Neocarzinostatin synthesis

Enediynes with ethylene carbonate fragment in the synthesis of dienediyne models of the biradical-forming and DNA-cleaving natural neocarzinostatin chromophore 99SL657. 

From a tactical perspective, early retrosynthetic removal of the epoxy dienediyne core must dominate all synthetic planning for (+ )-neocarzi-nostatin, since its presence in any intermediate will render that molecule highly susceptible to nucleophilic attack, and will jeopardise the success of all the remaining chemistry. In essence, it would be strategically advisable to install the epoxy dienediyne unit late in a forward total synthesis of ( + )-neocarzinostatin. 

Scheme 8,1 Myers retrosynthetic plan for the synthesis of (+)-neocarzinostatin.

Scheme 8.6 Myers total synthesis of the ( + )-neocarzinostatin aglycone.

Another interesting example of sulfone photochemistry pertains to diyne 92, which was investigated as an early approach for the synthesis of the highly unstable nine-membered ene-diyne ring of neocarzinostatin Chrom A 1 by Wender et al. [56]. The benzophenone-sensitized desulfonation of 92 resulted in the formation of the desired, but highly unstable, compound 93 in 9-15% yield (Scheme 2.22). 

The superior ability of alkynyltins to defer Pd-catalyzed alkynylation until after completion of the competing cyclic carbopalladation has been exploited in the synthesis of neocarzinostatin model compounds [85-87] (Scheme 28). 

The conversion of a diol or bromohydrin to the corresponding epoxide is a well-known and useful method. Recently two methods have been reported that significantly add to this chemistry. A synthesis of a key component of the natural product neocarzinostatin has been reported <07OL45>. In this work, an allenyl zinc bromide was added to a propargylic ketone to provide a chlorohydrin stereoselectively. Treatment of the chlorohydrin with base provided the epoxide. 

Magnus, P. Carter, R. Davies, M. Elliott, J. Pitterna, T. Studies on the synthesis of the core structures of the antitumor agents neocarzinostatin, kedarcidin, C-1027 and maduropeptin. Tetrahedron 1996, 52. 6283-6306. 

Martin s sulfurane has been used to prepare a variety of cyclopentenes for use in the total syntheses of complex natural products. Myers effectively employed the title reagent to prepare synthetic intermediates for use in his total synthesis of the neocarzinostatin chromophore.43 (For dehydrations to yield alkenes in the nine-membered ring of this compound, see Section 3.7.5.4.) One example is reaction of tertiary alcohol 86 to furnish alkene 87 in 93% yield. In Phillips s total synthesis of cylindramide A, he employed a conjugate addition-reduction-elimination sequence (88—>89) to generate the... 

Much synthetic work has been carried out on systems relating to the neocarzinostatin chromophore, some of it aimed toward the synthesis of the chromophore and other parts inspired by the mechanism of action of the chromophore resulting in novel systems and triggering devices. Some of the strategies successfully utilized toward these goals are described in this section. 

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