Cytochalasans synthesis

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

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. 

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. 

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... 

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

Thomas EJ, Whitehead JWF (1989) Cytochalasan Synthesis Total Synthesis of the Naturally Occmring [13]Cytochalasan Proxiphomin. J Chtan Soc Perkin Trans 1 499... 

Thomas EJ, Whitehead JWF (1986) Cytochalasan Synthesis Synthesis of an [11]-Memhered Ring Precursor of Cytochalasin H. J Chem Soc Chem Commun 724... 

Sauter R, Thomas EJ, Watts JP (1989) Cytochalasan Synthesis An Alternative Approach to Cytochalasin R J Chem Soc Perkin Trans 1 519... 

Dyke R Sauter R, Steel P, Thomas EJ (1986) Cytochalasan Synthesis Total Synthesis of Cytochalasin G. J Chem Soc Chtan Commun 1447... 

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],... 

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. 

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. 

In the late 1980s, the number of total syntheses for these compounds showed an upswing, and several were reported by Thomas et al., who accomplished the preparation of cytochalasins H (1099), D (1091), G (1098), and O (1160), following their Diels-Alder strategy for the stereoselective synthesis of many of the cytochalasan cores. 

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. 

Proxiphomin was the first [13]cytochalasan to be synthesized (745, 746). This synthesis was carried out by Thomas and Whitehead in 1985, after which several other cytochalasan syntheses followed using the same approach (intramolecular Diels-Alder reaction). In the next sections, the syntheses of cytochalasin H (1099) and G (1098) are outlined in detail. 

The first total synthesis of a tryptophan-derived cytochalasan - cytochalasin G (1098) - was accomplished in 1986 by Thomas and co-workers 751, 752). The same strategy as for cytochalasin H (1099), an intramolecular reaction,... 

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). 

Vedejs E, Reid JG (1984) Total Synthesis of Carbocyclic Cytochalasans. J Am Chem Soc 106 4617... 

Tapolczay DJ, Thomas EJ, Whitehead JWF (1985) Total Synthesis of Proxiphranin, a Natiually Occuring [13]Cytochalasan. H. J Chtan Soc Chem Cmnmun 143... 

This volume represents an excellent account of the biosynthesis of the mycotoxins. Dr. Steyn, himself an internationally accepted authority on the subject, has been able to persuade an outstanding group of authors to contribute chapters. This book will not only be the standard reference work for anyone concerned with mycotoxins, but it will also inspire a lot of challenging synthetic chemistry. Recent progress in the synthesis of the cytochalasans admirably illustrates this point. 

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