Synthesis of Macrosphelide

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

Scheme 21.5 Solid phase synthesis of macrosphelides (Takahashi et ai.)...

Synthesis of macrosphelides, natural potent cell-cell adhesion inhibitors having novel three ester linkages in their 16-membered macrocyclic skeleton 05H(65)1741, 05Y140. 

A combinatorial synthesis of macrosphelide analogs was carried out using a split-and-mix method using RF tags. Based upon 4 A units, 4 B units, and 8 C units, a 128-member library was possible (Scheme 10.11 and Scheme 10.13). The crude products obtained by cleavage from the polymer support were purified by automated reversed-phase preparative HPLC gave 122 products (0.2 to 1.5 mg from 30 mg of DHP resin 27) and included macrosphelides A, C, E, and F. 

SCHEME 10.13 A combinatorial synthesis of macrosphelide analogs using a split-and-mix method. 

FIGURE 11.20 Combinatorial synthesis of macrosphelide analogs. (From Takahashi, T. et al., Combinatorial synthesis of a macrosphelide library utilizing a palladium-catalyzed carbonylation on a polymer support, Angew. Chem. Int. Ed. Engl, 42, 5230, 2003.)... 

Sharma and Mouli [111] reported a carbohydrate-based approach for the synthesis of macrosphelides A 178 and E 179 from alcohol 195 and acids 199/199a. Diol... 

Macrosphelide M 191 is a 15-membered macrolide, whose absolute stereochemistry was reported by Yamada et al. based on spectroscopic analysis and some chemical transformations. Sharma and Reddy [114] reported a carbohydrate-based total synthesis of macrosphelide M 191, from diacetone glucose, adopting macrocyclization through RCM (Scheme 6.41 and Scheme 6.42). 

Scheme 7 Synthesis of Macrosphelide A on solid phase using Pd-catalyzed carbonylations...

SCHEME 34.9. Sharpless KR epoxidation step in the synthesis of macrosphelide A 31. 

Sunazaka T, Hirose T, Harigaya Y, Takamatsu S, Hayashi M, Komiyama K, Omura S. Relative and absolute stereochemistries and total synthesis of (+)-macrosphelides A and B, potent, orally bioavailable inhibitors of cell-cell adhesion. J. Am. Chem. Soc. 1997 19 10247 10248. 

Chakraborty TK, Purkait S, Das S. Synthesis of chiral 4-hydroxy-2,3-unsaturated carbonyl compounds from 3,4-epoxy alcohols by oxidation appHcation in the formal synthesis of macrosphelide A. Tetrahedron 2003 59 9127 9135. 

Sharma, G.V.M. and Mouli, C.C. (2002) The total synthesis of macrosphelides A and E from carbohydrate precursors. Tetrahedron Lett., 43, 9159-9161. 

Kawaguchi, T., Funamori, N., Matsuya, Y, and Nemoto, H. (2004) Total synthesis of macrosphelides A, B, and E first application of ring-dosing metathesis for macrosphelide synthesis. J. Org. Chem., 69, 505-509. 

Sunazuka, T., Hirose, T., Chikaraishi, N., Harigaya, Y., Hayashi, M., Komiyama, K., Sprengeler, P.A., Smith, A.B., and Omura, S. (2005) Absolute stereochemistries and total synthesis of ( )-macrosphelides, potent, orally bioavailable inhibitors of cell-cell adhesion. Tetrahedron, 61, 3789-3803. 

Matsuya, Y, Hori, A., Kawamura, T, Eman, H.F., Ahmed, K., Yu, D.-Y, Kondo, T, Toyooka, N., and Nemoto, H. (2010) Synthesis of macrosphelides containing a heterocyclic side chain as a novel apoptosis inducer. Heterocydes, 80, 579-591. 

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