Synthesis of Chaetomellic Anhydride A, a Potent Inhibitor of Ras Protein Farnesyltransferase

Novel route to chaetomellic acid A and analogues: Serendipitous discovery of a more competent FTase inhibitor

“…Indeed Singh tried the same Ras-CVLS with both FTases, and he did not raise any doubt about the results of his tests. 20c Interestingly Fierke, during his study on substrate recognition by wild FTase, 42 observed that dansyl-GCVIA and dansyl-GCVLS were similarly recognized, respectively: k cat /K M peptide 120 and 170 [mM −1 s −1 ], and k cat >0.2 and 0.4 [s −1 ]. In our IC 50 measurements, the concentration of rat FTase was 10 times increased (15 nM against 1.5 nM) to compensate a possible lower affinity of dansyl-GCVIA for the enzyme and to increase the rate at which the bound substrate is converted to product.…”

“…20c No modified ACA , however, showed more potent inhibition than 2 against the recombinant human FTase. Also the groups of Vederas and Poulter synthesized some ACA analogues, namely those with R = n -C 12 H 25 , farnesyl, or geranylgeranyl.…”

“…The synthetic strategies investigated can be roughly grouped into two general categories: i ) alkylation of maleic precursors 18a,19 and ii ) assembly of the pivotal 1,4-dicarbonyl group. 20 …”

Palladium-Catalyzed Carbonylative Cyclization of β-Bromo-α,β-unsaturated Carboxylic Acids Leading to Maleic Anhydrides

“…1 Thus, many synthetic methods have been developed for the construction of the structural core of maleic anhydrides. 2 Among them, in connection with this report, it is worth noting that carbomethoxyalkenyl triflates are carbonylatively cyclized to maleic anhydrides in the presence of a palladium catalyst under Ac 2 O and HCO 2 Na as the condensed source of carbon monoxide. 2,3 During the course of our ongoing studies directed towards palladium-catalyzed carbonylative cyclization reactions, we recently reported on the synthesis of several carbonyl-group-containing heterocycles such as furanones, 4 alkyl 2,5-dihydro-5-oxofuran-2-carboxylates, 5 hydroisoindol-1-ones, 6 N-alkylmaleimides, 7 and 1-aryl-1H-pyrrol-2(5H)-ones 8 from β-bromo-α,β-unsaturated aldehydes and their derivatives using such a carbonylative cyclization.…”

“…2 Among them, in connection with this report, it is worth noting that carbomethoxyalkenyl triflates are carbonylatively cyclized to maleic anhydrides in the presence of a palladium catalyst under Ac 2 O and HCO 2 Na as the condensed source of carbon monoxide. 2,3 During the course of our ongoing studies directed towards palladium-catalyzed carbonylative cyclization reactions, we recently reported on the synthesis of several carbonyl-group-containing heterocycles such as furanones, 4 alkyl 2,5-dihydro-5-oxofuran-2-carboxylates, 5 hydroisoindol-1-ones, 6 N-alkylmaleimides, 7 and 1-aryl-1H-pyrrol-2(5H)-ones 8 from β-bromo-α,β-unsaturated aldehydes and their derivatives using such a carbonylative cyclization. The β-bromo-α,β-unsaturated aldehydes and their derivatives can be readily prepared from the corresponding α-methylene containing ketones by the bromination conditions of the Vilsmeier-Haack reaction and subsequent transformation and used as a building block for the construction of various cyclic compounds.…”