Spirotryprostatin 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. 

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. 

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.

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. 

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). 

Due to the presence of these resonance forms in azomethine ylids, reaction with alkenes often leads to mixtures of regioisomeric cycloadducts. Resonance stabilizing substituents are usually employed to enhance the regioselectivity. Intramolecular reactions usually favor only one mode of addition. An example of an intermolecular reaction is taken from Williams synthesis of spirotryprostatin B,372 in which 5,6-diphenylmor-pholin-2-one (473) reacted with the aldehyde shown to give a mixture of ( )- and (Z)-azomethine ylids (474). This product was generated in situ with oxindole 475, and [3-i-2]-cycloaddition product 476 was obtained in 82% yield. 

The key step of the synthesis of spirotryprostatin B (133) by Trost and Stiles is an enantioselective Pd-catalysed decarboxylation-allylation reaction starting from the prenyl p-oxoester 145, which serves as a pre-nucleophile (Scheme 29) [124]. 

Use ofenamine or iminium electrophiles. In their synthesis of spirotryprostatin B (133), Fuji and co-workers started from rac-3-prenyl-2-oxindole (149) with an interesting enantioconvergent nitroolefination affording the C3-quatemised product 151 ee 78%, Scheme 30). The proline-derived nitroenamine 150 was used with the pyrrolidine section functioning as auxiliary [135, 136]. 

Scheme 30 Enantioconvergent step of Fuji s synthesis of spirotryprostatin B (133) [135]...

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 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. 

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