Studies Towards the Synthesis of Methionine Aminopeptidase Inhibitors: Diversification Utilizing a ROMP-Derived Coupling Reagent

Abstract

Efforts to synthesize potential methionine aminopeptidase inhibitors is described. Preliminary SAR and docking studies served as a guide to design the compound libraries. "Chromatography-free" synthesis of various heterocyclic amides was realized by using a high-load, soluble coupling reagent derived via ring-opening metathesis polymerization (ROMP). Subsequent microwave-assisted Suzuki reactions with ortho-substituted arylboronic acids, followed by chromatographic purification afforded a 55-member library in high yields and purities. While the biological testing was not satisfactory, concurrent X-ray crystallography studies revealed key structural features essential for inhibition of methionine aminopeptidase, which directed fruitful results reported in the accompanying manuscript. In addition, in silico Lipinksi profiles and ADME properties of the library are also reported.

Palladium‐Catalyzed Direct Arylations of Five‐Membered Heteroarenes Bearing N‐Monoalkylcarboxamide Substituents

“…6, 151.4, 147.5, 146.8, 136.6, 129.9, 128.8, 128.7, 127.6, 126.8, 126.5, 121.7, 117.9, 115.5, 108.2, 42.0 ppm. 8, 138.0, 134.4, 133.0, 131.8, 128.7, 128.4, 127.9, 127.6, 126.4, 119.1, 116.1, 111.4, 107.5, 43.3 (14): [20] 2-(Trifluoromethyl)bromobenzene (0.225 g, 1 mmol) and 3 (0.302 g, 1.5 mmol) afforded 14 in 80 % (0.276 g) yield.…”

“…9, 158.6, 154.6, 148.2, 133.9, 130.7, 130.6, 124.6, 116.8, 109.7, 71.6, 59.4, 52.7, 39.4 N-Phenyl-2-furamide (27): [22] The reaction of furan-2-carbonyl chloride (0.312 g, 2.4 mmol) and aniline (0.186 g, 2 mmol) in triethylamine (4 mL) and dichloromethane (30 mL) at room temperature over 3 h gave 27 in 83 % (0.155 g) yield after addition of an H 2 O/ HCl solution, extraction with dichloromethane, drying (MgSO 4 ), and purification by silica gel column chromatography. (28): [20] 2- (Trifluoromethyl) Thiophene-2-carboxylic Acid Benzylamide (32): [23] The reaction of thiophene-2-carbonyl chloride (0.350 g, 2.4 mmol) and benzylamine (0.214 g, 2 mmol) in triethylamine (4 mL) and dichloromethane (30 mL) at room temperature over 3 h gave 32 in 74 % (0. …”

“…Acid Benzylamide (39): [20] 2-(Trifluoromethyl)bromobenzene (0.225 g, 1 mmol) and 32 (0.325 g, 1.5 mmol) afforded 39 in 75 % (0.271 g) yield.…”

“Click”-Capture, Ring-Opening Metathesis Polymerization (ROMP), Release: Facile Triazolation Utilizing ROMP-Derived Oligomeric Phosphates

“…3 To this effect, a variety of reagents and scavengers possessing tunable properties have emerged from ring-opening metathesis polymerization (ROMP) technology. 4,5,6 We herein report the development of a new ROMP-derived oligomeric triazole phosphate (OTP) for application as a soluble, efficient triazolating reagent of nucleophilic species. Overall, these reagents are free flowing solids that are easy to handle, non-toxic, soluble, and air stable.…”

ROMP-Derived Oligomeric Phosphates for Application in Facile Benzylation

“…Despite many salient attributes of current immobilized platforms, limitations in load capacity, reaction kinetics, means of delivery and stability continue to warrant efforts in this area. 3 Among these, ring-opening metathesis (ROM) polymerization of functionalized norbornenes has surfaced as a powerful tool in the generation of high-load, immobilized reagents with tunable properties 4,5,6. In this regard, we report the development of new ROMP-based oligomeric benzyl phosphates (OBP n ) for use as soluble, stable benzylating reagents.…”