ASYMMETRIC SYNTHESES VIA METALATED CHIRAL HYDRAZONESOVERALL ENANTIOSELECTIVE α-ALKYLATION OF ACYCLIC KETONES

Article abstract of DOI:10.1016/S0040-4020(01)82420-0

A general method is described, which allows the overall enantioselective α-alkylation of acyclic ketones in good overall yields (44-86percent, 4 steps) and enantioselectivities ranging routinely from >94percent ee up to virtually complete asymmetric induction (99.5percent ee).The acyclic ketones are transformed to their corresponding "SAMP-hydrazones" (S)-2 by reaction with the enantiomerically pure hydrazine (S)-1-amino-2-methoxymethyl-pyrrolidine , readily available from (S)-proline.Metalation to form chiral azaenolates (S)-3 of E_CCZ_CN-configuration and then alkylation to product hydrazones 4, followed by hydrazone cleavage via acidic hydrolysis of methiodides 9 in a two phase system or ozonolysis, leads to α-substituted, enantiomerically enriched, acyclic ketones 5.In special cases, where a phenyl group is directly attached to the newly generated center of chirality (5n,o,p), only low enantiomeric excesses are observed. 17 Examples, including first applications in natural product synthesis (cf 5a,b,e, and h) are summarized.