Verrucarinic acid

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). 

In its retrosynthesis, the natural product 380 was disconnected through cleavage of the ester bonds to furnish verrucarol (454), verrucarinic acid (455), and ( ,Z)-muconic acid (456) as starting compounds (Scheme 8.14). 

For the second building block for verrucarin A (380), a derivative of verrucarinic acid (465) was synthesized in enantiomerically pure form from diester 461. Cleavage with pig liver esterase led to monoester 462, which was reduced to the alcohol with borane dimethylsulfide complex and protected with TBSCl to obtain the molecule 463. a-Hydroxylation with molybdenum oxide generated alcohol 464, and final protection and saponification afforded compound 465 (Scheme 8.16). 

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). 

Reaction of the verrucarinic acid derivative (247) with verrucarol (82), mediated by DCC and 4-N,N-dimethylaminopyridine (DMAP), yielded the monoester (250) by exclusive acylation at C-15. A similar esterification procedure attached the muconic acid (249) to C-4. Following desilylation the seco acid (251) was cyclized (52%) and deacetylated to yield verrucarin A (37). When alternative conditions for the esterification of acid (249) were employed, partial isomerization of the , Z-isomer (251) to an E,E-isomer was observed. However, lactonization of this mixture produced only the natural E,Z-macrocyclic (37) as the E,E-isomer failed to cyclize. Such reactivity differences have been observed with other trichothecanoid macrocycles (22, 148), although, as shall be seen, E,E-macrocycles can be prepared if so desired 115, 121). 

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. 

In addition to the route discussed in Scheme 31, Tamm and co-workers have developed two other syntheses of chiral verrucarinic acid derivatives (67). One of their newer routes (259->254) closely mimics Still s original work in the area (see Scheme 30) by utilizing a chiral epoxidation to establish the desired absolute stereochemistry. Their second alternative involves an enantioselective hydroboration (260 261) which proceeded with only mediocre optical induction. 

A tin-mediated ene reaction on the chiral glyoxylate ester (265, R = chiral group) has yielded the verrucarinic acid precursor (266) as virtually a single enantiomer (168). The selectivity of this metallo-ene process stands in sharp contrast to the proto-ene reaction (129) which produces a mixture of diastereomers (267) and (268) in low yield. 

Herold, P., P. Mohr, and Ch. Tamm Syntheses of optically active verrucarinic acid. Helv. Chim. Acta 66, 744 (1983). 

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

Veratramine, K3S Veratrenone, K9 Veratrobasine, K3S Verbanone, T8 Verbenalin, T13 Verbenols, T8 Verbenone, T8 Verrucarin A, T31 Verrucarinic acid, T31 Verrucarol, T31 Verruculotoxin, K6 Vertaline, K27 Verticillatine, dihydro-, K27 Verticillins, Yll Verticinone, K3S Vertisporin, T6 ... 

Further feeding experiments were necessary for investigations on the origin of verrucarinic acid (86) and on the mechanism of its formation. Upon hydrolysis, verrucarin A (32) that was obtained after incorporation of [2- " C]mevalonate yielded radioactive verrucarol (49) and verrucarino-lactone (87) as well as inactive muconic acid (83). The measured activity suggested that one mevalonate unit participates in the formation of verrucarinic acid (86). For the location of the labeled centers, the verrucarino-lactone from the [2-mevalonate experiment was reduced to the triol 99. Cleavage of the latter with HIO4 yielded 2-methyl-4-hydroxybutanal... 

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