Cytochalasans scheme

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]. 

Antiparasitic activities have been demonstrated for cytochalasins B (1088), D (1091), E (1096), and for dihydrocytochalasin B, which inhibit growth and differentiation and influence excystation/encystation of the dimoeha. Entamoeba invadens (720). Cytochalasin B (1088) is able also to influence monosaccharide transport systems (721-725) and hormone release (726, 727). Moreover, in 1992, the antiviral cytochalasan L-696,474 (1139, Scheme 14.3) was discovered, exhibiting an inhibitory effect on HIV-1-protease (728-730). 

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. 

The macrocarbocyclic cytochalasan L-696,474 (1139) was also synthesized from tricyclic precursor 1124 following a similar strategy that involved also a Julia-Kocienski olefination for attachment of an aliphatic chain (Scheme 14.3). 

A different approach to cytochalasan natural products was investigated by Trost et al. and resulted in the total synthesis of the leucine-derived [lljcytochalasan, (—)-aspochalasin B (1176), in 1989 (755). The strategy consisted in synthesizing an isoindolone part and the utilization of a palladium-catalyzed formation of the 11-membered carbocycle (Scheme 14.7). 

The great structural similarity among the four basic types of cytochalasans known as present, i.e., the [11] cytochalasans, [13] cytochalasans, 24-oxa-[14]cytochalasans, and 21,23-dioxa-[13]cytochalasans, and the experimental evidence available, permit one to postulate a common biogenetic scheme for all cytochalasans. Such a scheme is shown in Fig. 15. The tricyclic systems, which result from the combination of the amino acid with a Ci6- or Cig-polyketide or a biogenetic equivalent, may be structures of a lower oxidation state. It also is unknown at what stage of the biogenetic sequence the introduction of the additional units takes place. 

It is evident that the final validity of this general biogenetic scheme requires additional experimental data, e.g., incorporation of tryptophan into the chaetoglobosins and cytochalasin G, isolation of intermediates of the biogenetic sequence, and discovery of new cytochalasans, possibly with the as yet unknown basic skeletons and structural elements derived from other natural amino acids. 

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