From chiral bromo[ 13,14 C n ]acetyl sultams to complex molecules singly/multiply labelled with isotopic carbon

The chiral bromo[ 13,14 C n ]acetyl sultams (+)‐ and (−)‐[ 13,14 C n ]BABS 1a , 1b have been demonstrated to be highly efficient, versatile and practical synthons to numerous enantiomerically pure singly and multiply labelled building blocks. The trichlorotitanium enolates derived from 1a , 1b undergo aldol addition reactions with aldehydes providing easily purified, crystalline syn ‐2‐bromo‐3‐hydroxy [ 13,14 C n ]carboxylic acid derivatives with excellent diastereo‐selectivity. These can serve as starting materials for e.p. singly/multiply labelled α ‐substituted β ‐hydroxy acids, β ‐substituted/branched α ‐hydroxy acids and α ‐unsubstituted β ‐hydroxy acids. Furthermore, 1a , 1b can be easily converted to the (+)/(−)‐[ 13,14 C n ]DPMGBS 6 , (+)/(−)‐[ 13,14 C n ]ITCABS 8 and (+)/(−)‐[ 13,14 C n ]PABS 10 synthons, which significantly enlarges the spectrum of readiliy accessible intermediates. 6 Provides e.p. labelled α ‐amino acids, 8 can be employed for the preparation of e.p. labelled α ‐amino‐ β ‐hydroxy acids (threonine type). Synthon 10 reacts with aldehydes to chiral E ‐configured enoyl sultams 11 which serve as starting materials for a broad variety of e.p. singly/multiply labelled α , β ‐substituted/branched, acyclic and cyclic carboxylic acid derivatives. Finally, aldehydes, generated by reductive cleavage of the auxiliary from the primary α , β ‐substituted acyl sultams, react with Ph 3 P=COOR to give γ , δ ‐substituted α , β ,‐unsaturated esters, which in turn can be readily converted to highly functionalized e.p. labelled intermediates. This methodology has been extensively exploited for the synthesis of a broad spectrum of carbon‐14 labelled drug substances e.g. Taxol, Valsartan, Everolimus, Lipid X, NVP IMM125, SDZ ISQ844, SDZ PRI05 and the cyclosporin derivatives Valspodar, NVP IMM125, NVP NIM811. Copyright © 2002 John Wiley & Sons, Ltd.