Sunday, May 27, 2012
Unsymmetrical Steroidal Pyrazine Synthesis: Completion of Cephalostatin 1
The laboratory of Clayton Heathcock described the first preparation of an unsymmetrical bis-steroidal pyrazine in 1992. The Heathcock protocol combines an a-aminomethoxime with an a-acetoxyketone at high temperature (~ 140 oC) for 48 hours with modest isolated yields of the pyrazine product (< 40%). Fuchs and Guo improved upon Heathcock’s concept by coupling an a-azidoketone (e.g. 1) with an aminomethoxime (2) in the presence of dibutyltin dichloride. This reaction proceeds in only 3-6 hours under relatively mild thermal conditions (~ 80 oC). Weisheng Tian and co-workers applied the Fuchs pyrazine synthesis to the coupling of their western and eastern hemispheric cephalostatin fragments (1 and 2, respectively) and obtained a quite acceptable 67% isolated yield of the unsymmetrical bis-steroidal pyrazine product. Subsequent global deprotection then delivered the natural product (+)-cephalostatin 1. This effort constitutes only the third completed total synthesis of cephalostatin 1 since its isolation by Petit about 24 years ago.
The utilization of the a-azidoketone 1 (in place of Heathcock’s a-acetoxyketone) changes the mechanism of the condensation reaction to involve the extrusion of nitrogen gas (3 à 4) prior to an elimination/aromatization step (5 à 6). Polyvinylpyridine (PVP) is routinely used as an additive in order to suppress degradation of the acid-labile spiroketal functionality. The Fuchs-Guo protocol has been used extensively for the coupling of highly functionalized steroid spiroketals, most notably in the penultimate step of Shair’s recent synthesis of cephalostatin 1. Shair’s synthesis will be the topic of a subsequent post at this site.