Self-regeneration of stereocenters

Self-regeneration of stereocenters (SRS) particularly, the scope and limitations of the SRS synthetic principle in heterocycles 97AG(E)2708. 

D. Seebach, A. R. Sting, M. Hoffmann, Self-Regeneration of Stereocenters (SRS - Applications, Limitations, and Abandonment of a Synthetic Principle, Angew. Chem. Int. Ed. Engl. 1997, 35,2708-2748. J. E. McMurry, Ester Cleavages via SN2-Type Dealkylation, Org. React. 1976, 24, 187-224. 

SCHEME 91. The self-regeneration of stereocenters (SRS) strategy applied to the synthesis of BIRT-377 precursor442... 

The control of anomeric stereochemistry continues to fuel the investigation into the synthetic utility of (x-oxygenated radical intermediates. Moreover, it has proven to be a valuable tool in organic synthesis, especially in the stereoselective synthesis of various substituted tetrahydropyrans, y>>n-l,3-dioxanes, and carbohydrate derivatives. The recent discovery of non-equilibrium radical reactions and conformation-induced self-regeneration of stereocenters should provide new opportunities in the ever-expanding field of a-oxygenated radical chemistry. 

Two approaches to BIRT-377 (1) are discussed. The focus is the stereoselective synthesis of tran -imidazolidinones such as 16 and cu-oxazolidinones such as 29d. The kinetic and thermodynamic factors governing the cis/trans selectivity in the formation of 16 and 29d were studied, and it was found that neither can assure complete selectivity in favor of either form. It was then found in both cases that a crystallization-driven dynamic transformation can produce, in a very efficient manner, the desired cis isomer in virtually 100% selectivity in the case of 29d, whereas only the tmns isomer is obtained in the case of 16. Self-regeneration of stereocenters is then applied to the alkylation of the enolates derived from 16 and 29d with p-bromobenzyl bromide, followed by routine transformations, to produce 1 in >99.9% ee via two separate processes. 

In the literature, a variety of methodologies have been reported for the asymmetric synthesis of quaternary a-amino acids. [3] Among these methods, Seebach s self-regeneration of stereocenters [5] for the preparation of a-substituted amino acid derivatives (Scheme 3) was most attractive to us. The principal reasons are the ready availability of the required chiral imidazolidinones (up to 90% ds), the stability of the corresponding enolates at higher temperature (up to 0 C), and the predictability of the stereochemical outcome. 

The first observation of self-regeneration of stereocenters was done in 1981 by Seebach and Wasmuth, who synthesized enantiopure a-C-substituted a-amino acids... 

SCHEME 1.1. First observation of self-regeneration of stereocenters. 

Intraligand asymmetric induction. An instructive introduction to intraannular alkylations is the self-regeneration of chirality centers concept introduced by Seebach [62-66]. Scheme 3.9 illustrates the concept and Table 3.1 lists several representative examples. A chiral educt, such as an amino acid derivative, is condensed with pivaldehyde. This derivatization creates a new stereocenter selectively, and this second stereocenter then controls the selectivity of the subsequent alkylation by directing the electrophile to the face of the enolate opposite the tert-butyl group, a good example of intraannular 1,3-asymmetric induction. After purification of the alkylation product, hydrolysis affords enantiomerically pure products. 

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