CN116809115A - 一种以氯霉胺为手性源的柔性手性芳基碘催化剂及其合成方法与应用 - Google Patents
一种以氯霉胺为手性源的柔性手性芳基碘催化剂及其合成方法与应用 Download PDFInfo
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- CN116809115A CN116809115A CN202211728729.1A CN202211728729A CN116809115A CN 116809115 A CN116809115 A CN 116809115A CN 202211728729 A CN202211728729 A CN 202211728729A CN 116809115 A CN116809115 A CN 116809115A
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Abstract
本发明公开了一种以氯霉胺为手性源的柔性手性芳基碘催化剂及其合成方法与应用,其结构式如式(10)所示,其中R1选自羟基保护基,包括三甲基硅基、三乙基硅基、三乙丙基硅基、二乙基异丙基硅基、二甲基叔丁基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、乙酰基、三氟乙酰基、三氯乙酰基、叔丁基乙酰基、苯甲酰基或取代苯基,取代苯基上的取代基为单取代或多取代;取代基R2取代或不取代,取代时R2选自甲基、三氟甲基、甲酯或乙酯;R3,R4,R5,R6各自独立地选自烷烃、苯基或取代苯基。本发明反应条件温和,原料廉价易得,反应操作简单、产率较高、经济实用,对环境友好。
Description
技术领域
本发明属于有机化合物合成技术领域,具体涉及一种以氯霉胺为手性源的柔性手性芳基碘催化剂及其合成方法与应用。
背景技术
近几十年来,高价碘试剂的应用研究发展迅速。与反应性质类似的重金属氧化剂相比,有机高价碘试剂是绿色、温和、高效和多功能化的氧化剂,可应用于碳–碳、碳–氧、碳–氮或碳–卤键的构建;同时其具有制备容易和操作简单的特点。高价碘试剂的使用能够降低传统金属氧化剂带来的毒性和环境污染问题;因此,其在药物合成中逐步受到重视。
尽管化学家们在手性高价碘催化方面取得了众多的成果,但仍存在诸多挑战,诸如:1)构象更加柔性的手性高价碘催化剂种类有限,多手性中心的柔性芳基碘催化剂能实现催化剂手性口袋大小的调控,实现较好的催化活性。2)含有多重氢键的手性高价碘催化剂未有报道,而氢键强化策略则是实现催化剂对反应底物活性和立体选择性的控制的关键。3)手性碘催化剂的工业化生产难以实现。由于C2对称性结构的手性芳基碘催化剂基本依赖于Mitsunobu反应,副反应生成的三苯基氧磷和肼难以除去,在已经报道的文献中最大的产量仅为20g,未有更大量的报道。因此,设计和合成具有易获得性、高反应性的新型构象柔性催化剂库是极具重要意义的研究。
发明内容
本发明克服了传统构建手性芳基碘催化剂诸多缺点,创新性地发展了一种可在温和条件下以氯霉胺为手性源,设计了一条绿色、低毒、环境友好的手性芳基碘催化剂的合成方法。
一种以氯霉胺为手性源的柔性手性芳基碘催化剂,其结构式如式(10)所示,
其中R1选自羟基保护基,包括三甲基硅基、三乙基硅基、三乙丙基硅基、二乙基异丙基硅基、二甲基叔丁基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、乙酰基、三氟乙酰基、三氯乙酰基、叔丁基乙酰基、苯甲酰基或取代苯基,取代苯基上的取代基为单取代或多取代,取代基为甲基、甲氧基、三氟甲基、三氟甲氧基、乙基、异丙基、叔丁基、卤素或硝基;取代基R2取代或不取代,取代时R2选自甲基、三氟甲基、甲酯或乙酯;R3,R4,R5和R6各自独立地选自烷烃、苯基或取代苯基,取代苯基上的取代基为单取代或多取代,取代基为甲基、甲氧基、三氟甲基、三氟甲氧基、乙基、异丙基、叔丁基、卤素或硝基。
一种柔性手性芳基碘催化剂的合成方法,包括如下步骤:
1)式(1)所示氯霉胺经过二碳酸二叔丁酯保护氨基并通过溶剂重结晶析出得到式(2)所示的中间体;
2)将式(2)所示的中间体在碱的作用下与氯硅烷于溶剂中反应生成如式(3)所示的中间体;
3)将式(3)所示的中间体在咪唑和碱的作用下与氯化亚砜反应生成如式(4)所示的中间体;
4)将式(4)所示的中间体在氧化剂和催化剂的作用下于溶剂中反应,并通过重结晶得到如式(5)所示的中间体;
5)将式(5)所示中间体和式(6)所示2-碘苯二酚衍生物在碱的作用下反应生成式(7)所示的中间体;
6)将式(7)所示中间体在酸的作用下于溶剂中脱去保护基生成式(8)所示的中间体;
7)将式(8)所示中间体在碱的作用下与酰氯、磺酰胺、异氰酸酯或异硫氰酸酯反应,并通过溶剂重结晶得到式(9)所示的手性芳基碘催化剂;
8)将式(9)所示中间体在四丁基氟化铵的作用下脱去硅基得到中间体,之后继续与酰氯、磺酰胺、异氰酸酯或异硫氰酸酯反应,并通过溶剂重结晶得到式(10)所示的手性芳基碘催化剂,
反应过程如下:
其中R1选自羟基保护基,包括三甲基硅基、三乙基硅基、三乙丙基硅基、二乙基异丙基硅基、二甲基叔丁基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、乙酰基、三氟乙酰基、三氯乙酰基、叔丁基乙酰基、苯甲酰基或取代苯基,取代苯基上的取代基为单取代或多取代,取代基为甲基、甲氧基、三氟甲基、三氟甲氧基、乙基、异丙基、叔丁基、卤素或硝基;取代基R2和R12取代或不取代,取代时R2和R12选自甲基、三氟甲基、甲酯或乙酯;R3,R4,R5,R6各自独立地选自烷烃、苯基或取代苯基,取代苯基上的取代基为单取代或多取代,取代基为甲基、甲氧基、三氟甲基、三氟甲氧基、乙基、异丙基、叔丁基、卤素或硝基,R8,R9,R10和R11各自独立地选自烷烃、苯基或取代苯基,取代苯基上的取代基为单取代或多取代,取代基为甲基、甲氧基、三氟甲基、三氟甲氧基、乙基、异丙基、叔丁基、卤素或硝基。
进一步地,步骤1)所述二碳酸二叔丁酯的用量为式(1)所示化合物的1.0-10.0当量,中间体(2)重结晶所使用的溶剂为乙酸乙酯、甲醇或乙醚,反应温度为-20-0℃,反应时间为2-7h。
进一步地,步骤2)所述氯硅烷为叔丁基二苯基氯硅烷、叔丁基二甲基氯硅烷、三甲基氯硅烷、三乙基氯硅烷、三异丙基氯硅烷、二甲基异丙基氯硅烷或二乙基异丙基氯硅烷,所述氯硅烷的用量为式(2)所示中间体的1.0-5.0当量,溶剂为二氯甲烷、二氯乙烷、氯仿、四氢呋喃或N,N-二甲基甲酰胺,反应温度为-20-0℃,反应时间为2-5h。
进一步地,步骤3)所述的氯化亚砜的用量为式(3)所示中间体的1.0-5.0当量,咪唑的用量为式(3)所示中间体的1.0-20.0当量,碱为三乙胺或N,N-二异丙基乙胺,所述碱的用量为式(3)所示中间体的2.0-10.0当量,反应温度为-70-0℃,反应时间为2-5h。
进一步地,步骤4)所述的氧化剂为高碘酸钠,氧化剂的用量为式(4)所示中间体的1.0-5.0当量,催化剂为水合三氯化钌,催化剂的用量为式(4)所示中间体的1-30mol%,溶剂为乙腈和水或二氯甲烷和水,所述溶剂的用量为1:1,反应温度为0-30℃,反应时间为2-6h。
进一步地,步骤5)中式(5)所示中间体的用量为式(6)所示2-碘苯二酚衍生物的2.0-10.0当量,碱为氢化钠,碱的用量为式(6)所示2-碘苯二酚衍生物的2.0.-10.0当量,反应温度为-20-0℃,反应时间为2-6h。
进一步地,步骤6)所述溶剂为二氯甲烷、二氯乙烷或氯仿,酸为三氟乙酸、盐酸或硫酸,酸和溶剂的用量为1:3-1:10,反应温度为-20-0℃,反应时间为1-5h。
进一步地,步骤7)所述酰氯、磺酰胺、异氰酸酯或异硫氰酸酯的用量为式(8)所示中间体的2.0-10.0当量,碱为三乙胺,碱的用量为式(8)所示中间体的2.0-10.0当量,重结晶溶剂为四氢呋喃烷、甲基叔丁基醚或二氧六环,反应温度为-20-50℃,反应时间为1-8h;步骤8)中四丁基氟化铵所使用量为式(9)化合物的1.0-20.0当量,所述酰氯、磺酰胺、异氰酸酯或异硫氰酸酯的用量为式(9)的2.0-10.0当量,碱为三乙胺,碱的用量为式(9)化合物的2.0-10.0当量。
一种以氯霉胺为手性源的柔性手性芳基碘催化剂的应用,手性芳基碘催化剂通过分子内的氧化内酯化、醚化、酰胺化、芳基化反应,对映选择性地合成了γ-丁内酯、色满环、异色满环、噁唑烷酮、哌啶、吡咯烷、氮杂环丙烷。
本发明的应用:
本发明公开的以氯霉胺为手性源的催化剂可以应用于催化为以式(11)所示1-萘酚衍生物,经过一步反应生成式(12)所示的产物,也可以应用于式(13)所示的丙二酰胺衍生物,经过一步反应生成式(14)所示的产物,也可用于二羰基化合物(15)的α-氟化,得到产物(16)。
本发明的有益效果在于:
1)采用氯霉胺为手性源,设计并合成了多手性的柔性芳基碘碘催化剂;
2)本发明的化合物制备实现了百克级规模反应,具有实用性,具有广泛应用前景,适于工业化规模生产。
3)本发明反应高效,收率高,制备简单、稳定、并且无刺激性气味,反应条件温和。
具体实施方式
下面结合以下具体实施例对本发明作进一步地详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁鉴定。
一种以氯霉胺为手性源的手性芳基碘催化剂的合成反应,反应过程如下:
实施例1
(1S,2S)-1,3-二羟基-1-(4-硝基苯基)丙-2-基氨基甲酸叔丁酯的合成:
在三口烧瓶管中加入1S,2S-2-氨基-1-(4-硝基苯基)丙烷-1,3-二醇(70g,330mmol,1.0equiv.)和四氢呋喃(500mL),接着在室温下滴加二碳酸二叔丁酯(75.6g,347mmol,1.05equiv.),室温反应3h后,减压条件下去除溶剂,使用乙酸乙酯重结晶,得到产物2(93.6g,93%)。
实施例2
(4S,5R)-4-((叔丁基二苯基硅基)氧基)甲基)-5-(4-硝基苯基)-1,2,3-氧杂噻唑烷-3-羧酸叔丁酯2,2-二氧化物的合成:
在三口烧瓶管中加入(1S,2S)-1,3-二羟基-1-(4-硝基苯基)丙-2-基氨基甲酸叔丁酯(2)(93.6g,307mmol,1.0equiv.),咪唑(27.1g,399mmol,1.3equiv.)和二氯甲烷(500mL),接着在0℃的条件下滴加叔丁基二苯基氯硅烷(88.55g,322mmol,1.05equiv.)反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,得到粗产品3(210g)。
在氮气保护下,往三口烧瓶管中加入所得粗产品叔丁基((1S,2S)-3-(叔丁基二苯基硅氧基)-1-羟基-1-(4-硝基苯基)丙基-2-基)氨基甲酸酯(3)(210g)咪唑(67.0g,982mmol,3.0equiv.)和二氯甲烷(500mL),接着在-40℃的条件下滴加三乙胺(74.5g,737mmol,2.4equiv.),滴加完毕后继续滴加二氯亚砜(44.0g,369mmol,1.2equiv.)反应3h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,得到粗产品4(253g)。
在氮气保护下,往三口烧瓶管中加入所得粗产品(4S,5R)-4-((叔丁基二苯基硅基)氧基)甲基)-5-(4-硝基苯基)-1,2,3-氧杂噻唑烷-3-羧酸叔丁酯2-氧化物(4)(253g)溶于乙腈和水中(1:1)(450mL),依次加入三氯化钌三水合物(635mg,1mol%),高碘酸钠(73g,337mmol,1.1equiv.),20℃反应4h,用乙酸乙酯萃取,分离有机相,减压条件下去除溶剂后,加入甲醇,析出纯净产物5,共159g,三步收率86%。
1H NMR(400MHz,CDCl3)δ8.25–8.19(m,2H),7.70(dt,J=6.7,1.5Hz,2H),7.65(dt,J=6.5,1.6Hz,2H),7.52–7.41(m,8H),5.85(d,J=5.7Hz,1H),4.30–4.22(m,2H),3.78–3.66(m,1H),1.53(s,9H),1.13(s,9H);13C NMR(100MHz,CDCl3)δ148.7,148.2,141.1,135.8,135.7,132.5,132.2,130.4,130.3,128.2,128.1,127.7,124.3,86.1,79.1,64.6,59.6,28.0,26.9,19.4.
HRMS(ESI):calc.for[C30H36N2O8SSi+Na]+635.1854;found 635.1846.
实施例3
二叔丁基((1R,1'R,2S,2'S)-((2-碘-1,3-亚苯基)双(氧基))双(3-(叔丁基二苯基硅基)氧基)-1-(4-硝基苯基)丙烷-1,2-二基))二氨基甲酸酯的合成:
在氮气保护下,往三口烧瓶管中加入2-碘苯-1,3-二醇(6)(30.5g,130mmol,1equiv.)和N,N-二甲基甲酰胺(300mL),在0℃条件下缓慢加入氢化钠(质量浓度60%)(10.66g,266mmol,2.05equiv.),搅拌30min后缓慢滴加(4S,5R)-4-((叔丁基二苯基硅基)氧基)甲基)-5-(4-硝基苯基)-1,2,3-氧杂噻唑烷-3-羧酸叔丁酯2,2-二氧化物(5)(159g,261mmol,2.01equiv.),搅拌4h直至原料反应完毕。反应结束使用盐酸淬灭,加入乙酸乙酯萃取,分离有机相,减压条件下去除溶剂后,使用乙酸乙酯和水重结晶,得到糊状黄色固体,粗产物共得到207g。
1H NMR(400MHz,CDCl3)δ8.09(d,J=8.3Hz,4H),7.57–7.44(m,12H),7.36–7.31(m,2H),7.29–7.23(m,6H),7.20–7.12(m,4H),6.79(t,J=8.3Hz,1H),6.01(d,J=8.3Hz,2H),5.40(d,J=6.4Hz,2H),4.97(d,J=9.1Hz,2H),4.26(dd,J=10.6,5.1Hz,2H),4.21–4.09(m,2H),3.79(dd,J=10.6,3.2Hz,2H),1.27(s,18H),0.98(s,18H);13C NMR(100MHz,CDCl3)δ157.0,155.1,147.7,145.3,135.6,135.5,132.9,132.8,130.0,129.9,129.7,127.9,127.8,123.7,106.5,79.9,79.5,62.3,57.1,28.3,26.9,19.3.
HRMS(ESI):calc.for[C66H77IN4O12Si2+Na]+1323.4013;found 1323.4023.实施例4
1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)的合成:
往三口烧瓶管中加入粗产品(7)(207g)和二氯甲烷(200mL),在0℃条件下缓慢加入三氟乙酸(50mL),搅拌2h后缓慢NaOH淬灭,加入二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶,得到灰白固体,产物共得到106g,两步产率74%。
1H NMR(400MHz,CDCl3)δ8.06(d,J=8.7Hz,4H),7.57–7.48(m,8H),7.45–7.39(m,4H),7.35–7.24(m,8H),7.21–7.16(m,4H),6.73(t,J=8.3Hz,1H),5.97(d,J=8.3Hz,2H),5.31(d,J=5.8Hz,2H),3.88(dd,J=10.2,6.1Hz,2H),3.61(dd,J=10.2,5.0Hz,2H),3.37–3.28(m,2H),0.96(s,18H);13C NMR(100MHz,CDCl3)δ156.9,147.8,145.3,135.7,135.6,133.1,133.1,130.0,129.9,129.7,128.1,128.0,127.9,123.9,106.5,80.9,79.8,64.9,57.8,27.0,19.4.
HRMS(ESI):calc.for[C56H61IN4O8Si2+H]+1101.3145;found 1101.3154.
实施例5
N,N'-((1R,1'R,2S,2'S)-((2-碘-1,3-亚苯基)双(氧基)双(3-(叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-1,2-二基))双(4-硝基苯甲酰胺)合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.)和无水DCM(5.0mL),接着在0℃下滴加4-硝基苯甲酰氯(408.2mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到产物Cat-1(1.3g,93%)
1H NMR(400MHz,CDCl3)δ8.16(d,J=8.5Hz,4H),8.03(d,J=8.4Hz,4H),7.64(d,J=8.6Hz,4H),7.50–7.41(m,12H),7.34–7.27(m,4H),7.23–7.15(m,8H),6.77(t,J=8.3Hz,1H),6.60(d,J=8.5Hz,2H),5.98(d,J=8.4Hz,2H),5.49(d,J=5.5Hz,2H),4.65(dtd,J=9.2,5.9,3.4Hz,2H),4.37(dd,J=11.0,6.3Hz,2H),3.84(dd,J=11.1,3.4Hz,2H),0.92(s,18H);13C NMR(100MHz,CDCl3)δ165.2,157.2,149.8,147.9,144.4,139.3,135.6,135.6,132.6,130.2,130.1,128.1,128.1,128.0,127.4,124.0,123.9,107.1,79.9,79.4,61.7,56.6,26.9,19.3.
HRMS(ESI):calc.for[C70H67IN6O14Si2+Na]+1421.3191;found 1421.3219.
实施例6
N,N'-((1R,1'R,2S,2'S)-((2-碘-1,3-亚苯基)双(氧基)双(3-(叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-1,2-二基))双(2,2-二甲基丙酰胺)合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.)和无水DCM(5.0mL),接着在0℃下滴加特戊酰氯(266.2mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用乙酸乙酯和石油醚打浆纯化得到产物Cat-2(1.08g,85%)
1H NMR(400MHz,CDCl3)δ8.13(d,J=8.7Hz,4H),7.57–7.48(m,12H),7.41–7.37(m,2H),7.36–7.28(m,6H),7.25–7.19(m,4H),6.84(t,J=8.3Hz,1H),6.23(d,J=8.3Hz,2H),6.06(d,J=8.4Hz,2H),5.48(d,J=6.2Hz,2H),4.54–4.45(m,2H),4.35(dd,J=10.8,5.4Hz,2H),3.75(dd,J=10.8,3.3Hz,2H),1.03(s,18H),1.02(s,18H);13C NMR(100MHz,CDCl3)δ178.2,157.5,147.8,145.2,135.6,135.5,132.7,132.6,130.1,130.0,130.0,128.0,128.0,127.7,123.8,106.8,79.5,61.9,55.7,38.8,27.5,26.9,19.3.
HRMS(ESI):calc.for[C66H77IN4O10Si2+H]+1269.4296;found 1269.4279.
实施例7
N,N'-((1R,1'R,2S,2'S)-((2-碘-1,3-亚苯基)双(氧基)双(3-(叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-1,2-二基))二乙酰胺合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.)和无水DCM(5.0mL),接着在0℃下滴加乙酰氯(173.0mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化得到产物Cat-4(1.065g,90%)
1H NMR(400MHz,CDCl3)δ8.04(d,J=8.6Hz,4H),7.50–7.45(m,8H),7.41(d,J=8.5Hz,4H),7.34–7.27(m,4H),7.26–7.17(m,8H),6.75(t,J=8.3Hz,1H),5.95(d,J=8.4Hz,2H),5.80(d,J=8.7Hz,2H),5.38(d,J=5.4Hz,2H),4.45–4.37(m,2H),4.22(dd,J=11.0,6.2Hz,2H),3.72(dd,J=10.9,3.3Hz,2H),1.76(s,6H),0.94(s,18H);13C NMR(100MHz,CDCl3)δ169.9,157.2,147.7,144.9,135.6,132.9,132.8,130.1,130.0,130.0,128.0,128.0,127.5,123.9,106.8,79.7,79.5,61.8,56.0,26.9,23.3,19.3.
HRMS(ESI):calc.for[C60H65IN4O10Si2+Na]+1185.3362found 1185.3378.
实施例8
N,N'-((1R,1'R,2S,2'S)-((2-碘-1,3-亚苯基)双(氧基)双(3-(叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-1,2-二基))双(4-甲基苯甲酰胺)合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.)和无水DCM(5.0mL),接着在0℃下滴加4-甲基苯甲酰氯(341.2mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到产物Cat-5(1.097g,82%)
1H NMR(400MHz,CDCl3)δ7.98(d,J=8.4Hz,4H),7.51–7.40(m,16H),7.31–7.24(m,4H),7.21–7.12(m,12H),6.71(t,J=8.3Hz,1H),6.57(d,J=8.5Hz,2H),5.94(d,J=8.4Hz,2H),5.47(d,J=5.6Hz,2H),4.69–4.59(m,2H),4.34(dd,J=10.9,6.1Hz,2H),3.82(dd,J=10.9,3.4Hz,2H),2.30(s,6H),0.91(s,18H);13C NMR(100MHz,CDCl3)δ167.0,157.2,147.7,144.9,142.5,135.6,135.5,132.8,132.7,131.0,130.0,130.0,129.4,127.9,127.4,126.9,123.9,106.9,80.0,79.6,61.9,56.3,26.9,21.5,19.2.
HRMS(ESI):calc.for[C60H65IN4O10Si2+Na]+1359.3802found 1359.3774.实施例9
N,N'-((1R,1'R,2S,2'S)-((2-碘-1,3-亚苯基)双(氧基)双(3-(叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-1,2-二基))双(4-三氟甲基苯甲酰胺)合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.)和无水DCM(5.0mL),接着在0℃下滴加4-三氟甲基苯甲酰氯(459.8mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到产物Cat-6(1.127g,78%)
1H NMR(400MHz,Chloroform-d)δ8.02(d,J=8.7Hz,4H),7.65–7.55(m,8H),7.50–7.40(m,12H),7.33–7.25(m,4H),7.22–7.14(m,8H),6.76(t,J=8.3Hz,1H),6.58(d,J=8.5Hz,2H),5.97(d,J=8.4Hz,2H),5.48(d,J=5.5Hz,2H),4.71–4.60(m,2H),4.36(dd,J=11.0,6.2Hz,2H),3.83(dd,J=11.0,3.4Hz,2H),0.93(s,18H);13C NMR(100MHz,CDCl3)δ165.9,157.2,147.9,144.6,137.1,135.6,135.6,133.6(q,2JC-F=32.7Hz),132.7,132.7,130.2,130.1,128.0,128.0,127.4,125.8(q,3JC-F=3.7Hz),124.0,123.7(q,1JC-F=272.5Hz),107.1,80.0,79.5,61.8,56.5,26.9,19.3.19F NMR(376MHz,CDCl3)δ-62.86.
HRMS(ESI):calc.for[C72H67F6IN4O10Si2+Na]+1467.3237found 1467.3234.实施例10
N,N'-((1R,1'R,2S,2'S)-((2-碘-1,3-亚苯基)双(氧基)双(3-(叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-1,2-二基))双(2,4,6-三甲基苯甲酰胺)合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.)和无水DCM(5.0mL),接着在0℃下滴加2,4,6-三甲基苯甲酰氯(402.6mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到产物Cat-7(1.12g,86%)
1H NMR(400MHz,CDCl3)δ8.09(d,J=8.8Hz,4H),7.53–7.40(m,12H),7.30–7.24(m,4H),7.18–7.11(m,8H),6.78(t,J=8.3Hz,1H),6.73(s,4H),6.02(dd,J=8.2,2.3Hz,4H),5.69(d,J=4.9Hz,2H),4.71–4.59(m,2H),4.30(dd,J=11.2,6.8Hz,2H),3.81(dd,J=11.1,3.1Hz,2H),2.22(s,6H),1.88(s,12H),0.94(s,18H);13C NMR(100MHz,CDCl3)δ170.7,157.1,147.9,144.7,138.9,135.5,134.2,134.2,132.7,132.5,130.1,130.0,129.9,128.3,127.9,127.7,124.0,106.5,79.5,79.3,61.7,57.0,26.9,21.1,19.2,18.9.
HRMS(ESI):calc.for[C76H81IN4O10Si2+Na]+1415.4428found 1415.4434.实施例11
N,N'-((1R,1'R,2S,2'S)-((2-碘-1,3-亚苯基)双(氧基)双(3-(叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-1,2-二基))双(4-甲氧基苯甲酰胺)合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.)和无水DCM(5.0mL),接着在0℃下滴加4-甲氧基苯甲酰氯(376.2mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到产物Cat-8(1.231g,90%)
1H NMR(400MHz,CDCl3)δ8.10(d,J=8.3Hz,4H),7.61(d,J=8.4Hz,4H),7.58–7.50(m,12H),7.42–7.35(m,4H),7.31–7.24(m,8H),6.93(d,J=8.3Hz,4H),6.80(t,J=8.3Hz,1H),6.56(d,J=8.2Hz,2H),6.02(d,J=8.3Hz,2H),5.55(d,J=5.2Hz,2H),4.76–4.66(m,2H),4.42(dd,J=10.8,6.0Hz,2H),3.93–3.88(m,2H),3.88(s,6H),1.01(s,18H);13C NMR(100MHz,CDCl3)δ166.7,162.6,157.3,147.7,145.0,135.7,135.6,132.9,132.8,130.1,130.0,128.8,128.0,127.4,126.1,124.0,114.0,107.0,80.2,79.6,61.9,56.4,55.6,26.9,19.3.
HRMS(ESI):calc.for[C72H73IN4O12Si2+Na]+1369.3886found 1369.3877.
实施例12
N,N'-((1R,1'R,2S,2'S)-((2-碘-1,3-亚苯基)双(氧基)双(3-(叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-1,2-二基))双(苯甲酰胺)合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.)和无水DCM(5.0mL),接着在0℃下滴加苯甲酰氯(310.4mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到产物Cat-9(1.139g,87%)
1H NMR(400MHz,CDCl3)δ8.01(d,J=8.8Hz,4H),7.56–7.52(m,4H),7.49–7.41(m,14H),7.38–7.33(m,4H),7.32–7.25(m,4H),7.22–7.14(m,8H),6.73(t,J=8.3Hz,1H),6.55(d,J=8.5Hz,2H),5.94(d,J=8.4Hz,2H),5.47(d,J=5.5Hz,2H),4.68–4.60(m,2H),4.34(dd,J=10.9,6.1Hz,2H),3.81(dd,J=10.9,3.4Hz,2H),0.92(s,18H);13C NMR(100MHz,CDCl3)δ167.2,157.3,147.8,144.9,135.7,135.6,133.9,132.8,132.8,132.0,130.1,130.1,128.8,128.0,127.4,127.0,124.0,107.0,80.0,79.6,61.9,56.4,26.9,19.3.
HRMS(ESI):calc.for[C70H69IN4O10Si2+H]+1309.3670found 1309.3664.
实施例13
1,1'-((1R,1'R,2S,2'S)-((2-碘-1,3-亚苯基)双(氧基)双(3-(叔丁基二苯基硅基)氧基)-1-(4-硝基苯基)丙烷-1,2-二基)双(3-对甲苯基)脲)的合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.),DMAP(24.4mg,0.2mmol,0.2equiv.)和无水DCM(5.0mL),接着在0℃下滴加对甲苯异氰酸酯(293.0mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到产物Cat-10(1.19g,86%)
1H NMR(400MHz,CDCl3)δ7.99(d,J=8.4Hz,4H),7.43–7.37(m,8H),7.34(d,J=7.4Hz,4H),7.30–7.26(m,2H),7.20–7.15(m,6H),7.08–7.00(m,8H),6.93(d,4H),6.70(t,J=8.3Hz,1H),6.52(s,2H),5.92(d,J=8.4Hz,2H),5.36(d,J=6.4Hz,2H),5.27(d,J=8.5Hz,2H),4.39–4.31(m,2H),4.22(dd,J=10.7,5.0Hz,2H),3.68(dd,J=10.8,3.2Hz,2H),2.22(s,6H),0.82(s,18H);13C NMR(100MHz,CDCl3)δ157.1,155.7,147.7,145.4,135.5,135.5,135.2,134.9,132.7,132.6,130.3,130.0,129.8,127.9,127.9,127.8,123.8,123.3,106.5,79.3,79.3,77.5,77.2,76.8,62.3,56.6,26.8,21.0,19.2.
HRMS(ESI):calc.for[C72H75IN6O10Si2+H]+1367.4201found 1367.4210.
实施例14
1,1'-((1R,1'R,2S,2'S)-((2-碘-1,3-亚苯基)双(氧基)双(3-(叔丁基二苯基硅基)氧基)-1-(4-硝基苯基)丙烷-1,2-二基)双(3-间甲苯基)脲)的合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.),DMAP(24.4mg,0.2mmol,0.2equiv.)和无水DCM(5.0mL),接着在0℃下滴加间甲苯异氰酸酯(293.0mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到产物Cat-11(1.135g,83%)
1H NMR(400MHz,CDCl3)δ8.06(d,J=8.4Hz,4H),7.56–7.47(m,12H),7.40–7.35(m,2H),7.35–7.26(m,6H),7.23–7.16(m,6H),7.00(s,2H),6.98–6.92(m,4H),6.82(t,J=8.3Hz,1H),6.78(s,2H),6.05(d,J=8.5Hz,2H),5.53(d,J=6.0Hz,2H),5.48(d,J=8.4Hz,2H),4.54–4.45(m,2H),4.35(dd,J=10.8,5.4Hz,2H),3.84(dd,J=10.9,3.3Hz,2H),2.30(s,6H),0.96(s,18H);13C NMR(100MHz,CDCl3)δ157.1,155.5,147.6,145.3,139.6,137.7,135.5,135.5,132.8,132.7,130.0,129.9,129.4,127.9,127.9,127.7,125.7,123.8,123.0,119.3,106.5,79.5,79.2,62.2,56.7,26.8,21.5,19.2.
HRMS(ESI):calc.for[C72H75IN6O10Si2+H]+1367.4201found 1367.4189.
实施例15
N,N'-((1R,1'R,2S,2'S)-((2-碘-1,3-亚苯基)双(氧基)双(3-(叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-1,2-二基))双(4-甲基苯磺酰胺)合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.)和无水DCM(5.0mL),接着在0℃下滴加对甲基苯磺酰氯(420.2mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用乙酸乙酯石油醚重结晶纯化,得到产物Cat-12(1.323g,94%)
1H NMR(400MHz,CDCl3)δ7.86(d,J=8.5Hz,4H),7.40–7.17(m,18H),7.15–7.05(m,6H),7.00–6.90(m,4H),6.86(d,J=8.1Hz,4H),6.64(t,J=8.3Hz,1H),5.88(d,J=8.5Hz,2H),5.39–5.21(m,4H),4.16(dd,J=10.6,3.6Hz,2H),3.73–3.51(m,4H),2.12(s,6H),0.80(s,18H);13C NMR(100MHz,CDCl3)δ156.5,147.6,144.7,143.5,137.2,135.4,135.3,132.3,129.9,129.7,129.5,127.9,127.8,127.7,126.7,123.6,106.4,79.2,78.1,62.1,60.1,26.8,21.3,19.1.
HRMS(ESI):calc.for[C70H73IN4O12S2Si2+H]+1409.3328found 1409.3333.
实施例16
(2S,2'S,3R,3'R)-((2-碘-1,3-亚苯基)双(3-(4-硝基苯基)-2-(2,4,6-三甲基苯甲酰胺基)丙烷-3,1-二基)双(2,4,6-三甲基苯甲酸酯)的合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.)和无水DCM(5.0mL),接着在0℃下滴加2,4,6-三甲基苯甲酰氯(402.6mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到物产Cat-7(1.120g,86%).
将Cat-7溶于四氢呋喃中(10mL)中,然后滴加TBAF(2.5ml,1mol/L inTHF),室温搅拌2h,用水淬灭反应,用乙酸乙酯萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到白色固体。将白色固体、三乙胺(252.8mg,2.5mmol,2.5equiv.)溶于无水DCM(5.0mL)中,缓慢滴加2,4,6-三甲基苯甲酰氯(402.6mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到产物Cat-13(765.0mg,62%).
1H NMR(400MHz,CDCl3)δ8.21(d,J=8.8Hz,4H),7.65(d,J=8.8Hz,4H),6.91(t,J=8.3Hz,1H),6.80(s,4H),6.79(s,4H),6.28(d,J=8.5Hz,2H),6.14(d,J=8.4Hz,2H),5.76(d,J=4.4Hz,2H),5.01(tt,J=8.3,3.6Hz,2H),4.92(dd,J=11.6,7.1Hz,2H),4.57(dd,J=11.6,3.9Hz,2H),2.28(s,6H),2.27(s,6H),2.18(s,12H),1.97(s,12H).13C NMR(100MHz,CDCl3)δ170.5,169.4,156.9,147.8,143.9,139.9,139.0,135.3,133.9,133.7,130.1,129.6,128.5,128.3,127.5,124.0,106.8,79.9,79.5,77.5,77.2,76.8,62.2,53.8,21.1,21.0,20.0,18.7.
HRMS(ESI):calc.for[C64H65IN4O12Si2+H]+1209.3716found 1209.3719.实施例17
(2S,2'S,3R,3'R)-((2-碘-1,3-亚苯基)双(3-(4-硝基苯基)-2-(2,4,6-三甲基苯甲酰胺基)丙烷-3,1-二基)双(2,4,6-三甲基苯甲酸酯)的合成:
氮气氛围下,在干燥的schlenk管中加入1R,1'R,2S,2'S-(2-碘-1,3-亚苯基)双(氧基)双(3-叔丁基二苯基硅氧基)-1-(4-硝基苯基)丙烷-2-胺)(1.1g,1.0mmol,1.0equiv.),三乙胺(252.8mg,2.5mmol,2.5equiv.)和无水DCM(5.0mL),接着在0℃下滴加2,4,6-三溴苯甲酰氯(750.0mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到产物(1.54g,86%).
将所得产物溶于四氢呋喃中(10mL)中,然后滴加TBAF(2.5ml,1mol/L inTHF),室温搅拌2h,用水淬灭反应,用乙酸乙酯萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到白色固体。将白色固体、N,N-二异丙基乙胺(285mg,2.5mmol,2.5equiv.)溶于无水DCM(5.0mL)中,缓慢加入三苯基甲基氯(612mg,2.2mmol,2.2equiv.),反应2h后,用水淬灭反应,用二氯甲烷萃取,分离有机相,减压条件下去除溶剂后,使用甲醇重结晶纯化,得到产物Cat-3(1.083g,70%intwosteps).
1H NMR(400MHz,CDCl3)δ8.14(d,J=8.2Hz,4H),7.66(s,4H),7.52(d,J=8.5Hz,4H),7.37–7.31(m,12H),7.23–7.15(m,18H),6.84(t,J=8.3Hz,1H),6.11(s,2H),6.07(d,J=8.4Hz,2H),5.82(d,J=3.7Hz,2H),4.80–4.72(m,2H),3.84(dd,J=10.4,7.5Hz,2H),3.53(dd,J=10.4,3.6Hz,2H);13C NMR(100MHz,CDCl3)δ165.9,157.0,147.8,144.2,143.4,138.1,134.3,130.1,128.7,128.0,127.5,127.3,124.2,124.1,120.9,106.8,87.4,80.3,79.8,60.7,56.2
HRMS(ESI):calc.for[C75H55IBr6N4O10Si2+H]+1790.8080found 1790.8088.实施例18
1-萘酚衍生物的去芳构化:
氮气氛围下,在向含有Cat-1(0.03mmol,15mol%),mCPBA(0.26mmol,1.3equiv.),TFE(10mmol,50equiv.),H2O(2mmol,10equiv.)和MeNO2(3mL)的schlenk管中加入1-萘酚衍生物11(0.2mmol)。将反应混合物在-10℃搅拌72小时。反应混合物按照饱和Na2S2O3和NaHCO3水溶液的顺序淬灭。然后用乙酸乙酯萃取有机层,用盐水洗涤,用无水Na2SO4干燥,然后用硅胶柱层析纯化,得到产物12(57%yield,94%ee)。
1H NMR(400MHz,CDCl3)δ7.99(d,J=7.7Hz,1H),7.68-7.61(m,1H),7.44-7.30(m,3H),7.03-6.88(m,4H),6.03(d,J=9.6Hz,1H),3.29(s,3H);13C NMR(100MHz,CDCl3)δ194.1,172.8,144.9,138.3,135.4,129.4,129.3,128.7,128.7,128.4,128.1,127.8,123.5,123.1,109.0,64.5,27.0.
HRMS(ESI):calc.for[C18H13N2O2+H]+276.1025found 276.1020.
Optical Rotation:[α]25 D-4.2(c=1,CHCl3).
实施例19
丙二酰胺类化合物的交叉偶联:
氮气氛围下,向含有Cat-2(0.03mmol,15mol%),mCPBA(0.52mmol,2.6equiv.),TFA(0.6mmol,3equiv.)和H2O(0.6mmol,3equiv.)和MeCN(3mL)的schlenk管中加入丙二酰胺衍生物13(0.2mmol)。将反应混合物在25℃下搅拌16小时。反应混合物按照饱和Na2S2O3和NaHCO3水溶液的顺序淬灭。然后用乙酸乙酯萃取有机层,用盐水洗涤,用无水Na2SO4干燥,然后用硅胶柱层析纯化,得到产物14(72%yield,90%ee)。
1H NMR(400MHz,CDCl3)δ7.38(t,J=7.6Hz,2H),7.04(t,J=7.6Hz,2H),6.96(d,J=7.8Hz,2H),6.88(d,J=7.4Hz,2H),3.30(s,6H);13C NMR(100MHz,CDCl3)δ172.2,145.4,129.6,127.9,123.9,123.3,108.8,62.3,27.0.
HRMS(ESI):calc.for[C17H14N2O2+H]+279.1134found 279.1130.
Optical Rotation:[α]25 D-71(c=0.5,CHCl3).
实施例20
二羰基化合物的α-氟化:
氮气氛围下,在向含有Cat-3(0.03mmol,15mol%),mCPBA(0.3mmol,1.5equiv.),Et3N·3HF(10equiv.)和氯仿(10mL)的聚四氟乙烯管中加入二羰基化合物15(0.2mmol)。将反应混合物在25℃搅拌16小时。反应混合物按照饱和Na2S2O3和NaHCO3水溶液的顺序淬灭。然后用二氯甲烷萃取有机层,用盐水洗涤,用无水Na2SO4干燥,然后用硅胶柱层析纯化,得到α-氟化产物16(54%yield,85%ee)。
1H NMR(400MHz,CDCl3)δ7.80(d,J=7.7Hz,1H),7.69(t,J=7.5Hz,1H),7.50(d,J=7.7Hz,1H),7.44(t,J=7.8Hz,1H),4.25(q,J=7.1Hz,2H),3.78(dd,J=17.7,11.5Hz,1H),3.41(dd,J=23.4,17.7Hz,1H),1.22(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3)δ195.24(d,2JC-F=18.2Hz),167.16(d,2JC-F=27.9Hz),150.84(d,3JC-F=3.6Hz),136.66,133.03,128.48,126.52,125.33,94.36(d,1JC-F=201.0Hz),62.41,38.08(d,2JC-F=24.0Hz),13.80.19F NMR(376MHz,CDCl3)δ-164.4.
HRMS(ESI):calc.for[C12H10O3ClF+Na]+233.0770;found 233.0776
Optical Rotation:[α]25 D2.9(c=1,CHCl3).
Claims (10)
1.一种以氯霉胺为手性源的柔性手性芳基碘催化剂,其特征在于,其结构式如式(10)所示,
其中R1选自羟基保护基,包括三甲基硅基、三乙基硅基、三乙丙基硅基、二乙基异丙基硅基、二甲基叔丁基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、乙酰基、三氟乙酰基、三氯乙酰基、叔丁基乙酰基、苯甲酰基或取代苯基,取代苯基上的取代基为单取代或多取代,取代基为甲基、甲氧基、三氟甲基、三氟甲氧基、乙基、异丙基、叔丁基、卤素或硝基;取代基R2取代或不取代,取代时R2选自甲基、三氟甲基、甲酯或乙酯;R3,R4,R5和R6各自独立地选自烷烃、苯基或取代苯基,取代苯基上的取代基为单取代或多取代,取代基为甲基、甲氧基、三氟甲基、三氟甲氧基、乙基、异丙基、叔丁基、卤素或硝基。
2.一种如权利要求1所述的柔性手性芳基碘催化剂的合成方法,其特征在于,包括如下步骤:
1)式(1)所示氯霉胺经过二碳酸二叔丁酯保护氨基并通过溶剂重结晶析出得到式(2)所示的中间体;
2)将式(2)所示的中间体在碱的作用下与氯硅烷于溶剂中反应生成如式(3)所示的中间体;
3)将式(3)所示的中间体在咪唑和碱的作用下与氯化亚砜反应生成如式(4)所示的中间体;
4)将式(4)所示的中间体在氧化剂和催化剂的作用下于溶剂中反应,并通过重结晶得到如式(5)所示的中间体;
5)将式(5)所示中间体和式(6)所示2-碘苯二酚衍生物在碱的作用下反应生成式(7)所示的中间体;
6)将式(7)所示中间体在酸的作用下于溶剂中脱去保护基生成式(8)所示的中间体;
7)将式(8)所示中间体在碱的作用下与酰氯、磺酰胺、异氰酸酯或异硫氰酸酯反应,并通过溶剂重结晶得到式(9)所示的手性芳基碘催化剂;
8)将式(9)所示中间体在四丁基氟化铵的作用下脱去硅基得到中间体,之后继续与酰氯、磺酰胺、异氰酸酯或异硫氰酸酯反应,并通过溶剂重结晶得到式(10)所示的手性芳基碘催化剂,
反应过程如下:
其中R1选自羟基保护基,包括三甲基硅基、三乙基硅基、三乙丙基硅基、二乙基异丙基硅基、二甲基叔丁基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基、乙酰基、三氟乙酰基、三氯乙酰基、叔丁基乙酰基、苯甲酰基或取代苯基,取代苯基上的取代基为单取代或多取代,取代基为甲基、甲氧基、三氟甲基、三氟甲氧基、乙基、异丙基、叔丁基、卤素或硝基;取代基R2和R12取代或不取代,取代时R2和R12选自甲基、三氟甲基、甲酯或乙酯;R3,R4,R5,R6各自独立地选自烷烃、苯基或取代苯基,取代苯基上的取代基为单取代或多取代,取代基为甲基、甲氧基、三氟甲基、三氟甲氧基、乙基、异丙基、叔丁基、卤素或硝基,R8,R9,R10和R11各自独立地选自烷烃、苯基或取代苯基,取代苯基上的取代基为单取代或多取代,取代基为甲基、甲氧基、三氟甲基、三氟甲氧基、乙基、异丙基、叔丁基、卤素或硝基。
3.如权利要求2所述的合成方法,其特征在于,步骤1)所述二碳酸二叔丁酯的用量为式(1)所示化合物的1.0-10.0当量,中间体(2)重结晶所使用的溶剂为乙酸乙酯、甲醇或乙醚,反应温度为-20-0℃,反应时间为2-7h。
4.如权利要求2所述的合成方法,其特征在于,步骤2)所述氯硅烷为叔丁基二苯基氯硅烷、叔丁基二甲基氯硅烷、三甲基氯硅烷、三乙基氯硅烷、三异丙基氯硅烷、二甲基异丙基氯硅烷或二乙基异丙基氯硅烷,所述氯硅烷的用量为式(2)所示中间体的1.0-5.0当量,溶剂为二氯甲烷、二氯乙烷、氯仿、四氢呋喃或N,N-二甲基甲酰胺,反应温度为-20-0℃,反应时间为2-5h。
5.如权利要求2所述的合成方法,其特征在于,步骤3)所述的氯化亚砜的用量为式(3)所示中间体的1.0-5.0当量,咪唑的用量为式(3)所示中间体的1.0-20.0当量,碱为三乙胺或N,N-二异丙基乙胺,所述碱的用量为式(3)所示中间体的2.0-10.0当量,反应温度为-70-0℃,反应时间为2-5h。
6.如权利要求2所述的合成方法,其特征在于,步骤4)所述的氧化剂为高碘酸钠,氧化剂的用量为式(4)所示中间体的1.0-5.0当量,催化剂为水合三氯化钌,催化剂的用量为式(4)所示中间体的1-30mol%,溶剂为乙腈和水或二氯甲烷和水,所述溶剂的用量为1:1,反应温度为0-30℃,反应时间为2-6h。
7.如权利要求2所述的合成方法,其特征在于,步骤5)中式(5)所示中间体的用量为式(6)所示2-碘苯二酚衍生物的2.0-10.0当量,碱为氢化钠,碱的用量为式(6)所示2-碘苯二酚衍生物的2.0.-10.0当量,反应温度为-20-0℃,反应时间为2-6h。
8.如权利要求2所述的合成方法,其特征在于,步骤6)所述溶剂为二氯甲烷、二氯乙烷或氯仿,酸为三氟乙酸、盐酸或硫酸,酸和溶剂的用量为1:3-1:10,反应温度为-20-0℃,反应时间为1-5h。
9.如权利要求2所述的合成方法,其特征在于,步骤7)所述酰氯、磺酰胺、异氰酸酯或异硫氰酸酯的用量为式(8)所示中间体的2.0-10.0当量,碱为三乙胺,碱的用量为式(8)所示中间体的2.0-10.0当量,重结晶溶剂为四氢呋喃烷、甲基叔丁基醚或二氧六环,反应温度为-20-50℃,反应时间为1-8h;步骤8)中四丁基氟化铵所使用量为式(9)化合物的1.0-20.0当量,所述酰氯、磺酰胺、异氰酸酯或异硫氰酸酯的用量为式(9)的2.0-10.0当量,碱为三乙胺,碱的用量为式(9)化合物的2.0-10.0当量。
10.一种如权利要求1所述的以氯霉胺为手性源的柔性手性芳基碘催化剂的应用,其特征在于,手性芳基碘催化剂通过分子内的氧化内酯化、醚化、酰胺化、芳基化反应,对映选择性地合成了γ-丁内酯、色满环、异色满环、噁唑烷酮、哌啶、吡咯烷、氮杂环丙烷。
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