Danishefsky triene

Diels-Alder reaction between the Danishefsky triene 1659 and excess dimethyl-acetylene dicarboxylate or methylpropiolate in boiling benzene proceeds, via 1660 and 1661, with loss of trimethylsilanol 4, to give 1662 a and 1662b in 51 and 37% yield, respectively these are transsilylated with methanol to give 1663a and 1663b [40] (Scheme 10.18). 

In parallel investigations, Danishefsky and coworkers accomplished the preparation of the 16-membered lactone of a model epothilone system via an alternative C9,C10 disconnection [14] (Scheme 4). In this case, coupling of epoxy-alcohol 17 with acids 18a and 18b afforded trienes 19a and 19b respectively. RCM of 19a under the influence of ruthenium initiator 3 produced dienes 20a as a 1 1 mixture of Z -isomers. Under identical conditions, cyclization of 19b produced a single product 20b (tentatively assigned as the Z-isomer). The variable stereoselectivity observed in these reactions was inconsequential since the olefinic functionality could be reduced to afford the corresponding saturated macrolactones. Schrock s molybdenum initiator 1 promoted the cyclization of 19a and 19b with similar efficacy [14]. 

Danishefsky and coworkers also performed RCM of 29 using Schrock s molybdenum initiator 1 [14b]. In this case, the yield was identical to that obtained using 3 (86%) but the selectivity was reversed (Z =l 2). Additionally, trienes 33a and 33b were subjected to RCM to give epothilone A precursors 35 and 36 respectively [14b, 17b] (see Table 1). 

With the C12,C13 disconnection producing an effective solution to the synthesis of epothilone A (4), it would seem likely that the metathesis approach could be extended readily to the preparation of epothilone B (5). However, installation of the desired C12 methyl group requires ring-closure of a diene precursor in which one of the olefins is disubstituted. Recently, such reactions have been shown to be problematic for Grubbs initiator 3 but more successful with Schrock s molybdenum initiator 1 [19]. Consistent with these reports, Danishefsky demonstrated that triene 38 would not undergo RCM with 3, whereas 1 was effective in promoting the transformation of 38 into a 1 1 mixture of 39a and 39b in good yield [14b] (Scheme 8). 

The first total synthesis of racemic indolizomycin was accomplished by S.J. Danishefsky et a. The natural product s trienyl side chain was elaborated using the classical J-L olefination. The macrocyclic a, 3-unsaturated aldehyde was treated with an ( )-allylic lithiated sulfone to give epimeric acetoxy sulfones upon acetylation. The mixture of epimers was exposed to excess sodium amalgam in methanol to afford the desired ( , , ) triene stereospecifically. 

An advanced example of this simple approach was used by Danishefsky in the synthesis of the antibiotic indolizomycin.30 This example illustrates the compatibility of the Julia olefination with many sensitive functional groups. The enal 154 was combined with the lithium derivative of an allylic sulfone and the adduct acylated to give a mixture of isomers of the adduct 155. Elimination with sodium amalgam gave a good yield of the , , -triene 156. [The R s are protecting groups.]... 

Danishefsky and co-workers reported a total synthesis of antibiotic t//-indolizomycin 121. In which Julia olefination was successful employed to prepare the triene moiety. The intermediate 119, prepared by addition of 118 to aldehyde 117, was reduced to 120 by using 5% Na(Hg). 

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