Methods for enantioselective synthesis

Since Biot s discovery in 1815 of the optical rotatory powers of solutions of natural products such as sucrose, many people have studied the relationship between chemical structure and optical rotatory power. 

Chemical Synthesis of Hormones, Pheromones and Other Bioregulators Kenji Mori 2010 John Wiley Sons, Ltd 

Pasteur s success in 1848 of the first enantiomer separation (optical resolution) of racemic acid as ammonium sodium ( )-tartrate tetrahydrate together with McKenzie s success in 1904 of the first asymmetric synthesis prompted many chemists to synthesize optically active compounds without recourse to the vital force of organisms, although by employing the capacity of a special species of organism, Homo sapiens, to discriminate left from right. Pasteur remarked in 1883 that The universe is dissymmetric. Since then chemists efforts have been focused on the control of asymmetry in this world of chiral and nonracemic materials. 

---

Despite the progress made in the stereoselective synthesis of (R)-pantothenic acid since the mid-1980s, the commercial chemical synthesis still involves resolution of racemic pantolactone. Recent (ca 1997) synthetic efforts have been directed toward developing a method for enantioselective synthesis of (R)-pantolactone by either chemical or microbial reduction of ketopantolactone. Microbial reduction of ketopantolactone is a promising area for future research. 

The Prelog-Djerassi lactone (abbreviated here as P-D lactone) was originally isolated as a degradation product during structural investigations of antibiotics. Its open-chain equivalent 3 is typical of the methyl-branched carbon chains that occur frequently in macrolide and polyether antibiotics. The compound serves as a test case for the development of methods of control of stereochemistry in such polymethylated structures. There have been more than 20 different syntheses of P-D lactone.24 We focus here on some of those that provide enantiomerically pure product, as they illustrate several of the methods for enantioselective synthesis.25... 

A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of /V-acyl oxazolidinones.59 The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

There have been more than 20 different syntheses of P-D-lactone.132 We will focus here on some of those which provide enantiomerically pure product, since they illustrate several of the methods for enantioselective synthesis.133... 

Scriban C, Glueck DS (2012) Method for enantioselective synthesis of phosphorus-stereogenic phosphines. US 8,193,392 B2 http //www.lens.orgAens/patent/US 8193392 B2... 

The need to develop effective methods for enantioselective synthesis is becoming ever more important as only a single enantiomer of a racemic bioactive compoimd is generally required for pharmaceuticals [1], agrochemicals [1,2], flavour [1,3] or fragrance [1,3]. Homogeneous asymmetric catalysis has been used to perform a variety of transformations... 

Desymmetrization is the modification of a symmetric object that results in the loss of symmetry elements. When coupled with the catalytic asymmetric process, it provides an efficient method for enantioselective synthesis of chiral molecules with multiple stereogenic centers [116]. 

General acid catalysis is surely one of the best known catalytic processes in organic chemistry. Protonation enhances the electrophilic character of a molecule, leading to increased reactivity. Moreover, the formation of tight ion pairs or hydrogen-bonded complexes between a protonated reactant and the conjugate base of chiral acids has been a widely exploited method for enantioselective synthesis [71, 72]. 

Sharpless epoxidation (Chapter 14 Lagniappe) A method for enantioselective synthesis of a chiral epoxide by treatment of an allylic alcohol with ferf-butyl hydroperoxide, (CHa)3C—OOH, in the presence of titanium tetraisopropoxide and diethyl tartrate. 

A third method for enantioselective synthesis involves the use of a stoichiometric amount of a chiral auxiliary. This is an enantiomerically pure material that can control the stereochemistry of one or more reaction steps in such a way as to give product having the desired configuration. Once the chiral auxiliary has achieved its purpose, it can be eliminated from the molecule. As in syntheses involving resolution or enantiomerically pure starting materials, subsequent steps must be controlled to give the correct configuration of newly created chiral centers. 

Certainly a major advance in synthetic chemistry during the 1980s was the development of methods for enantioselective synthesis. We have increased the level of attention to stereochemistry in the discussion of many reactions. In areas in which new stereoselective methods have been well developed, such as in aldol condensations, hydroboration, catalytic reduction, and epoxidation, we discuss these methods. 

An efficient method for enantioselective synthesis of (3-nitroalkylphos-phonates (549) in good ee values (up to 84% ec), ia the Michael addition of diphenyl phosphite (547) to nitroalkenes (548), using the readily available quinidine thiourea organocatalyst (550), has been developed Zhao and coworkers (Scheme 136). ... 

---