Quinidine synthesis

Following Uskokovic s seminal quinine synthesis [40], Jacobsen has very recently reported the first catalytic asymmetric synthesis of quinine and quinidine. The stereospecific construction of the bicyclic framework, introducing the relative and absolute stereochemistry at the Cg- and expositions, was achieved by way of the enantiomerically enriched trans epoxide 87, prepared from olefin 86 by SAD (AD-mix (3) and subsequent one-pot cyclization of the corresponding diol [2b], The key intramolecular SN2 reaction between the Ni- and the Cg-positions was accomplished by removal of the benzyl carbamate with Et2AlCl/thioanisole and subsequent thermal cyclization to give the desired quinudidine skeleton (Scheme 8.22) [41],... 

Further evidence for the formation of intermediate compounds in catalytic reactions is afforded by the observation (a) that optically active camphor is formed from optically inactive (racemic) camphor carboxylic acid in the presence of the d- or /-forms of quinine, quinidine or nicotine and (6) that optically active bases, e.g., quinidine, catalyze the synthesis of optically active mandelonitrile from benzaldehyde and hydrocyanic acid.10 These results hardly admit of any other interpretation than the intermittent production of a catalyst-reactant compound. 

A simple method for asymmetric synthesis of 2//-azirine-2-phophonates 540 was described, using various alkaloids as bases (equation 241). Moderate to good asymmetric induction was observed (69-94% yield, 33-72% ee) when quinidine was used as the base (the S isomer was obtained). A solid-phase asymmetric synthesis was also performed (541 and 542 used as bases) and good yields were usually obtained (43-88%) but only low enantioselectivity was achieved (3-11%). 

Figure 44. Diagram of the quinine, quinidine and cinchonine synthesis pathway.

The tetracyclic alkaloid quinine 1 and the diastereomeric alkaloid quinidine 2 share a storied history. Eric Jacobsen of Harvard recently completed (J. Am. Chem. Soc. 2004, 126, 706) syntheses of enantiomerically-pure 1 and of 2. For each synthesis, the key reaction for establishing the asymmetry of the target molecule was the enantioselective conjugate addition developed by the Jacobsen group. 

A cursory examination of the Cinchona catalysts used in O Donnell-type alkylation [90] of methyl (diphenylimino)glycinate (Appendix 7.A) reveals that only minor modifications to the Cinchona scaffold are required for the synthesis of a catalyst the 8-substituent on the quinuclidine core may either be a vinyl group (as in the parent alkaloids, quinine and quinidine) or can be an ethyl substituent, introduced by hydrogenation. The quinoline system at the 2-position ofthe quinuclidine ring can be unsubstituted if the catalyst is derived from quinine or quinidine, but can contain a 6-methoxy group ifit is derived from cinchonine or cinchonidine. The 3-position ofthe quinuclidine ring may contain either a hydroxy group or else a vinyloxy or benzyloxy... 

The starting materials for the synthesis (few steps) of these phase-transfer catalysts, i.e. the cinchona alkaloids (—)-quinine, (+)-quinidine, (+)-cinchonine and (—)-cinchonidine, are commercially available in large quantities. 

Inagaki M, Hatanaka A, Mimura M, Hiratake J, Nishioka T, Oda J (1992) One-pot synthesis of optically active cyanohydrin acetates from aldehydes via quinidine-catalyzed transhydro-cyanation coupled with lipase-catalyzed kinetic resolution in organic solvent. Bull Chem Soc Jpn 65 111-120... 

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