SAMP/RAMP chiral auxiliaries hydrazone formation

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. 

In continuation of our efforts to explore the utility of the SAMP/RAMP hydra-zone methodology, we developed the first asymmetric synthesis of a-phosphino ketones via formation of a carbon-phosphorus bond in the a-position to the carbonyl group [70]. The key step of this asymmetric C—P bond formation is the electrophilic phosphinylation of the ketone SAMP hydrazone 87, giving rise to the borane-adduct of the phosphino hydrazone 88 with excellent diastereoselectiv-ity (de = 95-98%). Since these phosphane-borane adducts are stable with respect to oxidation, the chemoselective cleavage of the chiral auxiliary by ozonolysis leading to the a-phosphino ketones (R)-89 could be accomplished with virtually no racemization. Using RAMP as a chiral auxiliary, the synthesis of the enantiomer (S)-89 was possible (Scheme 1.1.25). 

Enders and coworkers reported studies in which the RAMP and SAMP chiral auxiliaries were employed in the aza-annulation process (Scheme 39).1,4 Condensation of 179 with RAMP provided a route to the optically active enamino hydrazone 473, which was then metalated with nBuLi to generate the corresponding anion. Aza-annulation of 473 with 474 produced intermediate 475, which could be cyclized slowly (2 d) at 60 °C to give 476. Alternatively, heterocycle formation could be facilitated by an increase in reaction temperature (toluene, heat). Removal of the chiral auxiliary gave 477 in 50-52% overall yield from 179 in >99 1 enantiomeric purity. Substituents on the aromatic ring did not have a measureable effect on the yield of the aza-annulation reaction. 

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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