Ireland-Claisen rearrangement natural product synthesis

In total synthesis of the structurally unique natural product calcimycin (15), Grieco and others used Ireland-Claisen rearrangement of the ester 17 to synthesize the key intermediate (18)7 (Scheme 1.3g). Monosilylation of the diol 16 followed by treatment with propionyl chloride in pyridine gave rise to the ester 17 in 90% yield. Treatment of 17 with LDA in THF at —78 C, subsequent addition of ferf-butyldimethylsilyl chloride in HMPA, and brief heating of the resulting silylketene acetal provided the corresponding silyl ester. Subsequent hydrolysis of the silyl ester and esterification with diazomethane gave 18 in 90% yield from 17. 

The potential of the ester enolate Claisen rearrangement for the stereocontrolled synthesis of highly functionalized, complex systems has been demonstrated in numerous applications in natural product synthesis. Utilizing the 1,3-chirality transfer Ireland has synthesized oxygen heterocycles with chiral side chains, such as are found as units in polyether antibiotics and macrolides, starting from enantiomerically pure furanoid or pyranoid glycal systems of type (41), which are easily accessible from carbohydrates (Scheme 65). ... 

Using this methodology, the first total synthesis of the natural product (-)-(19R)-ibogamin-19-ol was reported [106]. The crucial ISQ core containing the entire configurational stereochemistry of the final target compound was prepared in 15 steps. The two key steps involved chirality transfer in an Ireland-Claisen rearrangement and an intramolecular nitrone-olefin 1,3-dipolar cycloaddition described earlier. 

Allylic alcohol 846 is instrumental in controlling the stereochemistry in the synthesis of (+ )-roccellaric acid (864) [231] (Scheme 115). The key step is an Ireland-Claisen rearrangement of propionate 861, which produces 862 as a mixture of isomers (epimeric at the methyl group). The minor diastereomer is removed at the lactone stage (863). Debenzylation and oxidation of the alcohol to an acid furnishes the natural product. 

This section is devoted to illustrating the manifold applications of the Ireland-Claisen rearrangement in natural products synthesis. The examples were generally chosen because they illustrate the first example of a particular variant of the Ireland-Claisen rearrangement to natural products synthesis. 

Ireland recognized early on the potential for the Claisen rearrangement in the synthesis of furan and pyran containing natural products. In 1980 Ireland and Vevert published the syntheses of both (-)- and (+)-nonactic acid using the Claisen rearrangement to establish the C2,C3 stereocenters (Scheme 4.111). Rearrangement of the S-silyl ketene acetal via the boat transition state afforded the methyl ester with an 86 14 diastereoselectivity [104]. 

Burke et al. employed a cyclic variant of the glycolate Ireland-Claisen rearrangement in the asymmetric synthesis of (-I-)-breynolide (Scheme 4.128) [122]. The rearrangement of the Z-silyl ketene acetal via a boat transition state generated the C3,C4 stereochemistry of the natural product in high yield and stereoselectivity. 

Having thus established the main stereochemical features, the Claisen rearrangement of glycal esters could be further utilized to provide key intermediates for a number of natural product syntheses Carbohydrates served as starting materials in the total synthesis of the ionophore antibiotics lasalocid A 43 by Ireland et al. [15] and indanomycin 46 by Ley et al. [16] (Scheme 8), as well as the 3-acyl tetramic acid antibiotics tirandamycic acid 49 [17] and (+)-streptolic acid 52 [18] (Ireland et al.. Scheme 9). Several further examples have been reported in the literature [19-21]. 

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