Spirotryprostatins A and

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. ... 

More recently, the tryprostatins A and B [69], the spirotryprostatins A and B [70], and the cyclotryprostatins A-D [71] were isolated from Aspergillus fumigatus by Osada et al. and have been shown to be mammalian cell cycle inhibitors interfering with the cell cycle at the G2/M phase [72]. It should be noted that at least three different numbering systems have been used in the literature for this family of alkaloids and the numbering system adopted here is the one originally assigned by Yamazaki et al. [66] and most recently adopted by Osada et al. [69-71]. 

Cui CB, Kakeya H, Osada H. Novel mammalian cell cycle inhibitors, spirotryprostatins A and B, produced by Aspergillus fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron 1996 51 12651-12666. 

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). 

Home and co-workers showed in their S3mthesis of spirotryprostatin A that indole-2-chlorinated or -brominated tryptophan derivatives also imdergo a spiro-Pictet-Spengler condensation with participation of the indole 3-position [117, 118]. Imine formation with prenal proceeded quantitatively. However, acid-induced spirocyclisation afforded, as in the other syntheses of spirotryprostatins, a mixture of diastereomeric spiro products in only moderate yield. 

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

One particular skeleton belonging to this family is the heterocyclic spiroxindole framework (Figure 9.2), and different synthetic methods have been suggested to reach this polycyclic core [3]. The latter is the parent compound for a large number of natural products such as (-)-horsfiline (1) [4], elacomine (2) [5], and spirotryprostatin A (3) and B (4) [6], as well as drug candidates and clinical pharmaceuticals [7]. The... 

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. 

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. 

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... 

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. 

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. 

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