Stochastic aspects of asymmetric autocatalysis and absolute asymmetric synthesis

The main goal of the present review is to collect in a unified framework the deterministic and stochastic models of emergence and amplification of chirality by mechanisms such as asymmetric autocatalysis and absolute asymmetric synthesis. Empirical approach and modeling have recently provided a good insight into these phenomena. Our groups in Italy and Hungary have a wide variety of expertise both in fields of experiments and modeling. In the last decade important results have been achieved, however, more experiments and more detailed deterministic and stochastic models are needed for a better understanding of details and significance of asymmetric autocatalysis and absolute asymmetric synthesis.     

手性胶束的不对称诱导作用不对称苯偶姻缩合反应

胶束体系是模拟酶的简单模型之一。手性胶束对反应有手性诱导作用。在表面活性剂(1R，2S)-(-)-N-十二烷基-N-甲基麻黄素溴化物和(1R，2S)-(-)-N-十六烷基-N-甲基麻黄素溴化物形成的胶束体系中进行的苯偶姻缩合反应，生成了光学活性的α-羟基酮。     

Catalytic asymmetric phase-transfer reactions using tartrate-derived asymmetric two-center organocatalysts

A new highly versatile asymmetric two-center catalyst, tartrate-derived diammonium salt (TaDiAS), was designed and a catalyst library containing more than 70 new two-center catalysts was constructed. A variety of (S,S)- and (R,R)-TaDiAS were easily synthesized from diethyl l- and d-tartrate, respectively, using common and inexpensive reagents under operationally simple reaction conditions. TaDiAS was used in phase-transfer alkylations and Michael additions to afford various optically active α-amino acid equivalents in up to 93% yield. Moreover, dramatic counter anion effects were observed in phase-transfer catalysis (PTC) for the first time, making it possible to further improve reactivity and selectivity. These findings validate the usefulness of three-dimensional fine-tuning of the catalyst (acetal, Ar, and counter anion) for optimization. Recovery and reuse of the catalyst was also possible using simple procedures. The present asymmetric PTC was successfully applied to enantioselective syntheses of serine protease inhibitor aeruginosin 298-A and its analogues.     

The asymmetric power of chiral ligands determined by competitive asymmetric autocatalysis

Asymmetric autocatalytic reactions were initiated by using two competing chiral ligands bearing opposite configurations. The absolute configuration of the resulting highly enantioenriched product reflects the different efficiencies of the two catalysts. Thus, our method provides a simple and efficient way to compare the asymmetric power of chiral ligands for enantioselective catalysis both qualitatively and quantitatively.     

Dinuclear asymmetric Zn aldol additions: formal asymmetric synthesis of fostriecin

Direct asymmetric aldol reactions constitute a powerful methodology for the efficient synthesis of complex natural products. Herein we report the first application of our recently reported dinuclear Zn-catalyzed direct aldol addition of alkynyl ketones to aldehydes in a short and efficient formal asymmetric synthesis of fostriecin, a potent cyctotoxic natural product. This work highlights not only the power of the aldol methodology but also the utility of the akynyl silane aldol adducts, as it is subsequently utilized in a vinyl silane cross-coupling reaction which affords the target molecule in 14 steps for the longest linear sequence in 8.5% overall yield.     

Palladium-catalyzed asymmetric ring expansion of allenylcyclobutanols: an asymmetric Wagner-Meerwein shift

In this study, we developed a palladium-catalyzed atom economic asymmetric Wagner-Meerwein shift of allenylcyclobutanol substrates. It is an excellent method for creating functionalized cyclopentanones with an alpha-chiral O-tertiary center by ring expansion of allenylcyclobutanols. This reaction was initiated by hydropalladation and afforded excellent enantioselectivity as well as atom economy. This method provides an efficient route toward the synthesis of natural products such as trans-kumausyne's family, spiro ring systems. In addition, we obtained excellent diastereoselectivity and enantioselectivity at the same time by using 3-monosubstituted allenylcyclobutanol.     

Multifunctional asymmetric catalysis

Two types of general and practical enantioselective catalysts, namely, bimetallic complexes and Lewis acid-Lewis base bifunctional catalysts were developed based on the concept of multifunctional catalysis. In the first part of this review, the first example of a catalytic enatioselective nitro-Mannich reaction as well as a direct catalytic enantioselective aldol reaction of 2-hydroxyacetophenone using bimetallic complexes is discussed. The new complex, composed of ytterbium, potassium, and BINOL in a ratio of 1:1:3, promoted the nitro-Mannich reaction of nitromethane with up to 91% ee. On the other hand, second generation ALB catalyzed an enantioselective and diastereoselective nitro-Mannich reaction of nitroalkanes in up to 83% ee with a diastereomeric ratio up to 7:1. Moreover, the reaction of aldehydes with 2-hydroxyacetophenone in the presence of LLB, KHMDS, and H2O selectively gave the corresponding anti-alpha,beta-dihydroxy ketones in up to 95% ee and, in the presence of the catalyst prepared from linked-BINOL and 2 eq of Et2Zn, selectively afforded the syn-alpha,beta-dihydroxy ketones in up to 86% ee. In the second part, the development of new catalysts displaying a Lewis acidity and a Lewis basicity is described. The Lewis acid of the catalyst activates aldehydes, imines, acyl quinoliniums, and ketones. At the same time, the Lewis base activates the nucleophile (TMSCN). Catalysts of this type produced a highly enantioselective cyanation of these electrophiles. Application of the catalytic enantioselective cyanosilylation of aldehydes to a total synthesis of epothilones is also described.     

Low-loading asymmetric organocatalysis

Asymmetric organocatalysis is now recognized as the third pillar of asymmetric synthesis. Recent years have witnessed increasing interest towards the use of highly active and stereoselective organocatalysts. This critical review documents the advances in the development of chiral organocatalysts which are systematically used in ≤3 mol% loading in all the sub-areas of the field, namely aminocatalysis, Br?nsted acids and bases, Lewis acids and bases, hydrogen bond-mediated catalysis, phase transfer and N-heterocyclic carbene catalyses (194 references).     

Biomimetic asymmetric catalysis

Enzymes are the core for biological transformations in nature. Their structures and functions have drawn enormous attention from biologists as well as chemists since last century. The large demand of bioactive molecules and the pursuit of efficiency and greenness of synthesis have spurred the rapid development of biomimetic chemistry in the past several decades. Biomimetic asymmetric catalysis, mimicking the structures and functions of enzymes, has been recognized as one of the most promising sy...     

Amine-salt-controlled, catalytic asymmetric conjugate addition of various amines and asymmetric protonation

The combined use of chiral Pd complex 2 and amine salt enabled completely regulated release of free nucleophilic amine. Under these conditions, an efficient catalytic asymmetric conjugate addition of various amines was achieved to afford beta-amino acid derivatives in high chemical yields with up to 98% ee. Furthermore, a highly enantioselective protonation in 1,4-addition of amine was also developed. [reaction: see text]     

Helix-induced asymmetric polymerization

Asymmetric polymerization could be induced by an already formed optically active living prepolymer with one-handed screw sense helix conformation. The usually formed anionic active centre on the prepolymer could be changed to cationic, radical and even of Ziegler-Natta type. These living prepolymers with various kinds of active centre were all effective to induce a consequent asymmetric polymerization of a monomer which may be other than that in the prepolymer, to afford an optically active helical chain with the same screw sense as that of the prepolymer. Eight monomers have been used in the work. Optical rotation, circular dichroism and gelpermeation chromatography have been taken to prove the helix-induced asymmetric polymerization.     

Catalytic asymmetric fluorinations

The appearance of structurally diverse fluorinating reagents displaying a large spectrum of reactivity has been critical to the development of the catalytic asymmetric fluorination processes known to date. In this article, we discuss how this area of research emerged and which strategies have allowed for the successful development of both nucleophilic and electrophilic catalytic enantioselective fluorinations. We also present the fundamental understanding of catalytic activity and enantioselectivity for the most efficient processes and highlight the first synthetic application with the preparation of a complex fluorinated target.     

Optically active phenanthrolines in asymmetric catalysis. Rhodium-catalyzed asymmetric transfer hydrogenation of acetophenone

The catalyst formed in situ from [Rh(1,5-cyclooctadiene)Cl]₂ and (+)-(S)-3-s-butyl-1,10-phenanthroline promotes the asymmetric transfer hydrogenation of acetophenone in isopropanol solution; optical yields of up to 31% are obtained.     

Palladium-catalyzed asymmetric silaboration of allenes

An enantioselective silaboration of allenes was achieved using an achiral silylborane in the presence of a palladium catalyst bearing a chiral monodentate phosphine ligand. (R)-2-Bis(3,5-dimethylphenyl)phosphino-1,1'-binaphthyl gave the highest enantioselectivities in the addition of (diphenylmethylsilyl)pinacolborane to the internal C=C bond of terminal allenes at 0 degrees C, giving the corresponding beta-borylallylsilanes in high yields with high enantiomeric excesses. The enantioselectivity depended on the bulkiness of substituents of allenes: the enantiomeric excesses were found to be 91-93% ee (R = tert- and sec-alkyl), 88-90% ee (R = aryl), and 80-82% ee (R = prim-alkyl and Me) at 0 degrees C. Perfect chirality transfer was observed in the intramolecular cyclization reactions of the functionalized allylsilanes, affording highly enantioenriched cyclic alkenylboranes, which underwent Suzuki-Miyaura coupling with aryl halides.     

Proton NMR spectroscopy of asymmetric benzylamines. The long-range effects of an asymmetric environment

¹H NMR Spectra of the asymmetric benzylamines N-benzyl-N-butyl-2-hydroxy-1,3-propandiamine, N-benzyl-N-(2-ethylhexyl)-2-hydroxy-1,3-propandiamine, N-benzyl-N-butyl-2,3-epoxypropanamine and N-benzyl-N-(2-ethylhexyl)-2,3-epoxypropanamine, were analysed. A pronounced non-equivalance of the benzylic hydrogens is induced by asymmetric carbons in γ position with respect to the benzylic group. [Δδ=0.2–0.3 ppm; J(AB)～13.5 Hz]. Two sets of AB patterns were observed when two asymmetric carbons were present in the same molecule. RS+SR Diastereomers can thus be distinguished from the RR+SS enantiomers.     

First asymmetric synthesis of achaetolide

The first asymmetric synthesis of the 10-membered macrolide achaetolide is reported in this article. The main highlight of the synthetic strategy is the ring-closing metathesis (RCM) of intermediate 19, which in turn can be accessed from coupling between alcohol 11 and acid 18. The synthesis of 11 involves enzymatic kinetic resolution (EKR) coupled with a Mitsunobu inversion strategy, while 18 can be prepared by adopting a metal-enzyme combined dynamic kinetic resolution (DKR) reaction followed by functional group manipulation.     

Computer simulation of asymmetric transformations

In order to obtain the best strategy for organic synthesis, the simulation of the reaction course can be helpful. In this letter we present a facile mathematical system for the simulation of the reaction course based on the reaction kinetics. Reaction courses are described and displayed easily by dividing the whole process into several small intervals. Exemplarily this is demonstrated for kinetic resolutions and desymmetrizations. The Microsoft^® Excel tables used for these simulations are available herein.