Natural product synthesis Spirotryprostatin

Heterocyclic natural products represent particular challenges to organic synthesis, because a building block system of standard reactions often fails. The five so far completed total syntheses of spirotryprostatin B (2, Figure 1) described below have been developed by leading groups in the field and outline the difficulties involved when dealing with heterocycles. 

During the final stages of the asymmetric total synthesis of antimitotic agents (+)- and (-)-spirotryprostatin B, the C8-C9 double bond had to be installed, and at the same time the carboxylic acid moiety removed from C8. R.M. Williams et al. found that the Kochi- and Suarez modified Hunsdiecker reaction using LTA or PIDA failed and eventually the Barton modification proved to be the only way to achieve this goal. After the introduction of the bromine substituent at C8, the C8-C9 double bond was formed by exposing the compound to sodium methoxide in methanol. This step not only accomplished the expected elimination but also epimerized the C12 position to afford the desired natural product as a 2 1 mixture of diastereomers at C12. The two diastereomers were easily separated by column chromatography. 

The spirooxindole system is the core unit of many natural products such as spirotryprostatin A, isopeteropodine, etc. Perumal and co-workers have developed a fast, clean and simple method for the synthesis of spirooxindoles and spiroindenoquinoxaline derivatives catalyzed by silica gel impregnated indium(in) chloride under solvent-free microwave irradiation (Scheme 5.36). 

Overman and Rosen [76] reported a total synthesis of spirotryprostatin B (137), a structurally novel diketopiperazine alkaloid, that featured a cascade Mizoroki-Heck cyclization/jj -allylpalladium capture process and the exploration of a related catalytic asymmetric sequence (Scheme 16.36). The plan was to relay the relative configurations of the quaternary stereocentre and the adjacent tertiary stereocentre in the natural product from the geometry of the trisubstimted alkene in the Mizoroki-Heck cyclization substrate. It was anticipated that the favoured 5-exo intramolecular Mizoroki-Heck cyclization of enantiopure triene precursor 135 would generate an -allylpalladium intermediate, with a chiral palladium catalyst controlling the absolute configuration of the initially formed quaternary carbon stereocentre. 

The use of Heck reactions of dienes for the construction of nitrogen heterocycles has been applied to an elegant synthesis of (—)-spirotryprostatin B [88]. As shown below (Eq. (1-49)), the intramolecular Heck reaction of 121 afforded the complex pentacycle 122, which was converted to the natural product after cleavage of the SEM protecting group. 

The method was next applied to the total synthesis of (-)-spirotryprostatin B (4) (Figure 9.2) and three stereoisomers. These diketopiperazine alkaloids inhibit G2/M phase progression of the mammalian cell cycle at micromolar concentrations [6, 17]. The natural product was obtained in 9% yield from readily available starting materials (methyl acrylate and 2-methyl-2-butenal) in 10 steps only. 

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