Alexander E. Sorochinsky

Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001–2011)

Introduced to the Market in the Last Decade (2001−2011) Jiang Wang,† María Sańchez-Rosello,́‡,§ Jose ́ Luis Aceña, Carlos del Pozo,‡ Alexander E. Sorochinsky, Santos Fustero,*,‡,§ Vadim A. Soloshonok,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry, Faculty of Pharmacy, University of Valencia, Av. Vicente Andreś Estelleś, 46100 Burjassot, Valencia, Spain Laboratorio de Molećulas Orgańicas, Centro de Investigacioń Príncipe Felipe, C/ Eduardo Primo Yuf́era 3, 46012 Valencia, Spain Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastian, Spain IKERBASQUE, Basque Foundation for Science, Alameda Urquijo, 36-5 Plaza Bizkaia, 48011 Bilbao, Spain Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Street 1, 02660 Kyiv-94, Ukraine

Self-disproportionation of enantiomers via achiral chromatography: A warning and an extra dimension in optical purifications

This tutorial review describes the self-disproportionation of enantiomers (SDE) of chiral, non-racemic compounds, subjected to chromatography on an achiral stationary phase using an achiral eluent, which leads to the substantial enantiomeric enrichment and the corresponding depletion in different fractions, as compared to the enantiomeric composition of the starting material. The physicochemical background of SDE is a dynamic formation of homo- or heterochiral dimeric or oligomeric aggregates of different chromatographic behavior. This phenomenon is of a very general nature as the SDE has been reported for different classes of organic compounds bearing various functional groups and possessing diverse elements of chirality (central, axial and helical chirality). The literature data discussed in this review clearly suggest that SDE via achiral chromatography might be expected for any given chiral enantiomerically enriched compound. This presents two very important issues for organic chemists. First, chromatographic purification of reaction products can lead to erroneous determination of the stereochemical outcome of catalytic asymmetric reactions and second, achiral chromatography can be used as a new, nonconventional method for optical purifications. The latter has tremendous practical potential as the currently available techniques are limited to crystallization or chiral chromatography. However, a further systematic study of SDE is needed to develop understanding of this phenomenon and to design practical chromatographic separation techniques for optical purification of non-racemic mixtures by achiral-phase chromatography.

Biocatalytic approach to enantiomerically pure β-amino acids

β-Aryl-β-amino acids were prepared in good chemical yield and high enantiomeric purity (>95% ee) via penicillin acylase-catalyzed hydrolysis of the corresponding N-phenylacetyl derivatives. The (R)-enantiomers were the fast-reacting isomers in all cases studied. The biocatalytic procedure described employs very simple set of reactions using inexpensive commercially available chemicals and enzyme, and could be easily scaled up.

Recent advances in the synthesis of fluorinated aminophosphonates and aminophosphonic acids

This review article surveys recent achievements in the preparation and biological properties evaluation of fluorinated aminophosphonates and aminophosphonic acids. Recently, in view of various important biological applications of the fluorinated aminophosphonic acid derivatives, the development of suitable synthetic methodologies for their preparation in racemic and in optically pure form has been a topic of great interest. Considerable progress has been made in asymmetric synthesis of fluorinated acyclic aminophosphonates and aminophosphonic acids using catalytic enantioselective reduction of fluorinated α-iminophosphonates, catalytic enantioselective addition of alkyl phosphites to fluorinated imines, and diastereoselective addition of alkyl phosphites to chiral fluorinated imines. A new efficient access to CF3-substituted cyclic α-aminophosphonates has been developed based on metal-catalyzed carbene transfer reactions with diethyl 1-diazo-2,2,2-trifluoroethylphosphonate. New processes, e.g. enantioselective alkynylation and nucleophilic aromatic substitution involving fluorinated substrates are also considered.

Convenient, large-scale asymmetric synthesis of β-aryl-substituted α, α-difluoro-β-amino acids

Abstract The enantiopure p -toluenesulfinimines were found to be efficient as chiral imine equivalents in the high temperature Reformatsky-type additions with BrZnCF 2 COOEt affording an efficient approach to the enantiomerically pure α,α-difluoro-β-amino acids. High chemical and stereochemical yields (drs>9:1, and as high as 99:1) render this method immediately useful for preparing the target amino acids.

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases; Part 1: alkyl halide alkylations

Alkylations of chiral or achiral Ni(II) complexes of glycine Schiff bases constitute a landmark in the development of practical methodology for asymmetric synthesis of α-amino acids. Straightforward, easy preparation as well as high reactivity of these Ni(II) complexes render them ready available and inexpensive glycine equivalents for preparing a wide variety of α-amino acids, in particular on a relatively large scale. In the case of Ni(II) complexes containing benzylproline moiety as a chiral auxiliary, their alkylation proceeds with high thermodynamically controlled diastereoselectivity. Similar type of Ni(II) complexes derived from alanine can also be used for alkylation providing convenient access to quaternary, α,α-disubstituted α-amino acids. Achiral type of Ni(II) complexes can be prepared from picolinic acid or via recently developed modular approach using simple secondary or primary amines. These Ni(II) complexes can be easily mono/bis-alkylated under homogeneous or phase-transfer catalysis conditions. Origin of diastereo-/enantioselectivity in the alkylations reactions, aspects of practicality, generality and limitations of this methodology is critically discussed.

Chiral sulfoxide controlled asymmetric additions to CN double bond. An efficient approach to stereochemically defined α-fluoroalkyl amino compounds

Abstract This paper presents a full account of studies into the asymmetric addition reactions between α-lithium derivatives of enantiomerically pure methyl and benzyl p-tolyl sulfoxides and the N-(p-methoxyphenyl)aldimines, bearing trifluoromethyl, pentafluoroethyl and ω-hydrotetrafluoroethyl groups, to afford the corresponding α-fluoroalkyl β-sulfinylamines, synthetically versatile precursors of a series of enantiomerically pure biomedicinally important α-fluoroalkylalkylamines and α-fluoroalkyl-β-hydroxyalkylamines. The addition reactions were found to proceed under mild conditions allowing for convenient preparation of the corresponding α-fluoroalkyl β-sulfinylamines in excellent yields and good enantiomeric purity. The stereochemical outcomes of these reactions were shown to be subject to kinetic control, that is in sharp contrast to the corresponding reactions of fluorine-free imines. The absolute configurations of the addition products suggest that the fluoroalkyl group on starting imines plays a role of enantiodirecting, sterically larger substituent causing realization of an unusual for this type of reactions transition states.

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 2: Aldol, Mannich addition reactions, deracemization and (S) to (R) interconversion of α-amino acids

Abstract This review provides a comprehensive treatment of literature data dealing with asymmetric synthesis of α-amino-β-hydroxy and α,β-diamino acids via homologation of chiral Ni(II) complexes of glycine Schiff bases using aldol and Mannich-type reactions. These reactions proceed with synthetically useful chemical yields and thermodynamically controlled stereoselectivity and allow direct introduction of two stereogenic centers in a single operation with predictable stereochemical outcome. Furthermore, new application of Ni(II) complexes of α-amino acids Schiff bases for deracemization of racemic α-amino acids and (S) to (R) interconversion providing additional synthetic opportunities for preparation of enantiomerically pure α-amino acids, is also reviewed. Origin of observed diastereo-/enantioselectivity in the aldol, Mannich-type and deracemization reactions, generality and limitations of these methodologies are critically discussed.

Optical Purifications via Self-Disproportionation of Enantiomers by Achiral Chromatography: Case Study of a Series of α-CF3-containing Secondary Alcohols

This work demonstrates that self-disproportionation of enantiomers via achiral chromatography can be recommended as inexpensive and general method for optical purification of enantiomerically enriched compounds. In particular, the advantage of this approach over conventional recrystallization is that it can be used for both crystalline as well as liquid compounds.

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 3: Michael addition reactions and miscellaneous transformations

The major goal of this review is a critical discussion of the literature data on asymmetric synthesis of α-amino acids via Michael addition reactions involving Ni(II)-complexes of amino acids. The material covered is divided into two conceptually different groups dealing with applications of: (a) Ni(II)-complexes of glycine as C-nucleophiles and (b) Ni(II)-complexes of dehydroalanine as Michael acceptors. The first group is significantly larger and consequently subdivided into four chapters based on the source of stereocontrolling element. Thus, a chiral auxiliary can be used as a part of nucleophilic glycine Ni(II) complex, Michael acceptor or both, leading to the conditions of matching vs. mismatching stereochemical preferences. The particular focus of the review is made on the practical aspects of the methodology under discussion and mechanistic considerations.