Total Synthesis of Cytochalasin

Diels-Alder precursor 1143 was accessible from aldehyde 1140, dienylpho-sphonate 1141, and benzoyl pyrrolidinone 1142 in 18 steps. Elimination of the phenylselenyl group generated a double bond, which was subjected to an intramolecular, diastereoselective Diels-Alder reaction at elevated temperatures to yield 

In addition, the same research group conducted an alternative approach to cytochalasin H (1099) by formal synthesis. For this purpose, they prepared a phenylalanine analogue of cytochalasin G (1098) and treated it with a rf ihy -Grignard reagent to yield a key intermediate for the c34ochalasin H (1099) synthesis (750). 

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Stork, G., and Nakamura, E., A simplified total synthesis of cytochalasins via an intramolecular Diels-Alder reaction, 7. Am. Chem. Soc., 105, 5510, 1983. 

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. 

Scheme 14.2 Total synthesis of cytochalasin B (1088), starting Iran precursor 1124. Reagents and conditions a) dimethyldioxirane, acetone, rt, quant. b) trifluOToacetic acid, CH2CI2, 0°C ...

In 1990, Merifield and Thomas reported a total synthesis of cytochalasin D (1091) (755, 754). Some years later, they also achieved the total synthesis of cytochalasin O (1160) by functionalization of a late-stage intermediate of cytochalasin D (1091) (754). These syntheses proceeded similarly to the above-described syntheses of cytochalasins H (1099) (Scheme 14.4) and G (1098) (Scheme 14.5), in utilizing a Diels-Alder reaction to form the tricychc core. Therefore, only the total synthesis of cytochalasin O (1160), structurally characterized by the presence of a sy/i-diol moiety, is described in the following scheme starting from Diels-Alder product 1155 (Scheme 14.6). 

Scheme 14.6 Total synthesis of cytochalasin O (1160), starting from Diels-Alder product 1155. Reagents and conditions a) OSO4, pyridine, —20°C, 69% b) 2,2-dunethoxypropane, p-toluenesulfonic acid, CHQ3, rt c) LDA, PhSeCl, THF, —35°C, 52% over two steps d) NaOH, MeOH (aq.), rt e) H2O2 (aq.), pyridine, CH2CI2, rt, 88% over two steps f) NaBIl, CeCls H2O, MeOH, 10°C, 98% g) Ac O, NEts, DMAP, CH2CI2, rt, 81% h) p-toluenesulfonic acid, MeOH, rt, 74% i) oxalyl chloride, DMSO, NEtj, CH2CI2, -60 C to rt, 66% j) HCl (aq.), MeOH, reflux, 78%...

Stork G, Nakamura J (1983) A Simplified Total Synthesis of Cytochalasins via an Intramolecular Diels-Alder Reaction. J Am Chem Soc 105 5510... 

Thomas EJ, Whitehead JWF (1986) Cytochalasan Synthesis Total Synthesis of Cytochalasin H. J Chem Soc Chem Commun 727... 

Merifield E, Thomas EJ (1999) Total Synthesis of Cytochalasin D Total Synthesis and Full Structural Assignment of Cytochalasin O. J Chem Soc Perkin Trans 1 3269... 

Vedejs and Ahmad have used this Sml2-promoted macrocyclization technique as a key step in the total synthesis of a cytochalasin (equation 56). In this reaction, the 11-membered ring product is isolated in... 

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 second high point in this area during 1978 has been the total synthesis of the naturally occurring cytostatic substance cytochalasin B (13), by Stork et al In this synthesis the isolated stereocentres [A, B, and C in structure (13)] were derived from three distinct optically active starting materials [(+)-citronellol. 

Thus, (2R)-pumiliotoxin C (214) has been prepared from (R)-norvaline (212). The asymmetric center in the triene (213) controls the configuration at three carbon atoms 210). a-Kainic acid, isolated from the algae Digena simplex and Centrocerus clavulatum, was prepared by total synthesis. Its enantioselective synthesis involved a stereocon trolled intramolecular cycloaddition of a (S)-glutamic acid211). Asymmetric cycloadditions also play a decisive role in the synthesis of chiral cytochalasins. In this case 212> the primary chiral information was carried by (S)-alanine and (S)-phenylalanine, respectively. 

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. 

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