TOTAL SYNTHESIS OF CALICHEAMICIN-GAMMA-1(I) .2. DEVELOPMENT OF AN ENANTIOSELECTIVE ROUTE TO (-)-CALICHEAMICINONE

The first enantioselective total synthesis of (-)-calicheamicinone (3) , the naturally occurring antipode of the calicheamicin aglycon, has b een achieved. The key elements of the synthesis are as follows: (i) th e use of an asymmetric allylboration reaction to introduce asymmetry i nto the molecule (13 + 17 --> 18), (ii) the incorporation of the nitro gen atom of the urethane through an intramolecular 1,3-dipolar cycload dition reaction of an alkenyl nitrile oxide (22 --> 24), (iii) the app arently stereospecific introduction of the enediyne moiety through alk ylation of ketone 34, (iv) an unusual one-pot double oxidation of hydr oxy isoxazoline 39 to keto isoxazole 41, (v) the apparently stereospec ific introduction of the alkylidene side chain through Wittig olefinat ion of 41, (vi) the unveiling of key enamine-aldehyde functionalities through reductive ring opening of isoxazole 67, (vii) the bridging of the enediyne residue through intramolecular alkylation of an aldehyde (71 --> 72), and (viii) an unusual lactonization (72 --> 76) to correc t an errant stereocenter.