手性有机小分子催化的最新进展*

手性有机小分子催化是近年来不对称催化领域发展起来的一个研究热点。手性有机小分子催化具有反应条件温和,环境友好,催化剂易于回收利用等优点,符合绿色化学的要求。本文根据手性有机催化剂活化模式的不同,从烯胺催化、亚胺催化、氢键活化、卡宾催化、相转移催化以及光化学等方面对近年来的有机小分子催化的进展,特别是中国学者的工作做一简要评述。重点通过对不同催化体系下催化剂和反应底物之间立体效应和电子效应的考察,发现控制反应立体选择性以及活化惰性底物的规律,进而设计更加高效的手性有机小分子催化剂,完善和拓展有机小分子催化的不对称合成。     

Asymmetric nitrogen

The molecular structure of 3-methyl-1-((S)-1-tosylprolyl)1,2-diazacyclohex-2-ene, the product of the reaction of 5-methyl-1,6-diazabicyclo[3.1.0]hexane with (S)-N-tosylproline chloride, has been established by X-ray structural analysis. The pyrrolidine cycle has a half-chair conformation with the pyramidal nitrogen atom; the tosyl and pseudo axial carbamoyl groups havetrans orientations. The diazacyclohexene cycle has an envelope conformation with folding along the C(7)...C(9) line. The stereochemistry of the transition state of the above-mentioned reaction is discussed.For the previous communication, see Ref. 1.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 500–503, March, 1995.     

不对称环丙烷化反应

利用手性类卡宾分子对烯烃的加成,可合成非对称取代的环丙烷环。其不对称诱导一般受立体和电子因素控制。本文主要综述 Simmons-Smith 反应,重氮化合物,异丙叉三苯基膦,以及一些金属有机化合物的催化热解反应在不对称环丙烷环合成中的应用,并以潜在杀虫剂环丙烷甲酸化合物的合成为例进行了讨论。     

Asymmetric nitrogen

Reactions of the Tröger base (1) with HgBr₂ and Mel proceed with the participation of only one N atom. According to the data of X-ray diffraction analysis, the complex [(±)-1]₂·HgBr₂ crystallizes in the achiral space groupP _n . Unlike the complex [(+)-1]₂·HgBr₂, methiodide of (+)-1 in MeOH undergoes racemization at 20°C. The virtual spin-spin coupling constants⁴ J _HH observed for the base (C ₂ symmetry) are transformed into the “usual” constants in the case of the desymmetrized methiodide system.     

Asymmetric Activation

While nonracemic catalysts can generate nonracemic products with or without the nonlinear relationship in enantiomeric excesses between catalysts and products, racemic catalysts inherently give only a racemic mixture of chiral products. Asymmetric catalysts, either in nonracemic or racemic form, can be further evolved into highly activated catalysts with association of chiral activators. This asymmetric activation process is particularly useful in racemic catalysis through selective activation of one enantiomer of the racemic catalyst. Recently, a strategy whereby a racemic catalyst is selectively deactivated by a chiral additive has been reported to yield nonracemic products. However, reported herein is an alternative and conceptually opposite strategy in which a chiral activator selectively activates, rather than deactivates, one enantiomer of a racemic chiral catalyst. The advantage of this activation strategy over the deactivation counterpart is that the activated catalyst can produce a greater enantiomeric excess in the products-even with the use of a catalytic amount of activator relative to chiral catalyst-than that attained by the enantiomerically pure catalyst on its own. Therefore, asymmetric activation could provide a general and powerful strategy for not only the use of atropisomeric, racemic ligands but also chirally flexible and proatropisomeric ligands without enantiomeric resolution!     

Asymmetric nitrogen

The possibility of tranferring chirality from nitrogen to carbon by a three-step transformation of racemic dimethyl 1-methoxyaziridine-2,2-dicarboxylate into 3-amino-2-chloromethyl-2-methoxyaminopropan-1-ol was demonstrated. The first representative of 1-silyloxyaziridines,viz., dimethyl 1-(tert-butyldimethylsilyloxy)aziridine-2,2-dicarboxylate, was synthesized by acidolysis or thermolysis of triazoline, obtained by the reaction oftert-butyldimethylsilyloxime of dimethy mesoxalate with CH₂N₂     

Asymmetric organocatalysis

The field of asymmetric organocatalysis is rapidly developing and attracts an increasing number of research groups around the world. Here we present a brief overview of this area, guided by a mechanistic classification. Accordingly, organocatalysts are categorized as either Lewis base, Lewis acid, Br?nsted base, or Br?nsted acid catalysts.     

Asymmetric copper-catalyzed

The asymmetric copper-catalyzed generation and subsequent [2,3]-sigmatropic rearrangement of sulfur ylides is strongly dependent on the structure of the starting allyl sulfide. A series of alkyl and aryl substituted allyl sulfides (2a-i) were reacted with ethyl diazoacetate in the presence of copper triflate (CuOTf) and a C2-symmetric bis-oxazoline ligand (5a-c). The degree of asymmetric induction ranged from 2.8% for allyl methyl sulfide (2a) to 60% for (1S,2S,5R)-(+)-allyl menthyl sulfide (2d). The enantioselectivity of the reactions was also dependent on the electronic nature of the sulfide; allyl phenyl sulfide (2e) gave a 14% ee, whereas allyl p-methoxyphenyl sulfide (2i) produced only an 8% ee. The stereochemistry of 2d and (1R,2S,5R)-(+)-allyl menthyl sulfide (7) was assigned on the basis of NMR spectroscopic experiments.     

Asymmetric nitrogen

The¹H NMR spectra ofO-derivatives of 1-hydroxy-2,2-bis(trifluoromethyl)aziridine containing such substituents as EtO₂CCH₂, (R/S)-RO₂CCH(Me) (R=Me, Prⁱ, or Bu^t), (R/S)-H₂NC(O)CH(Me), and (R)-H₂NC(O)CH(Me) were analyzed. Both of the diastereomerically pure amides of the latter type were isolated. The validity of the¹H NMR criteria, which were suggested for the determination of absolute configurations of diastereomers ofN-alkoxyaziridines, was confirmed by X-ray diffraction study of the (R,R)-amide.     

催化不对称反应新进展—不对称活化

介绍了催化不对称催化反应中的一个新概念一不对称活化(asymmetric activation)及其研究的最新进展。运用不对称活化策略,一个光学活性的或者甚至外消旋的催化剂可以被另一种手性活化剂(chiral activator)选择性地活化,从而催化反应生成非外消旋产物。该方法较不对称去活化(asymmetric deactivation)方法的优点是被活化的催化剂能够产生较使用光学纯催化剂更高对映体过量的产物。     

非甾体消炎药萘普生不对称合成研究

萘普生[(S)-(+)-S-(6'-甲氧基-2'-萘基)丙酸]是一种非常重要的非甾体消炎镇痛药。以(2R,3R)-酒石酸二甲酯为手性辅助剂,2-甲氧基萘经溴代、丙酰化、缩酮化、不对称溴化、水解、立体专一性重排和催化氢转移氢解等反应合成了光学活性萘普生,化学收率44%。制备的萘普生的光学纯度([α]~D^2^5=+63.5ⅲ)符合中华人民共和国药典(1995年版)的要求。     

奈必洛尔的不对称合成

首先合成4-氟-2-(5-羟基戊烷基-3-烯)-苯酚(2), 再经Sharpless不对称环氧化等反应分别得到2-氨基-1-[6-氟- (2S)-3,4-二氢-2H-2-苯并吡喃]-(1R)-1-乙醇(6)和6-氟-2-[(2R)-2-环氧乙烷基]-(2R)-3,4-二氢苯并吡喃(10). 最后, 6和10发生亲核开环反应即得到目标产物奈比洛尔. 整个合成路线简单易行, 并在原有文献的基础上有较大改进, 使收率大大提高, 总收率由文献的2.1%提高到14.1%.