CN118125950A - 一种手性α-氨基酸衍生物及其制备方法和应用 - Google Patents

一种手性α-氨基酸衍生物及其制备方法和应用 Download PDF

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CN118125950A
CN118125950A CN202211544565.7A CN202211544565A CN118125950A CN 118125950 A CN118125950 A CN 118125950A CN 202211544565 A CN202211544565 A CN 202211544565A CN 118125950 A CN118125950 A CN 118125950A
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substituted
phenyl
hydrogen
straight
alkyl
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王天利
张红奎
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Sichuan University
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Sichuan University
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Abstract

本发明公开了一种手性α‑氨基酸衍生物及其制备方法和应用，制备方法包括以下步骤：在手性季鏻盐催化剂的作用下，将化合物(±)‑1溶于有机溶剂中，再加入碱，经过不对称动力学拆分反应制得手性化合物。本发明通过不对称动力学拆分反应对消旋的α‑氨基酸衍生物进行选择性的拆分，得到手性的α‑氨基酸衍生物，其合成方法操作简单，条件温和，合成的手性非天然α‑氨基酸衍生物具有高反应收率(yield)和高对映选择性(ee)。其合成方法简单，操作方便，不需要无水无氧条件，反应不涉及到过渡金属，没有金属残留问题，绿色环保。

Description

一种手性α-氨基酸衍生物及其制备方法和应用
技术领域
本发明涉及化工和医药技术领域，具体涉及一种手性α-氨基酸衍生物及其制备方法和应用。
背景技术
在化学上，任何含有羧基和氨基的分子都可以称为氨基酸。这类化合物种类繁多，任何含有这两种取代基的线性分子或环状分子都包含在其中。然而在生物领域，有一大类氨基酸残基在进化过程中被选为构建生物大分子蛋白质的基石，即22种遗传编码的氨基酸(20种常见标准氨基酸以及硒半胱氨酸和吡咯赖氨酸)，这些氨基酸通常被称为蛋白氨基酸。但是截止到上个世纪70年代末，科学家演技发现已经在天然蛋白质中发现了140多种非遗传编码的氨基酸及其衍生物，迄今已有数千种非蛋白氨基酸被化学和生物学家成功合成；此外，为了构建功能更多样的蛋白质或者肽链，越来越多的非蛋白氨基酸也被引入到了蛋白质的合成中。由于氨基酸在制药、食品、化妆品以及农业等领域有着重要的应用价值，科研人员对这类化合物的研究兴趣也在不断增长。作为蛋白质结构和功能基石的标准氨基酸几乎全是L-α-氨基酸(甘氨酸无手性中心)，其中只有一小部分(如L-谷氨酸和L-赖氨酸等)具有重要的经济价值；相比之下，非标准氨基酸种类丰富，其包含具有非常规侧链的氨基酸(如L-叔亮氨酸)、D构型的氨基酸以及非邻位氨基取代的氨基酸(如β-氨基酸，γ-氨基酸等)，这类氨基酸有着广阔的应用前景。
经过调研发现，比如L-α-芳基氨基酸及衍生物在化学和生物工程中被广泛关注，但是目前对此类手性化合物的合成方法和合成策略还非常有限。
发明内容
为了解决现有技术存在的上述不足，本发明的目的是提供一种手性α-氨基酸衍生物及其制备方法和应用，本发明通过不对称动力学拆分反应对消旋的α-氨基酸衍生物进行选择性的拆分，得到手性α-氨基酸衍生物，其合成方法操作简单，条件温和，合成的手性非天然α-氨基酸衍生物具有高反应收率(yield)和高对映选择性(ee)。
本发明解决上述技术问题的技术方案如下：提供一种手性α-氨基酸衍生物，包括：结构通式I及其相应的对映异构体、盐或其晶型：
其中，(1)当n＝0时
R为
R1为-OC1-20烷基，NH-芳基或取代的NH-芳基，NH-苄基或取代的NH-苄基，-OCOC1-20烷基，苯基或取代苯基，苯氧基或取代苯氧基，-OAd；
R2为氢，-OC1-20烷基或取代的-OC1-20烷基，-OCO2C1-20烷基，-OPh，苯基或取代苯基，萘基或取代萘基，卤素，杂芳环基，C3-20环烷基，C1-20直链或支链烷基或取代的C1-20直链或支链烷基；
R3为苯甲酰基或取代苯甲酰基，苯基乙酰基或取代苯基乙酰基，C1-20直链或支链烷基酰基，苯磺酰基或取代苯磺酰基，烷基磺酰基，甲酰基吡啶或取代甲酰基吡啶，甲酰基喹啉或取代甲酰基喹啉，二苯基磷氧基或二-(取代苯基)磷氧基，叔丁氧碳基，苄氧羰基或取代苄氧羰基，苄基或取代苄基，苯基或取代苯基，笏甲氧羰基，烯丙氧羰基，三甲基硅乙氧羰基，2,2,2-氯乙氧羰基，
R4为氢，苯基或取代苯基，卤素，萘基或取代萘基，杂芳环基，C3-20环烷基，C1-20直链或支链烷基；
R5为氢，苯基或取代苯基，卤素，萘基或取代萘基，杂芳环基，C3-20环烷基，C1-20直链或支链烷基；
R6和R7均为-Bn；
R8为氢，C1-10直链或支链烷基，烷氧基，卤素，杂原子，环烷基，-CF3，苯基或取代苯基；
X1、X2和X3均为H或杂原子；
X4为卤素；
(2)当n＝1，2时
R为
R1为-OC1-20烷基，NH-芳基或取代的NH-芳基，NH-苄基或取代的NH-苄基，OCOC1-20烷基，苯氧基或取代苯氧基，-OBn或取代的-OBn；
R3为氢，苯基或取代苯基，苯甲基，氰基，C1-10直链或支链烷基，C3-20环烷基，-OCOC1-20烷基；
R10为氢，C1-20直链或支链烷基，烷氧基，卤素，三氟甲基，三氟甲硫基，-OCOC1-20直链或支链烷基，-OCOC3-10环烷基，-OTs，TBDPSO-，TBSO-，SPTO-，-OBn， 苯基，氰基；
R9为氢，卤素，-OC1-20烷基，C1-20直链或支链烷基或取代的C1-20直链或支链烷基，-OTs或取代的-OTs；
R11为氢，C1-20直链或支链烷基，烷基苯，-OCOC1-20直链或支链烷基；
R12为氢；
R13为氢，C1-20直链或支链烷基，氰基，C3-10环烷基，-OCOC1-20直链或支链烷基，烷基苯。
在上述技术方案的基础上，本发明还可以做如下改进：
进一步，(1)当n＝0时，
R为
R1为甲氧基，乙氧基，丙氧基，丁氧基，-OPh，-OAd，苯基或取代苯基(如卤素取代)，NH-芳基或取代的NH-芳基，-OCOC1-20烷基；
R2为氢，-OMe，-OBn，-OPh，甲基，卤素，-CF3，-OCF3，苯基，乙基，环丙基，异丙基，-CHF2，杂芳环基；
R3为氢，-HTs，NH-苄基或取代的NH-苄基，苯磺酰基或取代苯磺酰基，烷基磺酰基(如甲基磺酰基，乙基磺酰基，叔丁基磺酰基，环己烷磺酰基，环戊烷磺酰基)，叔丁氧碳基，苄氧羰基或取代苄氧羰基，C1-20直链或支链烷基酰基，苯甲酰基或取代苯甲酰基，甲酰基吡啶，甲酰基喹啉，苯基乙酰基或取代苯基乙酰基，笏甲氧羰基，烯丙氧羰基，三甲基硅乙氧羰基，2,2,2-氯乙氧羰基，
R4为氢，苯基或取代苯基；
R5为氢，苯基或取代苯基，卤素，萘基或取代萘基，杂芳环基，C3-20环烷基，C1-20直链或支链烷基；
R6和R7均为-Bn；
R8为氢，C1-10直链或支链烷基，甲氧基，卤素，杂原子，环烷基，-CF3，苯基；
X1、X2和X3均为H，S，O，N；
X4为卤素。
(2)当n＝1时
R为
R1为-OC1-20烷基，-OPh，-OBn；
R3为氢，苯基或取代苯基(如三氟甲硫基取代等)，苯甲基，氰基，C1-10直链或支链烷基，C3-20环烷基(如环戊烷等)，-OCOC1-20烷基；
R10为氢，甲氧基，甲基，卤素，三氟甲基，三氟甲硫基，-OCOC1-20直链或支链烷基，-OCO-环丙基，-OTs，TBDPSO-，TBSO-，SPTO-，/>苯基，氰基；
R11为甲基，苯甲基，-OCOC1-20直链或支链烷基，异丙基；
R9为氢，卤素，甲氧基，三氟甲基；
(3)当n＝2时
R为
R1为-OC1-20烷基；
R12为氢，三氟甲硫基；
R13为甲基，氰基，环丙基，-OCOC1-20直链或支链烷基，苯甲基；
R3为氢。
上述结构通式中，当N键满时，R3不存在。
进一步，手性α-氨基酸衍生物具体结构式如下：
上述手性α-氨基酸衍生物的制备方法，包括以下步骤：
在手性季鏻盐催化剂的作用下，将化合物(±)-1溶于有机溶剂中，再加入碱，经过不对称动力学拆分反应制得手性α-氨基酸化合物(S)-1或(R)-1；其合成路线如下：
进一步，有机溶剂为二氯甲烷，氯仿，1，2-二氯乙烷，正己烷，环己烷，正戊烷，石油醚，四氢呋喃，乙醚，甲基叔丁基醚，乙酸乙酯，甲醇，乙醇，乙腈，氟苯，氯苯，溴苯，甲苯，邻二甲苯，间二甲苯，对二甲苯，二甲苯或三甲苯。
进一步，碱性物质为三乙胺，二异丙基乙基胺，DABCO，碳酸氢钾，碳酸氢钠，碳酸钾，碳酸钠，碳酸铯，磷酸钾，七水磷酸钾，三水磷酸钾磷酸钠，十水磷酸钠，亚硫酸钠，乙酸钠，苯酚钠，氢氧化钠，氢氧化铯，叔丁醇钾，氢氧化钾或氢氧化锂。
进一步，反应温度为-80～80℃，反应时间为3-72h。
进一步，手性季鏻盐催化剂为：
其中，化合物Ⅳ中，R7为氢，C1-20烷基，苯基或者取代的苯基，苄基或取代的苄基，杂环或取代的杂环；R5为Boc，Ts，酰基或取代的酰基，脲基，硫脲基或取代的硫脲基，羰基或取代的羰基；R6为C1-20烷基，苯基或者取代的苯基，苄基或取代的苄基，萘基或取代的萘基；X为卤素，BF4，PF6，NO2，NO3，OTf，OAc或OPh；
化合物Ⅴ中，R4为氢，C1-20烷基，硅基，Boc，Ts，苄基或取代的苄基；R5为Boc，Ts，酰基或取代的酰基，脲基，硫脲基或取代的硫脲基，羰基或取代的羰基；R6为C1-20烷基，苯基或者取代的苯基，苄基或取代的苄基，萘基或取代的萘基；X为卤素，BF4，PF6，NO2，NO3，OTf，OAc或OPh。
进一步，手性季鏻盐催化剂为：
上述手性α-氨基酸衍生物在制备手性非天然氮保护的氨基酸或者合成类天然产物分子中的应用。
本发明具有以下有益效果：
(1)本发明通过不对称动力学拆分反应对消旋的α-氨基酸衍生物进行选择性的拆分，得到手性的α-氨基酸衍生物，其合成方法操作简单，条件温和，合成的手性非天然α-氨基酸衍生物具有高反应收率(yield)和高对映选择性(ee)。其合成方法简单，操作方便，不需要无水无氧条件，反应不涉及到过渡金属，没有金属残留问题，绿色环保。
(2)本发明在合成过程中所用的催化剂是手性季鏻盐催化剂，该类催化剂对空气和水十分稳定，且具有良好的水溶性，对环境友好。
附图说明
图1为化合物1-2的消旋体HPLC谱图。
图2为化合物1-2的手性产物HPLC谱图。
图3为化合物1-21的消旋体HPLC谱图。
图4为化合物1-21的手性产物HPLC谱图。
图5为化合物1-50的消旋体HPLC谱图。
图6为化合物1-50的手性产物HPLC谱图。
图7为化合物1-94的消旋体HPLC谱图。
图8为化合物1-94的手性产物HPLC谱图。
图9为化合物1-125的消旋体HPLC谱图。
图10为化合物1-125的手性产物HPLC谱图。
图11为化合物1-138的消旋体HPLC谱图。
图12为化合物1-138的手性产物HPLC谱图。
图13为化合物1-151的消旋体HPLC谱图。
图14为化合物1-151的手性产物HPLC谱图。
图15为化合物1-165的消旋体HPLC谱图。
图16为化合物1-165的手性产物HPLC谱图。
图17为化合物1-202的消旋体HPLC谱图。
图18为化合物1-202的手性产物HPLC谱图。
图19为化合物1-207的消旋体HPLC谱图。
图20为化合物1-207的手性产物HPLC谱图。
图21为化合物1-125的消旋体HPLC谱图。
图22为化合物(R)1-125的手性产物HPLC谱图。
具体实施方式
本发明提供的手性α-氨基酸衍生物1-1～1-234，其制备过程中对应的原料即消旋体α-氨基酸衍生物通过以下方法制得：
化合物1-1～1-124：
将4-苄氧基苯乙酸(20mol)溶解在甲醇中，冷到到0℃，加入二氯亚砜(1.2当量)，回流4h，脱溶，加入二氯甲烷溶解，食盐水洗涤，无水硫酸钠干燥，脱溶，得到白色固体。将上一步固体溶解在乙腈中，加入对甲苯磺酰基叠氮(1.2当量)，缓慢加入DBU(0.2当量)，反应12h，用乙醚萃取，脱溶，得到黄色油状液体。将上一步产物溶解在甲叔醚中，依次加入对甲苯磺酰胺，催化剂，加热到60℃，反应12h，脱溶，过柱纯化，得到目标产物。
化合物1-125～1-155：
将苯乙酸(20mol)溶解在甲醇中，冷到到0℃，加入二氯亚砜(1.2当量)，回流4h，脱溶，加入二氯甲烷溶解，食盐水洗涤，无水硫酸钠干燥，脱溶，得到白色固体。将上一步固体溶解在二氯甲烷中，加入三乙胺(3.0当量)，酰氯或酸酐或硫代异硫酸酯(1.2当量)，反应4h，食盐水洗涤，脱溶，过柱纯化，得到目标产物。
化合物1-156～1-179：
将对甲氧基苯胺(20mol)与甲酰甲酸乙酯(20mol)溶解在甲苯中，反应26h，过柱纯化得到黄色油状液体。接着将上一步产物与苯乙炔溶解在二氯甲烷中，加入三氟甲磺酸银，氮气保护反应，得到目标产物。
化合物1-180～1-227：
将DL-苯丙氨酸(20mol)溶解在甲醇中，冷到到0℃，加入二氯亚砜(1.2当量)，回流4h，脱溶，加入二氯甲烷溶解，食盐水洗涤，无水硫酸钠干燥，脱溶，得到白色固体，不经纯化直接用于下一步骤。将产物溶解在二氯甲烷中，然后缓慢加入三乙胺(60mmol)。之后，乙酰氯(30mmol)缓慢滴加。将反应混合物在室温下搅拌3h，逐滴加入水以猝灭反应，用二氯甲烷萃取，然后洗涤合并的有机相，用盐水洗涤并用无水Na2SO4干燥。除去溶剂，得到粗产物，不经纯化直接用于下一步骤。在0℃下将上一步产物溶于二氯甲烷中，然后加入草酰氯(30mmol)，反应1小时，食盐水洗涤，萃取，冷去到0℃，加入FeCl3(30mmol)加热至室温并搅拌8小时，加入盐酸，搅拌1h，用二氯甲烷萃取，然后用盐水洗涤合并的有机相，干燥，脱溶，得到直接粗产物。直接投下一步无需纯化。将粗产物溶解在甲醇中，缓慢滴加H2SO4(10ml)。回流12小时。之后，将反应混合物冷却至室温，加入氢氧化钠碱化。食盐水洗涤，无水Na2SO4干燥。快速柱色谱纯化，得到所需化合物。
化合物1-227～1-234：
将DL-苯丙氨酸(20mol)溶解在盐酸中，加热反应，用乙酸乙酯萃取反应，干燥。得到的固体溶解在甲醇中，冷到到0℃，加入二氯亚砜(1.2当量)，回流4h，脱溶，加入二氯甲烷溶解，食盐水洗涤，无水硫酸钠干燥，脱溶，得到白色液体。接着在碘化亚铜催化与碘苯偶联，过柱纯化得到目标产物。
以下所举实例只用于解释本发明，并非用于限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
实施例1：甲基(S)-2-(4-甲氧基苯基)-2-((4-甲基苯基)磺酰胺)醋酸盐1-1的制备
将34.9mg化合物(±)-1-1(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到16.1mg产品1-1；收率46％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.67-7.57(m,2H),7.24-7.17(m,2H),7.17-7.08(m,2H),6.82-6.68(m,2H),5.64(d,J＝7.8Hz,1H),5.00(d,J＝7.8Hz,1H),3.76(s,3H),3.56(s,3H),2.39(s,3H)；13C NMR(100MHz,CDCl3)δ170.90,159.93,143.58,137.14,129.59,128.54,127.44,127.33,114.32,58.92,55.43,53.04,21.62；HRMS(ESI)m/z calcd for C17H18NO5S[M+H]+＝350.1057,found＝350.1055；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例2：2-(4-氟苯基)-2-((4-甲基苯基)磺酰胺)乙酸甲酯1-5的制备
将33.7mg化合物(±)-1-5(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到14.5mg产品1-5；收率43％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.70-7.53(m,2H),7.24-7.08(m,4H),6.97-6.78(m,2H),6.06(d,J＝7.9Hz,1H),5.05(d,J＝7.9Hz,1H),3.54(s,3H),2.36(s,3H)；13C NMR(100MHz,CDCl3)δ170.38,162.71(d,J＝246.3Hz),143.67,136.91,131.24(d,J＝3.3Hz),129.54,129.07(d,J＝8.4Hz),127.18,115.70(d,J＝21.7Hz),58.74,53.09,21.49；19F NMR(376MHz,CDCl3)δ-113.10(s)；HRMS(ESI)m/z calcd for C16H16NO4SF[M+Na]+＝360.0676,found＝360.0678；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例3：2-((4-甲基苯基)磺胺基)-2-(4-(三氟甲基)苯基)乙酸甲酯1-8的制备
将38.7mg化合物(±)-1-8(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到14.5mg产品1-8；收率46％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.61(d,J＝8.3Hz,2H),7.42-7.33(m,2H),7.21(d,J＝8.0Hz,2H),7.15-7.05(m,2H),5.92(d,J＝7.6Hz,1H),5.04(d,J＝7.6Hz,1H),3.60(s,3H),2.41(s,3H)；13C NMR(100MHz,CDCl3)δ170.12,143.83,136.88,134.38,131.95,129.62,129.00,127.24,122.83,58.89,53.28,21.62；HRMS(ESI)m/z calcd forC16H16NO4SBr[M+Na]+＝419.9876,found＝419.9880；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例4：2-((4-甲基苯基)磺胺基)-2-(间甲苯基)乙酸甲酯1-14的制备
将33.3mg化合物(±)-1-14(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到14.7mg产品1-14；收率44％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.67-7.57(m,2H),7.22-6.94(m,6H),5.96-5.71(m,1H),5.03(d,J＝8.0Hz,1H),3.55(s,3H),2.37(s,3H),2.23(s,3H)；13C NMR(100MHz,CDCl3)δ170.67,143.49,138.62,137.08,135.08,129.47,129.38,128.75,127.83,127.2,124.36,59.4,53.00,21.53,21.29；HRMS(ESI)m/z calcd for C17H19NO4S[M+Na]+＝356.0927,found＝356.0720；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例5：2-(3-氟苯基)-2-((4-甲基苯基)磺酰胺)乙酸甲酯1-21的制备
将33.7mg化合物(±)-1-21(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到14.2mg产品1-21；收率42％,98％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.69-7.53(m,2H),7.25-7.18(m,3H),7.06-7.00(m,1H),6.98-6.88(m,2H),5.76(t,J＝6.8Hz,1H),5.05(d,J＝7.6Hz,1H),3.59(s,3H),2.39(s,3H)；13C NMR(100MHz,CDCl3)δ170.15,162.87(d,J＝247.1Hz),143.89,137.70(d,J＝7.2Hz),136.89,130.49(d,J＝8.1Hz),129.68,127.30,123.04(d,J＝3.0Hz),115.72(d,J＝21.0Hz),114.41(d,J＝22.6Hz),58.92,53.35,21.62；19F NMR(376MHz,CDCl3)δ-112.00(s)；HRMS(ESI)m/z calcd for C16H16NO4SF[M+Na]+＝360.0676,found＝360.0683；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例6：2-(2-氯苯基)-2-(4-甲基苯基)磺胺基)乙酸甲酯1-31的制备
将35.3mg化合物(±)-1-31(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到15.5mg产品1-31；收率44％,98％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.65-7.57(m,2H),7.28-7.19(m,2H),7.19-7.07(m,4H),6.09(d,J＝6.3Hz,1H),5.45(d,J＝7.1Hz,1H),3.60(s,3H),2.33(s,3H)；13C NMR(100MHz,CDCl3)δ169.94,143.47,136.77,133.62,133.39,129.89,129.78,129.40,127.21,127.15,56.99,53.30,21.47；HRMS(ESI)m/z calcd for C16H16NO4SCl[M+Na]+＝376.0381,found＝376.0380；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例7：2-(3,5-二甲基苯基)-2-((4-甲基苯基)磺胺基)乙酸甲酯1-37的制备
将34.7mg化合物(±)-1-37(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到14.9mg产品1-37；收率43％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ8.11-7.96(m,1H),7.85-7.67(m,2H),7.58-7.41(m,4H),7.34-7.27(m,2H),7.01(d,J＝8.1Hz,2H),5.93(d,J＝7.5Hz,1H),5.78(d,J＝7.5Hz,1H),3.54(s,3H),2.30(s,3H)；13C NMR(100MHz,CDCl3)δ171.06,143.31,136.64,134.00,130.88,130.71,129.65,129.17,128.81,127.16,126.99,126.45,126.08,125.09,123.10,57.10,53.09,21.45；HRMS(ESI)m/z calcd for C20H19NO4S[M+Na]+＝392.0927,found＝392.0920；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例8：2-((4-甲基苯基)磺胺基)-2-(萘-2-基)乙酸甲酯1-50的制备
将36.9mg化合物(±)-1-50(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到15.5mg产品1-50；收率42％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.64-7.54(m,2H),7.18(d,J＝8.0Hz,2H),6.96-6.81(m,3H),5.52(d,J＝7.5Hz,1H),5.24(d,J＝7.5Hz,1H),3.56(s,3H),2.38(s,3H),2.30(s,3H),2.25(s,3H)；13C NMR(100MHz,CDCl3)δ171.23,143.51,138.67,137.13,136.52,131.81,130.80,129.49,127.28,127.22,127.00,56.12,53.04,21.63,21.12,19.28；HRMS(ESI)m/z calcd for C18H21NO4S[M+Na]+＝370.1083,found＝370.1087；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例9：甲基(R)-2-((4-甲基苯基)磺胺基)-2-噻吩-2-基)乙酸酯1-54的制备
将32.5mg化合物(±)-1-54(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到13.3mg产品1-54；收率41％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.81-7.48(m,2H),7.36-7.10(m,3H),6.97-6.92(m,1H),6.90-6.86(m,1H),5.71(d,J＝8.4Hz,1H),5.32(dd,J＝8.5,0.5Hz,1H),3.62(s,3H),2.40(s,3H)；13C NMR(100MHz,CDCl3)δ169.77,143.87,137.93,136.86,129.70,127.35,127.11,126.60,126.48,55.33,53.31,21.66；HRMS(ESI)m/z calcd forC14H15NO4S2[M+Na]+＝348.0335,found＝348.0336；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例10：苄基(S)-2-((4-甲基苯基)磺胺基)-2-苯乙酸1-69的制备
将39.5mg化合物(±)-1-69(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到17.4mg产品1-69；收率44％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.66(d,J＝8.3Hz,2H),7.34-7.22(m,8H),7.22-7.04(m,4H),5.96(d,J＝8.0Hz,1H),5.16(d,J＝8.2Hz,1H),5.10-4.93(m,2H),2.40(s,3H)；13C NMR(100MHz,CDCl3)δ170.00,143.51,136.99,135.28,134.76,129.56,128.82,128.60,128.57,128.49,127.98,127.21,67.71,59.50,21.58；HRMS(ESI)m/zcalcd for C22H21NO4S[M+H]+＝396.1264,found＝396.1263；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例11：(S)-2-((4-甲基苯基)磺胺基)-N，2-二苯基乙酰胺1-81的制备
将38.0mg化合物(±)-1-81(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到15.2mg产品1-81；收率40％,95％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.76-7.57(m,2H),7.35-7.28(m,2H),7.28-7.19(m,7H),7.18-7.03(m,3H),6.11(d,J＝6.3Hz,1H),5.04(d,J＝6.3Hz,1H),2.32(s,3H)；13C NMR(100MHz,CDCl3)δ167.35,143.98,137.03,136.42,136.23,129.77,129.23,129.03,128.91,127.62,127.40,125.00,120.19,61.36,21.59；HRMS(ESI)m/z calcd for C22H20N2O3S[M+H]+＝381.1267,found＝3381.1267；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例12：(S)-2-苯基-2-((4-(三氟甲氧基)苯基)磺胺基)乙酸甲酯1-94的制备
将38.9mg化合物(±)-1-94(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到15.9mg产品1-94；收率41％,93％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.84-7.75(m,2H),7.63-7.53(m,4H),7.52-7.37(m,3H),7.24(s,5H),6.00(d,J＝8.0Hz,1H),5.16(d,J＝8.0Hz,1H),3.58(s,3H)；13C NMR(100MHz,CDCl3)δ170.58,145.60,139.36,138.60,135.19,129.14,128.89,128.69,128.58,127.76,127.52,127.35,127.31,59.54,53.12；HRMS(ESI)m/z calcd forC21H19NO4S[M+H]+＝382.1108,found＝382.1115；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例13：(甲基(S)-2-((3-氟苯基)磺胺基)-2-苯乙酸1-103的制备
将32.3mg化合物(±)-1-103(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到13.9mg产品1-103；收率43％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.53-7.46(m,1H),7.40-7.30(m,2H),7.28-7.13(m,6H),5.89(d,J＝7.4Hz,1H),5.12(d,J＝7.6Hz,1H),3.62(s,3H)；13C NMR(100MHz,CDCl3)δ170.45,162.27(d,J＝249.4Hz),142.29(d,J＝6.7Hz),134.93,130.75(d,J＝7.7Hz),128.98,128.94,127.34,122.91(d,J＝3.3Hz),119.89(d,J＝21.2Hz),114.60(d,J＝24.5Hz),59.59,53.26；19F NMR(376MHz,CDCl3)δ-109.94(s)；HRMS(ESI)m/zcalcd for C15H14NO4SF[M+H]+＝324.0700,found＝324.0706；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例14：甲基(S)-2-((2-甲基苯基)磺胺基)-2-苯乙酸1-108的制备
将31.9mg化合物(±)-1-108(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到14.4mg产品1-108；收率45％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.87-.59(m,1H),7.42-7.33(m,1H),7.25-7.15(m,7H),5.96(d,J＝7.8Hz,1H),5.14-4.96(m,1H),3.55(s,3H),2.61(s,3H)；13CNMR(100MHz,CDCl3)δ170.62,137.68,137.39,135.15,132.88,132.40,129.44,128.77,128.63,127.07,125.99,59.32,53.01,20.22；HRMS(ESI)m/z calcd for C16H17NO4S[M+H]+＝320.0951,found＝320.0955；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例15：(S)-2-苯基-2-((2,4,6-三甲基苯基)磺胺基)乙酸甲酯1-115的制备
将34.7mg化合物(±)-1-115(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到16.0mg产品1-115；收率46％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.29-7.09(m,5H),6.85(s,2H),5.85(d,J＝7.4Hz,1H),4.99(d,J＝7.4Hz,1H),3.56(s,3H),2.58(s,6H),2.24(s,3H)；13C NMR(100MHz,CDCl3)δ170.65,142.38,139.14,135.25,133.68,131.81,128.66,128.51,127.02,59.16,52.99,22.87,20.88；HRMS(ESI)m/z calcd for C18H21NO4S[M+H]+＝348.1264,found＝348.1269；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例16：甲基(S)-2-(乙基磺胺基)-2-苯乙酸1-121的制备
将25.7mg化合物(±)-1-121(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到12.1mg产品1-121；收率47％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.37(s,5H),5.62(d,J＝6.7Hz,1H),5.20(d,J＝6.8Hz,1H),3.72(s,3H),3.01-2.55(m,2H),1.23(t,J＝7.4Hz,3H)；13C NMR(100MHz,CDCl3)δ171.06,136.16,129.21,129.07,127.45,59.53,53.28,48.63,8.08；HRMS(ESI)m/z calcd for C11H15NO4S[M+H]+＝258.0795,found＝258.0797；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例17：甲基(S)-2-(叔丁氧羰基)氨基)-2-苯乙酸1-125的制备
将26.5mg化合物(±)-1-125(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到11.9mg产品1-125；收率45％,97％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.37-7.31(m,5H),5.54(d,J＝7.3Hz,1H),5.32(d,J＝7.3Hz,1H),3.71(s,3H),1.43(s,9H)；13C NMR(100MHz,CDCl3)δ171.78,154.93,137.03,129.02,128.56,127.26,57.73,52.81,28.44,27.55；HRMS(ESI)m/z calcdfor C14H19NO4[M+H]+＝266.1387,found＝266.1382；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例18：甲基(S)-2-(3,5-双(三氟甲基)苯甲酰胺基)-2-苯乙酸1-131的制备
将40.5mg化合物(±)-1-131(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到16.2mg产品1-131；收率40％,97％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ8.25(s,2H),7.98(s,1H),7.83-7.63(m,1H),7.44-7.28(m,5H),5.77(d,J＝7.1Hz,1H),3.77(s,3H)；13C NMR(100MHz,CDCl3)δ171.39,164.02,135.77(d,J＝13.0Hz),132.19(q,J＝33.8Hz),129.15,128.93,127.74,127.57,127.03,125.37,124.31,121.60,118.89,57.25,53.10；19F NMR(376MHz,CDCl3)δ-62.90(s)；HRMS(ESI)m/z calcd for C18H13NO3F6[M+H]+＝406.0872,found＝406.0881；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例19：甲基(S)-2-(1-萘胺基)-2-苯乙酸1-138的制备
将31.9mg化合物(±)-1-138(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到15.0mg产品1-138；收率47％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ8.43-8.30(m,1H),7.93-7.78(m,2H),7.69-7.58(m,1H),7.56-7.45(m,4H),7.42-7.33(m,4H),7.24-7.15(m,1H),5.90(d,J＝7.3Hz,1H),3.74(s,3H)；13C NMR(100MHz,CDCl3)δ171.31,168.77,136.30,133.58,133.30,130.91,130.18,129.03,128.63,128.23,127.38,127.15,126.39,125.36,125.36,124.57,56.92,52.80；HRMS(ESI)m/z calcd for C20H17NO3[M+H]+＝320.1281,found＝320.1282；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例20：甲基(S)-2-(3-(4-硝基苯基)硫脲基)-2-苯乙酸1-151的制备
将34.5mg化合物(±)-1-151(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到13.8mg产品1-151；收率40％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ8.94(s,1H),8.31-8.04(m,2H),7.63(s,1H),7.58-7.48(m,2H),7.41-7.32(m,5H),6.16(s,1H),3.76(s,3H)；13C NMR(100MHz,CDCl3)δ179.61,172.11,144.43,143.41,135.26,129.34,129.20,127.68,125.41,122.33,61.42,53.42；HRMS(ESI)m/z calcd for C16H15N3O3S[M+H]+＝346.0856,found＝346.0851；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例21：4-(4-乙基苯基)-2-((4-甲氧基苯基)氨基)丁酸乙酯1-158的制备
将33.7mg化合物(±)-1-158(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到13.8mg产品1-158；收率41％,98％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.38-7.30(m,2H),7.17-7.09(m,2H),6.85-6.70(m,4H),4.95(d,J＝6.6Hz,1H),4.34-4.27(m,2H),3.75(s,3H),2.67-2.58(m,2H),1.33(t,J＝7.1Hz,3H),1.21(t,J＝7.6Hz,3H)；13C NMR(100MHz,CDCl3)δ169.20,153.44,145.23,139.63,131.99,127.91,119.41,116.14,114.88,84.64,83.57,62.46,55.76,50.78,28.92,15.44,14.20；HRMS(ESI)m/z calcd for C20H21NO4S[M+H]+＝372.1264,found＝372.1266；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例22：乙基(S)-4-(4-溴苯基)-2-((4-甲氧苯基)氨基)丁-3-炔诺酯1-165的制备
将38.8mg化合物(±)-1-165(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到16.3mg产品1-165；收率42％,98％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.47-7.40(m,2H),7.30-7.24(m,2H),6.85-6.80(m,2H),6.80-6.73(m,2H),4.95(s,1H),4.40-4.25(m,2H),3.77(s,3H),1.34(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3)δ168.79,153.67,139.22,133.46,131.67,123.14,121.19,116.35,114.92,85.42,83.53,62.66,55.78,50.85,14.22；HRMS(ESI)m/z calcdfor C18H16NO4SBr[M+H]+＝422.0056,found＝422.0053；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例23：(S)-2-((4-甲氧苯基)氨基)-4-(间甲苯基)丁-3-炔诺乙酯1-169的制备
将32.3mg化合物(±)-1-169(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到13.2mg产品1-169；收率41％,98％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.25-7.09(m,4H),6.84-6.79(m,2H),6.78-6.71(m,2H),4.95(s,1H),4.36-4.27(m,2H),3.76(s,3H),2.31(s,3H),1.33(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ169.15,153.46,139.61,138.06,132.58,129.67,129.09,128.26,122.06,116.15,114.91,84.62,83.92,62.51,55.78,50.75,21.29,14.22；HRMS(ESI)m/z calcd for C19H19NO4S[M+H]+＝358.1108,found＝358.1101；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例24：乙基(S)-4-(2-氯苯基)-2-((4-甲氧苯基)氨基)丁-3-炔诺酯1-177的制备
将34.3mg化合物(±)-1-177(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到14.4mg产品1-177；收率42％,98％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.35-7.29(m,2H),7.29-7.23(m,3H),6.84-6.78(m,2H),6.78-6.70(m,2H),4.94(s,1H),4.35-4.27(m,1H),3.75(s,3H),1.33(t,J＝7.1Hz,1H)；13C NMR(100MHz,CDCl3)δ168.88,153.61,139.35,134.89,133.25,128.73,120.73,116.27,114.92,85.29,83.40,62.64,55.78,50.78,14.22；HRMS(ESI)m/z calcdfor C18H16NO4SCl[M+H]+＝362.0857,found＝362.0856；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例25：甲基(S)-1,6-二甲基-3,4-二氢异喹啉-3-羧酸盐1-181的制备
将21.7mg化合物(±)-1-181(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到9.8mg产品1-181；收率45％,93％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.37(d,J＝7.8Hz,1H),7.09(d,J＝7.9Hz,1H),7.00(s,1H),4.25-4.07(m,1H),3.79(s,3H),2.90(d,J＝9.6Hz,2H),2.40(d,J＝2.0Hz,3H),2.33(s,3H)；13C NMR(100MHz,CDCl3)δ173.54,165.87,141.66,135.57,128.34,128.02,126.87,125.76,59.99,52.47,28.52,23.38,21.51；HRMS(ESI)m/z calcdfor C13H15NO2[M+H]+＝218.1176,found＝218.1173；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例26：甲基(S)-7-氟-1-甲基-3,4-二氢异喹啉-3-羧酸盐1-189的制备
将22.1mg化合物(±)-1-189(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到10.4mg产品1-189；收率47％,90％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.22-7.14(m,2H),7.10-7.03(m,1H),4.26-4.10(m,1H),3.80(s,3H),3.00-2.81(m,2H),2.42(d,J＝2.0Hz,3H)；13C NMR(100MHz,CDCl3)δ173.14,164.97(d,J＝2.0Hz),161.90(d,J＝244.2Hz),131.11(d,J＝3.3Hz),130.50(d,J＝6.7Hz),129.11(d,J＝7.4Hz),117.99(d,J＝21.4Hz),112.79(d,J＝22.3Hz),60.11,52.61,27.69,23.39；19F NMR(376MHz,CDCl3)δ-113.98(s)；HRMS(ESI)m/zcalcd for C12H12NO2F[M+H]+＝222.0925,found＝222.0926；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例27：甲基(S)-1-甲基-7-(十三烷氧基)-3,4-二氢异喹啉-3-羧酸盐1-192的制备
将41.5mg化合物(±)-1-192(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到17.4mg产品1-192；收率42％,97％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.25-7.20(m,2H),7.10(dd,J＝8.1,2.4Hz,1H),4.30-4.12(m,1H),3.82(s,3H),3.08-2.83(m,2H),2.56(t,J＝7.4Hz,2H),2.43(d,J＝2.1Hz,3H),1.90-1.65(m,3H),1.45-1.24(m,17H),0.87(t,J＝6.9Hz,3H)；13C NMR(100MHz,CDCl3)δ173.30,172.47,165.25,149.95,132.98,130.18,128.67,124.49,119.15,60.08,52.67,34.45,32.02,29.72,29.57,29.45,29.36,29.23,27.95,25.00,23.45,22.80,14.23；HRMS(ESI)m/z calcd for C25H37NO4[M+H]+＝416.2795,found＝416.2796；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例28：甲基(S)-1-甲基-7-(甲苯氧基)-3,4-二氢异喹啉-3-羧酸盐1-201的制备
将37.3mg化合物(±)-1-201(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到17.4mg产品1-201；收率46％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.4Hz,2H),7.31(d,J＝8.0Hz,2H),7.12(d,J＝8.2Hz,1H),7.03(d,J＝2.4Hz,1H),6.96(dd,J＝8.2,2.4Hz,1H),4.22-4.07(m,1H),3.78(s,3H),2.96-2.78(m,2H),2.42(s,3H),2.26(d,J＝2.1Hz,3H)；13CNMR(100MHz,CDCl3)δ172.95,164.61,148.60,145.76,134.36,132.14,130.08,129.89,128.85,128.61,125.03,119.89,59.80,52.58,27.72,23.15,21.74；HRMS(ESI)m/z calcdfor C19H19NO5S[M+H]+＝374.1057,found＝375.1056；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例29：甲基(S)-7-((叔丁基二苯基硅基)氧基)-1-甲基-3,4-二氢异喹啉-3-羧酸盐1-202的制备
将45.7mg化合物(±)-1-202(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到20.6mg产品1-202；收率45％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.78-7.64(m,4H),7.48-7.31(m,6H),6.94(d,J＝8.2Hz,1H),6.87-6.76(m,2H),4.18-4.05(m,1H),3.79(s,3H),2.92-2.71(m,2H),2.13(d,J＝2.1Hz,3H),1.13(s,9H)；13C NMR(100MHz,CDCl3)δ173.60,165.84,154.83,135.63,135.60,132.67,130.20,129.80,128.29,127.99,127.98,127.86,122.46,117.17,60.33,52.50,27.68,26.66,23.22,19.56；HRMS(ESI)m/z calcd for C26H31NO3Si[M+H]+＝458.2146,found＝458.2149；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例30：甲基(S)-2-苯基-1,2,3,4-四氢异喹啉-3-羧酸盐1-206的制备
将26.7mg化合物(±)-1-206(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到12.8mg产品1-206；收率48％,99％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.28-7.20(m,2H),7.19-7.07(m,4H),6.87-6.81(m,2H),6.80-6.73(m,1H),4.81-4.71(m,1H),4.64-4.42(m,2H),3.48(s,3H),3.36-3.21(m,2H)；HRMS(ESI)m/z calcd for C17H17NO2[M+H]+＝268.1332,found＝268.1335；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例31：甲基(S)-2-苯基-1,2,3,4-四氢异喹啉-3-羧酸盐1-207的制备
将26.7mg化合物(±)-1-207(0.1mmol)，三乙胺15.2mg(0.15mmol)，催化剂P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到11.2mg产品1-207；收率42％,91％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.36-7.28(m,3H),7.25-7.20(m,1H),3.75(s,3H),3.68-3.59(m,1H),2.65-2.45(m,4H),2.44(d,J＝1.1Hz,3H)；13C NMR(100MHz,CDCl3)δ174.06,171.25,138.23,137.46,129.92,128.55,126.93,126.24,62.11,52.27,37.06,29.67,26.69；HRMS(ESI)m/z calcd for C13H15NO2[M+H]+＝218.1176,found＝218.1175；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
实施例32：甲基(R)-2-(叔丁氧羰基)氨基)-2-苯乙酸(R)1-125的制备
将26.5mg化合物(±)-1-125(0.1mmol)，三乙胺15.2mg(0.15mmol)，反构型催化剂ent-P17(0.01mmol)和1mL乙腈加入到反应瓶中，搅拌混匀后在30℃下发生反应。该反应催化剂载量为1mol％，反应6h，直接浓缩，柱层析(石油醚/乙酸乙酯，v/v＝3/1)，得到11.9mg产品1-125；收率45％,-95％ee。
核磁和质谱数据：1H NMR(400MHz,CDCl3)δ7.37-7.31(m,5H),5.54(d,J＝7.3Hz,1H),5.32(d,J＝7.3Hz,1H),3.71(s,3H),1.43(s,9H)；13C NMR(100MHz,CDCl3)δ171.78,154.93,137.03,129.02,128.56,127.26,57.73,52.81,28.44,27.55；HRMS(ESI)m/z calcdfor C14H19NO4[M+H]+＝266.1387,found＝266.1382；由上述核磁和高分辨质谱数据可知，所得产物结构正确。
上述化合物及其制备方法仅仅是本发明列举的一些实例，而本发明保护的剩余化合物及其制备方法可以根据替换原料来完成不同化合物的制备，从而得到不同的化合物。
实验例1本发明化合物通过衍生合成手性氨基醇
操作步骤：将所得的39.5mg手性α-氨基酸酯1-69，溶解在四氢呋喃中，冷却到-20℃,缓慢加入LiAlH4，监控反应，反应结束后，加入5％氯化铵溶液猝灭反应，脱溶，过柱纯化，得到手性氨基醇化合物27.6mg(95％yield)。
1H NMR(400MHz,CDCl3)δ7.69-7.48(m,2H),7.24-7.00(m,7H),5.89(d,J＝7.0Hz,1H),4.52-4.34(m,1H),3.82-3.64(m,2H),2.35(s,3H)；13C NMR(100MHz,CDCl3)δ143.41,137.69,137.22,129.53,128.63,127.89,127.27,127.02,66.26,59.80,21.57；HRMS(ESI)m/z calcd for C15H17NO3S[M+H]+＝292.1002,found＝292.1008.
实验例2本发明化合物通过衍生合成手性氮保护羧酸
操作步骤：将所得的39.5mg手性α-氨基酸酯1-69，溶解在氢溴酸中，加热到50℃，反应12h，到反应结束后，乙酸乙酯萃取，脱溶，过柱纯化，得到手性氮保护羧酸30.2mg(99％yield)。
1H NMR(400MHz,CD3OD)δ7.77-7.55(m,2H),7.39-7.13(m,7H),4.95(s,1H),4.89(s,2H),2.37(s,3H)；13C NMR(100MHz,CD3OD)δ172.95,144.53,139.21,137.83,130.43,129.58,129.20,128.42,128.17,61.06,21.41；HRMS(ESI)m/z calcd for C15H17NO3S[M-H]-＝304.0649,found＝304.0642.
实验例3本发明化合物通过衍生合成非蛋白质基氨基酸衍生物
操作步骤：将所得的91.4mg手性α-氨基酸酯1-202，溶解在二氯甲烷中，冷却到0℃,再加入TBAF,反应12h，到反应结束后，加入少许水，萃取，脱溶，过柱纯化，得到中间体。将中间体用二氯甲烷溶解，加入氨基酸残基，加入DCC和DMAP,到反应结束后，加入少许水，萃取，饱和食盐水洗涤，脱溶，过柱纯化，得到手性非蛋白质基氨基酸衍生物39.8mg(70％yield)。
1H NMR(400MHz,CDCl3)δ7.23(t,J＝6.8Hz,2H),7.10(d,J＝8.2Hz,1H),6.30(dd,J＝8.0,8.0Hz,1H),5.23(d,J＝8.8Hz,1H),4.73(dd,J＝7.8,4.8Hz,1H),4.20(d,J＝8.2Hz,1H),3.90(d,J＝8.8Hz,1H),3.82(s,3H),3.15-2.90(m,2H),2.41(s,3H),2.40-2.297(m,1H),1.41(d,J＝8.4Hz,9H),1.09-0.96(m,15H)；13C NMR(100MHz,CDCl3)δ173.10,171.41,171.24,170.46,164.92,149.45,133.36,130.19,128.70,124.05,118.73,79.87,62.54,59.91,57.28,52.58,34.38,31.10,28.30,27.81,26.55,23.34,19.08,17.87,1.02；HRMS(ESI)m/z calcd for C28H41N3O7[M+H]+＝532.3017,found＝532.3019.
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

1.一种手性α-氨基酸衍生物，其特征在于，包括结构通式I及其相应的对映异构体、盐或其晶型：
其中，(1)当n＝0时
R为
R1为-OC1-20烷基，NH-芳基或取代的NH-芳基，NH-苄基或取代的NH-苄基，-OCOC1-20烷基，苯基或取代苯基，苯氧基或取代苯氧基，-OAd；
R2为氢，-OC1-20烷基或取代的-OC1-20烷基，-OCOC1-20烷基，-OPh，苯基或取代苯基，萘基或取代萘基，卤素，杂芳环基，C3-20环烷基，C1-20直链或支链烷基或取代的C1-20直链或支链烷基；
R3为苯甲酰基或取代苯甲酰基，苯基乙酰基或取代苯基乙酰基，C1-20直链或支链烷基酰基，苯磺酰基或取代苯磺酰基，烷基磺酰基，甲酰基吡啶或取代甲酰基吡啶，甲酰基喹啉或取代甲酰基喹啉，二苯基磷氧基或二-(取代苯基)磷氧基，叔丁氧碳基，苄氧羰基或取代苄氧羰基，苄基或取代苄基，苯基或取代苯基，笏甲氧羰基，烯丙氧羰基，三甲基硅乙氧羰基，2,2,2-氯乙氧羰基，
R4为氢，苯基或取代苯基，卤素，萘基或取代萘基，杂芳环基，C3-20环烷基，C1-20直链或支链烷基；
R5为氢，苯基或取代苯基，卤素，萘基或取代萘基，杂芳环基，C3-20环烷基，C1-20直链或支链烷基；
R6和R7均为-Bn；
R8为氢，C1-10直链或支链烷基，烷氧基，卤素，杂原子，环烷基，-CF3，苯基或取代苯基；
X1、X2和X3均为H或杂原子；
(2)当n＝1，2时
R为
R1为-OC1-20烷基，NH-芳基或取代的NH-芳基，NH-苄基或取代的NH-苄基，OCOC1-20烷基，苯氧基或取代苯氧基，-OBn或取代的-OBn；
R3为氢，苯基或取代苯基，苯甲基，氰基，C1-10直链或支链烷基，C3-20环烷基，-OCOC1-20烷基；
R10为氢，C1-20直链或支链烷基，烷氧基，卤素，三氟甲基，三氟甲硫基，-OCOC1-20直链或支链烷基，-OCOC3-10环烷基，-OTs，TBDPSO-，TBSO-，SPTO-，-OBn，/> 苯基，氰基；
R9为氢，卤素，-OC1-20烷基，C1-20直链或支链烷基或取代的C1-20直链或支链烷基，-OTs或取代的-OTs；
R11为氢，C1-20直链或支链烷基，烷基苯，-OCOC1-20直链或支链烷基；
R12为氢；
R13为氢，C1-20直链或支链烷基，氰基，C3-10环烷基，-OCOC1-20直链或支链烷基，烷基苯。
2.根据权利要求1所述的手性α-氨基酸衍生物，其特征在于，(1)当n＝0时，
R为
R1为甲氧基，乙氧基，丙氧基，丁氧基，-OPh，-OAd，苯基或取代苯基，NH-芳基或取代的NH-芳基，-OCOC1-20烷基；
R2为氢，-OMe，-OBn，-OPh，甲基，卤素，-CF3，-OCF3，苯基，乙基，环丙基，异丙基，-CHF2，杂芳环基；
R3为氢，-HTs，NH-苄基或取代的NH-苄基，苯磺酰基或取代苯磺酰基，烷基磺酰基，叔丁氧碳基，苄氧羰基或取代苄氧羰基，C1-20直链或支链烷基酰基，苯甲酰基或取代苯甲酰基，甲酰基吡啶，甲酰基喹啉，苯基乙酰基或取代苯基乙酰基，笏甲氧羰基，烯丙氧羰基，三甲基硅乙氧羰基，2,2,2-氯乙氧羰基，
R4为氢，苯基或取代苯基；
R5为氢，苯基或取代苯基，卤素，萘基或取代萘基，杂芳环基，C3-20环烷基，C1-20直链或支链烷基；
R6和R7均为-Bn；
R8为氢，C1-10直链或支链烷基，甲氧基，卤素，杂原子，环烷基，-CF3，苯基；
X1、X2和X3均为H，S，O，N。
(2)当n＝1时
R为
R1为-OC1-20烷基，-OPh，-OBn；
R3为氢，苯基或取代苯基，苯甲基，氰基，C1-10直链或支链烷基，C3-20环烷基，-OCOC1-20烷基；
R10为氢，甲氧基，甲基，卤素，三氟甲基，三氟甲硫基，-OCOC1-20直链或支链烷基，-OCO-环丙基，-OTs，TBDPSO-，TBSO-，SPTO-，/>苯基，氰基；
R11为甲基，苯甲基，-OCOC1-20直链或支链烷基，异丙基；
R9为氢，卤素，甲氧基，三氟甲基；
(3)当n＝2时
R为
R1为-OC1-20烷基；
R12为氢，三氟甲硫基；
R13为甲基，氰基，环丙基，-OCOC1-20直链或支链烷基，苯甲基；
R3为氢。
3.根据权利要求1或2所述的手性α-氨基酸衍生物，其特征在于，具体结构式如下：
4.权利要求1-3任一项所述的手性α-氨基酸衍生物的制备方法，其特征在于，包括以下步骤：
在手性季鏻盐催化剂的作用下，将化合物(±)-1溶于有机溶剂中，再加入碱性物质，经过不对称动力学拆分反应制得手性α-氨基酸衍生物(S)-1或(R)-1；其合成路线如下：
5.根据权利要求4所述的手性α-氨基酸衍生物的制备方法，其特征在于，有机溶剂为二氯甲烷，氯仿，1，2-二氯乙烷，正己烷，环己烷，正戊烷，石油醚，四氢呋喃，乙醚，甲基叔丁基醚，乙酸乙酯，甲醇，乙醇，乙腈，氟苯，氯苯，溴苯，甲苯，邻二甲苯，间二甲苯，对二甲苯，二甲苯或三甲苯。
6.根据权利要求4所述的手性α-氨基酸衍生物的制备方法，其特征在于，碱性物质为三乙胺，二异丙基乙基胺，DABCO，碳酸氢钾，碳酸氢钠，碳酸钾，碳酸钠，碳酸铯，磷酸钾，七水磷酸钾，三水磷酸钾磷酸钠，十水磷酸钠，亚硫酸钠，乙酸钠，苯酚钠，氢氧化钠，氢氧化铯，叔丁醇钾，氢氧化钾或氢氧化锂。
7.根据权利要求4所述的手性α-氨基酸衍生物的制备方法，其特征在于，反应温度为-80～80℃，反应时间为3-72h。
8.根据权利要求4所述的手性α-氨基酸衍生物的制备方法，其特征在于，手性季鏻盐催化剂为：
其中，化合物Ⅳ中，R7为氢，C1-20烷基，苯基或者取代的苯基，苄基或取代的苄基，杂环或取代的杂环；R5为Boc，Ts，酰基或取代的酰基，脲基，硫脲基或取代的硫脲基，羰基或取代的羰基；R6为C1-20烷基，苯基或者取代的苯基，苄基或取代的苄基，萘基或取代的萘基；X为卤素，BF4，PF6，NO2，NO3，OTf，OAc或OPh；
所述化合物Ⅴ中，R4为氢，C1-20烷基，硅基，Boc，Ts，苄基或取代的苄基；R5为Boc，Ts，酰基或取代的酰基，脲基，硫脲基或取代的硫脲基，羰基或取代的羰基；R6为C1-20烷基，苯基或者取代的苯基，苄基或取代的苄基，萘基或取代的萘基；X为卤素，BF4，PF6，NO2，NO3，OTf，OAc或OPh。
9.根据权利要求8所述的手性α-氨基酸衍生物的制备方法，其特征在于，手性季鏻盐催化剂为：
10.权利要求1-3任一项所述的手性α-氨基酸衍生物在制备手性非天然氮保护的氨基酸或者合成类天然产物分子中的应用。
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