CN117924173A - 苯胺季铵盐类手性相转移催化剂及其在氨基酸衍生物不对称烷基化催化中的应用 - Google Patents
苯胺季铵盐类手性相转移催化剂及其在氨基酸衍生物不对称烷基化催化中的应用 Download PDFInfo
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- 239000003444 phase transfer catalyst Substances 0.000 title claims abstract description 32
- -1 Aniline quaternary ammonium salt Chemical class 0.000 title claims abstract description 30
- 238000005804 alkylation reaction Methods 0.000 title claims abstract description 17
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- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 15
- 150000003862 amino acid derivatives Chemical class 0.000 title claims abstract description 10
- GHBCIXGRCZIPNQ-MHZLTWQESA-N (3s)-2-(2,2-diphenylacetyl)-6-methoxy-5-phenylmethoxy-3,4-dihydro-1h-isoquinoline-3-carboxylic acid Chemical compound C([C@H](N(CC1=CC=C2OC)C(=O)C(C=3C=CC=CC=3)C=3C=CC=CC=3)C(O)=O)C1=C2OCC1=CC=CC=C1 GHBCIXGRCZIPNQ-MHZLTWQESA-N 0.000 claims abstract description 3
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
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- ANYSGBYRTLOUPO-UHFFFAOYSA-N lithium tetramethylpiperidide Chemical compound [Li]N1C(C)(C)CCCC1(C)C ANYSGBYRTLOUPO-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于手性催化和医药技术领域,具体涉及一种苯胺季铵盐类手性化合物,可作为相转移催化剂。本发明通过在联萘骨架的手性季铵盐催化中心N(氮)原子上引入苯基,首次合成了系列苯胺季铵盐类手性相转移催化剂。与申请人前期开发的手性相转移催化剂(催化中心N原子上为脂肪碳链)相比,本发明开发的催化剂通过引入苯基,使N原子与芳环直接相连,改变催化中心的电子效应和空间位阻效应、构建Π‑Π堆积效应等,以提高催化产物的对映选择性。该系列催化剂通过对甘氨酸衍生物进行不对称烷基化催化反应,制备α‑手性氨基酸衍生物,效率高,对映选择性优异,成功应用于Olodanrigan的关键手性氨基酸中间体制备,为手性氨基酸砌块制备提供了可行方案。
Description
技术领域
本发明属于手性催化和医药技术领域,具体涉及苯胺季铵盐类手性相转移催化剂及其在用于氨基酸衍生物不对称烷基化中的应用。
背景技术
过去十年,针对诸如糖尿病、癌症、骨质疏松症、多发性硬化症、艾滋病毒感染和慢性疼痛等各种疾病,成功的治疗靶点和改进的给药方法越来越多。因此在世界医药市场中,多肽类药物的发展日新月异。此外,临床上有超过80种候选肽类药物,目前世界各地正在进行大量的临床前研发项目。现阶段,以高纯度和低成本的方法来高效合成各种类型的非天然氨基酸的需求与日俱增。用于氨基酸席夫碱的不对称烷基化反应中的不对称相转移催化剂,为大规模合成非天然氨基酸的工艺开发中打造了经济和质量上的独特优势。而基于树枝状大分子的手性相转移催化剂的报道实例匮乏。
发明内容
针对本课题组前期开发的简化型Maruoka催化剂中手性季铵盐催化中心的N原子上为脂肪碳链,因脂肪链在催化过程中与反应物之间的弱相互作用比较单一,导致催化中心的作用模式和效应具有相对单一的缺陷,以及催化反应类型受限等现状,而芳环则可以通过改变催化中心的电子效应,位阻效应、共轭效应等丰富催化剂活性中心的作用模式进而拓宽催化反应类型和催化活性。因此,本发明的首要目的是通过在催化中心引入苯基,通过改变手性相转移催化剂催化中心的电子效应、改变空间位阻效应、构建Π-Π堆积效应等,以提高催化剂的催化选择性,开发和拓展不对称催化反应类型。本发明提供了一系列苯胺季铵盐类手性相转移催化剂的设计和合成,以及它们在手性氨基酸衍生物的不对称合成中的应用。
本发明通过在手性季铵盐催化中心的N(氮)原子上引入苯基,合成了一系列苯胺季铵盐类手性相转移催化剂。该系列催化剂通过甘氨酸衍生物席夫碱的不对称烷基化进行了评估。尤其是,结果发现R为3,4,5-F3-C6H2的催化剂具有优异的对映选择性,且产物的对映选择性不受催化剂N上柔性链长度的影响。
为实现以上目的,本发明采用的技术方案是:
一种苯胺季铵盐类手性相转移催化剂,结构式如式(i)或式(ii)所示:
;
其中,R为H原子,苯基,3,4,5-F3-C6H2,(3, 5-CF3-C6H3)或萘基,n为0至21中任一自然数。
作为一种更优选的技术方案,式(i)中n为0、1、2、3、5、11、13、15、17或21。
作为一种优选的技术方案,式(ii)中n为0、1、2或3。
具体所需要保护的化合物结构式如下:
本发明同时保护所述苯胺季铵盐类手性相转移催化剂在用于氨基酸衍生物不对称烷基化催化中的应用。反应式如下所示:
。
催化剂活性中心N原子的脂肪链在催化过程中与反应物之间的弱相互作用比较单一,导致催化中心的作用模式和催化反应类型受限。而芳环则可以通过改变催化中心的电子效应,位阻效应、共轭效应等丰富催化剂活性中心的作用模式进而拓宽催化反应类型和催化活性。然而,芳香胺烷基化的活性比脂肪胺弱,尤其是在具有空间位阻的联萘骨架的手性相转移催化剂的N原子上引入芳基,将脂肪季铵盐转变为芳香胺类季铵盐有一定的难度和挑战。本发明首次尝试在联萘骨架的手性相转移催化剂的N原子上引入芳基并首次取得了成功。催化应用研究表明:手性相转移催化剂PTC系列的N原子上含有两个烷基的情况下(例如甲基),其催化不对称烷基化的产物(氨基酸衍生物)的ee值较低,无法较好的应用于此类不对称催化应用。本申请人发现,将PTC系列上的N原子上的一个烷基(甲基)改造为芳基(苯基)后,其ee值得到较大提高,表明在相转移催化剂的N催化中心上引入苯基有利于催化选择性的提高。尤其是,当R为3,4,5-F3-C6H2的催化剂具有优异的对映选择性。
与现有技术相比,本发明的有益效果是:
本发明通过在催化中心引入苯芳基,改变手性相转移催化剂催化中心的电子效应、改变空间位阻效应、构建Π-Π堆积效应等,设计并合成了一系列苯胺季铵盐类手性相转移催化剂,该系列催化剂通过对甘氨酸席夫碱进行不对称烷基化催化反应构建手性氨基酸,具有优异的对映选择性。
附图说明
图1为消旋的苯丙氨酸乙酯消旋体的手性HPLC谱图。
图2为催化剂1~3催化甘氨酸乙酯席夫碱的不对称苄基化反应,催化产物苯丙氨酸乙酯的手性HPLC谱图。
图3为Olodanrigan核心氨基酸砌块的消旋的手性HPLC谱图。
图4为催化剂1~3催化制备的Olodanrigan核心氨基酸砌块的手性HPLC谱图。
具体实施方式
下面将结合本发明实施例,对本发明的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
实施例1:合成方法:
(1)PTC-1~-3合成如下示意:
具体合成和表征如下:
;
在-78 ℃和氩气保护的条件下,向(S)-联萘酚(10.02 g, 35 mmol)和三乙胺(13.90 mL, 100 mmol)的二氯甲烷(85 mL)溶液中缓慢滴加三氟甲磺酸酐(14.3 mL, 85mmol)。 随后在室温下搅拌2 h。反应结束后将所得混合物缓慢倒入冰水浴的1N HCl溶液中,用正己烷萃取,有机相用饱和的碳酸氢钠洗涤后再用饱和食盐水洗涤,然后用无水硫酸钠干燥,过滤,减压浓缩,得到粗产品经硅胶柱层析(乙酸乙酯:正己烷=1:20)分离纯化后得到白色固体(S)-1(17.9 g,32.6 mmol,收率93%)。
1H NMR (400 MHz, CDCl3): δ 8.14‒8.12 (d, J = 9.2 Hz, 2H), 8.01‒7.99(d, J = 8.3 Hz, 2H), 7.63‒7.61 (d, J = 9.2 Hz, 2H), 7.60‒7.56 (ddd, J = 8.3,6.8, 1.2 Hz, 2H), 7.42‒7.38 (ddd, J = 8.3, 6.8, 1.2 Hz, 2H), 7.26‒7.24 (d, J= 8.3 Hz, 2H).
13C NMR (100 MHz, CDCl3): δ 145.6, 133.4 , 132.6, 132.2, 128.6, 128.2,127.6, 127.0, 123.7, 119.6, 118.4(q, J C-F = 318.2 Hz).
;
在氩气保护条件下,将(S)-1(3.3 g, 6.0 mmol),醋酸钯(135 mg,10 mol %),1,3-双(二苯膦)丙烷(371 mg,15 mol%),二异丙基乙胺(12 mL, 72 mmol),甲酸苯酯(6.5mL,60 mmol)依次加入到120 mL的耐高压反应瓶中,混合物加热至120℃搅拌过夜。反应结束后将所得混合物冷却至室温并静置分层,然后分液取下层有机相,所得混合物用乙酸乙酯稀释后倒入水中洗涤,用盐水洗涤,有机相经过无水硫酸钠干燥,过滤,减压浓缩,得到粗产品经硅胶柱层析(乙酸乙酯:正己烷=1:10)分离纯化后得到白色固体(S)-2(1.78 g,3.6mmol,收率60%)。
1H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), δ 7.56 (ddd, J = 8.0, 6.8, 1.2 Hz, 2H),7.31 (ddd, J = 8.8, 6.8, 1.2 Hz, 2H), 7.24‒7.17 (m, 6H),δ 7.08 (dt, J = 8.4Hz, 2H), 6.66‒6.63 (m, 4H).
13C NMR (100 MHz, CDCl3): δ 165.6, 150.7, 140.6, 135.3, 133.1, 129.3,128.4, 128.2, 127.5, 127.2, 127.1, 126.3, 125.7, 121.4.
;
在室温下,向(S)-2 (2.27 g, 4.6 mmol)的乙醇溶液(143.5 mL)中加入 40% KOH溶液(13.8 mL),将反应混合物加热至回流搅拌24 h。反应结束后将体系冷却至室温,然后用2M的HCl溶液将体系pH值调节至1,所得混合物用乙酸乙酯萃取后分液,保留有机相。所得有机相用1M的KOH溶液将体系pH值调节至13,分液后保留水相。然后将水相pH调节至1后用乙酸乙酯萃取,所得有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗产品通过重结晶(乙酸乙酯/正己烷)得到白色固体(S)-3(1.46 g,4.28 mmol, 收率93%)。
1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.8Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), δ 7.46 (ddd, J = 8.0, 7.2, 0.8 Hz, 2H),7.12 (ddd, J = 8.0, 7.2, 0.8 Hz, 2H), 6.87 (d, J = 8.4, 6H).
13C NMR (100 MHz, CDCl3): δ 172.2, 141.8, 135.3, 132.8, 128.0, 127.9,127.8, 127.4, 126.6, 126.5, 125.5.
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将四丁基硫酸氢铵(238 mg,0.7 mmol)和二水合氟化钾(3.2 g,34 mmol)的四氢呋喃(34 mL)混合溶液放置室温下搅拌1 h,随后加入 (S)-3(1.17 g,3.4 mmol)和2-溴丙烷(3.1 mL,34 mmol), 并将混合物加热至回流搅拌24 h。反应结束后将体系倒入水中,用乙酸乙酯萃取,无水硫酸钠干燥,过滤,减压浓缩。得到粗产品经硅胶柱层析(乙酸乙酯:正己烷=1:5)分离纯化后得到白色固体(S)-4(1.1 g,2.58 mmol,收率76%)。
1H NMR (400 MHz, CDCl3): δ 8.17 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.50 (ddd, J = 8.0, 6.8, 1.2 Hz, 2H), 7.24(ddd, J = 8.4, 6.8, 1.2 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 4.75 (m, 2H), 0.76(d, J = 6.2 Hz, 6H), 0.44 (d, J = 6.2 Hz, 6H).
13C NMR (100 MHz, CDCl3): δ 166.8, 139.7, 134.8, 133.2, 128.4, 127.7,127.7, 127.6, 127.5, 126.6, 126.2, 67.7, 21.1, 20.7.
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在氩气保护下,将超干的四氢呋喃(18 mL)加入到镁粉(438 mg,18 mmol)中并加热至回流,随后缓慢滴加1,2-二溴乙烷(1.55 mL,18 mmol)至体系中, 得到MgBr2溶液(灰白色悬浮液)。在氩气保护下,向另一个烧瓶中加入蒸馏过的2,2,6,6-四甲基哌啶(6.1 mL,36 mmol)和四氢呋喃(18 mL),随后在0℃下缓慢滴加正丁基锂(2.5 M in hexane,6.1 mL,15 mmol),并在0℃下继续搅拌45 min后得到LiTMP(黄色澄清溶液)。将MgBr2溶液冷却至0℃后缓慢加入LiTMP,然后在0℃下继续搅拌2 h得到Mg(TMP)2的四氢呋喃溶液(棕色澄清溶液)。
在0℃和氩气保护下,向制备好的Mg(TMP)2溶液(0.31 M,27.1 mL,8.4 mmol)中加入 (S)-4 (899.5 mg, 2.1 mmol)的四氢呋喃溶液(10 mL),在室温下搅拌3 h。随后将体系冷却至 -78℃后缓慢加入溴素(860 µL,16.8 mmol),并在室温下继续搅拌1 h。反应结束后将混合物倒入冰水浴的1M的HCl溶液中,用饱和亚硫酸钠洗涤,乙酸乙酯萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,得到粗产品经硅胶柱层析(二氯甲烷:正己烷=1:1)分离纯化后得到白色固体(S)-5(1.01 g, 1.73 mmol, 收率82%)。
1H NMR (400 MHz, CDCl3): δ 8.24 (s, 2H), 7.82 (d, J = 8.4 Hz, 2H),7.52 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H),4.78 (m, 2H), 0.79 (d, J = 6.2 Hz, 6H), 0.67 (d, J = 6.2 Hz, 6H).
13C NMR (100 MHz, CDCl3): δ 165.5, 134.2, 134.2, 133.9, 132.2, 131.5,128.1, 127.7, 127.3, 126.9, 115.9, 69.0, 21.0, 20.7.
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在氩气保护下,将(S)-5(866 mg, 1.48 mmol),3,4,5-三氟苯硼酸(1041.3 mg,5.92 mmol),醋酸钯(16.8 mg,5 mol%),三苯基膦(60.4 mg,15 mol%),碳酸钾(615 mg,4.45 mmol),N,N-二甲基甲酰胺(14.8 mL)依次加入到反应瓶中,随后加热至90℃反应16h。反应结束后将体系冷却至室温后倒入饱和氯化铵溶液洗涤,乙酸乙酯萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,得到粗产品经硅胶柱层析(乙酸乙酯:正己烷=1:20)分离纯化后得到白色固体(S)-6(915 mg,1.33 mmol,收率90%)。
1H NMR (400 MHz, CDCl3): δ 7.94 (s, 2H), 7.94 (d, J = 8.0 Hz, 2H),7.56 (ddd, J = 8.0, 6.8, 1.2 Hz, 2H), 7.38 (ddd, J = 8.8, 6.8, 1.2 Hz, 2H),7.31 (d, J = 8.4 Hz, 2H), 7.20‒7.13 (m, 4H), 4.62‒4.52 (m, 4H), 0.62 (d, J =6.2 Hz, 6H), 0.55 (d, J = 6.2 Hz, 6H).
13C NMR (100 MHz, CDCl3): δ 166.9, 151.0(ddd, J C-F = 248.9, 9.9, 4.1Hz), 139.5(ddd, J C-F = 250.6, 15.2, 15.1 Hz), 137.0(ddd, J C-F = 8.1, 7.8, 4.8Hz ), 134.8, 134.4, 133.0, 132.4, 132.2, 129.5, 128.1, 128.0, 127.6, 113.1(dd, J C-F = 15.8, 5.9 Hz ), 68.6, 20.8, 20.6.
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在0℃下,将(S)-6(1158 mg,1.7 mmol)的四氢呋喃溶液(5.0 mL)缓慢滴加至氢化铝锂(356.8 mg,8.5 mmol)的四氢呋喃溶液中(5.0 mL),反应混合物在室温下搅拌5 h。反应结束后,冰水浴下将混合物用水淬灭,然后用1M的HCl溶液酸化,所得混合物用二氯甲烷萃取,有机相经饱和食盐水洗涤后,用无水硫酸钠干燥,过滤,减压浓缩,所得粗产物 (S)-7无需纯化即可进行下一步反应。
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在0℃下,将三溴化磷(240 µL, 2.55 mmol)缓慢滴加至(S)-7(988.2 mg, 1.7mmol)的四氢呋喃溶液(5.0 mL)中,并将反应放置在室温下搅拌1 h。反应结束后将体系倒入水中,用乙酸乙酯萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,得到粗产品经硅胶柱层析(乙酸乙酯:正己烷=1:20)分离纯化后得到白色固体(S)-8(1148 mg, 1.63 mmol,两步反应收率为96%)。
1H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.2 Hz, 2H), 7.89 (s, 2H),7.56 (ddd, J = 8.0, 6.9, 1.0 Hz, 2H), 7.34 (ddd, J = 8.4, 7.0, 1.1 Hz, 2H),7.29‒7.25 (m, 4H), 7.13 (d, J = 8.5 Hz, 2H), 4.18 (s, 4H).
13C NMR (100 MHz, CDCl3): δ 150.9(ddd, J C-F = 253.8, 9.8, 4.3 Hz),139.6(d, J C-F = 250.9 Hz), 137.9, 136.4, 136.1, 133.0, 132.1, 131.7, 130.7,128.1, 127.8, 127.4, 127.2, 114.1(dd, J C-F = 16.1, 5.8 Hz ), 31.1.
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将(S)-8’(350 mg,0.5 mmol),甲基苯胺(263 µL,1.5 mmol),碳酸钾(110.6 mg,0.8 mmol),乙腈(5.0 mL)依次加入到反应瓶中,随后加热至回流并搅拌10 h。反应结束后将所得混合物倒入水中,二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,得到粗产品经硅胶柱层析(甲醇:二氯甲烷=1:30)分离纯化后得到白色固体简化型Maruoka催化剂(PTC-1) (307 mg,0.41 mmol,收率78%)。
1H NMR (400 MHz, CDCl3) δ 7.99 – 7.94 (m, 2H), 7.80 (d, J = 8.3 Hz,1H), 7.73 (d, J = 8.3 Hz, 2H), 7.66 – 7.56 (m, 3H), 7.43 (t, J = 7.5 Hz, 1H),7.34 (m, 4H), 7.28 – 7.19 (m, 4H), 7.15 (t, J = 7.9 Hz, 2H), 6.04 (d, J =14.1 Hz, 1H), 4.76 (d, J = 12.7 Hz, 1H), 4.60 (d, J = 12.7 Hz, 1H), 4.11 (d,J = 14.1 Hz, 1H), 3.33 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 150.20 (d, J C-F = 254.1 Hz), 149.54 (d, J C-F= 254.1 Hz), 143.15, 138.91 (d, J C-F = 254.2 Hz), 138.47 (d, J C-F = 254.3 Hz),137.70, 137.13, 136.06, 133.86 (m), 133.03 (m), 132.81, 132.73, 130.61,130.10, 129.93, 129.78, 129.21, 129.05, 127.86, 127.65, 127.60, 127.45,127.21, 126.76, 126.64, 126.52, 123.56, 122.16, 120.70, 113.97(m), 112.93(m),64.88, 57.26, 53.44.
MS(ESI): calcd for C41H26F6N+ [M-Br]+ 646.19, found 646.13.
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季铵盐催化剂PTC-2的合成方法与合成催化剂PTC-1类似,选用合适催化剂前体代替即可(收率72%)。
1H NMR (400 MHz, CD2Cl2) δ 8.11 (s, 1H), 8.09 (d, J = 7.9 Hz, 1H),7.94 (d, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.68 (ddd, J = 8.2, 6.0, 2.1 Hz, 1H),7.58 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.48 – 7.41(m, 6H), 7.41 – 7.32 (m, 3H), 7.27 – 7.21 (m, 2H), 5.88 (d, J = 13.9 Hz, 1H),4.82 (d, J = 12.7 Hz, 1H), 4.62 – 4.56 (m, 1H), 4.54 (d, J = 12.1 Hz, 1H),4.28 (d, J = 14.0 Hz, 1H), 3.33 – 3.24 (m, 1H), 0.10 (t, J = 7.0 Hz, 3H).
13C NMR (101 MHz, CD2Cl2) δ 151.95 (d, J C-F = 252.8 Hz), 150.78 (d, J C-F = 252.3 Hz), 140.59, 139.12, 138.85 (d, J C-F = 252.7 Hz), 138.23 (d, J C-F =253.1 Hz), 138.44, 137.41, 136.94, 135.40(m), 134.67(m), 134.07, 133.95,131.92, 131.35, 131.26, 130.92, 130.28, 130.23, 128.80, 128.72, 128.50,128.11, 127.81, 127.73, 124.38, 123.52, 122.64, 115.29, 115.10, 114.53(m),113.92(m), 66.04, 58.97, 52.50, 8.56.
MS(ESI): calcd for C42H28F6N+ [M-Br]+ 660.21, found 660.15.
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季铵盐催化剂PTC-3的合成方法与合成催化剂PTC-1类似,选用合适催化剂前体代替即可(收率42%)。
1H NMR (400 MHz, CD2Cl2) δ 8.01 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H),7.84 (d, J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.60 – 7.52 (m, 3H), 7.53 – 7.41 (m,3H), 7.39 – 7.27 (m, 5H), 7.26 – 7.19 (m, 2H), 7.13 (t, J = 8.0 Hz, 2H), 5.96(d, J = 13.8 Hz, 1H), 4.79 (d, J = 12.9 Hz, 1H), 4.68 – 4.59 (m, 1H), 4.55(d, J = 12.9 Hz, 1H), 4.14 (d, J = 13.8 Hz, 1H), 3.04 – 2.94 (m, 1H), 1.25 –1.07 (m, 2H), 0.81 – 0.68 (m, 2H), 0.43 (t, J = 7.2 Hz, 3H).
13C NMR (101 MHz, CD2Cl2) δ, 151.15 (d, J C-F = 254.1 Hz), 148.98 (d,J C-F = 254.3 Hz),141.46, 139.26, 138.45, 138.35 (d, J C-F = 252.7 Hz), 138.04(d, J C-F = 253.1 Hz)137.46, 136.97, 135.48(m), 134.62(m), 134.02, 133.92,131.80, 131.33, 131.28, 130.89, 130.11, 128.75, 128.69, 128.39, 128.08,127.79, 127.73, 127.63, 124.39, 123.61, 122.69, 114.79(m), 113.71(m), 66.14,63.25, 49.66, 25.58, 19.03, 13.08.
MS(ESI): calcd for C44H32F6N+ [M-Br]+ 688.24, found 688.17.
(2)PTC-4~-6合成如下所示:
具体合成和表征如下:
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取100 mL三口烧瓶,分别将 (S)-1(4.17 g,6.8 mmol),[1,3-双(二苯基膦)丙烷]二氯化镍(Ⅱ)(370 mg,10 mol%)加入至烧瓶中,抽真空置换氩气三次。0℃下加入乙醚(5.0mL),缓慢滴加甲基碘化镁(3M in ether,11.4 mL,34 mmol)的乙醚溶液,滴加完毕后放置在室温下继续搅拌30小时。反应结束后,在0℃下缓慢滴加1N的盐酸溶液淬灭反应,硅藻土过滤除去催化剂,所得滤液用乙酸乙酯(50 mL×3)萃取,合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥并过滤,减压浓缩,所得粗产物通过硅胶柱层析(PE:EA = 10:1体积比)得白色固体 (S)-9(2.21 g,收率95%)。
1H NMR (400 MHz, CDCl3) δ 8.00 (t, J = 8.4 Hz, 4H), 7.62 (d, J = 8.4Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.7 Hz, 2H), 7.19 (d, J = 8.5Hz, 2H), 2.16 (s, 6H).
13C NMR (101 MHz, CDCl3) δ 135.26, 134.39, 132.89, 132.35, 128.86,128.06, 127.57, 126.23, 125.77, 125.03, 20.17.
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取25 mL三口烧瓶,将 (S)-9(501.6 mg,0.93 mmol),N-溴代丁二酰亚胺(NBS,431mg,2.6 mmol),偶氮二异丁腈(AIBN,31.2 mg,0.19 mmol)分别加入至烧瓶中,抽真空置换氩气三次,随后加入苯(4.6 mL)作溶剂,将体系加热至80℃回流,持续搅拌3小时。反应结束后,加水淬灭反应,所得混合溶液用乙酸乙酯(50 mL×3)萃取,合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥并过滤,减压浓缩,所得粗产物通过硅胶柱层析(PE)得白色固体(S)-10(342 mg,收率34%)。
1H NMR (400 MHz, CDCl3): δ 8.03 (d, J = 8.6 Hz, 2H), 7.93 (d, J = 8.2Hz, 2H), 7.76 (d, J = 8.6 Hz, 2H), 7.50 (t, J = 7.2 Hz, 2H), 7.28 (t, J = 7.4Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H).
13C NMR (100 MHz, CDCl3): 134.1, 134.1, 133.3, 132.6, 129.4, 128.1,127.8, 126.9, 126.9, 126.9, 32.3.
;
将(S)-10(350 mg,0.5 mmol),甲基苯胺(263 µL,1.5 mmol),碳酸钾(110.6 mg,0.8 mmol),乙腈(5.0 mL)依次加入到反应瓶中,随后加热至回流并搅拌10 h。反应结束后将所得混合物倒入水中,二氯甲烷萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩,得到粗产品经硅胶柱层析(甲醇:二氯甲烷=1:30)分离纯化后得到白色固体简化型Maruoka催化剂(PTC-4)(307 mg,0.41 mmol,收率72%)。
1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.3 Hz, 1H), 8.16 (d, J = 8.3Hz, 2H), 8.01 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 8.3Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.53 – 7.35 (m, 5H), 7.35 – 7.29 (m, 2H),7.24 (m, 3H), 5.83 (d, J = 13.6 Hz, 1H), 5.81 (d, J = 12.0 Hz, 1H), 4.31 (d,J = 12.0 Hz, 1H), 4.03 (d, J = 13.6 Hz, 1H), 3.78 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 143.96, 135.98, 135.86, 133.51, 133.26,130.18, 130.05, 129.65, 129.64, 129.47, 129.34, 128.69, 127.69, 127.68,127.55, 126.56, 126.53, 126.48, 126.45, 126.11, 126.05, 126.02, 125.67,120.99, 66.94, 63.15, 53.96.
MS(ESI): calcd for C29H24N+ [M-Br]+ 386.19, found 386.09.
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季铵盐催化剂PTC-5的合成方法与合成催化剂PTC-4类似,由(S)-10与乙基苯胺反应得到,收率56%。
1H NMR (400 MHz, CD2Cl2) δ 8.23 (d, J = 8.3 Hz, 2H), 8.19 (d, J = 8.4Hz, 1H), 8.12 – 8.02 (m, 2H), 7.92 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 8.4 Hz,1H), 7.69 – 7.58 (m, 3H), 7.58 – 7.49 (m, 2H), 7.46 (t, J = 8.0 Hz, 2H), 7.42– 7.28 (m, 3H), 5.87 (d, J = 13.6 Hz, 1H), 5.51 (d, J = 12.2 Hz, 1H), 4.42 –4.32 (m, 1H), 4.28 (d, J = 12.4 Hz, 1H), 4.10 (d, J = 13.6 Hz, 1H), 4.06 –3.92 (m, 1H), 1.16 (t, J = 7.1 Hz, 3H).
13C NMR (101 MHz, CD2Cl2) δ 141.47, 137.32, 137.00, 134.69, 134.37,131.34, 131.14, 130.72, 130.55, 130.41, 129.71, 128.64, 128.50, 128.00,127.65, 127.59, 127.53, 127.48, 127.15, 126.93, 126.46, 123.08, 66.46, 61.07,50.21, 29.69.
MS(ESI): calcd for C30H26N+ [M-Br]+ 400.20, found 400.12.
;
季铵盐催化剂PTC-6的合成方法与合成催化剂PTC-4类似,由(S)-10与丁基苯胺反应得到,收率70%。
1H NMR (400 MHz, CD2Cl2) δ 8.29 (d, J = 8.2 Hz, 2H), 8.18 (d, J = 8.3Hz, 1H), 8.06 (t, J = 7.3 Hz, 2H), 7.92 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.4Hz, 1H), 7.61 (t, J = 7.6 Hz, 3H), 7.53 (t, J = 9.0 Hz, 2H), 7.48 – 7.38 (m,3H), 7.38 – 7.28 (m, 2H), 5.95 (d, J = 13.6 Hz, 1H), 5.54 (d, J = 12.2 Hz,1H), 4.27 (d, J = 12.4 Hz, 2H), 4.10 (d, J = 13.5 Hz, 1H), 3.94 (t, J = 12.5Hz, 1H), 1.38 – 1.16 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H).
13C NMR (101 MHz, CD2Cl2) δ 142.06, 137.36, 136.99, 134.67, 134.36,131.36, 131.12, 130.67, 130.46, 130.39, 129.68, 128.62, 128.49, 128.00,127.65, 127.61, 127.51, 127.45, 127.14, 126.93, 126.90, 126.53, 66.88, 65.18,61.51, 25.35, 19.53, 13.39.
MS(ESI): calcd for C32H30N+ [M-Br]+ 428.23, found 427.99.
应用实施例 催化试验:
N-二苯亚甲基甘氨酸叔丁酯和1 mol% 的苯胺季铵盐类手性相转移催化剂PTC-1~-8(PTC-7和PTC-8是N原子上含有柔性脂肪链的手性相转移催化剂,作为对比催化剂),在甲苯50% 氢氧化钾水溶液条件下,进行不对称苄基化反应,结果如表1所示,反应式如下所示:
表 1苯胺季铵盐类手性相转移催化剂PTC-1~-6,相转移催化剂PTC-7~-8催化甘氨酸席夫碱的不对称苄基化反应
数据表征如下:
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将PTC-1催化剂(2.35 mg,1mol%)加入至10 mL的反应管中,随后加入甘氨酸乙酯的席夫碱 (67.7 mg, 0.3 mmol), 然后在真空下置换氩气三次后加入甲苯(1.5 mL)。随后在 0℃下缓慢滴加50 wt% KOH溶液(0.5 mL)和苄基溴(43 µL, 0.36 mmol),并在相同温度下剧烈搅拌。反应结束后将反应混合物倒入水中,用二氯甲烷萃取,有机相经过无水硫酸钠干燥,过滤,减压浓缩,得到粗产品经硅胶柱层析(乙酸乙酯:正己烷=1:50)分离纯化后得到无色油状苯丙氨酸乙酯 ee值为98%,见图2所示(图1为苯丙氨酸乙酯消旋体的手性HPLC谱图)。通过HPLC(Daicel Chiralcel AD-H分析测定对映体过量值,正己烷:异丙醇= 97:1,流速 0.5 mL/min,保留时间: 19.2 min (R),21.0 min (S)。相应合成产物的HPLC谱图对比如图1和图2所示。
1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.34(d, J = 8.5 Hz, 2H), 4.35 (d, J = 1.3 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 1.26(t, J = 7.1 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 169.94, 163.97, 137.17, 134.10, 129.66,128.89, 61.90, 61.12, 14.20.
如表1中所示,手性相转移催化剂PTC-7的N原子上含有两个甲基,其催化不对称烷基化的产物(氨基酸衍生物)的ee值为5%,与之相对比,在相同的不对称相转移条件下,将PTC-7的N原子上的一个甲基改造为苯基获得苯胺季铵盐类手性相转移催化剂PTC-4,ee值提高到21%。在保留PTC-4的N上的苯基的前提下,将N上的另一个甲基改造为乙基或丁基,其催化不对称烷基化产物的ee值分别为17%和15%,其对映选择性均优于PTC-7。该结果表明在相转移催化剂的N催化中心上引入苯基有利于催化选择性的提高。
为了获得具有高催化选择性(对映选择性)的催化剂,我们进一步在催化剂的3和3’位引入3,4,5-三氟苯基。如表1所示,在催化剂PTC-7的3和3’位引入3,4,5-三氟苯基,得到催化剂PTC-8。在相同的不对称相转移催化条件下,PTC-8催化不对称烷基化,所得氨基酸的ee值为7%。与之形成鲜明对比的是,在相同的不对称相转移条件下,将PTC-8的N原子上的一个甲基改造为苯基获得苯胺季铵盐类手性相转移催化剂PTC-1,其催化手性氨基酸合成,所得产物的ee值提高到98%。在保留PTC-1的N上的苯基的前提下,将N上的另一个甲基改造为乙基或丁基,其催化不对称烷基化产物的ee值均为98%,对映选择性均远远优于PTC-8。该结果表明:(1)在相转移催化剂的N催化中心上引入苯基有利于催化选择性的显著提高;(2)对苯胺季铵盐类手性相转移催化剂N原子上除苯基之外的另一个烷基进行改造,改变烷基链的长度,即将甲基改造为乙基或丁基,对不对称烷基化反应的对映选择性的催化效果同样可以得到提升。
催化剂在手性药物中间体催化合成上的应用:以甘氨酸衍生物席夫碱为原料合成Olodanrigan手性核心结构的方法,反应过程和数据表征如下:
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向甘氨酸叔丁酯席夫碱(76.1 mg, 0.3 mmol, 1 当量)和PTC-1(2.35 mg,1mol%)在甲苯(3 mL)和50%KOH水溶液(1.0 mL)的溶液中加入2-苄氧基-3-甲氧基苄溴(91.4mg,0.36 mmol,1.2当量)在0°C下在氩气气氛下缓慢加入。将反应混合物在相同温度下剧烈搅拌8小时。将反应混合物倒入冰冷水(10 mL)中,然后用CH2Cl2 (30 mL)萃取。将有机层在减压下浓缩,并将残留物溶解在THF(6 mL)中。加入0.5M柠檬酸水溶液(6 mL),将混合物在室温下搅拌1小时。减压除去THF后,用固体NaHCO3碱化混合物,并用CH2Cl2(30 mL)萃取。有机层用Na2SO4干燥,过滤并减压浓缩。残留物在硅胶上通过快速柱层析纯化(用石油醚/乙酸乙酯 = 5:1–1:1,梯度洗脱),得到化合物23,两步总收率78%,ee值为95%,见图4所示(图3为消旋体的手性HPLC谱图)。通过HPLC(Daicel Chiralcel AD-H分析测定对映体过量值,正己烷:异丙醇= 97:1,流速 0.5 mL/min,保留时间: 43.6 min (R),60.2 min (S)。
1H NMR (500 MHz, CDCl3) δ 7.43 – 7.40 (m, 2H), 7.39 – 7.35 (m, 2H),7.33 – 7.29 (m, 1H), 5.03 (t, J = 0.8 Hz, 3H), 4.03 – 3.90 (m, 1H), 3.85 (s,3H), 3.36 (dd, J = 15.7, 6.2 Hz, 1H), 3.14 (dd, J = 15.7, 6.2 Hz, 1H), 1.78(d, J = 6.3 Hz, 2H), 1.46 (s, 9H).
13C NMR (125 MHz, CDCl3) δ 173.32, 150.78, 148.02, 137.69, 128.46,128.33, 127.99, 127.41, 124.54, 124.44, 110.86, 81.34, 74.51, 55.70, 55.06,33.43, 27.96。
公斤级验证:
向甘氨酸叔丁酯席夫碱(1.52 kg, 6.0 mmol, 1 当量)和PTC-1(47.0 mg,1mol%)在甲苯(60 mL)和50%KOH水溶液(20 mL)的溶液中加入2-苄氧基-3-甲氧基苄溴(1.83kg,7.2 mmol,1.2当量)在0°C下在氩气气氛下缓慢加入。将反应混合物在相同温度下剧烈搅拌8小时。将反应混合物倒入冰冷水(500 mL)中,然后用CH2Cl2 (600 mL)萃取。将有机层在减压下浓缩,并将残留物溶解在THF(600 mL)中。加入0.5M柠檬酸水溶液(120 mL),将混合物在室温下搅拌2小时。减压除去THF后,用固体NaHCO3碱化混合物,并用CH2Cl2(600 mL)萃取。纯化后目标产物总收率为85%,ee值为95%。相应合成产物的HPLC谱图对比如图3和图4所示。
显然,以上所述的具体实施方案,只是对本发明的目的、技术方案和有益效果进行了进一步的详细说明,所应理解的是,以上所述仅为本发明的具体实例而已,并不用于限制本发明,凡在本发明的精神和原则之内,所做的任何修改、同等替换、改进等,均应包含在本发明的保护范围之内。
Claims (2)
1.一种苯胺季铵盐类手性相转移催化剂,其特征在于,所述苯胺季铵盐类手性相转移催化剂的结构式为如下所示结构的任意一种:
。
2.权利要求1所述手性相转移催化剂在氨基酸衍生物不对称烷基化催化中的应用,其特征在于,所述手性相转移催化剂用于合成Olodanrigan手性核心结构,所述氨基酸衍生物不对称烷基化催化反应如下:
。
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