Lithium diisopropylamide SAMP/RAMP chiral

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

The synthesis of (-)-Cio-desmethyl arteannuin B, a structural analog of the antimalarial artemisinin, was developed by D. Little et a. In their approach, the absolute stereochemistry was introduced early in the synthesis utilizing the Enders SAMP/RAMP hydrazone alkylation method. The sequence begins with the conversion of 3-methylcyclohexenone to the corresponding (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone. Deprotonation with lithium diisopropylamide, followed by alkylation in the presence of lithium chloride at -95 °C afforded the product as a single diastereomer. The SAMP chiral auxiliary was removed by ozonolysis. 

Lithium diisopropylamide. 13, 163-164 15, 188-189 16, 196-197 17, 165-167 Ester enolates. Procedures for the preparation of ( )- and (Z)-ketene silyl acetals are well developed. Enolates have been generated from conjugate esters by way of Michael addition, and when a remote halide is present, they are quenched by cyclization. Chiral Michael donors such as carbanions of the SAMP/RAMP hydra-zones initiate formation of trani-2-(2 -oxoalkyl)cycloalkanecarboxylic esters with excellent diastereomer excess and enantiomer excess. 

The ketone 18 forms a hydrazone 19 with SAMP. Due to asymmetric induction by the chiral auxiliary, the subsequent alkylation (a-metalation with lithium diisopropylamide in diethyl ether, followed by 1-iodopropane at —110°C) occurs stereoselectively with formation of the diastereomer 20. In the final step, the auxiliary SAMP is removed from 20 by hydrolysis and the a-alkylated ketone 21 is obtained with ee = 99.5%. The use of RAMP as auxihary produces the (R)-enantiomer of 21. 

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