Total Synthesis Of Calicheamicinone - New Arrangements For Actuation Of The Reductive Cycloaromatization Of Aglycon Congeners

The total synthesis of dl-calicheamicinone (1) has been accomplished. The key elements of the synthesis were (i) an application of the Becker-Adler reaction to reach compound 91, (ii) an application of the concept of in situ protection to deliver lithiated enediyne 35 to a ketone group in the nominal presence of an aldehyde, (iii) an apparently stereospecific aldol-like cyclization of 93 to reach 94, (iv) intramolecular Emmons-like closure (cf. 102 to 103), (v) exploitation of vinylogous urethane character to provide stabilization to an otherwise labile primary enamine (see compound 104), and (vi) generation of an allylic thiolate and its conversion to the allylic trisulfide emanating from the C1 bridge (see transformation 111 --> 112). Much of the strategy used in the synthesis of 1 had been worked out in a synthesis of the descarbamate system 9. The propensity for reductive cycloaromatization of calicheamicin has been simulated with these simpler substrates (see compounds 9, 68, 115, 117, 124, and its unstable reduction product).