Asymmetric synthesis of the cis- and trans-stereoisomers of 4-aminopyrrolidine-3-carboxylic acid and 4-aminotetrahydrofuran-3-carboxylic acid

The diastereoselective conjugate addition of lithium (S)-N-benzyl-N-[small alpha]-methylbenzylamide has been successfully applied to the first asymmetric syntheses of cis-(3S,4R)- and trans-(3R,4R)-4-aminotetrahydrofuran-3-carboxylic acids (26% and 25% overall yield respectively, >98% d.e. and >97% e.e. in each case). Furthermore, the most efficient asymmetric synthesis to date of cis-(3R,4R)- and trans-(3R,4S)-4-aminopyrrolidine carboxylic acids is delineated: for cis-(3R,4R), four steps, >98% d.e., 52% overall yield; for trans-(3R,4S), five steps, >98% d.e., 50% overall yield.     

New chiral didehydroamino acid derivatives from a cyclic glycine template with 3,6-dihydro-2H-1,4-oxazin-2-one structure: applications to the asymmetric synthesis of nonproteinogenic alpha-amino acids

New chiral (Z)-alpha,beta-didehydroamino acid (DDAA) derivatives with 3,5-dihydro-2H-1,4-oxazin-2-one structure 11a-f have been stereoselectively prepared after condensation of chiral glycine equivalent 7 with aldehydes in the presence of K(2)CO(3) under mild solid-liquid phase-transfer catalysis reaction conditions. These new systems have been used in diastereoselective cyclopropanation reactions using Corey's ylide for the asymmetric synthesis of 1-aminocyclopropane-1-carboxylic acids (ACCs) such as allo-corononamic and allo-norcoronamic acids. The hydrogenation reaction of these systems at ambient pressure in the presence of formaldehyde affords saturated oxazinones and N-methylated oxazinones which have been transformed into the N-methyl-alpha-amino acids (N-MAAs) (S)-2-(methylamino)butanoic acid and (S)-N-methylleucine. In addition, the parent alpha, beta-didehydroalanine derivative 11g has been prepared by a direct aminomethylation-elimination sequence from 7 and Eschenmoser's salt and has been used in Diels-Alder cycloaddition with endo selectivity for the synthesis of the enantiomerically pure bicyclic alpha-amino acids (-)-2-aminobicyclo[2.2.1]heptane-2-carboxylic and (-)-2-aminobicyclo[2.2.2]octane-2-carboxylic acids.     

Synthese der 1-aminocyclopropan-1-carbonsäure

Zusammenfassung Durch Addition von Diazomethan an -Acetamidoacrylsäuremethylester (I) und Pyrolyse des erhaltenen Pyrazolins wurde eine neue Synthese der 1-Aminocyclopropan-1-carbonsäure gefunden.

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The synthesis of 1-aminocyclopropane-1-carboxylic acid

A new synthesis of 1-aminocyclopropane-1-carboxylic acid has been achieved using the addition of diazomethane to methyl -acetamido acrylate (I) and subsequent pyrolysis of the resulting pyrazoline.

     

Enantioselective nitrile anion cyclization to substituted pyrrolidines. A highly efficient synthesis of (3S,4R)-N-tert-butyl-4-arylpyrrolidine-3-carboxylic acid

[reaction: see text] A practical asymmetric synthesis of N-tert-butyl disubstituted pyrrolidines via a nitrile anion cyclization strategy is described. The five-step chromatography-free synthesis of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid (2) from 2-chloro-1-(2,4-difluorophenyl)-ethanone achieved a 71% overall yield. The cyclization substrate was prepared via a catalytic CBS asymmetric reduction, t-butylamine displacement of the chlorohydrin, and a conjugate addition of the hindered secondary amine to acrylonitrile. The key nitrile anion 5-exo-tet cyclization concomitantly formed the pyrrolidine ring with clean inversion of the C-4 center to afford 1,3,4-trisubstituted chiral pyrrolidine in >95% yield and 94-99% ee. Diethyl chlorophosphate and lithium hexamethyldisilazide were shown to be the respective optimum activating group and base in this cyclization. The trans-cis mixture of the pyrrolidine nitrile undergoes a kinetically controlled epimerization/ saponification to afford the pure trans-pyrrolidine carboxylic acid target compound in >99.9% chemical and optical purity. This chemistry was also shown to be applicable to both electronically neutral and rich substituted phenyl substrates.     

Asymmetric total synthesis of the 1-epi-aglycon of the cripowellins A and B

[structure: see text] The unusual [5.3.2]-bicyclic structure of the insecticidal Amaryllidaceae alkaloids cripowellin A (1) and B (2) has been synthesized for the first time via a sequence of Sharpless dihydroxylation, ring-closing metathesis, and intramolecular Heck reaction. The asymmetric synthesis of the 1-epi-aglycon 82 proceeds with virtually complete diastereo- and enantioselectivity (de, ee > or = 98%) in 13 steps and an overall yield of 5.6%. In addition, three alternative approaches toward the aglycon 3 are also described focusing on (1) the alkylation of the 2-benzazepinedithianes 35 and 36 with the electrophile 11, (2) a radical cyclization of the precursor (R/S,S,S)-39, and (3) an intramolecular arylation reaction of the aryl ketone 47.     

A Novel Synthesis of 1-Aminocyclopropane-1-carboxylic Acid (ACC)

A novel synthetic route of 1-aminocyclopropane-1-carboxylic acid (ACC) has been built via cyclopropanedicarboxylic acid monohydrazide III in moderation to good yield.     

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.     

手性膦酸二酯类化合物的合成与结构

手性呋喃酮1a1b与亚磷酸三酯2a2b通过串联的不对称Michael加成/分子内Michalis-Arbazov重排反应,得到含磷官能团的新手性化合物5-(S)-(1S)-冰片氧基-4-膦酸二酯基-3-卤素-2(5H)-呋喃酮(3a～3d).该反应具有条件温和,产率高(69%～93%),光学纯度单一(d.e.≥98%)等特点.通过元素分析,IR,UV¹HNMR¹³CNMR,MS,[α]_D²⁰等分析数据以及X射线四圆衍射确定了它们的化学结构和绝对构型.     

Asymmetric allylboration of acyl imines catalyzed by chiral diols

Chiral BINOL-derived diols catalyze the enantioselective asymmetric allylboration of acyl imines. The reaction requires 15 mol % (S)-3,3'-Ph2-BINOL as the catalyst and allyldiisopropoxyborane as the nucleophile. The reaction products are obtained in good yields (75-94%) and high enantiomeric ratios (95:5-99.5:0.5) for aromatic and aliphatic imines. High diastereoselectivities (diastereomeric ratio > 98:2) and enantioselectivities (enantiomeric ratio > 98:2) are obtained in the reactions of acyl imines with crotyldiisopropoxyboranes. This asymmetric transformation is directly applied to the synthesis of Maraviroc, the selective CCR5 antagonist with potent activity against HIV-1 infection. Mechanistic investigations of the allylboration reaction including IR, NMR, and mass spectrometry studies indicate that acyclic boronates are activated by chiral diols via exchange of one of the boronate alkoxy groups with activation of the acyl imine via hydrogen bonding.     

手性4-膦酸二酯基-3-卤-2(5H)-呋喃酮的合成与结构

手性呋喃酮1a-1b与亚磷酸三酯2a-2b通过串联的不对称Michael加成/分子内Michalis-Arbazov重排反应,得到了含磷官能团的新手性化合物,5-(S)-(l-孟氧基)-4-膦酸二酯基-3-卤素-2(5H)-呋喃酮4a-4d。该反应具有条件温和,产率高(86%-95%),光学纯度单一(d.e.≥98%)的特点。通过元素分析,IR,UV,^1HNMR,^1^3CNMR,MS,[α]~D^2^0波谱分析数据以及X射线四圆衍射数据确定了它们的化学结构和绝对构型。     

Design of sulfides with a locked conformation as promoters of catalytic and asymmetric sulfonium ylide epoxidation

[reaction: see text] A new generation of 2,5-dimethylthiolanes with a locked conformation was developed to promote the asymmetric addition of chiral sulfonium ylides to aldehydes. The novel chiral sulfur derivative 4 succeeded the synthesis of trans-stilbene oxide derivatives with enantiomeric ratios ranging from 95:5 to 98:2. This user-friendly organocatalytic process proved to be efficient with 20-10% of sulfide 4 in 1 or 2 days of reaction. An insight into the ylide intermediate conformation is given on the basis of a computational ab initio study.     

Microbial enantioselective ester hydrolysis for the preparation of optically active 4,1-benzoxazepine-3-acetic acid derivatives as squalene synthase inhibitors

Microbial enantioselective ester hydrolysis for the preparation of optically active (3R,5S)-(-)-5-phenyl-4,1-benzoxazepine-3-acetic acid derivatives as potent squalene synthase inhibitors was investigated. Pseudomonas diminuta and Pseudomonas taetrolens hydrolyzed the racemic ethyl ester of the 5-(2-chlorophenyl) analogue to yield the (-)-carboxylic acid with excellent enantiomeric excess (>99% ee). We found that the (-)-enantiomer was an active inhibitor. Bulkiness of the ester moiety did not affect the enantioselectivity but did affect reactivity. The racemic ethyl ester of the 5-(2-methoxyphenyl) analogue, 5-(2,3-dimethoxyphenyl) analogue and 5-(2,4-dimethoxyphenyl) analogue were also hydrolyzed with Pseudomonas taetrolens to afford enantiomerically pure (-)-carboxylic acids in large scale. As another route to (3R,5S)-(-)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetic acid [(-)-1c], the earlier intermediate (-)-2-amino-5-chloro-alpha-(2,3-dimethoxyphenyl)benzyl alcohol [(-)-12] was successfully obtained by asymmetric hydrolysis of (+/-)-5-chloro-alpha-(2,3-dimethoxyphenyl)-2-pivaloylaminobenzyl acetate with Pseudomonas sp. S-13 with >99% ee in kilogram scale followed by alkaline treatment. The product (-)-12 was converted to (-)-1c without racemization.     

Development of versatile cis- and trans-dicarbon-substituted chiral cyclopropane units: synthesis of (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes and their enantiomers as conformationally restricted analogues of histamine

The cyclopropane ring can be used effectively in restricting the conformation of biologically active compounds to improve activity and also to investigate bioactive conformations. We designed (1S,2R)- and (1R,2R)-2-aminomethyl-1-(1H-imidazol-4-yl)cyclopropanes (1 and 2, respectively) and their enantiomers (ent-1 and ent-2) as conformationally restricted analogues of histamine. The four types of chiral cyclopropanes bearing two differentially functionalized carbon substituents in a cis or trans relationship on a cyclopropane ring, (1S,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (7) and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (8) and their enantiomers (ent-7 and ent-8), were developed as the key intermediates for synthesizing 1, 2, ent-1, and ent-2. The reaction between (R)-epichlorohydrin [(R)-12] and phenylsulfonylacetonitrile (13a) in the presence of NaOEt in EtOH followed by treatment with acid gave the chiral cyclopropane lactone 11a with 98% ee in 82% yield. Compound 11a was converted into both the cis- and trans-chiral cyclopropane units 7 and 8, respectively, via reductive desulfonylation with Mg/MeOH as the key step. The corresponding enantiomers, the cis-substituted ent-7 and the trans-substituted ent-8, were also prepared starting from (S)-epichlorohydrin [(S)-12]. The four conformationally restricted target histamine analogues 1, 2, ent-1, and ent-2 were successfully synthesized from 7, 8, ent-7, and ent-8, respectively. The chiral cyclopropane units 7, 8, ent-7, and ent-8 should be useful as versatile intermediates for synthesizing various compounds having an asymmetric cyclopropane structure.     

SuperQuat N-acyl-5,5-dimethyloxazolidin-2-ones for the asymmetric synthesis of alpha-alkyl and beta-alkyl aldehydes

The proclivity of alpha-branched N-2'-benzyl-3'-phenylpropionyl derivatives of (S)-4-benzyl-5,5-dimethyl-, (S)-4-phenyl-5,5-dimethyl-, (S)-4-isopropyl-5,5-dimethyl-, (S)-4-benzyl- and (S)-4-benzyl-5,5-diphenyl-oxazolidin-2-ones to generate directly 2-benzyl-3-phenylpropionaldehyde upon hydride reduction with DIBAL is investigated. The (S)-4-benzyl-5,5-dimethyl-derivative proved optimal for inhibition of endocyclic nucleophilic attack, giving 2-benzyl-3-phenylpropionaldehyde in good yield upon reduction. Application of this methodology for the asymmetric synthesis of chiral aldehydes via diastereoselective enolate alkylation of a range of (S)-N-acyl-4-benzyl-5,5-dimethyloxazolidin-2-ones to afford and array of alpha-substituted-N-acyl-5,5-dimethyloxazolidin- 2-ones (85-94% de) and subsequent reduction with DIBAL afforded directly non-racemic alpha-substituted aldehydes without loss of stereochemical integrity (87-94% ee). The extension of this protocol for the asymmetric synthesis of beta-substituted aldehydes is demonstrated, via the diastereoselective conjugate addition of a range of organocuprates to (S)-N-acyl-4-phenyl-5,5-dimethyloxazolidin-2-ones which proceeds with high diastereoselectivity (generally > 95% de). Reduction of the conjugate addition products with DIBAL gives non-racemic beta-substituted aldehydes in high yields and in high ee (generally > 95% ee). This methodology is exemplified by the asymmetric synthesis of (R)-3-isopropenylhept-6-enal, which has previously been used in the synthesis of (3Z,6R)-3-methyl-6-isopropenyl-3,9-decadien-1-yl acetate, a component of the sex pheromones of the California red scale.     

Single and double asymmetric induction in Diels-Alder cycloadditions with chiral acylnitroso dienophiles

Diels-Alder reaction of the achiral 1-silyloxybutadiene 1a with the chiral acyinitroso dienophile 2a gave cycloadduct 4 in high diastereomeric excess (d.e. > 98 %), a result which is undoubtedly due to the C-2 symmetrical chiral dimethylpyrrolidine inductor. Excellent d.e. was also observed when the (R)-prolinol dienophile 2d was reacted with the chiral diene 1b (d.e. = 96 %), whereas cycloaddition of the (S) enantiomer 2e with 1b gave only poor asymmetric induction (d.e. = 4 %). These two latter examples nicely illustrate the influence of “matched pair” (1b/2d) versus “mismatched pair” (1b/2e) upon double asymmetric induction. All herein reported Diels-Alder cycloadditions were regiospecific.     

Neighboring group participation of the indole nucleus: An unusual DAST-mediated rearrangement reaction

A rearrangement reaction involving the indole nucleus was investigated using stereochemical markers and low-temperature NMR experiments. Treatment of (3S, 4S)-3-hydroxy-4-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (>90% ee) with diethylaminosulfur trifluoride gave stereospecifically (3S, 4S)-4-fluoro-3-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (>90% ee) with complete regioselectivity. The initial formation of a reactive spirocyclopropyl-3H-indole intermediate is believed to be responsible for the stereo- and regiochemical outcome of the reaction.     

Enantioselective synthesis of (1S,4R)-N-(benzylcarbamoyl)-4-aminocyclopent-2-en-1-ol by Candida antarctica lipase B

An efficient biocatalytic process has been developed to obtain optically pure (1S,4R)-N-(benzylcarbamoyl)- 4-aminocyclopent-2-en-1-ol which can be used as the key intermediate of ticagrelor. In this research, several N-(benzylcarbamoyl)-4-aminocyclopent-2-en-1-ol derivatives have been investigated in which Candida antarctica lipase B (CALB) was used to catalyze the asymmetric hydrolysis reaction. As expected, some of these substrates successfully gave (1S,4R)-N-(benzylcarbamoyl)-4-aminocyclopent- 2-en-1-ol in >98% enantiomeric excess (ee) with conversion yields up to 45%.     

Ring-expansion of thioacetal ring via bicyclosulfonium ylide. Effect Of protic nucleophile on ylide intermediate

The reaction of 2-(3-diazo-2-oxopropane-1-yl)-2-methyldithiolane 9a, 2-(4-diazo-3-oxobutane-2-yl)-2-methyldithiolane 9c, and 2-(3-diazo-2-oxopropane-1-yl)-2-methyl-1,3-dithiane 9b with Rh(2)(OAc)(4) gave three-carbon ring-expansion products dithiocan-2-en-1-ones 13a, 13c and dithionan-2-en-1-one 13b, respectively. 2-(5-Diazo-4-oxopentyl)-2-methyldithiolane 9e also gave the five-carbon ring-expansion products dithionan-3-en-1-one 13e and 5-methylenedithionane-1-one 13'e. On the other hand, reaction of 2-(4-diazo-3-oxobutyl)-2-methyldithiolane 9d in the presence of AcOH gave the four-carbon ring-expansion product 16d substituted by an acetoxyl group. In addition, the reaction of 2-(3-diazo-2-oxopropyl)-2-methyl-3-oxathiolane 9f in the absence of AcOH gave 4-oxa-7-thiocan-2-en-1-one 19 via a sulfonium ylide intermediate, whereas, in the presence of AcOH, an alternative regioisomer 20 was also formed competitively with 19 via an oxonium ylide intermediate.     

Total synthesis of myxothiazols, novel bis-thiazole beta-methoxyacrylate-based anti-fungal compounds from myxobacteria

Convergent total syntheses of myxothiazols A and Z are described. The syntheses are based on elaboration of the (S)-E,E-diene thioamide 22, conversion of 22 into the bis-thiazole 27 and Wittig reactions between 27c and the aldehyde 30. The substituted beta-methoxyacrylate aldehyde 30 was produced via an Evans asymmetric aldol protocol or via the 2H-pyran-2-one 31. An E-selective Wittig reaction between the ylide derived from the phosphonium salt 27c and the (+)-aldehyde 30 led to (+)-myxothiazol Z (1b), and a corresponding reaction with the (+/-)-acrylamide aldehyde 44 gave (+/-)-myxothiazol A (1a). Complementary studies led to synthesis of the ester 47b, corresponding to myxothiazol R and myxothiazol S.     

An efficient enantioselective synthesis of (S)-(-)-acromelobic acid

[reaction: see text] A highly efficient enantioselective synthesis of (S)-(-)-acromelobic acid (1) was achieved via asymmetric hydrogenation of dehydroamino acid derivative (3) using (R,R)-[Rh(DIPAMP)(COD)]BF(4) catalyst followed by removal of protective groups in >98% ee and good over all yield. The key intermediate (3) was prepared from the commercially available citrazinic acid (4) in six steps.