Practical Stereochemistry

Abstract

The relationship between fundamental and applied is often uneasy, particularly in modern political climates. A familiar political view, aimed negatively at the scientific community, is that the former is a waste of money whereas the latter gives value for investment. The answer that fundamental is required as the basis for practical suffers from the fact that the timelines between fundamental and practical are often long and the routes contorted and unexpected. This has been my experience. In this Account, examples are given from the research in which I have been involved wherein quite fundamental considerations have led to various applications. The longer the time, the clearer and broader the relationship. Fundamental can and does lead to application. They need and depend on each other. I have seen this both from the side of academia and from small companies. In the course of the past 40 plus years, I have been involved in various aspects of stereochemistry and, in particular, chirality. It has been rewarding to see that several of the developments, most originally grounded in fundamental research considerations, have been used in the chemical community and given new dimensions and often practical applications by others. In this Account, a path-not planned deliberately by me-from orbital symmetry and Woodward-Hoffmann rules through crown ethers to conformational analysis to diastereomeric resolutions to deracemizations powered by Ostwald ripening and the Gibbs-Thomson effect to nucleation to helicenes is described. In order of discussion, the orbital symmetry aspects have via an unusual and unpredicted path has resulted in, among other things, a synthesis of hindered alkenes useful for the production of molecular motors. The crown ether aspects led to discovery of the utility of cesium salts particularly for racemization sensitive nucleophilic substitutions. Work on diastereomeric resolutions has concentrated on the mechanistic as well as practical/commercial aspects of the use of multiple resolving agents (Dutch resolution). During this work the complex relationship between nucleation and chirality in diastereomeric resolutions began to reveal itself. In general, nucleation, especially with involvement of chirality, is a topical challenge that has attracted the attention of many groups. The contribution of this knowledge to the development of attrition driven deracemizations of racemizable conglomerates is described. This remarkable technology allows, without intervention of chiral aids, conversion of certain racemates in quantitative yield and absolute enantiomeric excess to a single enantiomer. From a practical standpoint, this methodology has been used for the production in enantiomerically pure form of commercially interesting compounds like naproxen and clopidogrel (Plavix). Finally an STM investigation of the nucleation behavior of a helicene, prepared via a remarkably short and efficient route, on a metal surface is described.

Asymmetric Catalytic (2+1) Cycloaddition of Thioketones to Synthesize Tetrasubstituted Thiiranes

“…The elaborations of some enantioenriched thiiranes were also carried out. Unfortunately, it was found that tetrasubstituted alkenes D1 – D4 via desulfuration of thiirane C1 or C33 , namely Barton–Kellogg olefination, [4c, 14] were afforded in decent results under varied conditions (Scheme 2c, see the Supporting Information for details). These results indicate that the high tense strain of the 3‐membered ring of thiirane was more likely to be released via desulfuration, [4c, 6] rather than substitution reaction, ring opening or expansion [15] .…”

Tandem crystallization strategies for resolution of 3,3,3‐trifluorolactic acid [CF3CH(OH)COOH] by chiral benzylamines

“…Resolution via diastereomeric salt formation is a classical method which is becoming somewhat neglected partly due to the development of new routes to efficient asymmetric syntheses with enantiomeric control such as organocatalysis . However, the combined use of powder diffraction and modern single crystal X‐ray structure determination can be of value in understanding the mechanism of resolution and in identifying the issues when such resolutions are not fully efficient.…”

Enantioselective synthesis of heterocyclic compounds using photochemical reactions

“…When particular crystallization methods, e.g. seeding crystallization with the desired homochiral crystal, the achiral starting compound can be selectively transformed into only one of the enantiomorphous crystals [126]. This method enables the controlled preparation of one desired enantiomer.…”