Concise stereocontrolled formal synthesis of (+/-)-quinine and total synthesis of (+/-)-7- hydroxyquinine via merged Morita-Baylis-Hillman-Tsuji-Trost cyclization.
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 the N-protecting group 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. Deoxygenation of the N-Cbz-protected allylic acetate 22 provides 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.
Webber
Peter
P
University of Texas at Austin Department of Chemistry and Biochemistry Austin, Texas 78712, USA.
Krische
Michael J
MJ
D000588:Amines / Q000737:chemistry; D002244:Carbon / Q000737:chemistry; D002384:Catalysis; D002625:Chemistry, Organic / Q000379:methods*; D006912:Hydroxyquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D008956:Models, Chemical; D011809:Quinones / Q000138:chemical synthesis* / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism
D000588:Amines; D006912:Hydroxyquinolines; D011809:Quinones; D012997:Solvents; D002244:Carbon; C547246:7-hydroxyquinoline