Macrosphelides, synthesis

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. 

Matsuya, Y. and Nemoto, H. (2005) Recent advances in macrosphelide synthesis. Heterocycles, 65,1741-1749. 

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. 

An example of the efficient formation of an electron-deficient double bond by RCM was disclosed by a Japanese group in a novel total synthesis of the macrosphelides A (209) and B (208) (Scheme 41) [100]. When the PMB-pro-tected compound 204 was examined as a metathesis substrate, the ring closure did not proceed at all in dichloromethane using catalysts A or C. When the reaction was carried out using equimolar amounts of catalyst C in refluxing 1,2-dichloroethane, the cyclized product 205 was obtained in 65% yield after 5 days. On the other hand, the free allylic alcohol 206 reacted smoothly at room temperature leading to the desired macrocycle 207 in improved yield. 

The unified highly convergent total and formal syntheses of ( + )-macro-sphelides B (441 X = O) and A (441 X = a-OH, p-H), respectively, have been described (483). Key features of the syntheses include the concise synthesis of the optically active S-hydroxy-y-keto a, 3-unsaturated acid fragment 442 via the direct addition of a fra/i.s-vinylogous ester anion equivalent to a readily available Weinreb amide, and the facile construction of the 16-membered macrolide core of the macrosphelide series via an INOC. 

INOC was successfully employed in the total synthesis of the 16-membered macrolactone (+)-macrosphelide B 53. Interestingly, the cycloaddition of nitrile oxide generated in situ from 51 was more stereoselective in dioxane than in CH2CI2 (dr 10 1 vs 2 1). The major isomer was then converted into 53 by reductive N-0 bond cleavage, dehydration and MEM deprotection <05OL3159>. 

The macrosphelides were isolated in the mid-1990s and found to inhibit cell-adhesion [35], bringing these natural products into the chemical biology spotlight Takahashi and coworkers reported a combinatorial synthesis of 122 macrosphelides, including the natural ones based on two palladium-catalyzed chemoselective carbonylations of vinyl halide, first in an intermolecular fashion and then in a... 

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 10.11 Molecular diversity design of macrosphelide analogs by a solid-phase combinatorial synthesis utilizing palladium-catalyzed carbonylation. Copyright 2006 Taylor Francis Group, LLC... 

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

Takahashi, T. et al., A combinatorial synthesis of a macrosphelide library utilizing a palladium-catalyzed carbonylation on a polymer support, Angew. Chem., Int. Ed. Engl, 42, 5230, 2003. 

Nicolaou, K.C. et al.. Designed epothilones combinatorial synthesis, tubuhn assembly properties, and cytotoxic action against Taxol-resistant tumor cells, Angew. Chem. Int. Ed. Engl, 36, 2097, 1997. Fukami, A. et al., Macrosphelide B suppressed metastasis through inhibition of adhesion of sLe /E-selectin molecules, Biochem. Biophys. Res. Commun., 291, 1065, 2002. 

Carbonylative macrolactonization is also possible. Takahashi and coworkers successfully prepared a library of macrosphelide targets using solid phase synthesis under Pd(0) catalysis (Scheme 2.5). By using the split-and-pool technique, 122 compounds were synthesized [15]. 

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). 

Owing to the reliability and versatility of this reagent, it has been extensively utilized in the synthesis of complex natural products and some of the very recent examples include sominone 29, lauli-malide 30, macrosphelide 31, bryostatin 32, superstolide 33, hyptolide 34, and so on (Figure 25.4). ... 

Chemoselective carbonylation of a vinyl iodide 34 with alcohol containing a vinyl bromide moiety 35 has been successfully employed for the solid-phase synthesis of a macrosphelide precursor 36 [43]. After the 4-methoxyphenylmethyl (MPM) group was removed, the palladium-catalyzed carbonylative macrolactonization of the vinyl bromide 37 achieved the synthesis of the macrosphelide-supported derivative 38 (Scheme 9.13). The combinatorial synthesis of a 122-member macrosphelide library has been performed by the three-component strategy based on the palladium-catalyzed chemoselective carbonylation/macrolactonization reaction. 

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

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