Organic Chemistry Portal
Organic Chemistry Highlights

Monday, May 8, 2006
Douglass Taber
University of Delaware

Stereocontrolled Construction of Azacyclic Natural Products

Yoshinori Yamamoto of Tohoku University has pioneered the Pd-catalyzed intramolecular hydroamination of alkynes. He has now demonstrated (Tetrahedron Lett. 2005, 46, 2101. DOI: 10.1016/j.tetlet.2005.01.139) that such cylizations can proceed with high diastereocontrol. Exposure of 2 to the reaction conditions they have developed delivered 3 as a single diastereomer. Hydrogenation converted 3 into the Dendrobatid alkaloid indolizidine 209D (4).

Four years ago, Jonathan Clayden of Manchester University reported the powerful cyclization of 5 to the bicyclic 6 in high enantiomeric excesss (86% ee, > 99% ee after recrystallization). He has now (J. Am. Chem. Soc. 2005, 127, 2412. DOI: 10.1021/ja042415g) described the conversion of 6 into the neuroexcitatory alkaloid isodomoic acid C (7).

One of the most powerful methods developed in recent years for the construction of polyazacyclic systems is the tandem Diels-Alder/azide insertion protocol introduced by Jeff Aubé of the University of Kansas. Professor Aubé recently reported (J. Am. Chem. Soc. 2005, 127, 15712. DOI: 10.1021/ja055629m) a short stereocontrolled synthesis of the Stemona alkaloid (±)-stenine (12) using this approach.

David A. Evans of Harvard University has reported (Angew. Chem. Int. Ed. 2005, 44, 6038. DOI: 10.1002/anie.200502296) an even more spectacular cascade cyclization. Exposure of the linear precursor 13 to base followed by acrylonitrile led, by two highly diastereoselective Michael additions, to 14. Reduction followed by hydrolysis and decarboxylation delivered the Lycopodium alkaloid clavolonine (15).

Atosiban 16 is an antagonist of the delivery-inducing cyclic peptide oxytocin that has been approved in Europe for the treatment of premature labor. John C. Vederas of the University of Alberta has used (J. Org. Chem. 2005, 70, 7799. DOI: 10.1021/jo050539l) ring-closing metathesis to prepare the carba analogues 17 and 18, and found that they are active. The saturated analogue 18 also has a longer placental halflife than does 16.

D. F. Taber, Org. Chem. Highlights 2006, May 8.