Thiourea-catalyzed highly enantio- and diastereoselective additions of oxindoles to nitroolefins: application to the formal synthesis of (+)-physostigmine.
Oxindoles and their indoline derivatives are common structural motifs found in a wide array of natural and biologically active molecules. Most catalytic methods for the asymmetric syntheses of these compounds rely heavily on the use of transition-metal catalysts. In contrast, alternative catalytic procedures involving organocatalysis are scarce. Herein we disclose a conceptually novel organocatalytic approach to the syntheses of these materials using thiourea-catalyzed asymmetric 1,4-additions of oxindole derivatives to nitroolefins as a key step. These addition reactions create up to two stereogenic centers, one of which is a quaternary center. These reactions are broad in scope with respect to both the oxindole and nitroolefin substrates and provide the desired products in good yields with enantioselectivities of up to 99% and diastereoselectivities of up to >20:1. To demonstrate the utility of this approach, (+)-esermethole was synthesized in good overall yield over 3 steps starting from the 1,4-addition product, thereby providing a formal synthesis of (+)-physostigmine.
Bui
Tommy
T
The Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Syed
Salahuddin
S
Barbas
Carlos F
CF
D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry*; D002384:Catalysis; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry*; D015394:Molecular Structure; D009574:Nitro Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D000078183:Oxindoles; D010830:Physostigmine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D013890:Thiourea / Q000737:chemistry*
D000475:Alkenes; D002800:Cholinesterase Inhibitors; D007211:Indoles; D009574:Nitro Compounds; D000078183:Oxindoles; C518152:esermethole; C022960:2-oxindole; D010830:Physostigmine; D013890:Thiourea