CN107382783A - 一种手性β‑氨基酸衍生物及其制备方法 - Google Patents

一种手性β‑氨基酸衍生物及其制备方法 Download PDF

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CN107382783A
CN107382783A CN201710579915.6A CN201710579915A CN107382783A CN 107382783 A CN107382783 A CN 107382783A CN 201710579915 A CN201710579915 A CN 201710579915A CN 107382783 A CN107382783 A CN 107382783A
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罗三中
尤扬恩
张龙
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Abstract

本发明公开了一种手性β‑氨基酸衍生物及其制备方法。本发明手性β‑氨基酸衍生物，其结构式如式I所示：

Description

一种手性β-氨基酸衍生物及其制备方法
技术领域
本发明涉及一种手性β-氨基酸衍生物及其制备方法，属于有机合成技术领域。
背景技术
20世纪初，Mannich等人报导了第一例Mannich反应，实现了对于N的α位的官能化过程，随后关于Mannich反应的报导以及应用得到广泛发展，其中关于应用不对称的方法的报导直到1997年由Kobayashi通过手性的Zr催化剂实现。应用Mannich反应实现手性骨架的构建随后得到进一步的发展，而这其中通过Mannich反应直接实现α位和β位的氨基酸的构筑也是一种合成的新方法。
手性氨基酸结构具有非常广泛的应用，可以应用于有机合成中配体的合成，新配体骨架的设计。目前应用比较广泛的配体往往都来源于廉价易得的天然氨基酸结构，而对于新配体骨架的改良以及设计，势必要从源头上改变氨基酸的结构，因而对于非天然氨基酸的合成提出了新的要求，这其中，非天然手性氨基酸得到越来越多的关注。
本世纪初，通过手性胺催化不对称Mannich反应构建手性小分子骨架得到较大的发展。其中Córdova发展了通过手性脯氨酸催化的三组分反应，实现了酮，甲醛与芳香胺的不对称Mannich过程。基于这一研究，随后这一方法得到广泛发展。在这些研究中，胺基往往都是芳香胺结构，需要进一步的保护/去保护过程，使得过程过于繁琐，应用性较差。居多的研究中，对于直接的合成β-氨基酸酯的报道，仅有几例，并且选择性不高，无法真正做到满足实际生产的光学纯的高效合成β-氨基酸，满足实际生产的需求。因此，发展绿色高效，简单的有机小分子催化剂在无溶剂条件下催化合成β-氨基酸骨架化合物具有重要意义。
发明内容
本发明的目的是提供一种手性β-氨基酸衍生物及其制备方法，本发明手性β-氨基酸衍生物采用具有简单结构的手性伯叔二胺有机小分子催化剂催化、无溶剂、一步法合成，简单、高效。
本发明提供的一种手性β-氨基酸衍生物，其结构式如式I所示：
式I中，R1为氢原子、烷基取代基和芳基取代基中的至少一种；
R2为氢原子、烷基取代基、芳基取代基和芳胺基中的至少一种；和/或烯丙基，和/或炔丙基；和/或，R1、R2为碳原子数为3～8之间整数的环烷基；
R3为氢原子、烷基取代基、CN、COR31、COOR32和CONHR33中的至少一种；R3中，R31为碳原子数1～5的烷基(COPh、COCH3、COCH2CH3、COCH2CH(CH3)2)，R32为碳原子数1～5的烷基和/或烯丙基；R33为对甲氧基苯基、对甲基苯基和苄基中的至少一种；
所述PG为氨基保护基。
上述的衍生物中，所述R1和所述R2中，所述烷基取代基为C1-C5的烷基；所述芳基取代基为苯基、对氯苯基、邻氯苯基、对甲氧基苯基和对甲基苯基中的至少一种；
所述R2中，所述芳胺基为苯胺基、苄胺基、对甲氧基苯胺基和对甲基苯胺基中的至少一种；
所述氨基保护基包括叔丁氧羰基(简称Boc)、苄氧羰基(简称Cbz)、芴甲氧基羰基(简称Fmoc)、对甲苯磺酰基(简称Ts)、三苯甲基(简称Tr)、乙酰基(简称Ac)、苄基(简称Bn)、邻苯二甲酰亚胺(英文名称Benzylideneamine)和三氟甲基乙酰基(英文名称Trifluoroacetamide)中的至少一种。
本发明还提供了一种N，O-缩醛，其结构式如式Ⅱ所示：
式Ⅱ中，PG为氨基保护基，所述氨基保护基包括叔丁氧羰基、苄氧羰基、芴甲氧基羰基、对甲苯磺酰基、三苯甲基、乙酰基、苄基、邻苯二甲酰基和三氟甲基乙酰基中的至少一种；
LG为离去基团，所述离去基团包括OAc、Cl、Br、OMe和OTs中的至少一种。
本发明所述N，O-缩醛除下式Ⅱ-1所示的化合物，所述N，O-缩醛结构式为式Ⅱ所示：
本发明还提供了所述N，O-缩醛的制备方法，包括如下步骤：将结构式为PGNH2的氨与甲醛混合，在溶剂中进行缩合保护反应，即得到所述N，O-缩醛；PG为氨基保护基，所述氨基保护基包括叔丁氧羰基、苄氧羰基、芴甲氧基羰基、对甲苯磺酰基、三苯甲基、乙酰基、苄基、邻苯二甲酰基和三氟甲基乙酰基中的至少一种。
上述制备方法中，所述结构式为PGNH2的氨与甲醛的摩尔比可为1：1.1～1.5，具体可为1：1.1；所述溶剂为乙酸和乙酸酐的混合物，所述乙酸和所述乙酸酐的体积比可为1:1～5，具体可为1:3；
所述缩合反应的温度可为20～80℃，具体可为60℃、20～60℃、60～80℃或30～70℃，时间可为1～5天，具体可为1天或1～4天。
本发明中，所述N，O-缩醛的制备方法，具体包括如下步骤：
将CbzNH2(氨基甲酸苄酯)、多聚甲醛按1：1.1～1.5的摩尔比混合，乙酸，乙酸酐以1:1～5的体积比混合作为反应的溶剂，在20～80℃下搅拌1～5天，除去未反应的乙酸酐及乙酸即可得到相应的稳定的直链Cbz保护胺基的N，O-缩醛化合物，具体的反应方程式如图2所示；
上述PG为Cbz、Ac、Boc、Fmoc和Ts中的一种。
本发明中，所述N，O-缩醛的制备方法能提高所述式Ⅱ所示的N，O-缩醛的产率，也能提高上述式Ⅱ-1所示的N，O-缩醛的产率。
本发明进一步提供了上述的手性β-氨基酸酯化合物的制备方法，包括如下步骤：
将羰基化合物与所述N，O-缩醛的混合物与手性伯叔二胺有机小分子催化剂、强酸和弱酸混合，反应，即得到所述手性β-氨基酸酯化合物；
所述羰基化合物包括醛和/或酮。
上述的制备方法中，所述羰基化合物的结构式如下式1或式2所示：
上述式1和式2中，R6为氢原子、烷基取代基和芳基取代基；R6中，所述烷基取代基为碳原子数1～5的烷基和/或烯丙基，所述芳基取代基为苯基、对氯苯基、对甲氧基苯基和对甲基苯基中的至少一种；
R7为氢原子、烷基取代基和芳基取代基；R7中，所述烷基取代基为碳原子数1～3的烷基，所述芳基取代基为苯基、苄基、对氯苯基和对甲氧基苯基中的至少一种；
R8为吸电子基，所述吸电子基包括酯基、酰胺基、酰基、氰基、三氟甲基和硝基中的至少一种；n2为0～5中的整数。
上述的制备方法中，所述手性伯叔二胺有机小分子催化剂的结构如下式3或4所示：
上述式3和4中，R4为氢原子、烷基取代基和芳基取代基；R5为氢原子、烷基取代基和芳基取代基中任何一种；n1为0～9中的整数；
R4和R5中，所述烷基取代基为碳原子数为1～6的烷基，所述芳基取代基为苯基和/或苄基。
本发明中，所述手性伯叔二胺有机小分子催化剂的结构式具体可为如下式5-1所示：
上述的制备方法中，所述强酸包括三氟乙酸、三氯乙酸、乙酸、三氟甲磺酸、甲磺酸、苯磺酸、对甲基苯磺酸、四氟硼酸、四芳基硼酸、六氟磷酸、高氯酸和次氯酸中的至少一种；
所述弱酸包括苯甲酸和/或带取代基的苯甲酸；所述带取代基的苯甲酸包括萘甲酸、2，4-二硝基苯甲酸、间硝基苯甲酸和邻硝基苯甲酸中的至少一种；
所述羰基化合物与所述N，O-缩醛的摩尔比可为1：1～5，具体可为1:1.5；
所述手性伯叔二胺有机小分子催化剂与所述羰基化合物的摩尔比可为0.5～30：100，具体可为1:20、0.5～5：100、5～30：100或1～20：100；
所述手性伯叔二胺有机小分子催化剂、所述强酸和所述弱酸的摩尔比可为1：0.5～2：0～5，具体可为1：1：5；
所述反应的温度可为20℃～100℃，具体可为60℃，时间可为1～6天，具体可为2天；
所述制备方法中，还包括分离提纯的步骤；所述提纯方法包括柱层析、减压蒸馏和重结晶中的至少一种。
本发明合成的手性β-氨基酸衍生物经1HNMR、13CNMR鉴定为纯的目标产物。
本发明手性β-氨基酸衍生物应用于手性β-氨基酸的制备，所述手性β-氨基酸衍生物脱掉保护基团即可得到手性β-氨基酸；
本发明手性β-氨基酸衍生物应用在制备手性配体骨架中。
本发明具有以下优点：
1、本发明所使用的催化剂结构简单，合成路线较短，合成方法简单、易于操作；
2、本发明制备方法采用一步法合成，大大降低了合成成本和合成周期；
3、本发明制备方法得到产物的光学选择性高，得到的目标产物即为光学纯的手性氨基酸衍生物，无需进一步的纯化，拆分等操作；
4、本发明所涉及的合成方法所用催化剂的量能降低到5mol％，催化效率高、对映选择性好；
5、本发明采用无溶剂的合成方法，绿色环保；
6、本发明所涉及的方法易于大规模生产，而且放大后产率和对映选择性都能够保持。
附图说明
图1为本发明手性伯叔二胺有机小分子催化剂的制备反应方程式。
图2为本发明直链N，O-缩醛的制备反应方程式。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下述实施例中，手性伯叔二胺有机小分子催化剂(化合物8)的结构式具体可为如下式5-1所示：
上述式5-1所示的手性伯叔二胺有机小分子催化剂的合成方法，是用L-叔亮氨酸(结构式如式7所示)为起始原料，经氨基保护、羧酸酰胺化、脱保护、酰胺还原制得；具体合成过程如图1所示；
本发明合成手性伯叔二胺有机小分子催化剂的具体方法，包括如下步骤：
(1)将氢氧化钠、L-叔亮氨酸、水按1:1:10的摩尔比加入反应器中，然后将和L-叔亮氨酸等摩尔量的(Boc)2O溶于10倍的1,4-二氧六环中，缓慢滴入反应器中，滴完后室温搅拌12小时，浓缩溶剂至一半后加入和浓缩后的反应液等体积的乙酸乙酯，再加入乙酸乙酯体积一半的4mol/L的盐酸，分液，有机相用等体积的水洗一次，无水硫酸钠干燥后蒸除溶剂即得化合物5，其结构是如式8所示；
(2)将化合物5和干燥的二氯甲烷按1:10的摩尔比加入反应器中，然后在冰水浴下缓慢滴加和化合物5等摩尔量的DCC(N,N’-二环己基碳二亚胺)的二氯甲烷溶液，滴完后再加入和化合物5等摩尔量的二甲胺盐酸盐与三乙胺，滴完后室温搅拌12小时，过滤除去白色沉淀，有机相分别用和反应液等体积的2％盐酸、4％碳酸氢钠、饱和食盐水洗涤，无水硫酸钠干燥后蒸除溶剂即得化合物6，其结构是如式9所示；
(3)将化合物6和无水甲醇按1:10的摩尔比加入反应器中，然后缓慢滴加化合物6摩尔量3倍的乙酰氯，加热回流1小时后蒸除溶剂，再加入和甲醇等体积的二氯甲烷和水，用稀盐酸调节水相pH值至弱酸性(pH值为6)，分出水相后再加入等体积的二氯甲烷，再用碳酸钾调节水相pH值至弱碱性，分出有机相，无水硫酸钠干燥后蒸除溶剂即得化合物7，其结构是如式10所示；
(4)将化合物7和干燥的四氢呋喃按1:5的摩尔比加入反应器中，然后在冰水浴下缓慢化合物7摩尔量2.5倍的氢化锂铝，加热回流4小时后冷却至室温；在冰水浴下加入四氢呋喃体积量一半的饱和硫酸钠水溶液，过滤除去沉淀，滤液用无水硫酸钠干燥后蒸除溶剂，再用油泵减压蒸馏，即得式5-1所示的手性伯叔二胺有机小分子催化剂(化合物8)。
实施例1、N，O-缩醛的制备
本发明制备N，O-缩醛，是用CbzNH2为起始原料，经胺与醛缩合再经过Ac保护羟基，即可得到N，O-缩醛类化合物，包括如下步骤：
将CbzNH2(氨基甲酸苄酯)、多聚甲醛按1：1.1的摩尔比混合，乙酸，乙酸酐以1:3的体积比混合作为反应的溶剂，在60℃下搅拌1天，除去未反应的乙酸酐及乙酸即可得到相应的非常稳定的Cbz保护胺基的N，O-缩醛化合物，具体的反应方程式如图2所示；
结构确证如下：1H NMR(400MHz,CDCl3)δ7.44–7.27(m,5H),5.97(s,1H),5.21(t,J＝7.9Hz,2H),5.14(s,2H),2.06(s,3H).13C NMR(101MHz,CDCl3)δ171.29,155.81,135.74,128.26,128.01,127.98,66.92,66.47,20.58.
实施例2、β-氨基酸酯的制备
按照如下所示的反应方程式进行制备：
将2-甲基乙酰乙酸乙酯(50mmol)与N,O-缩醛(75mmol)加入反应器中，再将化合物8(2.5mmol)用1ml二氯甲烷溶解，低温冰浴下滴入三氟甲磺酸(2.5mmol)，蒸除二氯甲烷后将此催化剂加入反应器中，最后加入间硝基苯甲酸(12.5mmol)，加热至60℃，搅拌3天后反应完成，柱色谱分离得到目标产物β-氨基酸酯83％，99％ee。
β-氨基酸酯结构确证的核磁数据如下：1H NMR(400MHz,CDCl3)δ7.42–7.26(m,5H),5.30(s,1H),5.07(s,2H),4.17(dt,J＝6.9,4.1Hz,2H),3.68–3.48(m,2H),2.18(s,3H),1.40(s,3H),1.24(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ205.68,171.72,156.63,136.57,128.64,128.26,128.20,66.96,61.92,60.60,45.18,26.46,18.02,14.08.
实施例3、
按照如下反应方程式如下制备：
将环己酮酸乙酯(50mmol)与N,O-缩醛(75mmol)加入反应器中，再将式5-1所示的手性伯叔二胺有机小分子催化剂(2.5mmol)用1ml二氯甲烷溶解，低温冰浴下滴入三氟甲磺酸(2.5mmol)，蒸除二氯甲烷后将此催化剂加入反应器中，最后加入间硝基苯甲酸(12.5mmol)，加热至60℃，搅拌2天后反应完成，柱色谱分离得到目标产物β-氨基酸酯86％，>99％ee。其结构确证的核磁数据如下：1H NMR(400MHz,CDCl3)δ7.40–7.26(m,5H),5.44(d,J＝19.0Hz,1H),5.13–4.99(m,2H),4.15(q,J＝7.1Hz,2H),3.61(dd,J＝13.8,7.8Hz,1H),3.43(dd,J＝13.8,5.5Hz,1H),2.63–2.49(m,1H),2.49–2.35(m,2H),2.01(dt,J＝9.6,6.1Hz,1H),1.79(d,J＝3.8Hz,1H),1.59(ddd,J＝22.2,13.7,7.2Hz,4H),1.23(dd,J＝14.0,6.9Hz,3H).13C NMR(101MHz,CDCl3)δ209.07,170.99,156.53,136.66,128.59,128.17,66.84,62.12,61.88,44.90,40.89,33.90,27.23,22.12,14.12.
同样的方法合成如下1-18的化合物：
1、
β-氨基酸酯，产率为81％,>99％ee。其结构确证的核磁数据如下：1H NMR(400MHz,CDCl3)δ7.40–7.26(m,5H),5.87(ddd,J＝16.4,10.8,5.6Hz,1H),5.36–5.30(s,1H),5.30–5.21(m,2H),5.07(s,2H),4.60(t,J＝5.6Hz,2H),3.72–3.52(m,2H),2.18(s,3H),1.42(s,3H).13C NMR(101MHz,CDCl3)δ205.50,171.42,156.63,136.52,131.39,128.63,128.26,128.19,119.33,66.96,66.41,60.69,45.18,26.48,18.02.
2、
β-氨基酸酯，产率为80％,>99％ee。其结构确证的核磁数据如下：1H NMR(400MHz,CDCl3)δ7.39–7.26(m,5H),5.30(s,1H),5.19–4.94(m,2H),3.56(ddd,J＝35.1,14.0,6.6Hz,2H),2.17(s,3H),1.43(s,9H).13C NMR(101MHz,CDCl3)δ206.06,170.71,156.60,136.59,128.64,128.25,128.23,82.75,66.93,61.17,45.16,27.91,26.47,18.02.
3、
β-氨基酸酯，产率为51％,>99％ee。相应的产物核磁数据如下：1H NMR(400MHz,CDCl3)δ7.41–7.28(m,5H),7.28–7.19(m,3H),7.09(d,J＝6.6Hz,2H),5.07(s,1H),5.06(s,2H),4.18(q,J＝7.1Hz,2H),3.58(dt,J＝14.2,7.0Hz,2H),3.24(dd,J＝38.9,14.1Hz,2H),2.21(s,3H),1.25(t,J＝7.1Hz,4H).13C NMR(101MHz,CDCl3)δ204.81,171.06,156.47,136.51,135.30,130.00,128.73,128.66,128.31,128.26,127.43,67.05,65.12,61.96,43.32,37.98,27.73,14.05.
4、
β-氨基酸酯，产率为51％,99％ee。相应的产物核磁数据如下：1H NMR(400MHz,CDCl3)δ7.40–7.27(m,9H),5.61(td,J＝17.2,7.5Hz,1H),5.13(dt,J＝21.9,11.0Hz,5H),5.06–4.97(m,2H),3.68(qd,J＝14.3,6.7Hz,2H),2.66(qd,J＝14.5,7.4Hz,2H),2.12(s,3H).13C NMR(101MHz,CDCl3)δ204.39,170.77,156.50,136.50,135.10,131.59,128.80,128.73,128.64,128.28,128.23,120.07,67.69,67.01,64.06,43.12,36.40,27.25.
5、
β-氨基酸酯，产率为54％，>99％ee。相应的产物核磁数据如下：1H NMR(400MHz,CDCl3)δ7.41–7.27(m,10H),5.16(q,J＝12.1Hz,3H),5.04(q,J＝12.2Hz,2H),3.90(dd,J＝14.5,7.3Hz,1H),3.80(dd,J＝14.5,6.2Hz,1H),2.82(d,J＝2.2Hz,2H),2.16(s,3H).13CNMR(101MHz,CDCl3)δ202.44,169.68,156.58,136.40,134.92,128.79,128.65,128.62,128.33,128.26,78.36,72.52,68.00,67.11,63.12,43.14,26.90,21.65.
6、
β-氨基羰基化合物，产率为99％，97％ee。相应的产物核磁数据如下：1H NMR(400MHz,CDCl3)δ7.40–7.27(m,5H),5.29(s,1H),5.05(s,2H),3.57(d,J＝6.6Hz,2H),2.48(q,J＝7.1Hz,2H),2.14(s,3H),1.41(s,3H),1.03(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ210.27,207.79,156.69,136.52,128.63,128.23,128.08,66.96,66.49,45.01,32.28,26.88,17.60,7.83.
7、
β-氨基羰基化合物，产率为97％，>99％ee。相应的产物核磁数据如下：1H NMR(400MHz,CDCl3)δ8.51(s,1H),7.49(d,J＝7.7Hz,2H),7.38–7.27(m,7H),7.13(d,J＝7.4Hz,1H),5.50(s,1H),5.13–5.02(m,2H),3.78(d,J＝6.8Hz,1H),3.70(dd,J＝14.4,6.8Hz,1H),2.33(s,3H),1.51(s,3H).13C NMR(101MHz,CDCl3)δ209.25,168.96,157.03,137.50,136.25,129.11,128.65,128.34,128.16,124.93,120.52,67.25,61.11,45.80,27.33,20.12.
8、
β-氨基羰基化合物，产率为99％，>99％ee。相应的产物核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.32(s,1H),7.44–7.27(m,8H),6.84(d,J＝9.0Hz,2H),5.47(s,1H),5.16–5.00(m,2H),3.86–3.73(m,4H),3.69(dd,J＝14.3,6.8Hz,1H),2.33(s,3H),1.51(s,3H).13C NMR(101MHz,CDCl3)δ209.29,168.74,156.90,136.30,130.55,128.68,128.35,128.18,122.30,114.28,67.25,60.95,55.63,45.82,27.33,20.17.
9、
β-氨基羰基化合物，产率为92％，99％ee。相应的产物核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.41–7.15(m,10H),6.72(s,1H),5.45(s,1H),5.04(s,2H),4.39(d,J＝5.7Hz,2H),3.69(dd,J＝14.1,6.7Hz,1H),3.62(dd,J＝14.1,6.7Hz,1H),2.23(s,3H),1.42(s,3H).13C NMR(101MHz,CDCl3)δ208.56,170.68,156.91,137.85,136.40,128.88,128.74,128.65,128.30,128.14,127.75,127.73,67.09,60.53,45.72,43.98,26.98,19.38.
10、
β-氨基酸酯，产率为99％，99％ee。相应的产物核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.44–7.27(m,5H),5.45(d,J＝9.7Hz,1H),5.09(s,2H),4.16(qd,J＝7.1,2.3Hz,2H),3.54(qd,J＝14.1,6.6Hz,2H),2.56–2.25(m,3H),2.17–1.89(m,3H),1.23(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ213.81,171.40,156.91,136.49,128.59,128.22,128.14,66.96,61.79,61.12,42.61,38.18,31.72,19.68,14.09.
11、
β-氨基酸酯，产率为91％，>99％ee。相应的产物核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.40–7.27(m,5H),5.44(s,1H),5.06(s,2H),4.26–3.98(m,2H),3.63(dd,J＝13.9,8.0Hz,1H),3.53(dd,J＝13.9,5.3Hz,1H),2.76–2.62(m,1H),2.52(dd,J＝16.4,5.9Hz,1H),2.07(dd,J＝12.8,9.0Hz,1H),1.87–1.73(m,2H),1.69(dd,J＝14.6,6.1Hz,1H),1.65–1.53(m,3H),1.53–1.42(m,1H),1.23(dd,J＝13.2,6.1Hz,3H).13CNMR(101MHz,CDCl3)δ210.25,171.73,156.58,136.67,128.58,128.15,100.10,66.80,63.55,61.72,45.61,42.69,31.64,30.04,25.59,25.15,14.09.
12、
β-氨基羰基化合物，产率为54％，94％ee。相应的产物核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.78(d,J＝7.7Hz,2H),7.51(t,J＝7.3Hz,1H),7.40(t,J＝7.6Hz,2H),7.36–7.23(m,5H),5.46(d,J＝3.8Hz,1H),5.00(s,2H),3.90–3.65(m,2H),2.77–2.50(m,2H),2.37(ddd,J＝14.5,9.2,5.5Hz,1H),2.01(d,J＝21.4Hz,1H),1.92–1.76(m,2H),1.76–1.56(m,2H).13C NMR(101MHz,CDCl3)δ211.30,199.20,156.61,136.47,135.87,132.97,129.00,128.65,128.59,128.48,128.06,127.97,67.09,66.79,44.98,41.35,34.31,27.28,21.59.
13、
β-氨基羰基化合物，产率为97％，>99％ee。相应的产物核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.44–7.11(m,11H),5.23(s,1H),5.13–4.97(m,2H),4.50–4.25(m,2H),3.55(dd,J＝14.0,7.1Hz,1H),3.44(dd,J＝14.0,5.6Hz,1H),2.58–2.25(m,3H),2.12–2.00(m,1H),1.94(td,J＝13.7,6.6Hz,2H).13C NMR(101MHz,CDCl3)δ218.65,168.75,156.64,137.99,136.31,128.84,128.61,128.29,128.17,127.60,67.11,60.76,45.31,43.74,38.83,30.95,18.75.
14、
β-氨基羰基化合物，产率为91％，99％ee。相应的产物核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.44(s,1H),7.47(d,J＝7.9Hz,2H),7.35(d,J＝4.6Hz,1H),7.32–7.21(m,7H),7.11(t,J＝7.4Hz,1H),5.50(s,1H),5.07–4.92(m,2H),3.79–3.57(m,2H),2.71(q,J＝14.9Hz,2H),2.31(d,J＝10.3Hz,1H),2.05–1.89(m,1H),1.83(s,4H).13C NMR(101MHz,CDCl3)δ212.29,168.58,156.97,137.49,136.29,129.08,128.61,128.25,128.05,124.86,120.73,67.13,62.28,45.73,41.16,34.58,26.73,21.55.
15、
β-氨基羰基化合物，产率为98％，99％ee。相应的产物核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.44–7.27(m,5H),5.44(s,1H),5.10(d,J＝6.8Hz,2H),3.64(dd,J＝14.3,7.4Hz,1H),3.52(dd,J＝14.2,6.1Hz,1H),2.58–2.28(m,3H),2.14(ddt,J＝33.9,14.4,7.1Hz,3H).13C NMR(101MHz,CDCl3)δ208.45,156.76,136.04,128.65,128.39,128.19,117.93,67.41,50.15,43.37,36.73,32.32,19.28.
16、
β-氨基酸酯，产率为92％，99％ee。相应的产物核磁数据如下：
1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.5Hz,2H),7.58(d,J＝7.5Hz,2H),7.40(t,J＝7.4Hz,2H),7.31(t,J＝7.4Hz,2H),5.33(t,J＝6.3Hz,1H),4.36(p,J＝10.6Hz,2H),4.21(q,J＝7.1Hz,2H),4.17(t,J＝7.0Hz,1H),3.71–3.50(m,2H),2.20(s,3H),1.42(s,3H),1.27(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ205.90,171.78,156.66,144.02,141.44,127.83,127.20,125.21,120.11,67.03,61.97,60.64,47.33,45.17,26.51,18.05,14.13.
17、
β-氨基酸酯，产率为99％，98％ee。相应的产物核磁数据如下：
1H NMR(400MHz,CDCl3)δ5.03(s,1H),4.19(qd,J＝7.1,2.4Hz,2H),3.50(dd,J＝14.0,7.1Hz,2H),2.17(s,3H),1.38(d,J＝6.1Hz,12H),1.26(s,3H).13C NMR(101MHz,CDCl3)δ205.82,171.92,156.03,79.53,61.79,60.74,44.71,28.45,28.41,28.21,26.46,17.99,14.11.
18、
β-氨基羰基化合物，产率为86％，>99％ee。相应的产物核磁数据如下：
1H NMR(400MHz,CDCl3)δ8.70(s,1H),8.14(s,1H),7.75(d,J＝7.5Hz,2H),7.56(d,J＝7.0Hz,2H),7.39(t,J＝7.4Hz,2H),7.33–7.25(m,2H),6.89(s,1H),5.42(s,1H),4.39(dd,J＝14.0,7.0Hz,2H),4.18(t,J＝6.8Hz,1H),3.87(s,3H),3.81(s,3H),2.31(s,3H),1.53(s,3H).

Claims (9)

1.一种手性β-氨基酸衍生物，其结构式如式I所示：
式I中，R1为氢原子、烷基取代基和芳基取代基中的至少一种；
R2为氢原子、烷基取代基、芳基取代基和芳胺基中的至少一种；和/或烯丙基，和/或炔丙基；和/或，R1、R2为碳原子数为3～8之间整数的环烷基；
R3为氢原子、烷基取代基、CN、COR31、COOR32和CONHR33中的至少一种；R3中，R31为碳原子数1～5的烷基，R32为碳原子数1～5的烷基和/或烯丙基；R33为对甲氧基苯基、对甲基苯基和苄基中的至少一种；
所述PG为氨基保护基。
2.根据权利要求1所述的衍生物，其特征在于：所述R1和所述R2中，所述烷基取代基为C1-C5的烷基；所述芳基取代基为苯基、对氯苯基、邻氯苯基、对甲氧基苯基和对甲基苯基中的至少一种；
所述R2中，所述芳胺基为苯胺基、苄胺基、对甲氧基苯胺基和对甲基苯胺基中的至少一种；
所述氨基保护基包括叔丁氧羰基、苄氧羰基、芴甲氧基羰基、对甲苯磺酰基、三苯甲基、乙酰基、苄基、邻苯二甲酰亚胺和三氟甲基乙酰基中的至少一种。
3.一种N，O-缩醛，其结构式如式Ⅱ所示：
式Ⅱ中，PG为氨基保护基，所述氨基保护基包括叔丁氧羰基、苄氧羰基、芴甲氧基羰基、对甲苯磺酰基、三苯甲基、乙酰基、苄基、邻苯二甲酰基和三氟甲基乙酰基中的至少一种；
LG为离去基团，所述离去基团包括OAc、Cl、Br、OMe和OTs中的至少一种。
4.权利要求3所述N，O-缩醛的制备方法，包括如下步骤：将结构式为PGNH2的氨与甲醛混合，在溶剂中进行缩合保护反应，即得到所述N，O-缩醛；
PG为氨基保护基，所述氨基保护基包括叔丁氧羰基、苄氧羰基、芴甲氧基羰基、对甲苯磺酰基、三苯甲基、乙酰基、苄基、邻苯二甲酰基和三氟甲基乙酰基中的至少一种。
5.根据权利要求4所述制备方法，其特征在于：所述结构式为PGNH2的氨与甲醛的摩尔比为1：1.1～1.5；所述溶剂为乙酸和乙酸酐的混合物，所述乙酸和所述乙酸酐的体积比为1:1～5；
所述缩合反应的温度为20～80℃，时间为1～5天。
6.权利要求1或2所述的手性β-氨基酸衍生物的制备方法，包括如下步骤：
将羰基化合物与所述N，O-缩醛的混合物与手性伯叔二胺有机小分子催化剂、强酸和弱酸混合，反应，即得到所述手性β-氨基酸衍生物；
所述羰基化合物包括醛和/或酮。
7.根据权利要求6所述的制备方法，其特征在于：所示羰基化合物的结构式如下式1或式2所示：
上述式1和式2中，R6为氢原子、烷基取代基和芳基取代基；R6中，所述烷基取代基为碳原子数1～5的烷基和/或烯丙基，所述芳基取代基为苯基、对氯苯基、对甲氧基苯基和对甲基苯基中的至少一种；
R7为氢原子、烷基取代基和芳基取代基；R7中，所述烷基取代基为碳原子数1～3的烷基，所述芳基取代基为苯基、苄基、对氯苯基和对甲氧基苯基中的至少一种；
R8为吸电子基，所述吸电子基包括酯基、酰胺基、酰基、氰基、三氟甲基和硝基中的至少一种；n2为0～5中的整数。
8.根据权利要求6或7所述的制备方法，其特征在于：所述手性伯叔二胺有机小分子催化剂的结构如下式3或4所示：
上述式3和4中，R4为氢原子、烷基取代基和芳基取代基；R5为氢原子、烷基取代基和芳基取代基中任何一种；n1为0～9中的整数；
R4和R5中，所述烷基取代基为碳原子数为1～6的烷基，所述芳基取代基为苯基和/或苄基。
9.根据权利要求6-8中任一项所述的制备方法，其特征在于：所述强酸包括三氟乙酸、三氯乙酸、乙酸、三氟甲磺酸、甲磺酸、苯磺酸、对甲基苯磺酸、四氟硼酸、四芳基硼酸、六氟磷酸、高氯酸和次氯酸中的至少一种；
所述弱酸包括苯甲酸和/或带取代基的苯甲酸；所述带取代基的苯甲酸包括萘甲酸、2，4-二硝基苯甲酸、间硝基苯甲酸和邻硝基苯甲酸中的至少一种；
所述羰基化合物与所述N，O-缩醛的摩尔比为1：1～5；
所述手性伯叔二胺有机小分子催化剂与所述羰基化合物的摩尔比为0.5～30：100；
所述手性伯叔二胺有机小分子催化剂、所述强酸和所述弱酸的摩尔比为1：0.5～2：0～5；
所述反应的温度为20℃～100℃，时间为1～6天；
所述制备方法中，还包括分离提纯的步骤；所述提纯方法包括柱层析、减压蒸馏和重结晶中的至少一种。
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