Synthesis of Naamidine A and Selective Access to N²-Acyl-2-aminoimidazole Analogues

Abstract

A short and scalable synthesis of naamidine A, a marine alkaloid with a selective ability to inhibit epidermal growth factor receptor (EGFR)-dependent cellular proliferation, has been achieved. A key achievement in this synthesis was the development of a regioselective hydroamination of a monoprotected propargylguanidine to deliver N3-protected cyclic ene-guanidines. This permits the extension of this methodology to prepare N2-Acyl analogues in a fashion that obviates the troublesome acylation of the free 2-aminoimidazoles, which typically yields mixtures of N2- and N2,N2-diacylated products.

Total synthesis and cytotoxicity of Leucetta alkaloids

“…Several general strategies can be envisioned for the preparation of the polysubstituted imidazoles, either through the intermediacy of α–substituted ketones ( 12 → 11 ), hydroamination of alkynes 10b, 16 or through the functionalization of pre-formed imidazoles ( 13 → 11 ). 17 In each case, the strategies are executed to avoid introducing the polar 2-amino substituent until the end of the synthetic sequence.…”

“…8 An Australian team has reported a modest exploration of the SAR of the naamine/naamidine A framework. 9 More recently, the Looper lab 10 and our group 11 have begun to evaluate the biological activity of synthetic versions of various other family members, specifically the naphthimidazole group. Very recently Jiang and coworkers have applied our synthetic methods to access the naamine framework to prepare derivatives at the 2-amino group with activity against P-glycoprotein mediated drug resistance in various cancer cell lines.…”

Catalytic Synthesis of 1,2,4,5‐Tetrasubstituted 1H‐Imidazole Derivatives: State of the Art

“…115) as a key step of a novel total synthesis of naamine A (1c). [174] As shown in Scheme 69, the total synthesis began with the CuBr-catalyzed reaction of aldehyde 108 with amine 109 and 1-alkyne 110 The resulting tert-propargylamine 111 was then converted into the corresponding sec-amine 113 by treatment with 2 equiv of thiosalicylic acid (112) in CH2Cl2 at room temperature in the presence of a catalytic quantity of Pd(PPh3)4. The subsequent reaction of 113 with benzyloxycarbonylcyanamide potassium salt (114) and Me3SiCl in MeCN at room temperature gave the monoacylguanidine 115 in quantitative yield.…”

Regioselective Base-Mediated Cyclizations of Mono-N-acylpropargylguanidines

“…6,7 Extending our methodology for the synthesis of naamidine A, we reported a number of first generation analogues. 8 Initial screening of these compounds identified a compound dubbed zinaamidole A (ZNA, 4a ) as a promising lead due to its antiproliferative activity (EC 50 = 8.8 μ M) against drug-resistant pleural effusion cells (PE1005339) derived from patients with breast cancer as well as immortalized, cancerous MCF-7 cells (EC 50 = 3.3 μ M). 9 In additional assays, ZNA showed negligible cytotoxicity against normal primary epithelial cells or the untransformed breast cancer cell line MCF-10A and was significantly more selective than its natural product inspiration naamidine A.…”

“…7 Our solution relied on treatment of mono-Cbz-protected propargylguanidines with AgNO 3 , yielding a N 3 -Cbz-ene-guanidine bearing an exocyclic alkene as a single regioisomer. 8 This allowed for the selective acylation of N 2 , followed by Cbz deprotection of N 3 to yield N 2 -acyl-2-aminoimidazoles such as ZNA. We reasoned that deprotonation of the mono- N -acylpropargylguanidine might allow for preferential cyclization through the more reactive, nonacylated guanidine nitrogen to directly give N 2 -acyl-2-aminoimidazoles without the need for this protection/deprotection sequence.…”