Verrucarinic acid synthesis

Another regioselective addition to an epoxide was used as one step in a synthesis of the r-butyldiphenylsilyl ether (7) of verrucarinic acid from 5.3 The diol was converted into the optically active epoxy alcohol by the Sharpless method (10, 64-65) and then oxidized to the epoxy acid 6 by the new ruthenium-catalyzed oxidation of Sharpless et al. (this volume). This epoxy acid undergoes almost exclusive / -addition with trimethylaluminum to give the desired product 7. 

Although the ready availability of only the (+)-longifolene enantiomer potentially limits the use of Lgf2BH as a reagent for natural product synthesis, this form proved appropriate for the preparation of an optically enriched intermediate in a synthesis of the naturally occurring enantiomer of verrucarinic acid (eq 4). ... 

Chart 1, may be used for a synthesis of verrucarinic acid 21 as outlined in equation 6 the acid is produced as its bis t-butyl-dimethylsilyl ether for incorporation into verrucarin A J8). 

Having verrucarol (454), the derivative of verrucarinic acid (465), and the half ester of ( ,Z)-muconic acid (456) all on hand, the total synthesis of verrucarin A (380) could be completed in a further five steps. Thus, verrucarol (454) was esterified first with compound 465 and second with compound 460. Then, molecule 467 was desilylated, macrolactonized under Yamaguchi conditions, and finally deprotected to achieve the natural product verrucarin A (380) (Scheme 8.17). 

Most synthetic work directed toward the macrocyclic trichothecenes has focused on the verrucarins, particularly verrucarin A (37) and verrucarin J (40). For verrucarin A there now exist two total syntheses 106, 133), starting from verrucarol (82), as well as innumerable reports on the synthesis of verrucarinic acid derivatives, a principal component of the macrocyclic ribbon (see Scheme 32). 

As part of the recent surge in methodology related to control of acyclic stereochemistry, numerous reports have appeared on the synthesis of racemic and chiral verrucarinic acid derivatives. These are summarized in Scheme 32. In most instances, the eventual synthesis of verrucarin A is not the primary concern of these efforts. 

Trost, B. M., and P. G. McDougal Synthesis of optically active verrucarinic acid derivatives. Tetrahedron Letters 23, 5497 (1982). 

The successful synthesis of optically active 7 then led to the first synthesis of verrucarin A (8), a macrotrilactone with significant cytostatic activity. The synthesis involved esterification of the primary alcohol of verrucarol (the tricyclic fragment) with the acetate of 7 (DCC, 4-pyrrolinopyridine) and then with a protected derivative of (E, Z)-muconic acid. After deprotection (Bu4NF), lactonization was effected by the Mitsunobu procedure (7,405-406). 

This procedure has been used by Roush and Blizzard [33] in the synthesis of the macrocyclic mycotoxin verrucarin J (55). Thus, seco acid 54 was treated with 2 equiv of pivaloyl chloride and 3 equiv of triethylamine in dichloromethane (0.01 M) and the resultant mixed anhydride was treated in situ with 4-pyrrolidinopyridine (4-PP) to effect the ring closure at 23 °C. Verrucarin J (55) was obtained in up to 60% yield (Scheme 17). The mixed pivalic anhydride method has also been applied, e.g. to the synthesis of verrucarin B [34] and 4-epiverrucarin A [35] as the key cyclization step. 

The first synthesis of a member of this class, verrucarin A (116) is a result of the efforts of Still and is outlined in Scheme 4.20. 2" Construction of the muconic acid fragment began with pseudoacid 107, available from the electrochemical oxidation of furfural. A one-carbon homologation with a stabilized ylide afforded solely the ( ,Z)-isomer of (3-trimethylsilylethyl ester 108 in 72% yield. 

Tamm has also completed a synthesis of verrucarin A (116), as described in Scheme 4.21. The muconic acid unit was obtained via peroxide oxidation of catechol to produce diacid 117, which was esterified to provide the ( ,Z)-half-ester 108. 

The work of Fraser-Reid and Jarvis, shown in Scheme 4.23 culminated in the total synthesis of trichoverrin B (132) and its conversion into verrucarin J (124). Construction of the pentanoic acid segment began with the protection of keto alcohol 133. Two-carbon homologation of the resulting ketone by a Wadsworth-... 

A new synthesis of verrucarin J uses a PO-olefination reaction of the phos-phonate (181) with malealdehydic acid as a key step to give verrucarin J seco acid (182) which can be cyclized to verrucarin J. The all ( )-triene (183) has been synthesized en route to a total synthesis of compactin. ... 

General Synthesis.—greatly improved procedure for the ruthenium tetroxide-catalysed oxidation of olefins, alcohols, and aromatic rings to carboxylic acids has been reported. Acetonitrile is added to the traditional CCU-water solvent system yields are good over a wide range of examples, and the method has already been independently applied in a synthesis of verrucarin A (Scheme 1). ... 

The synthesis of another macrocyclic model compound was communicated by Notegen, Tori and Tamm in 1981 and is summarized in Scheme 28 (109). Selective protection (72%) of the C-4 hydroxy moiety as the acetal (237) allowed esterification with acid (238) to take place at C-15. The hydroxy acid (239), devoid of protecting groups, was then lactonized, this time onto the C-4 hydroxy group of verrucarol, to yield the model macrocycle (240). These early examples established that macrolactonization, either at C-4 (Scheme 28) or at the primary hydroxy group of the side chain (Scheme 27) would be equally valid approaches to the naturally occurring verrucarins, a fact which has since been substantiated by synthesis of the natural products 121, 133). 

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