Enantio- and diastereoselective construction of α,α-disubstituted α-amino acids for the synthesis of biologically active compounds

Natural and unnatural compounds possessing an alpha,alpha-disubstituted a-amino acid substructure have received significant attention because of their structural complexity and potent biological activity. Many methods have been developed for the enantio- and diastereoselective synthesis of alpha,alpha-disubstituted a-amino acids, many of which are focused on the total synthesis of natural products and related bioactive compounds. This microreview highlights recent advances in synthetic methods utilized for the synthesis of (1) alpha-substituted serine analogs, which were extensively transformed into glutamate and enkephalin analogs, and (2) natural products such as lactacystin, manzacidins, kaitocephalin, altemicidin,Natural and unnatural compounds possessing an alpha,alpha-disubstituted a-amino acid substructure have received significant attention because of their structural complexity and potent biological activity. Many methods have been developed for the enantio- and diastereoselective synthesis of alpha,alpha-disubstituted a-amino acids, many of which are focused on the total synthesis of natural products and related bioactive compounds. This microreview highlights recent advances in synthetic methods utilized for the synthesis of (1) alpha-substituted serine analogs, which were extensively transformed into glutamate and enkephalin analogs, and (2) natural products such as lactacystin, manzacidins, kaitocephalin, altemicidin, sphingofungins, and neooxazolomycin. The key methods for the construction of these higher-order structures are the asymmetric Strecker synthesis and enolate-Claisen rearrangements used by our group, and aldol condensation of an enolate or bislactim, mercurio- or iodo-cyclization, alkylation of an oxazoline, rearrangement of a trichloroacetimidate, nitrene insertion into a C-H bond, carbene insertion into a C-N bond, a Diels-Alder reaction, Lewis acid-induced epoxide opening, and other methods by other groups. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005).