Spirotryprostatins total synthesis

Azomethine ylides derived from (55,6/ )-2,3,5,6-tetrahydro-5,6-diphenyl-1,4-oxazin-2-one (53) and various aldehydes have been prepared by Williams and co-workers (87,88) (Scheme 12.19). In a recent communication they reported the application of the azomethine ylide 54 in the asymmetric total synthesis of spirotryprostatin B 56 (88). The azomethine ylide 54 is preferentially formed with ( )-geometry due to the buLkiness of the aldehyde substituent. The in situ formed azomethine ylide 54 reacted with ethyl oxindolylidene acetate to give the 1,3-dipolar cycloaddition adduct 55 in 82% yield as the sole isomer. This reaction, which sets four contiguous stereogenic centers, constmcts the entire prenylated tryprophyl moiety of spirotryprostatin B (56), in a single step. 

Scheme 2. Total synthesis of spirotryprostatin B (2) by Sebahar and Williams (2000).

A domino total synthesis of spirotryprostatin B (2) and three of its isomers has been published by Overman and Rosen, who apply two sequential palladium-catalyzed reactions (one-pot) to assemble the two spiro-fused rings [10] (Scheme 3). This work again makes it clear that complex heterocyclic systems may represent a harder challenge to synthetic... 

Scheme 3. Total synthesis of spirotryprostatin B (2) by Overman and Rosen (2000). The products 30, 31, 36, and 37 are deprotected with Me2AICI/ Pr2NEt in 90-95% yields.

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 total synthesis of spirotryprostatin B was accomplished by K. Fuji et al using an asymmetric nitroolefination to establish the quaternary stereocenter." The conversion of the nitroolefin to the corresponding aldehyde was carried out under reductive conditions using excess titanium(lll) chloride in aqueous solution. The initially formed aldehyde oxime was hydrolyzed in situ by the excess ammonium acetate. 

Edmondson S, Danishefsky SJ, Sepp-Lorenzino L, Rosen N (1999) Total synthesis of spirotryprostatin A, leading to the discovery of some biologically promising analogues. J Am Chem Soc 121 2147-2155... 

Ganesan et al. reported the total synthesis of the cell cycle inhibitor (-)-spirotryprostatin B (622) in 2000 (411). Their synthesis started with L-tryptophan methyl ester 616, which was treated with senecialdehyde to give imine 617. The indole derivative reacted in a iV-acyl-iminium Pictet-Spengler condensation to yield the tetrahydro-p-carboline derivative 618 (412) (Scheme 10.2). 

Wang H, Ganesan A (2000) A Biomimetic Total Synthesis of (-)-Spirotryprostatin B and Related Studies. J Org Chem 65 4685... 

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. 

Sebahar, P.R. et al.. Asymmetric, stereocontroUed total synthesis of (+) and (-)-spirotryprostatin B via a diastereoselective azomethine ybde [l,3]-dipolar cycloaddition reaction. Tetrahedron, 58, 6311, 2002. 

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. 

Oyerman, L. E., Rosen, M. D. (2000). Total synthesis of (—)-Spirotryprostatin B and three stereoisomers. Angewandte Chemie International Edition, 39, 4596-4599. 

Spirotryprostatin A 142 and B 143 are two powerfully bioactive indole alkaloids. Both compounds inhibit the cell cycle in the G2/M phase, and 143 shows cytotoxic activity on the growth of human leukemia cell lines. Meyers and Carreira reported a total synthesis of 143. The Kocienski modified Julia olefmation was used in the formation of trisubstituted olefin without scrambling at Ci8. The alkene 146 was prepared in 78% yield by reacting sulfone 145 with aldehyde 144. The final product 143 was obtained by four-step reaction from the intermediate 146. 

The spirocyclic oxindole core structure was constructed by an asymmetric 1,3-dipolar cycloaddition in the total synthesis of (—)-spirotryprostatin B. A reaction of oxazi-none 137 with aldehyde 138 and oxindole 139 resulted in spirooxindole 141 via the chiral azomethine yhde 140, simultaneously creating three bonds and four stereogenic centers in one step (Scheme 16.20). ... 

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. 

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