Brefeldin A, synthesis

Scheme 1.33. Crabbe and Greene s first brefeldin A synthesis.

The redcdon shown in Eq. 7.120 hdS been dpphed to d todil synthesis of l+ -brefeldin-A. ... 

A direct application of the ring-opening reaction of an epoxide by a metal enolate amide for the synthesis of a complex molecule can be found in the synthesis of the trisubstituted cyclopentane core of brefeldin A (Scheme 8.35) [68a]. For this purpose, treatment of epoxy amide 137 with excess KH in THF gave a smooth cyclization to amide 138, which was subsequently converted into the natural product. No base/solvent combination that would effect cyclization of the corresponding aldehyde or ester could be found. 

The fungal metabolite (+)-brefeldin A (325) displays potent antitumor, antifungal, antiviral, antimitotic, and immunosuppressive activities. Recently, Romo and Wang described a highly concise total synthesis of 325 by a combined /J-lactone-CM approach (Scheme 63), that again underlines the high tolerance of sensitive functionality exhibited by the second-generation Ru catalysts [ 145]. 

The reaction shown in Eq. 7.120 has been applied to a total synthesis of (+)-brefeldin-A.166... 

Synthesis of tritium-labelled brefeldin-A by catalytic isotope exchange with tritium gas... 

Three novel stereo- and regioselective schemes for the total synthesis of (+ )-brefeldin A 440 have been accomplished. Each of them exploit intermolec-ular nitrile oxide cycloaddition for constructing the open chain and introducing substituents, but differ in subsequent stages. The first (480) and the second (481) use intramolecular cycloaddition for the macrocycle closure. However, in the second scheme INOC is followed by C=C bond cis-trans-isomerization. In the third scheme (481) intermolecular cycloaddition is followed by ring closing metathesis as the key step. 

The key step in the formal total synthesis of ( )-brefeldin A utilized the acid catalyzed ring opening of (289) to (290) 99>. 

Vance, J.E., Aasman, E.J., and Szarka, R., 1991, Brefeldin A does not inhibit the movement of phosphatidylethanolamine from its sites for synthesis to the cell surface. J. Biol. Chem. 266 8241-8247. 

This chemistry has been used to synthesize cyclopentanoid derivatives used in the synthesis of sarko-mycin and brefeldin A.22 Azulene derivatives were also synthesized using this chemistry (Scheme 14).23... 

The Heck reaction of 4,7-dihydro-l,3-dioxepins has found further applications in the total synthesis of naturally occurring compounds. For example, 4,5-dihydro-l,3-dioxepin 241 was prepared as an intermediate in the synthesis of Brefeldin A <1999JOC3800>, and the /fV/-butyl derivative of 106 in the synthesis of (-l-)-curcuquinone and (—)-curcuhydroquinone (Scheme 72) <2003ARK232>. 

Methylthiomethyl ethers are comparable in stability to alkoxymethyl ethers towards strongly basic conditions or mild acid. For example, methylthiomethyl ethers survive aqueous acetic acid under conditions that hydrolyse TBS ethers, dioxolanes or tetrahydropyranyl protectors. They can be removed under rather specific and mild conditions that do not affect most acetal-type protectors such as MEM. MOM. etc. (see above). The presence of the sulfur makes this group liable to oxidation by strong oxidants such as peracids. Cr(VI), and N-bromo-succinimide, and it will poison Pd catalysts. The methylthiomethyl group was First introduced by Corey and co-workers586 and its virtues exploited by them in a synthesis of the antibiotics Erythronolide587 588 and Brefeldin.589... 

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