This article summarizes recent progress in catalytic asymmetric epoxidation of α, β-unsaturated carbonyl compounds. Asymmetric epoxidation of α, β-unsaturated carbonyl compounds remains one of the most important functional group manipulations in organic synthesis, because of the usefulness of the corresponding enantiomerically enriched α, β-epoxy carbonyl compounds. Since the initial report by Juliá and co-workers, catalytic asymmetric epoxidation of α, β-epoxy ketones (enones) has been studied using several methodologies. In recent years, we and others have achieved efficient catalytic asymmetric epoxidation of enones using a variety of catalysts, including phase-transfer catalysts, polyamino acid catalysts, chiral ligand-metal peroxide complexes, and so on. On the other hand, there are only a few reports of catalytic asymmetric epoxidation of α, β-unsaturated carboxylic acid derivatives. Very recently we have reported the first example of a general catalytic asymmetric epoxidation of α, β-unsaturated carboxylic acid imidazolides to afford the corresponding α, β-epoxy peroxycarboxylic acid tert-butyl esters, which are transformed efficiently into α, β-epoxy esters, amides, aldehydes, and γ, δ-epoxy β-keto esters. The mechanism of the several reactions and applications to a catalytic asymmetric synthesis of biologically active compounds are also described briefly.
The first part of this article is concerned with the synthesis, structure, and reactions of the inner salt (R2N) 2C+CS2- 1. The most characteristic structural feature of 1 is represented by the findings that the plane of (R2N) 2C+ unit and that of CS2- unit are nearly perpendicular, while the most abnormal and interesting reactivity of 1 is characterized by reactions with nucleophiles, where a series of negatively charged R-M+ (M=MgX, Li) attacks the negatively charged sulfur atom to provide ethene-1, 1-dithioates. The second part describes the chemistry of (R2N) 2C+CSe2- 2, whose successful synthesis was accomplished in our laboratory. The last part deals with the chemistry of (R2N) 2C+CR2CS2- 3, where (R2N) 2C+ and CS2- units are insulated by an sp3 carbon atom.
Reactions of p-tolyl α-lithio-β-silylethyl sulfoxides with various electrophiles proceed with high stereoselectivity. Reactions of α-sulfinyl carbanions of the β-trimethylsilylethyl sulfoxides with aldehydes, ketones, or trimethylphosphate, give the products with high stereoselectivity. The high stereoselectivity of these reactions can be ascribed to the trialkylsilyl group at the β-position. New interaction between the silicon and the carbonyl oxygen in the transition state is demonstrated by the MO calculation. Reaction of the α-sulfinyl carbanion of the β-trimethylsilylethyl sulfoxide with α, β-unsaturated carbonyl compounds gives the conjugate addition products with extremely high stereoselectivity. The intermediate enolates are also stereoselectively trapped with various alkyl halides or aldehydes to give the corresponding products having 4 or 5 consecutive chiral centers. Intramolecular cyclization of the enolates gives chiral cycloalkanecarboxylates and this reaction opens a route to convenient synthesis of the optically pure chrysanthemate. The stereo- and regioselective elimination of the sulfinyl group is achieved by the action of the β-silyl group. It is demonstrated that acceleration of the sulfenic acid-elimination from the β-silylethenyl sulfoxide is mainly ascribed to the β-effect of the silyl group by the MO calculation. These reaction features show that p-tolyl α-lithio-β-silylethyl and p-tolyl α-lithio-β-silylethenyl sulfoxides are useful chiral vinyl and ethynyl anion synthetic equivalents, respectively.
Replacement of α-hydrogen atom of α-amino acids with alkyl substituents affords α, α-disubstituted α-amino acids, which are non-proteinogenic amino acids. This kind of modification changes the conformational freedom of peptides containing such residues. 2-Aminoisobutyric acid (dimethylglycine, Aib) is a natural product, isolated as a component of peptaibol antibiotics, and is widely used among peptide chemists for the construction of helical secondary structure. Contrary to 310-helical structure of Aib homopeptides, the conformation of homopeptides prepared from diethylglycine or dipropylglycine is a fully planar C5-conformation. Besides achiral α, α-disubstituted α-amino acids, the conformation of homopeptides prepared from chiral α-methylated or α-ethylated α, α-disubstituted α-amino acids was recently reported. The conformation of homopeptides prepared from chiral α-methylated α, α-disubstituted amino acids is the 310-helical structure and the screw sense of helicity (P) or (M) depends on the chirality of quaternary carbon center of amino acids, while that of α-ethylated α, α-disubstituted amino acids is the fully planar C5-conformation. The application of α, α-disubstituted α-amino acids for the design of biologically active peptides and catalytic peptides is also described.
Recently reported oxidation process of alcohols using molecular oxygen as an oxidizing agent in the presence of catalytic amount of transition metals such as copper, ruthenium, palladium compounds will be reviewed. Oxidation of alcohols based on hydrogen transfer reaction between alcohols and simple olefins such as ethylene is also described. That is, some benzylic and allylic alcohols can be converted into the corresponding carbonyl compounds using a catalytic amount of palladium on activated carbon (Pd-C) under ethylene atmosphere. The combination of Pd (OAc) 2 and vinyl acetate also works efficiently. Selective oxidation of hydroxy groups on carbohydrates (D-glycals) and steroids as well as simpler systems has been achieved. These environmentally benign oxidation methods have potentialities to replace the conventional stoichiometric chromium and other metal oxides reagents.
Described herein are three types of anionic migration of silyl and stannyl groups observed during the lithiation (hydrogen-lithium exchange) of nucleosides. In the first example of 9- [2, 3, 5-tris-O- (tert-butyldimethylsilyl) -β-D-ribofuranosyl]-6-chloropurine, the 8-trimethylsilyl or 8-tributylstannyl group introduced by lithiation underwent migration to the 2-position (migration within the base) through further lithiation of the less acidic H-2. The second example was observed by using 1- (2-deoxy-D-erythro-pent-1-enofuranosyl) uracil as a substrate, wherein the lithiationbased migration took place from the 6-position of the nucleobase to the 2'-position of the sugar (furanoid glycal). The last example came from the lithiation of the 5'-O-silylated or -stannylated anti-HIV agent d 4 T (2', 3'-didehydro-3'-deoxythymidine). As a result of highly unusual vinylic lithiation in the presence of allylic hydrogen, these 5'-O-protecting groups were transferred to the 3'-position of the unsaturated sugar (migration within the sugar). Since stannyl group can be transformed in various ways, the above three examples have opened up access to nucleoside derivatives that have been difficult to be synthesized by other methods.
Cefditoren Pivoxil was synthesized in the course of study on a series of cephalosporins having various heterocycles attached to the C 3-position of the cephem nucleus through Z- and E-etheno groups. Introduction of the side chains to the cephalosporins was achieved by a Wittig reaction. The reaction showed rather poor Z-E selectivity (Z : E=1 : 1 to 4 : 1) in the stage of screening research. Investigation was started for improvement of the Z-selectivity soon after determining Cefditoren Pivoxil as a development candidate substance, and relatively high Z-selectivity (Z : E=94 : 6) was finally achieved. The overall yield of Cefditoren Pivoxil was 49.6% in the established manufacturing synthetic method. Cefditoren, the active form of Cefditoren Pivoxil, has remarkably potent activity to penicillin-resistant Streptococcus pneumoniae (PRSP) and β-lactamase-negative-ampicillin resistant Haemophilus influenzae (BLNAR) among the oral β-lactam antibiotics.