Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, November 2, 2009
Douglass F. Taber
University of Delaware

The Kobayashi Synthesis of (-)-Norzoanthamine

The Zoanthus alkaloids, exemplified by (-)-norzoanthamine (3a) and zoanthamine (3b), show promising activity against osteoporosis. Susumu Kobayashi of the Tokyo University of Science assembled (Angew. Chem. Int. Ed. 2009, 48, 1400, DOI: 10.1002/anie.200804544; Angew. Chem. Int. Ed. 2009, 48, 1404, DOI: 10.1002/anie.200804546) the challenging tricyclic core of 3a employing the intramolecular Diels-Alder cyclization of 1 to 2. The cyclopentane of 1 served as useful scaffolding, even though it was cleaved en route to 3a.

The cyclohexane ring of 1 has five of its six positions substituted, including three that are alkylated quaternary centers. The starting point for the preparation of 1 was the enantiomerically-pure Hajos-Parrish ketone 4, containing the first of the those quaternary centers. Conjugate addition of MeLi established the second quaternary center. The less stable endo alkyl branch of 1 was installed by conjugate addition to the more reactive α-methylene ketone of the cross-conjugated 5, followed by kinetic quench. Addition of vinyl cuprate across the open face of the enone 7 then established the final quaternary center, setting the stage for the intramolecular Diels-Alder reaction. The silyl enol ether from the cyclization of 1 was not stable, so it was directly oxidized to the enone 2.

The keto phosphonate 16 for the last two rings of 3a was prepared from the previously-reported crystalline glutamic acid-derived mesylate 12. Reduction and homologation delivered the ester 14, that was condensed with the phosphonate anion 15 to give 16.

The congested cyclopentanone 17, derived from 2, was most efficiently deprotonated with n-BuLi. Exposure of the resulting silyl enol ether to ozone led to the α-hydroxylated product 18. Unexpectedly but happily, oxidative cleavage of 18 delivered, after deprotection and reprotection, the more congested aldehyde 19. This cleavage may be proceeding by tautomerization of 18 to the regioisomeric keto alcohol. The aldehyde 19 was condensed with the keto phosphonate 16, to give, after hydrogenation, the keto lactone 20. A series of oxidation state adjustments then completed the synthesis of (-)-norzoanthamine (3a).

The preparation of 3a outlined here underlines the importance of developing new methods for concise stereocontrolled carbocyclic construction. The utility of an enantiomerically-pure bicyclic scaffold such as 4 for subsequent relative stereocontrol is particularly apparent.

D. F. Taber, Org. Chem. Highlights 2009, November 2.