Bunnage Mark E, Davies Stephen G, Parkin Richard M, Roberts Paul M, Smith Andrew D, Withey Jonathan M
Discovery Chemistry, 1PC 818, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK.
Org Biomol Chem. 2004 Nov 21;2(22):3337-54. doi: 10.1039/B407559E. Epub 2004 Oct 20.
High levels of stereocontrol are observed in the conjugate addition of lithium dibenzylamide to tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn), with addition occurring exclusively anti- to the 3-alkyl substituent. Treatment of a range of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn, (i)Pr, (t)Bu) with lithium (RS)-N-benzyl-N-[small alpha]-methylbenzylamide indicates that good enantiorecognition is observed (E > 80) in their mutual kinetic resolution. In these reactions, conjugate addition of the lithium amide occurs exclusively anti- to the 3-alkyl substituent, with subsequent C(1)-protonation occurring preferably anti- to the 2-amino group in the 3-Et, 3-Bn and 3-(i)Pr cases, giving predominantly the corresponding 1,2-syn-2,3-anti-diastereoisomers. Conjugate addition to (RS)-3-tert-butyl cyclopentene-1-carboxylate results in exclusive 2,3-anti -addition and a reversal in C(1)-protonation selectivity, giving predominantly the 1,2-anti-2,3-anti-diastereoisomer. Furthermore, the kinetic resolution of the tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn, (i)Pr, (t)Bu) with lithium (S)-N-benzyl-N-alpha-methylbenzylamide proceeds efficiently, giving, at between 47 and 51% conversion, the resolved 3-alkylcyclopentene-1-carboxylates in >85 to >98% ee and the beta-amino ester products of conjugate addition in high de, consistent with E > 80 in each case. Subsequent deprotection of the 1,2-syn-2,3-anti-3-alkyl-beta-amino esters (alkyl = Et, Bn, (i)Pr) by hydrogenolysis and ester hydrolysis gives the corresponding 1,2-syn-2,3-anti-3-alkylcispentacins in >98% de and 98 +/- 1% ee. Selective epimerisation of the 1,2-syn-2,3-anti-3-alkyl-beta-amino esters (alkyl = Et, Bn, (i)Pr, (t)Bu) by treatment with KO(t)Bu in (t)BuOH gives the corresponding 1,2-anti-2,3-anti-3-alkyl-beta-amino esters in quantitative yield and in >98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving the corresponding 1,2-anti-2,3-anti-3-alkylcispentacin hydrochlorides in >98% de.
在二苄基锂酰胺与叔丁基（RS）-3-烷基环戊烯-1-羧酸酯（烷基 = 乙基、苄基）的共轭加成反应中观察到了高度的立体控制，加成反应仅以反式方式发生在3-烷基取代基上。用锂（RS）-N-苄基-N-α-甲基苄基酰胺处理一系列叔丁基（RS）-3-烷基环戊烯-1-羧酸酯（烷基 = 乙基、苄基、异丙基、叔丁基）表明，在它们的相互动力学拆分中观察到了良好的对映体识别（E > 80）。在这些反应中，锂酰胺的共轭加成仅以反式方式发生在3-烷基取代基上，在3-乙基、3-苄基和3-异丙基的情况下，随后的C(1)-质子化优选以反式方式发生在2-氨基上，主要生成相应的1,2-顺式-2,3-反式非对映异构体。与（RS）-3-叔丁基环戊烯-1-羧酸酯的共轭加成导致唯一的2,3-反式加成以及C(1)-质子化选择性的反转，主要生成1,2-反式-2,3-反式非对映异构体。此外，叔丁基（RS）-3-烷基环戊烯-1-羧酸酯（烷基 = 乙基、苄基、异丙基、叔丁基）与锂（S）-N-苄基-N-α-甲基苄基酰胺的动力学拆分反应高效进行，在47%至51%的转化率下，得到ee值>85%至>98%的拆分后的3-烷基环戊烯-1-羧酸酯以及高de值的共轭加成β-氨基酯产物，这与每种情况下E > 80一致。随后通过氢解和酯水解对1,2-顺式-2,3-反式-3-烷基-β-氨基酯（烷基 = 乙基、苄基、异丙基）进行脱保护，得到de值>98%且ee值为98 ± 1%的相应1,2-顺式-2,3-反式-3-烷基顺戊菌素。通过在叔丁醇中用叔丁醇钾处理1,2-顺式-2,3-反式-3-烷基-β-氨基酯（烷基 = 乙基、苄基、异丙基、叔丁基）进行选择性差向异构化，以定量产率得到相应的1,2-反式-2,3-反式-3-烷基-β-氨基酯，de值>98%，随后通过氢解和酯水解进行脱保护，得到de值>98%的相应1,2-反式-2,3-反式-3-烷基顺戊菌素盐酸盐。
