Total Synthesis of Tryprostatins A and B

Abstract

Multiple-drug resistance toward cell-cycle inhibitors frequently becomes an obstacle in cancer chemotherapy. One strategy for circumventing this problem is to develop antimitotic agents that operate by a new mode of action. Two such compounds, tryprostatins A and B, were isolated in 1995 from the fermentation broth of Aspergillus fumigatus BM939 by Osada and co-workers.[1] Tryprostatin A holds great promise, because it selectively arrests the cell cycle at the mitotic phase in tsFT210 cells.[2] Interesting biological activity combined with an apparently simple structure has stimulated the synthetic community, and several total syntheses have already been reported. [3,4] Our research group has long been involved with the radical-mediated construction of a variety of indole cores and the application of these methods to natural product synthesis. [5,6] We envisioned that our method could also be applied to the synthesis of the 2,3-disubstituted indole moiety of the tryprostatins. The interesting structural features as well as the therapeutic potential of tryprostatin A analogues indicated in a recent structure-activity-relationship study [4e] prompted us to launch a program toward the synthesis of tryprostatins.We reasoned that radical-mediated cyclization and subsequent palladium-mediated coupling with a prenyl-group donor would enable facile construction of the 2,3-disubstituted indole core structure 3 (Scheme 1). The requisite orthoalkenyl isocyanide 4 would be prepared from the alkyne 5, which in turn could be accessed by Sonogashira coupling of the aromatic iodide 6 with the terminal alkyne 7. To enable synthesis of the target compounds with high enantiomeric purity, the alkyne 7 derived from the Garner aldehyde (8) [7] was employed as a latent amino acid unit to be incorporated into the diketopiperazine.Initially, we focused our efforts on the synthesis of the isocyanide 12 as a radical-cyclization precursor (Scheme 2). The alkyne 7 was prepared from 8 according to the known protocol [8] with a slight modification. After the Sonogashira coupling between 7 and 2-iodoformanilide (9), partial reduction of the triple bond was examined. Whereas the use of the Lindlar catalyst, Pd/C, nickel boride, [9] or diimide [10] resulted in no reaction or overreduction, treatment with Zn/LiCuBr 2 in ethanol [11] gave the desired product 11 along with the corresponding amine. The use of 2,2,2-trifluoroethanol [12] as the solvent suppressed the undesired solvolysis and improved the yield of 11 to 99 %. Subsequent dehydration with bis(trichloromethyl) carbonate (triphosgene) gave the ortho-alkenyl isocyanide 12 and thus set the stage for a radical-mediated cyclization.When isocyanide 12 thus obtained was subjected to our previously established radical-cyclization conditions,[5a] the desired 5-exo adduct 13 was obtained in moderate yield after acidic treatment with silica gel along with a considerable amount of products 14 and 15 of a 6-endo cyclizationcleavage process (Scheme 3). We were aware of the tendency of this imidoy...

Mild Rhodium(III)‐Catalyzed Direct CH Allylation of Arenes with Allyl Carbonates

“…The C2-selective allylation of indoles is highly interesting but also challenging. [16] We were pleased to find that by using a removable pyrimidyl directing group, the C2-allylation was successfully accomplished with complete selectivity. However, the use of phenyl-substituted allyl carbonate 2 e gave an inseparable mixture of C2-and C3-allylated product.…”

C7-Prenylation of Tryptophan-Containing Cyclic Dipeptides by 7-Dimethylallyl Tryptophan Synthase Significantly Increases the Anticancer and Antimicrobial Activities

“…Consequently, synthesis of prenylated cyclic dipeptides has drawn remarkable attention and different strategies have been developed. The synthetic routes usually deal with anhydrous or anaerobic conditions, environment hazardous chemicals and high or very low temperature [ 18 , 19 , 20 ]. Meanwhile, additional steps are usually necessary for protection and deprotection of the functional groups [ 21 ].…”

Free-radical cyclization approach to polyheterocycles containing pyrrole and pyridine rings

“…Although the intramolecular free-radical cyclization is widely used for the synthesis of heteroaromatic compounds [23][24][25][26], only a few examples of the successful use of radical cyclization for the synthesis of pyrrole-containing fused heteroaromatics are known in the literature [23][24][25][26][27][28][29][30]. We initiated our study with the attempts to carry out the cyclization of 4-(2bromophenyl)pyrrole 1a under standard radical cyclization conditions (azobisisobutyronitrile (AIBN)/Bu 3 SnH), which previously had been successfully used for the cyclization of 2-bromophenyl-substituted pyrroles into 7-oxa-2a 1azabenzo[b]-cyclopenta[pq]pleiadenes [30].…”