Alkaloid Synthesis: (+)-Preussin (Britton), (±)-Xenovenine (Livinghouse), (+)-Subincanadine F (Li), (±)-Strychnine (Reissig), (-)-Virginiamycin M2 (Panek)

Aldehydes such as 1 are readily available by direct enantioselective chlorination. Robert Britton of Simon Fraser University found (Org. Lett. 2010, 12, 4034. DOI: 10.1021/ol101631e) that the addition of the kinetic ketone enolate 2 gave the anti aldol 3. Condensation of the chlorohydrin 3 with a primary amine led to the cyclic pyrrolinium salt, that was reduced with high diastereocontrol to (+)-Preussin (4).

Tom Livinghouse of Montana State University developed Sc catalysts for the cyclization of γ-amino terminal alkenes such as 5. In contrast, addition to internal alkenes was sluggish. He has now shown (Org. Lett. 2010, 12, 4271. DOI: 10.1021/ol101646t) that a thiophene substituent activated the internal alkene for addition, enabling the facile synthesis of (±)-Xenovenine (7).

Chaozhong Li of the Shanghai Institute of Organic Chemistry found (Chem. Commun. 2010, 46, 8436. DOI: 10.1039/C0CC03428B) that ferrocenium ion cleanly oxidized the enolate of the β-keto ester 8, effecting cyclization to 9. The D-tryptophan-derived ester that directed the relative and absolute configuration of the cyclization could readily by removed, delivering (+)-Subincanadine F (10).

In a complementary approach to indole alkaloid synthesis, Hans-Ulrich Reissig of the Freie Universität Berlin devised (Angew. Chem. Int. Ed. 2010, 49, 8021. DOI: 10.1002/anie.201003320) the elegant SmI₂-mediated double cyclization of 11 to 12. This set the stage for the assembly of (±)-Strychnine (13).

James S. Panek of Boston University used (Angew. Chem. Int. Ed. 2010, 49, 6165. DOI: 10.1002/anie.201002220) the enantiomerically-pure allylic silanes that he has developed to construct the chloroaldehyde 14. He found that the reductive cyclization to 15 was best carried out with SmI₂ in benzene.

SmI₂ has the virtue that it is soluble in common organic solvents, so it can readily be deployed even on a micromole scale. It is also versatile, because its reducing power can be tuned by the solvent in which it is dissolved.