Organic Chemistry Portal
Organic Chemistry Highlights

Search Org. Chem. Highlights:

Match: or and

 

Total Synthesis

Monday, March 4, 2013
Douglass F. Taber
University of Delaware

The Carreira Synthesis of (-)-Dendrobine

The tetracyclic alkaloid (-)-Dendrobine (3) has at its core a cyclohexane that is substituted at each of its six positions, including one quaternary center. Erick M. Carreira of ETH Zurich chose (Angew. Chem. Int. Ed. 2012, 51, 3436. ) to assemble this ring by the Ireland-Claisen rearrangement of the lactone 1.

The absolute configuration of the final product stemmed from the commercial enantiomerically-pure acetonide 4, that was selectively converted to the Z-ester 5. Following the precedent of Costa, TBAF-mediated conjugate addition of 2-nitropropane to 5 proceeded with high diastereocontrol, to give, after free radical reduction, the ester 6, that was carried on the aldehyde 7.

Exposure of the alkyne 9 to in situ generated Schwartz reagent followed by iodination gave 10 with 10:1 regioselectively. It was possible to separate 10 from its regioisomer by careful silica gel chromatography. Metalation followed by addition to 7 gave an intermediate that was conveniently debenzoylated with excess ethyl magnesium bromide to deliver the diol 11. Selective oxidation led to the lactone 1.

Exposure of 1 to LDA and TMS-Cl induced rearrangement to the cyclohexene acid, that was esterified to give 2. Deprotection and oxidation then gave the enone 12. Cyclohexene construction by tethered Claisen rearrangement is a powerful transformation that has been little used in target-directed synthesis.

Selective addition of pyrrolidine to the aldehyde of 12 generated an enamine, leading to an intramolecular Michael addition to the enone. This selectively gave the cis ring fusion, as expected, but the product was a mixture of epimers at the other newly formed stereogenic center. This difficulty was overcome by forming the enamine from N-methyl benzylamine. After cyclization, hydrogenation set the additional center with the expected clean stereocontrol, and also effected debenzylation, to give 14.

To close the last ring, the ketone 14 was brominated with the reagent 15, that was developed (Can. J. Chem. 1969, 47, 706) for the kinetic bromination of ketones. Exposure of the crude α-bromo ketone to 4-dimethylaminopyridine then effected cyclization to 16. Following the literature precedent, reduction of the ketone of 16 with NaBH4 followed by gentle warming led to (-)-Dendrobine (3).

D. F. Taber, Org. Chem. Highlights 2013, March 4.
URL: https://www.organic-chemistry.org/Highlights/2013/04March.shtm