[reaction: see text] The stereoselective aldol reaction of 3-silyloxyfurans with aldehydes in the presence of a Lewis acid is described. N-Bromosuccinimide (NBS)-mediated cyclization of the aldol product leads to the formation of the 2,7-dioxa-bicyclo[2.2.1]heptan-3-one ring system, which represents the formal product of hetero Diels-Alder reaction of the furan with the aldehyde.
Supporting Information
General MethodsAll solvents and reagents were obtained from commercial suppliers and used without purification.Reactions were conducted under an atmosphere of nitrogen with a suitable outlet to accommodate modest pressure changes. Reaction temperatures were monitored by internal thermocouple. Reaction progress and compound purity were determined by HPLC analysis, using an Eclipse XDB C8, 4.6 x 150 mm, 5 µm column, with a gradient method using 0.1% (v/v) 70% HClO 4 /water and acetonitrile as mobile phase. Assay yield and purity were assessed using HPLC comparison to high purity reference standards, and confirmed by quantitative 1 H NMR in DMSO-d 6 (vs. internal standards benzyl benzoate, or N-benzyl benzamide). 1 H NMR spectra were obtained using a Bruker 400 MHz spectrometer; chemical shifts are reported in ppm using the solvent internal standard (CDCl 3 : δ 7.27, DMSO-d 6 : δ 2.50, CD 3 OD: δ 3.31). 13 C NMR spectra were recorded on a 100 MHz spectrometer with complete proton decoupling; chemical shifts are reported in ppm with the solvent as the internal reference (CDCl 3 : δ 77.0, DMSO-d 6 : δ 39.5). HRMS (ESI-TOF) spectra were obtained using Agilent 1100 systems. Liquid chromatography purification was performed on an ISCO Combiflash Companion apparatus; chromatographic purifications and isolated yields are unoptimized.
[reaction: see text] The synthesis of stereochemically defined tri- and penta-heterocyclic ring systems 9 and 28, respectively, via the metathesis reaction of substituted oxanorbornanes derived from 3 is described.
The reaction of enone 1, bearing an internal nucleophilic moiety, i.e., furan or pyrrole (X = O, NR'), with isocyanides is presented. The formation of products resulting from the reaction of the zwitterionic intermediate 2 with a second equivalent of isocyanide prior to cyclization to give 3, as well as the direct formation of 4 from 2, is described.
Presented are two case studies where polymorphic behavior of a process intermediate was identified and the relationship was investigated for form control. Case study I: 1 is a process intermediate for a novel apoptosis signal-regulating kinase 1 (ASK1) inhibitor that was isolated as an unsolvated hydrochloride salt (1-HCl). Initial research lots and the first delivery batch yielded form I of 1-HCl; however, during process optimization to support a second delivery, form II was identified. This discovery left limited time to map the thermodynamic relationship between the two phases prior to the second production, and based on limited knowledge at the time, form I was selected and successfully scaled even though it was determined to be the room temperature metastable phase. Case study II: 2 is a process intermediate for a novel toll-like receptor 8 (TLR8) agonist. Applying lessons learned from case study I, polymorph screening identified unsolvated forms I and II, whose relative stabilities were mapped so that a crystallization could be designed to ensure phase control for the thermodynamically most stable form at room temperature prior to production, which ultimately benefited superior impurity rejection.
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