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Monday, January 8, 2007
Douglass Taber
University of Delaware

Enantioselective Synthesis of C-N Ring Containing Natural Products

Enantioselective addition to a prochiral ring is a powerful approach for the preparation of C-N rings in high ee. This is elegantly illustrated by the report (J. Org. Chem. 2006, 71, 3287. ) by Horacio F. Olivo of the University of Iowa of the condensation of 1 with 2, followed by the addition of the product to cinnamaldehyde (3). This net three-component coupling delivered 4, having one of the rings and three of the four contiguous stereogenic centers of (-)-stemoamide (5).

A complementary strategy for the simultaneous control of both ring and sidechain configuration was described (Org. Lett. 2006, 8, 745. ) by Sanghee Kim of Seoul National University. The ester 6, as a diastereomeric mixture, was readily prepared from pyroglutamic acid. On deprotonation followed by silylation, Ireland-Claisen rearrangement proceeded with high diastereocontrol. The product 7 was carried on to (-)-lepadiformine 8.

Two recent syntheses of (-)-γ-lycorane (12) started with prochiral carbocyclic rings. Hiromichi Fujioka and Yasuyuki Kita of Osaka University began (Chem. Commun. 2006, 832. ) with the dihydrobenzene derivative 9. Condensation with the diaryl diamine 10 followed by N-bromosuccinimide gave the tricyclic amine 11, the stereogenic centers of which were preserved in its conversion to (-)-γ-lycorane (12).

Iwao Ojima of SUNY Stony Brook focused (Org. Lett. 2006, 8, 1395. ) on the enantioselective coupling of the β-keto ester 13 with the diastereomerically-pure bis-benzoate 14. Judicious ligand choice improved this coupling from the previously reported 54% to 99% ee. The product 15 was carried on to (-)-γ-lycorane (12) following a modification of the procedure of Mori.

The key to the synthesis of the physostigmine alkaloids, exemplified by (-)-esermethole (18), is the establishment of the alkylated quaternary center. The Pd-catalyzed allylation of 3-methyl indoles had been described. Barry M. Trost of Stanford University found (J. Am. Chem. Soc. 2006, 128, 6314. ) that using the ligands they had developed, the allylation could be carried out with high ee. The optimization of the trialkylborane was the key to the success of this transformation. The product 17 was carried on to (-)-esermethole (18).

(+)-Lactacystin (22) is a potent and selective inhibitor of the 26S proteasome. In the synthesis of 22 recently reported (J. Am. Chem. Soc. 2006, 128, 6810. ) by Eric N. Jacobsen of Harvard University, the chirality was set by the Al-salen catalyzed conjugate addition of the cyano ester 20 to the silyl amide 19. The silyl group in the adduct 21 served as a surrogate for one the ring alcohol of 22.

D. F. Taber, Org. Chem. Highlights 2007, January 8.