"The Total Synthesis of Quinine".

Concise stereoselective syntheses of (±)-quinine and (±)-7-hydroxyquinine are achieved using a catalytic enone cycloallylation that combines the nucleophilic features of the Morita-Baylis-Hillman reaction and the electrophilic features of the Tsuji-Trost reaction. Cyclization of enone-allyl carbonate 11 delivers the product of cycloallylation 13 in 68% yield. Diastereoselective conjugate reduction of the enone 13 (>20:1 dr) followed by exchange of N-protecting groups provides the saturated N-Boc-protected methyl ketone 19, which upon aldol dehydration provides quinoline containing enone 15, possessing all carbon atoms of quinine. Exposure of ketone 15 to L-selectride enables diastereoselective carbonyl reduction (>20:1 dr) to furnish the allylic alcohol 16. Stereoselective hydroxyl-directed epoxidation using an oxovanadium catalyst modified by N-hydroxy-N-Me-pivalamide delivers epoxide 17 (17:1 dr). Cyclization of the resulting amine-epoxide 17 provides (±)-7-hydroxyquinine in 13 steps and 11% overall yield from aminoacetaldehyde diethyl acetal. Notably, highly stereoselective formation of five contiguous stereocenters is achieved through a series of 1,2-asymmetric induction events. A formal synthesis of (±)-quinine is achieved upon deoxygenation of the N-Cbz-protected allylic acetate 22 to provide olefin 23, which previously has been converted to quinine. Thus, (±)-quinine is accessible in 16 steps and 4% overall yield from commercial aminoacetaldehyde diethyl acetal, making this route the most concise approach to quinine, to date.

The Total Synthesis of Quinine - Journal of the …

A Review of Three Total Syntheses of Quinine and Quinidine
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19/02/2007 · “The Total Synthesis of Quinine ..

We report concise stereoselective syntheses of quinine and 7-hydroxyquinine using a catalytic enone cycloallylation that combines the nucleophilic features of the Morita-Baylis-Hillman reaction and the electrophilic features of the Tsuji-Trost reaction. In accordance with this strategy, quinine is accessible in 16 steps and 4% overall yield from commercial aminoacetaldehyde diethyl acetal, making it the most concise approach to quinine, to date. Additionally, 7-hydroxyquinine is prepared in 13 steps and 11% overall yield from aminoacetaldehyde diethyl acetal through a sequence wherein five contiguous stereocenters are formed with high levels of relative stereocontrol through a series of 1,2-asymmetric induction events. Our route delivers 7-hydroxyquinine in less than half the number of manipulations previously reported.

Quinine total synthesis - Revolvy

Subsequent to Woodward’s seminal work, total syntheses of quinine 1 were reported by Uskoković, Gates, Taylor, Stork, Jacobsen, and Kobayashi. Uskoković and co-workers at Hoffman-La Roche developed four different routes to quinine. Although the group at Hoffman-La Roche was unable to develop a highly stereoselective approach, many of their discoveries, especially the N-1 to C-8 amine-epoxide cyclization strategy and the diastereoselective C-9 hydroxylation, have been utilized frequently in subsequent syntheses. In 2001, Stork reported the first stereoselective synthesis of quinine 1 in 20 steps from trans-butene-1,4-diol employing a novel N-1 to C-6 disconnection strategy. Completion of this synthesis resulted in optimization of the Hoffman-La Roche C-9 hydroxylation. In 2004, Jacobsen and Kobayashi published synthetic approaches relying on the N-1 to C-8 amine-epoxide cyclization initially reported by Hoffman-La Roche. These syntheses cleverly provide access to both quinine and quinidine 1. Jacobsen’s catalytic asymmetric synthesis of quinine 1 is achieved in 17 steps from N-(chloroacetyl)-benzamide but is not fully stereocontrolled. The C-3 stereocenter is obtained in a 3:1 epimeric ratio after epimerization of an initially formed 1:1.7 mixture favoring the undesired isomer. Finally, in a recent effort to prepare quinine, Williams disclosed the synthesis of 7-hydroxyquinine in 27 steps which took advantage of a unique C-3 to C-4 bond construction. Despite these enormous advances, a concise route to quinine that addresses both relative and absolute stereocontrol remains absent (, Bottom).

Woodward and the total synthesis of quinine
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