Preparation and Structure−Activity Relationship of Novel P1/P1‘-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors

Abstract

A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.

Synthesis of Novel Amino‐Acid‐Derived Sulfinamides and Their Evaluation as Ligands for the Enantioselective Transfer Hydrogenation of Ketones

“…To this end, we wanted to determine which one of the chosen protecting groups (Cbz, Boc, Fmoc) would be most easily cleaved in the last step. The aldehydes 2a – c were first prepared by means of a known reaction sequence, comprising the conversion of the N ‐protected carboxylic acids into the corresponding Weinreb amides 3a – c ,16 and the subsequent chemoselective reduction of the latter with LiAlH 4 in THF at 0 °C 17. Although we were able to prepare all three aldehydes 2a – c , we noticed that the last reductive step afforded the Fmoc‐protected species 2c in only 31 % yield, as opposed to 55–63 % for the other two aldehydes, alongside with a more polar by‐product 18.…”

Novel Strategy for the Synthesis of the Butenolide Moiety of Peridinin

“…After acetalization of 11 (→ 12 ,14 Scheme ), formation of the double Weinreb amide furnished 13 ; the yield (99 %) was better than that of the published procedure (77 %),15 provided that the temperature was kept below −15 °C throughout reaction and workup. Bis(amide) 13 thereby became available on the 40‐g scale.…”

Eine neue Strategie für die Synthese des Butenolid‐Teils von Peridinin

“…11 wurde zu 12 ketalisiert14 (Schema ) und dieses in das doppelte Weinrebamid 13 überführt; dabei war die Ausbeute höher (99 %) als beim publizierten Verfahren (77 %15), sofern die Temperatur während Reaktion und Aufarbeitung unter −15 °C gehalten wurde. Auf diese Weise wurde das Bisamid 13 im 40‐g‐Maßstab verfügbar.…”