2005
DOI: 10.1021/ol0503081
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Efficient Synthesis of an Imidazole-Substituted δ-Amino Acid by the Integration of Chiral Technologies

Abstract: Two methods to produce (2S)-5-amino-2-(1-n-propyl-1H-imidazol-4-ylmethyl)-pentanoic acid were investigated. Diastereoisomeric salt resolution, using the quinidine salt, gave the desired intermediate in 98% ee and 33% yield. Asymmetric hydrogenation of various substrates gave high conversions, with up to 83% ee. Integration of these two approaches via asymmetric hydrogenation of a quinidine salt substrate followed by crystallization provided the desired intermediate in 94% ee and 76% yield.

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Cited by 16 publications
(15 citation statements)
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“…The key step is the Rh‐catalyzed hydrogenation of the enantiopure quinidine salt of its N ‐Boc derivative (Scheme 12). Although the best enantioselectivity was found with the Rh complex of the t Bu, t Bu‐FerroTANE ligand 8 c (82 % ee , S/C=100), the 1,1′‐bisphospholanoferrocene 17 displayed a much higher activity, thus allowing the reaction to be performed with a catalyst loading as low as 0.02 mol % (S/C=5000) 79. After crystallization from ethyl acetate the ee value of the product was enriched from 62 % to 94 %.…”
Section: Asymmetric Hydrogenation Of Alkenes Ketones and Iminesmentioning
confidence: 99%
“…The key step is the Rh‐catalyzed hydrogenation of the enantiopure quinidine salt of its N ‐Boc derivative (Scheme 12). Although the best enantioselectivity was found with the Rh complex of the t Bu, t Bu‐FerroTANE ligand 8 c (82 % ee , S/C=100), the 1,1′‐bisphospholanoferrocene 17 displayed a much higher activity, thus allowing the reaction to be performed with a catalyst loading as low as 0.02 mol % (S/C=5000) 79. After crystallization from ethyl acetate the ee value of the product was enriched from 62 % to 94 %.…”
Section: Asymmetric Hydrogenation Of Alkenes Ketones and Iminesmentioning
confidence: 99%
“…An integrated approach of the asymmetric hydrogenation and diastereomeric recrystallization was adopted. The quinidine salt of 23 was hydrogenated with high TON (s/c ¼ 5000), followed by recrystallization of the diastereomeric salt to afford the final product in 76% yield and 94% ee [27]. However, only 27% overall yield (97% ee) was obtained for this chiral inhibitor via a traditional resolution procedure and the work up is very difficult to handle.…”
Section: C-centered Chiral Diphosphine Ligandsmentioning
confidence: 99%
“…In addition, throughput was hampered by the high molecular mass of quinidine in relation to the carboxylic acid 158 . Therefore, an enantioselective transformation was sought to obviate these problems . A straightforward approach would be via asymmetric hydrogenation, since the racemic acid was obtained from the α,β-unsaturated acid 161 by hydrogenation over Pd/C.…”
Section: 7 Asymmetric Synthesis Of (2s)-5-amino-2-(1-n-propyl-1h-imid...mentioning
confidence: 99%
“…The hydrogenation of β-substituted itaconic acid derivatives was carried out at 100 psi in 50 mL glass-lined Parr microreactors 103b. The hydrogenation of an imidazole-substituted acrylate was investigated in another study . Possible substrate modifications (salt formation, esterification) were investigated in addition to a screening of possible metal/ligand combinations in a process typical for process definition.…”
Section: Screening In Industrial Laboratoriesmentioning
confidence: 99%