Bressin, RK; Osman, S; Pohorilets, I; Basu, U; Koide, K
Meayamycin B is currently the most potent modulator of the splicing factor 3b subunit 1 and used by dozens of research groups. However, current supply for this natural product analogue is limited because of the lengthy synthetic scheme. Here, we report a more concise, more cost-effective, and greener synthesis of this compound by developing and employing a novel asymmetric reduction of a prochiral enone to afford an allylic alcohol with high enantioselectivity. In addition to this reaction, this synthesis highlights a scalable Mukaiyama aldol reaction, Nicolaou-type epoxide opening reaction, stereoselective Corey-Chaykovsky-type reaction, and a modified Horner-Wadsworth-Emmons Z-selective olefination. We also discuss a Z-E isomerization during the α,β-unsaturated amide formation. The new synthesis of meayamycin B consists of 11 steps in the longest linear sequence and 24 total steps. Copyright © 2020 American Chemical Society.
Amides; Condensation reactions; Ketones; Asymmetric reduction; Current supplies; Epoxide openings; High enantioselectivity; Mukaiyama aldol reaction; Natural products; Unsaturated amides; Wadsworth-emmons; Cost effectiveness; 1 bromo 4 hydroxy 4 methylpentan 2 one; 1 ethoxy 1 oxopropan 2 yl morpholine 4 carboxylate; 2 methyl 6 phenylhex 5 ene 2,4 diol; 2,2,4,4,8,8 hexamethyl 6 methylene 3,7 dioxa 2,8 disilanonane; 2,6 dihydroxy 2 methyloct 7 en 4 one; 3 (tert butyl) 4 methyl 2,2,5 trimethyloxazolidine 3,4 dicarboxylate; 3 methyl 1 (3 vinyloxiran 2 yl)butane 1,3 diol; 4 hydroxy 4 methyl 1 (triphenyl l5 phosphaneylidene)pentan 2 one; 4 [(morpholine 4 carbonyl)oxy]pent 2 enoic acid; 5 hydroxy 2,2 dimethyl 6 vinyltetrahydro 4h pyran 4 one; 5 hydroxy 5 methyl 1 phenylhex 1 en 3 one; 5 [(6 allyl 2,5 dimethyltetrahydro 2h pyran 3 yl)amino] 5 oxopent 3 en 2 yl morpholine 4 carboxylate; 5 [[2,5 dimethyl 6 (3 methyl 4 oxobut 2 en 1 yl)tetrahydro 2h pyran 3 yl]amino] 5 oxopent 3 en 2 yl morpholine 4 carboxylate; 5 [[2,5 dimethyl 6 (3 methylpenta 2,4 dien 1 yl)tetrahydro 2h pyran 3 yl]amino] 5 oxopent 3 en 2 yl morpholine 4 carboxylate; 6 allyl 2,5 dimethyltetrahydro 2h pyran 3 amine; 7,7 dimethyl 5 vinyl 1,6 dioxaspiro[2.5]octan 4 ol; alcohol; amide; epoxide; fr 901464; meayamycin b; natural product; tert butyl (2,5 dimethyl 6 oxo 3,6 dihydro 2h pyran 3 yl)carbamate; tert butyl (2,5 dimethyl 6 oxotetrahydro 2h pyran 3 yl)carbamate; tert butyl (6 allyl 2,5 dimethyltetrahydro 2h pyran 3 yl)carbamate; tert butyl (6 allyl 6 hydroxy 2,5 dimethyltetrahydro 2h pyran 3 yl)carbamate; tert butyl 4 (3 ethoxy 2 methyl 3 oxoprop 1 en 1 yl) 2,2,5 trimethyloxazolidine 3 carboxylate; unclassified drug; Article; chemical analysis; chirality; corey chaykovsky type reaction; cost effectiveness analysis; drug synthesis; enantioselectivity; isomerization; Mukaiyama reaction; stereoselectivity