Octalactin

Hydroboration/oxidation, acetalation, bromination, and halogen-metal exchange 

Buszek also intended to add a soft acid silver(I) salt8 to the reaction mixture. Its role would be to complex with the softly basic sulfur atom of the thioester moiety, and thereby assist in this group s departure. Thus, it will be recognised that every possible artifice was employed by Buszek to maximise his chances of forming 4 from 5. 

Although lower-order cuprate reagents will often engage in displacement reactions with alkyl halides, such reactions are usually slow. They are generally much less facile than 1,4-addition reactions to a,P-unsaturated enones or enoates. The latter processes are particularly facile when trimethylsilyl chloride is employed as an additive. It was Corey and Boaz10 who first recognised the accelerating effect of trimethylsilyl chloride on cuprate addition reactions to a,p-unsaturated carbonyls. Buszek therefore capitalised on Corey s earlier observations in his reaction of 10 with lithium dimethylcuprate to obtain 15. 

A Kishi-Nozaki-Takai Ni(II)-Cr(II) coupling5 was next implemented between vinyl iodide 3 and aldehyde 2. This afforded a separable 1.5 1 mixture of the two diastereoisomers 1 and 21. Of particular note here was the superb chemoselectivity of this coupling, the labile lactones in 2, l and 21 all surviving intact from this critical C—C bond forming step. 

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. 

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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... 

Scheme 27 Influence of remote substrate substituents on RCM efficiency, observed during total synthesis of octalactin A (148) [81]...

Scheme 15 Synthesis of the vinylogous aldol segment of octalactin...

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]. 

Octalactin A, via ring-closing diene metathesis, 11, 230 Octamethylcyclotetrasiloxane, in polymerization, 3, 654 Octamethyl[3]ruthenocenophane, preparation, 6, 637... 

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. 

The Buszek (—)-octalactin A synthesis is notable for its useage of the Corey-Nicolaou thiopyridyl ester7 protocol for saturated eight-mem-bered lactone construction. Prior to this synthesis, no eight-membered lactone ring had ever been prepared in high yield from the cyclisation of a saturated hydroxy carboxylic acid precursor. This reaction therefore broke important new ground in the arena of complex natural product synthesis. 

The alkylation of intermediates 161 or 162 can be performed with allylic, propargylic and benzylic chlorides, as well as primary alkyl bromides and iodides. Some recent selected examples of monoalkylation of compound 161174 with the bromide 164 and the iodide 166 afforded products 165 and 167, respectively, which are intermediates in the synthesis of the marine natural products, octalactin A185 and leucascandrolide A186, respectively (Scheme 46). 

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>. 

A variation of the mixed-anhydride lactonization process was developed for the synthesis of lactone 107, an intermediate in the synthesis of octalactin B. In this case, 2-methyl-6-nitrobenzoic anhydride (MNBA) and a catalytic amount of DMAP are used and the reaction occurs at room temperature (Scheme 22) <2004TL543, 2005SL2851>. The yield of this transformation was increased to 90% by conducting the reaction in DCM and using 4-dimethylaminopyridine 1-oxide (DMAPO) instead of DMAP <2005CEJ6601>. 

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]. 

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. 

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