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Organic Chemistry Highlights

Total Synthesis

Monday, December 1, 2008
Douglass F. Taber
University of Delaware

The Takayama Synthesis of (-)-Cernuine

(-)-Cernuine (3) falls in the subset of the Lycopodium alkaloids that feature a bicyclic aminal core. There had not been a total synthesis of this class of alkaloids until the recent (Org. Lett. 2008, 10, 1987. DOI: 10.1021/ol800574v) work of Hiromitsu Takayama of Chiba University. The key step in this synthesis was a diastereoselective intramolecular reductive amination, converting 1 to 2. As is apparent from the 3-D projection, (-)-cernuine (3) has a tricyclic trans-anti-trans aminal core, with an appended six-membered ring, both branches of which are axial on the core. While the branch that is part of the aminal could be expected to equilibrate, the other branch had to be deliberately installed.

The synthesis began with (+)-citronellal (4), each enantiomer of which is commercially available in bulk. After protection and ozonolysis, the first singly-aminated stereogenic center was installed by enantioselective, and therefore diastereoselective, addition of 5 to the azodicarboxylate 6, mediated by the organocatalyst 7. Reductive cleavage of the N-N bond followed by acetal methanolysis converted 8 to 9. Ionization followed by allyl silane addition then delivered 11, having the requisite axial alkyl branch.

The next two tasks were the assembly of the second of the four rings of 3, and the construction of the second single-aminated stereogenic center. The ring was assembled by deprotection of 11 followed by acylation with acryloyl chloride, to give 12. Grubbs cyclization followed by hydrogenation then led to 13. Homologation of 13 to the aldehyde 14 set the stage for condensation with the camphor-derived tertiary amine 15, following the protocol developed by Kobayashi. Sequential imine formation, aza-Cope rearrangement, and hydrolysis led to 1 in 94% de.

One could envision reduction of the lactam carbonyl of 1 to an aldehyde equivalent, that would then, under acidic conditions, condense to form the desired aminal 2. This approach was, however, not successful. As an alternative, conditions were developed to convert 1 to the amidine 16. Reduction then proceeded with the expected high diastereocontrol, to give the cis 1,3-fused aminal 2. This was not isolated, but was directly acylated with acryloyl chloride, to 17.

The synthesis of (-)-cernuine 3 was concluded by Grubbs cyclization of 17 to 3, followed again by hydrogenation. Note that there was a key difference between this cyclization and the Grubbs cyclization of 12 that led to 13, in that 17 contained a basic N, while 12 did not. For the cyclization of 12, the first generation Grubbs catalyst was sufficient, while for the cyclization of 17, the second generation catalyst was required.

This synthesis illustrates the efficacy of the Grubbs cyclization for polycyclic construction. The approach outlined here also highlights the power of current methods for enantioselective allylation of imines for the construction of enantiomerically pure, and, in the context of this synthesis, diastereomerically pure, aminated secondary stereogenic centers.

D. F. Taber, Org. Chem. Highlights 2008, December 1.