Bunnage Mark E, Chippindale Ann M, Davies Stephen G, Parkin Richard M, Smith Andrew D, Withey Jonathan M
Discovery Chemistry, IPC 675, Pfizer Global Research and Development, Sandwich, Kent, UK CT13 9NJ.
Org Biomol Chem. 2003 Nov 7;1(21):3698-707. doi: 10.1039/b306935b.
Conjugate addition of lithium dibenzylamide to tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate occurs with high levels of stereocontrol, with preferential addition of lithium dibenzylamide to the face of the cyclic alpha,beta-unsaturated acceptor anti- to the 3-methyl substituent. High levels of enantiorecognition are observed between tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate and an excess of lithium (+/-)-N-benzyl-N-alpha-methylbenzylamide (10 eq.) (E > 140) in their mutual kinetic resolution, while the kinetic resolution of tert-butyl (+/-)-3-methylcyclopentene-1-carboxylate with lithium (S)-N-benzyl-N-alpha-methylbenzylamide proceeds to give, at 51% conversion, tert-butyl (1R,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate consistent with E > 130, and in 39% yield and 99 +/- 0.5% de after purification. Subsequent deprotection by hydrogenolysis and ester hydrolysis gives (1R,2S,3R)-3-methylcispentacin in > 98% de and 98 +/- 1% ee. Selective epimerisation of tert-butyl (1R,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate by treatment with KO'Bu in 'BuOH gives tert-butyl (1S,2S,3R,alphaS)-3-methyl-2-N-benzyl-N-alpha-methylbenzylaminocyclopentane-1-carboxylate in quantitative yield and in > 98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving (1S,2S,3R)-3-methyltranspentacin hydrochloride in > 98% de and 97 +/- 1% ee.
二苄基锂酰胺与叔丁基（±）-3-甲基环戊烯-1-羧酸酯的共轭加成反应具有高度的立体控制，二苄基锂酰胺优先加成到环状α,β-不饱和受体的与3-甲基取代基反式的面上。在叔丁基（±）-3-甲基环戊烯-1-羧酸酯与过量的（±）-N-苄基-N-α-甲基苄基锂酰胺（10当量）（E>140）的相互动力学拆分中观察到高度的对映体识别，而叔丁基（±）-3-甲基环戊烯-1-羧酸酯与（S）-N-苄基-N-α-甲基苄基锂酰胺的动力学拆分在51%的转化率下得到叔丁基（1R,2S,3R,αS）-3-甲基-2-N-苄基-N-α-甲基苄基氨基环戊烷-1-羧酸酯，与E>130一致，纯化后产率为39%，de值为99±0.5%。随后通过氢解和酯水解进行脱保护，得到>98%de值和98±1%ee值的（1R,2S,3R）-3-甲基顺式喷他辛。用叔丁醇钾在叔丁醇中处理叔丁基（1R,2S,3R,αS）-3-甲基-2-N-苄基-N-α-甲基苄基氨基环戊烷-1-羧酸酯，使其选择性差向异构化，得到定量产率且de值>98%的叔丁基（1S,2S,3R,αS）-3-甲基-2-N-苄基-N-α-甲基苄基氨基环戊烷-1-羧酸酯，随后通过氢解和酯水解进行脱保护，得到>98%de值和97±1%ee值的（1S,2S,3R）-3-甲基反式喷他辛盐酸盐。
