Asymmetric 1,4-addition of oxazolones to nitroalkenes by bifunctional cinchona alkaloid thiourea organocatalysts: synthesis of alpha,alpha-disubstituted alpha-amino acids

An easy and simple synthetic approach to optically active alpha,alpha-quaternary alpha-amino acids using asymmetric organocatalysis is presented. The addition of oxazolones to nitroalkenes catalyzed by thiourea cinchona derivatives provides the corresponding alpha,alpha-quaternary alpha-amino acid derivatives with good yields, excellent diastereoselectivities (up to 98 % dr), and from moderate to good enantioselectivities (up to 92 % ee). The reaction can be performed on a large scale. The optically active oxazolone-nitroalkene addition products can be opened in a one-pot reaction to the corresponding ester-amide derivatives. Additional transformations are also presented, such as the synthesis of amino esters, amino acids, and transformation into 3,4-disubstituted pyrrolidin-2-ones.     

Facile approach to enantiomerically pure alpha-amino ketones by Friedel-Crafts aminoacylation and their conversion into peptidyl ketones

In this article we describe a versatile and straightforward preparative approach to chiral aryl alpha-amino ketones via a Friedel-Crafts-type reaction of stable and enantiomerically pure N-Fmoc protected L-amino acid chlorides with toluene in the presence of aluminum trichloride. The developed methodology provided aryl alpha-amino-p-methylphenyl ketones, which can be obtained and isolated as free bases or recovered as their N-acetyl derivatives, after treatment with acetic anhydride in chloroform at room temperature, subsequent to the Lewis acid induced removal of the 9-fluorenylmethoxycarbonyl protecting group. The Friedel-Crafts-like process and the cleavage of the amino function masking group can selectively be performed since, as verified in all cases, the alpha-aminoacylation step occurred with kinetics that were faster than those required to remove the N-protection. The presented approach was also explored as a facile and useful synthetic tool for the preparation of optically pure ketone di- and tripeptides. These compounds can be obtained in exceptionally overall yields without need of chromatographic purification. Moreover, either aryl alpha-amino ketones or modified di- and tripeptides, in all cases, can be isolated in very high chemical and optical purity without recourse to resolution of diastereomeric mixtures, since the chiralities of the asymmetric amino acid educts were completely conserved throughout the entire process.     

Asymmetric interaction of optically active polymers with asymmetric small molecules. IV. Effect of hydrophobic groups on asymmetric interaction

In order to investigate the mechanism of the asymmetric interaction between optically active polymers and small molecules, optically active copolymers of N-acrylyl L-amino acids(N-acrylyl-L -phenylalanine, N-acrylyl-L -tryptophan, and N-acrylyl-L -leucine, respectively) and N,N′-hexamethylene diacrylylamide were synthesized, and interaction of these polymers with the optical isomers of phenylalanine and tryptophan was investigated. In the interaction of these acidic polymers with amino acids performed at pH 5.0, significant difference in amount of adsorption between the D and L isomers of amino acids were observed, and the L form of amino acids was adsorbed preferentially. The interaction between optically active small molecules was also investigated: these results showed a similarity to the results for interaction between optically active polymers and amino acids. In some instances of asymmetric interaction the influence of hydrophobic interaction between a polymer and substrate was clearly perceived. The stereoselective effects on the asymmetric interaction are discussed.     

TiCl4-promoted multicomponent reaction: a new entry to functionalized alpha-amino acids

TiCl(4)-promoted multicomponent reactions involving N-tosyl imino ester, cyclic enol ether, and silane reagents in a single one-pot operation provide functionalized alpha-amino acids with multiple stereogenic centers in good to excellent yields. Cis/trans selectivities with optically active substituted dihydrofurans have been investigated.     

Acetoxy Meldrum's acid: a versatile acyl anion equivalent in the Pd-catalyzed asymmetric allylic alkylation

Acetoxy Meldrum's acid can serve as a versatile acyl anion equivalent in the Pd-catalyzed asymmetric allylic alkylation. The reaction of this nucleophile with various meso and racemic electrophiles afforded alkylated products in high yields and enantiopurities. These enantioenriched products are versatile intermediates that can be further functionalized using nitrogen- and oxygen-centered nucleophiles, affording versatile scaffolds for the synthesis of nucleoside analogues. These scaffolds were used to complete formal syntheses of the anti-HIV drugs carbovir, abacavir, and the antibiotic aristeromycin.     

Efficient Enantioselective Syntheses of Chiral Natural Products Facilitated by Ligand Design

The employment of enantioselective transition‐metal‐catalyzed transformations as key steps in asymmetric natural product syntheses have attracted considerable attention in recent years owing to their versatile synthetic utilities, mild conditions and high efficiency in chirality generation. The chiral catalysts or supporting ligands are believed to be crucial for the requisite reactivity and enantioselectivity. Therefore, the rational design of chiral ligands is at the heart of developing new asymmetric transition‐metal catalyzed reactions and provides an avenue to the asymmetric synthesis of natural products. Our group has been engaged in the development of transition‐metal‐catalyzed enantioselective cross‐coupling, cyclization and other related reactions and the application of these methodologies to natural product syntheses. In this account, we summarized our recent synthetic efforts towards the efficient total syntheses of several different types of natural products including terpenes, alkaloids and polyketides facilitated by the design of a series of versatile P‐chiral phosphorous ligands.     

Substitution with retention in organoboranes and utilization of the phenomenon for a general synthesis of pure enantiomers

Organoboranes, readily available via the hydroboration of unsaturated organic compounds, exhibit a remarkable versatility in their reactions. The boron atom in these organoboranes can be readily converted into a wide variety of organic groups under very mild conditions, providing simple versatile syntheses of organic compounds. Exploration of these substitution reactions reveal that, with rare exceptions, the organoboranes transfer the alkyl group to other elements of synthetic interest with complete retention of stereochemistry. Recently we have discovered a method of synthesizing essentially optically pure organoborane intermediates. These optically active alkyl groups attached to boron can also be transferred with complete retention of optical activity. Consequently, it is now possible to achieve by a rational synthesis the preparation of almost any optically active compound with a chiral center, either R- or S-, in essentially 100% enantiomeric excess.     

Recent developments in the catalytic asymmetric synthesis of alpha- and beta-amino acids

The stereoselective synthesis of amino acids is of great importance for the construction of optically active natural products and pharmaceuticals. Apart from enzymes, a broad repertoire of chiral reagents, auxiliaries, and catalysts can be used for the formation of amino acids. Asymmetric reactions using catalytic amounts of chiral molecules provide efficient methods for the generation of optically active proteinogenic and nonproteinogenic amino acids. This minireview collects recent work on catalytic asymmetric synthesis of alpha- and beta-amino acids.     

Organocatalytic asymmetric 1,6-additions of beta-ketoesters and glycine imine

The first organocatalytic enantioselective 1,6-addition of beta-ketoesters and benzophenone imine to electron-poor delta-unsubstituted dienes using cinchona alkaloids under phase-transfer conditions is demonstrated. The scope of the reaction for the beta-ketoesters is outlined for reactions with different delta-unsubstituted dienes having ketones, esters, and sulfones as electron-withdrawing substituents giving the corresponding optically active products in good yields and enantioselectivities in the range of 90-99% ee. The 1,6-addition also proceeds with a number of cyclic beta-ketoesters having different ring sizes, ring systems and substituents in high yields and enantioselectivities. The potential of this new organocatalytic 1,6-addition for beta-ketoesters is demonstrated by a two-step synthesis of the bicyclo[3.2.1]octan-8-one structure, a bicyclic bridged skeleton occurring in a variety of natural compounds. Benzophenone imines also undergo the organocatalytic asymmetric 1,6-addition to the activated dienes in high yields and with enantioselectivities from 92% to 98% ee, except in one case. The synthetic utility of this asymmetric reaction is demonstrated by the two-step transformation of the allylated alpha-amino acid derivative to highly attractive optically active pyrrolidines.     

Direct asymmetric intermolecular aldol reactions catalyzed by amino acids and small peptides

In nature there are at least nineteen different acyclic amino acids that act as the building blocks of polypeptides and proteins with different functions. Here we report that alpha-amino acids, beta-amino acids, and chiral amines containing primary amine functions catalyze direct asymmetric intermolecular aldol reactions with high enantioselectivities. Moreover, the amino acids can be combined into highly modular natural and unusual small peptides that also catalyze direct asymmetric intermolecular aldol reactions with high stereoselectivities, to furnish the corresponding aldol products with up to >99 % ee. Simple amino acids and small peptides can thus catalyze asymmetric aldol reactions with stereoselectivities matching those of natural enzymes that have evolved over billions of years. A small amount of water accelerates the asymmetric aldol reactions catalyzed by amino acids and small peptides, and also increases their stereoselectivities. Notably, small peptides and amino acid tetrazoles were able to catalyze direct asymmetric aldol reactions with high enantioselectivities in water, while the parent amino acids, in stark contrast, furnished nearly racemic products. These results suggest that the prebiotic oligomerization of amino acids to peptides may plausibly have been a link in the evolution of the homochirality of sugars. The mechanism and stereochemistry of the reactions are also discussed.     

Carbohydrates as Chiral Auxiliaries in Stereoselective Synthesis. New Synthetic Methods (90)

Carbohydrates are inexpensive natural products in which numerous functional groups and stereogenic centers are combined in one molecule. By directed regio-and stereoselective formation of derivatives they can be converted into efficient chiral auxiliaries for controlling asymmetric syntheses. Stereoelectronic effects and pre-orientation of the reactive and shielding groups through formation of complexes can often be used for effective diastereofacial differentiation. In aldol reactions and alkylations on carbohydrate ester enolates intramolecular complexation promotes simultaneous elimination with formation of ketene. The steric, stereoelectronic, and coordinating properties of carbohydrate templates can also be used selectively to attain high levels of asymmetric induction in processes such as Diels–Alder reactions, hetero-Diels–Alder reactions, [2 + 2] cycloadditions, cyclopropanations, and Michael additions. It was possible with bicyclic, strongly stereodifferentiating carbohydrate auxiliaries to achieve a diastereoselective synthesis of carboxylic acid derivatives branched in the β position by a new 1,4-addition of alkylaluminum halides to α,β-unsaturated N-acylurethanes, in which methylaluminum halides and higher alkyl- or arylaluminum compounds behave mechanistically in a strikingly different manners. As complex ligands in chiral reagents and promoters, carbohydrates allow highly stereoselective reductions and aldol reactions that lead, amongst others, to chiral alcohols and β-hydroxy-α-amino acids in excellent enantiomeric excesses. Glycosylamines offer the possibility of versatile stereoselective applications: in the presence of Lewis acids the corresponding aldimines permit high-yielding syntheses of enantiomerically pure α-amino acids by Strecker and Ugi reactions, controlled by steric and stereoelectronic effects and by complex formation. They can be used with equal efficiency for asymmetric syntheses of chiral homoallylamines and for asymmetric Mannich syntheses of β-amino acids and chiral heterocycles, for example alkaloids.     

Stereocontrolled synthesis of vicinal diamines by organocatalytic asymmetric Mannich reaction of N-protected aminoacetaldehydes: formal synthesis of (-)-agelastatin A

The 1,2-diamine (vicinal diamine) motif is present in a number of natural products with interesting biological activity and in many chiral molecular catalysts. The efficient and stereocontrolled synthesis of enantioenriched vicinal diamines is still a challenge to modern chemical methodology. We report here both syn- and anti-selective asymmetric direct Mannich reactions of N-protected aminoacetaldehydes with N-Boc-protected imines catalyzed by proline and the axially chiral amino sulfonamide (S)-3. This organocatalytic process represents the first example of a Mannich reaction using Z- or Boc-protected aminoacetaldehyde as a new entry of α-nitrogen functionalized aldehyde nucleophile in enamine catalysis. The obtained optically active vicinal diamines are useful chiral synthons as exemplified by the formal synthesis of (-)-agelastatin A.     

Asymmetric synthesis of protected arylglycines by rhodium-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl imino esters

A new method for the Rh(I)-catalyzed addition of arylboronic acids to N-tert-butanesulfinyl imino esters has been developed for the asymmetric synthesis of arylglycine derivatives. This method provides high yields (61-90%) and diastereoselectivities (>98:2) for a variety of functionalized arylboronic acids. The N-sulfinyl arylglycine ester products are versatile intermediates for further transformations, including selective protecting group removal, conversion to beta-amino alcohols, and direct incorporation into peptides.     

A novel synthesis of N-methyl asparagine,arginine, histidine,and tryptophan

[reaction: see text] N-Methyl amino acid residues in peptides modify several pharmacologically useful parameters, but synthesis of alkylated peptides is hampered by unavailability of N-methylated monomers. The syntheses of four N-methyl amino acids with basic side chains are presented. The side chains of these basic amino acids needed to be specially protected or constructed. This completes the set of 20 common L-amino acid N-methyl derivatives prepared via 5-oxazolidinone intermediates by our group.     

Recent progress on direct catalytic asymmetric vinylogous reactions

Direct catalytic asymmetric vinylogous reaction serves as a powerful tool to introduce stereocenter(s) at the γ- or/and even more remote position(s) of the vinylogous products in an atom-economical and efficient way. A variety of direct catalytic asymmetric vinylogous reactions with broad substrate scope and mild reaction conditions has been developed. Both metal catalysis and organocatalysis contributed in this field and led to the vinylogous products in high stereoselectivity. These vinylogous reactions provided efficient pathways for the synthesis of highly functionalized optically pure compounds, especially these with potential biological activity and pharmacological activity. This digest paper mainly focuses on the most recent developments in this field, including both nucleophilic addition and nucleophilic substitution.     

Azabicyclo[3.1.0]hexane-1-ols as frameworks for the asymmetric synthesis of biologically active compounds

Azabicyclo[3.1.0]hexane-1-ols, easily obtained by Ti(IV)-mediated cyclopropanation of amino acid derivatives, constitute versatile, and unprecedented intermediates for the asymmetric synthesis of pharmacologically active products. Indeed, through selective rearrangement, these compounds undergo unusual ring cleavage to lead to pyrrolidinones. Fe(III)-promoted ring opening followed by basic dehydrohalogenation furnishes optically active dihydropyridinones, while Ce(IV)-promoted ring opening provides chiral tricyclopiperidinones via a radical process.     

Lessons from nature: biomimetic organocatalytic carbon-carbon bond formations

Nature utilizes simple C2 and C3 building blocks, such as dihydroxyacetone phosphate (DHAP), phosphoenolpyruvate (PEP), and the "active aldehyde" in various enzyme-catalyzed carbon-carbon bond formations to efficiently build up complex organic molecules. In this Perspective, we describe the transition from using enantiopure chemical synthetic equivalents of these building blocks, employing our SAMP/RAMP hydrazone methodology and metalated chiral alpha-amino nitriles, to the asymmetric organocatalytic versions developed in our laboratory. Following this biomimetic strategy, the DHAP equivalent 2,2-dimethyl-1,3-dioxan-5-one (dioxanone) has been used in the proline-catalyzed synthesis of carbohydrates, aminosugars, carbasugars, polyoxamic acid, and various sphingosines. Proline-catalyzed aldol reactions involving a PEP-like equivalent have also allowed for the asymmetric synthesis of ulosonic acid precursors. By mimicking the "active aldehyde" nucleophilic acylations in Nature catalyzed by the thiamine-dependent enzyme, transketolase, enantioselective N-heterocyclic carbene-catalyzed benzoin and Stetter reactions have been developed. Finally, based on Nature's use of domino reactions to convert simple building blocks into complex and highly functionalized molecules, we report on our development of biomimetic asymmetric multicomponent domino reactions which couple enamine and iminium catalysis.     

Amino acid catalyzed neogenesis of carbohydrates: a plausible ancient transformation

Hexose sugars play a fundamental role in vital biochemical processes and their biosynthesis is achieved through enzyme-catalyzed pathways. Herein we disclose the ability of amino acids to catalyze the asymmetric neogenesis of carbohydrates by sequential cross-aldol reactions. The amino acids mediate the asymmetric de novo synthesis of natural L- and D-hexoses and their analogues with excellent stereoselectivity in organic solvents. In some cases, the four new stereocenters are assembled with almost absolute stereocontrol. The unique feature of these results is that, when an amino acid is employed as the catalyst, a single reaction sequence can convert a protected glycol aldehyde into a hexose in one step. For example, proline and its derivatives catalyze the asymmetric neogenesis of allose with >99 % ee in one chemical manipulation. Furthermore, all amino acids tested catalyzed the asymmetric formation of natural sugars under prebiotic conditions, with alanine being the smallest catalyst. The inherent simplicity of this catalytic process suggests that a catalytic prebiotic "gluconeogenesis" may occur, in which amino acids transfer their stereochemical information to sugars. In addition, the amino acid catalyzed stereoselective sequential cross-aldol reactions were performed as a two-step procedure with different aldehydes as acceptors and nucleophiles. The employment of two different amino acids as catalysts for the iterative direct aldol reactions enabled the asymmetric synthesis of deoxysugars with >99 % ee. In addition, the direct amino acid catalyzed C(2)+C(2)+C(2) methodology is a new entry for the short, highly enantioselective de novo synthesis of carbohydrate derivatives, isotope-labeled sugars, and polyketide natural products. The one-pot asymmetric de novo syntheses of deoxy and polyketide carbohydrates involved a novel dynamic kinetic asymmetric transformation (DYKAT) mediated by an amino acid.     

硝基化合物的不对称迈克尔加成反应

从以下三方面对硝基化合物的不对称迈克尔加成反应进行了较为详细的综述： （1）手性催化剂催化的迈克尔加成，（2）共轭硝基物与手性亲核试剂的迈克加成 ，（3）脂肪族硝基物对手性迈克加成受体的迈克尔加成。     

Catalytic Asymmetric 1,2‐Addition of α‐Isothiocyanato Phosphonates: Synthesis of Chiral β‐Hydroxy‐ or β‐Amino‐Substituted α‐Amino Phosphonic Acid Derivatives

α‐Amino phosphonic acid derivatives are considered to be the most important structural analogues of α‐amino acids and have a very wide range of applications. However, approaches for the catalytic asymmetric synthesis of such useful compounds are very limited. In this work, simple, efficient, and versatile organocatalytic asymmetric 1,2‐addition reactions of α‐isothiocyanato phosphonate were developed. Through these processes, derivatives of β‐hydroxy‐α‐amino phosphonic acid and α,β‐diamino phosphonic acid, as well as highly functionalized phosphonate‐substituted spirooxindole, can be efficiently constructed (up to 99 % yield, d.r. >20:1, and >99 % ee). This novel method provides a new route for the enantioselective functionalization of α‐phosphonic acid derivatives.