Synthesis of Heterocyclic Natural Products - -Ephedradine

Synthesis of Heterocyclic Natural Products (-)-Ephedradine A, (-)-a-Tocopherol, (-)-Lepadin D, and (-)-Phenserine 

Stereocontrol led syntheses of niatrolides and mncrolactams are well developed. Much remains to be done toward the efficient enantioselective construction otfive and sw-membered cyclic ethers and amines. Four recent natural product syntheses illustrate the current state of the art. 

In the first synthesis of the hypotensive alkaloid (-)-ephedradine A 3 (Tetrahedron 2004,60,9615), Tohru Fukuyama of the University of Tokyo faced the challenging of constructing the central five-membered ring ether with control of relative and absolute configuration. While neither chiral Rh catalysts nor chiral auxiliaries alone gave satisfactory results, a combination of the two worked efficiently, yielding the two trans diastereomers of 2 in a 13 1 ratio. 

Vitamin E is a collective term for all of the tocopherols and tocotrienols. Of these, one of the most active is (-)-a-tocopherol 6. Lutz Tietze of the Universitfit Gottingen has reported (Angew. Chem. hit. Ed. 2005,44, 257) that the Pd-catalyzed cascade cyclization of 4 to 5 proceeds with 96 ee. 

Larry Overman also used (J. Am. Chem. Soc. 2004, 126, 14043) a chiral pool starting material, but in a different way. The prochiral enolate 12 showed substantial diastereoselectivity in its reaction with the bis-triflate 13, almost 10 1. Through the power of algebra, it followed that the three diastereomers of 14 were formed in a ratio of 90 9 I. The crystalline 14 was easily isolated in diastereomerically-pure form, and carried on to phenserine 15. This is a new method for the stereocontrolled construction of chiral quaternary centers. 

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