Catalysis of the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde by mixtures of L-Arg and of L-Glu in wet dimethyl sulfoxide (DMSO) takes place with higher enantioselectivity (up to a 7-fold enhancement in the anti-aldol for the 1:1 mixture) than that observed when either L-Glu or L-Arg alone are used as the catalysts. These results can be explained by the formation of a catalytically active hydrogen-bonded complex between both amino acids, and demonstrate the possibility of positive cooperative effects in catalysis by two different α-amino acids. Chirality 28:599–605, 2016. © 2016 Wiley Periodicals, Inc.

The aldol reaction between acetone and 4-nitrobenzaldehyde run in the nominal absence of any enantioselective catalyst was monitored by chiral HPLC with the aid of an internal standard. The collected data show the presence of a detectable initial enantiomeric excess of the aldol product in the early stages of the reaction in about 50 % of the experiments. Only a small fraction of the reaction contained the non-racemic aldol product after 24 h. This temporary emergence of natural optical activity could be the signature of a coupled reaction network that leads to a spontaneous mirror-symmetry-breaking process, which originates at very low conversions (i.e., strongly depends on events taking place at the very first stages of the process). The reaction is not autocatalytic in the aldol product, which rules out a simple Frank-type reaction network as the source of the observed symmetry breaking. On the other hand, the isolation and characterisation of a double-aldol adduct suggested a reaction network that involved both indirect autocatalysis and indirect mutual inhibition between the enantiomers of the reaction product.

α-Branched α,β-unsaturated aldehydes have been tested in the organocatalytic tandem Michael addition/cyclization with N-(benzyloxycarbonyl)hydroxylamine, a reaction which until now has been restricted to α-unsubstituted enals. Starting from cyclopentene-2-carbaldehyde, and using diphenylprolinol trimethylsilyl ether as a chiral amine catalyst, this approach has led to the development of a practical, high yielding (93–98 % overall yield, three steps), and highly enantioselective (up to 98:2 er) route to the cyclic β-amino acid cispentacin, which compares favourably with previously described asymmetric syntheses of this biologically active natural product. When using acyclic α-branched α,β-unsaturated aldehydes as substrates, the reaction yields depend on the substitution pattern of the aldehydes, and mixtures of cis- and trans-isomers are obtained. Nevertheless, this strategy has proved to be successful in some instances, and (3R,4R)-benzyl 3-ethyl-4-methyl-5-oxoisoxazolidin-2-carboxylate could be obtained in 70 % overall yield (two steps) from the reaction of 2-ethylcrotonaldehyde and N-(benzyloxycarbonyl)hydroxylamine under catalysis with diphenylprolinol trimethylsilyl ether, and with high enantiomeric purity (99:1 er).

For the first time, the addition of anthrones to maleimides catalyzed by bifunctional thiourea catalysts is reported. The thiourea moiety is able to activate the maleimide and the tertiary amine deprotonates the anthrone, furnishing the final Diels–Alder or Michael adducts in excellent yields and enantioselectivities.

An organocatalytic, highly enantioselective addition of 1-fluoro-1-nitro(phenylsulfonyl)methane to α,β-unsaturated aldehydes is reported. The reaction is simply catalyzed by secondary amines and furnishes the corresponding fluorinated derivatives in good yields, with moderate diastereoselectivities and excellent enantioselectivities. The absolute configuration of the major diastereomers was unambiguously ascertained by X-ray diffraction analysis.

Herein we present the design, synthesis, and evaluation of a structurally novel library of 20 peptidyl 3-aryl vinyl sulfones as inhibitors of cathepsins L and B. The building blocks, described here for the first time, were synthesized in a highly efficient and enantioselective manner, starting from 3-aryl-substituted allyl alcohols. The corresponding vinyl sulfones were prepared by a new approach, based on a combination of solid-phase peptide synthesis using the Fmoc/tBu strategy, followed by solution-phase coupling to the corresponding (R)-3-amino-3-aryl vinyl sulfones as trifluoroacetate salts. The inhibitory activity of the resulting compounds against cathepsins L and B was evaluated, and the compound exhibiting the best activity was selected for enzymatic characterization. Finally, docking studies were performed in order to identify key structural features of the aryl substituent.

The first highly diastereo- and enantioselective organocatalytic synthesis of 2,2-disubstituted-2H-oxazol-5-ones is described. The addition of oxazolones to maleimides is promoted by bifunctional thiourea catalysts, which afford the corresponding 2,2-disubstituted-2H-oxazol-5-ones with total regio- and stereocontrol.

A new, easy, and highly enantioselective method for the synthesis of quaternary α-alkyl-α-amino acids based on organocatalysis is reported. The addition of oxazolones to 1,1-bis(phenylsulfonyl)ethylene is efficiently catalyzed by simple chiral bases or thioureas. The reaction affords α,α-disubstituted α-amino acid derivatives with complete C4 regioselectivity and with excellent yields and enantioselectivities. This methodology is complementary to previously reported enantioselective approaches to quaternary α-amino acids and allows the synthesis of α-phenyl-α-alkyl-α-amino acids and α-tert-butyl-α-alkyl-α-amino acids. It has distinct advantages in terms of operational simplicity, enviromentally friendly conditions, and suitability for large-scale reactions.

Rearrangement reactions often lead to the regio- and stereoselective formation of carbon–carbon or carbon–heteroatom bonds, and allow the construction of otherwise hard-to-access molecular frameworks. Research disclosed in the present decade, especially in the last two years, has shown that organocatalytic modes of activation can be successfully applied to a variety of rearrangements. In this Minireview we discuss the advances achieved so far in asymmetric organocatalytic rearrangement reactions.

A convenient and novel oxazol-5-one addition to nitrostyrenes is reported. The reaction is catalyzed by tertiary amines and yields the corresponding adducts with total regio- and diastereoselectivity. The addition exclusively takes place at the C-2 position of oxazol-5-ones, furnishing diastereopure N,O-aminals. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

An enantiocontrolled synthesis of α-ferrocenylalanine methyl ester (S)-24 and of the corresponding N-Boc derivative (S)-25 is presented. We have found that an important source of instability for α-ferrocenyl-α-amino acid derivatives is the high reactivity of the α-hydrogen, and its replacement by a methyl group has proven to be essential for the stability of these compounds. The synthesis of (S)-24 requires only six steps from the readily available 2-propenylferrocene which is converted into the diol (S)-16 by Sharpless catalytic dihydroxylation. Regio- and stereoselective azide substitution of the tertiary hydroxy group affords the azido diol (S)-17. Swern oxidation gives the corresponding aldehyde which is smoothly oxidized to the carboxylic ester by means of the Smith–Kozlowski protocol. Transesterification and azide reduction lead to the α-amino ester (S)-24 in a good overall yield and enantiomeric purity. A cyclic voltammetric study of this compound showed that oxidation takes place by a simple reversible one-electron-transfer process. Half a century after the initial unsuccessful attempts to obtain ferrocenylglycine, this is the first synthesis of a stable α-amino acid derivative incorporating a ferrocene unit at the α-position.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)