Synthesis octalactin

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...

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. 

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). 

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>. 

Having streamlined the synthesis of acyl chloride 54, the indirect preparation of methyl enol ester 51a was addressed. As previously discussed, attempts to synthesize 53a from formyl Meldrum s acid 58 had proven unsuccessful. However, Cossy and coworkers have reported the preparation of 53a via the ozonolysis of alkene 82 and subsequent use of the crude aldehyde in the total synthesis of octalactin. Thus, methyl vinyl acetate (82) was subjected to ozonolysis at —78 °C, followed by a reductive quench to provide formyl acetate 53a (Scheme 24). The crude methyl formyl acetate was acylated with acyl chloride 54, using the previously optimized conditions, to afford methyl enol ester 51a in 74% yield over two steps. This modification to the synthesis removes a further two reactions from the sequence with a formal synthesis of (—)-7-deoxyloganin (24) now achieved in 10 steps, a length more in keeping with the complexity of this target. 

Other applications of the Mitsunobu/RCM approach are shown in the figure below. The respective arrows indicate the use of the Mitsunobu reaction to prepare the acyclic precixrsor and the olefin formed in the ringclosing metathesis reaction. The first example shows an advanced intermediate (58) in the preparation of octalactin ketone. McLeod and coworkers employed a Mitsunobu reaction to set up an ROM precursor for the preparation of a key intermediate (59) for the synthesis of (-)-dactylolide. An alternative approach towards (+)-zampanolide and (+)-dactylolide was taken by Smith et al., their approach, which is not shown, attached a diethylphosphonacetic acid moiety to an alcohol via a Mitsunobu reaction and yielded the desired macrocycle after deprotonation and reaction with a pendant aldehyde via an intramolecular olefination reaction. ... 

Hulme accomplished the model synthesis of the octalactin eight-membered ring system possessing a side chain by the Evans-Tishchenko intramolecular cyclization using the Sm(lll) reagent (Scheme 5.24) [70]. This unique strategy for accessing the... 

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... 

As an application of the stereoselective synthesis of anti-aldol adducts, the asymmetric total synthesis of octalactins, peculiar eight-membered polyketides, was accomplished starting from these chiral templates generated by enantioselective aldol reaction using Sn(II) catalysts (Scheme 10.44) [68]. Details of the asymmetric... 

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. 

Dinh, M.-T, Bouzbouz, S., Peglion, J.-L., and Cossy, (. (2008) Synthetic efforts toward the synthesis of octalactins. Tetrahedron, 64, 5703-5710. 

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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