The overall yield for the preparation of the C8 methyl derivative 17 from the common aldehyde starting material was 18%. Open in a separate window Scheme 3 Synthesis of C8 Methyl Bicyclo Bis-Arylimidazole Derivative Conditions: (a) allylmagnesium bromide, CH2Cl2, ?78 C to rt, 92% (sole diastereomer); (b) 4N HCl, CH3OH, 94%; (c) 4-fluorophenyl tosylmethyl Trimethobenzamide hydrochloride isonitrile,3 glyoxylic acid, K2CO3, DMF; (d) TBDPSCl, em i /em Pr2NEt, DMAP, CH2Cl2, 78% (over 2 methods); (e) [RhCl(coe)2]2, PCy3, MgBr2, toluene, 180 C, 52%, 92% ee; (f) Br2, CH2Cl2, ?78 C, 80%; (g) 2-methylthio-4-trimethylstannylpyrimidine,6 Pd2(dba)3CHCl3, PPh3, LiCl, CuI, dioxane, 170 C, 84%; (h) OXONE?, THF, H2O; (i) propylamine, 91% (over 2 methods); (j) TBAF, THF, 99%. The ability of compounds 13 and 17, and their enantiomers ent-13 and ent-178 prepared by employing ( em RS /em )- em tert /em -butanesulfinamide in the previously explained synthetic sequences, to inhibit JNK3 were identified (Table 1). affinity and particularly selectivity, which remains a key challenge in kinase inhibitor drug discovery efforts. Open in a separate window Number Rabbit Polyclonal to Parkin 1 Retrosynthesis of Bicyclic Bis-Arylimidazole Kinase Inhibitors Bicyclic bis-arylimidazole inhibitors, exemplified by inhibitor 1, represent demanding synthetic targets. Indeed, the synthesis of Trimethobenzamide hydrochloride 1 required 14 linear methods and was accomplished in less than 6% overall yield.1 Herein, we statement an efficient asymmetric synthesis of 1 1 in 11 linear methods and 13% overall yield with the key bicyclic imidazole core generated through catalytic C-H relationship functionalization. We also successfully integrated substituents in the C7 and C8 positions, substitution patterns hard to access from the previously reported synthetic route, and in doing so observed the 1st examples of acyclic stereocontrol in metal-catalyzed C-H relationship activation. Moreover, evaluation of the compounds synthesized by this route resulted in the identification of a JNK3 inhibitor even more potent than 1. In our retrosynthetic analysis of the bicyclic bis-arylimidazole platform, we envisioned installing the C5 pyrimidine by a cross-coupling with 2 (Number 1). Synthesis of the bicyclic imidazole core would be accomplished via rhodium-catalyzed C-H activation/annulation of 3. A vehicle Leusen cycloaddition could be employed to generate 3 from 4, which can be readily prepared from commercially available starting material. The synthesis of Trimethobenzamide hydrochloride inhibitor 1 commenced with the condensation of ( em SS /em )- em tert /em -butanesulfinamide and commercially available em tert /em -butyldimethylsiloxyacetaldehyde to provide 5 in 86% yield (Plan 1).2 The addition of vinylmagnesium bromide to 5 proceeded with 91:9 dr, and after chromatography, the major diastereomer was acquired in 69% yield. Acidic cleavage of the silyl and em tert /em -butanesulfinyl organizations offered 6 in nearly quantitative yield.2 Condensation of 6 with glyoxylic acid followed by treatment with 4-fluorophenyl tosylmethyl isonitrile3 generated the desired enantiomerically genuine imidazole in 92% yield.4 Protection of the producing primary alcohol like a em tert /em -butyl diphenyl silyl (TBDPS) ether offered 7 in 98% yield. Open in a separate window Plan 1 Synthesis of Inhibitor 1 Conditions: (a) ( em SS /em )- em tert /em -butanesulfinamide, CuSO4, CH2Cl2, 86%; (b) vinylmagnesium bromide, CH2Cl2, 0 C to rt, 69% (solitary diastereomer); (c) 4N HCl, CH3OH, 99%; (d) 4-fluorophenyl tosylmethyl isonitrile3, glyoxylic acid, K2CO3, DMF, 92%; (e) TBDPSCl, em i /em Pr2EtN, DMAP, CH2Cl2, 98%; (f) [RhCl(coe)2]2, PCy3, MgBr2, toluene, 180 C, 50%, 92% ee; (g) Br2, CH2Cl2, ?78 C, 94%; (h) 2-methylthio-4-trimethylstannylpyrimidine,6 Pd2(dba)3CHCl3, PPh3, LiCl, CuI, dioxane, 170 C, 85%; (i) OXONE?, THF, H2O, 79%; (j) propylamine, 78%; (k) Bu4NF, THF, 100%. Due to the steric hindrance launched from the C6 substituent, forcing conditions were required to accomplish good conversion in the C-H activation/annulation step. Ultimately, cyclization of 7 was accomplished by using 5% [RhCl(coe)2]2 and 15% PCy3 to generate the active catalyst with 5% MgBr2 as an additive and toluene as solvent at 180 C to provide 8 in 50% yield and with 92% ee (Plan 1).5 Olefin isomerization and olefin reduction products were also isolated in 11% and 6% yield, respectively. Competitive olefin isomerization offers been shown to occur under these conditions and is likely responsible for the small erosion of enantiomeric excessive observed during the cyclization.5c Treatment of 8 with Br2 resulted in bromination of the imidazole ring in the C5 position in 94% yield. The producing bromide was subjected to Stille mix coupling conditions in the presence of 2-methylthio-4-trimethylstannylpyrimidine6 to provide 9 in 85% yield (Plan 1).7 The requisite amine was generated by oxidation of the thioether to the sulfone (79% yield) followed by addition of propylamine (78% yield). Quantitative Bu4NF cleavage of the silyl ether offered 1 in 13% overall yield. To demonstrate the flexibility of our synthetic approach toward bicyclic bis-arylimidazole systems and to explore acyclic stereocontrol in the C-H activation/annulation step, we generated derivatives of 1 1 comprising methyl substituents in the C7 or C8 positions. By employing isopropenylmagnesium bromide in place of vinylmagnesium bromide in the previously explained sequence we were poised to generate a derivative having a C7 methyl substituent (Plan 2). The.
February 23, 2023