Monday, October 26, 2009

Piperazimycin A: A Cyctotoxic Cyclic Hexadepsipetide

Li, Gan, and Ma's recent natural product synthesis of piperazimycin A, the structure of which was reported in 2007, in Angewante Chemie (doi: 10.1002/anie.200904603), attracted me admittedly because of how gorgeous the 18-membered ring with 6 carbonyls pointed toward each other is - seriously, look at it!  Stare into the center of the ring - the oxygens are sort of mesmerizing in a hypnotic sort of way, no?

Amino acid chemistry is not my favorite; it's kind of... blah.  Feels archaic somehow. But these amino acids are pretty funky - each fragment was formed with pretty standard chemistry (protections/deprotections and all).  The N-N bonds were introduced with benzyl carbazate and t-butyl carbazate.  The cyclization to form the leftmost-indicated piperazic ring occurred via Mitsunobu condition-induced Fmoc deprotection of the amine (which appears to be novel according to the article) followed by substitution of an alcohol, while the left occurred via Boc deprotection-induced displacement of a triflate and the top via Troc-deprotection induced displacement of a triflate.  Don't forget the structures of these (the deprotection conditions used in the paper alongside):

The most interesting part is the macrocyclization; rather than doing a macrolactonization between an acid or ester and an alcohol, the authors used a substitutive strategy by a carboxylate anion attacking a chlorine-turned-iodide leaving group to produce Piperazimycin A in 3.6% overall yield in 26 linear steps.  Tight.  Note the hexachloroacetone (HCA) used for chlorination in the Appel reaction instead of CCl4. Equally toxic reagent, but way cooler. 

1 comment:

  1. This is really interesting because it reminded me when I was in the high school, now this is interesting because I understand everything I'd like to get a little bit more information , thanks for it.


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