No abstract

Using Fujisawa's B2R agonist FR-190997, we recently demonstrated for the first time that agonism at the bradykinin receptor type 2 (B2R) produces substantial antiproliferative effects. FR-190997 elicited an EC 50 of 80 nM in the triple-negative breast cancer cell line MDA-MB-231, a much superior performance to that exhibited by most approved breast cancer drugs. Consequently, we initiated a program aiming primarily at synthesizing adequate quantities of FR-190997 to support further in vitro and in vivo studies toward its repurposing for various cancers and, in parallel, enable the generation of novel FR-190997 analogs for an SAR study. Prerequisite for this endeavor was to address the synthetic challenges associated with the FR-190997 scaffold, which the Fujisawa chemists had constructed in 20 steps, 13 of which required chromatographic purification. We succeeded in developing a 17-step synthesis amenable to late-stage diversification that eliminated all chromatography and enabled access to multigram quantities of FR-190997 and novel derivatives thereof, supporting further anticancer research based on B2R agonists.

The synthesis of fully substituted fused pyrroles through a multicomponent reaction between a thioamide, an aldehyde, and ammonium acetate is described. This process improves on a route commonly employed in the patent literature by avoiding the use of potentially hazardous oxidants, which cause the formation of side products and require a stringent process of derisking to be utilized on scale. The reaction proceeds under mild conditions, displays excellent functional group tolerance, and facilitates diversification through multiple vectors.N ovel methods for the rapid production of highly substituted heterocycles are of interest to organic chemists due to their application as pharmaceutical and agrochemical agents. 1 Fully substituted pyrroles are of particular value, as demonstrated by Pfizer's blockbuster statin, Lipitor. 2 Recently, compounds containing the fused 3-amino-2-aryltetrahydropyrrolopyridinone core have received attention in the oncology therapeutic area as inhibitors of EGFR, 3 HER2, 4 MAPKAP-K2, 5 BRAF, 6 Casein kinase, 7 and other significant targets for the treatment of cancer (Scheme 1a).The existing syntheses of this motif proceed through an intramolecular oxidative cyclization reaction of a thioamide, such as 1, with oxidizing agents such as H 2 O 2 or mCPBA (Scheme 1b). 8,3a The mechanism of this cyclization is reported to proceed through the generation of cyclic intermediate 2, which undergoes a base-promoted or spontaneous elimination of S 0 to produce fused pyrrole 3. 9 Although this process has been used successfully to support medicinal chemistry campaigns, it suffers from drawbacks that limit its applicability for scale-up; specifically, lengthy linear routes to access starting materials, difficult-to-separate side products resulting from overoxidation of the lactam ring, and the use of oxidizing agents with thermal liabilities that require a stringent process of derisking to ensure process safety requirements are satisfied. 10 We envisaged that these issues would be overcome by employing reagents at the oxidation level required for cyclization. Specifically, a multicomponent reaction between enol 4, an ammonia source, and an aldehyde would directly generate cyclic intermediate 2 without the need for additional oxidants (Scheme 1c). Extrusion of S 0 would then generate the desired compounds. This procedure would also reduce the

The controlled programming of regiochemical outcomes in nucleophilic fluorination reactions with alkali metal fluoride is a problem yet to be solved. Herein, two synergistic approaches exploiting hydrogen bonding catalysis are presented. First, we demonstrate that modulating the charge density of fluoride with a hydrogen-bond donor urea catalyst directly influences the kinetic regioselectivity in the fluorination of dissymmetric aziridinium salts with aryl and ester substituents. Moreover, we report a urea-catalyzed formal dyotropic rearrangement, a thermodynamically controlled regiochemical editing process consisting of C−F bond scission followed by fluoride rebound. These findings offer a route to access enantioenriched fluoroamine regioisomers from a single chloroamine precursor, and more generally, new opportunities in regiodivergent asymmetric (bis)urea-based organocatalysis.