Verrucarol synthesis

In a projected synthesis of verrucarol in which the tetrahydropyranone 175 is envisioned to play a role, the lactone 176 can serve as a viable intermediate (Scheme 6)7S>. Using cyclobutanone annulation methodology, 177 becomes the required intermediate. The geminal substitution of 177 can also be recognized to derive from a spiroannulation approach as previously analyzed. 

Scheme 6. Retrosynthetic Analysis and Synthesis of Potential Verrucarol Intermediate " See secosulfenylation section and ref. 75) b 30 then TsOH, PhH, H20, 62 % c NaOH, H202...

Mono- and bi-cyclic cyclopentanes, known precursors of variety of sesquiterpenes, have been prepared by the acid-catalysed rearrangement of 1-methylcyclo-butylmethanols. An acid-catalysed rearrangement (see Scheme 77) has been found to afford a practical method for converting a bicyclo[4.2.0]octene system (221) into a bicyclo[3.2.1]octene framework (222) in a recent synthesis of verrucarol. ... 

D. B. Tulshian and B. Fraser-Reid, Studies directed at the synthesis of verrucarol from D-glucose The A-B moiety. Tetrahedron 40 2083 (1984). 

The final steps in a recent synthesis of the sesquiterpenoid mycotoxin verrucarol (6) required selective epoxidation of a 2,2-disubstituted double bond in the presence of a IriNuhstiiutcd one. This reaction was effected, in 85% yield, by treatment of 4 with t-Inilyl hydroperoxide and Mo(CO)6. Use of VO(acac), as catalyst resulted in some decomposition in addition to the desired epoxidation. The final step was deprotection ol 8 with lluoridc ion to give 6.2... 

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). 

The bicyclic lactone (117) has been considered as a useful synthon for the synthesis of verrucarol (118). A second synthesis of this lactone has been described (Scheme 22)7° Starting from verrucarol (118), Tamm et have appended the two requisite side-chains (119) which can be lactonized with di-(2-pyridyl) disulphide and triphenylphosphine to give tetrahydroverrucarin J (120). A recent investigation of the biosynthesis of trichodermin (121) using [l- C]acetate is in accord with an earlier result although some reassignments of certain chemical shifts have been suggested, ... 

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. 

Trost also found that treatment of these cyclobutanones with sodium methoxide and diphenyl disulfide leads to in situ bisulfenylation and ring cleavage (secosulfenylation). This was applied to the total synthesis of verrucarol, a complex tetrahydrochromanone substituted at the ring junction by a hydroxymethyl substituent. The synthetic strategy twice used the cyclobutanone formation from 1-lithiocyclo-propyl phenyl sulfide and a ketone, followed by the secosulfenylation process and Baeyer-Villiger type rearrangement of cyclobutanone. Only this part of the synthesis is described in Scheme 28. 

The Barton decarboxylation procedure was used in the total synthesis of (-)-verrucarol by K. Tadano et al. The initially formed thiohydroxamic ester was decarboxylated to leave a methylene radical on the cyclopentyl ring, which was then trapped by molecular oxygen. Reductive work-up in the presence of f-BuSH finally provided the hydroxylated product. ... 

Kraus, G. A., Roth, B. Synthetic studies toward verrucarol. 2. Synthesis of the AB ring system. J. Org. Chem. 1980, 45, 4825-4830. 

As with other diazoalkanes, diazomethane reacts with alkenes to form cyclopropane derivatives (sec. 13.9.C.i).272 Reaction with aromatic derivatives leads to ring expansion to cycloheptatriene derivatives.223 Both of these reactions (addition to an alkene or arene insertion) involve generation of an intermediate carbene and addition to a jt bond they will be discussed below. Many of the reactions of diazomethane tend to be ionic in nature and are, therefore, set aside from the other diazoalkane chemistry in this section. One of the commonest uses of diazomethane itself is esterification of small quantities of acids, especially acids that are precious for one reason or another. The reaction is quantitative and gives good yields of a single product, as in Tadano s conversion of 338 to the methyl ester of 339224 in a synthesis of (-)-verrucarol. 

Fig. (2). (+)-Eremantholide A and (-)-verrucarol, targets for our total synthesis detailed herein.

Trost and co-workers reported their total synthesis of racemic verrucarol in 1982 [67]. Their approach, illustrated in Scheme 14, featured a ring enlargement reaction of a 6/5/5-ring system to the 6/6/5-ring system for the B/C ring construction in a later stage of the total synthesis. At the... 

In the initial stage of the total synthesis of (-)-verrucarol (9) from 2, we utilized the above Knoevenagel-type intramolecular cyclization strategy for the construction of the A-ring as illustrated in Scheme 18. Hydride reduction of 2 followed by a modified Mitsunobu reaction [86] of the... 

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