Brevetoxin

Synthesis of Medium-size Oxygen Heterocydes by Ring-closing Alkene Metathesis 

84% yield. RCM using [Ru]-I catalyst provided an 81% yield of the H-ring oxodne and the fully intact brevetoxin B skeleton as 271. Oxidation of the A-ring and the allylic ether side chain completed the synthesis of brevetoxin B. 

Cambierol, Cambieric Acid, Olefinic-ester Cyclizations 

1) Grubbs has proposed a related mechanism for ring-opening metathesis, carbonyl-olefination reactions. 

2 For recent reviews describing the generation of heterocycles see (a) Deiters, 

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Total synthesis of brevetoxin B, a fused polycyclic marine-derived saturated 0-heterocycle 97YGK686. 

Since the syntheses of urea and acetic acid in 1828 and 1845, respectively, synthetic chemists have come a long way in terms of the complexity of the target molecules they can reach. Progress was at first steady, but became rather dramatic in the second half of the 20th century. Vitamin Bi2, ginkgolide B, calicheamicin yi1, taxol, palytoxin, and brevetoxin B (Figure 3) are arguably six of the most impressive molecules to be synthesized to date. 

The striking constitution of brevetoxin B, unprecedented at the time of its discovery in 1981, presents a formidable challenge to organic synthesis. The unique and fascinating molecular architecture of brevetoxin B (1), its association with the red tide catastrophes, its potent biological activity, and the prospects for expanding the arsenal of synthetic methods all contributed in roughly equal measure to our decision to pursue a total synthesis of 1. This chapter addresses the efforts that culminated in the total synthesis of brevetoxin B (1 ).6... 

In order to overcome the special problems posed by brevetoxin B s tetrahydropyran systems, the decision was made to develop and test regio- and stereoselective ring closures employing two types of substrates hydroxy epoxides and hydroxy a,/ -unsaturated esters. The basic concepts of these reactions are shown in Schemes 1 and 2, respectively. 

The intramolecular Michael addition11 of a nucleophilic oxygen to an a,/ -unsaturated ester constitutes an attractive alternative strategy for the synthesis of the pyran nucleus, a strategy that could conceivably be applied to the brevetoxin problem (see Scheme 2). For example, treatment of hydroxy a,/ -unsaturated ester 9 with sodium hydride furnishes an alkoxide ion that induces ring formation by attacking the electrophilic //-carbon of the unsaturated ester moiety. This base-induced intramolecular Michael addition reaction is a reversible process, and it ultimately affords the thermodynamically most stable product 10 (92% yield). 

Scheme 14. Structure of brevetoxin B (1) and hypothetical polyepoxide precursors 71a and 71b.

Scheme 17b. Retrosynthetic analysis of brevetoxin B (1) the third-generation approach (continued).

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