Journal of the American Chemical Society

Asymmetric total synthesis of (-)-quinocarcin.

PMID 18454525


(-)-Quinocarcin (1) has been synthesized in a longest linear sequence of 22 steps from 3-hydroxybenzaldehyde in 16% overall yield. The Pictet-Spengler reaction of L-tert-butyl-2-bromo-5-hydroxy phenylalanate (17), synthesized according to Corey-Lygo's enantioselective alkylation process, with benzoxyacetaldehyde (12) under mild acidic conditions afforded 1,3-cis tetrahydroisoquinoline 20 as an only isolable stereomer in 91% yield. The diazabicycle[3,2,1]-octane ring system of 28 was constructed by a silver tetrafluoroborate-promoted intramolecular Mannich reaction using amino thioether as a latent N-acyliminium species and tethered silyl enol ether as a nucleophile. Using amino thioether instead of aminal as a precursor of N-acyliminium was of high importance to the success of this otherwise disfavored 5-endo-Trig cyclization. A Hf(OTf)4-catalyzed (0.1 equiv) transformation of aminal to amino thioether was uncovered in the course of this study, allowing the conversion of tricyclic aminal 24 to amino thioether 25 to be realized in high yield. From the bridged tetracyclic compound 28, a sequence of oxidation of aldehyde to acid, global deprotection under hydrogenolysis conditions, and one-pot partial reduction of lactam to aminal/oxazolidine formation completed the total synthesis of the pentacyclic (-)-quinocarcine.