Sarkomycin A

Racemic (1 alpha, 2 alpha, 5 alpha)- and (1 beta, 2 alpha, 5 beta)-2- bromobicyclo[3.2.0]heptan-6-one (rac-7, rac-10, respectively), (1 alpha, 2 alpha, 5 beta)- and (1 beta, 2 alpha, 5 beta)-2- benzyloxybicyclo[3.2.0]heptan-6-one (rac-15, rac-13, respectively), (1 beta, 2 alpha, 5 beta)-2-hydroxybicyclo[3.2.0]heptan-6-one (rac-17) and cis-bicyclo[3.2.0]hept-2-en-7-one (rac-18) were subjected to a microbial Baeyer-Villiger reaction by Acinetobacter calcoaceticus NCIB 9871. In each case both regioisomeric lactones were formed (67-93% yield) having always the opposite configuration (20 to > 99 % e.e.). Both the ratio of the regioisomers and the enantiomeric excess proved to be dependent on the type of substitution. Analogously cis-bicyclo[3.2.0]heptan-2,6-dione (rac-1) gave besides other products cyclosarkomycin (1b) (7 % yield, 97 % e.e.). Compound 1b was also obtained from the Baeyer-Villiger product of rac-17 by Swern oxidation (total yield starting from rac-17 9 %, > 98 % e.e.).

(R)-Sarkomycin was prepared using a five-step total synthesis. Key steps in the enantioselective construction of the targeted scaffold were a rhodium-catalyzed asymmetric conjugate alkenyl addition with subsequent silyl trapping and a Mukaiyama aldol reaction with aqueous formaldehyde. Protection of the hydroxy group as a THP acetal and oxidative cleavage of the C,C-double bond provided a stable direct precursor to the natural product. The final liberation was carried out under slightly acidic conditions in a microwave-assisted reaction, resulting in a high yield of the "deceptive" sarkomycin. This represents the shortest enantioselective synthesis of this rather unstable compound to date and the first to employ asymmetric catalysis to introduce the stereogenic center.