CD-spiroacetal

Hie Ci -C28 fragment of spongistatin 1, comprising the CD-spiroacetal 5, exhibits an axial equatorial disposition of the two acetal oxygen atoms and hence, unlike the A B-spiroacctal system, benefits from only one stabilising anomcric effect (Figure 4). 

The kinetic control approach to constructing the CD-spiroacetal segment envisaged a hetero-Michael cyclisation of the dihydropyrone 28 (derived from 26 by sequential oxidation to the P-diketone, PMB removal and cyclisation to provide the D-ring), where axial attack might be favoured (Scheme 7). In practice, treatment of 28 with DBU led to installation of the C-ring via hetero-Michael reaction, with a small preference (60 40) for formation of the desired spiroacetal 29 over 30. Despite the modest selectivity observed in this mode of spiroacetal formation, the endeavour highlighted an important new means for... 

The desired spiroacetal 36 was converted to the TBS ether and the terminal alkene moiety was elaborated to the corresponding ethyl ketone in four steps, to provide the fully-functionalised CD-spiroacetal ketone 5, now ready for aldol union with the AB-spiroacetal aldehyde 4. This route was found to be highly scalable, enabling production of multi-gram quantities of the desired C16-C28 fragment 5 with little need to repeat the synthetic sequence. 

The CD-spiroacetal subunit of the spongistatins proved to be of an appropriate level of complexity that several different synthetic strategies were evaluated. Access to the desired spiroacetal 5 was readily achieved by acid catalysed equilibration of the mixture of spiroacetals in aprotic solvents, followed by separation and recycling of the undesired isomer. Furthermore, the 1,5-anti aldol reaction of methyl ketones proved invaluable for construction of certain portions of the target molecule. 

Smith and coworkers have used a Ca(II)-mediated equilibration strategy to access the singly anomeric CD spiroacetal of spongistatin-1, 15 [26] (Scheme 5). Oxidative removal of the dithiane 11 and subsequent spirocyclization afforded spiroacetals 12a and 12b in excellent yield, favoring the undesired doubly anomeric... 

Paterson, I., Wallace, D.J., and Gibson, K.R. (1997) Studies in marine macrolide synthesis synthesis of a C16-C28 subunit of spongistatin 1 (altohyrtin A) incorporating the CD-spiroacetal moiety. Tetrahedron Lett., 38, 8911-8914. 

Terauchi, T, Terauchi, T, Sato, L, Tsukada, T, Kanoh, N., and Nakata, M. (2000) Synthetic studies on altohyrtins (spongistatins) synthesis of the C15-C28 (CD) spiroacetal portion. Tetrahedron Lett., 41, 2649-2653. 

Paterson, 1. and Coster, M.J. (2002) Total synthesis of altohyrtin A (spongistatin 1) an alternative synthesis of the CD- spiroacetal subunit C16-C28. Tetrahedron Lett., 43,3285-3289. 

Flowers, C.L. and Vogel, P. (2010) Short diastereoselective synthesis of the C1-C13 (AB spiroacetal) and C17-C28 fragments (CD spiroacetal) of spongistatin 1 and 2 through double chain-elongation reactions. Chem. Eur. J., 16,14074-14082. 

Their structures were mainly determined by spectral studies using EI-MS, IR, H-NMR, NOE, and CD spectra (75). They consist of a main spiroether moiety, corresponding to 1-oxaspiro[5. 5]undec-4-ene-8-one ring system, (including seven asymmetric centers and possessing a (Z)-olefin, a mefa-substituted phenol, and a P-ketocarboxylic acid functions) and a P-hydroxy-y-lactone moiety. Oscillatoxin Ds are present as esters of both moieties. On the other hand, aplysiatoxins are present as macro bis-lactones including a spiroacetal. We are interested in the relationship between oscillatoxins and aplysiatoxins from a biosynthetic point of view. 

Jacobs, M.F., Glenn, M.P., McGrath, M.J., Zhang, H., Brereton, L, and Kitching, W. (2001) Stereoselective synthesis and stereochemistry of seven isomeric spiroacetal structures based on the C17-C28 fragment (CD rings) of spongistatin 1. ARKIVOC, 114-137. 

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