Brefeldins

Methylsulfinyl enolates are more recently developed d -reagents. They are readily prepared from carboxylic esters and dimsyl anion. Methanesulfenic acid can be eliminated thermally after the condensation has taken place. An example is found in Bartlett s Brefeldin synthesis (P.A. Bartlett. 1978). 

A key intermediate, 163, which possesses all but one chiral center of (+ )-brefeldin, has been prepared by the enantiocontrolled cycloaddition of the chiral fi,/3-unsaturated ester 162 to 154[107], Synthesis of phyllocladane skeleton 165 has been carried out by the Pd-catalyzed cycloaddition of the unsaturated diester 164 and cobalt-catalyzed cycloaddition of alkynes as key reactions[108]. Intramolecular cycloaddition to the vinylsulfone in 166 proceeds smoothly to give a mixture of the trans and cis isomers in a ratio of 2.4 1[109], Diastereocontrolled cycloaddition of the hindered vinylsulfone 167 affords a single stereoisomeric adduct, 168, which is used for the synthesis of the spirocarbocyclic ring of ginkgolide[l 10],... 

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. 

Total synthesis of brefeldins, 13-member lactones with four asymmetric centers 97YGK110. 

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

Numerous applications of the Ni(n)/Cr(ii)-mediated coupling reaction in total synthesis have already been reported.11 Some of the more noteworthy examples derive from Kishi s laboratories and played a role in the syntheses of such complex molecules as (+)-ophiobolin C16 and halichondrin B17 (see Scheme 5). Another elegant application can be found in the enantioselective total syntheses of (+)-brefeldin C and 4-ep/-brefeldin C by Schreiber and Meyers (see Scheme 5).18... 

BCX3 protecting group 624 bombykol 589 f. boron trichloride 535 (+)-brefeldin C 716 f. 

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>. 

---