. Chem. Soc. 1997 119 5075. 26 Y. Masaki N. Tanaka and T. Miura Chem. Lett. 1997 55. 27 W.-C. Chen M.D. Vera and M.M. Joullie Tetrahedron Lett. 1997 38 4025. 28 M. Honda H. Morita and I. Nagakura J. Org. Chem. 1997 62 8932. 29 F. Mohanazadeh and Y. Ranjbar Iran. J. Chem. Chem. Eng. Int. Eng. Ed. 1996 15 35. 30 R. P. Iyer D. Yu J. Xie W. Zhou and S.Agrawal Bioorg. Med. Chem. Lett. 1997 7 1443. 31 M.P. Reddy N. B. Hanna and F. Farooqui Nucleosides Nucleotides 1997 16 1589. 32 V. T. Ravikumar Z. S. Cheruvallath and D.L. Cole Nucleosides Nucleotides 1997 16 1709. 33 A. Pu� schl J. Kehler and O. Dahl Nucleosides Nucleotides 1997 16 145. 34 A. D. Proud J. C. Prodger and S. L. Flitsch Tetrahedron Lett. 1997 38 7243. 35 E. C. L. Gautier A. E. Graham A. McKillop S. P. Standen and R. J. K. Taylor Tetrahedron Lett. 1997 38 1881. 36 T. S. Li Z. H. Zhang and C. G. Fu Tetrahedron Lett. 1997 38 3285. 37 S. E. Sen S. L. Roach J. K. Boggs G. J. Ewing and J. Magrath J. Organomet. Chem. 1997 62 6684. 38 S. Chandrasekhar B. Muralidhar and S. Sarkar Synth. Commun. 1997 27 2691. 39 B. H. Lipshutz P. Mollard C. Lindsley and V. Chang Tetrahedron Lett.1997 38 1873. 40 T. S. Jin Y. R. Ma Z. H. Zhang and T. S. Li Synth. Commun. 1997 27 3379. 41 D. Albanese F. Corcella D. Landini A. Maia and M. Penso J. Chem. Soc. Perkin Trans. 1 1997 247. 42 N. C. R. van Straten H. I. Duynstee E. de Vroom G. A. van der Marel and J. H. van Boom Liebigs Ann./Recueil 1997 1215. 43 H. Waldmann and A. Reidel Angew. Chem. Int. Ed. Engl. 1997 36 647. 86 A. C. Spivey and S. J. Woodhead 44 C. A. Costello A. J. Kreuzman and M. J. Zmijewski Tetrahedron Lett. 1997 38 1. 45 J. S. Debenham S. D. Debenham and B. FraserReid Biorg. Med. Chem. 1996 4 1909. 46 B. H. Wang and A. L. Zheng Chem. Pharm. Bull. 1997 45 715. 47 S. Lemaire-Audoire M. Savignac E. Blart J.-M. Bernard and J. P. Genet Tetrahedron Lett. 1997 38 2955. 48 N. Thieriet J. Alsina E. Giralt F.Guibe and F. Albericio Tetrahedron Lett. 1997 38 7275. 49 T. Vorherr A. Trzeciak and W. Bannwarth Int. J. Pept. Protein Res. 1996 48 553. 50 W. Hollweck N. Sewald T. Michel and K. Burger Liebigs Ann./Recueil 1997 2549. 51 X. P. Qian and O. Hindsgaul Chem. Commun. 1997 1059. 52 E. F. Evans N. J. Lewis I. Kapfer G. Macdonald and R. J. K. Taylor Synth. Commun. 1997 27 1819. 53 H. Miel and S. Rault Tetrahedron Lett. 1997 38 7865. 54 J. Roby and N. Voyer Tetrahedron Lett. 1997 38 191. 55 L. A. Carpino M. Philbin M. Ismail G. A. Truran E.M. E. Mansour S. Iguchi D. Ionescu A. ElFaham C. Riemer R. Warrass and M.S. Weiss J. Am. Chem. Soc. 1997 119 9915. 56 D. C. Hill L. A. Flugge and P. A. Petillo J. Organomet. Chem. 1997 62 4864. 57 T. Fukuyama M. Cheung C.-K. Jow Y. Hidai and T. Kan Tetrahedron Lett. 1997 38 5831. 58 P. Sun S. M. Weinreb and M. Y. Shang J. Org. Chem. 1997 62 8604. 59 D. J. Hartley and B. Iddon Tetrahedron Lett. 1997 38 4647. 60 E. DiezBarra A. delaHoz R. I. RodriguezCuriel and J. Tejeda Tetrahedron 1997 53 2253. 61 Y. Okada J. D. Wang T. Yamamoto T. Yokoi and Y. Mu Chem. Pharm. Bull. 1997 45 452. 62 T. Voelker T. Ewell J. Joo and E. D. Edstrom Tetrahedron Lett. 1998 39 359. 63 K. Karupaiyan V. Srirajan A. Deshmukh and B. M. Bhawal Tetrahedron Lett. 1997 38 4281. 64 G.M. Dubowchik and S. Radia Tetrahedron Lett. 1997 38 5257. 87 Synthetic methods Part (v) Protecting groups

ISSN:0069-3030    

DOI:10.1039/oc094077

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

3 Organometallic chemistry Part (i) Palladium and nickel catalysed methods By VISUVANATHAR SRIDHARAN* and PAUL C. WOLSTENHOLME-HOGG Department of Chemistry Leeds University Leeds UK LS2 9JT 1 Introduction Pd and Ni salts/complexes are exceptionally versatile and robust catalysts for the construction of carbon–carbon and carbon–heteroatom bonds with excellent regioand stereochemical control. The discovery of new homogeneous catalysts 1–31,2 and heterogeneous catalysts,3–6 including water-soluble polymer-bound catalysts and glass bead technology,7 continues to strengthen the catalytic processes making them even more adaptable and e¶cient. Reported herein are recent developments in Pdand Ni-catalysed carbon–nitrogen and carbon–oxygen bond formations inter- and intramolecular enyne and ynyne cascade reactions concluding with miscellaneous cascade reactions.R1 R1 P R R OAc OAc R1 R1 R R P Pd PPri 2 PPri 2 TFA Pd PR2 PR2 TFA Pd Pd 1 a R = o-tolyl R1 = H b R = mesityl R1 = Me 2 3 a R = Pri b R = Bu t 2 Carbon–nitrogen bond formation Pd and Ni catalysed amination of aryl halides and triflates Aromatic amines are an important class of compounds. They are present in many natural products and continue to be exploited for their unique functionality in numer- *Corresponding author. 89 Br O Me H2N O Me NH Me Me Br H2N + DPPFPdCl2 Me Me + Pd2(dba3) BINAP HN 96% 83% Scheme 1 H R H H (BINAP)Pd ArBr (BINAP)Pd(Ar)Br A (BINAP)Pd(Ar)Br N B (BINAP)PdArNR C NaOBut NaBr ArNHR Scheme 2 ous synthetic organic materials. Buchwald’s8 and Hartwig’s groups9 have independently reported the Pd-catalysed amination (using secondary amines) of aryl iodides and bromides in the presence of a strong base such as an alkoxide or amide.Both groups have also independently developed catalytic systems which utilise DPPF [1,1@-bis(diphenylphosphino)ferrocene] or BINAP ligands for Pd- or Ni-catalysed amination processes.10–12 These catalytic systems a§ord high yields for secondary amines derived from aryl halides and primary amines (Scheme 1). A catalytic cycle for the reactions above (Scheme 1) is presented in Scheme 2 utilizing BINAP as the ligand. Oxidative addition of Pd(0) into the aryl bromide a§ords A which readily forms pentacoordinate complex B. Deprotonation of the coordinated amine by base would give C which reductively eliminates to give (BINAP)Pd and the aryl amine.Both Buchwald’s and Hartwig’s groups conclude that chelating phosphines possessing modest bite angles are important for favourable reductive elimination (C to product Scheme 2)† as opposed to the b-hydride elimination pathway (C to product Scheme 3). Use of the second generation catalytic systems minimises the b-hydride elimination product in these processes. Buchwald et al. have further developed Hayashi-type P–N and P–O ligands 4–6 to couple acyclic secondary amines with aryl halides.13 Complex formation with ligands 5 or 6 to Pd(0) in the presence of NaOBut enables †Note added in proof recent studies from Hartwig’s group shows that catalysts containing electron-rich modestly hindered bidentate phosphines with bite angles (\90°) gave the best results for the coupling of aryl bromides and primary amines.See B. C. Hamann and J. F. Harting J. Am. Chem. Soc. 1998 120 3694. 90 V. Sridharan and P.C. Wolstenholme-Hogg Pd N R1 H H PdH NH R1 + + Pd(0) Scheme 3 Br But N But + Bu Bu Bu2NH 92–97% Pd2(dba)3 ligand 6 Scheme 4 PPh2 Me NMe2 PPh2 PPh2 Me NMe2 PPh2 Me OMe Fe Fe Fe Fe Me O Me PdL P Ph2 NH R R1 4 P P 5 CF3 6 7 CF3 Fe 2 2 8 the coupling of secondary cyclic or acyclic amines to aryl halides in good yields. However this catalytic system is not e§ective for the coupling of primary amines (Scheme 4). Palladium complex 7 gives rise to a reduction in electron density around Pd due to poor r-donation of the methoxy moiety relative to the PAr 2 substituent. This in turn favours the rate of reductive elimination for the above process. Buchwald has further enhanced the scope of this process by altering the base to Cs 2 CO 3 allowing the incorporation of more labile functional groups into the system.Thus simple aryl bromides underwent coupling with secondary amines using 1.5mol% Pd 2 (dba) 3 and 4.5mol% racemic PPFOMe 6 in dioxane at 100 °C whereas electron deficient aryl 91 Organometallic chemistry Part (i) Pd and Ni catalysed methods Br MeO2C O HN MeO2C N O Br + HN N But But + 86% Pd2(dba)3 ligand 6 Cs2CO3 Pd2(dba)3 BINAP Cs2CO3 92% Scheme 5 NH CO2H I N CO2H Me I HN + Pd(0) / Cu / TEABr Me + N Pd2dba3 BINAP NaOBut 18-crown-6 85% 95% K2CO3 Scheme 6 N Cl O HN N N O N N Cl F NH2 NH O OEt N N NH F NH O OEt + + 87% Ni(COD)2,DPPF 98% Pd2(dba)3 BINAP Scheme 7 bromides underwent coupling in the presence of Pd 2 (dba) 3 and BINAP in toluene at 100 °C (Scheme 5).Aryl iodides have also been successfully coupled to both a-amino acids14 and secondary amines15,16 at room temperature using THF and 18-crown-6 (Scheme 6). Aryl chlorides17,18 have been converted to aniline derivatives using a catalytic amount of Ni(COD) 2 and DPPF (or 1,10-phenanthroline) in the presence of NaOBut. Electron-rich or electron-deficient aryl chlorides can be used successfully in the above process as shown in Scheme 7. In contrast to aryl iodides and bromides neutral aryl triflates19,20 gave higher yields of aryl amines than electron-deficient aryl triflates due to the increased rate of base-promoted triflate cleavage in electron deficient triflates 92 V. Sridharan and P.C. Wolstenholme-Hogg MeO OTf H2N MeO N H OTf O Ph HN N O 64% Ph + + 42–92% Pd(OAc)2 BINAP NaOBut Pd(OAc)2 BINAP NaOBut Scheme 8 OTf Me O Ph Ph NH NH2 Me O + i ii Scheme 9 Reagents i Pd(OAc) 2 /BINAP Cs 2 CO 3 ; ii cat.HCl wet THF. Br Br H2N NH2 NH N Br n + n Pd2(dba)3 BINAP 2 n N + N N N 3 LiNPh2 Pd[P( o-tol]3)2 P( o-tol)3 84% 86% NaOBut Scheme 10 (Scheme 8). Utilising Cs 2 CO 3 as base has improved the amination of electron-deficient triflates from 42 to 92% (Scheme 8).21 Primary arylamines have also been obtained via Pd-catalysed coupling of triflates and benzophenone imine (Scheme 9).22 One particular application of the amination process is the synthesis of polyamines. Polyamines,23 together with linear and triarylamine dendrimers,24 have been obtained via Pdcatalysed coupling procedures (Scheme 10). 3 Carbon–oxygen bond formation Aryl ethers are an important class of compounds in natural products.Buchwald’s25,26 93 Organometallic chemistry Part (i) Pd and Ni catalysed methods Br NC Me Me Me OH CN O HO Br + Pd2(dba)3 TolBINAP 73% O Pd(OAc)2 DPPF 69% NaH NaH Me Me Me Scheme 11 Br PdBr PdOR OR Pd(0) NaOR NaBr Scheme 12 Pd O H R2 R1 Pd H R2 O R1 + + Pd(0) Scheme 13 and Hartwig’s27 groups have reported the use of either Pd or Ni catalysed aryl carbon–oxygen bond forming processes. Both inter- and intramolecular processes have been reported and selected examples are shown in Scheme 11. A catalytic cycle similar to the amination process is shown in Scheme 12. The catalytic cycle involves oxidative addition of Pd(0) to aryl bromide followed by substitution of the bromide with the alkoxide. Reductive elimination then a§ords the aryl ether and Pd(0) catalyst.94 V. Sridharan and P.C. Wolstenholme-Hogg NC Br NaO + NC Pd2dba3 ligand 8 74% Pd2(dba)3 DPPF 50% O Scheme 14 Br O O + Br O KN(SiMe3) 51% O Pd(PPh3)2Cl2 Cs2CO3 71% Pd2(dba)3 DPPF Scheme 15 This process can sometimes give low yields due to b-hydride elimination as shown in Scheme 13. Hartwig has developed a new ligand 8,28 for the coupling of electron-poor aryl bromides and electron-rich alkoxides (Scheme 14). Closely related Pd-catalysed processes for the a-arylation of ketones,29,30 both inter- and intramolecularly have also been reported (Scheme 15). 4 Cascade reactions Cascade reactions may be defined as multi-reaction one-pot sequences in which the first reaction creates the functionality to trigger the second reaction and so on.This section is concerned with Pd- and Ni-catalysed processes in which two or more C–C/C–heteroatom bonds are formed. Enyne and ynyne systems Intermolecular processes Yamamoto et al. have reported palladium catalysed benzannulation of conjugated enynes (Scheme 16).31 These processes are regiospecific thus 1,3-disubstituted benzene or trisubstituted arenes were not observed. Yamamoto has also investigated regiospecific Pd-catalysed [4]2] cycloadditions of enyne–diyne systems.32 These also occurred in good yields with the process believed to proceed via a pallado cycle (Scheme 17). Regiospecific Pd-catalysed cyclotrimerisation of 1,3-diyne to 1,3,5-unsymmetrically substituted benzene occurs in good yield (Scheme 18).33,34 Palladiumcatalysed reactions of disulfides with alkynes35 and addition of terminal alkynes to acceptor alkynes36 have also been reported.95 Organometallic chemistry Part (i) Pd and Ni catalysed methods R R Pd(PPh3)4 a R = n-C6H13 77% b R = Me 70% c R = Me2CHOHCH2CH2 81% R Scheme 16 R R1 R1 R R1 R1 • R R1 + R1 Pd(PPh3)4 Pd R =Me R1 = Bu n 80% R = Me R1 = Ph 99% Scheme 17 R H R R R Pd(PPh3)4 R = n-hexyl 64% R = PhCH2CH2 51% Scheme 18 Intramolecular processes Grigg et al. have developed a three component polycyclisation cascade using allene (1 atm) and sodium benzenesulfinate (Scheme 19).37 This process yields 9 as a single diastereomer via the formation of five new bonds and two stereocentres. Grigg et al.37 have also extended the cascade cyclisation anion capture methodology to ynynyne systems. Triscyclisation anion capture is illustrated in Scheme 20.Organotin reagents RSnBu 3 and RSnMe 3 comprise a valuable source of diversity and added complexity in the cascade cyclisation anion capture processes (Scheme 20). Palladium-catalysed Stille coupling reactions continue to dominate catalytic carbon–carbon bond formation. The development of fluorous tin reagents,38 new tin reagents39 and novel iminophosphine ligands40 for cross coupling are the topic of numerous papers41–60 which appeared throughout the year including Nicolaou’s application to complex 96 V. Sridharan and P.C. Wolstenholme-Hogg EtO2C EtO2C I • EtO2C EtO2C PdL • EtO2C EtO2C PdL + PhSO2Na EtO2C EtO2C + Pd(PPh3)4 SO2Ph PhSO2Na 9 66% Scheme 19 N CO2Me OCO2Me O O SnBu3 N CO2Me O • PdL N CO2Me • LPd N CO2Me O LPd N CO2Me O O Pd(0) / LiCl 74% Scheme 20 polyether frameworks.61 In the cascade theme a related biscyclisation–anion capture process has been applied to the synthesis of ([)-a-thujone (Scheme 21).62 A wide range of natural products have been synthesised utilising Pd-catalysed cyclisation processes as a key step.Such natural products include (^)-scopadulic acid B,63 ([)-pancracine,64 (])- pilocarpine,65 camptothecin analogues,66 vitamin D3,67 morphine analogues68 and cephalotoxine.69 An alternative to initiation by insertion of Pd(0) into a suitable C–X bond is to initiate a cascade process by hydropalladation. A combination of Pd 2 (dba) 3 with HOAc can be utilised as a source for the initiating palladium hydride species. This work originally pioneered by Trost,70 has been successfully applied to biscyclisation processes (Scheme 22).71 Genet et al.have reported Pd-catalysed cyclisation of an enyne system in the absence of HOAc with a mixed solvent of dioxane–water and TPPTS ligands.72 The results from their investigations showed a rather di§erent 97 Organometallic chemistry Part (i) Pd and Ni catalysed methods SO2Ph PhO2S O Me O SO2Ph PhO2S H Me Pd2(dba)3 H ii iii Me O Me3Zn i 91% Scheme 21 Reagents and conditions i PtO 2 H 2 AcOH 50 °C; ii,Al/Hg THF H 2 O; iii,LDA MoOPh. O OAc CO2Et CO2Et EtO2C EtO2C O OAc CO2Et CO2Et EtO2C EtO2C H H H H Pd2(dba)3 HOAc 50% Scheme 22 O Ph O OH Ph EtO2C CO2 Et B NMe NH SiMe2Ph EtO2C EtO2C B N Me HN SiMe2Ph MeO2C CO2 Me 85% PdCl2 / TPPS Pd(OH)2 / C MeO2C MeO2C Bu3SnH SnBu3 95% + Pd2(dba)3 85% + Scheme 23 cyclisation product (Scheme 23). Similarly Tanaka Lautens and co-workers73 have used borosilane or Bu 3 SnH as the initiator and substrate rather than HOAc in the cascade process of enyne and ynyne systems (Scheme 23).Oh et al. have recently reported the use of HCOOH (1 mol.) instead of HOAc to a§ord the reduced cascade product in good yield (Scheme 24).74 Alkenes and 1,2-dienes Intermolecular processes Yamamoto and co-workers have reported in a series of papers addition of C-pronuc- 98 V. Sridharan and P.C. Wolstenholme-Hogg OSiMe2But H XPd OSiMe2But PdX H OSiMe2But H PdCl2 / PPh3 HCOOH OSiMe2But 74% Scheme 24 H CO2Et Ph CN SnBu3 Ph CO2Et CN Ph NC EtO2C SnBu3 Cl Ph + CN CN Pd2(dba)3 51% + Ph CN + Pd(0) 91% Scheme 25 S I • S SO2Ph O OMe I + • CO (1 atm) + N (1 atm) Ts Pd(PPh3)4 H + PhSO2Na + CO (1 atm) OMe + O + N Pd(0) Ts 95% 97% Scheme 26 leophiles to alkenes,75 1,2-dienes76 and enynes77 to form carbon–carbon bonds.A typical cascade process is illustrated in Scheme 25. Pronucleophiles and vinyltin in the presence of Pd 2 (dba) 3 and DPPF a§orded the dimerisation product in good yield (Scheme 25). Grigg et al. have used the di§erence in rate for insertion of aryl Pd(II) species into CO and allenes to their advantage and devised a series of tetramolecular queuing cascades (Scheme 26).78 99 Organometallic chemistry Part (i) Pd and Ni catalysed methods OH I • O O + CO (20 atm) OH O + PdX 73% Pd(OAc)2 dppb Scheme 27 I • NH O N O O PdX O PdX O O PdX + CO O + O + PdX Pd(0) 75% Scheme 28 O H2N Me O CO2H + HN + Me O CO (60 bar) 99% (PPh3)2PdBr2 conc. H2SO4 LiBr Scheme 29 Intramolecular processes Alper and Okura have demonstrated an intramolecular version of the above process which occurred in good yield (Scheme 27).79 Grigg has further enhanced the process to pentamolecular queuing cascades and this is illustrated in Scheme 28.80 5 Miscellaneous cascade reactions Beller et al.have synthesised novel amino acids via three component cascade processes (Scheme 29).81 The above process may be modified by tuning the catalyst system to enantio/diastereoselective systems. Grigg et al. have reported the Pd-catalysed oxime 100 V. Sridharan and P.C. Wolstenholme-Hogg N HO N Pd O L L N O N O H H + Pd(II) – – + H+ – Pd(II) Scheme 30 Ph N N OH N Me O HN H H N O O Ph N Me O HN H N O O PdCl2(MeCN)2 Et3N NMM Ph + H 9 1 80% Scheme 31 OMe OMe OTf OTf B OTBPPS OMe OMe OTBDPS + 66% 82%ee Pd2(dba)3 R-BINAS Scheme 32 to metallonitrone to isoxazoline cascade in good yield (Scheme 30).82 In the aldoxime case oximes underwent a stereospecific and highly facially selective cascade under the reaction conditions above (Scheme 31) to a§ord enantiopure adducts in 80% yield (9 1).Cascade Suzuki83 cross coupling Heck reactions have been applied to the synthesis of polyfused systems in high enantioselectivity and good yield (Scheme 32). Tietz and Schirok have synthesised cephalotaxine via a Pd-catalysed cascade process (Scheme 33).69 Finally Mori has reported a nickel catalysed cascade process for the synthesis of pyrolizidine and indolizidine derivatives in good yield and high enantiomeric excess (Scheme 34). In utilizing the versatility of this process for the construction of pyrrolizidine and indolizidine skeletons Mori applied the technique to the formal total synthesis of ([)-elaeokanine C with great success.84 101 Organometallic chemistry Part (i) Pd and Ni catalysed methods O O HN AcO O O N P PdOAc oTol oTol N Pd(PPh3)4 H 85% 2 Bun 4NOAc I 80% I O O Scheme 33 N O N O H OSiPh3 N O H OSiPh3 Ni(COD)2 PPh3 Ph3SiH THF + 9.1 1 97%ee 99%ee 68% 9% Scheme 34 References 1 W.A.Hermann and B. Cornils Angew Chem. Int. Ed. Engl. 1997 36 1048; W. A. Hermann C. Brossmer C. P. Reisinger T. H. Riermeir M. Ofele and M. Beller Chem. Eu. 1997 3 1357; F. Robin F. Mercier L. Ricard F. Mathey and M. Spagnol Chem. Eu. 1997 3 1365. 2 M. Oh§ A. Oh§ M.E. Vanderboom and D. Milstein J. Am. Chem. Soc. 1997 119 11 687. 3 D. Villemin P. A. Ja§res B. Nechab and F. Courivaud Tetrahedron Lett.1997 38 6581. 4 D.E. Bergbreiter and Y. S. Liu Tetrahedron Lett. 1997 38 7843. 5 A. Hessler and O. Stelzer J. Org. Chem. 1997 62 2362. 6 C. Amatore. G. Broker A. Jutand and F. Khalil J. Am. Chem. Soc. 1997 119 5176. 7 L. Tonks M. S. Anson K. Hellgardt A. R. Mirza D. F. Thompson and M.J. Williams Tetrahedron Lett. 1997 38 4319. 8 A. S. Giuram R. A. Rennels and S. L. Buchwald Angew. Chem. Int. Ed. Engl. 1995 1348; J. P. Wolfe and S. L. Buchwald J. Org. Chem. 1996 61 1133. 9 J. Louie and J. F. Hartwig Tetrahedron Lett. 1995 36 3609; F. Paul and J. F. Hartwig Organometallics 1995 14 3030; J. F. Hartwig and F. Paul J. Am. Chem. Soc. 1995 117 5373. 10 J. F. Hartwig Synlett 1997 329; S. Driver and J. F. Hartwig J. Am. Chem. Soc. 1997 8232. 11 J. P. Wolfe S. Wagaw and S.L. Buchwald J. Am. Chem. Soc. 1996 7215. 12 J. F. Marcoux S. Wagaw and S. L. Buchwald J. Org. Chem. 1997 62 1568. 13 J. P. Wolfe and S. L. Buchwald Tetrahedron Lett. 1997 38 6359. 14 D. Ma and J. Yau Tetrahedron Asymmetry 1996 7 3075. 15 J. P. Wolfe and S.L Buchwald J. Org. Chem. 1997 62 6066. 16 J. P. Wolfe R. A. Rennels and S. L. Buchwald Tetrahedron 1996 52 7225. 17 J. P. Wolfe and S. L. Buchwald J. Am. Chem. Soc. 1997 119 6054. 18 Y. Hong G. J. Tanoury H. C. Wilkinson K. P. Bakale S. A. Wald and C. H. Senanayake Tetrahedron Lett. 1997 38 5607. 102 V. Sridharan and P.C. Wolstenholme-Hogg 19 J. P. Wolfe and S. L. Buchwald J. Org. Chem. 1997 62 1264. 20 B. C. Hamann and J. F. Hartwig J. Org. Chem. 1997 62 1268. 21 J. Ahman and S. L. Buchwald Tetrahedron Lett. 1997 38 6363.22 J. P. Wolfe J. Aham J. P. Sadighi K. A. Singer and S. L. Buchwald Tetrahedron Lett. 1997 38 6367. 23 T. Kanbara K. Izumi Y. Nakadai T. Narise and K. Haseyawa Chem. Lett. 1997 1185. 24 J. Louie and J. F. Hartwig J. Am. Chem. Soc. 1997 119 11 695. 25 M.P. John P. Wolfe and S. L. Buchwald J. Am. Chem. Soc. 1997 119 3395. 26 K. A. Widenoefer H. Annita and S. L. Buchwald J. Am. Chem. Soc. 1997 119 6787. 27 G. Mann and J. F. Hartwig J. Org. Chem. 1997 62 5413. 28 G. Mann and J. F. Hartwig Tetrahedron Lett. 1997 38 8005. 29 B. C. Hamann and J. F. Hartwig J.Am. Chem. Soc. 1997 119 12 382; M. Palucki and S. L. Buchwald J. Am. Chem. Soc. 1997 119 11 108. 30 H. Muratake and M. Natsume Tetrahedron Lett. 1997 38 7581. 31 S. Saito M. N. Salter V. Gevorgyan N. Tsuboya K. Tando and Y. Yamamoto J.Am. Chem. Soc. 1996 118 3970. 32 V. Gevorgyan A. Takeda and Y. Yamamoto J. Am. Chem. Soc. 1997 119 1313; M. Murakami K. Kenichiro and Y. Ito J. Am. Chem. Soc. 1997 119 7163. 33 A. Takeda A. Ohno I. Kadota V. Gevorgyan and Y. Yamamoto J. Am. Chem. Soc. 1997 119 4547. 34 V. Gevorgyan N. Sadayori and Y. Yamamoto Tetrahedron Lett. 1997 38 8603. 35 Y. Gareau and A. Orellana Synlett 1997 803. 36 B.M. Trost M. T. Sorum C. Chan A. E. Harms and G. Ruhter J. Am. Chem. Soc. 1997 119 698. 37 R. Grigg R. Rasul and V. Savic Tetrahedron Lett. 1997 38 1825. 38 M. Larhed M. Hoshino S. Hadida D. P. Curran and A. Hallberg J. Org. Chem. 1997 62 5583; M. Hoshino P. Degenkolb amd D. P. Curran J. Org. Chem. 1997 62 8341. 39 G. Fouquet M. Pereyre and A. L. Rodriguez J. Org. Chem. 1997 62 8341. 40 E. Shirakawa Y.Murota Y. Nakao and T. Hiyama Syn. Lett. 1997 1143. 41 E. Shirakawa H. Yoshidaand and H. Takaya Tetrahedron Lett. 1997 38 3759. 42 K.W. Stagliano and H. Malinakova Tetrahedron Lett. 1997 38 6617. 43 F. Clerici E. Erba M. L. Gelmi and M. Valle Tetrahedron 1997 53 15 859. 44 L. Lu and D. J. Burton Tetrahedron Lett. 1997 38 7673. 45 C. Chen K. Wilcoxen K. Kim and J. R. McCarthy Tetrahedron Lett. 1997 38 7677. 46 H. Tanaka H. Yamada A. Matsuda and T. Takahashi Synlett 1997 381. 47 J. Thibonnet M. Abarbri J. L. Pavrain and A. Duchene Synlett 1997 771. 48 P. A. Evans J. D. Nelson and T. Manangun Synlett 1997 968. 49 E. Wright T. Gallagher C. G. V. Sharples and S. Wonnacott Bioorg. Med. Chem. Lett. 1997 2867. 50 T. Gan G. Scott and J. M. Cook Tetrahedron Lett. 1997 38 8453. 51 G.T. Grisp Y. L. Jaing P. J. Pullman and C. DeSavi Tetrahedron Lett. 1997 38 17 489. 52 M.I. Konaklieva H. Shi and E. Turos Tetrahedron Lett. 1997 38 8647. 53 M. Suzuki H. Doi M. Bjorkman Y. Andreson B. Langstrom Y. Wantanabe and R. Noyori Chem. Eur. J. 1997 2039. 54 E. Shirakawa K. Yamasaki and T. Hiyama J. Chem. Soc. Perkin Trans. 1 1997 2449; E. Shirakawa H. Yoshida and T. Hiyama Tetrahedron Lett. 1997 38 5177. 55 T. Luker H. Heimstra H. and W. N. Speckamp J. Org. Chem. 1997 62 8131. 56 M. Benaglia S. Toyota R. Craig C. R. Woods and J. S. Siegel Tetrahedron Lett. 1997 38 4737. 57 S. H. Chen Tetrahedron Lett. 1997 38 4741. 58 G. Barbarella M. Zambianchi G. Sotgiu and A. Bongini Tetrahedron 1997 53 9401. 59 M. Iyoda M. Miura S. Sasaki S. M. Humaynkabir Y. Kuwatani and M. Yoshida Tetrahedron Lett.1997 38 4581. 60 S. Khatib A. Mamai G. Guillaumet M. Bouzoubaa and G. Coudert Tetrahedron Lett. 1997 38 5993. 61 K. C. Nicolaou G. Shi J. L. Gunzner P. Gartner and Z. Yang J. Am. Chem. Soc. 1997 119 5567. 62 W. Oppolzer A. Pimm B. Stammen and W. E. Hume Helv. Chim. Acta 1997 80 623. 63 L. E. Overman D. J. Ricca and V. D. Tran J. Am. Chem. Soc. 1997 119 1203. 64 J. Jin and S. M. Weinreb J. Am. Chem. Soc. 1997 119 5773; G. R. Friestad and B. P. Branchaud Tetrahedron Lett. 1997 38 5933. 65 Z. Wang and X. Lu Tetrahedron Lett. 1997 38 5213. 66 F. G. Frang D. D. Bankson E. M. Huie M.R. Johnson M. C. Kang and C. S. Leitouller Tetrahedron 1997 53 10 953. 67 S. Hatakeyama T. Ikeda J. Maeyama T. Esumi Y. Iwabuchi and H. Irie Bioorg. Med. Chem. Lett. 1997 7 2871; H. Yokoyama K. Miyamoto Y.Hirai and T. Takahashi Synlett 1997 187. 68 C. Y. Hong L. E. Overman and A. Romero Tetrahedron Lett. 1997 38 8439; C. Y. Chang J. P. Liou and M.J. Lee Tetrahedron Lett. 1997 38 4571. 69 L. F. Tietze and H. Schirok Angew. Chem. Int. Ed. Engl. 1997 36 1124. 70 B.M. Trost Acc. Chem. Res. 1990 23 34. 71 C.W. Holzapfel and L. Marais Tetrahedron Lett. 1997 38 8585. 103 Organometallic chemistry Part (i) Pd and Ni catalysed methods 72 J. Christophe M. Savignac and J. P. Genet Tetrahedron Lett. 1997 38 8695. 73 S. Onozawa Y. Hatanaka and M. Tanaka Chem. Commun. 1997 1229; M. Lautens N. D. Smith and D. Ostrorsky J. Org. Chem. 1997 62 8970. 74 C. H. Oh Y. Rhim and S. K. Hwang Chem. Lett. 1997 777. 75 I. Nakamura N. Tsukada M. A. Masum and Y. Yamamoto Chem. Commun. 1997 1583.76 M.A. Masum M. Meguro and Y. Yamamoto Tetrahedron Lett. 1997 38 6071. 77 V. Gevorgyan C. Kadowaki M.M. Saltzer I. Kadota S. Saito and Y. Yamamoto Tetrahedron 1997 9097. 78 R. Grigg S. Brown V. Sridharan and M.D. Uttley Tetrahedron Lett. 1997 38 5031. 79 K. Okuro and H. Alper J. Org. Chem. 1997 62 1566. 80 R. Grigg and R. Pratt Tetrahedron Lett. 1997 38 4489. 81 M. Beller M. Eckert F. Vollmuller S. Bogdanoic and H. Geissler Angew. Chem. Int. Ed. Engl. 1997 36 1494. 82 M. Frederickson R. Grigg J. Markandu M. Thornton-Pett and J. Redpath Tetrahedron Lett. 1997 38 7777. 83 A. Kojima S. Honzawa C. D. J. Boden and M. Shibasaki Tetrahedron Lett. 1997 38 3455. 84 Y. Sato N. Saito and M. Mori Tetrahedron Lett. 1997 38 3931. 104 V. Sridharan and P.C. Wolstenholme-Hogg

ISSN:0069-3030    

DOI:10.1039/oc094089

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

3 Organometallic chemistry Part (ii) Stoichiometric methods By GUY C. LLOYD-JONES School of Chemistry University of Bristol Cantock’s Close Bristol UK BS8 1TS 1 Introduction Despite continued growth in transition metal catalysis many areas of organic synthesis –particularly C–C bond forming reactions–are still underdeveloped and require stoichiometric methodology. A selection from the chemical literature of 1997 is reviewed below and is organised by transition metal group with further subdivisions by reaction or intermediates. 2 Applications Scandium Ytterbium and the Lanthanides The triflate salts of these metals show remarkable properties as catalysts for a variety of reactions but stoichiometric applications are scarce. Titanium Zirconium and Hafnium Olefination Despite the rapid rise of catalytic olefin metathesis the oxophilicity of titanium-based reagents currently assures that they remain a powerful methodology for carbon –carbon double bond forming reactions from carbonyl compounds.For example reaction of thioacetals with Cp 2 Ti[P(OEt 3 )] 2 generates reagents that react with ketones and aldehydes carboxylic acids and lactones to generate alkenes and enol ethers in good yield.1 Sequential treatment of lithiated N-benzyl or N-allyl benzotriazoles with ketones and then low-valent titanium gives olefins in good yield and with high trans selectivity.2 The titanium ylide (Me 2 N) 3 P CHTi(Pr*O)Cl 2 reacts with aldehydes and ketones to a§ord vinylphosphonium salts which can be deprotonated and reacted with a further aldehyde or ketone thereby generating an allene through a double olefination sequence.3 This was further extended to e§ect a one-pot ring closure of two tethered aromatic aldehydes.When the tether is a binaphthol ether the allene macrocycle is generated diastereoselectively (ca. 66% de).4 Intramolecular McMurry type coupling has been used to prepare photochromic cyclohexenes from the corresponding 1,6-diones5 and four configurational isomers of the intriguing macrocycle 1 whose dynamics were studied by NMR spectroscopy.6 Zirconium also 105 N Br N 3 2 i Scheme 1 Reagents i Cp 2 Zr(g2-butene) O O O O 1 facilitates olefination and active zirconium metal may be prepared simply by reduction of ZrCl 4 with lithium.7 Metallocenes Reaction of Me 3 Al with Cp 2 TiCl 2 a§ords a reagent which methyltitanates diphenylacetylene with [98% Z-selectivity; dec-5-yne reacts analogously but then undergoes b-H elimination to yield the allene 6-methyldeca-4,5-diene.Tebbe-type products (metallacyclobutenes) are not observed under these conditions.8 Treatment of b,c-unsaturated thioacetals with titanocene–alkene complexes yields vinylcyclopropanes. Usefully 1,2-dibromoalkenes serve as alkene precursors in this reaction thereby reducing problems associated with volatility of low molecular weight alkenes.9 Zirconocene(g2-butene) undergoes reductive cyclisation with bromodienes e.g. 2 and the unstable intermediate undergoes b-bromo elimination to a§ord pyrollidine derivative 3 bearing an exocyclic methylene (Scheme 1). Analogous carbocyclic products can also be formed from appropriate precursors.10 Diastereoselective skeletal rearrangement to carbocyclic 5 occurs on treatment of cis- or trans-2-vinylpiperidine derivative 4 with zirconocene,11 and reaction of triethyl orthoacrylate with zirconocene a§ords an a,b-unsaturated acyl anion equivalent which reacts with aldehydes to a§ord 2,2-diethoxybut-3-en-1-ol derivatives.12 Sequential addition of Cp 2 ZrBu 2 MeMgBr and then O 2 to enantiomerically pure allylic amine (S)-6 gave hexahydroindole 7 as a single diastereomer which was further transformed to ([)-mesembrane and ([)- mesembrine (Scheme 2).13 Zirconocene(g2-butene) induces regioselective ring opening of vinylcyclopropanes–this was applied to the stereocontrolled synthesis of steroidal side-chains14–and on reaction with 1,2-bis(TMS)acetylene and then vinyl bromide a§ords 2,3-bis(TMS)-buta-1,3-diene in 95% yield.This reaction which probably proceeds via a cyclobutene intermediate cleaves the vinyl bromide double bond. The reaction sequence is also successful with other acetylenes e.g. 1-phenyl-2-TMSacetylene and 1,2-diphenyl acetylene.15 Methylaluminoxane catalyses the regio- and stereocontrolled a-addition of allylzirconium species (prepared by hydrozirconation of allenes) to C2 of alk-1-ynes,16 and reaction of Cp 2 ZrCl 2 with two equivalent EtMgBr followed by an alkyne and then CO/I 2 yields cyclopentenone derivatives in analogy to 106 G. C. Lloyd-Jones N Boc TsO OMe OMe N OMe OMe N OH H N H Boc Ph Ph Ph Ph 7 (±)-4 (±)-5 6 i ii iii iv Scheme 2 Reagents i Cp 2 Zr; ii Cp 2 ZrBu 2 ; iii MeMgBr; iv O 2 Cp2Zr Ph Ph Zr(Cl)Cp2 8 9 i Scheme 3 Reagents i allyl chloride CuCl the Pauson–Khand reaction.17 Zirconacycle 8 reacts with allyl chloride in the presence of copper(I) chloride to give 9 as a result of highly regioselective insertion ([98% de Scheme 3).18 Miscellaneous Duthaler’s chiral titanium(IV) enolate 10 introduced the required anti stereochemistry at C6–C7 and C18–19 in a total synthesis of tautomycin 11.19 Cyclopropylamines are readily prepared from amides by a new reagent mixture formed from MeTi(Pr*O) 3 and one equivalent of Grignard reagent.Intramolecular examples a§orded bicyclo[n.1.0] alkylamines–e.g. 13 is formed from 12 (Scheme 4).20 The cyclic titanium chelate formed by transmetallation of a-methyl-b-siloxy ketones with TiCl 4 reacts with high diastereoselectivity with Grignard reagents to a§ord a-methyl-b-siloxy tertiary alcohols.21 Diisopropoxy Ti–TADDOLate complexes can be used to kinetically resolve racemic chiral 1,3-dioxolan-4-ones azalactones anhydrides and axially chiral biaryl lactones through isopropoxy ring-opening transfer esterification.22 Reaction of planar chiral all-1-en-7-ynes with (g2-propene)Ti(Pr*O) 2 occurs with complete chirality transfer to a§ord after quenching of the intermediate titanacycle 1-alkenyl-2-alkylidenecyclopentanes. 23 107 Organometallic chemistry Part (ii) Stoichiometric methods Ti O O O O O O O O O O OH O OMe OH O OH O O H H O 11 10 7 18 2 6 19 Reduction Nitro-aromatics are reduced under mild and neutral conditions to the corresponding anilines by use of a combination of Cp 2 TiCl 2 and samarium metal.24 Reaction of a-keto acids with Ti(Pr*O) 4 a§ords titanates which can then be reduced by LDA to the corresponding a-hydroxy acid.When the alkoxy ligands in the titanate are preexchanged with di-O-isopropylidine-D-mannitol the reduction proceeds with up to 44% ee.25 Lewis acids The addition of 1,1-diarylethenes to 1,2-naphthoquinones and derivatives proceeds e¶ciently in the presence of Ti(Pr*O)Cl 3 to a§ord the 4-(2,2-diarylethenyl) substituted products.26 Both zirconium(IV) and hafnium(IV) chlorides have been found to signifi- cantly extend the range of the sulfone based alkoxymethylene homologation procedure that converts ketones into their a-methoxylated homologues.27 Vanadium Niobium and Tantalum Of these metals thus far only vanadium has been used significantly in organic synthesis. Asymmetric quaternary carbons may be constructed directly from carbonyl compounds by sequential allylation with an allyl metal reagent (metal\Li Zn MgBr etc.) and then reaction with allyl propargyl or benzyl bromide and the strongly oxophilic vanadium(II) complex VCl 2 (tmeda) 2 .28 Dialkylzinc reagents react with vanadium(III) and (IV) chlorides to a§ord organovanadates which both alkylate and pinacol couple aldehydes.29 Chromium Molybdenum and Tungsten Carbene complexes Fischer carbene complexes (FCC) continue to be of great interest particularly those of chromium.Lithioacetylenes undergo [1,2] addition to FCC to give species that behave as propargyl metallics. Quenching a§ords enynes or enones–dependent upon 108 G. C. Lloyd-Jones NMe2 NMe2 Br O (OC)5Cr OMe OMe Bu Fe Fe ii i 12 13 14 15 Scheme 4 Reagents i MeTi(Pr*O) 3 EtMgBr; ii pent-1-ene the pH during work-up–whilst reaction with aldehydes imines orCO 2 a§ords furans pyrroles and butenolides respectively.30 a,b-Unsaturated chromium FCC react with BH 3 ·Me 2 S to a§ord on oxidative work-up 1,3-diols.31 2-Arylalkenyl chromium FCC cyclopropanate terminal alkenes with good diastereoselectivity for example 14 reacted with pentene to give 15 (97% de Scheme 4).32 Vinyl tungsten FCC undergo Diels–Alder addition with 2-amino-1,3-dienes to a§ord after hydrolysis cyclohexan- 4-one carbenes33 and chromium FCC undergo diastereoselective cycloaddition with diazomethane derivatives to yield dihydropyrazoles.34 A quite remarkable dimerisation with loss of one methylene occurs on treatment of a diene e.g.16 with FCC 17. The MeO2C OTBDMS CO2Me TBDMSO CO2Me MeO2C OTBDMS TBDMSO (OC)5Cr OMe Ph 17 16 18 resulting vinylcyclopentene 18 is obtained essentially quantitatively and as a single diastereomer.The carbene ligand of 17 is not incorporated in the product.35 Tungsten( II) FCC of type 19 react with aldehydes e.g. benzaldehyde in the presence of BF 3 ·Et 2 Oto give cycloalkenylated salts 20. These salts have a rich chemistry and react with nucleophiles as diverse as water cyanoborohydride Grignard reagents and organocuprates. The latter add 1,3- whilst the former three add 1,1-. Salt 20 is cyclopropanated diastereoselectively by diazomethane to give after hydrolysis 21 (Scheme 5).36 Enantiomerically pure ephedrine derived imidazolidinone FCC 22 exists as a pair of stable atropisomers which were separated. On cyclohexadienone annulation with alkynes the atropisomers generate a quaternary carbon centre in 23 with very high diastereoselectivity (Scheme 6).Opposite diastereomers with di§erent colours are formed from the two atropisomers.37 109 Organometallic chemistry Part (ii) Stoichiometric methods 19 20 (±)-21 O (CO)3CpW R Ph O O R Ph R HO (CO)3CpW H i ii Scheme 5 Reagents i PhCHO; ii CH 2 N 2 N N Ph N Cr(CO)5 O N N Ph O N O R' 22 23 24 (±)-25 R (CO)3CpW OHC O H n–2 i n ii,iii Scheme 6 Reagents i hex-1-ene; ii TsOH MeOH; iii NOBF 4 NaI p-Complexes Chromium tricarbonyl arene complexes that possess planar chirality remain an area of much endeavour–particularly in the development of methodology for their asymmetric synthesis rather than resolution. Asymmetric deprotonation of anisole derived (g6-arene)Cr(CO) 3 complexes with chiral lithium amide bases followed by electrophilic quench proceeded with up to 99% ee.38 The enantiomerically pure chromium tricarbonyl complexes of o-tolualdehyde and o-anisaldehyde underwent SmI 2 - mediated coupling with methyl acrylate to yield the corresponding c-butyrolactones as single disastereomers.39 Photochemical cycloaddition of 2-methyl- and 2,3- dimethyl-butadiene to Cr(CO) 3 (COT) followed by CAN oxidation a§ords bicyclotetraenes.40 Treatment of propargyl tungsten species 24 with acidic methanol a§ords 110 G. C. Lloyd-Jones O O O O H OSiPh2But O OTES MeO Br O O O OH OSiPh2But O OTES MeO 26 28 27 i Scheme 7 Reagents i CrCl 2 NiCl 2 (1% w/w) p-allyl tungsten complexes which generate fused a-methylenebutyrolactones of five six and seven membered rings 25 on intramolecular cyclisation triggered by addition of NO`–NaI (Scheme 6).41 Highly stereoselective methylation and ethylation of 2-ethyland 2-methyl-(g6-indan-1,3-dione)tricarbonylchromium respectively allowed access to 2,2-dialkylated(g6-indan-1,3-dione)tricarbonylchromium complexes which were not preparable by conventional means.42 The g6-chromiumtricarbonyl complex of chlorobenzene phenylates N,N-dimethyl hydrazone cuprates LiM[Me 2 NN––(R)CHR@] 2 CuN to a§ord the corresponding ketones RCOCHR@Ph on work-up.43 Miscellaneous The determination of the absolute configuration of chiral 1,3-diols by CD spectroscopy is greatly aided by complexation with [Mo 2 (OAc) 4 ].44 The polymeric complex derived from pyrazine and oxodiperoxochromium(VI) is a highly versatile reagent for oxidation of common organic functionality including alcohols diols thiols sulfides phosphines electron rich aromatics phenols and amines.45 An allylic chromium intermediate derived from 26 added smoothly to aldehyde 27 to give homoallylic alcohol 28 in a stereoselective synthesis of phorboxazole A (Scheme 7),46 and a vinylic chromium reagent was employed in a total synthesis of halicholactone.47 Manganese Technetium and Rhenium Of these metals only manganese appears in mainstream organic synthetic applications.Organomanganese r-compounds Lithium–halide exchange at low temperature followed by manganese–lithium exchange converts aryl and alkenyl halides to their corresponding aryl and alkenyl manganese halides. Usefully these species react cleanly with acyl halides to a§ord ketones48 and may be cross coupled with aryl halides or triflates through palladium catalysis.49 A range of organomanganese chlorides RMnCl (R\Bu dodecyl Pr* But Ph hept-1-ynyl) were reacted with the butyrolactone acyl chloride derived from L-glutamic acid to a§ord d-ketobutanolides in enantiomerically pure form.50 Organomanganese p-compounds Nucleophiles attack the allyl terminus of tetracarbonyl(p-allyl)manganese complex and the allylated products are obtained in moderate to excellent yield on oxidative 111 Organometallic chemistry Part (ii) Stoichiometric methods (OC)3Fe H2N n-Hept OMe OMe (OC)3Fe NH n-Hept OMe OMe H H NH n-Hept O O 29 31 32 30 i Scheme 8 Reagents i MeCN air decomplexation.Interestingly the pK! of the pro-nucleophile determines the degree of allylation non-stabilised nucleophiles are monoallylated whilst stabilised carbon nucleophiles are bis-allylated.51 Manganese ‘ate’ complexes The use of manganates is steadily increasing–particularly as transmetallating species in combination with catalysts such as Ni and Cu.Tributyl manganates readily generated by addition of butyllithium or magnesium species to manganese(II) salts induce cyclisation of allylic-2-halogenoaryl ethers to give 3-alkyl-2,3-dihydrobenzofurans in good yields. Analogous reactions with anilines a§orded indolines.52 Curiously manganate(II) complexes dehalogenate a-halogen bearing ketones esters and amides to a§ord the corresponding manganese enolate regiospecifically. a-Siloxy and a-acetoxy ketones behave analogously. An oxidative addition/reductive elimination type mechanism is suggested.53 Miscellaneous The BuLi-generated anions of manganese carbenes (Me-Cp)(CO) 2 Mn––C(OEt)CH 2 R react with a,b-unsaturated ketones to a§ord after decomplexation with CO or PPh 3 substituted cyclohexen-2-ones.54 Iron Ruthenium and Osmium p-Complexes Reaction of aniline 29 with g5-cyclohexadienyl iron cation 30 a§orded cycloadduct 31.This was further elaborated and demetallated to a§ord the potent lipid peroxidation inhibitor carbazoquinocin C 32 (Scheme 8).55 Chiral iron complexes continue to be of interest for the conduction of diastereoselective transformations prior to demetalla- 112 G. C. Lloyd-Jones Fe CO CO PMBO H H Fe CO CO O O Ph OCu Ph O CO2Me OH 34 33 35 36 i,ii iii iv Scheme 9 Reagents i LiMe 2 Cu; ii PMB-OH; iii CAN NaOMe CO; iv DDQ Fe H MeO2C H OC CO CO CO2Me MeO2C CO2Me H CO2Me MeO2C 38 37 i Scheme 10 Reagents i CAN tion.Enantiomerically enriched (g4-methylhexa-3,5-dienoate)Fe(CO) 3 (83% ee) was prepared by resolution with (R)-a-methylbenzylamine. Subsequent deprotonation and alkylation alpha to the carboxylate proceeded with 69–92% de.56 Optically active dicarbonyl cyclopentadienyl (vinyl ether) iron cations function as 3-hydroxypropionate 2,3-dication equivalents. Transetherification allows a range of optically active vinyl ether complexes to be obtained. For example complex 33 was transetherified to 34 and then reacted with enolate 35 to a§ord after deprotection optically active 3-hydroxyketo ester 36 (Scheme 9).57 Tricarbonyliron(pentenediyl) complexes e.g. 37 undergo reductive elimination (triggered by oxidation) to a§ord vinylcyclopropanecarboxylates e.g.38 in up to 70% yield. Deuterium labelling was employed to elucidate stereochemical aspects of the mechanism (Scheme 10).58 Intermediates in the stereoselective synthesis of all trans- and 9-cis-retinoic acids have been prepared by [1,2] addition of lithio acetonitrile and lithio ethyl acetate to the keto functionality of (g4-b-ionone)Fe(CO) 3 59 and addition of stannyl enolate 39 to C5 of g5-hexadienyl iron salt 40 generated two contiguous quaternary centers in 41 which were further manipulated in the construction of the A ring of racemic stemodinone (Scheme 11).60 Chelated allyl–iron carbene salts react with enolates at the allyl terminus61–this was applied to a synthesis of the terpene alcohol hotrienol.62 g2-Coordination of substituted anisoles to osmium(II) allows reaction at C4 with a range of carbon electrophiles.63 Chiral but racemic (g6-bromoarene)(g4-COD)ruthenium(0) complexes readily undergo lithium–halogen exchange with BuLi. The resulting anions are quenched with ([)-menthyl chloroformate to a§ord a 1 1 mixture of diastereomeric (g6- menthyl benzoate)(g4-COD)ruthenium(0) complexes which may be separated to afford enantiomerically pure compounds.64 Miscellaneous Dimethyldioxirane oxidation of the thioether complex of 4-phthalimidobutyl methyl sulfide with cyclopentadienyl ruthenium-(R,R)-chiraphos cation followed by cleavage of the phthalimido group with hydrazine and liberation of the sulfoxide with NaI 113 Organometallic chemistry Part (ii) Stoichiometric methods O O OSnBu3 MeO Fe OC OC CO 39 40 41 5 MeO Fe OC OC CO i O O O H Scheme 11 Reagents i MeCN,[78 °C Ph H CO2Et Ph H H H CO2Et O 42 43 i ii Scheme 12 Reagents i Co 2 (CO) 8 ; ii norbornene O O O O O O 45 44 i Scheme 13 Reagents i Co 2 (CO) 8 NMO a§ords (R)-sulforaphane MeS(O)(CH 2 ) 4 NCS in 80% ee.65 Polymer supported peruthenate provides a very convenient method for the oxidation of primary and secondary alcohols to aldehydes and ketones without conventional work-up.66 Cobalt Rhodium and Iridium Pauson–Khand Reactions Cyclopropane 42 undergoes a Pauson–Khand reaction (PKR) with norbornene to a§ord tricycle 43 with moderate regioselectivity (Scheme 12).67 The tandemPKR of 44 occurs with perfect regioselectivity to a§ord dicyclopenta[a,e]pentalene 45 (Scheme 13),68 and PKR reactions of alkynyl N-allyl FCC (Cr W) e.g.46 have been successfully carried out to give e.g.47.69 Near perfect regioselectivity ([99%) was observed in the PKR of[96% ee 48 to give cyclopentenone[96% ee 49 (Scheme 14).70 Miscellaneous Stereospecific intramolecular nucleophilic attack in p-allyl cobaloxime 50 proceeds with retention of configuration to generate intermediate 51 which underwent a photochemical cross coupling with styrene to give enantiomerically pure tetrahydrofuran derivative 52 (Scheme 15).71 Cobalt complexes bearing Ph 3 P or Me 3 P e¶ciently 114 G. C. Lloyd-Jones NH W(CO)5 NH W(CO)5 O H Ph Ph O H OBn HO OBn HO H 48 49 47 46 i i Scheme 14 Reagents i Co 2 (CO) 8 BzO OH Co(dmgH)2Py O Co(dmgH)2Py O Ph 51 50 52 iii i ii Scheme 15 Reagents i 1%NaOH MeOH; ii HCl PPTS; iii hl styrene mediate the equivalent of a Reformatsky reaction between a-haloketones and ketones or aldehydes to produce b-hydroxyketones in fair yield.72 Cobalt(I)(salen) anions undergo S N 2@ addition to allenic electrophiles to a§ord cobalt(III)–buta-1,3-diene complexes which react with a range of dienophiles.The resulting cycloadducts are readily demetallated to a§ord Diels–Alder type products in good yield.73 Reaction of Co 2 (CO) 8 with 1-allenylcyclopropan-1-ols followed by acetic anhydride yields derivatives of 1,4-diacetoxy-2-methylbenzene.74 Nickel Palladium and Platinum Palladium mediated reaction of 3-haloalkenoates with thiostannyl reagents Bu 3 SnSR generates 3-arylthio or alkylthio propenoates. Reactions with alkoxystannyl reagents proceed analogously.75 The intriguing tricyclobutyl 53 and radialene 54 were prepared in 16 and 24% yields via a one-pot procedure in which hexakis(dibromomethyl) benzene was heated with [(Bu 3 P) 2 Ni(COD)].76 o-Palladated complex 55 undergoes a highly diastereoselective Diels–Alder reaction with vinyldiphenylphosphine to a§ord after decomplexation P-chiral diphosphine ligand 56 in which four 115 Organometallic chemistry Part (ii) Stoichiometric methods Br Br Br Br Br Br Br Br Br Br Br Br 53 54 N Pd P Ph Cl P Ph i Ph2P 56 55 Scheme 16 Reagents i CH 2 ––CHPPh 2 i i Et S p-Tol OMs Ph O Et S p-Tol OMs Ph S p-Tol Et Me O Ph S p-Tol Et Me 57 58 Ph 59 60 Scheme 17 Reagents i MeCuCNMgBr asymmetric centres are generated (Scheme 16).77 (Dppe)PtCl 2 mediates the cyclocoupling of diazoesters and alk-3-yn-1-ols to give tetrahydrofuran-2-ylidene esters.78 Copper Silver and Gold Organocuprates Not surprisingly organocuprates continue to be used extensively in organic synthesis.For example stereoselective methylcuprate addition to allylic mesylates 57 and 59 occurs in an S N 2@ manner and the stereochemical outcome may be controlled by the oxidation state at the vinylic sulfur centre–57 gives 58 whilst 59 gives 60 (Scheme 17).79 S N 2@ anti displacement of allylic phosphate 61 by Grignard derived methylcuprate was employed in a synthesis of vitamin D 2 analogue 62 (Scheme 18).80 A 116 G. C. Lloyd-Jones OTBDMS TBDMSO H O H OH HO H HO H OP(O)(OEt)2 O 62 61 i Scheme 18 Reagents i MeMgBr CuCN LiCl methylcuprate was reacted with enol triflate 63 with ultrasonication to generate the required trisubstituted olefin 64 in a total synthesis of FK-506 (Scheme 19).81 Interestingly in toluene solution and in the absence of ethers LiBu 2 Cu adds [1,2] to a,b- unsaturated ketone 65.On addition of two molar equivalents of diethyl ether a near-complete switch to [1,4] addition occurs. The ether is proposed to stabilise the formally copper(III) intermediate 66.82 A zinc-modified cuprate derived from serine reacts with enantiomerically pure 1-methyl-3-(phenylsulfonyl)allylirontetracarbonyl cation to a§ord vinyl sulfones stereospecifically.83 The combination of tin with cuprates is also becoming popular–for example the higher order cuprate formed from bis-stannyl reagent 67 undergoes [1,4] addition to 4-siloxycyclohexenone 68 with perfect stereoselectivity to a§ord vinyl stannane 69 which is a useful substrate for Stille type cross coupling in a synthetic approach to TaxolTM (Scheme 20).84 Also Z-stannyl diene 71 a key intermediate in the synthesis of multidrug resistance reversal agent 6,7-dehydrostipiamide was prepared by carbocupration of acetylene 70 with a vinyl tin cuprate (Scheme 21).85 Cyclodimerization of iodostannane 72 mediated by copper( I) thiophene-2-carboxylate provided a novel synthesis of elaiophylin 73 (Scheme 22).86 a-Stannyl epoxides may be coupling with electrophiles by employing Cu 2 S87 and vinyltributyl tin compounds homocoupled to produce dienes by treatment with CuCl.88 Cuprates generated in situ by reaction of Grignard reagents with CuI react smoothly with tosylates.This process is employed for the enantioselective synthesis of threonine analogues 75 from 74 (Scheme 23).89 (a-Aminoalkyl)cuprates prepared from N-tert-BOC-pyrollidine or N-tert-BOC-dimethylamine undergo smooth conjugate addition to acyclic a,b-unsaturated esters thiol esters imides and a,b-ynoates,90 and couple stereospecifically with dialkylvinyl iodides and with 1-iodoalkynes.91 Cuprates derived from primary organolithium species attack aziridine tosylates derived from 117 Organometallic chemistry Part (ii) Stoichiometric methods OTf OTES O O O H TESO BDPSO MeO Me OTES O O O H TESO BDPSO MeO OEE OEE 63 64 i Scheme 19 Reagents i,Me 2 CuLi ultrasound O O Cu Li O Et Et Bu Bu 65 66 serines ([97% ee) exclusively at the least substituted aziridine carbon thereby allowing access to b,c-disubstituted 2-aminopropan-1-ol derivatives in high enantiomeric purity.92 Analogous regioselectivity is reported for N-phosphorylated aziridines.93 Although TMSCl is often used as an accelerant for cuprate additions a combination of Bu 2 BOTf–TMEDA was found to be much more e§ective in the conjugate addition of benzylic and allylic organocuprates to enantiomerically pure ephedrine-derived imidazolidinone 76.94 At [78 °C in the presence of Bu 3 P dialkyl cyanocuprates R 2 Cu(CN)Mg readily insert CO to a§ord a-hydroxy ketones RCOCH(OH)R in good yield.95 Diastereoselective conjugate addition of the silylcuprate Me(PhMe 2 Si)CuLi to enantiomerically pure 77 generates 78 which on protonation and stereoselective oxidation [mercury(II)/AcOOH] a§ords 79 ([99% ee Scheme 24).96 On lithiumbromine exchange and then transmetallation with CuCN (2-bromoaryl) allyl ethers rearrange to the corresponding 2-allylphenolates with the allyl terminus being delivered to the ortho position.97 118 G.C. Lloyd-Jones i Bu3Sn SnBu3 O OTES 67 O OTES 68 69 Bu3Sn Scheme 20 Reagents i,Me 2 CuCNLi 2 LiCl SnBu3 OEt i 71 70 O O OEt Scheme 21 Reagents i Bu 3 Sn(Me)CuCNLi 2 acetylene O OH O O O OH OH O O I SnMe3 OH O O I Me3Sn i 73 72 72 Scheme 22 Reagents i Cu(I) thiophene-2-carboxylate Halide abstraction and addition AgOTf abstracts chloride from a-ketoimido chlorides e.g. 80 and thereby induces cyclisation to a§ord pyrroline derivatives e.g. 81 (Scheme 25).98 Treatment of hydrazones with copper(II) halides and triethylamine in methanol proves a convenient method for preparing geminal dihalides from ketones.99 119 Organometallic chemistry Part (ii) Stoichiometric methods N O O O Ph OTs N O O O Ph R 74 i 75 Scheme 23 Reagents i RMgBr–CuI N N O Ph O R 76 O O O Ph O OLi O Ph PhMe2Si O O O Ph OH i 77 78 79 ii Scheme 24 Reagents i Me(PhMe 2 Si)CuLi; ii Hg(OAc) 2 AcO 2 H Miscellaneous Ullmann-like reductive coupling of aryl hetero-aryl and alkenyl halides occurs at ambient temperature by employing copper(I) 2-thiophenecarboxylate,100 and an asymmetric Ullmann coupling of oxazoline 82 was employed in the synthesis of (S)-gossypol.101 Treatment of 1,2-disubstituted cyclohexane-1,2-diols with CuBr 2 and LiOBut results in oxidative cleavage to a§ord the corresponding 1,6-diketones.102 Copper(I) was used to template the preparation of catenane 86 from 83 84 and 85 (Scheme 26).103 Zinc Cadmium and Mercury Addition of dialkylzinc reagents to aldehydes The enantioselective addition of dialkylzinc to aldehydes catalysed by chiral ligands is 120 G.C. Lloyd-Jones i N Cl O TMS TMS 80 N O TMS 81 Scheme 25 Reagents i AgOTf Br N O OMe O MeO MeO 82 now ubiquitous–particularly the diethylzinc–benzaldehyde reaction. However the following asymmetric amplification reaction is remarkable a trace amount of 2- methyl-1-(2-methyl-5-pyrimidyl)propan-1-ol of ca. 0.2–0.3% ee autocatalyses the addition of diisopropylzinc to 2-methylpyrimidone-5-carbaldehyde. The ee of the product which is itself the catalyst for its further generation rises rapidly throughout the reaction reaching a terminal value of up to 90% ee.104 Organozinc and mercury nucleophiles Transmetallation of lithium enolate 87 with ZnBr 2 at [90 °C gave 88 (after quenching) as a 97 3 ratio of diastereomers via a 5-exo trig cyclisation onto a non-activated double bond (Scheme 27).105 Lithiation (at the propargylic site) of homoallyl propargyl ethers followed by transmetallation with ZnBr 2 allows the preparation of substituted tetrahydrofuran derivatives via a zinca–ene–allene reaction.106 Nucleophilic attack by a range of organozinc species on enones with tethered alkynes in the presence of a nickel catalyst led to carbocyclisation.For example 89 gave 90 on reaction with MeZnCl (Scheme 27).107 Cyclopentenylzinc intermediate 91 underwent Pd-catalysed cross coupling with dienyl iodide 92 to a§ord after deprotection and oxidation nakienone A 93 (Scheme 28).108 The diazo substituted mercury compound 94 reacted cleanly with acyl halides RCOX to a§ord 1,3-dicarbonyl diazo reagents of type 95 (Scheme 29).109 Hydroboration of phenylcyclopentene 96 with Et 2 BH and then transmetallation with Pr* 2 Zn then CuCN and finally reaction with 2-bromo-1- phenylacetylene gave (^)-97 with 96% anti selectivity (Scheme 29).110 Secondary alkyl iodides undergo smooth I–Zn exchange with Pr* 2 Zn allowing access to functionalised secondary alkylzincs.111 Homoallylic hydroxylamines can be prepared by addition of allylzinc bromides to nitrones,112 and reaction of aldehydes with TMS–dialkylamine in the presence of LiClO 4 to generate an intermediate O-silyl aminol followed by addition of organozinc bromide a§ords b-dialkylamino esters in good yield and high purity.113 The a-zinciohydrazone 98 reacts with vinylmagnesium bromide to form 121 Organometallic chemistry Part (ii) Stoichiometric methods N N O O O N N O O O O O O O O O N N O O O O O O N N O O O i ii iii HO OH O I I 83 86 85 84 Scheme 26 Reagents i Cu(MeCN) 4 PF 6 ; ii Cs 2 CO 3 ; iii KCN bimetallic 99.This bimetallic may then be trapped with two electrophiles. For example trapping with Me 2 S 2 then allyl bromide gives 100 in what is a four-component sequential one-pot synthesis of polyfunctional ketones (Scheme 30).114 Ketones are readily prepared by addition of dialkylzincs to acyl chlorides in the presence of one equivalent AlCl 3 as Lewis acid promoter.115 Diethylzinc can be added to chalcone in a conjugate manner with up to 83% ee by use of camphor-derived cobalt catalysts.116 Zinc carbenoids Enantioselective cyclopropanation of allylic alcohols with bis(iodomethyl)zinc occurs with high selectivity in the presence of a catalytic quantity of enantiomerically pure 1,2-trans-N,N@-bismethylsulfonamidocyclohexane.The pre-formation of the zinc alkoxide of the allylic alcohol prior to reaction is essential for high selectivity.117 A 122 G. C. Lloyd-Jones N OLi OEt Ph Me N O OEt Ph Me 87 O Ph 88 O Ph 90 89 i ii Scheme 27 Reagents i ZnBr 2 ; ii MeZnCl Ni cat O OH OH TMSO OTBDMS OTBDMS ZnI I 93 92 91 i ii iii iv Scheme 28 Reagents i 5mol% PdCl 2 [P(furyl) 3 ] 2 10 mol% BuLi; ii K 2 CO 3 ; iii PCC; iv Bun 4 NF Hg N2 N2 O EtO O OEt N2 O OEt O R Ph Ph Ph 94 95 96 97 i ii iii iv v Scheme 29 Reagents i RCOX; ii Et 2 BH; iii Pr* 2 Zn; iv CuCN; v 2-bromo-1- phenylacetylene tartramide-derived dioxaborolane ligand is used to e§ect analogous reactions with functionalised iodoalkylzinc reagents.118 Repeated asymmetric cyclopropanation of allylic alcohols was used to build the multicyclopropane antifungal agent FR- 900848.119 b-Keto esters are homologatively transformed to c-keto esters on reaction with CH 2 I 2 –Et 2 Zn.120 123 Organometallic chemistry Part (ii) Stoichiometric methods N N R ZnBr N N R ZnBr MgBr N N R SMe 98 100 99 i ii iii Scheme 30 Reagents i CH 2 ––CHMgBr; ii Me 2 S 2 ; iii allyl bromide O O OH 101 102 i ii Scheme 31 Reagents i Hg(O 2 CCF 3 ) 2 ; ii LiAlH 4 MeO2C CO2 Me CO2Me SePh TMS CO2Me CO2Me H CO2Me H PhSe TMS H 103 104 105 i Scheme 32 Reagents i ZnBr 2 Lewis acids Homo Diels–Alder cycloadducts of type 101 allow access to diquinane precursors e.g.102 (Scheme 31) on reaction with mercury(II).121 These electrophilic ring opening reactions are usually concerted.In contrast bi- and tetra-cyclopropane arrays open via stabilised carbocations. Attack by tethered hydroxy proceeds with high stereoselectivity. 122 Zinc(II) bromide activates tricarbonyl olefins (e.g. 103) su¶ciently for attack by 1-seleno-2-silylethenes (e.g. 104) to a§ord cyclopropanes (e.g. 105) with near-perfect cis-selectivity (Scheme 32).123 A range of enantiomerically pure bisoxazoline zinc triflate complexes act as enantioselective Lewis acid promoters for the allylation of oxazolidinone imides with allylsilanes as allylating reagents.124 Miscellaneous (DABCO)–Zn(BH 4 ) 2 is a stable and useful reducing agent for the selective reduction of aldehydes ketones a,b-unsaturated ketones a-diketones and acyl chlorides at room temperature.125 Diethylzinc in the presence of a Pd catalyst induces reductive homocoupling of alkynyl or phenyl iodonium salts to a§ord biaryls or diynes.126 HMPA accelerated reaction of Zn(N 3 ) 2 ·2Py–2,4,6-tetrabromocyclohexa-2,5- dienone–PPh 3 with primary and secondary alcohols yields the primary and secondary azides (with inversion of stereochemistry) in excellent yield.127 Radical chain aromatic 124 G.C. Lloyd-Jones tert-butylation by tert-butylmercury halides in the presence of DABCO is highly para selective with monosubstituted benzenes.128 References 1 Y. Horikawa M. Watanabe T. Fujiwara and T. Takeda J. Am. Chem. Soc. 1997 119 1127. 2 A.R. Katritzky and J. Li J. Org. Chem. 1997 62 238. 3 K.A. Reynolds P. G. Dopico M. S. Brody and M.G. Finn J. Org. Chem. 1997 62 2564. 4 M.S. Brody R. M. Williams and M.G. Finn J. Am. Chem. Soc. 1997 119 3429. 5 Z.N. Huang S. Jin and M. G. Fan Chin. Chem. Lett 1997 8 7. 6 G. Maerkl J. Stiegler P. Kreitmeier T. Burgemeister F. Kastner and S. Dove Helv. Chim. Acta 1997 80 14. 7 J. S. Lee Y. Tae K. S. Choi M. K. Park and B. H. Han Bull. Korean Chem. Soc. 1997 18 224. 8 E. Negishi D. Y. Kondakov and D. E. Van Horn Organometallics 1997 16 951. 9 Y. Horikawa T. Nomura M. Watanabe T. Fujiwara and T. Takeda J. Org. Chem. 1997 62 3678. 10 D. B. Millward and R. M. Waymouth Organometallics 1997 16 1153. 11 Y. Hanzawa H. Kiyono N. Tanaka and T. Taguchi Tetrahedron Lett. 1997 38 4615. 12 H. Ito and T. Taguchi Tetrahedron Lett. 1997 38 5829. 13 M. Mori S. Kuroda C.-S. Zhang and Y. Sato J. Org. Chem. 1997 62 3263. 14 S. Harada H. Kiyono R.Nishio T. Taguchi Y. Hanzawa and M. Shiro J. Org. Chem. 1997 62 3994. 15 T. Takahashi Z. Xi R. Fischer S. Huo C. Xi and K. Nakajima J. Am. Chem. Soc. 1997 119 4561. 16 S. Yamanoi T. Imai T. Matsumoto and K. Suzuki Tetrahedron Lett. 1997 38 3031. 17 T. Takahashi Z. Xi Y. Nishihara S. Huo K. Kasai K. Aoyagi V. Denisov and E. Negishi Tetrahedron 1997 53 9123. 18 T. Takahashi Y. Nishihara R. Hara S. Huo and M. Kotora Chem. Commun. 1997 1599. 19 J. E. Sheppeck II W. Liu and A. R. Chamberlin J. Org. Chem. 1997 62 387. 20 V. Chaplinski H. Winsel M. Kordes and A. de Meijere Synlett 1997 111. 21 G. Bartoli M. Bosco L. Sambri and E. Marcantoni Tetrahedron Lett. 1997 38 3785. 22 D. Seebach G. Jaeschke K. Gottwald K. Matsuda R. Formisano D. A. Chaplin M. Breuning and G. Bringmann Tetrahedron 1997 53 7539.23 H. Urabe T. Takeda D. Hideura and F. Sato J. Am. Chem. Soc. 1997 119 11 295. 24 Y. Huang L. Puhong Y. Zhang and Y. Wang Synth. Commun. 1997 27 1059. 25 D. Xin-Fang and C.-L. Yin Synth. Commun. 1997 27 825. 26 A. Takuwa I. Kameoka A. Nagira Y. Nishigaichi and H. Iwamoto J. Org. Chem. 1997 62 2658. 27 N. Phillipson M. S. Anson J. G. Montana and R. J. K. Taylor J. Chem. Soc. Perkin Trans. 1 1997 2821. 28 Y. Kataoka I. Makihira H. Akiyama and K. Tani Tetrahedron 1997 53 9525. 29 Y. Kataoka I. Makihira M. Utsunomiya and K. Tani J. Org. Chem. 1997 62 8540. 30 N. Iwasawa K. Maeyama and M. Saitou J. Am. Chem. Soc. 1997 119 1486. 31 J. Barluenga A. Granados F. Rodriguez J. Vadecard and F. J. Fananas Tetrahedron Lett. 1997 38 6465. 32 J. Barluenga A. Fernandez-Acebes A.A. Trabenco and J. Florez J. Am. Chem. Soc. 1997 119 7591. 33 J. Barluenga F. Aznar A. Martin and S. Barluenga Tetrahedron 1997 53 9323. 34 J. Barluenga F. Fernandez-Mari A. L. Viado E. Aguilar and B. Olano J. Chem. Soc. Perkin Trans. 1 1997 2267. 35 M. Ho§man M. Buchert and H.-U. Reissig Angew. Chem. Int. Ed. Engl. 1997 36 283. 36 K.-W. Liang W.-T. Li S.-M. Peng S.-L. Wang and R.-S. Liu J. Am. Chem. Soc. 1997 119 4404. 37 J. F. Quinn T. S. Powers W. D. Wul§ G. P. A. Yap and A. L. Rheingold Organometallics 1997 16 4945. 38 R. A. Ewin A. M. MacLeod D. A. Price N. S. Simpkins and A. P. Watt J. Chem. Soc. Perkin Trans. 1 1997 401. 39 N. Taniguchi and M. Uemura Tetrahedron Lett. 1997 38 7199. 40 C. G. Kreiter and R. Eckert Chem. Ber./Recl. 1997 130 9. 41 S.-J. Shieh C.-C. Chen and R.-S.Liu J. Org. Chem. 1997 62 1986. 42 P. Hrnciar P. Hrnciar V. Gajda E. Svanygova and S. Toma Collect. Czech. Chem. Commun. 1997 62 479. 43 T. Mino T. Matsuda K. Maruhashi and M. Yamashita Organometallics 1997 16 3241. 44 J. Frelek W. Szczepek V. Wojciech and W. Voelter J. Prakt. Chem./Chem.-Ztg. 1997 339 135. 45 B. Tamami and H. Yeganeh Tetrahedron 1997 53 7889. 46 R. D. Cink and C. J. Forsyth J. Org. Chem. 1997 62 5672. 47 D. J. Critcher S. Connolly and M. Wills J. Org. Chem. 1997 62 6638. 48 I. Klement H. Stadtmueller P. Knochel and G. Cahiez Tetrahedron Lett. 1997 38 1927. 49 E. Riguet M. Alami and G. Cahiez Tetrahedron Lett. 1997 38 4397. 50 G. Cahiez and E. Metais Tetrahedron Asymmetry 1997 8 1373. 51 W.S. Vaughan H. H. Gu and K. F. McDaniel Tetrahedron Lett. 1997 38 1885. 125 Organometallic chemistry Part (ii) Stoichiometric methods 52 J.Nakao R. Inoue H. Shinokubo and K. Oshima J. Org. Chem. 1997 62 1910. 53 M. Hojo H. Harada H. Ito and A. Hosomi J. Am. Chem. Soc. 1997 119 5459. 54 C. Mongin N. Lugan and R. Mathieu Organometallics 1997 16 3873. 55 H.-J. Knoelker and W. Froehner Tetrahedron Lett. 1997 38 1535. 56 J. T. Wasicak R. A. Craig R. Henry B. Dasgupta H. Li and W. A. Donaldson,Tetrahedron 1997 53 4185. 57 W. Zhen K.-H. Chu and M. Rosenblum J. Org. Chem. 1997 62 3344. 58 Y. K. Yun and W.A. Donaldson J. Am. Chem. Soc. 1997 119 4084. 59 A. Wada S. Hiraishi N. Takamura T. Date K. Aeo and M. Ito J. Org. Chem. 1997 62 4343. 60 A. J. Pearson and X. Fang J. Org. Chem. 1997 62 5284. 61 W. Fortsch F. Hampel and R. Schobert Chem. Ber./Recl. 1997 130 863.62 J. Boehmer F. Hampel and R. Schobert Synthesis 1997 661. 63 S. P. Kolis M.E. Kopach R. Liu and W. D. Harman J. Org. Chem. 1997 62 130. 64 F. Heinemann J. Klodwig F. Knoch M. Wuendisch and U. Zenneck Chem. Ber./Recl. 1997 130 123. 65 W. A. Schenk and M. Duerr Chem. Eur. J. 1997 3 713. 66 B. Hinzen and S. V. Ley J. Chem. Soc. Perkin Trans. 1 1997 1907. 67 O. Kretschik M. Nieger and K. H. Do� tz Chem. Ber./Recl. 1997 130 507. 68 S. G. Van Ornum and J. M. Cook Tetrahedron Lett. 1997 38 3657. 69 L. Jordi S. Ricart J. M. Vinas and J. M. Moreto Organometallics 1997 16 2808. 70 N.M. Heron J. A. Adams and A. H. Hoveyda J. Am. Chem. Soc. 1997 119 6205. 71 L. M. Grubb and B. P. Branchaud J. Org. Chem. 1997 62 242. 72 F. Orsini J. Org. Chem. 1997 62 1159. 73 J. J. Chapman and M. E. Welker Organometallics 1997 16 747.74 Y. Owada T. Matsuo and N. Iwasawa Tetrahedron 1997 53 11 069. 75 R. Rossi F. Bellina and L. Mannina Tetrahedron 1997 53 1025. 76 A. Stanger N. Ashkenazi R. Boese D. Blaeser and P. Stellberg Chem. Eur. J. 1997 3 208. 77 B.-H. Aw T. S. A. Hor S. Selvaratnum K. F. Mok A. J. P. White D. J. Williams N. H. Rees W. McFarlane and P.-H. Leung Inorg. Chem. 1997 36 2138. 78 G. L. Casty and J. M. Stryker Organometallics 1997 16 3083. 79 J. P. Marino A. Viso J.-D. Lee R. Fernandez de la Pradilla P. Fernandez and M.B. Rubio J. Org. Chem. 1997 62 645. 80 M. Torneiro Y. Fall L. Castedo and A. Mourino J. Org. Chem. 1997 62 6344. 81 R. E. Ireland L. Liu and T. D. Roper Tetrahedron 1997 53 13 221. 82 C. L. Kingsbury and R. A. J. Smith J. Org. Chem. 1997 62 7637. 83 R.F. W. Jackson D. Turner and M. H. Block Synlett 1997 789. 84 F. Delaloge J. Prunet A. Pancrazi and J.-Y. Lallemand Tetrahedron Lett. 1997 38 237. 85 M. B. Andrus and S. D. Lepore J. Am. Chem. Soc. 1997 119 2327. 86 I. Paterson and J. Man Tetrahedron Lett. 1997 38 695. 87 J. R. Falck R. K. Bhatt K. M. Reddy and J. Ye Synlett 1997 481. 88 E. Piers E. J. McEachern M. A. Romero and P. L. Gladstone Can. J. Chem. 1997 75 694. 89 G. D. Monache M.C. Di Giovanni D. Misiti and G. Zappia Tetrahedron Asymmetry 1997 8 231. 90 R. K. Dieter and S. E. Velu J. Org. Chem. 1997 62 3798. 91 R. K. Dieter and R. R. Sharma Tetrahedron Lett. 1997 38 5937. 92 S. C. Bergmeier and P. P. Seth J. Org. Chem. 1997 62 2671. 93 T. Gajda A. Napieraj K. Osowska-Pacewicka S. Zawadzki and A. Zwierzak Tetrahedron 1997 53 4935.94 P. S. van Heerden B. C. B. Bezuidenhoudt and D. Ferreira Tetrahedron Lett. 1997 38 1821. 95 G.W. Kabalka N.-S. Li and S. Yu Tetrahedron Lett. 1997 38 2203. 96 S. Schabbert R. Tiedemann and S. Schaumann Liebigs Ann./Recl. 1997 879. 97 J. Barluenga R. Sanz and F. J. Fananas Tetrahedron Lett. 1997 38 6103. 98 T. Kercher and T. Livinghouse J. Org. Chem. 1997 62 805. 99 T. Takeda R. Sasaki S. Yamauchi and T. Fujiwara Tetrahedron 1997 53 557. 100 S. Zhang D. Zhang and L. S. Liebeskind J. Org. Chem. 1997 62 2312. 101 A. I. Meyers and J. J. Willemsen Chem. Commun. 1997 1573. 102 T. Fujiwara Y. Tsuruta K. Arizono and T. Takeda Tetrahedron Lett. 1997 38 962. 103 J.-C. Chambron J.-P. Sauvage and K. Mislow J. Am. Chem. Soc. 1997 119 9558. 104 T. Shibata T. HayasJ. Yamamoto and K.Soai Tetrahedron Asymmetry 1997 8 1717. 105 P. Karoyan and G. Chassaing Tetrahedron Lett. 1997 38 85. 106 E. Lorthois I. Marek and J.-F. Normant Bull. Soc. Chim. Fr. 1997 134 333. 107 J. Montgomery E. Oblinger and A. V. Savchenko J. Am. Chem. Soc. 1997 119 4911. 108 M. Pour and E. Negishi Tetrahedron Lett. 1997 38 525. 109 A. Padwa M.M. Sa and M. D. Weingarten Tetrahedron 1997 53 2371. 110 L. Micouin M. Oestreich and P. Knochel Angew. Chem. Int. Ed. Engl. 1997 36 245. 111 L. Micouin and P. Knochel Synlett 1997 327. 112 A. Fiumana M. Lombardo and C. Trombini J. Org. Chem. 1997 62 5623. 113 M. R. Saidi H. R. Khalaji and J. Ipaktschi J. Chem. Soc. Perkin Trans. 1 1997 1983. 126 G. C. Lloyd-Jones 114 E. Nakamura K. Kubota and G. Sakata J. Am. Chem. Soc. 1997 119 5457. 115 M. Arisawa Y.Torisawa M. Kawahara M. Yamanaka A. Nishida and M. Nakagawa J. Org. Chem. 1997 62 4327. 116 A. H. de Vries and B. L. Feringa Tetrahedron Asymmetry 1997 8 1377. 117 S. E. Denmark and S. P. O’Connor J. Org. Chem. 1997 62 584. 118 A. B. Charette and J. Lemay Angew. Chem. Int. Ed. Engl. 1997 36 1090. 119 A. G. M. Barrett W. W. Doubleday D. Hamprecht K. Kasdorf G. J. Tustin A. J. P. White and D. J. Williams Chem. Commun. 1997 1693. 120 J. B. Brogan and C. K. Zercher J. Org. Chem. 1997 62 6444. 121 M. Lautens W. Tam and J. Blackwell J. Am. Chem. Soc. 1997 119 623. 122 A. G. M. Barrett and W. Tam J. Org. Chem. 1997 62 4653. 123 S. Yamazaki H. Kumagai T. Takada S. Yamabe and K. Yammamoto J. Org. Chem. 1997 62 2968. 124 N. A. Porter J. H. Wu G. Zheng and A. D. Reed J. Org. Chem. 1997 62 6702.125 H. Firouzabadi and B. Zeynizadeh Bull. Chem. Soc. Jpn. 1997 70 155. 126 S.-K. Kang R.-K. Hong T.-H. Kim and S.-J. Pyun Synth. Commun. 1997 27 2351. 127 A. Saito K. Saito A. Tanaka and T. Oritani Tetrahedron Lett. 1997 38 3955. 128 G. A. Russell P. Chen B. H. Kim and R. Rajaratnam J. Am. Chem. Soc. 1997 119 8795. 127 Organometallic chemistry Part (ii) Stoichiometric methods mmmm

ISSN:0069-3030    

DOI:10.1039/oc094105

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

4 Aromatic chemistry By M. JOHN PLATER Department of Chemistry University of Aberdeen Meston Walk Aberdeen UK AB24 3UE 1 Theoretical and structural studies Computational calculations have demonstrated that the D 6) symmetry of benzene is determined by the r-framework and that the p-electrons would cause distortion to a localised D 3) structure.1 An experimental probe supporting this theory is provided by the cyclohexatriene motif 1 which shows alternating double and single bonds in the X-ray single crystal structure. However the excited state 1B 26 owing to a p–p* electron transition is calculated to be almost symmetrical. This suggests that p- bonding in the ground state of 1 which is disrupted in the excited state does indeed cause bond fixation and gives the D 3) structure. 1 2 3 The isomeric syn-2 and anti-bismethano[14]annulenes 3 are known to have di§erent structures and magnetic properties.2 In syn-annulene 2 the p-electrons are delocalised and the C–C double bonds are of nearly equal length.The diamagnetic ring current causes deshielding of the perimeter protons (d\7.4–7.9 ppm) while the signals of the methano bridge protons are shifted upfield (d\0.9 and [1.2 ppm). No ring current is apparent from the chemical shifts of protons in the anti-isomer 3. The perimeter protons occur at d\6.2 ppm and the methano bridge protons at 2.5 and 1.9 ppm. The delocalised and localised structures of syn-2 and anti-3 have now been investigated with common computational methods. Semiempirical PM3 and ab initio RHF/6-31G* methods favour bond localised structures for both isomers whereas MP2/6-31G*//RHF/6-31G* single point calculations favour the delocalised structure for both isomers.These conflicting results illustrate how predictions of delocalised or localised structures should be made with caution. The magnitude and direction of errors for each type of calculation should be considered. The authors conclude that aromatic stabilisation energies of planar p-systems are not altered drastically either by bond localisation or by modest out of plane deformations as long as the p-overlap is maintained. Similarly diamagnetic ring currents decrease only modestly upon bond 129 localisation and disappear only in twisted structures such as 3 in which p-overlap is eliminated. Bond localisation in 2 can occur with a comparatively small loss in energy (6.0 kcal mol~1) and also in benzene (4.3 kcal mol~1) by a simple ‘breathing’ distortion.4 5 6 Molecular mechanics calculations semiempirical calculations and full geometry optimisations have been performed on [14]annulene 4 and on [18]annulene 5.3 The X-ray structure of [14]annulene 4 showed it to be aromatic with C–C bond lengths in the range 1.350 to 1.407Å. However calculations have not reproduced the small bond lengths which are thought to have arisen as a consequence of the small number of reflection data points in the structure refinement. The X-ray structure of [18]annulene 5 shows it to have approximately D 6) symmetry with 1.385Å inner and 1.405Å outer C–C bond lengths confirming the aromatic structure. The bond length di§erence of 0.020Å is much smaller than the value of 0.037Å previously extracted from X-ray data and smaller than the value of 0.052Å from a recent theoretical calculation.It is however well reproduced by BLYP B3LYP and MP2 methods. One important observation of electron correlation calculations on [14]annulene 4 and [18]annulene 5 is that irrespective of the chosen starting symmetry the geometry optimisations invariably gave delocalised more symmetrical structures. This observation casts doubt on the validity of using HF and semiempirical methods for determining relative stabilities of localised and delocalised structures of conjugated molecules. The suitability of RHF/DF methods to predict the structure of annulenes has been demonstrated by calculations on [18]annulene 5.4 The molecular geometry predicted by correlated computations agrees well with the recently determined disordermodelled crystal structure of 5 at 110 K.The use of correlated methods and extensive polarisation functions is necessary to predict the molecular geometry with experimental accuracy. The authors predicted that annulene 6 which is on the border of the breakdown of the Hu� ckel rule would possess significant bond localisation and loss of ring current. Computational calculations have been used to predict the structure of a series of fulvenes 7–9 and fulvalenes 10–15.5 Fulvenes 7–9 were all found to be planar. Pentaheptafulvalene 14 was slightly nonplanar while heptafulvalene 15 was predicted to have an anti-folded C 2) structure in accord with X-ray crystal structure data. Calculations predict that the unknown smallest fulvalene 10 is destabilised with localised bonding and that triapentafulvalene 11 is stabilised with delocalised electrons in line with Hu� ckel theory.1,4-Biphenylenequinone 17 was generated by teatment of 16 with Et 3 N.6 Its antiaromatic character precluded isolation; only the dimer 18 was obtained. It could be intercepted by cyclopentadiene to give the two isomers 19 and 20 (Scheme 1). 130 M. John Plater H Br O O 16 O O 17 O O O 18 O O O O + i ii 19 20 O Scheme 1 Reagents i Et 3 N rt; ii cyclopentadiene 7 8 9 10 11 12 13 14 15 Alkali metal reduction of 1,3,5,7-tetra-tert-butyl-s-indacene 21 with lithium or potassium metal gives the corresponding dianions [(Li`) 2 (212~)(thf) 4 ] 22 and [(K`) 2 (212~)(18-crown-6) 2 ] 23.7 The 1HNMRchemical shifts for the methine protons of [(Li`) 2 (X2~)(thf) 4 ] 22 are d\6.77 and 8.28ppm for the C-2,6 and C-4,8 positions respectively.These protons are significantly deshielded in comparison to the corresponding shifts in the starting material 21 (d\5.29 and 6.90 ppm respectively) probably owing to an increase in the ring current. The 13C NMRsignals for dianion 22 are significantly shielded (d\103.7 108.4 111.7 122.8) compared to those of the starting material (d\124.9 129.1 132.0 164.3 ppm) also owing to the increased electron 131 Aromatic chemistry O2N N NO2 NO2 NHTs O2N NO2 NO2 – O2N NO2 NO2 H 27 28 i 26 Scheme 2 Reagents i NaH THF heat But But But But 21 M But But But But 22 M = Li 23 M = K 2– 2M+ H H 24 25 – density. The crystal structure of the indacene dianion [(Li`) 2 (212~)(OEt 2 ) 2 (thf) 2 ] (prepared by recrystallisation of dianion 22 from diethyl ether) reveals a planar structure in which each lithium cation is bonded symmetrically to all five carbon atoms of the terminal indacene rings.The average Li–C bond length is 2.34Å. This contrasts with most previous metal s-indacene complexes in which the metal is bonded o§-centre from the centroid five-membered ring. Computational calculations on dianion 22 show good agreement for bond lengths and angles compared with the experimental data. The gas phase acidity of benzocyclopropene 24 has been measured experimentally and calculated as *H0 !#*$ \386 kcal mol~1.8 This is only 4 kcal mol~1 more acidic than the value for toluene and 34.5 kcal mol~1 more acidic than that for cyclopropene. However the benzocyclopropene anion 25 is significantly more stable than the benzyl anion in solution.This is explained by the greater electronegativity of the methylene carbon owing to the greater percentage of s character and owing to the diminished importance of delocalisation in solution owing to solvation. The anion 25 is calculated to show more bond fixation than benzocyclopropene 24 as shown in the canonical form drawn for compound 25. This may be to avoid an unfavourable 4p interaction in the three-membered ring. The cyclopropenyl anion 28 was calculated to have a triplet ground state 74 kJ lower in energy than the lowest single state.9 The precursor trinitrotriphenylcyclopropene 27 132 M. John Plater 29 30 31 • • 32 i i Scheme 3 Reagent i hl was prepared by decomposition of the tosylhydrazone 26 (Scheme 2). However all attempts to form the anion 28 by treatment of precursor 27 with either potassium hydride and 18-crowlithium tetramethylpiperidide or BunLi were unsuccessful.Irradiation of hydrocarbon 29 in methyltetrahydrofuran at 89K generates the coloured species 30 but the EPR spectrum gave no signals assignable to a triplet.10 However irradiation of hydrocarbon 31 under the same conditions gave a persistent species 32 whose EPR spectrum was diagnostic for a randomly orientated triplet (Scheme 3). This is the first Kekule� hydrocarbon with a triplet ground state observed at 89 K and is representative of an exciting new class of high spin molecules. R1 R1 R1 R1 33a R1 = CN 33b R1 = H hn heat R1 R1 R1 R1 34a 34b The thermal transformation of a strained paracyclophane into the corresponding Dewar isomer has been observed for the first time.11,12 Irradiation of Dewar isomer 33a at 365nm in isopentane–diethyl ether at 77K gave the [4]paracyclophane 34a which was su¶ciently stable at[50 °C to allow its 1HNMRspectrum to be recorded.When the mixture was thawed briefly warmed to room temperature and recooled to 77K a nearly quantitative thermal conversion back to Dewar isomer 33a had occur- 133 Aromatic chemistry Cl Cl Cl Cl Cl Cl 35 Cl Cl Cl Cl 36 Cl OH Cl Cl CH3 38 37 i Scheme 4 Reagents i Bu5OK DMSO rt red. The half-life of paracyclophane 34a was determined as 15^5 min at[20 °C. Treatment of metacyclophane precursor 35 with Bu5OK in DMSO gave two products 37 and 38 along with some polymeric material presumably via the strained intermediate 7,14-dichloro[1.1]metacyclophane 36 (Scheme 4).13 The parent compound [1.1]metacyclophane still remains elusive.Compound 36 was studied in the hope that it might have greater thermal stability. The strained compounds 39 and 40 have unusually long C–C bond lengths. Compound 39 has a C–C bond length of 1.720(4)Å and compound 40 has long C–C bond lengths of 1.710(5)Å and 1.724(5)Å. These are the longest C–C bond lengths reliably determined to date. However semiempirical calculations underestimate the long C–C bond length of 39 by 0.05Å showing the inadequacy of these methods. Discrepancies between experiment and theory on the long bond lengths in compounds 39 and 40 Ph Ph Ph Ph Cl Cl 39 Ph Ph Ph Ph Ph Ph Ph Ph Cl Cl Cl Cl 40 O O Me Me Me 41 have now been resolved by the use of full geometry optimisations based on Hartree –Fock and density functional theory.14 Becke’s 1988(B) and his three parameter hybrid (B3) functionals incorporating exact exchange were used as gradient-corrected density functionals in combination with the Lee Yang and Parr (LYP) correlation functional in the calculation.Good agreement between experimental and theory is obtained by these methods which include electron correlation e§ects. The X-ray crystal structure of dimer 41 has long C–C bond lengths of 1.602(7)Å and 1.649(6)Å holding it together.15 The dimer undergoes a rapid degenerate [3,3] Cope rearrangement in solution. These may be the longest C–C bond lengths determined for a molecule that can dissociate in solution. 134 M. John Plater NNH2 H2NN 42 i I I 43 44 ii I NC NC I 46 NC NC iv NC NC 45 NC NC Li But NC NC But Li + 47 49 CN NC X But CN NC But X 48a X = Li 48b X = H 50a X = Li 50b X = H v iii Scheme 5 Reagents i I2 Et3 N; ii dicyanoacetylene 100 °C 96 h; iii ButLi; iv 1,2-dimethylenecyclopentane; v ButLi 3,4-Dicyanotricyclo[4.2.2.2]dodeca-1,3,5,7,9,11-hexaene 45 was generated by treatment of the diiodo precursor 44 with tert-butyllithium in THF at [78 °C.16 The cleaving bonds in precursor 44 are ideally disposed antiperiplanar to each other.The formation of products 48b and 50b was explained by the addition of ButLi to intermediate hexaene 45 followed by electrocyclic ring opening to the lithio species 48a and 50a and subsequent protonation (Scheme 5). Cycloadduct 46 was formed by interception of hexaene 45 with dimethylenecyclopentene. Tetradehydrodianthracene (TDDA) 51 reacts with tetrazines 52 at 20 °C in CH 2 Cl 2 in a 1 1 molar ratio to give the monoadducts 53a–d (Scheme 6).17 The unsubstituted tetrazine also forms the 2 1 products 54a–d with each of the adducts 53a–d under the same conditions.Cycloaddition of TDDA 51 with a-pyrone and 1,2-diazine gives Kammermeierphane 1 58 via the loss of either CO 2 or N 2 to give intermediate 57 followed by electrocyclic ring opening (Scheme 7).18 The X-ray crystal structure of compound 58 shows that the bridging ethene unit is syn with respect to the two bridging quinoid double bonds. This is in agreement with a thermochemically allowed 135 Aromatic chemistry 51 N N N N R R R R + N2 N N N N R R H H N N N N H H 53a R = H 53b R = CH3 53c R = CO2CH3 53d R = CF3 54a R = H 54b R = CH3 54c R = CO2CH3 54d R = CF3 52 N N Scheme 6 ring opening of diene 57.Irradiation of Kammermeierphane 1 58 and TDDA51 with a 150W high-pressure mercury lamp leads directly to cyclophane 60 of molecular formula C 60 H 36 via ring opening of the initially formed 2]2 adduct 59. The two butadiene units have the s-trans configuration. According to AM1 calculations the s-cis/s-trans and s-cis/s-cis configurations are not possible for steric reasons. The dimensions of the cavity are calculated to be 7.9]4.8Å. Treatment of dibromo bicyclooctene-annelated benzene 61 with BunLi at[78 °C in THF generated the aryne 62 which gave the cycloadduct 63 in the presence of furan and the dimer 64 in the absence of an intercepting reagent (Scheme 8).19 Decomposition of the diazonium carboxylate 65 in refluxing dichloroethane gave none of the dimer 64 but a low yield of the acridone 66.Dimer 64 showed a reversible oxidation wave at E 1@2 \]0.33V versus a ferrocene–ferricenium couple indicating the formation of a stable radical cation. The anthracene derivative 67 also showed a low oxidation potential at E 1@2 \]0.21 V.20 Pronounced stabilisation results from inductive hyperconjugative and steric e§ects of the bicyclo[2.2.2]octene framework. Coloured solutions of the radical cations were generated by treatment with NO`SbCl 6 ~ in CH 2 Cl 2 . The radical cations could be isolated and gave the same EPR spectrum upon redissolution in CH 2 Cl 2 . 68a 68b S S Me S S Me 9-Methyl-2,11-dithia[3.3](1,4)triphenylenometacyclophane was synthesised as a mixture of syn-68a and anti-68b isomers.21 The major isomer was confirmed as the syn-isomer 68a owing to the upfield shift of the methyl group of the anti-isomer 68b to 136 M.John Plater O O 55 O O 51 N N N N 56 57 –CO2 –N2 58 H H 59 51 / hn 60 Scheme 7 d 0.85 ppm. The cyclisation reaction was kinetically controlled as calculations suggested that the anti-isomer 68b was the more stable isomer. Treatment of tetrachlorocyclopropene 70 with 6 equivalents of the lithio carbanion of the bisarylmethanes 69a–e in THF–DMSO at 0 °C followed by aerial oxidation gave the corresponding radialenes 71a–e (Scheme 9).22 These were isolated as stable crystalline solids. The X-ray crystal structure of radialene 71e showed that the three radialene alkenes were all in the same plane. 137 Aromatic chemistry N CO2 N + – Br Br i ii O 63 62 61 64 65 D N O H 67 66 Scheme 8 Reagents i BunLi; ii furan R R 69a R = H 69b R = Br 69c R = I 69d R = CO2Me 69e R = CN i ii iii R R R R R R Cl Cl Cl Cl 70 71a–e Scheme 9 Reagents i CH 3 SOCH 2 Li THF–DMSO; ii 70; iii O 2 0 °C 2 Fullerene fragments Fullerene fragments are generally di¶cult to form by pyrolysis of unfunctionalised polycyclic aromatic hydrocarbons.A study of the pyrolysis of halogenated benzo[c] phenanthrenes 72a–e was therefore carried out by the author.23 They were expected to 138 M. John Plater R4 R3 R2 R1 72a R1 = H R2 = H R3 = H R4 = Cl 72b R1 = Cl R2 = H R3 = H R4 = Cl 72c R1 = F R2 = H R3 = H R4 = Cl 72d R1 = Cl R2 = H R3 = H R4 = I 72e R1 = F R2 = H R3 = H R4 = F R3 R2 R1 73a (53%) 73b 73c 73b 73c (38%) (46%) (75%) (23%) 72e (32%) X –X 72 X = halogen –HX –H 74 75 73 FVP 950–1150 °C • Scheme 10 undergo easier ring coupling reactions by the generation of a reactive intermediate such as an aryradical 74 or benzyne 75 at the ring coupling site (Scheme 10).Each benzo[c]phenanthrene contains a halogen in the hindered fiord region. Flash vacuum pyrolysis gives the corresponding benzo[ghi]fluoroanthenes 73a–c far more easily than by pyrolysis of the parent compound benzo[c]phenanthrene. This model study has now been exploited for the synthesis of larger fullerene fragments. Pyrolysis of 6,12,18-tribromobenzo[c]naphtho[2,1-p]chrysene 76 gave the ring coupled half-bowl 77 by three consecutive ring coupling reactions.24 The ring coupling reactions could either proceed by the elimination of HBr to generate a benzyne as in the above model study or by fragmentation of a carbon–bromine bond followed by a 1,2-hydrogen shift to give an aryl radical at the ring coupling position.Pyrolysis of the dibromo precursor 78 gave C 27-semibuckminsterfullerene 79 by two consecutive ring coupling reactions (Scheme 11).25 Pyrolysis of 7,10-bis(2-bromophenyl)benzo[k]fluoranthene 80 gave bucky bowl 81 by four ring coupling reactions.26 The crystal structure of the fullerene shaped hydrocarbon 82 has been obtained.27 The bowls have a depth of 3.107Å and radius of 4.068Å. The bowls are stacked inside each other and are all aligned in one direction with the non-symmetric space group R 3#. 139 Aromatic chemistry Br Br Br 76 77 1050 °C N2 mbar Br Br 1150 °C N2 0.5 mm 78 79 80 81 Br Br 1100 °C 82 Scheme 11 140 M. John Plater 3 Molecular boards The soluble polycyclic molecular boards 86 and 87 were prepared by the cycloaddition of bis-dienophile 83 with cyclopentadienones 84 and 85 respectively.28 Compound 87 is probably the largest fully characterised polycyclic aromatic hydrocarbon known to date.Compound 87 is green with j.!9 \611nm and compound 86 is red with j.!9 \582 nm. R R R R R R O R R O CO2R CO2R R R R R R R R R R R R R R R R R CO2R CO2R CO2R CO2R 83 84 85 86 87 Cycloaddition of the arylacetylenes 88 91 and 94 with tetraarylcyclopentadienones 97a or 97b gave the corresponding polyaromatic compounds 89 92 and 95 respectively (Scheme 12).29–31 Treatment of the unsubstituted precursors 89a 92a and 95a with Cu(CF 3 SO 3 ) 2 and AlCl 3 gave some of the cyclodehydrogenated polycyclics 90a 141 Aromatic chemistry 88 R R R R R R R R R R R R R R R R 91 R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R R O R2 R1 R1 R2 R 89a R = H 89b R = Bu t 90a R = H 90b R = Bu t 92a R = H 92b R = Bu t 93a R = H 93b R = Bu t 95a R = H 95b R = Bu t 94 96a R = H 96b R = Bu t 97a R1 = R2 = H 97b R1 = H R2 = Bu t i ii ii i i ii Scheme 12 Reagents i 97a or b Ph 2 O 250 °C; ii CuCl 2 AlCl 3 CS 2 rt or FeCl 3 CH 2 Cl 2 rt 142 M.John Plater C6H13 C6H13 C6H13 C6H13 C6H13 C6H13 C6H13 C6H13 C6H13 C6H13 C6H13 C6H13 99 C6H13 (RO)2B C6H13 Br 98a R = H 98b R = –C(CH3)2C(CH3)2– i Scheme 13 Reagents i [PdMP(o-tol) 3N3 ] Na 2 CO 3 toluene * RO RO O O RO O O O O RO + OR OR O O + RO O OR O O i i 100a R = C12H25 100b R = (Pri)3Si 102a R = CH3 102b R = n-C12H25 103a,b 101a,b O Scheme 14 Reagents i toluene basic alumina * 143 Aromatic chemistry OH CHO CHO HO OR RO + H2N NH2 105 104 O O RO RO N M N O OR RO RO RO RO OR O N M N O O O OR OR N M N O RO OR OR OR OR RO M N N M N etc.etc. 106 Scheme 15 93a and 96a respectively whose presence was shown by laser-desorption time-of-flight mass spectrometry (LD-TOF-MS). Cyclodehydrogenation of the tert-butyl substituted precursors 89b 92b and 95b with FeCl 3 in CH 2 Cl 2 gave some of the desired polycyclic boards 90b 93b and 96b respectively along with some chlorinated products. Presumably loss of the solubilising tert-butyl groups might also occur under these conditions. The novel cyclodehydrogenated products were too insoluble to obtain 1H NMR spectra. The driving force for smooth cyclodehydrogenations is probably the production of a stable conjugated polycyclic aromatic hydrocarbon from a more energetic strained oligophenylene precursor.144 M. John Plater The soluble macrocyclic oligophenylene 99 was prepared by Suzuki cross-coupling of the bromo boronic acids 98a–b (Scheme 13).32 This and related compounds are of interest for their aromaticity host–guest chemistry aggregation behaviour and for further molecular construction. [5] and [6]Helicenebisquinones 101a–b and 103a–b were prepared by the reaction of enol ethers of 1,4-diacetylbenzene 100a–b or 2,7-diacetylnaphthalene 102a–b with p-benzoquinone (Scheme 14).33 The yields are greatly improved over those obtained from the use of diethenyl aromatics which have no alkoxy groups either on the double bond or have the alkoxy groups on the aromatic ring.The helicenes can be made in quantity (30 g scale) which is a great improvement over previous small scale photochemical syntheses. A conjugated helical ladder polymer 106 was prepared by condensation of helicene 104 with ortho-phenylenediamine 105 (Scheme 15).34 Conjugation is maintained by the novel metal salophen units that bind adjacent helicenes. Evidence for the polymeric structure was provided by the TOF mass spectrum of the nickel containing polymer which consisted of clusters of peaks whose first members (at m/z 1890 2900 3910 and 4917) are separated by 1010 Da which is the mass of the repeat unit C 58 H 66 NiO 10 of the polymer. 4 Polyyyne chemistry The chemistry of cyclic polyynes and of substructures of graphyne 107 and graphdiyne 108 are attracting considerable interest.35,36 Hexaethynyltribenzocyclynes 109a,b were prepared and converted to the circularly conjugated oligophenylenes 110a,b and 111a,b by treatment with [CpCo(CO) 2 ] in refluxing xylene.35 Complete ring closure to the as yet unknown circular phenylene 112 did not occur.Circulene 112 is of interest owing to its 4n electron count or antikekulene structure. The substructures 116a,b of graphdiyne 108 were prepared by the selective deprotection of acetylenes 113a,b palladium catalysed coupling with 1,2,4,5-tetraiodobenzene followed by ring closure under Eglington coupling conditions (Scheme 16).36 Treatment of precursors 113a,b under standard Eglington coupling conditions with potassium carbonate gave the precursors 117a,b by a one-pot selective desilyation–dimerisation reaction which were then cyclised to the [32]annulenes 118a,b (Scheme 17).37 A series of bicyclo[2.2.2] octene fused dehydroannulenes 121–126 were prepared from acetylene precursors 119 and 120 by copper or palladium catalysed coupling reactions.38 The X-ray crystal structure of annulene 122 showed that the system was planar while that of annulene 126 was tub-shaped like that of cyclooctatetraene.The 1H NMR signal for the bridgehead proton of the BCO unit in annulene 122 indicated diatropic ring current. [2.2.2]Metacyclophane-1,9,17-triyne128 was prepared by bromination of triene 127 followed by dehydrobromination with ButOK in diethyl ether (Scheme 18).39 Triyne 145 Aromatic chemistry R R R R R R R R R R R R R R R R 109a R = Pr 109b R = CH2C6H11 110a R = Pr 110b R = CH2C6H11 111a 111b 112 R R 146 M.John Plater R SiMe3 SiPri 3 113a R = Bu t 113b R = Dec n I I I I i 114 R R R R R R R R R R R R 115a R = Bu t 115b R = Dec n 116a R = Bu t 116 b R = Dec n ii iii Scheme 16 Reagents i KOH [Pd(PPh 3 ) 3 ] [Pd(PPh 3 ) 3 Cl 2 ] CuI Et 3 N; ii Bu 4 NF; iii Cu(OAc) 2 pyridine 147 Aromatic chemistry SiMe3 SiPri 3 113a R = Bu t 113b R = Dec n R SiPri 3 117a R = Bu t 117b R = Dec n R SiPri 3 R i R R R R ii iii 118a R = Bu t 118b R = Dec n Scheme 17 Reagents i Cu(OAc) 2 K 2 CO 3 pyridine; ii Bu 4 NF; iii Cu(OAc) 2 pyridine i ii iii 127 128 129 Scheme 18 Reagents i Br 2 HCCl 3 rt; ii ButOK Et 2 O *; iii cyclopentadiene 148 M. John Plater H Br 119 H 120 H 122 123 124 125 126 121 149 Aromatic chemistry But But H H But But 130 But But But But But But But But But But But But 131a n = 0 131b n = 1 131c n = 2 n i Scheme 19 Reagents i CuCl TMEDA acetone O 2 128 is a fairly stable colourless crystalline substance whose structure was solved by X-ray crystallography.The average sp bond angle was 158.6° similar to that of cyclooctyne (158.5°). Triyne 128 reacts at room temperature with cyclopentadiene to give the bis-adduct 129. Octaalkynyldibenzooctadehydro[12]annulenes131a–c were prepared by Eglington coupling of hexaethynylbenzene 130 (Scheme 19).40 Compound 131a is a stable yellow crystalline solid. The higher homologues 131b,c were obtained as an inseparable mixture. 1,3,5/2,4,6 Di§erentiality functionalised hexaethynylbenzene derivatives 133 and 134 were prepared by palladium catalysed coupling of 4-bromonitrobenzene and 4- dimethylaminophenylacetylene with derivative 132 respectively (Scheme 20).41 These compounds could lead to new discotic liquid crystals and may exhibit second order non-inear optical properties.PhS SPh PhS PhS SPh PhS SPh SPh SPh PhS 135 PhS SPh PhS PhS SPh PhS SPh PhS SPh PhS SPh SPh SPh PhS 136 150 M. John Plater Et3Si SiEt3 SiEt3 Br NO2 NO2 NO2 NO2 i Et3Si SiEt3 SiEt3 Br Br Br NMe2 i H Et3Si SiEt3 SiEt3 NMe2 Me2N NMe2 134 133 132 Scheme 20 Reagents i (PPh 3 ) 2 PdCl 2 CuI Pr* 2 NH Diacetylene linked nanoscale poly(phenylsulfonyl)-substituted benzenes 135 and 136 are of interest as reducible molecular wires for the development of molecular and supramolecular electronic and photonic devices.42 They may serve as connectors between components and may possess novel non-linear optical properties owing to extended p-conjugation.The nanoscale molecular wires 140 were prepared by a novel iterative coupling strategy (Scheme 21).43 This involved dividing the precursor 137 into two portions. In one portion the triazene was converted to an aryl iodide 138 and in the other portion the silylacetylene was deprotected to give 139. The two portions were then mixed and coupled. The selective deprotection and coupling was repeated to give longer chains. The synthesis was also carried out on solid phase. 151 Aromatic chemistry Et2N3 R SiMe3 I R SiMe3 Et2N3 R H Et2N3 R SiMe3 137 n = 1 2 4 8 ii i iii 2 n n 139 138 140 n n Scheme 21 Reagents i MeI; ii K 2 CO 3 or BunN 4 N; iii Pd(dba) 2 CuI References 1 A. Shurki and S. Shaik Angew. Chem. Int. Ed. Engl. 1997 36 2205.2 M. Nendel K. N. Houk L. M. Tolbert E. Vogel H. Jiao and P. Rague Schleyer Angew. Chem. Int. Ed. Engl. 1997 36 748. 3 C. Ho Choi and M. Kertesz J. Am. Chem. Soc. 1997 119 11 994. 4 K.K. Baldridge and J. S. Siefel Angew. Chem. Int. Ed. Engl. 1997 36 745. 5 A.P. Scott I. Agranat P. U. Biedermann N. V. Riggs and L. Radom J. Org. Chem. 1997 62 2026. 6 H. Kilic and M. Balci J. Org. Chem. 1997 62 3434. 7 D.R. Cary J. C. Green and D. O’Hare Angew. Chem. Int. Ed. Engl. 1997 36 2618. 8 L. Moore R. Lubinski M. C. Baschky G. D. Dahlke M. Hare T. Arrowood Z. Glasovac M. Eckert- Makisc and S. R. Kass J. Org. Chem. 1997 62 7390. 9 J. Klicic Y. Rubin and R. Breslow Tetrahedron 1997 53 4129. 10 D. R. McMasters and J. Wirz J. Am. Chem. Soc. 1997 119 8568. 11 M. Okuyama M. Ohkita and T. Tsuji Chem.Commun. 1997 1277. 12 M. Okuyama and T. Tsuji Angew. Chem. Int. Ed. Engl. 1997 36 1085. 13 M.J. van Eis F. J. J. de Kanter W. H. de Wolf and F. Bickelhaupt J. Org. Chem. 1997 62 7090. 14 C. Choi and M. Kertesz Chem. Commun. 1997 2199. 15 M.J. Plater D. M. Schmidt and R. A. Howie J. Chem. Res. (S) 1997 390. 16 T. Tsuji M. Okuyama M. Ohkita T. Imai and T. Sukuki Chem. Commun. 1997 2151. 17 J. Sauer J. Breu U. Holland R. Herges H. Neumann and S. Kammermeier Liebigs Ann. 1997 1473. 18 S. Kammermeier P. G. Jones and R. Herges Angew. Chem. Int. Ed. Engl. 1997 36 2200. 152 M. John Plater 19 A. Matsuura T. Nishinaga and K. Komatsu Tetrahedron Lett. 1997 38 4125. 20 A. Matsuura T. Nishinaga and K. Komatsu Tetrahedron Lett. 1997 38 3427. 21 Y. Lai Y. Yong and S. Wong J. Org. Chem.1997 62 4500. 22 T. Enomoto T. Kawase H. Kurata and M. Oda Tetrahedron Lett. 1997 38 2693. 23 M.J. Plater J. Chem. Soc. Perkin Trans. 1 1997 2903. 24 S. Hagen M. S. Bratcher M. S. Erickson G. Zimmermann and L. T. Scott Angew. Chem. Int. Ed. Engl. 1997 36 406. 25 G. Mehta and G. Panda Chem. Commun. 1997 2081. 26 M.D. Clayton and P. W. Rabideau Tetrahedron Lett. 1997 38 741. 27 D.M. Forkey S. Attar B. C. Noll R. Koerner M.M. Olmstead and A. L. Balch J. Am. Chem. Soc. 1997 119 5766. 28 B. Schlicke A. Dieter-Schluter P. Hauser and J. Heinze Angew. Chem. Int. Ed. Engl. 1997 36 1996. 29 V. S. Iyer M. Wehmeier J. Diedrich Brand M.A. Keegstra and K. Mullen Angew. Chem. Int. Ed. Engl. 1997 36 1604. 30 F. Morgenroth E. Reuther and K. Mullen Angew. Chem. Int. Ed. Engl. 1997 36 631. 31 M. Muller V.S. Iyer C. Kubel V. Enkelmann and K. Mullen Angew. Chem. Int. Ed. Engl. 1997 36 1607. 32 V. Hensel K. Lutzow J. Jacob K. Gessler W. Saenger and A. Dieter Schluter Angew. Chem. Int. Ed. Engl. 1997 36 2654. 33 T. J. Katz L. Liu N. D. Willmore J. M. Fox A. L. Rheingold S. Shi C. Nuckolls and B. H. Rickman J. Am. Chem. Soc. 1997 119 10 054. 34 Y. Dai and T. J. Katz J. Org. Chem. 1997 62 1274. 35 C. Eickmeier H. Junga A. J. Matzger F. Scherhag M. Shim and K. P. C. Vollhardt Angew. Chem. Int. Ed. Engl. 1997 36 2103. 36 M.M. Haley S. C. Brand and J. J. Pak Angew. Chem. Int. Ed. Engl. 1997 36 836. 37 M.M. Haley M.L. Bell S. C. Brand D. B. Kimball J. J. Pak and W. Brad Wan Tetrahedron Lett. 1997 38 7483; M. M. Haley M.L. Bell J. J. English C. A. Johnson and T. J. R. Weakley J. Am. Chem. Soc. 1997 119 2956; M.M. Haley and B. L. Langsdorf Chem. Commun. 1997 1121. 38 T. Nishinaga T. Kawamura and K. Komatsu J. Org. Chem. 1997 62 5354. 39 T. Kawase N. Ueda and M. Oda Tetrahedron Lett. 1997 38 6681. 40 Y. Tobe K. Kubota and K. Naemura J. Org. Chem. 1997 62 3430. 41 J. E. Anthony S. I. Khan and Y. Rubin Tetrahedron Lett. 1997 38 3499. 42 M. Mayor J. M. Lehn K.M. Fromm and D. Fenske Angew. Chem. Int. Ed. Engl. 1997 36 2370. 43 L. Jones J. S. Schumm and J. M. Tour J. Org. Chem. 1997 62 1388. 153 Aromatic chemistry mmmm

ISSN:0069-3030    

DOI:10.1039/oc094129

出版商:RSC    

年代:1998

数据来源: RSC

摘要:

O O O O O Ph OCH3 O Ph OCH3 O O O (i) 76% ee = 91% 2 1 Scheme 1 Reagents (i) Oxone' 1 K 2 CO 3 MeCN Na 2 B 4 O 7 ·10H 2 O (0.05 M) 5 Heterocyclic chemistry By ANDREW MARSH Department of Chemistry University of Warwick Coventry UK CV4 7AL This review covers the chemistry of heterocyclic compounds published during 1997. The subject is divided according to ring size and further grouped according to reaction type or nature of the heterocycle to guide the reader through the diverse material covered. 1 Three-membered rings Asymmetric synthesis is an important theme within this and other areas of heterocyclic chemistry. Dioxiranes continue to be investigated for the stereocontrolled epoxidation of alkenes. Ketone 1 was used to epoxidise 2 with good enantioselectivity in a catalytic process although pH was found to be a key factor in determining the e¶ciency of conversion (Scheme 1).1 That dioxiranes are the active agents in ketonecatalysed epoxidations with Oxone' has been confirmed by careful 18O-labelling studies.2 A novel method for the generation of this useful class of reagents uses arenesulfonylimidazoles and hydrogen peroxide in the presence of the ketone usually acetone (Scheme 2).3 Yields of epoxidations carried out using this in situ generation of dimethyldioxirane were good and this may be a useful method when more valuable ketones are used.It has been found that poly-(L)-leucine will epoxidise enones with good enantioselectivity in the presence of urea and hydrogen peroxide (Scheme 3).4,5 Another important class of enantioselective oxidants are sulfonyloxaziridines and an improved method for their synthesis using hydrogen peroxide has been reported.6 155 O O O (i) Scheme 2 Reagents (i) ArSO 2 imidazole H 2 O 2 NaOH Ph Ph O O Ph H H Ph O (i) 85% er > 97:3 Scheme 3 Reagents (i) poly-(L)-leucine urea H 2 O 2 DBU (1.2 equivs.) THF r.t.3 h R O R O H H (i) 60–95% Scheme 4 Reagents (i) Et 2 Zn (2 equivs.) ICH 2 Cl (2 equivs.) tetrahydrothiophene (3 equivs.) Ph CH3 Mn O Ph CH3 X Ph CH3 O H H Mn O X Mn O Ph CH3 Path A Path B + reductive elimination collapse Path A Path B Path B Scheme 5 A novel application of Simmons–Smith reagents is the synthesis of terminal epoxides. 7,8 This process relies upon the generation of a sulfur ylide from tetrahydrothiophene which then reacts with an aliphatic or aromatic aldehyde to give epoxides (Scheme 4).The mechanism of the Jacobsen–Katsuki epoxidation has attracted some controversy9 and whilst there are a number of possible pathways by which it may proceed the simplest (Path A; Scheme 5) now appears to be favoured.10 Direct proof of the postulated manganese(V) oxo complex has also been o§ered.11 Aziridine precursors to 3 are now available in enantiomerically pure form by a number of routes. A problem with their application in organic synthesis has been the removal of the group used to activate their ring opening by nucleophiles. The use of nitroarenesulfonyl (nosyl) aziridines 3 alleviates this problem; cleavage was e§ected with thiophenol in good yield (Scheme 6).12 Some novel heterospirocyclic 3-amino-2H-azirenes 4 have been used as synthons for heterocyclic a-amino acids and incorporated into model tripeptides (Scheme 7).13 156 A.Marsh N R O2S NO2 R Nu HN NO2 R Nu H2N (45–99%) (i) (46–99%) (ii) R = Me R = Ph 3 Scheme 6 Reagents (i) NuH; (ii) PhSH K 2 CO 3 MeCN X O N Ph X N N Ph X NH S N Ph O Ph (i) (ii) (iii) (iv) 4 Scheme 7 Reagents (i) LDA THF 0 °C; (ii) DPPCl THF 0 °C; (iii) NaN 3 THF r.t. 3 days; (iv) PhCOSH CH 2 Cl 2 S Ar Ar CO2Me MeO2C O Ar Ar Ar Ar S CO2Me CO2Me H NHPh Ar Ar S CO2Me NHPh H CO2Me + + + (i) 5 6 Scheme 8 Reagents (i) phenyl azide 80 °C Diastereomeric thiiranes 5 and 6 were produced in the three-component reaction of a thioketone dimethyl fumarate and phenyl azide (Scheme 8).14 2 Four-membered rings Multi-component couplings such as the Ugi reaction used to generate b-lactams 7 continue to be investigated since they potentially allow considerable diversity to be introduced rapidly into a molecular framework (Scheme 9).15 A polymer-supported b-lactam 8 has been reported as an intermediate in the synthesis of 4-amino-3,4- dihydroquinolin-2(1H)-ones (Scheme 10).16 In the continued study of cyclisations onto the anomeric centre of glycosidic rings bicyclic oxetanes have been obtained through the closure of silyl enol ethers such as 9 in the presence of diethylaluminium chloride (Scheme 11).17 A four-membered ring which underwent an unusual base-induced reaction was thiazetidine 10.Treatment with sodium hydride gave the ring expanded 11 which could be trapped with dimethyl sulfate leading to 12 or allowed to react further to give 13 (Scheme 12).18 157 Heterocyclic chemistry Ph CHO Ph N CONH c-C6H11 R O Cl Ph N R O CONH c-C6H11 (i) (ii) 7 Scheme 9 Reagents (i) ClCH 2 CO 2 H c-C 6 H 11 NC RNH 2 ; (ii) KOH MeOH NH O R1 N O2N R2 NH O R1 N OR3 O NO2 R2 NH O R2 HN R3O R1 O (i) (ii) 8 Scheme 10 Reagents (i) R3OCH 2 COCl triethylamine,CH 2 Cl 2 ; (ii) SnCl 2 DMF r.t.O SO2 Ph O TIPSO O O But OTBDMS O TIPSO O O O H H CO2But O TIPSO O O O H H CO2But 4 (i) 1 9 Scheme 11 TIPS\triisopropysilyl. Reagents (i) Et 2 AlCl r.t. An even more exotic four-membered heterocycle was produced in excellent yield when phosphorous substituted 2H-azirine 14 was exposed to light (Scheme 13). The azirine had been made by the unprecedented cycloaddition reaction of a carbene to a nitrile.19 3 Five-membered rings The use of tandem palladium-catalysed cross-couplings and base-mediated cyclisations has been extended to the synthesis of a number of classes of heterocycles.In particular ring closures leading to indoles have been reported by several authors. The cyclisation of oxygen-substituted aromatic o-tert-butoxycarbonylaminoalkynes 15 158 A. Marsh S NH O O O S N O O O R N S O O O NH S O O O N S O O O R CH3 CH3 R R N S O O O R R HN O H (i) (ii) (iii) (43–91%) (iv) 11 10 12 13 Scheme 12 Reagents (i) NaH RCH 2 Br; (ii) NaH DMF 0 °C; (iii) MeOSO 2 OMe [20 °C; (iv) 0 °C P SiMe3 R R N P SiMe3 R R Ph P N R R SiMe3 Ph (i) R = ( c-C6H11)2N 98% 85% (ii) 14 Scheme 13 Reagents (i) PhCN 25 °C; (ii) hm NHBoc RO TMS NH RO 15 (i) 70–79% Scheme 14 Reagents (i) ButOK ButOH took place e¶ciently in the presence of potassium tert-butoxide (Scheme 14).20 This augments previous work which had demonstrated a concise synthesis of indole derivatives using similar chemistry.Tetramethylguanidine was the base of choice to e§ect closure of amide 16 on solid phase resin (Scheme 15),21 but when a more potent electron withdrawing group such as trifluoroacetamide is used the cyclisation becomes possible in the presence of potassium carbonate in dimethylformamide.22 Sodium hydride was used for the cyclisation of a related series of trifluoroacetamides on solid phase resin.23 An alternative disconnection was used to make indoles 17 on Rink amideAMresin this time through closure of iodoaromatic 18 using palladium(II) (Scheme 16).24,25 This strategy also featured in the asymmetric Heck-type cyclisation of iodide 19 or triflate 20 in the presence of an (R)-BINAP palladium(0) catalyst to give 21 with impressive 159 Heterocyclic chemistry NH TMS I NH O CH3 O CH3 N O CH3 (i) in situ 16 Scheme 15 Reagents (i) Pd(PPh 3 ) 2 Cl 2 CuI dioxane tetramethylguanidine I X O HN X CONH2 18 X = O NH (i) (ii) 17 Scheme 16 Reagents (i) PdII; (ii) CF 3 COOH N O RO X CH3 N CH3 OR O 19 X = I 20 X = OTf (i) 45–76% ee = 43–95% 21 Scheme 17 Reagents (i) Pd0-(R)-BINAP (10 mol%) 1,2,2,6,6-pentamethylpiperidine N,N-dimethylacetamide 100 °C selectivity (Scheme 17).26 The enhanced enantioselectivity observed by the addition of halide salts gave some additional mechanistic insight.Two groups have independently developed the cyclisation of propargyl tosyl carbamates 22 (propargyl\prop-2-ynyl) (Scheme 18) using palladium(0)27 or palladium(II) catalysis in the presence of potassium tert-butoxide.28 Similar yields were obtained in either case.The closure of a carboxylic acid function onto an alkyne gave butenolide products 23 (Scheme 19) in the presence of either tetrakis(triphenylphosphine)palladium or even silver nitrate in methanol which led to the synthesis of rubrolides A C,Dand E.29 The competing formation of a six-membered ring was found to be catalyst dependent. A one-pot procedure for the preparation of functionalised pyrazoles has been reported using a palladium dichloride-mediated ring closure (Scheme 20).30 The investigation of alternatives to organotin-promoted radical cyclisations continues to be an active area of research. An example of a radical cyclisation leading to benzofuran and indole products has been described using trialkylmanganate initiation 160 A.Marsh NHTs O H R1 R2 NTs O O R1 R2 O Ar ArI (i) 22 Scheme 18 Reagents (i) either Pd(PPh 3 ) 4 K 2 CO 3 DMF 60 °C (50–80%) or Pd(OAc) 2 But OK CH 3 CN 25 °C (46–76%) COOH Ph Ph O O Ph O O Ph Ph Ph + catalyst solvent PdCl2(PhCN)2 CH3CN 50% 44% Pd(PPh3)4 CH3CN 83% 6% AgNO3 CH3OH 95% 5% 23 Scheme 19 N NH2 Ts NH N Ar ArX + (i) (ii) (iii) 28–69% Scheme 20 Reagents (i) Pd(OAc) 2 (PPh 3 ) 2 Et2 NH THF r.t.; (ii) PdCl 2 MeCN 90 °C; (iii) ButOK DMF r.t. O O I (i) 88% Scheme 21 Reagents (i) Bun3 MnLi or Bun3 MnMgBr (Scheme 21).31 A catalytic variant was also reported through the addition of manganese( II) chloride to a Grignard reagent in the presence of oxygen leading to 70% yield vs. 88% for the stoichiometric reaction. A review covering the synthesis of heterocycles by radical cyclisation has been published.32 The use of dipolar cycloadditions in the controlled synthesis of five-membered heterocycles has produced a number of particularly striking results.An azomethine ylide is implicated33 in the unusual process shown in Scheme 22. Heating b-lactam- 161 Heterocyclic chemistry N CO2R H O N CO2R H O R R N O CO2R O (i) 32% + via 24 25 Scheme 22 Reagents (i) MeCN heat O N O CH3 Bn O SiMe3 O N Bn CH3 SiMe3 N Bn O SiMe3 O OH O (i) (ii) 39–67% 26 27 Scheme 23 Reagents (i) Ac 2 O 70 °C 1 h; (ii) 125 °C 3 h N CH3 O O NH Ph HO O N NMe O O O Ph R2Si O N O O O Ph NMe O R2Si (ii) 30 (i) 29 28 Scheme 24 Reagents (i) hl quartz MeCN; (ii) HF MeCN 0 °C based azolidinone 24 in the presence of an alkene gave compound 25; other 1,3- dipolarophiles were also used.34,35 Azomethine ylides e.g.26 have been cyclised onto a tethered alkene which after elimination of carbon dioxide gave bicyclic pyrroles 27 in moderate yields (Scheme 23).36A silicon-tethered variant allows the temporary connection of the 1,3-dipole and dipolarophile.37 Hence in this work a mu� nchnone was generated from the corresponding aziridine 28 which led to the formation of 29 (Scheme 24). Removal of the tether allowed cyclisation to the pyrrolidine 30. The diasterofacial selectivity of the process was controlled by the length of the tether with shorter tethers leading to the desired endo-re adduct. Intramolecular nitrone cycloadditions have been used to generate heterocycles e.g. 31.38 The dipolarophile was generated by extrusion of sulfur dioxide from sulfolene (2,5-dihydrothiophene 1,1-dioxide) 32 (Scheme 25).The type of complex molecule which can be rapidly constructed using an intramolecular nitrone cycloaddition is illustrated by 33 (Scheme 26). This isoxazolidine was formed cleanly upon heating epoxide 34 in toluene.39 An intramolecular dipolar cycloaddition under mild conditions has been used to access pyrrolidine N-oxides in a diastereoselective fashion (Scheme 27).40 162 A. Marsh S O2 S(O) xPh O H S(O) xPh N+ R O– N O H H S(O) xPh R n = 1 2 x = 0 2 (i) (ii) 60–73% 31 32 ( ) n ( ) n Scheme 25 Reagents (i) RNHOH·HCl (R\Me R\Bn) MeONa r.t.; (ii) PhMe 95 °C N OH O N O– OH N O OH H (i) 90% 33 34 Scheme 26 Reagents (i) xylene 140 °C N O H Ph PhSO2 N PhSO2 Ph O– N PhSO2 Ph O– + 88 12 (i) >95% Scheme 27 Reagents (i) CHCl 3 20 °C 96 h N Ph O– CH3 N O Ph H3C X H X (i) X = CN SO2Ph CO2Et Scheme 28 Reagents (i) MeCN reflux (X\CN 100%; X\CO 2 Et 91%; X\SO 2 Ph 92%) Analogues of cocaine have been produced using pyridinium betaine-based dipolar cycloadditions.Regiochemical control in the cycloaddition was reasonable although diastereoselection was not as good. In the case where the electron withdrawing group X was a nitrile (Scheme 28) the a-isomer was isolated in 42% yield compared with 37% for the b-isomer with the other regioisomers totalling 21%.41 The regioselectiv- 163 Heterocyclic chemistry N O Me2N Me N2 O CO2Me O N O Me Me2N CO2Me N O Me2N Me MLn O CO2Me N N O Me CO2Me O Me Me O MeO2C CO2 Me CO2Me N Me Me N O Me O Me2N CO2 Me CO2Me CO2Me 35 (i) (iv) (ii) 37 38 (iii) or (iv) 36 Scheme 29 Reagents (i) Rh 2 (OAc) 4 ; (ii) PhMe reflux (65–70%); (iii) DMAD; (iv) DMAD Rh 2 (OAc) 4 O N O N2 CO2Et O O Ph H O N O CO2Et O Ph H N O O O R O N O CO2Et O Ph H N O O O R (i) R = Me 54% 20% R = Ph 56% 24% 39 + Scheme 30 Reagents (i) Rh 2 (OAc) 4 (1 mol%) dipolarophile PhH reflux ity for the addition of the corresponding enantiomerically pure vinyl sulfoxide dienophile was found to be complete and the b-isomer was isolated in 44% yield.42 Isomu� nchnones have been used in the preparation of a variety of five-membered rings.Interestingly the isolation of a stable N-acylammonium ylide 35 allowed the elucidation of its X-ray crystal structure. Reaction of isolated 35 with dimethyl acetylenedicarboxylate (DMAD) gave 36. In the presence of DMAD and dirhodium tetraacetate however the isomu� nchnone 37 is formed and reacts with the dipolarophile to give after the loss of methyl isocyanide the highly substituted oxazole 38 along with the product of the other pathway 36 (Scheme 29).These observations allowed the preparation of a stable yet dipolarophile-reactive isomu� nchnone.43 The addition of dipolarophiles to the isomu� nchnone derived from 39 gave moderate selectivity (Scheme 30).44 In the case of the [3]2] cycloaddition of the 1,3-dipoles derived from 40 the diastereofacial selectivity was found to depend upon the nature of the stereogenic centre and exo-selectivity was enhanced by the inclusion of substituents at any position of the five-membered ring betaine (Scheme 31).45 164 A. Marsh O R3 N R2 O N2 R1 O +O N R3 O O R1 R2 N B A O O R2 R3 COR1 (i) (ii) 40 Scheme 31 Reagents (i) Rh2`; dipolarophile (A–– B) heat O O H H OH (i) 70% 41 Scheme 32 Reagents (i) c-Hex 2 BH PhH cat.2,6-di-tert-butyl-4-methylphenol re- flux O Si R O Si R O R R1 O R R1 + 91–95% (i) (ii) 73–84% 75 25 dr > 42 43 Scheme 33 Reagents (i) (PCy 3 ) 2 RuCl 2 (––CHPh) CH 2 Cl 2 r.t.; (ii) R1CHO Lewis acid CH 2 Cl 2 An intramolecular Diels–Alder approach to a number of bicyclic systems including trans-fused tetrahydrofurans 41 has been reported (Scheme 32).46 The key steps are addition of dicyclohexylborane and thermolysis in benzene followed by oxidation. The remarkable diastereofacial selectivity of this process was rationalised through the involvement of boron in the transition state. A diastereoselective route to functionalised tetrahydrofurans has been reported through the Lewis-acid promoted addition of aldehydes to conformationally controlled seven-membered allylsilanes 42.47 These compounds were produced through ring closing metathesis of dienes 43 with the now commercialised Grubbs’ catalyst (Scheme 33).Other saturated heterocycles have been produced by a variety of other carbon –heteroatom ring closures. A biomimetic haloetherification gave tetrahydrofuran 44 which was an intermediate in the synthesis of trans-(])-deacetylkumausyne (Scheme 34).48 Closure of 45 by very brief exposure to potassium tert-butoxide (Scheme 35) was found to give pyrrolidine 46 an intermediate in this enantiospecific synthesis of (])-monomorine.49 A change of plan was required in the total synthesis of the enantiomer of the furanocembrane rubifolide.50 Due to the failure of a planned enynol cyclisation a new strategy emerged based on the cyclisation of the macrocyclic allene 47 (Scheme 36).In the event this was achieved in a very respectable yield and taken further to demon- 165 Heterocyclic chemistry HO OTIPS OTHP O BrOTIPS OTHP O H H (i) then (ii) 79% 44 Scheme 34 Reagents (i) as Scheme 33; (ii) HCl MeOH PhSO2 OAc NHAc N Bz PhSO2 (i) 46 45 73% Scheme 35 Reagents (i) ButOK ButOH,\1 min • CH3 H O MOMO H3C MeO2CO O MOMO H3C (i) 89% 47 Scheme 36 Reagents (i) AgNO 3 SiO 2 strate the absolute stereochemistry of rubifolide. An unusual 1,2-silyl migration led to the stereoselective intramolecular addition of an alcohol to a vinylsilane. The thermodynamic product of this rearrangement 48 was obtained in good yield and excellent diastereoselectivity (Scheme 37).51 A succinct route to stereodefined oligotetrahydrofurans has been reported.52 Lewisacid promoted addition of a furan to 49 gave after reduction of the double bonds a 60 40 mixture of the erythro and threo isomers 50 and 51 respectively (Scheme 38).After suitable derivatisation this was repeated and an array of conformationallycontrolled tetrahydrofurans was rapidly generated. When organic chemists use Hu� nig’s base (diisopropylethylamine 52) they do so usually because they want an unreactive nitrogen base. In the presence of disulfur dichloride and 1,4-diazabicyclo[2.2.2]octane (DABCO) however the isopropyl 166 A. Marsh HO R SiMeR1R2 O R SiMeR1R2 34–93% >99:1 trans cis (i) 48 Scheme 37 Reagents (i) TiCl 4 CHCl 3 r.t. O O O C10H21 OTBDMS OAc C10H21 OTBDMS O O O C10H21 OTBDMS O (ii) 92% (i) + O OTMS 50 51 49 Scheme 38 Reagents (i) TiCl 4 (cat.); (ii) H 2 Pd/C N S N S S S S S S N S S S S S S (i) 40% (ii) 52 53 54 Scheme 39 Reagents (i) S 2 Cl 2 DABCO ClCH 2 CH 2 Cl; (ii) heat groups (only) become functionalised in a remarkable synthesis of di[1,2]dithiolopyrroles 53 (Scheme 39).53 The initial product is a di[1,2]dithiolo[1,4]thiazine 54 which was characterised by X-ray crystallography.Variation of the solvent and reaction time allowed selective replacement of the thiocarbonyl with an oxygen atom. It was noted that whatever the precise mechanism of this conversion it requires some 15 (very high yielding!) separate steps.54 Methods for the formation of heterocycles on solid supports55 are of current interest especially for the rapid production of pharmaceutical analogues.56 Substituted thiophenes 55 have been prepared from intermediate resin-bound isothiocyanates (Scheme 40).57 In an example of a resin-bound [3]2] cycloaddition reaction to an intermediate nitrile oxide the formation of isoxazoles 56 from alkynes 57 was monitored by the loss of the acetylenic C–H stretch in the infrared spectrum (Scheme 41).58 At the end of a sequence carried out on a polymer support a rearrangement analogous to an ‘aspartamide’ reaction seen in peptides takes place after cleavage from the resin.Prolonged treatment of 58 with trifluroacetic acid–water (9 1) gave succinimide 59 (Scheme 42).59 Methods for the cyclisation of peptidic substrates to generate diversity have also been reported including the reduction of amide bonds with borane then cyclisation with carbonyldiimidazole to 60 (Scheme 43)60 and the reduction of ester 61 followed by cyclisation (Scheme 44).61 167 Heterocyclic chemistry S R2 O N R1 H Z NH2 N H CN S O R2 Z R1 (iv) (v) 55 N H H R1 (i) (ii) (iii) Scheme 40 Reagents (i) CSCl 2 Pr* 2 NEt; (ii) ZCH 2 CN DBU DMF; (iii) R2CH 2 Br; (iv) DBU; (v) CF 3 COOH O O O2N OTHP O O N O R (i) PhNCO 56 57 Scheme 41 Reagents (i) PhH reflux Et 3 N (cat.) S O NH H2N O SBn O NHBn S O NH NBn O O BnS (i) 90% 58 59 Scheme 42 Reagents (i) CF 3 COOH–H 2 O 9 1 or 1% conc.HCl MeOH N O HN O NH R3 R4 O R1 R2 N N R4 X NH R1 R2 (i) (ii) (iii) X = O S 60 Scheme 43 Reagents (i) B 2 H 6 THF 65 °C; (ii) carbonyldiimidazole or thiocarbonyldiimidazole; (iii) HF anisole Ion exchange resins have proven useful as temporary supports for the formation of a variety of heterocycles and one example is the synthesis of pyrrolidine-2,4-diones 62 by Amberlyst base-mediated Dieckmann condensation (Scheme 45).62 Imidazoles e.g.63 have been made in a useful synthesis from the addition of monosubstituted amidines to 2-halo-3-alkoxyprop-2-enals and propionitriles (Scheme 46).63 Although the yields were modest there was no evidence of competing pyrimidine formation under the cyclisation conditions. An intramolecular entry to imidazoles was possible in good to excellent yield through the treatment of 64 with methyl iodide and base or oxidation under basic conditions (Scheme 47).64 This method also allows access to unusual 4,4-disubstituted imidazoles. The synthesis of benzisoxazoles 65 was achieved through dehydration of nitroaromatics 66 with trimethylsilyl chloride and triethylamine (Scheme 48).65 Following abstraction of the benzylic proton the ring closure and dehydration to form the 168 A.Marsh R NH NH OAlkyl X R1 O NH N X R R1 H X = O S 64–93% (i) (ii) 61 Scheme 44 Reagents (i) Bu*2 AlH PhMe–CH 2 Cl 2 [78 °C; (ii) H 3 O` O RO N R2 O R3 R1 N O R1 R2 HO R3 (i) (ii) 62 Scheme 45 Reagents (i) Amberlyst A-26 (OH~); (ii) H` NH R1 NHR2 N N R2 R1 X N N R2 R1 X OR Br X + X = CHO X = CN 63 8 1 2 9 Scheme 46 Reagents (i) K 2 CO 3 H 2 O CHCl 3 N N S R2 R4 R3 R1 N N R1 R2 R4 R3 (i) or (ii) or (iii) 64 Scheme 47 Reagents (i) H 2 O 2 MeOH; (ii) I 2 Et 3 N; (iii) MeI base NO2 Y R O N Y R (i) 20–71% Y = CN SO2Ar CO2R1 66 65 Scheme 48 Reagents (i) Me 3 SiCl Et 3 N DMF 169 Heterocyclic chemistry NC NC NH3•OTs R O OH N O CN NH2 R (i) 67 22–86% Scheme 49 Reagents (i) dicyclohexylcarbodiimide pyridine HN N R2 O R1 N HN NH R2 O R1 CN HN NH2 R1 (i) (ii) (iii) 35–62% 39–95% 68 Scheme 50 Reagents (i) BrCN Et 2 O; (ii) R2COCl Et 3 N; (iii) heat N N N N R N N N N R N3 CHO 78–95% (i) (ii) 27–95% 69 70 71 Scheme 51 Reagents (i) RCH 2 CN piperidine or NaOEt CH 3 CN 0 °C; (ii) RCH 2 CN piperidine or NaOEt in EtOH O MeO2C SPh O MeO2C SO2Ph (i) 85% 72 Scheme 52 Reagents (i) m-CPBA oxazole is facilitated by silylation of an oxygen atom of the nitro group.Highly functionalised 1,3-oxazoles 67 have been synthesised in a one-pot procedure from aminomalononitrile tosylate (Scheme 49).66 A sigmatropic rearrangement of 1-aryl-2-acyl-2-cyanohydrazines led to a convenient synthesis of benzimidazole derivatives 68 (Scheme 50).67 Addition of cyanocarbanions to 2-azidoarylaldehyes 69 has been found to give either 1,2,3-triazolo[1,5-a]- quinazolines 70 or tetrazolo[1,5-a]quinazolines 71 in aprotic or protic solvents respectively (Scheme 51).68 In protic solvents initial Knoevenagel condensation of the anion with the aldehyde is believed to take place followed by an intramolecular 1,3-dipolar cycloaddition.In the absence of a proton source however reaction across the azide takes place first followed by closure onto the aldehyde. 2-Alkylthiopyrroles have been prepared by metallation of allyl isothiocyanate using LDA followed by alkylation. A second equivalent of base in the form of potassium tert-butoxide was found to be necessary to promote the isomerisation to the prod- 170 A.Marsh NH Cbz Pr N Pr Cbz N Pr H (i) (ii) 52% 98% 74 73 Scheme 53 Reagents OsO 4 NaIO 4 ; (ii) H 2 Pd/C Ts O NH2 N O Ts H (i) (ii) 75 Scheme 54 Reagents (i) NaH DMF; (ii) Br(CH 2 ) 3 Br N O CHO R N O H OSiR3 N O H OSiR3 + (i) 1 76 + 1 Scheme 55 Reagents (i) Ni(cod) 2 (20 mol%) PPh 3 (40 mol%) R 3 SiH (5 equivs.) THF uct.69 A direct synthesis of tetrazoles has been found to be possible from aryl primary amides using triazidochlorosilane in acetonitrile.70 Intramolecular cyclisation of alkynone 72 was promoted by an electron-withdrawing group attached to the unsaturated bond. Thus oxidation of the sulfide to a sulfone with m-CPBA led to the formation of a furan in excellent yield (Scheme 52).69 4 Six-membered rings Many saturated six-membered nitrogen heterocycles have important biological activity which is one reason why methods for their synthesis are pursued with such interest.The alkaloid coniine 74 has been synthesised in enantiomerically pure form by the cyclisation of protected amine 73 onto the aldehyde derived from oxidative cleavage of the alkene (Scheme 53).71 A one-pot synthesis of another class of alkaloid namely indolizidine derivatives has been developed from vinyl sulfone 75 (Scheme4).72 A formal total synthesis of the indolizidine alkaloid ([)-elaeokanine C was accomplished using the novel nickel-promoted cyclisation of aldehyde 76 with a 1,3-diene (Scheme 55).73 The ring closure of a urethane derivative 77 was found to occur in the presence of palladium(II) to give a single diastereoisomer 78 in good yield.This was then transformed into (])-prospinine (Scheme 56).74 Two-step four-component 171 Heterocyclic chemistry HN O MOMO O H OCOPh N O H OCOPh H O (i) 72% 77 78 Scheme 56 Reagents (i) PdCl 2 (CH 3 CN) 2 (20 mol%) THF r.t. OTMS EtS R1 R2 O SEt N R3 O R4 R1 R2 O SEt + + (i) (ii) SEt R3 O R1 R2 NHR4 O SEt + R3 N R4 79 Scheme 57 Reagents (i) SbCl 5 –Sn(OTf) 2 CH 2 Cl 2 ,[78 °C; (ii) Sc(OTf) 3 ,[78 to 0 °C O BnO CH3 H H OH OH O H H OH O BnO H CH3 H (i) 42–52% 80 Scheme 58 Reagents (i) Pd(OAc) 2 HOAc CH 2 Cl 2 couplings led to the formation of d-lactams 79 in good yield. The first process is a Lewis-acid catalysed Michael addition followed by an imino–aldol reaction catalysed by a second Lewis acid (Scheme 57).75 Following the failure of a planned tungsten-mediated ring closure the enantioselective formation of bicyclic oxygen heterocycle 80 a substructure of the marine poison brevetoxin was carried out using palladium(II) catalysis in moderate yield (Scheme 58).76Aring-closing metathesis reaction has also been used to access this bicyclic motif (Scheme 59) as well as larger rings from the same class of natural products.77,78 The Grubbs ruthenium catalyst was found not to be e§ective in this instance.Hydroboration then allows the process to be repeated. The isomerisation of the double bond produced from the ring closing metathesis reaction of 81 will similarly also allow an iterative process to be carried out (Scheme 60).79 The compatibility of the Grubbs and Schrock metathesis catalysts with sulfur functionality has been demonstrated through the formation of cyclic disulfides.80 172 A.Marsh O O R2 R1 O O H H R1 R2 O O H H R1 OH H R2 (i) + diastereomer (ii) (iii) 41–67% Scheme 59 Reagents (i) Schrock [Mo] cat. C 5 H 12 25 °C; (ii) RBH 2 ; (iii) NaOH H 2 O 2 O O BnO OMe BnO O O H H OMe OBn OBn (i) 81 93% Scheme 60 Reagents (i) (PCy 3 ) 2 RuCl 2 (––CHPh) PhMe r.t. O R CO2 Me O OAc R CO2 Me Me3Si O OAc R CO2 Me SiMe3 O R CO2 Me (i) dr > 95:5 (i) dr > 89:11 82 83 Scheme 61 Reagents (i) BF 3 ·OEt 2 or SnCl 4 The geometry of the vinylsilane moiety was found to strongly influence the boron trifluoride-induced cyclisation of 82 or 83 to cis- or trans-dihydropyrans respectively (Scheme 61).81 Cycloaddition reactions naturally play a central role in the synthesis of many classes of heterocycles. Trifluoromethanesulfonic acid was found to be an e¶cient catalyst in the hetero Diels–Alder reaction of aldehydes (Scheme 62).82 Enantioselective catalysis was observed using a range of oxazolidine ligands (e.g.84 85) in the copper(II)- mediated hetero Diels–Alder reaction of Danishefsky’s diene 86 with aldehyde 87 (Scheme 63).83 The product stereochemistry was 2S from 84 (85% ee) and 2R from 85 (87% ee). Ytterbium triflate was used to promote the cycloaddition of N-acryloyl dienophile 88 with 89 with excellent diastereoselectivity (Scheme 64).84–86 The generation of ortho-thioquinones has allowed a regiospecific synthesis of 1,4-benzoxathiines through an inverse electron-demand Diels–Alder reaction (Scheme 65).87 173 Heterocyclic chemistry O R O R + (i) 5–85% Scheme 62 Reagents (i) 80% HOTf (1 mol%) PhMe 20 °C TMSO OCH3 O S S O S S O H N N O O N N O O (i) 5–85% + 84 85 86 87 Scheme 63 Reagents (i) Cu2` ligand (10 mol%) S Ph Ph O O N O Ph S Ph Ph O O N O Ph + (i) > 99% de 88 89 Scheme 64 Reagents (i) Yb(OTf) 3 (20 mol%) OH S NPhthalimido Y S O Y + Y = OR SR OSiR3 NCOR Ar (i) CH3O CH3 O 58% Scheme 65 Reagents (i) pyridine CHCl 3 60 °C 50 h 3-Methoxy-6-methylthio-1,2,4,5-tetrazine has been prepared and found to undergo a regioselective [4]2] cycloaddition based on the electron-rich character of the dienophile (Scheme 66).88 2-Aminopyridines and 2-pyridones have been accessed through the reaction of benzotriazole-substituted nitriles 90 with unsaturated ketones (Scheme 67).89 Intermolecular Diels–Alder reactions of tetrazines have been carried out with silyl- 174 A.Marsh Ph OTMS N N N N OCH3 SCH3 N N OCH3 SCH3 + (i) 90% Scheme 66 Reagents (i) dioxane 100 °C 20 h O Ph R N Bt N R NR1 R2 Ph HN R O Ph + (i) (ii) 90 Scheme 67 Reagents (i) R1R2NH EtOH; (ii) NaOH EtOH N N N N R1 R2 N N R1 R2 N N Ar (i) + (ii) 51–93% R1 = SnBu3 R2 = H 76% 91 92 Scheme 68 Reagents (i) toluene r.t.12 h; (ii) ArX Pd(PPh 3 ) 4 germyl- and stannyl-substituted alkynes leading to the synthesis of synthetically useful metallated 1,2-diazines 91. These were readily cross-coupled under palladium(0) catalysis to give aryl substituted diazines 92 (Scheme 68).90 The synthesis of a pyridine ring through the intramolecular addition of an oxazole to a dienophile was found to proceed in good yield leading to the first chiral synthesis of the alkaloid ([)-normalindine (Scheme 69).91 The intramolecular Diels–Alder reaction of furan 93 was found to take place upon silica gel chromatography–an example of exceptionally mild Lewis acid catalysis in such a process (Scheme 70).92 The oxidation of nitrogen heterocycles is a well established process but two interesting examples have appeared in the literature.Firstly a highly stereoselective formation of pipecolic acid N-oxide was possible by simple oxidation of amine 94 with m-CPBA (Scheme 71).93 Secondly the sterically congested monochloro-1,10-phenanthroline di-N-oxide 95 long believed to be inaccessible has been prepared (Scheme 72) and found to be stable under neutral or basic conditions.94 The production of abasic sites in nucleosides is one method for inducing DNA cleavage and the self-cleaving nucleoside 96 seems to be able to do just that (Scheme 73).95 The supramolecular structure of the complex of the unusual boron heterocycle 97 with cytosine has been investigated using 1H NMR titration in acetonitrile and indicated Watson–Crick-like base pairing as the most likely mode of association.96 The conformation adopted by a heterocyclic molecule has potential for the induction of higher order structure in polymers for example and 98 has been found to be helical in solution as well as the solid state.97 175 Heterocyclic chemistry NH N Me O N CO2Et NH N N EtO2C Me NH N N EtO2C Me O (i) (ii) 40% (18%) Scheme 69 Reagents (i) heat; (ii) HOAc heat O HO O S O O OCH3 S O OCH3 OHC O O S OCH3 O (i) 31% (ii) 60–80% 93 Scheme 70 Reagents (i) LiBr PhMe reflux 10 min; (ii) SiO 2 N Ph CO2R N CO2 R Ph O– N CO2 R Ph O– (i) 53% + 94 R = H R = Me R = Bu t 100 8.5 25 1 1 1 Scheme 71 Reagents (i) m-CPBA CH 2 Cl 2 ,[78 °C N N Cl N N Cl Cl N N Cl Cl –O –O N N Cl –O (i) (ii) –O (iii) 95 Scheme 72 Reagents (i) NaOCl; (ii) m-CPBA,[25 °C; (iii) Pr*ONa 0 °C 176 A.Marsh N N N N N H O O P O O O O DNA N N N+ N N H O O P O O O O DNA I N N N N N H I O O DNA O OH + (ii) (i) DNA DNA DNA Scheme 73 Reagents (i) I 2 ; (ii) H 2 O N NH NH2 H3C S N OH H3C N N NH2 H3C S N O H3C H N N H3C N NH S CH3 OH Cl– Cl– (i) (ii) 100 99 101 Scheme 74 Reagents (i) NaBH(OCH 3 ) 3 [12 °C MeOH–H 2 O; (ii) Na 2 CO 3 H 2 O heat N N B O H H O N N ribose N H H 97 N N N N N N N N N 98 177 Heterocyclic chemistry N N Br OCH3 N N R3Sn OCH3 (i) 85–91% 102 Scheme 75 Reagents (i) R 3 Sn–SnR 3 Pd(PPh 3 ) 4 DME 15 h 80 °C N Cl Cl NH NH2 PhSO2 CO2Me CO2Me H N Cl Cl N NH O CO2Me PhSO2 N Cl Cl N N O Et (i) (ii) 53–65% steps + 103 104 105 Scheme 76 Reagents (i) HCl DMF; (ii) NaHCO 3 EtO O HN OEt N N NH2 NH2 N N HN N O NH2 + (i) 80% 106 107 Scheme 77 Reagents (i) EtOH reflux 2 h The reduction of vitamin B 1 thiamine 99 with borohydride reducing agents has apparently been the subject of long-standing controversy.The publication of the X-ray crystal structures of the initial reduction product 100 and the product of rearrangement with base and heat 101 corrects previous mis-assignments (Scheme 74).98 The generation of organotin intermediates often involves a two-step lithiation procedure but direct stannylation of bromopyridines such as 102 has been found to be possible with the aid of palladium(0) catalysis (Scheme 75).99 The pyrimidinone herbicide 103 resisted attempts at its synthesis by the usual methods and required the development of a new route involving the addition of amidine 104 to the extremely active Michael acceptor 105 (Scheme 76).100 178 A.Marsh O O NEt2 G O G O (i) 60–93% 109 108 Scheme 78 Reagents (i) LDA (2.4 –3.3 equivs.) THF 0 °C N OH S S N Cl O N CN S N CN + (i) or (ii) 110 111 112 Scheme 79 Reagents (i) NaH THF reflux 111 112 55 5 (44%); (ii) PPh 3 (2 equivs.) CH 2 Cl 2 reflux 111 112 0 100 (58%) N S N R O CN N N S O H R N N S O O O F3C R CN O CF3 (i) 35% 113 via Scheme 80 Reagents (i) (CF 3 CO) 2 O CH 2 Cl 2 0 °C N O O SO2Ph N2 N SO2Ph O Me HO SO2Ph + (i) 68% 114 Scheme 81 Reagents (i) Rh 2 (OAc) 4 dipolarophile Pteridinones such as 106 have been conveniently prepared with complete regioselectivity from diamines through the addition of ethoxycarbonylformimidate 107 (Scheme 77).101 The lithiation of 108 gives a regiospecific route to xanthen-9-ones 109 (Scheme 78).102 Chemoselective cyclisation of 110 was observed to give either 111 or 112 depending on whether sodium hydride or triphenylphosphine was used for the cyclisation (Scheme 79).103 An unusual ring-enlargement reaction of 113 with trifluoroacetic anhydride has been found to give rise to novel 5,6-dihydro-2H-1,2,4-thiadiazin-3(4H)-ones (Scheme 80).104 Rhodium(II) carbenoid chemistry has found new application in the synthesis of 2-pyridones such as 114 via an isomu� nchnone intermediate (Scheme 81).105 A range of pyrimidines including the amino acid L-lathyrine has been prepared by the addition of amidines to acetylenic ketones 115 (Scheme 82).106 A similar reaction has also been reported on a polymeric support (Scheme 83).107 179 Heterocyclic chemistry N N X R CO2 H NH2 O R CO2But NHBoc H2N NH2 X n n + (i) (ii) (iii) 115 28–95% X– Scheme 82 Reagents (i) EtOAc or MeCN Na 2 CO 3 H 2 O (cat.) reflux; (ii) CF 3 COOH anisole; (iii) Dowex 50X8-100 ion-exchange resin S NH2 NH2 O R COOBut S N N COOH R Cl– + (i) (ii) Scheme 83 Reagents (i) Pr*2 NEt DMF 24 h r.t.; (ii) CF 3 COOH (50%) CH 2 Cl 2 r.t.15 h O X X HO RO RO RO RO X = S NBoc (i) X = S 91% ee = 89% 116 117 Scheme 84 Reagents (i) chiral lithium amide base PhH 5 °C 1 h NH R N R O R2 NH O R2 R (i) (ii) 73–85% 2 steps 118 Scheme 85 Reagents (i) (R2CO) 2 O Et 3 N DMAP CH 2 Cl 2 ; (ii) LiHMDS THF [78 °C to r.t.5 Seven-membered rings Seven-membered rings are less common in heterocyclic chemistry but nonetheless a number of novel approaches to their synthesis have been reported. When meso-bicyclic heterocycles such as 116 are treated with a chiral base the result is the enantioselective synthesis of azepines or thiepines 117 (Scheme 84).108 Exposure of aziridines 118 to strong base at low temperature results in a stereoselective aza-[3,3]-Claisen rearrangement giving seven-membered lactams in good yield (Scheme 85).109 Another route to this class of heterocycles is by the ring expansion of ketone 119 via an oxaziridine intermediate (Scheme 86).110 The intramolecular Diels–Alder reaction of oxazoline 120 generated 121 an intermediate in this synthesis of (^)-stemoamide (Scheme 87).111 180 A.Marsh O BocNH N O CO2Me R BocNH H2N CO2 Me R (i) (ii) (iii) + 119 Scheme 86 Reagents (i) Bu 2 SnCl 2 (20 mol%) NaHCO 3 (2 equivs.) 5Å molecular sieves; (ii) m-CPBA; (iii) hl N Me H O N MeO Me O N O Me O O H H (i) (ii) 53% 120 121 Scheme 87 Reagents (i) 182 °C (ii) H 2 O Si O R O Si R n m (i) n m >90% 122 Scheme 88 Reagents (i) (PCy 3 ) 2 RuCl 2 (––CHPh) O O O O O O O O n (i) mixture of geometric isomers n Scheme 89 Reagents (i) (PCy 3 ) 2 RuCl 2 (––CHPh) (5 mol%) Li`/Na`/K` ClO 4 ~ (5 equivs.) 6 Larger rings Ring closing metathesis reactions have dominated the new methods for the synthesis of larger rings. Treatment of acyclic silicon-tethered dienes 122 where n\0–2 and m\0–4 takes place in excellent yield with the ruthenium-based catalyst (Scheme 88).112 A template e§ect was observed in the synthesis of unsaturated crown ether analogues in the presence of monovalent cations of di§erent ionic radii (Scheme 89).113 The mild conditions of this reaction are demonstrated by the closure of 123 to give medium ring annulated b-lactams (Scheme 90).114 Very large [2]catenanes were the 181 Heterocyclic chemistry N O X N X O n n (i) 123 X = CH2 n = 0 81% Scheme 90 Reagents (i) (PCy 3 ) 2 RuCl 2 (––CHPh) (5 mol%) CH 2 Cl 2 N N O O O O O O N N N N Cu2+ (i) (ii) 124 Scheme 91 Reagents (i) (PCy 3 ) 2 RuCl 2 (––CHPh) (5 mol%); (ii) CN~ N N N N H H H H N N N N H H O R O R (i) 40–98% Scheme 92 Reagents (i) RCOCl pH\2–3 N N N N O O O O Ph Ph Ph Ph Eu3+ 125 182 A.Marsh result of the copper(II) templated ring-closing metathesis reaction of 124 using the ruthenium catalyst (Scheme 91).115 The pH-controlled selective protection of polyaza macrocycles has been achieved thanks to the predictable protonation behaviour of the di§erent amine nitrogens in the ring (Scheme 92).116 Finally the complexation properties of large heterocycles are often even more exciting than their synthesis and the phenomenon of chiral luminescence from the rigid europium(III) complex 125 upon irradiation has been demonstrated.117 References 1 Z.X. Wang Y. Tu M. Frohn and Y. Shi J. Org. Chem. 1997 62 2328. 2 S.E. Denmark Z. C. Wu C.M. Crudden and H. Matsuhashi J. Org. Chem. 1997 62 8288. 3 M. Schulz S. Liebsch R. Kluge and W. Adam J. Org. Chem. 1997 62 188. 4 J.V. Allen M.W. Cappi P. D. Kary S. M. Roberts N.M. Williamson and L. E. Wu J. Chem.Soc. Perkin Trans. 1 1997 3297. 5 P.A. Bentley S. Bergeron M. W. Cappi D. E. Hibbs M.B. Hursthouse T. C. Nugent R. Pulido S.M. Roberts and L. E. Wu Chem. Commun. 1997 739. 6 P.C. B. Page J. P. Heer D. Bethell A. Lund E. W. Collington and D.M. Andrews J. Org. Chem. 1997 62 6093. 7 V.K. Aggarwal A. Ali and M. P. Coogan J. Org. Chem. 1997 62 8628. 8 A.H. Li L. X. Dai and V. K. Aggarwal Chem. Rev. 1997 97 2341. 9 T. Linker Angew. Chem. Int. Ed. Engl. 1997 36 2060. 10 N. S. Finney P. J. Pospisil S. Chang M. Palucki R. G. Konsler K. B. Hansen and E. N. Jacobsen Angew. Chem. Int. Ed. Engl. 1997 36 1720. 11 D. Feichtinger and D. A. Plattner Angew. Chem. Int. Ed. Engl. 1997 36 1718. 12 P. E. Maligres M. M. See D. Askin and P. J. Reider Tetrahedron Lett. 1997 38 5253. 13 C. Strassler A.Linden and H. Heimgartner Helv. Chim. Acta 1997 80 1528. 14 G. Mloston J. Romanski A. Linden and H. Heimgartner Helv. Chim. Acta 1997 80 1992. 15 R. Bossio C. F. Marcos S. Marcaccini and R. Pepino Tetrahedron Lett. 1997 38 2519. 16 Y. Z. Pei R. A. Houghton and J. S. Kiely Tetrahedron Lett. 1997 38 3349. 17 D. Craig J. P. Tierney and C. Williamson Tetrahedron Lett. 1997 38 4153. 18 D. Glasl G. Rihs and H. H. Otto Helv. Chim. Acta 1997 80 671. 19 V. Piquet A. Baceiredo H. Gornitzka F. Dahan and G. Bertrand Chem. Eur. J. 1997 3 1757. 20 Y. Kondo S. Kojima and T. Sakamoto J. Org. Chem. 1997 62 6507. 21 M.C. Fagnola I. Candiani G. Visentin W. Cabri F. Zarini N. Mongelli and A. Bedeschii Tetrahedron Lett. 1997 38 2307. 22 S. Cacchi G. Fabrizi F. Marinelli L. Moro and P. Pace Synlett 1997 1363.23 M.D. Collini and J. W. Ellingboe Tetrahedron Lett. 1997 38 7963. 24 H. C. Zhang and B. E. Maryano§ J. Org. Chem. 1997 62 1804. 25 H. C. Zhang K. K. Brumfield and B. E. Maryano§ Tetrahedron Lett. 1997 38 2439. 26 L. E. Overman and D. J. Poon Angew. Chem. Int. Ed. Engl. 1997 36 518. 27 A. Arcadi Synlett 1997 941. 28 D. Bouyssi M. Cavicchioli and G. Balme Synlett 1997 944. 29 M. Kotora and E. Negishi Synthesis 1997 121. 30 S. Cachi G. Fabrizi and A. Carangio Synlett 1997 959. 31 J. Nakao R. Inoue H. Shinokubo and K. Oshima J. Org. Chem. 1997 62 1910. 32 F. Aldabbagh and W. R. Bowman Contemp. Org. Synth. 1997 4 261. 33 S. R. Martel D. Plchenault R. Wisedale T. Gallagher and N. J. Hales Chem. Commun. 1997 1897. 34 D. Planchenault R. Wisedale T. Gallagher and N. J. Hales J. Org.Chem. 1997 62 3438. 35 S. R. Martel R. Wisedale T. Gallagher L. D. Hall M. F. Mahon R. H. Bradbury and N. J. Hales J. Am. Chem. Soc. 1997 119 2309. 36 N. K. Nayyar D. R. Hutchison and M. J. Martinelli J. Org. Chem. 1997 62 982. 37 P. Garner P. B. Cox J. T. Anderson J. Protasiewicz and R. Zaniewski J. Org. Chem. 1997 62 493. 38 S. S. P. Chou and Y. J. Yu Tetrahedron Lett. 1997 38 4803. 39 J. Markandu H. A. Dondas M. Frederickson and R. Grigg Tetrahedron 1997 53 13 165. 40 A. R. Wheildon D.W. Knight and M. P. Leese Tetrahedron Lett. 1997 38 8553. 41 A. P. Kozikowski G. L. Araldi and R. G. Ball J. Org. Chem. 1997 62 503. 42 G. L. Araldi K. R. C. Prakash C. George and A. P. Kozikowski Chem. Commun. 1997 1875. 183 Heterocyclic chemistry 43 C. O. Kappe Tetrahedron Lett. 1997 38 3323.44 R. Angell M. G. B. Drew M. Fengler Veith H. Finch L. M. Harwood A. W. Jahans and T. T. Tucker Tetrahedron Lett. 1997 38 3107. 45 A. Padwa and M. Prein J. Org. Chem. 1997 62 6842. 46 R. A. Batey D. Lin A. Wong and C. L. S. Hayhoe Tetrahedron Lett. 1997 38 3699. 47 J. H. Cassidy S. P. Marsden and G. Stemp Synlett 1997 1411. 48 T. Martin M.A. Soler J. M. Betancort and V. S. Martin J. Org. Chem. 1997 62 1570. 49 M. B. Berry D. Craig P. S. Jones and G. J. Rowlands Chem. Commun. 1997 2141. 50 J. A. Marshall and C. A. Sehon J. Org. Chem. 1997 62 4313. 51 K. Miura T. Hondo H. Saito H. Ito and A. Hosomi J. Org. Chem. 1997 62 8292. 52 B. Figade` re J. F. Peyrat and A. Cave J. Org. Chem. 1997 62 3428. 53 C. F. Marcos C. Polo O. A. Rakitin C. W. Rees and T. Torroba Chem. Commun. 1997 879.54 C. F. Marcos C. Polo O. A. Rakitin C. W. Rees and T. Torroba Angew. Chem. Int. Ed. Engl. 1997 36 281. 55 P. H. H. Hermkens H. C. J. Ottenheijm and D. C. Rees Tetrahedron 1997 53 5643. 56 A. Nefzi J. M. Ostresh and R. A. Houghten Chem. Rev. 1997 97 449. 57 H. Stephensen and F. Zaragoza J. Org. Chem. 1997 62 6096. 58 E. J. Kantorowski and M. J. Kurth J. Org. Chem. 1997 62 6797. 59 J. A. Girdwood and R. E. Shute Chem. Commun. 1997 2307. 60 A. Nefzi J. M. Ostresh J. P. Meyer and R. A. Houghten Tetrahedron Lett. 1997 38 931. 61 J. A. Markwalder R. S. Pottorf and S. P. Seitz Synlett 1997 521. 62 B. A. Kulkarni and A. Ganesan Angew. Chem. Int. Ed. Engl. 1997 36 2454. 63 S. C. Shilcrat M.K. Mokhallalati J. M. D. Fortunk and L. N. Pridgen J. Org. Chem. 1997 62 8449. 64 A. Rolfs and J.Liebscher J. Org. Chem. 1997 62 3480. 65 Z. Wrozbel Synthesis 1997 753. 66 F. Freeman T. Chen and J. B. van der Linden Synthesis 1997 861. 67 M. Carvalho A. M. Lobo P. S. Branco and S. Prabhaker Tetrahedron Lett. 1997 38 3115. 68 T. C. Porter R. K. Smalley M. Teguiche and B. Purwono Synthesis 1997 773. 69 N. A. Nedolya L. Brandsman H. D. Verkruijsse and B. A. Trofimov Tetrahedron Lett. 1997 38 7247. 70 A. A. S. El Ahl S. S. Elmorsy A. H. Elbeheery and F. A. Amer Tetrahedron Lett. 1997 38 1257. 71 C. J. Moody A. P. Lightfoot and P. T. Gallagher J. Org. Chem. 1997 62 746. 72 F. Caturla and C. Najera Tetrahedron Lett. 1997 38 3789. 73 Y. Sato N. Saito and M. Mori Tetrahedron Lett. 1997 38 3931. 74 Y. Hirai J. Watanabe T. Nozaki H. Yokoyama and S. Yamaguchi J. Org. Chem. 1997 62 776. 75 S.Kobayashi R. Akiyama and M. Moriwaki Tetrahedron Lett. 1997 38 4819. 76 M. M. Gleason and F. E. McDonald J. Org. Chem. 1997 62 6432. 77 J. S. Clark and J. G. Kettle Tetrahedron Lett. 1997 38 127. 78 J. S. Clark and J. G. Kettle Tetrahedron Lett. 1997 38 123. 79 M. A. Leeuwenburgh H. S. Overkleeft G. A. van der Marel and J. H. van Boom Synlett 1997 1263. 80 Y. S. Shon and T. R. Lee Tetrahedron Lett. 1997 38 1283. 81 C. Semeyn R. H. Blaauw H. Hiemstra and W. N. Speckamp J. Org. Chem. 1997 62 3426. 82 V. K. Aggarwal G. P. Vennall P. N. Davey and C. Newman Tetrahedron Lett. 1997 38 2569. 83 A. K. Ghosh P. Mathivanan and J. Cappiello Tetrahedron Lett. 1997 38 2427. 84 T. Saito K. Takekawa J. Nishimura and M. Kawamura J. Chem. Soc. Perkin Trans. 1 1997 2957. 85 T. Saito H. Suda M. Kawamura J.Nishimura and A. Yamaya Tetrahedron Lett. 1997 38 6035. 86 T. Saito M. Kawamura and J. Nishimura Tetrahedron Lett. 1997 38 3231. 87 G. Capozzi C. Falciani S. Menichetti and C. Nativi J. Org. Chem. 1997 62 2611. 88 S. M. Sakya K. K. Groskopf and D. L. Boger Tetrahedron Lett. 1997 38 3805. 89 A. R. Katritzky S. A. Belyakov A. E. Sorochinsky S. A. Henderson and J. Chens J. Org. Chem. 1997 62 6210. 90 D. K. Heldmann and J. Sauer Tetrahedron Lett. 1997 38 5791. 91 M. Ohba H. Kubo T. Fujii H. Ishibashi M. V. Sargent and D. Arbain Tetrahedron Lett. 1997 38 6697. 92 F. Ponten and G. Magnusson J. Org. Chem. 1997 62 7978. 93 I. A. O’Neil and A. J. Potter Tetrahedron Lett. 1997 38 5731. 94 R. Antkowiak and W.Z. Antkowiak Tetrahedron Lett. 1997 38 1857. 95 V. Gupta and E. T. Kool Chem.Commun. 1997 1425. 96 M. P. Gorziak L. Y. Chen L. Yi and P. D. Robinson J. Am. Chem. Soc. 1997 119 7817. 97 D.M. Bassani J.-M. Lehn G. Baum and D. Fenske Angew. Chem. Int. Ed. Engl. 1997 36 1845. 98 J. A. Zoltewicz C. D. Dill and K. A. Abboud J. Org. Chem. 1997 62 6760. 99 M. Benaglia S. Toyota C. R. Woods and J. S. Siegel Tetrahedron Lett. 1997 38 4737. 100 E. C. Taylor P. Zhou C. M. Tice Z. Lidert and R. C. Roemmele Tetrahedron Lett. 1997 38 4339. 101 A. McKillop S. K. Chattopadhyay A. Henderson and C. Avendano Synthesis 1997 301. 102 O. B. Familoni I. Ionica J. F. Bower and V. Snieckus Synlett 1997 1081. 103 T. Besson G. Gauillaumet C. Lamazzi and C. W. Rees Synlett 1997 704. 184 A. Marsh 104 T. Tanaka W. Takase X. Fang T. Azuma S. Uchida T. Ishida Y. In and C. Iwata Synlett 1997 316.105 S. M. Sheehan and A. Padwa J. Org. Chem. 1997 62 438. 106 R.M. Adlington J. E. Baldwin D. Catterick and G. J. Pritchard Chem. Commun. 1997 1757. 107 D. Obrecht C. Abrecht A. Grieder and J. M. Villlalgordo Helv. Chim. Acta 1997 80 65. 108 M. Lautens E. Fillion and M. Sampat J. Org. Chem. 1997 62 7080. 109 U.M. Lindstrom and P. Somfai J. Am. Chem. Soc. 1997 119 8385. 110 M. S. Wolfe D. Dutta and J. Aube J. Org. Chem. 1997 62 654. 111 P. A. Jacobi and K. Lee J. Am. Chem. Soc. 1997 119 3409. 112 S. B. Chang and R. H. Grubbs Tetrahedron Lett. 1997 38 4757. 113 M. J. Marsella H. D. Maynard and R. H. Grubbs Angew. Chem. Int. Ed. Engl. 1997 36 1101. 114 A. G. M. Barrett S. P. D. Baugh V. C. Gibson M.R. Giles E. L. Marshall and P. A. Procopiou Chem. Commun. 1997 155. 115 B.Mohr M. Weck J.-P. Sauvage and R. H. Grubbs Angew. Chem. Int. Ed. Engl. 1997 36 1308. 116 Z. Kovacs and A. D. Sherry Synthesis 1997 759. 117 R. S. Dickins J. A. K. Howard C. W. Lehmann J. Moloney D. Parker and R. D. Peacock Angew. Chem. Int. Ed. Engl. 1997 36 521. 185 Heterocyclic chemistry mmmm

ISSN:0069-3030    

DOI:10.1039/oc094155

出版商:RSC    

年代:1998

数据来源: RSC