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Synthesis of 9-amino(9-deoxy)epi cinchona alkaloids, general chiral organocatalysts for the stereoselective functionalization of carbonyl compounds
Carlo Cassani1,4, Rafael Martn-Rapn2,4, Elena Arceo1, Fernando Bravo2 & Paolo Melchiorre1,3
1Institute of Chemical Research of Catalonia (ICIQ), Tarragona, Spain. 2Catalyst Selection and Optimization Laboratory (CSOL), ICIQ, Tarragona, Spain.
3Instituci Catalana de Recerca i Estudis Avanats (ICREA), Barcelona, Spain. 4These authors contributed equally to this work. Correspondence should be addressed to F.B. ([email protected]) or P.M. ([email protected]).
Published online 17 January 2013; corrected online 25 January 2013 (details online); doi:10.1038/nprot.2012.155
We describe two procedures for the synthesis of primary amines derived from 9-amino(9-deoxy)epi cinchona alkaloids, valuable catalysts used in the asymmetric functionalization of carbonyl compounds. The first approach allows the one-pot 5-g-scale syntheses of four cinchona-based analogs (1, 3, 5 and 7) from the alkaloids quinine (QN), quinidine (QD), dihydroquinine (DHQN) and dihydroquinidine (DHQD), respectively, performed by means of a Mitsunobu reaction to introduce an azide group, followed by reduction and hydrolysis. Demethylation of 1, 3, 5 and 7 with BBr3 provided direct access to the bifunctional aminocatalysts 2,4, 6 and 8. A second approach, more convenient for scale-up (tested to a 20-g scale), is also provided. In this second procedure, the azides, formed from the O-mesylated derivatives of QN and QD, are selectively reduced with LiAlH4 to afford catalysts 1 and 3, whereas hydrogenation (Pd/C) provides 5 and 7. Demethylation of 1, 3, 5 and 7 using an alkylthiolate affords 2, 4, 6 and 8 in a process in which the less-expensive QN and QD are the only starting materials used.
2013Nature America, Inc. All rights reserved.
INTRODUCTION
The emergent field of asymmetric aminocatalysis1,2, exploiting the ability of chiral primary3 and secondary4 amines to generate active intermediates in situ via reversible condensation with unmodified carbonyl reagents, has greatly expanded the chemists resources to catalytically and asymmetrically functionalize carbonyl compounds. The use of enantiopure chiral cyclic secondary amine catalysts, in particular l- or d-proline5 and its derivatives4,6, has demonstrated excellent versatility and efficiency, providing a reliable synthetic platform for the asymmetric functionalization of linear aldehydes and enals at their (ref. 7), (ref. 8), (ref. 9) and even positions10. The recent developments in this area show that the appropriate choice of a primary amine catalyst can overcome the restrictions that secondary...