It has been reported that substitution of the Met31 residue in Boc-CCK4 (Boc-Trp30-Met31-Asp32-Phe33-NH2, CCK33 numbering) by trans-3-propyl-L-proline yields a highly potent and selective CCK-B agonist. To further explore the structural requirements of the Met31 side chain in the receptor-bound conformation of CCK4, we have synthesized several Ac-CCK4 analogs containing substitution of Met31 by 3- and 4-(alkylthio)-substituted proline derivatives. To this end we have developed novel synthetic routes to enantiomerically pure N-Boc-4-cis- and -trans-(methylthio)prolines and racemic N-Boc-3-cis and -trans-[(4-methylbenzyl)thio]prolines. The protected mercaptoprolines were incorporated into Ac-CCK4 analogs using SPPS and were alkylated using various electrophiles following cleavage from the solid support. Binding assays reveal that 3-(alkylthio)prolines analogs have higher affinities at the CCK-B receptor than the corresponding 4-(alkylthio)proline analogs, and that trans-3-(alkylthio)proline analogs had higher affinities than corresponding cis-3-(alkylthio)proline analogs. Within both the cis- and trans-3-(alkylthio)proline series, the order of potency was found to be Me < Et < n-Pr. The trans-3-(n-propylthio)-L-proline analog demonstrates a higher affinity than that reported for Boc-CCK4[trans-3-propyl-L-Pro31]. Comparison of the low-energy structures calculated for several high-affinity Ac-CCK4 analogs reveal a common geometry which we propose to be the CCK-B receptor-bound conformation. This model shows grouping of the hydrophobic side chains of Trp, Met, and Phe at one side of the molecule and the hydrophilic side chain of Asp and the C-terminal carboxamide at the other side.
A concise, convergent multikilogram synthesis of CI-1034 (1), a potent endothelin receptor antagonist, is described. A 15-step preparation from commercially available o-vanillin and benzenesulfonyl chloride employs a remarkably robust Suzuki coupling between a boronic acid and an aromatic sulfonate ester as the key synthetic step. A scalable route capable of producing multikilogram quantities of CI-1034 with no chromatographic steps is described in this contribution. Improvements to the process included using a 4-fluorobenzenesulfonate ester as a suitable substitute for the triflate group in the Suzuki reaction and the use of MgCl 2 as a substitute for TiCl 4 in a Dieckmann condensation to provide the benzothiazine dioxide core.
Olefinic ß-keto esters 8, 17, and 20, prepared by either carbomethoxylation of the parent ketone or alkylation of the dianion of methyl acetoacetate with the allylic bromide, underwent cyclization with stannic chloride in dichloromethane to give mono-and bicyclic keto esters 10 and 18, respectively. The latter was transformed via ketone 24 to A8(u)-podocarpen-13-one ( 27) and to keto acid 29, an intermediate in the synthesis of ambreinolide. Keto ester 46, prepared by condensation of the dianion of methyl acetoacetate with ß-cyclocitral, gave 56 as the major product upon irradiation in neutral solution but, in the presence of sodium methoxide, a mixture (ca. 1:1) of 45 and 65 was produced in 66% yield. Enol derivatives 52, 53, and 54 of 46 underwent 1,5-hydrogen migration upon photolysis to give 55, 58, and 59. The dark transformation of 56 to 47 with triethylamine revealed a pathway to this pyranoid structure unrecognized in previous photochemical studies of ß-ionone, and the conversion of 47 to 45 and 65 upon irradiation in the presence of sodium methoxide suggests a mechanistic hypothesis for these light-induced reactions involving a manifold of equilibrating enolates which terminate at 45.
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