DIASTEREOSELECTIVE BROMINE/LITHIUM-EXCHANGE APPLIED TO THE SYNTHESIS OF A C-1/C-9-SEGMENT OF BRYOSTATINS

The alpha-bromo-alkyllithium compounds 5 are generated by diastereoselective bromine/lithium exchange on the dibromo-compound 4, The minor carbenoid 5b generated cyclizes spontaneously at -110 degrees C to the bicyclo[3.1.0]hexane 6, thus, leaving the major carbenoid 5a in diastereomerically pure form. Application of the boronate extension reaction to this carbenoid 5a led to 1,3- or 1,6-diol derivatives, viz. 9, 13, 16, with complete stereocontrol. This technique was applied to the synthesis of racemic 22, corresponding to the segment C-1/C-9 of the bryostatins.