4 Reaction Mechanisms Part (ii) Free-radical Reactions By S. CADDICK School of Chemistry and Molecular Sciences University of Sussex Falmer Brighton BNI SQJ UK 1 Introduction Research into the development offree-radical processes continues to attract significant interest and many notable advances have been published in the 1993 literature. This year’s highlights will focus on four general themes but there will inevitabIy be some overlap between the areas initiators promoters and mediators; intramolecular reactions; intermolecular reactions; applications of radical processes to synthetic and bioIogica1 chemistry. 2 Initiators Promoters and Mediators Fraser-Reid’ and coworkers have demonstrated the utility of di-t-butylhyponitrite (DBH) as a convenient reagent for the generation of carbon-centred radicals.Many synthetically useful applications have been illustrated; the hydroxymethylation of enone (1) is a particularly good example. MeOH. DBH Reflux. 1Sh. 77% OEt I OEt (1) (2) Given the popularity of the SnBu,H/AIBN system new methods for the generation of tributyltin radicals are of considerable interest. Previous work had examined the utility of bis(trimethy1stannyl)benzopinacolatefor the generation of trimethylstannyl radicals. Two recent reports2v3 demonstrate the ability of bis(tri-n-butylstann-y1)benzopinacolate (3) to generate tributyltin radicals and benzophenone under thermal conditions. Silicon reagents continue to attract interest as promoters; Chatgilialoglu’s group ’ B.Venkateswara Rao J. B. Chan N. Moskowitz and B. Fraser-Reid Bull. SOC.Chim. Fr. 1993 130,428. D.J. Hart R. Krishnamurthy L. M. Pook,and F.L. Seely Tetrahedron Left. 1993 34,7819. M.J. Tomaszewski and J. Warkentin J. Chem. SOC.,Chem. Commun. 1993 1407. 81 S. Caddick has in an interesting report demonstrated that care must be taken when choosing initiators for these reagents. Thus reduction of (5) with tris(trimethylsily1)silane (TTMSS)gave markedly different ratios of products (6) depending on the initiator Z E AIBN 17 83 (PhC02)~ 71 29 used. When AIBN is used the E isomer predominates; initiation using benzoyl peroxide leads to the 2 isomer. Further experiments suggest that AIBN is more efficient as an initiator than benzoyl peroxide when utilizing TTMSS as a radical promoter.The tris(trimethylsify1) radicals can undergo reversible addition to the aIkene to furnish the E alkene. Recently Murphy and coworkers have developed a particularly interesting radical process utilizing tetrathiofulvene (TTF)as a promoter.' Thus treatment of diazonium [oo\R1] R2 BF~A2 t-r) C. Ferreri M. Ballestri and C,Chatgilialoglu Tetrahedron Lett. 1393,34,5147. C. Lampard J.A. Murphy and N.Lewis J. Chem. SOC.,Chem. Comun. 1993,295. Reaction Mechanisms -Part (ii) Free-radical Reactions ion (7) with TTFinmoist solvent leads to the adducts (10).The proposed mechanism of these reactions is electron transfer from the electron donor TTF,to the diazonium speciesto generate anaryl radical (8).Thisthen undergoes cyclization and capture with TTFradical-tion to generate (9),which reactswith water to provide product (10).Intermediate (9) has been characterized and shown to react with methanol and acetonitrile to give products (11) and (12). Rhodiumand ruthenium are also beginning to gain an accepted place in the armoury of reagents used to promote free-radical reactions in synthesis. In a full account Ishibashi et at. have reported the synthesis of the naturally occurringalkaloid skeleton (14) using an interesting chiorine atom transfer cyclization. Giese Hartung et al. have been examining rhodium complexes as alkyl radical precursors.’ Although alkylrhodoximes (15) are much less photoreaciive than the ‘H.Ishibashi,N.Ucmurs H.Nakatani M.Okazaki T.&to N.Nakamura and M.Ikcda J.Org. Chem. 1993.58.2360. ’B.Giese J. Hartung C. Kesselheim H.3. Lindner and I. Svoboda Gem.Ber. 1993,126 1193. S. Caddick corresponding cobaloxime reagents they have been shown to participate in a number of reactions. One of the advantages these stable reagents may have over their cobalt counterparts is the ability to act as precursors to tertiary radicals. Hill and co-workers have been investigating the utiIity of polyoxotungstate photocatalysed radical-addition reactions.8 They have found that secondary and tertiary radicals can be generated from the corresponding alkanes oia C-).I activation. These radicals have been utilized in addition reactions with alkenes and alkynes; the reported yields are high at low conversion rates (<10%).Samarium diiodide continues to attract attention as a useful promoter and numerous synthetic applications have been reported. Many transformations promoted by samarium diiodide require additives such as HMPA or DMPU to proceed efficiently. A highly significant study by Nasegawa and Currangdetails investigations of alkyl/aryl halide and carbonyl group reductions with SmI,.They have shown that water is a safeand convenient alternative to the traditional additives and that in halide reductions water accelerates the rate of the reaction. The origin of the enhancement is unclear but it appears that the water does not act solely as a proton source. 3 Intramolecular Reactions General.-In recent years tin and silicon promoted diene and enyne cyclizations have been shown to be synthetically useful procedures.Recently Sirnpkins and coworkers have reportedlo*l analogous cyclizations using the reagents TolS0,SePh or (Ph),PH. The introduction of usefui functionality into the products as illustrated in the isolation of (17) and f19) is idways an attractive feature of this type of transformation. Acyl tellurides have been shown to act as acyl radical precursors;” cyclization of telluride (20) can be promoted by photolysis in very good chemical yields. The retention of the useful vinyl aryl telluride functionality is particularly attractive as the * B.S.Jaynes and C. L. Hill J. Am. Ckem. Sac. 1993 115 i2212. E.Hasegawa and D. P.Curran 3. Org. Chem. 1993. 58 5008.lo J. E.Brumwcll N.S. Simpkins and N. K. Terrett Tetrahedron Lett. 1993,34,1219. J. E. Brurnwcll N. S. Simpkins and N. K. Terrett Tetrahedron Lett. 1993,34 1215. C. Chen and D. Crich Tetrnhedron Lett. 1993,34 1545. Reaction Mechanisms -Part (ii) Free-radical Reactions products can undergo further synthetic elaboration its exemplified in the production of the phenyl selenide product (21) shown. Uneyama and coworkers have also utilized tehride precursors for useful rad-ical-based transformations; in this case however vinyl radicals rather than acyl radicalsare generated. Precursors suchas (22)' have been utilized in an appealingnew indole synthesis; photolysis of (22) leads to good yields of indole (23). Intramolecular radical addition to aromatic systems has also been of recent interest.Ziegler and co-workers have continued their workin the indole area by demonstrating that both di~xolanyl'~ and oxiranyl' radicals derived from thiohydroxamate ester precursors (24) and (26) undergo intramolecular addition to provide entry into enantiomericallypure dihydroindoles (25) and (27).Theinitial photoadduct is a dimer Y.Ueda H.Watanabe J. Wernura and K. Uneyama Tetrahedron Lett. 1993 34,7933. l4 F.E.Ziegler and P.G. Harran J. Org. Chem. 1993 58 2748. Is F. E.Ziegler and P.G. Harran Tetrahedron tett. 1993 34,4505. S. Caddick which can then undergo dissociation and disproportionation to give tbe products shown in moderate yields. ips0 Substitutia-Some recent approaches to the formation of carbon-carbon bonds in aromatic systems employ ipso-substitution processes.Treatment of aryl ether (28) with Bu,SnH/AIBN gives the C-substituted aromatic system (29),16possibly uia an addition-ehnination process. These reactions can proceed efficiently to give rear- ranged products in good yield; however the competing reduction processcandominate if the aromatic ring is not suitably activated with electron withdrawing or donating substituents. An alternative ipsu substitution using sulfonesubstituted aromatic systems has also been reported. Treatment of sulfones (30)with Bu,SnH/AIBN leads to the fused indofe systems (31) in moderate to good yields." (30)n= 1,2,3 (31)n= 1,2,3 In an interesting recent report Cadogan McNab and coworkers" have demon- strated the ability of carboxylic esters to act as radical leaving groups.Flash vacuum pyrolysis (FVP) of aryl ally1 ether (32) leads to the benzofuran derivatives (33) in moderate to good yields (3945%). fpso-substitution is of course not Iimited to aromatic systems; it is now known that acyl germanes can also participate as exemplified in the transformation of (34) to (35). However the related acyl silane (36)undergoes addition and then formally a 'radical Brook' rearrangement to give a cyclopentanol isolated as the benzoate (37). This process has recently been put to excellent synthetic utility; treatment of (38) with alIyl tributylstannane and AIBN followed by desiIylative lactonization gives (40) in reasonable yield." Rearrrrngemeat&-Hydrogen-atom transfer.1,5-€iydrogen abstractions continue to interest synthetic chemists. A notable example is reported by Kraus and Andersh;20 l6 E. Lee,C. Lee,J.S. Tac H. S. Whang and K.S.Li Tetrahedron Lett. 1993,34,2343. l7 S.Caddick K.Aboutayab and R.West SI"LET7+ 1993 231. M. Black J. I.G. Cadogan G.A. Cartwright H. McNab and A. D. MacPhemn J. Gem. Soc. Gem. Commm. 1993,959. l9 D. P. Curran W.-T. Jiaang M. Palovich and Y.-M.Tsai SYNLETT 1993,403. *' G.A. Kraus and B. Andersh J. Chem. Soc. Chem. Commun. 1993,646. Reaction Mechanisms -Part (ii) Free-radical Reactions 0 GePh Ph3Q.H (0.1). AIBN (10%) c 95$ 0 8 ?corn S. Caddick here 1,5-translocation of aryl radical (41) is used to initiate an interesting radical sequence which leads to the formation of (42).MeOvOMe CI CI CJ QWH3 OMe The well-established hydrogen-atom abstraction capability of vinyl radicals is the subject of an illuminating full account by Curran and Shem2' They investigate the effect of substituentson these processesand calculate rate constants (typically lo6s-I). The authors conclude that these hydrogen translocation reactions proceed via an early transition state and parallel 5-exo hexenyl cyclizations with respect to substituent effects. They also suggest that they will find significant use in synthesis. The ability of oxygen radicals to undergo translocation reactions is of course a particularly well known and useful process. In a nice extension of their previously developed chemistry Rawal er al.illustrate a useful isomerization of (43) to OH (431 (44) Although catalytic in principle and practice the authors found that the highest yields were obtained when mediated full equivalent each of Bu,SnH and AI3N was used. 21 D.P.Curran and W. Shen,J. Am. Chem. Soc. 1993,115 6051. 22 V.H.Rawal V.Krishnamurthy and A. Fabre. Tetrahedron ktt. 1993,34,2899. Reaction Mechanisms -Part (ii) Free-radical Reactions Group Transfer. Exciting possibilities exist for radical transformations which involve the transfer of groups as opposed to atoms. Kim and Lim have been investigating the hornolytic 1,5-and 1,6-transfer of the tributyltin group; their recent work has demonstrated that these transfers “45) to (46) and (47); (48) to (49) and (50) (46) (47) (46):(47) 66:34 OH OH (49) (50) (49):(50) 8&:12 respectively] are more favourable than the analogous hydrogen-atom The authors estimate the rate constants for 1,5-and 1,6-Bu3Sn transfer at ca.lo9s-’; the reported rate constant for 1,5-hydrogen transfer is ca. lo8s-’. The 1,2-radical migration reaction generalized below as (51) to (52) has attracted significant interest because of its application to a range of synthetically useful systems. The reaction mechanism is complex and recent studies on B-acyloxytetrahydropyranyl radicals by Beckwith and D~ggan~~ have suggested three mechanistic possibilities concerted via a five-membered transition structure (53a); dissociation into an intermediate radical-cation-anion pair (53b); or 1,2-oxygen shift via a three-membered transition structure (53c).The development of related migration reactions and associated mechanistic investigations are ongoing.26 One particularly nice example is reported by Crich and Yao; treatment of vinyl ether (54) with Bu,SnH leads to the formation of ketone (55) uia a carbon-arbon bond-forming migration process. 27 23 S. Kim and K.M. Lirn Tetrahedron Lett. 1993,34,4851. ’* S.Kim and K.M. Lim J. Chem. Soc. Chem. Commun. 1993,1152. 25 A.L. J. Beckwith and P.J. Duggan J. Chem. Soc. Perkin Trans. 2 1993 1673. 26 D. Cnch and Q. Yao Tetrahedron Lett. 1993 34,5677. *’D. Crich and Q. Yao J. Chem. Soc. Chem. Commun. 1993,1265. 90 S. Cuddick These and other related group-transfer reactions have found synthetic utility in the carbohydrate area.Jung and Tinachoe have recently utilized a stereospecific formyl group transfer for the transformation of (56) to (56a).28 Ring Expansions. Zhang and Dowd continue to demonstrate the generality and synthetic applications of ring expansions which are initiated by addition of car-bon-centred radicals to carbonyl groups.29 In a nice recent development Kim and coworkers have shownJo that aminyl radicals generated from azide precursor (57) will undergo intramolecular addition to a ketone to generate an oxygen radical (57b).This then undergoes j?-scission to give the ring-expanded product (57c) in good to excellent yields. The B-scission ofalkoxy radicals is now a weIl-estabIished path for the initiation of ring-expansion reactions.Recently Pattenden and Schulz have an impres- sive cascade process in which the primary cyclization stepinvolves addition ofa carbon radical to an imine. Thus treatment of cyclobutanone oxime (58) with TTMSSleads to (59) in good yield by the sequence shown below. Met hylene cyclopropanes also serve as useful precursors for ring-expansion reactions oia addition-fragmentation processes asdemonstrated in the transformation of (60) to (61) by Destabel Kilburn and Knight.32 la M.E.Jung and S.W. Tinachoe Tetrahedron Lett. 1993,34,6247. l9 W. Zhang and P. Dowd,Tetruhedron. 1993 49 1965. 'O S.Kim G.H.Joe and J.Y. Do,J. Am. Chem. Soc. 19!33,lt5,3328. G. Pattenden and D.J. Schulz Tetrahedron Lett. 1993 34,6787. 32 C. Destabcl J.D.Kilburn and J. Knight,TetrdedroR Lett. 1993,34 3151. Reaction Mechanisms -Part (ii) Free-radical Reactions (57) Many radicalmediated ring-expansionmethods are based upon the propensity of oxygen radicals to undergo &scission. There are of course a range of methods which can be used €orthe formation of such radicals and these have been used to promote ring-expansion sequences. Rawal and Zhong have dernon~trated.’~that radical- induced ring opening of epoxidescan lead to ring-expanded products; this process can be incorporated into a useful tandem sequenceas shown in the transformations below. 33 V. H.Rawal and H. M.Zhong Tetrahedron Lett.. t993,34 5197. 92 S.Caddick Care is required when choosing the optimum experimental conditions in order to isolate the desired product.0 Im 1-&'3u3SnH (5eq.)AiBN -I0.02MJw.. 15h. 566 benzene C02Et CO2Et Mowbray and Pattenden have used alcohols in impressive sequences;34photolysis of the readily available precursor (68) with iodosylbenzene diacetate and iodine leads to the isolation of (59) in reasonable yield. Further investigations also highlight a potential limitation of the methodology; if a competing hydrogen-atom abstraction is geometrically possible it can lead to significantly reduced yields of desired products. This is however a potential drawback with most methodologies incorporating oxygen-radical intermediates. Booker-Milburn and Thompson have utilized ferric chloride to promote a range of diastereoselective ring-expansion-cyclization reaction^;^' more recently this group 3* C.E.Mowbray and G. Pattenden Tetrahedron Lett. 1993,34 127. 35 K. 1. Booker-Milbum and D. F. Thompson,SYNLETT 1993,592. Reaction Mechanisms -Part (ii) Free-radical Reactions has demonstrated the potential of alternative iron(In) salts. Treatment of (70) with iron(xn) nitrate leads to the isolation of (71) in reasonable yield (49%). Tandem CycUzatioas.-Tstndem cyclizations continue to attract attention from synthetic chemists as methods for formingcomplex polycydic systems. Applications in natural product synthesis are now very common; recent examples include Curran and Shen’s approachj6 to Modhephene utilizing sequential 5-exo-trig cyclizations (72) to (731 and Parson and cowurkers’ tandem approach to lysergic acid derivatives (74) to (75).37 €7’ AC Ac (74) (751 The enediynes have attracted a huge amount of synthetic interest because of their ability to generate diradicals which can be utilized to good effect in biological systems.Grissom et al. have utilized similar materials in ingenious tandem cyclization reactions;38 simple thermolysis of the trienediyne (76)leads to (771 uiu bis-cyclization of the aromatic diradical (75a) itself produced by a Bergman cyclization. A spectacular example of tandem cyclization has been used in a very elegant synthesis of a tetracyclic steroidal skeleton using enyne-allene~.~~ Thermolysis of 36 D. P. Curran and W. Shen Tetrahedron.,1993 49,755. 37 Y.Ozlu D. E. Cladingbocl and P.J.Parsons SYNLETT 1993,357. 38 J. W.Grissom,T. L.Calkins and H. A. McMiIlen J. Urg. Chern. 1933 58 5556. 39 Y. W. Andemichaet Y. Huang and K.K. Wang J. Org. Chem. 1993,s. 1651. S. Caddick precursor (78) leads to the tetracyclic product (79) via the radical cycliz-ation-cycloaddition sequence shown. This useful transformation is particularly noteworthy becauseof the absence of any reagents although the yields are moderate in the cases reported; the authors propose this to be a consequenceof the cycloaddition component of the sequence. The utilization of radical reactions in sequence with efficient cycloaddition reactions is potentially very powerful and likely to find considerable synthetic application in future years. Another unusual and noteworthy tandem cyclization sequence is reported by Harro~ven.~* Treatment of ketenethioacetal (80) with SnBu,H/AIBN leads to thiophene (81); the proposed sequence fox this novel transformation is shown below.4 inte~olecularReactions GeneraLA synthetically useful intermolecular radical reaction is reported by Barton and Zhw4’ White-light irradiation of PTOC esters (82) in the presence of two equivalents of white phosphorus followed by oxidation leads to good yields (70-86%) of aikyl phosphonic acids (83). Competition experiments demonstrated that white phosphorus is a highly efficient trap for alkyf radicals. Some interesting and synthetically useful carbonylation reactions have recently been published demonstrating that the use of ‘slow’ hydride donors such as triphenylger-maniurn hydride leads to improved conversion into carbonylation produ~ts.~’ Thus Gupta and Kahne incorporate a carbonylation into their hydroxymethylation approach using in situ triphenylgermaniurn hydride.Reductive carbonylation of iodide (84) led to (85) in moderate yield. Ryu and coworkers are also active in this area and have recently demonstrated the benefits of TTMSS in mediating free-radical carbonylation. Alkyl and vinyl halides undergo carbonylation using Bu,SnH or TTMSS as promoter; however TTMSS permits the use of lower CO pressures.43 A useful alternative vinylation-allylation sequence has been recently developed by Huval and Singleton;44 in contrast to the use of tin reagents described by Keck and others this work utilizes vinyl and ally1 halides inciuding (86) and (88) to give good yields of addition products (87) and (89).’* D.C. Harrowven Tetrakedron Lett. 1993 34,5653. D.H.R. Barton and J. Zhu J. Am. Ckem. Soc. 1993,lf5,2071. ‘’ V. Gupta and D. Kahne Tetrahedron Lett. 1993 34,591. 43 1. Ryu M. Hasegawa A. Kurihara A. Ogawa S. Tsunoi and N.Sonoda SYNLETT 1993 143. C.C. Huvaf and D.A. Singleton Tetruhedron Lett. 1993 34,3041. Reaction Mechanisms -Part (ii) Free-radical Reactions r- v-L (7w -vw r p H H 195046 Intermolecular addition to aromatic systems continues to be a subject of intensive in~estigation?'~'The Bacchiochi group has demonstrated that a range of systems (Fe"/H,O,; Et,B/O,; Mn'") can promote addition of various alkyl radicals to aromatic systems exemplified in the transformation of (90) to (91).48-51 Other work has demonstrated the ability of organostannyl radicals to undergo " Q-Y-Chen and 2.-T.Li J. Chem. Soc. Perkin Trans. 1 1993 1705. '' M.Yoshida R. Imai Y. Kornatsu Y. Morinaga N. Kamigata and M. Iyoda J. Chem. Soc. Perkin Trans. 1 1993,501. " Q.-Y. Chen and Z.-T. Li J. Chem. Sor. Perkin Trans. I 1993,645. 48 E. Baciocchi and E. Muragha Tetrahedron Lett. 1993 34 5015. '' E. Baciocchi and E. MuragIia Tetrahedron Lett. 1993.34 3799. E. Baciocchi and E. Muraglia J. Org. Chem. 1993,58 7610. E. Baciocchi B. Floris and E. Muraglia J-Org. Chem. 1993 58 2013. S.Caddick 0 (82) (87) (69:31 E:Z) Reaction Mechanisms -Part (ii) Free-radical Reactions (83) (23:77E:Z) (W (911 Reagents i Et,B 0,,benzene or DMSO RI; ii FeSO, H,O, DMSO RI;iii Mn(OAc), NaOAc RH addition to sulfone-substituted aromatic systems as shown in the transformation of (92) to (93).'2 Acyclic Stereocontrol-R-Substituted Radicals.One of the most important recent synthetic developments in free-radical chemistry is the stereocontrolled formation of C-C bonds in acyclic systems. Most investigations in this area have concentrated on substrate-controlkd reactions and further important contributions have been reported in the last year. Giese et al. have recently demonstrated5' that polar groups can enhance the stereoselectivity of 'enolate radical' reductions. In earlier work it had been demonstrated that substituted enolate radicals e.g.from (94),give products which can be explained by invoking a conformation which minimizes A-strain effects. By incorporating polar groups it was found that the degree of stereocontrol was significantly enhanced [from 66 33 (X = Me) to >95 :5 (X= F OMe)] because of the additional unfavourable dipoledipole interactions between X and CO,R in conformer (94b). (Ha) (Mb) '' S. Caddick and S. Khan Tetrahedron Left. 1993 34,7463. 53 B.Giese W. Darnrn F. Wetterich H.-G. Zeitz J. Rancourt and Y. Guindon Tetrahedron Lett. 1993,34 5885. S. Caddick ROZC H (97) (97@ (97u In keeping with this analysis it is found that introduction of a polar substituent at the radicalcentre e.g. from (97),reduces the energy difference between the two conformers.In these cases selectivity decreases when X = Cl OMe and is optimal when X = CH,. Although the use of the A-strain model is useful for predicting stereoselectivity in cases of this type recently Curran and Ramamoorthy have discussed at length54 the fact that such models are not particularly tolerant to substituent effects. In addition to being substrate dependant the stereochemical outcome of many reactions of this type may be additionally dependant on the nature of the incoming reagent. Heteroafom-substituted Radicals. Recent work has suggested that in general a-alkoxy radicals show selectivity which can be explained using the Felkin-Anh rule. Thus Giese and coworkers have optimized the transition states of radicaI (lOO) which undergoes reduction with hydride donor TTMSS.” There are similarities between this type of reduction proposed by Giese to proceed via conformer (lOOa) and the analogous hydride-mediated reduction.Eksterowicz and Houk’s ~alculations’~ support this proposal and go on to show that the radical transition structure is more pyramidahed than the transition state for the corresponding ionic reduction. (100) R = H Si(SiMe& syn :anti 7525 SiiSiMe& Pi (1OOa) s4 D. f.Curran and f.S.Ramamoorthy Tetrahedron,1993.19 4841. ’’ W. Damm J. Dickhaut F. Wcttcrich and B. Giese Tetruhedron Lett. 1993.54.431. s6 J. E. Eksterowicz and K.N.Houk Tetrahedron Lett. 1993 34,427. Reaction Mechanisms -Part (ii) Free-radical Reactions Curran and Sun have examined related systems; early work had demonstrated that nitrogen substituted radicals give syn products which can be explained using the A-strain model.However with a-H-N substituted radicals anti products are obtained; treatment of (101) with TTMSS provides the products (102) and (103).The high degree of anti selectivity can be rationalized by invoking a ‘steric’ Felkin-Anh conformation (101a) or a Cram chelate conformation (lOlb).” I k-SI(SiMe3)3 H-Si(SiMea)j {lola) (101b) Previous studies had demonstrated that simple aIkyl radicals can also participate in highly stereoselective reactions. In a recent investigation Curran Giese and co-workers examined the iodine atom transfer reaction of (104)and (105) which gives in a highly syn-selective manner (106)as the major product (98 :2 syn :anti).These authors propose that the iodine donor approaches conformer (106a) between the medium and large groups and anti to the smallest This transition state minimizes torsional strain as the radical centre pyramidalizes in the transfer process.’’ D. P.Curran and S. Sun TetrahedronLett. 1993,34* 4181. ’* G.Thoma D. P. Curran S. V.Geib 8.Giese W.Damrn and F. Wetterich J. Am Chem. Soc. 1993,115 8585. 100 S. Caddick Reagent-controlled Stereoselectiuity. Some highly diastereoselective reactions have been recently reported by Toru and coworkers.sg In this very exciting development a-sulfinylcyclopentenones (108)were found to undergo jl-addition with t-butyl radicals to give adducts (109) and (110).In the presence of Lewis acid product (109)could be isolated in good yieId; the high degree of diastereoselectivity can be attributed to chelation of the sulfoxide and the carbonyl with the Lewis acid.3x1 the absence of Lewis acid the other diastereoisorner predominated. 0 OV R',LA R k Radicai Sequences.-The use of inter- and intramolecular radical reactions in sequence provides opportunity for the rapid assembIy of complex organic materials. Lee and coworkers have developed an approach to cyclohexenecarboxylates using this type of approach as shown in the transformation of (lll) (112) and (113) to (114).60 Bachi recently disclosed an elegant approach to 8-lactams as illustrated in the transformation of (115) to (l16).61 C02CMe3 C02Me (115) (116) This impressive transformation involves a radical sequence incorporating an inter-molecular radical addition to give (115a) an intramolecular hydrogen atom transfer to provide (115b) and an intramolecular cyclization-fragmentation to give (1 1 Sd).Treatment of (115d) with DBU gives the observed product (116) in reasonable yield. It is interesting to note that this sequence incorporates a relatively unusual '' T.Tom Y.Watanabe M. Tsusaka and Y.Ueno J. Am. Chem. Soc. 1993 115 10444. E. Lee C.U. Hur Y. H.Rhee Y.C. Park and S. Y.Kim J. Chem. Soc. Chem. Commun. 1993,1456. E. Bosch and M.D. Bachi J. Org. Chem. 1993,58 5581. Reaction Mechanisms -Part (ii) Free-radical Reactions (115a) 1115b) 1 1,6-hydrogen atom transfer step.A similar transformation incorporating a 1$transfer was also attempted; treatment of (117) with SnBu,H led to the isolation of (119) as the major product; the desired product (118) was isolated in a disappointing 19% yield. 0qb *q Sn3u3.A'BN 0 Sn0u3 C02Me co*w C02Me (117) (118) 19% (119) 56% A carbonylation component can also be incorporated into synthetically efficient radical sequences as exemplified by the transformation of (I20) to (l2l)in 72% yield.62 5 Applications of Radical Process to Synthetic and Biological Chemistry Synthetic Chemistry.4orey and HeIal have recently developed a convenient enantioselective synthesis of monosubstituted ~xiranes;~~ the utilization of a selective radical dechlorination of chloroalkanes nicely illustrates the potentia1 for radical reactions in sensitive systems.Selective bis-dechlorination of an enantiomerically pure trichloromethyl carbinol (122) gives (123) which under basic work-up gives the oxirane (124) in good yields (>90% ee). The iodine atom transfer method developed by Curran and coworkers is finding significant utility in synthesis; in a full accoud4 Ziegler and Fields describe the application of this powerful methodology to the synthesis of functionaIized penicillins '' I. Ryu H. Yamazaki A. Ogawa N. Kambe and N. Sonoda J. Am. Chem. Soc. 1993 115 1187. 63 E. J. Corey and C.J. Helal Tetrahedron Lett. 1993,34 5227. 64 C.B. Ziegler Jr and T. L. Fieids Tetrahedron. 1993,49 3919. 102 S. Caddick [(125 to (12611.Kawecki and Welch have exploited the iodine atom transfer methodology in the synthesis of functionalized fluoro-8-lactams (128).65 .. n Various alkaloid syntheses have incorporated free-radical t ransformations; Schultz and coworkers have utilized a simple intramolecular Bu,SnH mediated cydization of (129) to give (130) in their synthesis of (+)-l-deoxylycorine.66 The application ofBn,SnH in alkaloid synthesis is niceIy expIoited by Bonjoch Sulk and Bosch; in an impressive one-pot transformation (13 1) undergoes desulfurization and reductive cyclization to give tubifolidine (132) in 50% Biotogicrrl Ckntistry.-The enediynes continue to attract a great deal of attention; C-1027 chromophore is a particularly interesting addition to this fascinating family of natural products.Yoshida and coworkers have recently shown that this molecule (133) which exhibits DNA cleaving capabilities can undergo a direct rapid cyc-" R. Kawecki and J.T. Welch Tetruhedron Lett. I993,34 3087. 66 A.G. Schult M.A. Holoboski and M.S. Smyth J. Am. Chem. SQC. 1993 115,7904. 6' J. Bonjoch D. Sole and J. Bosch. J. Am. Chem. Sm. 1993 115 2064. Reaction Mechanisms -Part (ii) Free-radical Reactions ioaromatization to give the potentially DNA-damaging benzenoid diradical (134).68 The enediynes have stimuIated an increased interest in the interaction of car-bon-centred radicals with DNA because of the prospect of developing therapeutic agents. Breem and Murphy have shown69 that certain simply vinyl epoxides react with thiol radicals to generate DNA-damaging oxygen-centred radicals; they "K.Yoshida Y.Minami R.Azuma M. Sacki and T.Otani Tetrahedron Lett. 1993,34 2637. 69 A. P.Breen and J.A. Murphy J. Chem. Soc. Chem. Convnun. 1993 191. 104 S. Caddick then report7* the DNA-cleaving capabilities of substrate (135) which is readily synthesized and incorporates a phenanthrohium unit fa known DNA intercalator). Treatment of commercially available supercoiled DNA with (1351 glutathione and horseradish peroxidase leads to DNA strand cleavage; control experiments show that the deavage is dependant upon the presence of the glutathionyl radicals. '* A.P. Breen and J. A. Murphy J. Chem. SOC. Perkin Trans. I 1993 2979.