Saturated nitrogen heterocycles Bn02C SO~CIZ TrNH-*.R OH JOHN STEELE m z e r Central Research, Sandwich, Kent CT13 9NJ, UK Tr Reviewing the literature published between January 1992 and May 1993 1 1.1 1.2 2 2.1 2.2 2.3 3 3.1 3.2 3.3 3.4 3.5 3.6 4 4.1 4.2 4.3 5 6 Three- and four-membered rings A zirid ine s Azetidines Five-membered rings with one nitrogen atom Pyrrolidines Pyrrolidinones Pyrrolizidines and related compounds Six-membered rings with one nitrogen atom Piperidines Tetrahydroisoquinolines and related compounds Indolizidines Quinolizidines Aza Diels-Alder reactions Piperidinones Rings with two or more nitrogen atoms Five-membered rings Six-membered rings Seven-membered rings Seven-, eight-, and nine-membered rings References 1 Three- and four-membered rings 1.1 Aziridines A useful new aziridination of alkenes has appeared.Thus, the N-arylhydroxamic acid 2 reacts efficiently with electron-deficient alkenes 1 to generate the functionalized aziridines 3. The mechanism of the transformation has not been fully resolved. 1 (EWG = Electron Withdrawing Group) 3 Two separate reports have described the utility of Payne-like rearrangements of aminomethyl oxiranes for aziridine synthesis. In the first of these,* the epoxide 5, prepared by straightforward mCPBA oxidation of the allylsulfonamide 4, rearranges in aqueous sodium hydroxide to afford the tosyl aziridine 6. Predictably, no product from the alternative 4-endo-tet cyclization mode is observed. In the second report, Vaultier and co-workers3 describe the trimethylaluminium-mediated rearrangement of the N-unsubstituted epoxy amines 7 into the aziridinemethanols 8 in good yield.3 An alanate complex is a proposed intermediate.4 5 6 (i) BuLi, AIMe3 R W N H Z PhMe, -80 "C c OH 0 (ii) NaF, H f l 7 8 The synthesis of homochiral aziridines has featured prominently in several publications. Thus, Berry and Craig have highlighted a simple but nonetheless effective reduction/ring closure sequence for conversion of the a-amino acids 9 into the chiral monosubstituted aziridines Yields are generally excellent. Continuing the 'chiral pool' theme, the trityl serine and threonine esters 11 [R = H, Me] are converted into the cyclic sulfamidates 12 using sulfuryl chloride and triethylamine. The sulfamidates 12 are inherently unstable and rearrange in situ to give the chiral aziridines 13.5 (i) LiAIH4 or BH, (ii) TsCI.DMAP N CHzCIz Ts NHTs 9 10 I- 1 L J 11 13 12 Finally, Fujisawa and his group6 have described remarkable metal-dependent diastereoselectivity in the condensation reactions of the chloroketene acetals 15 with the chiral imine 14. The lithium enolate 15, M = Li affords only the 2R, 3 s aziridine 16, whilst metal exchange to a zinc enolate 15, M = ZnCl generates only the 2S, 3 R isomer 17. Steele: Saturated nitrogen heterocycles 95F O B " ' " 15 B''osw R* (K Bub& 8w' R* N THF. -78 "c N H 14 I I A1 Ar 16 17 M = Li M = ZnCl Molina et al. have achieved a short and regioselective entry into the fused azirino[ 1,2-a]indole ring system 22 (Scheme 1).7 The method relies on generation of the intermediate iminophosporanes 19 from appropriate azide precursors 18, followed by cyclization to the betaines 20 which then rearrange to 2 1.Cyclization of 2 1 and concomitant elimination of phosphine oxide finally produces 22 in 45-95% yield. r 1 18 L 19 J \ R' R' "h- - Ph3PO 22 R2&06Ph3 1 21 Scheme 1 1.2 Azetidines Developments in the synthesis of /3-lactams will be reviewed in a separate article in this Journal. Toda and co-workers8 have exploited the efficient aminolysis of the epibromohydrin derivatives 23 to prepare homochiral3-hydroxyazetidines like 24. RNH, R' P h L 0 MeOH, 20 "C - 23 24 The benzhydryl azetidine-2-carboxylate 27 is a key intermediate in the synthesis of the oxazaborolidine catalyst 28 and, in a new twist to some standard chemistry, this intermediate has been prepared by bis-alkylation of benzhydrylamine 26 with the dibromobutyrate 25 under microwave irradiation." The use of microwaves shortened the reaction time from 24 hours to 15 minutes and enhanced the yield considerably.Ph Ph 26 Br+fco2Bn Br MeCN )-w hv, Microwave H 28 2 Five-membered rings with one nitrogen atom 2.1 Pyrrolidines The intramolecular addition of nitrogen to double and triple bonds continues to extend the scope of available pyrrolidine syntheses. As part of a chirospecific synthesis of pyrrolizidines, Takahata and Momoselo have exploited a selective amidomecuration of the terminal alkene in 29 to generate the trans-2,5-disubstituted species 30. Demercuration then affords the prolinol3 1. Cbz 29 30 n 31 By contrast, butyllithium-mediated cyclization of the secondary amines 32 is remarkably selective in favour of the cis-2,5-disubstituted pyrrolidine products 33.l' The reaction proceeds optimally in the presence of only a catalytic amount of alkyllithium.BuLi -78 "C Me 32 33 The intramolecular addition of azide to double bonds is a well established route to pyrrolidines, and Pearson et al. have now used the procedure in a concise synthesis of racemic y-lycorane 36.'* Thus, thermolysis of the azide 34 first generated the transient iminium ion 35 which was reduced selectively in situ to generate lycorane 36 (Scheme 2). 96 Contemporary Organic Synthesisr 1 (i) Cpgr(1-butene) 47 (ii) CO (iii) HCI N3 R 0 I CI 34 35 n 36 Scheme 2 With suitable catalysis, amines will also add readily to sp-centres.Livinghouse and his colleagues have described the titanium-catalysed cyclization of the acetylenic amine 37 via a formal [2 + 21 cycloaddition of a metalloimine complex, generating the intermediate metallacycle 38. Aqueous hydrolysis of 38 then liberates the A'-pyrroline 39 in excellent yield.I3 37 38 39 Moving from N-C to C-C bond forming reactions, Livinghouse et al. have also prepared more-functionalized pyrrolines using the cyclization of acyliminium ions. Thus, the 2,3-diacyl derivatives 41 are assembled in good yield by a one-pot ac ylation/silver-mediated c yclization of the isonitriles 40.14 H- -tt- - R' (ii) AgBF,, -78 "C " 1 R' +!\ "/y2 0 1C 41 40 The enyne 42 reacts with Fischer carbene complexes like 43, in the presence of the iron catalyst 44, to generate the unusual bicyclic pyrrolidine 45.15 The reaction is assumed to proceed via two intermediate chromacyclobutanes. In a structurally related enyne cyclization, Mori and co-workers have shown that perhydroindole derivatives like 4 8 can be constructed, albeit in modest yields, by a reductive coupling of the silyl acetylene 46 promoted by the zirconium complex 47.16 The product 48, R = Bn was then used in a formal synthesis of dendrobine.OEt Me (i) (C0)5Cr=( 43 (ii) [FeCI,][Fe(DMF)3C12] 44 Ts Ts 42 45 O L SiMe3 46 48 Several research groups have published details of new dipolar cycloaddition routes to pyrrolidines or embellishments of existing methods. Takano and his group17 report that deprotonation of the C2 symmetric N-oxide 49 produces the dipolar species 50 which presumably equilibrates to the isomer 5 1 before undergoing an intramolecular cycloaddition to afford the tricyclic pyrrolizidine-like structure 52 (Scheme 3).50 52 L 51 Scheme 3 This represents the first disclosure of an intramolecular 1,3-dipolar cycloaddition of a non-stabilized ylide generated from an amine oxide. At the other thermal extreme, Heathcock et al. have used flash vacuum pyrolysis to accelerate the intramolecular cycloaddition reactions of stabilized ylides with unactivated dipolarophiles.18 Thus the aziridine 53 is converted into the functionalized bicyclic system 54 by brief heating at 350°C. Finally, Jung and his collaborators have exploited the 3-hydroxypyridinium salt 55 as a useful ylide precursor. Treatment of 55 with acrylonitrile 56 and triethylamine affords a roughly equal mixture of the diastereoisomeric azabicyclo[3.2.l]octenones 57 and 58.The latter isomer, 58, is an intermediate in the authors' synthesis of Bao Gong Teng A, a natural antiglaucoma agent." FVP 350 "C. 0.02 Torr w - R H 53 54 0 0 . ._ 57 58 1:1.5 55 Steele: Saturated nitrogen heterocycles 97The synthesis of substituted prolines is a well represented area, and two related dipolar cycloaddition approaches are particularly worthy of note. Williams et al. have established the diphenylmorpholinone 59 as a valuable cycloaddition template. Reaction of 59 with an aldehyde generates a transient, stablized ylide 60 which is trapped in situ by, for example, dimethyl maleate 61 to afford the bicyclic adduct 62 (Scheme 4).The chiral auxiliary is then discarded by hydrogenation to give the tetrasubstituted pyrrolidine 6 3 .20 Bu3SnH p h F o RCHO ~ H N A 0 PTSA. PhH AlBN 59 H Me02C' R--c7--cozH 'C0,Me 63 Scheme 4 HdPd-C 60 THF I 61 t 62 Harwood and Lilley have shown that the intramolecular variant of this cycloaddition sequence proceeds in high yield and with excellent diastereoselectivity, notably with unactivated akenes as dipolarophiles.21 Thus, the phenylmorpholinone 65 and 5-hexenal64 afford the tricyclic pyrrolidine 66 in boiling benzene, and hydrogenation then liberates the bicyclic proline analogue 67. 65 66 HdPd(OH), cat. TFA H 1 *C02H H 67 As part of a synthetic approach to the hydroindole core of Stemona alkaloids, Wipf and Kim have demonstrated an effective oxidative cyclization of tyrosine 68 by iodobenzene diacetate to yield the bicyclic enone 69.** In the absence of sodium bicarbonate only ips0 spirolactonization is observed.H OH .. 68 69 R = Cbz or Boc Radical cyclizations have also provided new entries to substituted prolines. The thioaminals 70 serve as precursors for carbon-centred glycine radicals, and their treatment with tributylstannane affords a mixture of the five- and six-membered products, 71 and 72.23 t '$CO,Me + 'D CO,Me C0,Et CO, Et 71 72 (2:l) The transformation is reasonably tolerant of substituents although yields are variable. The homochiral4-exomethyleneproline 74 has been prepared by a tributylstannane-promoted 5-exo-dig cyclization of the acetylene 73.24 The neuroexcitatory prolinoid kainic acid and its congeners have attracted continued synthetic attention.Thus, Knight and his co-workers have employed a particularly elegant transannular ester-enolate Claisen rearrangement reaction as part of their total synthesis of ( - )-a-kainic acid.*5 Deprotonation of the nine-membered azalactone 75, by LDA, followed by warming effects rearrangement via a boat-like transition state leading to the key functionalized pyrrolidine 76. I S02Ph 73 0 I kO,Ph 74 I C02Et 75 I COzEt 76 Baldwin et al. have shown that samarium iodide cyclizes the alkene substituted aminoaldehydes 77 to diastereoisomeric mixtures of the kainoid precursors 78;26 an N-acyl substituent is apparently essential for the transformation to proceed. 98 Contemporary Organic SynthesisSml, THWHMPA D R'O 77 78 Finally, Takano and colleagues have developed conditions for the intramolecular Pauson-Khand cyclization of the dicobalt carbonyl protected acetylene 79.The bicyclic enone product 80 is a key intermediate in the authors' enantiospecific synthesis of ( - )-kainic acid.27 I C02Me 79 Me' + CH2C12 0 "C OR XOB" I C02Me 80 2.2 Pyrrolidinones The intramolecular addition of amide nitrogen centres to unsaturated bonds is a popular route to y-lactams. Knapp et al. have extended their earlier work in this area by developing an efficient, stereoselective iodolactamization of the primary amide 8 1 affording the hydroxypyrrolidinone 82 after removal of the transient protecting group.28 0 9 * (i) Me3SiOTf (3 equiv.) Et3N HO (iii) aq. Na2S03 81 1 82 Although amide bond formation per se is outside the remit of this review, several noteworthy y-lactam syntheses are appropriately included.A simple asymmetric synthesis of 5-substituted 2-pyrrolidinones which relies on the chiral auxiliary phenylglycinol84 has been reported by Meyers et al. (Scheme 5). R fO" Ph"NH, 04 PhMe, reflux 83 Pti 0 85 I TiCI. H O T N ? Li, NH3 EtOH 0 Ph 0 Condensation of 84 with y-ketoacids 83 yields the bicyclic aminals 85. Stereoselective reduction of 85 with alane or triethylsilane/Lewis acid next generates the substituted lactams 86. Removal of the residual auxiliary, liberating the 5-substituted pyrrolidinones 87 is then achieved by a dissolving metal reduction.29 Schollkopf has described a synthesis of the novel 5-phosphonate 90 in the course of studies on phosphonoproline analogues.A Michael addition of the chiral metallated imine 88 to methyl acrylate 89 gives the homochiral lactam 90 after hydrolytic work-up. Zinc appears to be essential since the reaction fails when a lithiated imine is employed.30 a0 The use of transition metals is affording some effective new syntheses in this area. Thus, the chiral rhodium catalyst Rh,( 4S-MEOX), 92 almost quantitatively converts the diazoamide 9 1 into the lactam 93 with a moderately good e.e. (78%). The authors also describe several related catalysts which give varying amounts of azetidine by-prod~cts.~~ I 1 93 N2 91 r Many radical-based approaches to polyhalogenated pyrrolidinones have appeared in recent years, and three recent reports add to this list.Itoh and co-workers3* have reported that N-ally1 trichloroacetamides such as 95, which are readily prepared from the appropriate ally1 alcohols 94 by an Overman-type [ 3,3]-sigmatropic rearrangement, are converted into the pyrrolidinones 96 in good yield under ruthenium catalysis. (11)14U 'G 95 JV 87 86 Scheme 5 96 Steele: Saturated nitrogen heterocycles 99Jones and Storey have assembled the oxindoles 98 by a tin-mediated radical cyclization of the bromoanilide 97 although, in some cases, small amounts of corresponding dihydroquinolone products were formed by the alternative 6-endo cy~lization.~~ No competitive addition to the isolated ally1 double bond in 97 was obseved. Finally, Ikeda and his colleagues have documented the radical cyclization of N-vinyl chloroacetamides such as 99, affording the bicyclic pyrrolidinone 100.This chemistry has then been extended to a useful synthesis of perhydr~erythrinane.~~ Bu3SnH PhMe reflux I I 97 98 Bu3SnH AIBN PhMe, reflux A Me Me 99 100 Two interesting pericyclic approaches to pyrrolidinones have emerged recently. In the first, the pyrrolo[3,4-b]pyrrolidinone 103 is assembled quickly and efficiently by a thermal intramolecular Diels-Alder reaction of the acetylenic imidazole 10 1. The presumed intermediate adduct 102 is not observed and almost certainly extrudes HCN in sit^.^^ In the second report, the homochiral aminoacrylamide 104 undergoes an asymmetric intramolecular ene reaction on heating at 150°C. Hydrolysis of the separated diastereoisomeric products then gives the enantiomeric spiropyrrolidinones 105 and 106 in a ratio of 77 : 2 3 , corresponding to 52% e.e.for the ene reaction.36 101 102 R 104 (iii) AcOH 1 (i) A, 150 "C neat (ii) Separate diastereomers Ring expansion reactions are frequently serendipitous discoveries, and Black and his co-workers have now described such an expansion of P-lactams which may have considerable synthetic scope. The reaction of chlorosulfonyl isocyanate (CSI) with simple 1,l-disubstituted alkenes 107, bearing at least one allylic proton is presumed to generate the classical P-lactam intermediates 108. On heating the reaction mixture, however, only the sulfonyl pyrrolidinones 109 are isolated, in 60-70% yield.37 L 108 109 In an unrelated ring expansion, the N-phenylazetidinone 1 10 is converted stereospecifically into the iminopyrrolidinone 11 1 on treatment with cyanotrimethylsilane and aluminium chloride .tt-8 Ph AICl3, Me3SiCN PhH * {<+. MeH NH Me H 110 111 Smith and Hirschmann have described a short synthesis of the homochiral3-pyrrolidinones 114 which are readily assembled into oligomeric P-strand pep ti do mimetic^.^^ The synthesis of 114 relies on imine formation between the aldehyde 112 and the unnatural amino acids 1 13, followed by KHMDS-induced cyclization. Bn 113 NHBM PhMe - O H C d C O , M e (ii) KHMDS THF 112 H 114 2.3 Pyrrolizidines and related compounds A new route to pyrrolizidine alkaloids, developed by Anderson and Ba~kvall,~~ relies on a palladium catalysed tandem cyclization of the dienyl amide 1 15 generating the bicyclic lactam 116 which was then converted into ( k )-heliotridane 1 17. Me I I1 0 115 117 II 0 116 An intramolecular amidocarbonylation of the pyrrolidinone 1 18 proceeds under rhodium catalysis 105 ?7:23 106 and very high pressures of carbon monoxide and 100 Contemporary Organic Synthesishydrogen ( > 100 atmospheres) to give the aminall19 as a 2 : 1 mixture of isomers. The isomers of 119 were then transformed into isoretronecanol and trachelantha~nidine.~~ 1:l CO/H, 16OOpsi f OTBS HCiOEt)3 .HRh(CO)(PPh& 0 OEt 118 119 Significant developments in radical-mediated ring closure reactions have emerged. Bowman and his c o - ~ o r k e r s ~ ~ have prepared the tetracyclic pyrrolizidine analogue 124 from the bicyclic sulfenamide 120 (Scheme 6). The reaction proceeds by generation of the aminyl radical intermediate 12 1 which then undergoes tandem cyclizations via 122 and 123 before abstracting hydride and regenerating the catalytic tin radical.SPh 120 121 / 124 Scheme 6 123 The a-amino radical generated by photolysis of 125 in the presence of 1,4-dicyanonaphthalene 126 as an electron-transfer agent cyclizes stereoselectively to afford the pyrrolizidine 127. Less than 3% of the a-methyl isomer is produced during the ring closure.43 hv, >280 nM * NC 127 125 @ , pi*" ~ 3 % a-Me isomer NC 126 In a reaction analogous to the formation of the pyrrolidinone 96, the vinyl pyrrolidine 129, which is readily available from cbz-proline 128, is shown to cyclize under copper ( I ) catalysis to generate the trichlorolactam 130 in 93% ~ield.4~ Dechlorination 6 steps cN?;C*.H--- Cbz 128 129 CUCl MeCN 150 "C ____c H CC' and amide reduction then completes a synthesis of pseudoheliotridane. In the last radical cyclization example, the tin mediated cyclization of thioacetall31 provides a 1 : 1 mixture of the bicyclic lactams 132 and 133; the mixture has then been used to complete a synthesis of racemic ~upinidine.~~ 0 131 Bu3SnH AIBn (SiMe3 1 Bu3SnYiMe3 0 0 132 (28%) 133 (29%) Finally, Hassner and his co-workers have described the intramolecular oxime-olefin cycloaddition reaction of the prohe-derived vinyl pyrrolidine 134 to afford the tricyclic adduct 135.46 Despite the need to heat the oxime neat at 180°C for 15 hours, the product 135 is isolated in 56% yield, and has also been converted into supinidine. 134 180 "C neat 15h 135 3 Six-membered rings with one nitrogen atom 3.1 Piperidines An excellent review of synthetic approaches to the Daphniphyllum alkaloids has appeared.47 Amongst a wealth of chemistry, the review contains a valuable summary of fused piperidine ring constructions.Returning to the theme of nitrogen addition to unsaturated bonds, Weinreb et al. have described a regioselective synthesis of the piperidine 137 by palladium-mediated sequential cyclizations of the aminodiene 1 36.48 The azidoboronates 138, prepared via hydroboration of a suitable alkene with HBC1, and an alcohol, are readily cyclized by treatment with boron trichloride to give the intermediate dichloroboranes 139. Basic hydrolysis efficiently liberates the bicyclic perhydroquinolines 1 40.49 Me 136 130 138 137 140 BClz 139 Steele: Saturated nitrogen heterocycles 101Overman and his colleagues have extended their existing work on the Mannich-like intramolecular addition reactions of alkynes to imines by demonstrating that the imines 142, prepared by condensation of the amines 14 1 with a range of aldehydes, readily undergo an iodide-promoted cyclization to form the alkylidenepiperidines 143.s0 L 143 141 142 Angle and his group have published more details of their elegant, stereoselective pipecolic acid synthesis.Conversion of the oxazinones 144 into their corresponding TIPS ketene acetals facilitates a conformationally restricted Claisen rearrangement which proceeds by a boat-like transition state to generate the pipecolic acids 145.51 The procedure has also been applied to the synthesis of enantiomerically pure piperidine derivatives.Angle has also described an unrelated synthesis of piperidines which relies on silver oxide oxidation of the phenol 146 to the quinonoid species 147. Addition of zinc chloride then catalyses cyclization of the enecarbamate 147, generating the intermediate 148 which can be isolated as a mixture of 149 and 150 in which the new enecarbamate 149 predominates (Scheme 7).s2 manzamines, Marko and his group have detailed a remarkable anionic cyclization of the indole 15 1 to give the tetracyclic system 152. Overall, the transformation is the equivalent of an indole-based IMDA reaction. The authors suggest a plausible mechanism involving kinetic addition of the indolyl anion to the dienoate followed by a fast, intramolecular Mannich reaction.53 Finally, as part of a synthetic approach to OH 0 Cbz 146 Scheme 7 Cbz 147 CO,R H C02R 151 152 3.2 Tetrahydroisoquinolines and related compounds Two similar reports of the utility of intramolecular Pummerer reactions in the synthesis of tetrahydroisoquinolines have appeared.In the first, by Craig and co-worker~,~~ treatment of the p-aminosulfoxides 153 with TMS triflate generates the presumed thionium ion intermediates 154 which then cyclize to generate moderate yields of the tetrahydroisoquinolines 155. Takano has described essentially the same cyclization of 156 to 157 catalyzed by TFAA.55 ?- TSN/\/SPh Me,SiOTf R15Q * R2 153 L 154 1 155 156 157 The venerable Pictet-Spengler reaction continues to show new facets. As part of a synthetic approach to tetracyclic eudistomins, a stereoselective synthesis of the tetrahydro-P-carbolines 159 has been achieved by reduction of the esters 158 followed by in situ cyclization of the resulting aldehydes with TFA.56 OH Cbz 148 150 (5%) 102 Contemporary Organic SynthesisR (ii) TFA R' .-H ) -70 "C S Me Me 159 158 165 Photolysis of the tryptamine analogues 160 in the presence of TMSCN and 9,lO-dicyanoanthracene 162 as a photosensitizer produces the tetracyclic indoloquinolizidines 16 1 after acidification. The reaction proceeds by cyanation to generate intermediate a-aminonitriles which afford Pictet-Spender products on treatment with acid.57 h3 160 r YN 1 IDCA=QJp] CN 162 A 3 161 Appropriately substituted tryptophan derivatives can give excellent stereoselectivity in cyclocondensations with aldehydes.Thus the N-benzhydryl tryptophan isopropyl ester 163 condenses with aldehydes to generate the trans tetrahydro-p-carbolines 164 excl~sively.~~ 163 R 164 Tietze and Wichmann have established a short and neat entry to corynanthe type alkaloids which relies on tandem Pictet-Spengler and intramolecular Michael reactions (Scheme 8).59 Thus, treatment of the amino triene 165 with TFA generates the intitial cyclization product 166 which is not isolated. Exposure of 166 to tin tetrachloride then mediates a stereoselective Michael reaction producing the tetracyclic amine 167. Interestingly, no single Bronsted or Lewis acid alone could be found to achieve both cyclizations.Two somewhat unusual tetrahydroisoquinoline syntheses have been published. Kihara and co-workers60,h have reported the lithiation and cyclization of 168 to generate the carbinoll69 on exposure to butyllithium (a so-called intramolecular Barbier reaction). Lastly, MaryanofF2 has shown that reaction of the formyltryptamine 170 with paraformaldehyde generates a formyliminium ion which then cyclizes spontaneously to the formamide Scheme 8 17 1. The reaction has not been extended to aldehydes other than formaldehyde. 168 1 69 (CH20)" TFA, refiw 'CHO 170 171 3.3 Indolizidines A comprehensive, 94-reference, review of synthetic approaches to castanospermine, its stereoisomers and analogues has a~peared."~ The total syntheses of several complex indolizidines have recently been described.A pivotal step in the construction of the dendrobatid alkaloid ( + )-allopumiliotoxin 339A by Overmad4 is the generation and cyclization of an iminium ion from 172 leading to the vinyl iodide 173. In a second synthesis of allopumiliotoxin 339A, the vinyl iodide 174 is converted into an organochromium intermediate by Nozaki chemistry. The subsequent cyclization gives the advanced intermediate 1 75.65 Me-'T/ acetone-Hfl OBn Me OBn 1 172 173 crc12 cat. NiC12, DMF 20 "C 174 175 Steele: Saturated nitrogen heterocycles 103The elegant synthesis of indolizomycin by Danishefsky et aZ.66 achieves the requisite pendant functionality by assembling and then fragmenting an indolizidine-like core unit (Scheme 9). Thus, the dihydropyridone 176 is ring enlarged to first give the azonine 177.After further modification to 178, deprotection of the ring nitrogen initiates a spontaneous transannular cyclization affording indolizomycin 179. 1 176 1302C > / lT7 / 1 - R02C -?- Me Me 1 78 179 Scheme 9 An enantioselective synthesis of ( - )-slaframine 18 1 exploits a chemoselective hydrogenation of the azide 180 followed by tandem cyclization of the resulting amine. Acetylation and deprotection then liberate the alkaloid 18 1 .67 0 (1) HI, Pd-C A H I (ii) K&03 Ac I 1 CbZ N3 180 181 Oxidation of the homochiral hydroxamic acid 182 transiently generates the acylnitrosodiene 183 which then undergoes an IMDA cyclization, affording the key adduct 184 as a mixture of diastereomers (Scheme These intermediates 184 have been used as Me 1 182 185 Scheme 10 183 1 common precursors for several of the gephyrotoxin , alkaloids including 209B 185.Wasserman et ~ 1 . ~ ' have shown that the vicinal tricarbonyl derivative 186 is converted via the acyliminium ion 187 into the bicyclic amine 188 simply by the action of silica gel. 186 L 187 J $W0 C02But 188 3.4 Quinolizidines A useful aza-annulation has been devised as the key component of a stereocontrolled route to lupinine 19 1. Reaction of the B-aminocrotonate 189 with acryloyl chloride generates only the lactam 190 in 80% yield.70 Two related cyclizations of acyliminium ions derived from hemi-aminals have been used to assemble quinolizidines. In the first,71 exposure of the hemi-aminall9 2 to TFA promotes iminium ion formation and interception by the pendant allylsilane then affords the isomeric bicyclic lactams 193.The second report uses identical conditions, but an acetylenic terminator rather than an allyl~ilane;~~ thus 194 affords the lactams 195 C02Et 189 OH O Me 192 194 1 90 I 191 H qqy 0 Me [P:u = 7:3] 1 93 0 195 104 Contemporary Organic Synthesis3.5 Aza Diels-Alder reactions The synthesis of six-membered rings containing nitrogen has fuelled continued interest in aza-variants of [4 + 21 cycloadditions, with the majority of recent developments in the azadienophile domain. Abraham and Stella73 have achieved near total diastereocontrol in the cycloaddition of the homochiral imine 196 with, for example, cyclopentadiene 197 to afford the adduct 198. A critical development is the use of a catalytic mixture of TF’A and BF, to optimize the process.203 g;B - OAr 204 ,C02Me II TI p;u” +a- Cti+lz I Y .. \ C’ 196 198 197 Me ‘A-BF3 _I_) . . ^. Diethylaluminium chloride has been established as an excellent catalyst for the cycloaddition reactions of a-alkoxyimines such as 199.74 Diastereoselectivity in the reaction of 199 with the diene 200, to afford the lactams 201, varies from moderate to very good. I 200 OBn 199 dBn 201 Variation of the diene substitution can result in a complete reversal of the cycloaddition regiochemistry. In contrast to the previous example, the imine 202 reacts with the dienes 203 to provide the 4-pyridone derivatives 205. Use of the BINAP-based boronate 204 results in up to 90% e.e.75t76 OMe T O s i M e 3 ZnCI, 207 II + Me3Si0Y N/Bn 2 Ph Ph H** &jR Bn 205 Waldmann and his co-workers have demonstrated some useful levels of diastereocontrol in the zinc chloride catalysed reaction of the tryptophan-based imines 206 with Danishefsky’s diene 207.77 The dihydropyridones 208 are isolated typically as ca.3 : 1 mixtures. The actual mechanism of this, and related cycloadditions, is the subject of a study by the same research OMe 0 207 206 208 [p:0l-3:1] The imines 209 react with the diene 207 as in the previous example, to give the dihydropyridones 2 10 together with a trace impurity 2 1 1 arising from residual nucleophile incorporation. The authors have detected no intermediates akin to 2 12 which would be consistent with a concerted [4 + 21 cycloaddition. However, the observation of 2 1 1 is circumstantial evidence for a tandem Mannich-Michael sequence via intermediates such as 2 13 (Scheme 1 1).0 0 OSiMe3 via lR’$OMe 21 2 Scheme 11 Steele: Saturated nitrogen heterocycles or I C’ 21 0 21 1 (trace only) 21 3 1053.6 Piperidinones Alper and his group7' have continued their explorations of carbonylative ring expansion reactions by demonstrating an efficient, cobalt-mediated conversion of the pyrrolidines 2 14 into the &lactams 2 15. The reaction is regioselective in that only the more substituted ring carbon migrates to CO. Although the Diels-Alder reaction primarily assembles C-C bonds, a corollary may be the generation of new heterocycles, and two research groups have recently used this protocol to advantage in alkaloid synthesis. Firstly, Yamaguchi and his co-workerss4 have achieved a quick entry to the yohimbane system which relies on nucleophilic addition of the dienylstannane 227 to a suitable cyclic imine 226 followed by in situ acylation with acryloyl chloride 228 to yield the bicycloannulated product 230.The triene intermediates 229 are not observed (Scheme 12). In the second report, by Leonard and his transiently the amidotriene 232 which rapidly cyclizes to generate the bicyclic amide 233. thermolysis of the sulfolene 231 liberates f+ 21 4 A' 21 5 The alkenamides 2 16 react with aryl aldehydes 2 17 typically in hot polyphosphoric acid to afford the unsaturated lactams 218 in good yield and with useful levels of diastereoselectivity in the C-C bond forming process.*" Momose and his colleagues* have disclosed that thioimidates 220, prepared from the unsaturated thioamides 2 19, undergo an efficient iodolactamization to provide the functionalized 2-piperidinones 22 1.0 0 Ar PPA or PPE 60 "C A4 21 7 21 6 + 21 8 Bn 21 9 Bn 220 22 1 The hydration-cyclization of y-ketonitriles such as 222 under ruthenium hydride catalysis generates the ene-lactams 223 in high yield, and Murahashi et aLS2 have applied this procedure to a relatively short synthesis of ( - )-pumiliotoxin C. Radical-initiated carbon-carbon bond formation is now almost ubiquitous in heterocyclic synthesis, and Gennari et a1.*3 have described an enantioselective synthesis of the tricyclic lactams 225 by a tin hydride facilitated cyclization of the aryl bromide 224. 0 R u H ~ ( P ~ ~ P ) ~ Cat.R' R' VCN H20 + 222 $?SPh Br I k' 223 Bu3SnH Alan - R m N R x - 229 L Scheme 12 231 PhMe reflux - 0 (..$ NMe2 ' 232 - v 230 -3 0 NMf+ 233 A useful Stevens [ 1,2]-shift route to 3-piperidinones has emerged. Thus, West et aZ.86 report that exposure of the aminopropyl diazoketones 234 to standard rhodium carbenoid conditions affords the cyclic aminoketones 236, presumably by a [ 1,2]-alkyl shift of the intermediate ylides 235. Using a similar protocol, the 5-oxopipecolic acids 238 have been assembled by a rhodium-mediated insertion of the carbenoid derived from the diazoketone 237.s7 r 1 kbz 237 Cbz 238 106 224 225 [P:a = 851 51 Contemporary Organic SynthesisLastly, reaction of the azapropenylium salts 239 with the enamine 240 generates the bicyclic imines 241, which are readily hydrolysed to the azabicyclo[3.2.l]octenones 242 (Scheme 13).88 R’ OEt EtO MRZ B Fq- 239 + 6 240 242 Scheme 13 4 Rings with two or more nitrogen atoms 4.1 Five-membered rings Treatment of the a-bromoacyl phenylhydrazones 243 with tributylstannane generates the radical intermediate 244 which then cyclizes to give the pyrazolidinones 245 rather than the anticipated diazetidinone 4-exo-trig products.89 As part of a new BugSnH I Me\! 243 244 synthesis of a-amino acids (Scheme 14), the chiral amidal246 has been converted into the organomercurial imidazolidinone 247.This versatile intermediate can then either be demetallated reductively, affording 249, or oxygenated, generating the alcohol 248.’O Baldwin and his co-workers have synthesized the conformationally restricted, bicyclic y-lactam dipeptide analogue 2 5 1, utilizing as the key transformation a cyclization of the acyliminium ion derived from the hemi-aminal 250.91 ‘!Cbz 247 n 246 Me TogoH NvNCbz 248 249 Scheme 14 CbzHN ph$pH cat.TFA 5;fk ~ C02Bn 250 25 1 4.2 Six-membered rings An efficient synthesis of both enantiomers of piperazic acid, a constituent of the anti-tumour antibiotic azinothricin, has been reported.92 The lithium enolate of the bromovaleryl carboximide 252 adds to the azodicarboxylate 253 giving direct access to the piperazine 254.Hydrolysis of 254 with lithium hydroxide then liberates bis-Boc (3 R )-piperazic acid 255. A further example of nucleophilic amide additions to acyliminium ions is provided by Wasserman and co-~orkers’~ as part of a synthetic route to azadethiacephams. The hemi-aminal256 liberates the iminium ion 257 on heating with pyridinium tosylate and subsequent cyclization then provides the bicyclic amidal258.0 LDA BU‘O~C-N=N -CO~BU’ * 253 252 r 256 Boc 254 LiOH THF J H*O Ho2cn BocO ‘y Boc 255 1 L 257 C0,Me I 0 258 In the course of an impressive enantioselective synthesis of ( - )-decarbamoylsaxitoxin, Hong and KishP4 have developed a remarkable trimolecular cyclization of the /I-amino unsaturated ester of the aminocrotonate 259, R-glyceraldehyde acetonide 26 1 and silicon tetraisothiocyanate 260 affording the cyclic thiourea 264 in 72% yield, Scheme 15. The reaction presumably proceeds by formation of the thiourea 262 which next undergoes a [ 3,3] cyclization, generating the zwitterion 263.A proton shift then gives 264. Steele: Saturated nitrogen heterocycles 107Me02C (SCN)3SiN=C= S 260 M e t o d Me O? H N k l 259 OHC 261 1 I 264 263 Scheme 15 Miknis and William~'~ have shown that reaction of the benzofuran 265 with N-bromosuccinimide generates stereoselectively the spirodiketopiperazine 266, an intermediate in the authors' completed synthesis of the fungal metabolite aspirochlorine. NR7 NH.OMe CI 0 266 4.3 Seven-membered rings As part of a programme to prepare analogues of the anti-HIV- 1 agent TIBO, Parker and Coburng6 have reported a regioselective synthesis of the benzodiazepines 268 by cyclization of the difluoronitrobenzenes 267. No attack at the para-fluoro position is observed. 02y *2N H K2C03 140 "C &>--Me N R H DMF R F F 268 267 5 Seven-, eight-, and nine-membered rings Two new azepane syntheses rely on photocyclization reactions.Thus, Piva and co-~orkers'~ have shown that photolysis of the vinylogous ketoamide 269 at 366 nm affords the tricyclic [2 + 21 cycloaddition product 270. In a study of intramolecular stilbene amine photoadditions, Lewis and Reddyg8 have demonstrated that the substrates 271 show a clear preference for seven-membered rings formation regardless of amine side chain length. Thus photolysis at 300 nm leads to either 272 or 273 with no formation of six- or eight-membered by-products (Scheme 16). 0 0 I f Ph 270 272 271 (n = 1 or2) Scheme 16 e N M e \ 273 Hydrogen chloride effects the cyclization of the keto-aminal274 via an intermediate iminium ion, to provide the azepane 275 as a mixture of isomers.Yg The product 275 has then been used to complete a Synthesis of ( + )-anatoxin a.274 V 275 Garner and his grouploo have used a 173-dipolar cycloaddition reaction between the acryloyl sultam 277 and a dipole generated by photolysis of the aziridinylimide 276 to provide the adduct 278 in good yield. This chemistry forms the basis of an asymmetric synthesis of ( - )-quinocarcin. OfloMe hv, 254 nm 276 dioxan 278 Overman et al. have established a useful, general route to medium-ring nitrogen heterocycles based on an iodide-promoted Mannich cyclization of alkynylamines such as 279.Io' The product 108 Contemporary Organic Synthesisdistribution favours the azepanes 280 over azocanes 28 1. A general route to monocyclic medium-ring lactams has been reported by Holmes and co-workers.lo2 The method relies on a Claisen rearrangement of the ketene aminals 282, which are generated in situ by selenoxide elimination, to afford the lactams 283. Yields are generally high for the assembly of seven-, eight-, and nine-membered rings.7" Bn 0 R (CH20)n Bu4NI ~ GR + (JJ, camphor sulonic acid I 279 I 280 281 Major Minor II. A PhMe or mxylene Cb! 0 _ _ _ 283 282 ( n = 0,1,2) The reaction of optically active p-ketoesters such as 284 with hydrazoic acid and a Lewis acid generates the tetrazoloazocanes 285 via the Schmidt rearrange- ment.lo3 The products 285 are then readily reduced by LAH to the homochiral azocane carbinols 286. C02Me R HN3, BFfOEt2 OH OR 284 285 286 As a key step in the synthesis of the fungal metabolite FR-900482, the lactone 287 was reduced to an intermediate aldehyde followed by a novel macrocyclic reductive alkylation to provide the benzazocane 2 88 .Io4 OAr 287 H 288 Finally, Moody and his grouplo5 have published full details of their synthesis of ( - )-indolactam V.In the course of this work, the authors describe photocyclizations of the tryptophan-derived amide 289. Photolysis in dry acetonitrile affords only the eight-membered lactam 290 but, in the presence of trace amounts of water, the major reaction product is the lactone 291. 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