Verrucarin synthesis

Verdazyls — see 1,2,4,5-Tetrazinyl, 3-hydro-Verrucarin E synthesis, 1, 432 Vertical stack conductors, 1, 351 Veterinary products... 

The power of Muchowski s method is seen by the fact that these bromopyrroles can be subjected to bromine-lithium exchange to afford the versatile 3-lithio species that can be quenched with a variety of electrophiles in good to excellent yields [18-21]. This is illustrated by a synthesis of verrucarin E (11) [19]. 

Anderson and co-workers86 used the cycloaddition of acetylenic esters to 19a and 19 (R = COPh) in the synthesis of the antimitotic agent Verrucarin E (28). The pyrrole 19a and DMAD gave 35% of 21a, whereas 19 (R = COPh) gave 67% of 21 (R = COPh) and 23% of recovered starting material 1-benzoylpyrrole gave 54% of 29 with DEAD. Further transformations produced the natural product. 

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. 

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. 

In the synthesis of verrucarin J (55) by Fraser-Reid and coworkers [62], triol 109 was treated with pyridiniura dichromate (PDC) for 3 days, resulting in oxidative cleavage of the adjacent diol to the corresponding aldehyde and further oxidation of the presumed cyclic hemiacetal intermediate gave 55 in 50% yield (Scheme 37). 

Trichothecenes can be divided into two groups based on their site of action on protein synthesis. Trichothecenes with hydroxyl and acetyl substitutions at both C-3 and C-4, such as T-2 toxin, DAS, verrucarin A, preferentially inhibit initiation while DON, trichodermin, crotocin, and verucarol inhibit elongation and/or termination (McLaughlin et al, 1977). Trichothecenes inhibit both DNA and RNA synthesis... 

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). ... 

Ishihara, J, Nonaka, R, Terasawa, Y, Shiraki, R, Yabu, K, Kataoka, H, Ochiai, Y, Tadano, K.-i, Total synthesis of (—)-verrucarol, a component of naturally occurring verrucarin A, Tetrahedron Lett., 38, 8311-8314, 1997. 

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-... 

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). 

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. ... 

There exist just a few total syntheses of macrocyclic trichothecenes. However, all of these deal with the synthesis of verrucarol (454), a hydrolysis product of the naturally occurring verrucarin A (380). Venucarol (454) represents the sesquiterpenoid moiety of most macrocyclic trichothecene derivatives. To date, there are several syntheses of this moiety. In 1998, the most recent total synthesis was published by Tadano et al. (327). 

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