Regioselective Base-Mediated Cyclizations of Mono-N-acylpropargylguanidines

Abstract

A regioselective base-mediated cyclization of mono-N-acylpropargylguanidines is reported. A related Ag(I)-catalyzed hydroamination strategy was recently employed to yield N3-Cbz-protected ene-guanidines, which found utility in the synthesis of naamidine A. Herein, we report the base-catalyzed hydroamination of mono-N-acylpropargylguanidines, which proceeds with the opposite regiochemistry to deliver isomerized N2-acyl-2-aminoimidazoles with broad substrate scope, circumventing the problematic regiospecific acylation of free 2-aminoimidazoles.

A Cancer-Selective Zinc Ionophore Inspired by the Natural Product Naamidine A

“…To this end, we developed new chemistry to succinctly access N 2 -acyl-2-aminoimidazoles, thus maintaining a Lewis-base that could coordinate Zn 2+ , but not the plethora of heteroatoms as in the hydantoin that could lead to promiscuous binding. 12,13 A subset of these newly synthesized molecules was first evaluated in a preclinical cancer model previously developed in our laboratories, utilizing primary metastatic tumor cells derived from malignant pleural effusions (PEs) of breast cancer patients. 14 The use of these cells afforded the opportunity to model metastatic disease and chemoresistance as established during patient treatment from physiologically relevant exposure to clinical therapies.…”

“…To begin to understand the unique activity of these N 2 -acyl-C 5 -aryl-2 aminoimidazoles, we prepared a small, focused library of structurally related compounds drawing on synthetic methods developed previously by our group. 13 To elucidate whether the C 5 -aryl group or the N 2 -acyl group might dominate potency, two sets of compounds were generated with the first being varied in the N 2 -acyl group (compounds 1-7) and the second set (compounds 8-11) varied in the C 5 -aryl substituent (Figure 2A). MCF-10A and MCF-7 cells, untransformed mammary epithelial cells and a breast cancer cell line respectively, were used to evaluate this set of compounds (Figure 2B).…”

“…Our first attempt to decouple the complex activity of NA focused on removal of the N -Me-dehydrohydantoin. To this end, we developed new chemistry to succinctly access N 2 -acyl-2-aminoimidazoles, thus maintaining a Lewis-base that could coordinate Zn 2+ , but not the plethora of heteroatoms as in the hydantoin that could lead to promiscuous binding. , …”

“…Ten other NA analogues all possessed the C 4 -benzyl substituent as in the parent natural product and were either not active or not selective. To begin to understand the unique activity of these N 2 -acyl-C 5 -aryl-2-aminoimidazoles, we prepared a small, focused library of structurally related compounds drawing on synthetic methods developed previously by our group . To elucidate whether the C 5 -aryl group or the N 2 -acyl group might dominate potency, two sets of compounds were generated with the first being varied in the N 2 -acyl group (compounds 1 – 7 ) and the second set (compounds 8 – 11 ) varied in the C 5 -aryl substituent (Figure A).…”

Ultrasound-Assisted Synthesis of N-Acylcyanamides and N-Acyl-Substituted Imidazolones from Carboxylic Acids by Using Trichloroisocyanuric Acid/Triphenylphosphine

“…(9 examples, up to 78% over 3 steps) N-Acylcyanamides or N-cyanocarboxamides are versatile building blocks in organic synthesis. The two-nitrogen and one-carbon skeleton of the cyanamide moiety enable them to undergo numerous transformations towards a variety of interesting N-heterocycles such as quinazolinones, 1 benzimidazoles, 2 aminooxadiazoles, 3 N 2 -acyl-2-aminoimidazoles, 4 benzothiazinones and benzothiazoles. 5 Their use in radical cascade reactions also provides access to diverse compounds including luotonin A, 6 dihydroisoquinolinones, 6d guanidines, 7 as well as N-acylguanidines.…”