Concise enantiospecific, stereoselective syntheses of (+)-crispine A and its (-)-antipode

An enantiospecific and stereoselective total synthesis of the natural product (+)-crispine A has been demonstrated employing a Pictet-Spengler bis-cyclization reaction between commercially available (R)-(-)-methyl 2-amino-3-(3,4-dimethoxyphenyl)propanoate and 4-chloro-1,1-dimethoxybutane to preferentially provide the cis tricyclic adduct. Decarboxylation by a convenient two-step protocol provided the enantiopure natural product in three steps with an overall isolated yield of 32% from the amino acid. The unnatural antipode (-)-crispine A was similarly prepared in three steps from the commercially available (S)-(+)-amino acid.     

A new asymmetric synthesis of the anti-tumor alkaloid (R)-(+)-crispine A

We report a novel, facile, and asymmetric approach for the synthesis of the anti-tumor alkaloid (+)-crispine A via a highly diastereoselective N-acyliminium cyclization reaction as a key synthetic step.     

First asymmetric enantioselective total synthesis of phenanthridine alkaloid, (S)-(+)-asiaticumine and its enantiomer

In this study, the first asymmetric enantioselective total syntheses of (+)-asiaticumine A (2) and its enantiomer were accomplished through a seven-step sequence using the bond formation between the C4a and N5 positions of the phenanthridine framework based on the microwave-assisted electrocyclization of cyclohexenylbenzaldoxime methyl ether as an aza 6π-hexatriene system followed by the Sharpless asymmetric dihydroxylation as the key step. In addition, the absolute configuration of natural (+)-2 was determined to be S by Mosher’s method.     

Enantioselective synthesis for the (-)-antipode of the pyrazinone marine alkaloid, hamacanthin A.

A short enantioselective total synthesis for the (-)-antipode of the antifungal marine alkaloid, hamacanthin A, (6R)-3,6-bis(6-bromoindol-3-yl)-5,6-dihydro-2(1H)-pyrazinone, is described. This synthesis proceeds through the coupling of 3-indolyl-alpha-oxoacetyl chloride and 3-indolyl azidoethylamine, followed by intramolecular aza-Wittig type cyclization. A concise and useful approach for the synthesis of (1R)-1-(indol-3-yl)-2-azidoethylamine using the Sharpless asymmetric dihydroxylation reaction followed by stereospecific azidation is also presented.     

First enantioselective synthesis of the antitumour alkaloid (+)-crispine A and determination of its enantiomeric purity by 1H NMR

A simple enantioselective synthesis of the pyrrolo[2,1-a]isoquinoline alkaloid (+)-crispine A, based on the use of an asymmetric transfer hydrogenation as the key step, is described. The enantiomeric excesses of the obtained alkaloid samples were determined from ¹H NMR spectra recorded in the presence of (+)-(R)-t-butylphenylphosphinothioic acid as a chiral solvating agent.     

An efficient approach to Aspidosperma alkaloids via [4 + 2] cycloadditions of aminosiloxydienes: stereocontrolled total synthesis of (+/-)-tabersonine. Gram-scale catalytic asymmetric syntheses of (+)-tabersonine and (+)-16-methoxytabersonine. Asymmetric syntheses of (+)-aspidospermidine and (-)-quebrachamine

Described is a concise, highly stereocontrolled strategy to the Aspidosperma family of indole alkaloids, one that is readily adapted to the asymmetric synthesis of these compounds. The strategy is demonstrated by the total synthesis of (+/-)-tabersonine (rac-1), proceeding through a 12-step sequence. The basis for this approach was provided by a highly regio- and stereoselective [4 + 2] cycloaddition of 2-ethylacrolein with 1-amino-3-siloxydiene developed in our laboratory. Subsequent elaboration of the initial adduct into the hexahydroquinoline DE ring system was accomplished efficiently by a ring-closing olefin metathesis reaction. A novel ortho nitrophenylation of an enol silyl ether with (o-nitrophenyl)phenyliodonium fluoride was developed to achieve an efficient, regioselective introduction of the requisite indole moiety. The final high-yielding conversion of the ABDE tetracycle into pentacyclic target rac-1 relied on intramolecular indole alkylation and regioselective C-carbomethoxylation. Our approach differs strategically from previous routes and contains built-in flexibility necessary to access many other members of the Aspidosperma family of indole alkaloids. The versatility of the synthetic strategy was illustrated through the asymmetric syntheses of the following Aspidosperma alkaloids: (+)-aspidospermidine, (-)-quebrachamine, (-)-dehydroquebrachamine, (+)-tabersonine, and (+)-16-methoxytabersonine. Of these, (+)-tabersonine and (+)-16-methoxytabersonine were synthesized in greater than 1-g quantities and in enantiomerically enriched form ( approximately 95% ee). The pivotal asymmetry-introducing step was a catalyzed enantioselective Diels-Alder reaction, which proceeded to afford the cycloadducts in up to 95% ee. Significantly, the synthetic sequence was easy to execute and required only four purifications over the 12-step synthetic route.     

A Highly diastereoselective synthesis of (1R)-(+)-camphor-based chiral allenes and their asymmetric hydroboration-oxidation reactions

Synthesis of camphor derived chiral allenes and their hydroboration-oxidation reactions are described. Reaction of (1R)-(+)-camphor with alkynyllithium followed by the reduction of the resulted propargyl alcohol derivatives using AlH3 furnished chiral allenes 2a-g in excellent yields with high diastereoselectivity. Reduction of the propargyl alcohols with aluminum hydride proceeded through selective intermolecular anti-addition of hydride ion. The stereochemistry of the chiral allenes 2 was assigned based on lanthanide shift studies and chemical correlations. Diastereoselectivity was observed in the hydroboration-oxidation of 2 which produced a mixture of (E,R) and (E,S) stereoisomers in a ratio of 6:1 to 18:1.     

Short asymmetric synthesis of (-)- and (+)-cis-lauthisan

The asymmetric synthesis of both enantiomers of cis-lauthisan (3) is achieved in only six steps from diethyl pimelate (4), the key steps being the diastereodivergent reduction of beta-ketosulfoxide 7 and the highly cis-stereoselective Et(3)SiH/TMSOTf-promoted reductive cyclization of enantiopure hydroxy sulfinyl ketones (S)-14 and (R)-14.     

手性(salen)Co在不对称催化反应和天然产物合成中 的应用

手性(salen)Co是最近几年发展起来的一种重要的不对称催化剂,受到人们的广泛重视。综述了手性(salen)Co在不对称催化反应和天然产物合成中的一些最新研究进展。     

delta-Amino beta-keto esters, a designed polyfunctionalized chiral building block for alkaloid synthesis. Asymmetric synthesis of (R)-(+)-2-phenylpiperidine and (-)-SS20846A

[formula: see text] delta-Amino beta-keto esters 3 and 11 are designed polyfunctionalized chiral building blocks for alkaloid synthesis and are prepared in one step from the corresponding sulfinimine (N-sulfinyl imine). Concise highly enantioselective four-step syntheses of 2-phenylpiperidine (7) and SS20846A (14) from 3 and 11, respectively, are described.     

Novel asymmetric total synthesis of the natural (+)-6-epicastanospermine

An efficient noncarbohydrate-based enantioselective synthesis of (+)-6-epicastanospermine has been developed utilizing the Sharpless asymmetric aminohydroxylation of furyl acrylate and oxidation of α-furfurylamine derivative 17 as key steps.     

Concise asymmetric synthesis of (R)-(+)-tanikolide

A highly stereoselective total synthesis of (R)-(+)-tanikolide, a δ-lactonic marine natural product, was accomplished in seven steps from easily available starting materials with a 51% overall yield. An asymmetric synthesis of an α-hydroxy aldehyde having a stereogenic quaternary center, by the use of (S)-2-(anilinomethyl)pyrrolidine as a chiral auxiliary, was employed in a key step.     

Application of the Helquist annulation in Lycopodium alkaloid synthesis: unified total syntheses of (-)-8-deoxyserratinine, (+)-fawcettimine, and (+)-lycoflexine

A unified strategy for total synthesis of the Lycopodium alkaloids (-)-8-deoxyserratinine (7), (+)-fawcettimine (1), and (+)-lycoflexine (4) is detailed. The key features include a highly efficient Helquist annulation to assemble the cis-fused 6/5 bicycle, facile construction of the aza nine-membered ring system employing double N-alkylation strategy, providing access to the common tricyclic skeleton, asymmetric Shi epoxidation, delivering the desired β-epoxide stereospecifically to furnish (-)-8-deoxyserratinine (7), SmI(2) reduction of dihydroxylation derivative 35 to enable formation of (+)-fawcettimine (1), and a rapid biomimetic transformation of (+)-fawcettimine (1) into (+)-lycoflexine (4) via an intramolecular Mannich cyclization.     

First enantioselective syntheses of (+)- and (-)-wilforonide by using chiral auxiliaries derived from the same chiral source

[see structure]. The first enantioselective syntheses of both (+)-wilforonide (>98% ee) and (-)-wilforonide (>98% ee) have been accomplished by employing chiral auxiliaries derived from the same chiral source, (R)-pulegone. The bicyclic skeleton of wilforonide was constructed by using Mn(III)-based oxidative radical cyclization reactions of chiral beta-keto esters. The absolute configuration of natural wilforonide has been established to be (5aR,9aR).     

New asymmetric approach to natural pyrrolizidines: synthesis of (+)-amphorogynine A, (+)-amphorogynine D, and (+)-retronecine

Three natural pyrrolizidines, (+)-amphorogynines A and D and (+)-retronecine, have been prepared from a common lactam intermediate. This central compound, in turn, was synthesized in diastereomerically enriched form through a highly selective [2 + 2]-cycloaddition of dichloroketene with a chiral enol ether, followed by Beckmann ring expansion and reduction. Subsequent stereocenters were then cleanly introduced through internal induction.     

Alkylation of chiral alpha-hydroxy ketones derived from (1R)-(+)-camphor. An asymmetric variant of the classical acetylene route to carbonyl compounds

[reaction: see text]. The asymmetric version of the traditional route for transforming acetylene into alpha-branched carbonyl compounds is now feasible for the first time. The method involves the temporary attachment of camphor to acetylene and gives a remarkably high diastereo- and enantioselectivity.     

A diastereoselective intramolecular hydroamination approach to the syntheses of (+)-, (+/-)-, and (-)-pinidinol

A diastereoselective, lanthanocene-catalyzed, intramolecular hydroamination reaction was applied to the preparation of 2,6-disubstituted piperidines. Various metal/ligand arrays in the catalysts were examined using a model substrate to allow optimization of the diastereoselectivity. It was determined that the relationship between metal size and ligand bulk plays an integral role in the transformation. The complex Cp2NdCH(TMS)2 converted 2-substituted 8-nonen-4-amines to 2,6-disubsituted piperidines with greater than 100:1 selectivity for the formation of the cis isomer. A short synthesis of pinidinol, an alkaloid isolated from various pine and spruce species, was then carried out to exploit this stereoselective reaction.     

The first synthesis of (-)-asperpentyn and efficient syntheses of (+)-harveynone, (+)-epiepoformin and (-)-theobroxide

A generally applicable strategy for the synthesis of a range of polyoxygenated cyclohexane natural products has been developed. The enantioselective syntheses of (-)-theobroxide, a polyoxygenated cyclohexane natural compound with potent growth inducing properties in potato microtubers has been achieved via a 1,2 O-silyl migration between trans-hydroxyl groups and a remote hydroxyl directed epoxidation of an enone derived from quinic acid. A thus derived alpha-iodoenone was subjected to Stille coupling with tetramethylstannane to afford the first title compound. A similar strategy enabled a route to the complete asymmetric synthesis of the acetylenic phytotoxin (+)-harveynone. By selective reduction of (-)-theobroxide, (+)-epiepoformin was also prepared in enantiopure form and similarly, stereoselective reduction of (+)-harveynone completed the first enantioselective synthesis of (-)-asperpentyn, another natural compound with antimicrobial activity.