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Self-Regeneration of Stereocenters (SRS)-Applications, Limitations, and Abandonment of a Synthetic Principle

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Self-Regeneration of Stereocenters (SRS)-Applications, Limitations, and Abandonment of a Synthetic Principle In the same manner that the Nasobem, Stiimpke’s mythical creature, teaches his child the peculiar way of life of the species Nasobema lyricum, the work of Seebach et al. on the self-regeneration of stereocenters has been governed by a fanciful idea. On the way, many tricks have been learned and much knowledge gained. Finally, they have come back down to earth and find themselves once again in the unimaginative world of enantiomer separation for the synthesis of enantiomerically pure compounds. REVIEWS Self-Regeneration of Stereocenters (SRS)-Applications, Limitations, and Abandonment of a Synthetic Principle Dieter Seebach,* Andrea R. Sting, and Matthias Hoffmann Dedicated to our much-admired teacher and mentor, Professor Dr. Vladimir Prelog, on the occasion of his 90th birthday In order to replace a substituent at a atoms of cyclic or linear systems, and discuss the most useful findings gained single stereogenic center of a chiral mol- stereogenic planes of x-complexes can from investigations into both the self-re- ecule without racemization, a temporary also be used as the temporary chirality generation of stereocenters and the use center of chirality is first generated element in other approaches to the real- of chiral acetals in the synthesis of enan- diastereoselectively, the original tetrag- ization of the SRS principle. Enan- tiomerically pure compounds (EPC onal center is then trigonalized by re- tiomerically pure derivatives of, for ex- synthesis) : the formation and character- moval of a substituent, a new ligand is ample, glycine, hydroxy- and sulfanyl- istics of complexes obtained from introduced, again diastereoselectively, acetic acid, 3-aminopropanoic acid, and Li-enolates and other Li compounds and finally, the temporary center is re- 3-oxocarboxylic acids can be prepared with secondary amines; the application moved. By means of these four steps (the by resolution of racemic mixtures via of a-alkoxy and a-amino-Li-alkoxides “Self-Regeneration of Stereocenters”, diastereoisomeric salts or by chromato- as in situ bases and sources of aldehydes SRS), 2- and 3-amino-, hydroxy-, and graphy on a chiral column. Hence, the in C-C bond forming reactions with sulfanylcarboxylic acids have been suc- extensive reactivity of compounds de- unstable enolates or nitronates; the sig- cessfully alkylated with formation of veloped to test the SRS principle and, nificance of A’.’ effects on the stereo- tertiary carbon centers and without the above all, the outstanding stereoselec- chemical course of nucleophilic, radical, use of a chiral auxiliary. Use of this tivities of the reactions can be put to and electrophilic reactions of N-acylated methodology has allowed the potential good use even when no suitable chiral heterocycles and homo- or heterocyclic of these inexpensive chiral building precursor is availabl-ven though this carboxylic ester enolates; and the effects blocks to be expanded considerably. amounts to an abandonment of the of the amide protecting group on the This article aims to demonstrate (using, principle! The readily available 2-tert- reactivity of neighboring centers and in part, examples from natural product butyl-l,3-imidazolidin-3-one,-0xazolid- on the stereoselectivity of the reac- syntheses) that chiral heterocyclic ac- in-5-one, -dioxin-3-one, and -hydropy- tions at those centers. At the end of etals with enamine, enol ether, enolate, rimidinone (all of which contain a single this article we have included an ap- dienolate, enoate, radical, and acyli- stereogenic center at the acetal C atom) pendix containing tables, which are in- minium functionalities and also those can thus be used in the preparation of a tended to summarize all the examples that are potential reactants for Michael vast range of 2-amino- and 3-hydroxy- known in as complete a fashion as pos- additions and pericyclic processes (for carboxylic acids, and no chiral auxiliary sible. example, electron-rich and electron- has to be removed or regenerated during poor dienophiles and dienes) are now these procedures. (One example is the Keywords: asymmetric syntheses - chiral easily accessible, more often than not, in synthesis of 4-fluoro-MeBmt, a deriva- synthetic building blocks - enolates * both enantiomeric forms. Stereogenic tive of the C, amino acid found in cy- lithium compounds nitrogen atoms of aziridines, boron closporin.) In the final chapter we will 1. Introduction and Definition of the Problem [*] Prof. Dr. D. Seebach, Dr. A. R. Sting, DipLChem. M. Hoffmann Was nicht sein kann, Laboratorium fur Organische Chemie das nicht sein darJI[**’ der Eidgenossischen Technischen Hochschule ETH-Zentrum, Universitatstrasse 16, CH-8092 Zurich (Switzerland) It is a fundamental part of every basic lecture course in organ- Fax.: Int. code +(1)632-1144 e-mail: [email protected] ic chemistry that a reaction at a trigonal center bearing three [**I “Surely the impossible is just not possible.” different substituents in an achiral molecule results, if neither Anoou, rhrm Inf Fd Fnd 19%. 35. 2708-2748 173 VCH Verlacscesellschaft mbH 0-69451 Wemherm. 1996 0570-083319613523-2709$15 OOt,2510 2709 REVIEWS D. Seebach et al. the other reactants nor the surroundings are chiral, in the for- carbanion chemistry, there is also a cation, more often than not mation of a racemic product containing one center of chirality. a metal ion, which can be sufficiently strongly boundr5]to allow The consequence of this is that a substitution that proceeds in the formation of configurationally stable organometallic deriva- either a homolytic or heterolytic manner at a solitary stereo- tives[6-81 such as those shown in Scheme 1 f, a whole new genic center of a molecule yields enantiomeric products in a 1 : 1 branch of stereoselective synthesis developed.[’~l4] ratio and hence, a racemic mixture is formed (Scheme 1 a). If the Even in enolate chemistry there are exceptions to the rules trigonal center in the intermediate is cationic or part of a n-sys- formulated above (see the examples in Scheme 2). Although the tem, it will have a trigonal-planar geometry and if it is radical or sole center of chirality in the starting material is removed, enan- anionic in nature, it may have a trigonal-pyramidal geometry tiomerically pure or enantiomerically enriched products may but will be capable of rapid inversion, particularly in noncyclic result. This can be attributed to the formation of aggregates of systems. achiral enolates with chiral components in the reaction mixture There are, of course, exceptions that can be of practical signif- (Scheme 2 a)[”] or also to sufficiently conformationally stable icance. These include the SJ substitution of OH by C1 using enolate intermediates which possess axes of chirality (Scheme thionyl chloride (Scheme 1 b),[ll which proceeds with retention 2b-e).[16-201The cation also plays a decisive role in the reac- of configuration, and the cationic cyclization of linalol p-ni- tions of enolates. Owing to the successful creation of a variety trobenzoate to terpineol (Scheme 1 c) .[’I Stereoselective reac- of alternatives, today practically any type of imaginable reactiv- tions proceeding via carbanionic intermediates are also known. ity or selectivity of these nucleophiles, which are of central im- For example, the D/H exchange with retention of configuration portance in organic synthesis, can be achieved. possibilities shown in Scheme 1 d,[jl which is really of rather academic inter- include the participation of aggregates (“supramolecular” struc- est, and the decarboxylation, with retention, of an intermediate tures) of Li-, Na-, K- and Mg-en~lates[’~-’~~and their com- used in the preparation of the anaesthetic Desfl~ran[~I plexes with salts,[26,271 amides,[28]and amines,[21-24’ ’’3 301 the (Scheme 1 e). Once it had been appreciated that within so-called reduction of the coordination sphere of the participating meta from 1986 to 1989 at A. R.Sting D. Seebach M. Hoffmann the “Ingenieurschule Beider Basel” (IBB) in Muttenz (Canton Basel-Land) , where he earned the title Dipl.-Chem. HTL. Subsequently, he moved to the ETH in Zurich to continue his chemistry studies (Diploma 1992). In the spring of1993 he began working in the group of Prof. D. Seebach and completed his Ph.D. thesis on the synthesis of4$‘uoro-MeBmt in the spring of1996. He is now working in the Division of Crop Protection of Ciba-Geigy in Basel. Dieter Seebach was born in Karlsruhe (Germany) in 1937. He studied chemistry at the University of Karlsruhe and completed his Ph.D. thesis on small rings andperoxides under the supervision of’Prof. R. Criegee in 1964. After a two-year stay at Harvard University as postdoctoral co-worker (with Prof. E. J. Corey) and lecturer, he returned to Karlsruhe and, in 1969, completed his “habilitation” on the topic of S- and Se-stabilized carbanion and carbene derivatives. In 1971 he moved to the University of Giessen as afullprofessor and then in 1977 to the Eidgenossische Technische Hochschule (SwissFederal Institute of Technology) in Zurich. He has been a visiting professor at the Universities of Wisconsin- Madison, Strasbourg, Munich (TU), and Kaiserslautern and also at Caltech (Pasadena) and the Max Planck Institute in Miilheirn. A main emphasis of his research is the development of new synthetic methods; in the last decade the subject discussed here and the Ti-TADDOLates have been major interests. His work also involves mechanistic studies and determination of structures. More recent research topics include chiral dendrimers, the short-chain oligomers of 3-hydroxybutanoic acid, the bioploymer PHB. and backbone-modified peptides. Matthias Hoffmann was born in Zurich (SwGtzerland) in 1969. He completed his Diploma studies in chemistry at the ETH in Zurich in 1993 with research conducted in the group of Prof. D. Seebach. Later that year, he began working on his Ph.D. thesis in the same area. His research,focuses on the development ofmethodsfor the preparation ofenantiomerically pure, non-proteino- genic amino acids.
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