Macrocyclic cytochalasans

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

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). 

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]. 

A whole series of cytochalasans was identified from the same raw material, including three new ones penochalasins A (131 a colorless needle extraction yield 0.7 mg/ml), B (132 a colorless powder 0.4 mg/ml) and C (133 a colorless powder 0.2 mg/ml). The other two compounds isolated were already known chaetoglobosins A (134 0.5 mg/ml) and F (137 0.4 mg/ml). The stereostructure was determined on the basis of NMR studies and chemical transformations. Cytochalasins are highly substituted perhydroisoindol-l-one fused with a macrocyclic (a carbocycle, lactone or carbonate). Penochalasins constitute a novel class of... 

Structural characteristics of the cytochalasans include a highly substituted, fully hydrogenated and conserved isoindolone core, which is fused to a 11- to 16-membered macrocyclic ring - typically a carbocycle, a lactone, or a cyclic carbonate. The nitrogen atom of the perhydroisoindolone moiety results from... 

Fig. 14.2 Systematic nomenclature of the cytochalasan scaffold, where R derives from the incorporated amino acid and the number in brackets designates the size of the macrocycle...

Cytochalasin B (1088) belongs to the [14]cytochalasan group and was isolated from Helminthosporium dematioideum (696) and Phoma S298 (695). Its first total synthesis was accomplished by Stork et al. in 1978 (740). Later, this group published a more simplified synthesis, utilizing an intramolecular Diels-Alder reaction as the key step, forming both perhydroisoindolone and the macrocyclic moiety in a single reaction (741). 

In 2004, Myers and Haidle reported a convergent and modular total synthesis of cytochalasin B (1088) and the [lljcytochalasan L-696,474 (1139) (742), using a late-stage macrocyclization step involving an intramolecular Horner-Wadsworth-Emmons olefination. Their strategy is applicable for the synthesis of cytochalasans of different ring sizes, as exemplified by these two total syntheses. Both macrolactone and macrocarbocyclic cytochalasans can lead back retrosyntheticaUy to the same precursors. The synthesis of the tricyclic isoindolone precursor to cytochalasin B (1088) and L-696,474 (1139) is shown in Scheme 14.1. 

Thomas, EJ (1991) Cytochalasan Synthesis Macrocycle Formation vm Intramolecular Alder Reactions. Acc Chem Res 24 229... 

The past year has seen a number of applications of the intramolecular variant of the Diels-Alder reaction (see ref. 1). Two independent approaches to the synthetically challenging cytochalasans, e.g. (133), both utilize an intramolecular Diels-Alder cycloaddition, in one case simultaneously to assemble the macrocycle and six-membered ring, (131) (132), and in the other case to construct... 

Chemically, the cytochalasans are characterized by a highly substituted perhydroisoindolone group, to which is fused a macrocyclic ring which is either carbocyclic, a lactone, or a cyclic carbonate. Four types of naturally occurring basic skeletons are known (see Fig. 1) (1) [1 Ijcytochalasans (2) [13]cytochalasans (3) 24-Oxa-[14]cytochalasans and (4) 21,23-Dioxa-[13]cytochalasans. In the majority of the metabolites, in 20 compounds, the macrocyclic ring contains only carbon atoms. Three cytochalasans are macrolides (24-oxa-[14]cytochalasans), and only one is a diester of carbonic... 

The configuration of the isoindolole part of all cytochalasans is identical. This is also true for those sections of the macrocyclic system which possess identical structures. There are only two exceptions. The stereochemistry at C(18) of cytochalasin H and J is different from that established for the same functionality in other closely related cytochalasins, e.g., cytochalasin D. 

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