Cytochalasanes

Thomas E. J. Cytochalasan Synthesis Macrocycle Formation Via Intramolecular Diels-Alder Reactions Acc. Chem. Res. 1991 24 229 235... 

Sekita S, Yoshihira K, Natori S, Kuwano H, Structures of chaetoglobosins C, D, E, and F, cytotoxic indol-3-yl-[13]cytochalasans from Chaetomium globosum, Tetrahedron Lett 1351—1354, 1976. 

Zhou GX, Wijeratne EMK, Bigelow D, Pierson III LS, VanEtten HD, Gunatilaka AAL, Aspochalasins I, J, and K Three new cytotoxic cytochalasans of Aspergillus flavipes from the rhizosphere of Ericameria laricifolia of the Sonoran desert, J Nat Prod 67 328—332, 2004. 

Numata, A. Takahashi, C. Ito, Y. Minoura, K. Yamada, T. et al. (1996) Penochalasins, a novel class of cytotoxic cytochalasans from a Penicillium species separated from a marine alga. J. Ch n. Soc., Perkin Trans. 1, 239-45. 

The heterocycle 43 was needed as an intermediate in a cytochalasan synthesis.10 Disconnection of the 1,3-diCO relationship between the two ketones reveals the amide 44 that is the acetoacetyl derivative of phenylalanine ethyl ester 45. 

Finally, a thia Diels-Alder reaction representing a less common cycloaddition type in natural product synthesis shall be discussed. Thus, Vedejs et al. have included such a cycloaddition into an elegant strategy aimed at the synthesis of macrocyclic [ll]-cytochalasans such as zygosporin E 7-76 [536-538]. Thus, release of the thioaldehyde 7-73 from its phenacyl sulfide precursor in the presence of the silyloxydiene 7-74 yielded 7-75 as 2 1 mixture with its C20 epimer. Fortunately, equilibration of this mixture raised the ratio up to 10 1. Several subsequent steps yielded the tetracyclic intermediate 7-77 cleavage of its thioether moiety then liberated the 11-membered macrocycle present e.g. in zygosporin E 7-76 (Fig. 7-16). 

The sulfide bridge in medium sized rings can be used in stereocontrolled syntheses of complex molecules [65], (Chapter IX. 1), for example the synthesis of zygosporin E [66] and the synthesis of cytochalasans [67],... 

Pericyclic reactions were used successfully, too, to build up macrocycHc ring systems as found, for example, in natural peptides and peptide alkaloids. These reactions are carried out in general at moderate dilution conditions (10 -10 M). An example of a Diels-Alder reaction is the cyclization of 106 to 107, where the basic framework of cytochalasane B (108), a substance found in fungi, is built up in yet 27% yield [79]. 

Intramolecular Diels-Alder reaction can be used as a macrocyclization means. Thomas and Whitehead [167] apphed this approach to the synthesis of the 13-membered cytochalasan proxiphomin (280). As shown in Scheme 94, the long chain precursor 278 was heated in toluene at 100 °C for 5 h to give the 13-membered skeleton 279 and the endo adduct (52 48) in 52% yield. There are several other examples of the application of intramolecular Diels-Alder reaction to the synthesis of macrocyclic natural products [168]. 

In connection with the synthesis of cytochalasans, electrophilic selenylation of cycloalkenyl silanes provided exclusively the selenides with the endocyclic double bond. Treatment of the selenides with oxidizing agents (periodate, 3-chloroperbenzoic acid) resulted in the formation of allylic alcohols with the CO bonding at the less hindered /l-alkene face33 - 35. The methylthio group in the molecule is not oxidized under the conditions used for the oxidation of the selenide. 

The foregoing methods have been successfully applied to the synthesis of carbocyclic cytochalasans and the macrolide methynolide (191 equation 22). Iterative ring expansion of the five- and eight-mem-bered ring sulfonium salts (187) and (189) leads to the 11-membered ring sulfur heterocycle (190). Sulfonium salt (189) is a 1 1 mixture of stereoisomers that gives (190) with 16 1 selectivity in 76% yield. 

Harkin, S.A., Singh, O., and Thomas, E.J., Approaches to cytochalasan synthesis. Preparation and Diels-Alder reactions of 3-alkyl- and 3-acyl-A -pyrrolin-2-ones, J. Chem. Soc., Perkin Trans. 1, 1489, 1984. 

Schmidlin, T., and Tamm, C.. Approaches to the total synthesis of cytochalasans. A convergent synthesis of the octahydroisoindolone moiety related to proxiphomin, Helv. Chim. Acta, 61, 2096, 1978. 

G. S. Pendse, Recent Advances in Cytochalasans] Chapman Hall London, 1986 pp ix, 191p. 

Heterocyclic compound (24), an intermediate in a cytochalasan synthesis can be made from (25) by a 1.3-dicarbonyl route. Amide (25) is an acetoacetyi derivative of the naturally occurring artf.no acid phenylalanine (26) so this is a... 

Cytochalasin G, the major active component of the culture filtrate of an unidentified Nigrosabulum species," has the structure (18) other indole metabolites in the culture filtrate have not yet been investigated. Cytochalasin G is the first example of an [ll]-cytochalasan containing a 10-(indol-3-yl) group. 

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