Systematic synthesis of Bis-THF ring cores in annonaceous acetogenins

Systematic synthesis of bis-THF ring cores, synthetic intermediates of adjacent bis-THF annonaceous acetogenins, has been achieved by asymmetric alkynylation and subsequent stereodivergent THF ring formation. The asymmetric alkynylation of alpha-tetrahydrofuranic aldehyde with (S)-3-butyne-1,2-diol derivatives gave good yields of erythro- and threo-adducts with very high diastereoselectivity. These adducts were converted into four types of bis-THF cores via two kinds of one-pot THF ring formation. [reaction: see text]     

Highly stereoselective and stereodivergent synthesis of four types of THF cores in acetogenins using a C4-chiral building block

[reaction: see text] Four stereoisomers of the THF cores, synthetic intermediates of acetogenins, have been synthesized with high diastereoselectivity by asymmetric alkynylation and subsequent stereodivergent THF ring formation. The asymmetric alkynylation of alpha-oxyaldehyde with (S)-3-butyne-1,2-diol derivatives (C4-unit) gave good yields of syn and anti adducts with >97:3 dr and 94:6 dr, respectively. These adducts were converted into the four types of THF compounds via one-pot THF formation or via intramolecular Williamson synthesis.     

Systematic construction of a monotetrahydrofuran-ring library in annonaceous acetogenins by asymmetric alkynylation and stereodivergent tetrahydrofuran-ring formation

All eight diastereoisomers of the monotetrahydrofuran-ring cores of annonaceous acetogenins have been synthesized through utilization of asymmetric alkynylation and stereodivergent one-pot tetrahydrofuran-ring formation. In all cases, the asymmetric alkynylation proceeded with very high diastereoselectivity to give eight kinds of optically pure tetrahydrofuran core from a common alpha-oxyaldehyde. We also describe a comparison of the (1)H NMR, (13)C NMR, and CD spectral data of the eight isomers and give full details of the tetrahydrofuran-ring construction including a model study of asymmetric alkynylation.     

First total synthesis of murisolin

The first and concise total synthesis of murisolin (1) was accomplished using asymmetric alkynylation and Sonogashira coupling as the key steps. The threo/trans/threo-type THF ring moiety was constructed with excellent stereoselectivity by asymmetric alkynylation of 1,6-heptadiyne to alpha-tetrahydrofuranic aldehyde, which was also prepared via the asymmetric alkynylation.     

Convergent synthesis of stereoisomers of THF ring moiety of acetogenin thiophene analogue and their antiproliferative activities against human cancer cell lines

The convergent synthesis of thiophene-3-carboxamide analogues of annonaceous acetogenins was accomplished through the asymmetric alkynylation of a 2-formyl THF ring fragment with an alkyne having a thiophene ring as the key step. Eight stereoisomers of the THF ring moiety were synthesized by this convergent route and their antiproliferative activities against 39 human cancer cell lines were evaluated. It was revealed that derivatives having the threo configuration between C17–C18 positions showed more potent activities than the corresponding erythro ones.     

Asymmetric synthesis of (+)-chloriolide

An asymmetric synthesis of 12-membered ring macrolide, chloriolide has been accomplished by adopting a linear strategy. Lipase-catalyzed enzymatic kinetic resolution (EKR), asymmetric alkynylation using Trost pro-phenol catalyst followed by Yamaguchi macrolactonization has been successfully employed to achieve the target molecule.     

Molecular structures of THF-solvated alkali-metal 2,2,6,6-tetramethylpiperidides finally revealed: X-ray crystallographic, DFT, and NMR (including DOSY) spectroscopic studies

The often studied THF solvates of the utility alkali-metal amides lithium and sodium 2,2,6,6-tetramethylpiperidide are shown to exist in the solid state as asymmetric cyclic dimers containing a central M(2)N(2) ring and one molecule of donor per metal to give a distorted trigonal planar metal coordination. DFT studies support these structures and confirm the asymmetry in the ring. In C(6)D(12) solution, the lithium amide displays a concentration-dependent equilibrium between a solvated and unsolvated species which have been shown by diffusion-ordered NMR spectroscopy (DOSY) to be a dimer and larger oligomer, respectively. A third species, a solvated monomer, is also present in very low concentration, as proven by spiking the NMR sample with THF. In contrast, the sodium amide displays a far simpler C(6)D(12) solution chemistry, consistent with the solid-state dimeric arrangement but with labile THF ligands.     

亚胺及其类似物的催化不对称炔基化反应新进展

手性炔丙胺是天然产物和药物活性分子不对称全合成中常用的关键中间体,亚胺及其类似物的不对称炔基化反应可以为该砌块提供高效高对映选择性的合成路径;此外通过合理的底物和反应设计,亚胺的不对称炔基化反应还能作为一系列串联反应的起点,来合成多种结构新颖的含氮杂环化合物.因此,亚胺及其类似物的高效高对映选择性炔基化反应得到合成化学家们持续关注.按照底物类型,主要分为醛亚胺的不对称炔基化和酮亚胺的不对称炔基化两大部分,介绍了亚胺及其类似物的不对称炔基化反应在过去十年中的研究进展.对这些反应的机理、优势与不足之处以及该反应在合成中的应用进行简要讨论,从而为拓展该反应在合成中的应用提供一些有益参考和借鉴.     

Catalytic asymmetric syntheses of (−)-oudemanisin A and its diastereomer

The first asymmetric catalytic synthesis of (?)-oudemanisin A 1a and its diastereomer 1b has been achieved. The key steps of our strategy involved the asymmetric alkynylation of an unsaturated aliphatic aldehyde catalyzed by Trost’s ProPhenol ligand, chemoselective oxidation of the olefinic diol, base-induced ring opening of the lactone, and acylation–alkylation of the ester.     

Asymmetric alkynylation of aldehydes with propiolates without high reagent loading and any additives

The asymmetric alkynylation of aliphatic and aromatic aldehydes with propiolates was mediated by dialkylzinc and a novel prolinol catalyst without high reagent loading and any additives, such as Ti(Oi-Pr)(4), to give the corresponding γ-hydroxy-α,β-acetylenic esters with high enantiomeric excess of up to 95%.     

Chiral propargyl alcohols via the enantioselective addition of terminal di- and triynes to aldehydes

The enantioselective addition of di- and triynes to aldehydes is presented, including the first examples of an asymmetric triyne addition. Modification of the Carreira alkynylation protocol shows that addition of diynes and triynes to α-branched aldehydes can be complete in as little as 4 h, and these reactions give good yields and enantioselectivities (up to 98% ee) for di- and triynes tested (aryl, alkyl, and silyl). It is shown for two cases (20 and 24) that products of this asymmetric addition reaction can undergo further manipulation (desilylation and triazole formation) without affecting the enantiopurity.     

Synthesis of the C6–C18 bis-tetrahydrofuran fragment of the proposed structure of iriomoteolide-2a via stepwise double SN2 cyclization reactions

The C6–C18 bis-tetrahydrofuran (bis-THF) fragment of the proposed structure of iriomoteolide-2a has been synthesized via stepwise double intramolecular S_N2-type etherifications. The C11 and C16 stereogenic centers could be secured in the forms of propargyl alcohols by asymmetric transfer hydrogenation of the corresponding propargyl ketones. The C9–C12 THF ring was first constructed via a tandem asymmetric dihydroxylation (AD)–S_N2 sequence while the C13–C16 THF ring was later installed via an intramolecular S_N2 reaction of a chiral propargyl mesylate. During the latter THF ring formation, epimerization at the propargylic carbon was not observed. Since the initially proposed (9R,11S,12R) configuration of iriomoteolide-2a has recently been revised to (9S,11R,12S), the established synthesis of the C6–C18 bis-THF fragment could be easily amended by using the opposite enantiomers of the chiral ligands for AD and asymmetric transfer hydrogenation.     

Total synthesis of murisolins and evaluation of tumor-growth inhibitory activity

Convergent total syntheses of murisolin (1), natural 16,19-cis-murisolin 2, and unnatural 16,19-cis-murisolin 3 were accomplished by asymmetric alkynylation of alpha-tetrahydrofuranic aldehyde with a diyne and Sonogashira coupling with a gamma-lactone segment as the key steps. Stereoisomers of alpha-tetrahydrofuranic aldehyde were synthesized with high optical purity and the asymmetric alkynylation of these with 1,6-heptadiyne proceeded in good yield and with high diastereoselectivity. The cell-growth inhibition profile and COMPARE analysis of the synthetic compounds 1-3 were also investigated.     

Enantioselective alkynylation of aromatic aldehydes catalyzed by new chiral amino alcohol-based ligands

A series of binaphthyl-derived amino alcohols were synthesized and used as catalytic ligands in the asymmetric alkynylation of aromatic aldehydes in the presence of a dialkylzinc reagent. The alkynylation of a variety of aromatic aldehydes gave the corresponding chiral propargylic alcohols in 61–93% e.e.     

C2轴对称樟脑磺酰胺基醇配体催化环己烯乙炔对酮的不对称加成反应

应用C2轴对称的樟脑磺酰胺基醇配体和Cu(OTf)2催化带官能团的环己烯乙炔对酮的不对称加成反应. 芳香酮、脂肪酮和杂环酮都适用于此体系, 并且在室温下最高e.e.值约为89%, 其中脂肪酮首次被应用于此反应, 极大地扩展了底物的范围. 研究结果表明, 脂肪酮的立体位阻对反应的对映选择性起着至关重要的作用.     

Rhodium-catalyzed Asymmetric Ring Opening Reaction of Oxabenzo-norbornadiene with Substituted Phenolic Nucleophiles

Among the myriad of molecular architectures present in pharmacological agents, certain structures emerge with a higher frequency than others. Among these “privileged structures” is the hydronaphthalene skeleton which can be found in a wide range of comp…     

Asymmetric synthesis of the core structure of leucosceptroids A-D

The asymmetric synthesis of the core structure of leucosceptroids A-D has been achieved. The key steps of the synthesis includes the formation of the cis-2,5-disubstituted THF ring by TPAP catalytic oxidative cyclization followed by a highly diastereoselective intramolecular Diels-Alder reaction to fashion the fused tricyclic hydrindane ring system.     

Evaluation of enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol for catalytic asymmetric addition of organozinc reagents to aldehydes

A facile and practical approach to preparation of enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol was developed from cheap and easily available l-(+)-methionine. Synthetic highlights include the three-step, one-pot construction of the chiral azetidine ring and the development of an improved one-step procedure for the synthesis of the key intermediate l-2-amino-4-bromobutanoic acid. Enantiopure N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol was evaluated for catalytic asymmetric addition of organozinc reagents to aldehydes. The asymmetric ethylation, methylation, arylation, and alkynylation of aldehydes achieved enantioselectivity of up to 98.4%, 94.1%, 99.0%, and 84.6% ee, respectively, in the presence of a catalytic amount of chiral N-(ferrocenylmethyl)azetidin-2-yl(diphenyl)methanol. Our results demonstrated further that the four-membered heterocycle-based backbone was a good potential chiral unit for the catalytic asymmetric induction reaction, and the hindrance of the bulky ferrocenyl group, compared to a phenyl group, played an important role in the enantioselectivities. A possible transition for the catalytic asymmetric addition has been proposed on the basis of the crystal structure of the chiral ligand 3b including two HOAc molecules and previous studies.     

Stereoconservative Negishi arylation and alkynylation as an efficient approach to enantiopure 2,2'-diarylated 1,1'-binaphthyls

Negishi arylation and alkynylation of easily synthesized chiral 2,2'-diodo-1,1'-binaphthyl rapidly proceeds in refluxing THF utilizing controlled microwave irradiation, affording enantiopure 2,2'-diarylated 1,1'-binaphthyls in good to excellent yields.     

A novel and general synthetic pathway to strychnos indole alkaloids: total syntheses of (-)-tubifoline, (-)-dehydrotubifoline,and (-)-strychnine using palladium-catalyzed asymmetric allylic substitution

A method of palladium-catalyzed asymmetric allylic substitution for synthesizing 2-substituted cyclohexenylamine derivatives was established. Treatment of a 2-silyloxymethylcyclohexenol derivative with ortho-bromo-N-tosylaniline in the presence of Pd(2)dba(3).CHCl(3) and (S)-BINAPO in THF afforded a cyclohexenylamine derivative with 84% ee in 80% yield. The Heck reaction was carried out to produce an indolenine derivative in good yield. Using this method, we synthesized indolenine derivative 7, which was recrystallized from EtOH to give an optically pure compound. From this compound, tetracyclic ketone 13, which should be a useful intermediate for the synthesis of indole alkaloids, could be synthesized. The total syntheses of (-)-dehydrotubifoline, (-)-tubifoline, and (-)-strychnine were achieved from 13. All ring constructions for the syntheses of these natural products were achieved using a palladium catalyst.