Enders’ SAMP‐Hydrazone as Traceless Auxiliary in the Asymmetric 1,4‐Addition of Cuprates to Enones

Abstract

Conjugate additions of Gilman cyanocuprates to (S)-N-amino-2-(methoxymethyl)pyrrolidine (SAMP)-hydrazones 4, 5 derived from cyclic and acyclic a,b-unsaturated ketones were investigated. A protocol utilizing copper(II) sulfate/ammonium chloride was evolved, which allowed cleavage of SAMP (S)-1 under the hydrolysis and work-up conditions, followed by recovery of the auxiliary with ethylenediaminetetraacetic acid (EDTA). The enantioselectivity of cuprate additions was dominated for cyclic SAMP-hydrazones 4 by the cuprate alkyl substituent and the ring size, in the case of acyclic arylidene SAMP-hydrazones 5, however, by the nature of the aryl substituent. Electron-donating substituents gave poor enantiomeric excesses, whereas electron-withdrawing groups provided excellent ee values of 98-99%. The configuration of the new stereocenter was determined to be (R). Moreover, a reaction sequence was developed which integrates a tandem 1,4-addition/methylation and traceless hydrolytic cleavage of the auxiliary (S)-1 in a one-pot reaction, resulting in enantiomerically pure methyl ketones 11-13, each of them with > 99% ee.

Catalytic Asymmetric Construction of Chiral Hydropyridazines via Conjugate Addition of N-Monosubstituted Hydrazones to Enones

“…Hydrazones, which show very diverse reactivity, can be used as formyl anion equivalents in organic synthesis, where they participate in nucleophile–electrophile interactions . Conventionally, N , N -dialkylhydrazones were applied in the total synthesis of natural products as practical chiral auxiliary reagents and have been reported as useful ligands and catalysts in asymmetric reactions. Besides, differing from the reactions where they acted as electrophiles, conjugate additions where N , N -dialkylhydrazones were used as nucleophiles have been realized recently. − In comparison, asymmetric conjugate addition of N -monosubstituted hydrazones in organocatalysis still remains problematic and challenging due to the competitive aza-Michael addition and carbo-Michael addition (formal diaza-ene reaction).…”