Synthesis of (±)-calicheamicinone by two methods

Ketene acetal 25 was converted into silyl enol ether 20, which underwent a Diels-Alder reaction with methyl (E)-3-nitropropenoate to afford ketone 27. This was converted by two routes into (+/-)-calicheamicinone (1). In the first, modification of the nitro, ester, and allyl substituents gave ketone 38, which reacted stereoselectively with cerium trimethylsilylacetylide to place the acetylene unit syn to the nitrogen function (38 --> 39). Further elaboration took the route as far as aldehyde 42. A slightly different series of reactions served to convert ketone 27 into tricyclic ketone 43. This also reacted with cerium trimethylsilylacetylide, but in the opposite stereochemical sense to 38, so as to place the acetylene unit anti to the nitrogen function (43 --> 50). Further elaboration took this second route as far as lactone 44. Both 42 and 43 serve as advanced intermediates for the synthesis of (+/-)-calicheamicinone. The monoacetylenic aldehyde 42 reacted stereoselectively with cerium trimethylsilylacetylide to give the bis(acetylene) 53 as the major product. This was elaborated into lactone 60. which was desaturated (60 --> 68) and methoxycarbonylated on nitrogen. The acetylenic silyl groups were then removed, so as to generate syn bis(acetylene) 72, and the terminal acetylenic hydrogens were replaced by iodine. The resulting diiodide 81 formed the cyclic enediyne 82 on reaction with (Z)-1,2-bis(trimethylstannyl)ethene in the presence of (Ph3P)(4)Pd, and the enediyne was converted into (+/-)-calicheamicinone. syn-Bis(acetylene) 72 was also synthesized from the other advanced intermediate (lactone 44), using, as a key step, free radical bromination of the derived unsaturated lactone 77. The resulting bromo lactones 78 were converted into an aldehyde ester 79, and this reacted stereoselectively with cerium trimethylsilylacetylide to give 80, convertible by the action of TBAF into 72.