Spirotryprostatin

The tricyclic core of spirotryprostatin B can be formed via formation of the dihydropyrrole 325 <2000AGE4596>. Removal of the silyl protecting group of 322, followed by Dess-Martin oxidation, and reaction of the resultant aldehyde with the potassium salt of the diketopiperazine phosphonate 323 led to formation of the enamide 324. 

Subsequent Heck cyclization and trapping of the allylpalladium intermediate by the diketopiperazine nitrogen led to efficient formation of protected spirotryprostatin B 326 (Scheme 24). 

Spirotryprostatin B - diketopiperazine that inhibits mammaiian ceii cycie... 

Anaiogs of spirotryprostatins and fumitremorgin B were aiso isoiated... 

Compounds identified as cell cycle inhibitors are Trp-Pro DPK alkaloids isolated from the fungus Aspergillus fumigatus, namely, spirotryprostatin A and spirotryprostatin These compounds show potential as M-phase inhibitors of the mammalian cell cycle. ... 

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. 

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. 

In the alternative Mannich route to the spiro intermediate 14, the indole ring of 4 is oxidized first. The resulting oxoindoline 11 is then converted by treatment with senecialdehyde (5, prenal ) into a mixture of four diastereomers of compound 12, which are acetylated, as a mixture, to 14. The two total syntheses differ with respect to the formation of the diketopiperazine structure and the introduction of the C8-C9 double bond of spirotryprostatin B (2), with quite divergent overall yields. 

Scheme 1. Biomimetic syntheses of spirotryprostatin B (2), by Wang and Ganesan (2000) and by von Nussbaum and Danishefsky (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.

Fig. 2. Analogues of the spirotryprostatins from Danishefsky s synthetic program, with cytotoxicities 5000 times higher than those of the natural products.

The final step in a very brief synthesis of (-)-Spirotryprostatin B [Scheme 8.151] required the cleavage of an N-SEM group from a spiroindolone.340 After some experimentation, the N-SEM group was discharged in high yield by initial exposure to six equivalents of chlorodimethylalane followed by heating the resultant AMiydroxymethyl derivative with DIPEA in methanol to remove the unit of formaldehyde. 

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. 

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