Brefeldin A

Brefeldin A, an antiviral agent which impedes protein transport from the endoplasmic reticulum to the Golgi complex, was synthesized as the racemate using a number of interesting diastereoselective reactions. 

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]. 

Figure 46-7. Model of the steps in a round of anterograde vesicular transport. The cycle starts in the bottom left-hand side of the figure, where two molecules of ARF are represented as small ovals containing GDP. The steps in the cycle are described in the text. Most of the abbreviations used are explained in Table 46-7. The roles of Rab and Seel proteins (see text) in the overall process are not dealt with in this figure. (CGN, cis-Golgi network BFA, Brefeldin A.) (Adapted from Rothman JE Mechanisms of intracellular protein transport Nature 1994 372 55.) (Courtesy of E Degen.)...

Table 5 Effect of Anion-Channel Antagonists (Anthracene-9-carboxylic acid, ethacrynic acid each 100 fiM) and of Brefeldin A (Exocytosis Inhibitor 45 fiM) on Release of Phytosiderophores from Roots of Fe-Deficient Barley and Mai/.e...

Control (H,0) Anthracene-9- carboxylie acid Ethacrynic acid Brefeldin-A... 

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. 

Abbreviations lAA, iodoacetamide BFA, brefeldin A PMA, phorbol myristate acetate DNP, dinitrophenol ATPase, adinosine triphosphatase GTPase, guanosin triphosphatase. 

The apical clathrin-independent pathway is selectively stimulated by reagents that raise intracellular cAMP, such as mastoparan, fluoride, or cholera toxin. Apical endocytosis is also stimulated by brefeldin A (BFA) (106) or by PMA. For an excellent review on transcytosis, see Tuma and Hubbard (138). 

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