Octalactin A and

Tapiolas, D. M., Roman, M., Fenical, W., Stout, T. J., and Clardy, J. (1991). Octalactins A and B Cytotoxic eight-membered-ring lactones from a marine bacterium, Streptomyces sp. J. Am. 

An example of a surprisingly facile and stereoselective formation of an eight-membered lactone from an acyclic precursor diene ester was observed during the total synthesis of the antitumor agent octalactin A (148) (Scheme 27) [81]. The dense substitution pattern in cyclization substrate 146 presumably imposes... 

Marine sponges of the genus Haliclona contain a diverse array of active secondary metabolites, including highly potent cytotoxic macrolides, e g., halichondrin and related compounds, Fig. (56) [468], and salicylihalamides A and B, Fig. (57) [469], New macrolides chemically related to salicylihalamides, apicularens A and B, were recently isolated from the myxobacteria Chondromyces sp. [470], From marine bacteria, other cytotoxic macrolides have been isolated, such as octalactin A, Fig. (58) and B, which have been shown as a cell cycle-specific anticancer drug [471], and swinholide, Fig. (59), isolated from symbiotic cyanobacteria with the marine sponge Theonella swinhoei [472]. 

The key butenolide needed by Buszek, for his synthesis of (—)-octalactin A, had already been prepared by Godefroi and Chittenden and coworkers some years earlier (Scheme 13.4).9 Their pathway to 10 provides it in excellent overall yield, in three straightforward steps from l-ascorbic acid. The first step entails stereospecific hydrogenation of the double bond to obtain L-gulono-1,4-lactone 13. Reduction occurs exclusively from the sterically less-encumbered ot face of the alkene in this reaction. Tetraol 13 was then converted to the 2,6-dibromide 14 with HBr and acetic anhydride in acetic acid. Selective dehalogenation of 14 with sodium bisulfite finally procured 10. It is likely that the electron-withdrawing effect of the carbonyl in 14 preferentially weakens the adjacent C—Br bond, making this halide more susceptible to reductive elimination under these reaction conditions. 

Having successfully knitted together the entire carbon skeleton of (-)-octalactin A, all that now remained was to form the epoxy ketone and deprotect. Pleasingly, compound 1 underwent hydroxyl-directed epo-xidation with complete stereocontrol to give 22. Oxidation to the ketone, and protecting group cleavage under standard conditions, then completed this fine total synthesis of (—)-octalactin A. 

A SmI2-promoted intramolecular Reformatsky-type reaction was used for the cyclization of 5-(bromoacetoxy)alde-hyde 96 (Scheme 17) <1998SL735>. This reaction provided a 2 1 epimeric mixture of the oxocan-2-ones 97 and 98 in 63% yield. The isomer 97 could be converted almost quantitatively into 98 (a precursor of (—)-octalactin A) by sequential Dess-Martin oxidation and NaBH4 reduction. 

Lactone 103, an intermediate in the synthesis of (-F)-octalactin A, a potent cytotoxic natural product, was obtained in 81% yield by lactonization of the hydroxy acid 102. The cyclization was conducted with the water-soluble carbodi-imide EDCI (ethyldimethylaminopropylcarbodiimide hydrochloride, 5 equiv), DMAP (4-iV,iV-dimethylaminopy-ridine, 5equiv) and DMAP-HC1 (5 equiv) in refluxing CHCh (Scheme 20) <1996TL5049>. 

In addition, the highly enantioenriched propargylic alcohols obtained in such a way are versatile building blocks. Theyhave been applied to the syntheses of the alkyl side chains of zaragozic acids A and C,"several metabolites isolated from marine sponges, and the octalactin A ring. ... 

Two 8-membered ring macrolides, octalactins A (Fig. 2, 1) and B, are known to be produced by marine Streptomyces (see Chapter 2, Section II.A.l) [7]. Only one 9-membered ring macrolide, juglorubin (2), has been reported to be produced by actinomycetes [8]. 

The structure of octalactin A (15), m.p. 155-157°C, [a]o —14.0° (c 1.80, chloroform), derived from the marine microorganism Streptomyces sp., has been determined <91ja4682>. The solid-state structure shows the eight-membered ring to exist in the boat-chair conformation with an E-conformation for the lactone. Calculations (MM2) on a trisubstituted eight-membered model compound indicate that the observed boat-chair conformation is one of six conformations within 1 kcal mol of the ground state. (15) is cytotoxic to several tumor lines however, the closely related octalactin B (16) [ ]d — 12.3° (c 5.60, chloroform), from the naturally occurring sample, exists as a liquid at room temperature and shows no cytotoxicity. 

Bioactivity of novei eight-membered medium ring lactams inspired by octalactin A in murine and human tumor cell lines in vitro... 

Buszek and Jeong have reported a synthesis of the 8-membered lactone 96, a precursor of octalactin A 97 and B (which has an alkene in place of the side chain... 

Buszek, K.R., Sato, N., and Jeong, Y. (2002) Total synthesis of octalactin A via ring-dosing metathesis reaction. Tetrahedron Lett, 43,181-184. 

Shiina, I., Hashizume, M., Yamai, Y., Oshiutni, H., Shimazaki, T, Takasuna, Y, and Ibuka, R. (2005) Enantioselective total synthesis of octalactin A using asymmetric aldol reactions and a rapid lactonization to form a medium-sized ring. Chem, Ear, J 11, 6601-6608. 

Radesovich, A.T, Chan, V.S., Shih, H.-W, and Toste, F,D, (2008) Synthesis of (-)-octalactin A by a strategic vanadium-catalyzed oxidative kinetic resolution. Angeiv. Chem. Int. Ed., 120, 3815-3818,... 

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