Brevetoxin Nicolaou

I11 Nicolaou s total synthesis of brevetoxin B, for example, out of the eleven transfused six- to eight-membered cyclic ethers, THP rings B, F, G, and I are constructed by application of this methodology through cydization of the appropriate... 

Scheme 8.6 Nicolaou s approach for the construction of the F, G, and I rings of brevetoxin B.

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

Nicolaou and his group [139, 354,355] used this nucleophilic addition to thionolactones as a route to cyclic ethers, via an efficient desulfurization step with tin hydrides (Ph3SnH or n-Bu3SnH). ( )-Lauthisan and a brevetoxin A fragment were prepared according to this scheme. 

In their prominent synthesis of brevetoxin B, Nicolaou et al. have investigated, among some other methods for construction of oxepine ring system, the reductive cyclization of keto alcohol 37 with triethylsilane and trimethylsilyl triflate giving oxepane 38 (Equation 12) <1995JA1173>. 

In the synthetic studies of the marine natural products brevetoxins A and B, Nicolaou and coworkers [157] developed a highly efficient cyclization reaction of hydroxy dithioketals leading to oxocenes. As shown in Scheme 88, exposure of the hydroxy dithioketal 261 to 1.1 equiv of AT-chlorosuccinimide (NCS) in CH3CN in the presence of 2 equiv of 2,6-lutidine, 1.1 equiv of AgNOj, molecular sieves and silica gel at 25 °C for 5 min led to the oxocene 262 in 95% yield. 

Gawley, R.E., Rein, K.S., Jeglisch, G., Adams, D.J., Theodorakis, E.A., Tiebes, J., Nicolaou, K.C., Baden, D.G. 1995. The relationship of brevetoxin length and a-ring functionality to binding and activity in neuronal sodium channels. Chemistry Biology , 533-541. 

Nicolaou, K.C., et al. 1995c. Total s>ndiesis of brevetoxin B (2). Final stotegy and completion. Journal of the American Chemical Society 111, 10252-10263. 

Nicolaou, K C, The total synthesis of brevetoxin B a twelve-year odyssey in organic synthesis, Angew. Chem. Int. Ed. Engl., 35, 589-607, 1996. 

Nicolaou and coworkers have not only used thioxocarboxylic esters as precursors of the first stable l,2-dithietane, ° but also as a photochemical approach to the oxepane system (equation 40), ° ° which could be useful in a total synthesis of brevetoxin... 

The modified Corey-Nicoiaou macroiactonization was applied for the construction of the BCD ring system of brevetoxin A by K.C. Nicolaou and co-workers. The dihydroxy dicarboxylic acid substrate was subjected to a one-pot bis-lactonization. After the formation of the bis-2-pyridinethiol ester, the lactonization was conducted at low substrate concentration (0.013 M) in toluene at reflux temperature. 

Nicolaou, K.C., Duggan. M.E.. Hwang. C.K., and Somers, P.K., Activation of 6-endo over 5-exo epoxide openings. Ring-selective formation of tetrahydropyran systems and stereocontrolled synthesis of the ABC ring framework of brevetoxin B, J. Chem. Soc.. Chem. Commun.. 1359. 1985. 

Stereoselective hydrogen transfer reactions on oxacyclic radical intermediates are useful as shown in the synthesis of lauthisan (32) [126]. A key step in the total synthesis of brevetoxin B by Nicolaou [127] (Scheme 65) features conversion of the hydroxy dithioketal 189 into the oxoeene system 190 via cyclic hemithioketal formation and stereoselective radical-mediated desulfurization. More recently, Tachi-bana employed the same reaction sequence in the partial synthesis of ciguatoxin ]128]. 

In the brevetoxin area of polyether ionophores, Nicolaou s group has developed two methods for the synthesis of brevetoxin part-structures based on sulphur chemistry. In the first method, the problem of forming medium-size rings is tackled by generating a... 

Ring closing metathesis is a fundamental part of the strategy for the synthesis of Brevetoxin subunits employed by Clark and Kettle <97TL123>. This approach, complementary to that of Nicolaou and co-workers <96JA1565>, involves cyclisation of 26 to 27 by molybdenum catalysis. Yields of over 90% have been achieved The approach may also useful in the preparation of the 6,6-cyclic ethers, but not for 6,8-cyclic ethers of the brevetoxins. An alternative system for the latter has been proposed <97TL127>. 

Kenso Soai at the University of Tokyo discovers an auto-catalytic reaction that yields an absolute asymmetric synthesis K. C. Nicolaou, Scripps Research Institute, completes the total synthesis of brevetoxin B John R. Cronin and Sandra Pizzarello, Arizona State University, discover significant excesses of L-enantiomers of uncommon amino acids on the Murchison meteorite... 

The search for biologically active compounds (natural and synthetic) continued to be a significant inspiration for organic synthesis. Asymmetric catalysis, new synthetic reactions, and advances in separation techniques (HPLC) and analytical techniques (NMR and mass spectrometry) support these advances. In 1995, Kyriacos Costa (K.C.) Nicolaou (1946- ) at Scripps Research Institute reported the total synthesis of brevetoxin B (see the figure on page 375). This toxic substance is produced by algae in red tide and is very deadly to fish. It binds to sodium channels in membranes of muscle and nerve cells producing an excessive influx of Na. ... 

Under these circumstances, considerable efforts have been devoted toward their total syntheses over the past two decades [24-27]. In 1995, Nicolaou and co-workers completed the total synthesis of brevetoxin-B (1) after a 12-year endeavor, which is the first synthesis of a highly complex molecule of the polycyclic ether class [28-33]. This seminal work was followed by the synthesis of brevetoxin-A (2) by the same group in 1998 [34-38]. These outstanding achievements in the total synthesis of polycycUc ether natiual products revealed the power of contemporary organic synthesis and, at the same time. 

Much time has passed since the first organic synthesis of urea by Wohler in 1828, and the extraordinary ability of synthetic organic chemists has reached levels of real excellence in the research field of total syntheses of highly complex molecules with dramatic selectivities (e.g., palytoxin by Kishi in 1994 and brevetoxin B by Nicolaou in 1998). 

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