Asymmetric synthesis of (1R,2S,3R)-3-methylcispentacin and (1S,2S,3R)-3-methyltranspentacin by kinetic resolution of tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate

Conjugate addition of lithium dibenzylamide to tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate occurs with high levels of stereocontrol, with preferential addition of lithium dibenzylamide to the face of the cyclic alpha,beta-unsaturated acceptor anti- to the 3-methyl substituent. High levels of enantiorecognition are observed between tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate and an excess of lithium (+/-)-N-benzyl-N-alpha-methylbenzylamide (10 eq.) (E > 140) in their mutual kinetic resolution, while the kinetic resolution of tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate with lithium (S)-N-benzyl-N-alpha-methylbenzylamide proceeds to give, at 51% conversion, tert-butyl (1R,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate consistent with E > 130, and in 39% yield and 99 +/- 0.5% de after purification. Subsequent deprotection by hydrogenolysis and ester hydrolysis gives (1R,2S,3R)-3-methylcispentacin in > 98% de and 98 +/- 1% ee. Selective epimerisation of tert-butyl (1R,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate by treatment with KO'Bu in 'BuOH gives tert-butyl (1S,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate in quantitative yield and in > 98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving (1S,2S,3R)-3-methyltranspentacin hydrochloride in > 98% de and 97 +/- 1% ee.     

Synthesis of trimethyl (2S,3R)- and (2R,3R)-[2-2H1]-homocitrates and dimethyl (2S,3R)- and (2R,3R)-[2-2H1]-homocitrate lactones-an assay for the stereochemical outcome of the reaction catalysed both by homocitrate synthase and by the Nif-V protein

Trimethyl (3R)-homocitrate 17, trimethyl (2S,3R)-[2-2H1]-homocitrate 17a and (2R,3R)-[2-2H1]-homocitrate 17b, as well as dimethyl (3R)-homocitrate lactone 18, (2S,3R)-[2-2H1]-homocitric lactone 18a and (2R,3R)-[2-2H1]-homocitric lactone 18b have been synthesised. D-quinic acid 12 was used as the source of the (3R)-centre in the unlabelled target compounds 17 and 18. (2)-Shikimic acid 19 and the (2)-[2-2H]-shikimic acid derivative 32 respectively were used in the synthesis of the labelled compounds. In the latter syntheses, Sharpless directed epoxidation of the olefin in the 5-deoxy ester diols 23 and 35 ensured a reaction from the same face as the allylic and homoallylic alcohols, and the reduction of the protected epoxides 25 and 37 ensured that the label was introduced in a stereoselective manner. The 1H NMR spectra of the labelled products present an assay for the stereochemistry of the biological reactions catalysed by homocitrate synthase and by the protein from the nifV gene.     

Chiral recognition and resolution of the enantiomers of supramolecular triangular hosts: synthesis, circular dichroism, NMR, and X-ray molecular structure of [Li subset(R,R,R)-[CpRh(5-chloro-2,3-dioxopyridine)]3][Delta-Trisphat

The racemic triangular supramolecular host [CpRh(5-chloro-2,3-dioxopyridine)](3) (1) was prepared in high yield. Treatment with LiCl followed by addition of silver salt AgOTf gave the triflate salt species [Li subset[CpRh(5-chloro-2,3-dioxopyridine)](3)][OTf] (2). Subsequent anion metathesis using the optically pure chiral shift reagent [Cinchonidinium][Delta-Trisphat] produced a pair of diastereomers [Li subset(R,R,R)-[CpRh(5-chloro-2,3-dioxopyridine)](3)][Delta-Trisphat] (3a) and [Li subset(S,S,S)-[CpRh(5-chloro-2,3-dioxopyridine)](3)][Delta-Trisphat] (3b). The resolution of these diastereomers was achieved by fractional crystallization, and their stereochemistry relationship was established by circular dichroism studies. The X-ray molecular structure of 3a is reported and shows as an outstanding feature a chiral recognition between the Delta-Trisphat anion and a single enantiomer cation [Li subset(R,R,R)-[CpRh(5-chloro-2,3-dioxopyridine)](3)](+) manifested through a pi-pi interaction. (1)H NMR and circular dichroism studies in solution support the solid-state behavior.     

(-)-(R)- and (+)-(S)-Carvone in the Synthesis of Optically Active Acetylenic Alcohols,Ethers, and Dichlorosilyl Derivatives

Reaction of butyllithium with acetylene and 1-hexyne gave the corresponding lithium acetylides which reacted with (-)-(R)- and (+)-(S-carvone in a stereospecific fashion to give lithium (1-ethynyl- or 1-hexynyl)-5-isopropenyl-2-methyl-2-cyclohexenolates. Hydrolysis of the latter gave individual optically active tertiary terpene alcohols having both acetylenic and p-menthene fragment. Their treatment with methyl iodide in the presence of hexamethylphosphoric triamide afforded the corresponding methyl ethers. The reaction of 3-ethynyl-5-isopropenyl-3-methoxy-2-methylcyclohexene with butyllithium and trichloro(vinyl)silane yielded optically active dichlorosilyl-containing acetylenic compounds.     

Asymmetric Reduction Using Lithium Aluminum Hydride Modified with Chiral Ligand Prepared from (1R)-(-)-Myrtenol

The reduction of prochiral ketones with a chiral reducing reagent, prepared from lithium aluminum hydride and (1R,2S,3S,5R)-(-)-10-methoxypinanediol (2), produced secondary chiral alcohols in good chemical yields (57–98%) and moderate enantiomeric excess (8–72%).     

Studies in polyphenol chemistry and bioactivity. 2. Establishment of interflavan linkage regio- and stereochemistry by oxidative degradation of an O-alkylated derivative of procyanidin B2 to (R)-(-)-2,4-diphenylbutyric acid

The assignment of interflavan bond regio- and stereochemistry in oligomeric proanthocyanidins has in the past relied on empirical spectroscopic techniques which are influenced by the conformation of the C rings. Only recently was the 4,8-regiochemistry of procyanidin B2 (3b) firmly established by 2-dimensional NMR methods. We describe herein the proof of 4beta-stereochemistry in 3b by oxidative degradation of the derivative 3d bearing differential (O-benzyl and O-methyl) protecting groups in its "top" and "bottom" epicatechin moieties, to (R)-(-)-2,4-diphenylbutyric acid. The key elements of the degradative process are (1) removal of the C-3 alcohol functions through a modified Barton deoxygenation employing hypophosphorous acid as the reducing agent; (2) deprotection of the "top" unit by hydrogenolysis, followed by exhaustive aryl triflate formation with N,N-bis(trifluoromethanesulfonyl)aniline and DBU in DMF; (3) hydrogenolytic deoxygenation of the "top" unit over Pearlman's catalyst with concomitant scission of the O-C2 bond; (4) selective oxidation of the "bottom" unit with NaIO4/RuCl3. The hitherto unreported absolute configuration of (-)-2,4-diphenylbutyric acid was established as R by X-ray crystal structure analysis of the (R)-(+)-alpha-methylbenzylamine salt. As a corollary, the selectivity of hydrogenolytic and solvolytic reactions of epicatechin-derived tetrasulfonates has been investigated.     

(-)-(1R,2S)-肉豆蔻木脂素的不对称合成

报道了天然产物(-)-肉豆蔻木脂素的全合成. 以香草醛为起始原料, 经Wittig反应、LiAlH₄还原和Sharplass不对称双羟化等反应构建了苏式结构的中间体; 以焦性没食子酸为原料, 经Claisen重排反应制得另一种苯丙素片段; 2个中间体通过Mitsunobu反应, 缩合并使构型翻转, 得到赤式-(-)-肉豆蔻木脂素. 为赤式8-O-4′新木脂素的合成提供了一种新方法.     

Asymmetric syntheses of the homalium alkaloids (-)-(s,s)-homaline and (-)-(r,r)-hopromine

The highly diastereoselective conjugate additions of the novel lithium amide reagents lithium (R)-N-(3-chloropropyl)-N-(α-methylbenzyl)amide and lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to α,β-unsaturated esters were used as the key steps in syntheses of the homalium alkaloids (-)-(S,S)-homaline and (-)-(R,R)-hopromine. The asymmetric synthesis of (-)-(S,S)-homaline was achieved in 8 steps and 18% overall yield, and the asymmetric synthesis of (-)-(R,R)-hopromine was achieved in 9 steps and 23% overall yield, from commercially available starting materials in each case. These syntheses therefore represent by far the most efficient total asymmetric syntheses of these alkaloids reported to date. A sample of the (4'R,4'S)-epimer of hopromine was also produced using this approach, which provided the first unambiguous confirmation of its absolute configuration and therefore that of natural (-)-(R,R)-hopromine.     

Enantioselective synthesis of (-)-pentalenene

A short, enantioselective synthesis of (-)-pentalenene is described. Catalytic enantioselective cyclopropenation with (R,R)-Rh2(OAc)(DPTI)3 was used to set the absolute stereochemistry, and an intramolecular Pauson-Khand reaction of the resulting cyclopropenyne was used to establish the quaternary center.     

Synthesis, resolution, and absolute stereochemistry of (1R, 2S)-(+)-cis-1-methoxycarbonyl-2-methylcyclobutane

Racemic cis-1-methoxycarbonyl-2-methylcyclobutane uncontaminated with the trans isomer was prepared efficiently in five steps; the corresponding amides from (R)-(-)-phenylglycinol were separated. An X-ray crystallographic structure determination of the amide from (+)-cis-1-methoxycarbonyl-2-methylcyclobutane showed that it was of (1R,2S) absolute stereochemistry, a revision of configurational assignment.     

Asymmetric synthesis of (4R,5R)-cytoxazone and (4R,5S)-epi-cytoxazone

(4R,5R)-Cytoxazone has been prepared in four steps and in 61% overall yield and >98% ee. Conjugate addition of lithium (R)-N-benzyl-N-[small alpha]-methylbenzylamide to tert-butyl (E)-3-(p-methoxyphenyl)prop-2-enoate and subsequent in situ diastereoselective enolate oxidation with (+)-(camphorsulfonyl)oxaziridine gave tert-butyl (2R,3R,[small alpha]R)-2-hydroxy-3-(p-methoxyphenyl)-3-(N-benzyl-N-[small alpha]-methylbenzylamino)propanoate in >98% de. Subsequent N-benzyl deprotection to the primary [small beta]-amino ester via hydrogenolysis, oxazolidinone formation with C(2)-retention by treatment with diphosgene and chemoselective ester reduction furnishes (4R,5R)-cytoxazone. The synthesis of the C(5)-epimer, (4R,5S)-epi-cytoxazone in 44% overall yield, has also been completed via a protocol involving N-Boc protection of the primary [small beta]-amino ester, utilization of the N-Boc group to facilitate simultaneous C(2)-inversion and oxazolidinone formation, and subsequent reduction.     

Reactivity of cyclooligophosphanes: synthesis and structural characterisation of cyclo-1,4-(BH3)2(P4Ph4CH2) and cyclo-1,2-(BH3)2(P5Ph5)

The borane complexes cyclo-1,4-(BH3)2(P4Ph4CH2) (3) and cyclo-1,2-(BH3)2(P5Ph5) (4) were prepared by reaction of cyclo-(P4Ph4CH2) and cyclo-(P5Ph5) with BH3(SMe2). Only the 2:1 complexes 3 and 4 were isolated, even when an excess of the borane source was used. In solution, 3 exists as a mixture of the two diastereomers (R(P)*,S(P)*,S(P)*,R(P)*)-(+/-)-3 and (R(P)*,R(P)*,R(P)*,R(P)*)-(+/-)-3. However, in the solid state the (R(P)*,S(P)*,S(P)*,R(P)*)-(+/-) diastereomer is the major stereoisomer. Similarly, while only one isomer of 4 is observed in its X-ray structure, NMR spectroscopic investigations reveal that it forms a complex mixture of isomers in solution. 3 may be deprotonated with tBuLi to give the lithium salt cyclo-1,4-(BH3)2(P4Ph4CHLi) (3 x Li), though this could not be isolated in pure form.     

Chiroptical properties of (R)-3-chloro-1-butene and (R)-2-chlorobutane

Coupled cluster and density functional models of specific rotation and vacuum UV (VUV) absorption and circular dichroism spectra are reported for the conformationally flexible molecules (R)-3-chloro-1-butene and (R)-2-chlorobutane. Coupled cluster length- and modified-velocity-gauge representations of the Rosenfeld optical activity tensor yield significantly different specific rotations for (R)-3-chloro-1-butene, with the latter providing much closer comparison (within 3%) to the available gas-phase experimental data at 355 and 633 nm. Density functional theory overestimates the experimental rotations for (R)-3-chloro-1-butene by approximately 80%. For (R)-2-chlorobutane, on the other hand, all three models give reasonable comparison to experiment. The theoretical specific rotations of the individual conformers of (R)-3-chloro-1-butene are much larger than those of (R)-2-chlorobutane, in disagreement with previous studies of the temperature dependence of the experimental rotations in solution. Simulations of VUV absorption and circular dichroism spectra reveal large differences between the coupled cluster and density functional excitation energies and the rotational strengths. However, while these differences lead to very different specific rotations for (R)-3-chloro-1-butene, they have much less impact on the computed specific rotations for (R)-2-chlorobutane. In addition, the coupled cluster VUV absorption spectrum of (R)-2-chlorobutane compares well to experiment.     

Total syntheses of beta-carboline alkaloids, (R)-(-)-pyridindolol K1, (R)-(-)-pyridindolol K2, and (R)-(-)-pyridindolol.

The total syntheses of beta-carboline alkaloids, (R)-(-)-pyridindolols (1, 5, and 6) are described. The two key steps involved are (1) a thermal electrocyclic reaction of the 3-alkenylindole-2-aldoxime 10 and (2) a thermal cyclization of 3-alkynylindole-2-aldoxime 11 to construct the beta-carboline N-oxides 8, which upon heating with acetic anhydride and sequential treatment with trifluoromethanesulfonic anhydride gave the triflates 18. The Stille coupling reaction of 18 with vinylstannane, followed by cleavage of MOM ether, afforded the 1-ethenyl-3-hydroxymethyl-beta-carboline (7a). Subsequent acetylation of 7a yielded the acetate 7b, which was subjected to the Sharpless asymmetric 1,2-dihydroxylation by AD-mix-beta to produce (R)-(-)-pyridindolol K2 (6). Selective acetylation of 6 was effected by Ac(2)O and collidine to form (R)-(-)-pyridindolol K1 (5). By contrast, hydrolysis of 6 provided (R)-(-)-pyridindolol (1).     

Molecular modeling of salt (lithium chloride) effects on the enantioselectivity of diethylzinc addition to benzaldehyde in the presence of chiral beta-amino alcohols

Beta-amino alcohols (S,S,S)-1 and (R,R,S)-1, derived from cyclohexene oxide and containing alpha-phenylethyl auxiliaries, were examined as chiral promoters in the addition of diethylzinc to benzaldehyde. In agreement with literature precedent, the N-alpha-phenylethyl chiral auxiliary had no significant impact on enantioinduction, which is determined by the configuration of the framework's C(OH), with unlike induction. Contrary to some literature reports, stereoinduction by lithium salt derivatives of (S,S,S)-1 and (R,R,S)-1 was lower than that obtained with the free amino alcohol. Remarkable lithium chloride salt effects were observed in the reaction. In particular, an opposite chiral induction was found with (S,S,S)-1-Li(2) as ligand and in the presence of "inert" salt. N-Alkylated derivatives (S,S,S)-3-7 proved to be more efficient ligands, providing higher yields and enantioselectivities in the formation of carbinols (R)- or (S)-2. BP86/DN**//PM3 theoretical calculations proved remarkably successful in reproducing the experimental observations and permitted expansion of Noyori's catalytic cycle [J. Am. Chem. Soc. 1995, 117, 6327] to understand the relevant N-substitution and medium salt effects that determine the enantioselection in this catalytic asymmetric reaction.     

Asymmetric synthesis of anti-(2S,3S)- and syn-(2R,3S)-diaminobutanoic acid

Conjugate addition of homochiral lithium N-benzyl-N-alpha-methylbenzylamide to tert-butyl (E)-cinnamate or tert-butyl (E)-crotonate and in situ amination with trisyl azide results in the exclusive formation of the corresponding 2-diazo-3-amino esters in > 95% de. Amination of the lithium (E)-enolates of tert-butyl (3S,alphaR)-3-N-benzyl-N-alpha-methylbenzylamino-3-phenylpropanoate or tert-butyl (3S,alphaS)-3-N-benzyl-N-alpha-methylbenzylaminobutanoate with trisyl azide gives the (2R,3R,alphaR)- and (2S,3S,alphaS )-anti-2-azido-3-amino esters in good yields and in 85% de and > 95% de respectively. Alternatively, tert-butyl anti-(2S,3S,alphaS)-2-hydroxy-3-N-benzyl-N-alpha-methylbenzylaminobutanoate may be converted selectively to tert-butyl anti-(2S,3S,alphaS)-2-azido-3-N-benzyl-N-alpha-methylbenzylaminobutanoate by aziridinium ion formation and regioselective opening with azide. Deprotection of tert-butyl (2S,3S,alphaS)-2-azido-3-aminobutanoate via Staudinger reduction, hydrogenolysis and ester hydrolysis furnishes anti-(2S,3S)-diaminobutanoic acid in 98%, de and 98% ee. The asymmetric synthesis of the diastereomeric syn-(2R,3S)-diaminobutanoic acid (98% de and 98% ee) was accomplished via functional group manipulation of tert-butyl anti-(2S,3S,alphaS)-2-hydroxy-3-N-benzyl-N-alpha-methylbenzylaminobutanoate in a protocol involving azide inversion of tert-butyl (2S,3S)-2-mesyloxy-3-N-Boc-butanoate and subsequent deprotection.     

Total synthesis of nominal (11S)- and (11R)-cyclocinamide A

The cyclocinamides possess a unique β(2)αβ(2)α 14-membered tetrapeptide core. The initially reported biological data and intriguing structure, which was without full stereochemical identification, necessitated synthesis of both nominal (all-S) cyclocinamide A and the 11R isomer. The completed synthesis is highlighted by the use of a (cyclo)asparagine-containing dipeptide as a turn inducing fragment. Due to inconsistencies in analytical data between natural and synthetic samples, a re-evaluation of the natural product stereochemistry appears necessary.     

Enantioselective inclusion of methyl phenyl sulfoxides and benzyl methyl sulfoxides by (R)-phenylglycyl-(R)-phenylglycine and the crystal structures of the inclusion cavities

Crystalline (R)-phenylglycyl-(R)-phenylglycine [(R,R)-1] includes methyl phenyl sulfoxides (2 and 3) and benzyl methyl sulfoxides (4) with high enantioselectivity. The dipeptide exhibited different stereoselectivity depending on four structural isomers of methyl tolyl sulfoxide (C(8)H(10)OS): R for methyl 2-tolyl sulfoxide, S for methyl 3-tolyl sulfoxide, and racemic for methyl 4-tolyl sulfoxide. A structural isomer, benzyl methyl sulfoxide, was included in racemic form. Chlorophenyl methyl sulfoxides 3 (C(7)H(7)ClOS) with a similar volume showed the same enantioselectivity for their recognition. By single-crystal X-ray analyses of these inclusion compounds, it was elucidated that (R,R)-1 molecules self-assembled to form layer structures and included the sulfoxides between these layers and that the origin of the enantioselectivity based on chiral cavities was induced by conformation of the C-terminal phenyl group of the dipeptide. The relative position between the ammonio proton and the C-terminal phenyl group in one molecule of the dipeptide determined the stereochemistry of the methyl sulfinyl groups to be recognized. Various positional isomers of methyl xylyl sulfoxide having the formula of C(9)H(12)OS were subjected to the enantioselective inclusion by (R,R)-1 crystals and these results are also discussed.     

A synthesis of (+/-)-sparteine

In a synthesis of racemic sparteine, Diels-Alder reaction between dimethyl bromomesaconate 14 and dicyclopentenyl 4, followed by cyclopropane formation, set up the stereochemistry at C-1 and C-5 as S and R, respectively, in a meso intermediate 8. The stereochemistry at C-2 and C-4 was then secured by a moderately diastereoselective protonation of the bis-enolate 17 derived from the diester 8 by reductive cleavage with lithium in liquid ammonia. The C=C in the racemic diester 19 was ozonolysed and the diketone converted by Beckmann rearrangement into the bis-lactam . Reduction of the bis-lactam with lithium aluminium hydride and intramolecular nucleophilic displacement gave racemic sparteine 1. Some ideas for making this synthesis amenable to a synthesis of enantiomerically enriched sparteine are presented.     

Total synthesis of (-)- and (+)-dysibetaine

Glycidamides 6R and 6S were elaborated to (R,R)- and (S,S)-dysibetaines (1R and 1S) by intramolecular alkylation and functional group modification in 23% overall yield. The absolute stereochemistry of natural dysibetaine was established as S,S by comparison of the optical rotation of the natural product with that of the synthetic materials.