Kinetic resolution and parallel kinetic resolution of methyl (+/-)-5-alkyl-cyclopentene-1-carboxylates for the asymmetric synthesis of 5-alkyl-cispentacin derivatives

Conjugate addition of lithium dibenzylamide to methyl 5-isopropyl, 5-phenyl- and 5-tert-butyl-cyclopentene-1-carboxylates occurs with high levels of substrate control (>88% de), with preferential addition to the face of the cyclic alpha,beta-unsaturated acceptor anti- to the stereodirecting 5-alkyl substituent. Treatment of a range of methyl (+/-)-5-alkyl-cyclopentene-1-carboxylates with both lithium (+/-)-N-benzyl-N-alpha-methylbenzylamide and lithium (+/-)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide indicates significant enantiorecognition in their mutual kinetic resolutions, with preferential addition anti- to the 5-alkyl substituent, giving the 1,2-syn-1,5-anti-arrangement (E >16) after enolate protonation anti- to the amino functionality. The kinetic resolution of a range of methyl (+/-)-5-alkyl-cyclopentene-1-carboxylates with lithium (S)-N-benzyl-N-alpha-methylbenzylamide, and their efficient parallel kinetic resolution with a pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-alpha-methylbenzylamide and lithium (R)-N-3,4-dimethoxybenzyl-N-alpha-methylbenzylamide are also demonstrated, giving a range of 5-alkyl-cispentacin derivatives in >98% de and high ee after N-deprotection.     

Parallel kinetic resolution of tert-butyl (RS)-3-oxy-substituted cyclopent-1-ene-carboxylates for the asymmetric synthesis of 3-oxy-substituted cispentacin and transpentacin derivatives

tert-Butyl (RS)-3-methoxy- and (RS)-3-tert-butyldiphenylsilyloxy-cyclopent-1-ene-carboxylates display excellent levels of enantiorecognition in mutual kinetic resolutions with both lithium (RS)-N-benzyl-N-(alpha-methylbenzyl)amide and lithium (RS)-N-3,4-dimethoxybenzyl-N-(alpha-methylbenzyl)amide. A 50 : 50 pseudoenantiomeric mixture of lithium (S)-N-benzyl-N-(alpha-methylbenzyl)amide and lithium (R)-N-3,4-dimethoxybenzyl-N-(alpha-methylbenzyl)amide allows for the efficient parallel kinetic resolution of the tert-butyl (RS)-3-oxy-substituted cyclopent-1-ene-carboxylates, affording differentially protected 3-oxy-substituted cispentacin derivatives in high yield and >98% de. Subsequent N-deprotection and hydrolysis provides access to 3-oxy-substituted cispentacin derivatives in good yield, and in >98% de and >98% ee, while stereoselective epimerisation and subsequent deprotection affords the corresponding transpentacin analogues in good yield, and in >98% de and >98% ee.     

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.     

Kinetic resolution of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates for the synthesis of homochiral 3-alkyl-cispentacin and 3-alkyl-transpentacin derivatives

High levels of stereocontrol are observed in the conjugate addition of lithium dibenzylamide to tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn), with addition occurring exclusively anti- to the 3-alkyl substituent. Treatment of a range of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn, (i)Pr, (t)Bu) with lithium (RS)-N-benzyl-N-[small alpha]-methylbenzylamide indicates that good enantiorecognition is observed (E > 80) in their mutual kinetic resolution. In these reactions, conjugate addition of the lithium amide occurs exclusively anti- to the 3-alkyl substituent, with subsequent C(1)-protonation occurring preferably anti- to the 2-amino group in the 3-Et, 3-Bn and 3-(i)Pr cases, giving predominantly the corresponding 1,2-syn-2,3-anti-diastereoisomers. Conjugate addition to (RS)-3-tert-butyl cyclopentene-1-carboxylate results in exclusive 2,3-anti -addition and a reversal in C(1)-protonation selectivity, giving predominantly the 1,2-anti-2,3-anti-diastereoisomer. Furthermore, the kinetic resolution of the tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn, (i)Pr, (t)Bu) with lithium (S)-N-benzyl-N-alpha-methylbenzylamide proceeds efficiently, giving, at between 47 and 51% conversion, the resolved 3-alkylcyclopentene-1-carboxylates in >85 to >98% ee and the beta-amino ester products of conjugate addition in high de, consistent with E > 80 in each case. Subsequent deprotection of the 1,2-syn-2,3-anti-3-alkyl-beta-amino esters (alkyl = Et, Bn, (i)Pr) by hydrogenolysis and ester hydrolysis gives the corresponding 1,2-syn-2,3-anti-3-alkylcispentacins in >98% de and 98 +/- 1% ee. Selective epimerisation of the 1,2-syn-2,3-anti-3-alkyl-beta-amino esters (alkyl = Et, Bn, (i)Pr, (t)Bu) by treatment with KO(t)Bu in (t)BuOH gives the corresponding 1,2-anti-2,3-anti-3-alkyl-beta-amino esters in quantitative yield and in >98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving the corresponding 1,2-anti-2,3-anti-3-alkylcispentacin hydrochlorides in >98% de.     

Parallel kinetic resolution of acyclic γ-amino-α,β-unsaturated esters: application to the asymmetric synthesis of 4-aminopyrrolidin-2-ones

Conjugate addition of a 50:50 pseudoenantiomeric mixture of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide and lithium (S)-N-3,4-dimethoxybenzyl-N-(α-methylbenzyl)amide to a range of racemic acyclic γ-amino-α,β-unsaturated esters (derived from the corresponding α-amino acids) effects their efficient parallel kinetic resolution, allowing the preparation of enantiopure β,γ-diamino esters. The β,γ-diamino ester products of these reactions are readily converted into the corresponding substituted 4-aminopyrrolidin-2-ones via N-debenzylation and cyclization.     

Asymmetric synthesis of (1R,2S,3R)-gamma-methyl-cis-pentacin by a kinetic resolution protocol

The asymmetric synthesis of (1R,2S,3R)-3-methyl-2-amino-cyclopentane carboxylic acid has been achieved via kinetic resolution of racemic tert-butyl 3-methyl-cyclopentene-1-carboxylate with homochiral lithium (S)-N-benzyl-N-alpha-methylbenzylamide.     

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.     

Asymmetric synthesis of (alphaR)-polyfluoroalkylated prolinols based on the perfluoroalkyl-induced highly stereoselective reduction of perfluoroalkyl N-Boc-pyrrolidyl ketones

Reduction of the obtained chiral (S)- tert-butyl 2-(perfluoroalkanoyl)pyrrolidine-1-carboxylate with sodium borohydride or lithium aluminum hydride proceeded smoothly to give the corresponding (S)- tert-butyl 2-((R)-perfluoro-1-hydroxyalkyl)pyrrolidine-1-carboxylate in yields of 73-97% with excellent diastereoselectivities (up to >98% de), compared with the reduction of nonfluorinated (S)-tert-butyl 2-pentanoylpyrrolidine-1-carboxylate.     

Asymmetric synthesis of aziridines by reduction of N-tert-butanesulfinyl alpha-chloro imines

Reduction of (RS)-N-tert-butanesulfinyl alpha-halo imines afforded chiral aziridines in good to excellent yields. Upon reduction of (RS)-N-tert-butanesulfinyl alpha-halo imines with NaBH4 in THF, in the presence of 10 equiv of MeOH, (RS,S)-beta-halo sulfinamides were formed in excellent yield (up to 98%) with very good stereoselectivity (>98:2). Simple treatment of the latter (RS,S)-beta-halo-tert-butanesulfinamides with KOH afforded the corresponding (RS,S)-N-(tert-butylsulfinyl)aziridines in quantitative yields. On the contrary, its epimer, (RS,R)-N-(tert-butylsulfinyl)aziridine was synthesized by switchover of the reducing agent from NaBH4 to LiBHEt3. (RS,R)-N-(tert-Butylsulfinyl)aziridines were synthesized in good yields (up to 85%) and diastereoselectivity (up to 92:8) by reduction of (RS)-N-tert-butanesulfinyl alpha-halo imines with LiBHEt3 in dry THF and subsequent treatment with KOH. All chiral aziridines were obtained as a single diastereomer after recrystallization (overall yield up to 91%) or after flash chromatography.     

Preparation of optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (threo-beta-phenylserine) via optical resolution

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1), (2RS,3SR)-2-benzoylamino-3-hydroxy-3-phenylpropanoic acid [(2RS,3SR)-2] was first optically resolved using (1S,2S)- and (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol as the resolving agents to afford (2R,3S)- and (2S,3R)-2 in yields of 73% and 66%, based on half of the starting amount of (2RS,3SR)-2. Next, the racemic structures of ammonium and some organic ammonium salts of (2RS,3SR)-2 were examined based on melting point, solubility, and infrared spectrum, with the aim of optical resolution by preferential crystallization. The benzylammonium salt of (2RS,3SR)-2 was suggested to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. The optical resolution by preferential crystallization of the racemic salt afforded the (2R,3S)- and (2S,3R)-salts with optical purities of 90-97%. The (2R,3S)- and (2S,3R)-2 obtained from the purified salts were hydrolyzed by reflux in hydrochloric acid to give (2R,3S)- and (2S,3R)-1.     

General asymmetric hydrogenation of alpha-branched aromatic ketones catalyzed by TolBINAP/DMAPEN-ruthenium(II) complex

[reaction: see text] A catalyst system consisting of RuCl2[(S)-tolbinap][(R)-dmapen] and t-C4H9OK in 2-propanol effects asymmetric hydrogenation of arylglyoxal dialkylacetals to give the alpha-hydroxy acetals in up to 98% ee. Hydrogenation of racemic alpha-amidopropiophenones under dynamic kinetic resolution predominantly gives the syn alcohols in up to 99% ee and >98% de, while the reaction of racemic bezoin methyl ether gives the anti alcohols in excellent stereoselectivity.     

Preparation of optically active (2RS,3SR)-2-amino-3-hydroxy-3-phenylpropanoic acid (threo-beta-phenylserine) via optical resolutions by replacing and preferential crystallization

To obtain optically active threo-2-amino-3-hydroxy-3-phenylpropanoic acid (1) via optical resolutions by replacing and preferential crystallization, the racemic structure of (2RS,3SR)-1 hydrochloride [(2RS,3SR)-1.HCl] was examined based on the melting point, solubility, and infrared spectrum. (2RS,3SR)-1.HCl was indicated to exist as a conglomerate at room temperature, although it forms a racemic compound at the melting point. When, in optical resolution by replacing crystallization, L-phenylalanine methyl ester hydrochloride (L-2) was used as the optically active co-solute, (2R,3S)-1.HCl was preferentially crystallized from the supersaturated racemic solution; the use of D-2 as the co-solute afforded (2S,3R)-1.HCl with an optical purity of 95%. In addition, optical resolution by preferential crystallization was successfully achieved to give successively (2R,3S)- and (2S,3R)-1.HCl with optical purities of 90-92%. The (2R,3S)- and (2S,3R)-1.HCl purified by recrystallization from 1-propanol were treated with triethylamine in methanol to give optically pure (2R,3S)- and (2S,3R)-1.     

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.     

Asymmetric synthesis and applications of beta-amino Weinreb amides: asymmetric synthesis of (S)-coniine

Conjugate addition of lithium (S)-N-benzyl-N-alpha-methylbenzylamide to a range of alpha, beta-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The beta-amino Weinreb amide products may be transformed into beta-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes beta-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral delta-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.     

Lithium amide conjugate addition for the asymmetric synthesis of 3-aminopyrrolidines

Conjugate addition of homochiral lithium amides to methyl 4-(N-benzyl-N-allylamino)but-2-enoate, chemoselective N-deprotection and concomitant cyclisation, followed by enolate functionalisation and deprotection allows access to syn- and anti-3,4-disubstituted aminopyrrolidines in > 98% d.e. and > 98% e.e.     

Structure-enantioselectivity effects in 3,4-dihydropyrimido[2,1-b]benzothiazole-based isothioureas as enantioselective acylation catalysts

The catalytic activity and enantioselectivity in the kinetic resolution of (±)-1-naphthylethanol with a range of structurally related 3,4-dihydropyrimido[2,1-b]benzothiazole-based catalysts is examined. Of the isothiourea catalysts screened, (2S,3R)-2-phenyl-3-isopropyl substitution proved optimal, giving good levels of selectivity in the kinetic resolution of a number of secondary alcohols (S values up to >100 at ~50% conversion). Low catalyst loadings (0.10-0.25 mol%) of the optimal isothiourea can be used to generate enantiopure alcohols (>99% ee) in good yields.     

Asymmetric synthesis of hexapropionate synthons by sequential enantiotopic group selective enolization of meso diketones

Meso 1,9-diketones (six to seven stereocenters) are readily obtained by stepwise or simultaneous two-directional aldol reactions of tetrahydro-4H-thiopyran-4-one with a thiopyran-derived aldehyde or dialdehyde. Enantioselective enolizations of these diketones with the lithium amide from (R,R)-bis(1-phenylethyl)amine occur with simultaneous kinetic resolution to give the mono-TMS enol ethers in >90% yields (BORSM) and >95% ee. The products are applicable to polypropionate synthesis. [reaction: see text]     

Bischler-Napieralski Reaction of 2-(3,4-Dimethoxy-2-nitrophenyl)-N-[2-(3,4-dimethoxyphenyl)ethyl]-N-[(S)-1-phenylethyl] acetamide Accompanied by Elimination of Chiral Auxiliary

Chiral 1-benzyltetrahydroisoquinoline alkaloids can be asymmetrically synthesized via Bischler-Napieralski (B-N) cyclization followed by stereoselective NaBH4 reduction (Polniaszek抯 method) of the N- (2-phenylethyl)-2-phenylacetamides bearing chiral auxiliary such as (S)-1-phenylethyl group on the nitrogen atom1-4. Recently Y. Ohishi and co-workers found an unusual B-N reaction on the carbon at 2-position of the A ring, which bears a bromine atom5, 6. They indicated that the steric ef…     

Optically active cyclohexene derivative as a new antisepsis agent: an efficient synthesis of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242)

Two new synthetic methods were established for the efficient synthesis of optically active cyclohexene antisepsis agent, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate [(R)-1: TAK-242)]. The first method involved recrystallization from methanol of the diastereomeric mixture (6RS,1'R)-7, obtained by esterification of carboxylic acid 3 with (S)-1-(4-nitrophenyl)ethanol [(S)-5)] to give the desired isomer (6R,1'R)-7 with 99% de in 32% yield. Subsequent catalytic hydrogenolysis and esterification gave (R)-1 with >99% ee. The second method employed enantioselective hydrolysis of acetoxymethyl ester 9a (prepared by alkylation of 3 with bromomethyl acetate) with Lipase PS-D to give the eutomeric enantiomer (R)-9a with excellent enantioselectivity (>99% ee) and high yield (48%). The desired (R)-1 was then obtained by transesterification with ethanol in the presence of concentrated sulfuric acid without loss of ee. Of these, the procedure employing enzymatic kinetic resolution using Lipase PS-D is the more efficient and practical preparation of (R)-1.     

«3-Fluorisopren» (2-Fluor-3-methyl-1,3-butadien) und einige heterosubstituierte Abkömmlinge

‘3-Fluoroisoprene’ (2-Fluoro-3-methyl-1,3-butadiene) and Some Hetero-substituted Derivatives Thereof The readily accessible 1-chloro-1-fluoro-2-iodomethyl-2-methylcyclopropane undergoes zinc-promoted ring-cleavage yielding 2-fluoro-3-methyl-1, 3-butadiene (‘3-fluoroisoprene’) in almost quantitative yield. Alternatively the iodine atom may be replaced by electron-attracting groups such as cyano, benzenesulfonyl or triphenylphosphonio. Ring-opening of the resulting derivatives can then be brought about by various bases and leads to substituted fluorodienes. - The chemical reactivity of ‘3-fluoroisoprene’ has been studied in some detail. For example, it was found to add bromine at temperatures below 0° under kinetic control and to afford mainly the 1,4-adduct having the (Z)-configuration besides smaller quantities of the 1,2- and 3,4-adduct. At room temperature this mixture slowly undergoes a transformation yielding, as the sole products, both stereoisomeric 1, 4-adducts in a 1:1 ratio.