Enders SAMP/RAMP hydrazone-alkylation reaction

The Enders SAMP/RAMP hydrazone alkylation reaction is an asymmetric carbon-carbon bond formation reaction facilitated by pyrrolidine chiral auxiliaries. It was pioneered by E. J. Corey and Dieter Enders in 1976, and was further developed by Enders and his group. This method is usually a three-step sequence. The first step is to form the hydrazone between (S)-1-amino-2-methoxymethylpyrrolidine (SAMP) or (R)-1-amino-2-methoxymethylpyrrolidine (RAMP) and a ketone or aldehyde. Afterwards, the hydrazone is deprotonated by lithium diisopropylamide (LDA) to form an azaenolate, which reacts with alkyl halides or other suitable electrophiles to give alkylated hydrazone species with the simultaneous generation of a new chiral center. Finally, the alkylated ketone or aldehyde can be regenerated by ozonolysis or hydrolysis.

This reaction is a useful technique for asymmetric α-alkylation of ketones and aldehydes, which are common synthetic intermediates for medicinally interesting natural products and other related organic compounds. These natural products include (-)-C10-demethyl arteannuin B, the structural analog of antimalarial artemisinin, the polypropionate metabolite (-)-denticulatin A and B isolated from Siphonaria denticulata, zaragozic acid A, a potent inhibitor of sterol synthesis, and epothilone A and B, which have been proven to be very effective anticancer drugs.