CN116568658A - 经由环化c-h/c-h偶联快速构建四氢化萘、色原烷和二氢化茚模体 - Google Patents
经由环化c-h/c-h偶联快速构建四氢化萘、色原烷和二氢化茚模体 Download PDFInfo
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- CN116568658A CN116568658A CN202180082432.XA CN202180082432A CN116568658A CN 116568658 A CN116568658 A CN 116568658A CN 202180082432 A CN202180082432 A CN 202180082432A CN 116568658 A CN116568658 A CN 116568658A
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- 238000005859 coupling reaction Methods 0.000 title abstract description 25
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical class C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 title abstract description 10
- 238000010168 coupling process Methods 0.000 title description 12
- 230000008878 coupling Effects 0.000 title description 10
- 238000010276 construction Methods 0.000 title description 6
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 title description 4
- 150000001843 chromanes Chemical class 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 81
- 150000001875 compounds Chemical class 0.000 claims description 68
- 239000003446 ligand Substances 0.000 claims description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 239000007800 oxidant agent Substances 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- 230000001590 oxidative effect Effects 0.000 claims description 14
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 12
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
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- 125000000217 alkyl group Chemical group 0.000 claims description 9
- VTIIJXUACCWYHX-UHFFFAOYSA-L disodium;carboxylatooxy carbonate Chemical group [Na+].[Na+].[O-]C(=O)OOC([O-])=O VTIIJXUACCWYHX-UHFFFAOYSA-L 0.000 claims description 9
- 229940045872 sodium percarbonate Drugs 0.000 claims description 9
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- 238000004519 manufacturing process Methods 0.000 claims 1
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- KWZSDDCXILDZQR-UHFFFAOYSA-N CCOC(CC1=C(C)C(I)=CC=C1C)=O Chemical compound CCOC(CC1=C(C)C(I)=CC=C1C)=O KWZSDDCXILDZQR-UHFFFAOYSA-N 0.000 description 4
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- UXXPWRBCHVCRAQ-UHFFFAOYSA-N 2-ethyl-1,3-dihydroindene-2-carboxylic acid Chemical compound C1=CC=C2CC(CC)(C(O)=O)CC2=C1 UXXPWRBCHVCRAQ-UHFFFAOYSA-N 0.000 description 2
- OJGQVOARYFNMJA-UHFFFAOYSA-N 2-ethyl-3,4-dihydro-1h-naphthalene-2-carboxylic acid Chemical compound C1=CC=C2CC(CC)(C(O)=O)CCC2=C1 OJGQVOARYFNMJA-UHFFFAOYSA-N 0.000 description 2
- VWCCBMWZNOWFDT-UHFFFAOYSA-N 2-methyl-1,3-dihydroindene-2-carboxylic acid Chemical compound C1=CC=C2CC(C)(C(O)=O)CC2=C1 VWCCBMWZNOWFDT-UHFFFAOYSA-N 0.000 description 2
- NZWGWZMCDWLRON-UHFFFAOYSA-N 2-methyl-3,4-dihydro-1h-naphthalene-2-carboxylic acid Chemical compound C1=CC=C2CC(C)(C(O)=O)CCC2=C1 NZWGWZMCDWLRON-UHFFFAOYSA-N 0.000 description 2
- UGAGZMGJJFSKQM-UHFFFAOYSA-N 3,4-dihydro-2h-chromene-3-carboxylic acid Chemical compound C1=CC=C2CC(C(=O)O)COC2=C1 UGAGZMGJJFSKQM-UHFFFAOYSA-N 0.000 description 2
- LTBPSLQNFNJHNW-UHFFFAOYSA-N 3-methyl-8-(trifluoromethyl)-2,4-dihydrochromene-3-carboxylic acid Chemical compound CC1(COc2c(C1)cccc2C(F)(F)F)C(O)=O LTBPSLQNFNJHNW-UHFFFAOYSA-N 0.000 description 2
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- DSVHLKAPYHAYFF-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1C(C(O)=O)CCC2=CC(OC)=CC=C21 DSVHLKAPYHAYFF-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
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- 238000010485 C−C bond formation reaction Methods 0.000 description 2
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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Abstract
本文公开了用于使用作为导向基团的天然游离羧酸、氨基酸配体和氧化剂实现钯催化的环化C(sp3)‑H/C(sp2)‑H偶联反应的方法。所述方法可用于合成一系列生物学上重要的母核,包括四氢化萘、色原烷和二氢化茚。
Description
优先权要求
本申请要求于2020年11月11日提交的美国临时申请第63/112,464号的优先权权益,该申请如同完整阐述一样并入本文。
政府支持的声明
本发明是在国立卫生研究院(National Institutes of Health)授予的基金号2R01GM084019和国家科学基金会(National Science Foundation)授予的基金号CHE-1700982的政府支持下完成的。政府对本发明享有某些权利。
背景技术
碳-碳(C-C)键形成构成有机合成中最重要的反应类别之一。因为这样的键形成具有缩短合成的潜力,过去二十年见证了在使用C-H活化策略构建C-C键方面的快速发展。1虽然大多数偶联方法需要预官能化的偶联配偶体(例如有机硼和有机卤化物),但C-H/C-H偶联反应提供了直接由两个简单的C-H键构建C-C键的互补策略。2与传统的偶联方法相比,这种绿色且原子经济的方法极具吸引力,因为水可能是该过程的唯一化学计量副产物。先前的报道集中于使两个相对反应性的C(sp2)-H键偶联以用于联芳基合成,3而仅报道了少数用于构建更具挑战性的C(sp3)-C(sp2)键的反应。由于这些现有的反应方案需要外源导向基团(directing group,DG)以促进环金属化,因此需要另外的步骤来设置和去除DG。5,6此外,报道的方法存在实际限制,例如报道了化学计量使用贵的银盐4b,c,5,6b,c以及严苛的条件4b,c,5a,b,6(其中温度高至160℃)。此外,目前由C(sp3)-H活化引发的C(sp3)-H/C(sp2)-H偶联的方法在很大程度上局限于更具反应性的杂环C(sp2)-H键。5a,b,6因此,使用实用氧化剂和天然底物二者的C(sp3)-H/C(sp2)-H偶联反应的发展仍然是重大挑战。
C-H官能化的最新进展为化学工作者提供了创造性和策略性的逆合成切断,否则这使用传统方法难以实现。7然而,为了C-H官能化策略真正改善合成的整体效率,应满足三个标准:(1)使用宽范围的简单起始材料以能够合成各种各样的天然产物家族的能力;(2)使用天然官能团作为DG;(3)C-H官能化反应的位点选择性应是精确可控的。然而,可以满足上述标准的方法具有挑战性且不常见。7a,8
发明内容
本公开内容在多个实施方案中通过提供用于制备式(2)的化合物的方法克服了这些挑战和另外的挑战:
所述方法包括使式(1)的化合物:
与式(L)的配体:
接触。
所述接触在钯(II)源和氧化剂的存在下发生,由此形成式(2)的化合物。
在本文描述的方法中:
X为CH2或O;
n为选自0和1的整数;
o和m为独立地选自0、1和2的整数,其中o和m之和不大于4;
x和y为独立地选自0和1的整数;
z为选自0、1和2的整数;
R1选自H和C1-C6-烷基;
各R2和R3独立地选自C1-C6-烷基、C1-C6-烷氧基、卤素、C1-C6-卤代烷基和(C6-C10-芳基)(C1-C6-烷基)-;
或者相邻的R2和R3与它们所结合的碳原子一起形成稠合的C5-C6-环烷基或苯基;以及
各R4和R5独立地选自H、C1-C6-烷基和(C6-C10-芳基)(C1-C6-烷基)-;
或者,当z为1时,则R4和R5与它们所结合的碳原子一起形成5元至6元环烷基,其中环烷基除了具有如所示的-NHAc和-CO2H取代基之外,还任选地取代有选自卤素、C1-C6-烷基、C1-C6-烷氧基和C6-C10-芳基中的1至2个取代基。
在附图和具体实施方式中描述了本公开内容的另外的实施方案。
附图说明
图1.具有生物学意义的天然产物包括四氢化萘、色原烷和二氢化茚框架。
图2.在示例性环化C(sp3)-H/C(sp2)-H偶联反应中的配体研究。条件:1a(0.1mmol),Pd(OAc)2(10mol%),配体(L)(10mol%),LiOAc(1.0当量),Na2CO3·1.5H2O2(2.0当量),HFIP(1.0mL),60℃,12小时。产率使用CH2Br2作为内标通过粗产物的1H NMR分析确定。c分离产率。
图3.示例性环化C(sp3)-H/C(sp2)-H偶联反应的底物范围以及分离产率。条件A:1(0.1mmol),Pd(OAc)2(10mol%),L9(10mol%),LiOAc(1.0当量),Na2CO3·1.5H2O2(2.0当量),HFIP(1.0mL),60℃,12小时。c条件B:1(0.1mmol),Pd(CH3CN)4(BF4)2(10mol%),Ag2CO3(1.0当量),1-氟-2,4,6-三甲基吡啶四氟硼酸盐(2.0当量),HFIP(1.0mL),90℃,12小时。
图4.伊鲁烷型(Illudalane)倍半萜具有包含季中心的二氢化茚核。
图5(±)-russujaponol F的全合成。条件:(a)SOCl2,EtOH,回流,过夜;I2(0.5当量),选择性氟试剂(Selectfluor)(0.5当量),CH3CN,60℃,3小时。(b)Pd(OAc)2(10mol%),L12(10mol%),新戊酸(3.0当量),CsOAc(1.0当量),Ag2CO3(2.0当量),HFIP,80℃,12小时。(c)Pd(CH3CN)4(BF4)2(10mol%),Ag2CO3(1.0当量),1-氟-2,4,6-三甲基吡啶四氟硼酸盐(2.0当量),HFIP,90℃,12小时。(d)氢化铝锂(LAH)(3.0当量),四氢呋喃(THF),0℃至室温,过夜。
具体实施方式
本公开内容部分地涉及用于使用天然游离羧酸作为导向基团(DG)的环化C(sp3)-H/C(sp2)-H偶联反应的方法。在示例性实施方案中,基于环戊烷的单-N-保护的β-氨基酸配体和实用且便宜的氧化剂过碳酸钠(Na2CO3·1.5H2O2)证实可用于该方法。例如,作为天然产物中常见框架的四氢化萘、色原烷和二氢化茚(图1)容易通过该方法制备。该方法的合成应用通过以下进一步被证明:由容易获得的苯乙酸和新戊酸以四个步骤经由多次C-H官能化简洁地全合成(±)-russujaponol F(迄今为止最简短且产率最高)(方案1C),证明了C-H活化切断提高合成的理想状态的潜力9。
定义
“Ac”是指具有式-C(=O)-CHa的乙酰基。
“烷基”是指包含1至约20个碳原子的直链或支链烃基。例如,烷基可以具有1至10个碳原子或1至6个碳原子。示例性烷基包括直链烷基,例如甲基(“Me”)、乙基(“Et”)、丙基、丁基(包括叔丁基(“tBu”))、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基等,并且还包括直链烷基的支链异构体,例如但不限于-CH(CH3)2、-CH(CH3)(CH2CH3)、-CH(CH2CH3)2、-C(CH3)3、-C(CH2CH3)3、-CH2CH(CH3)2、-CH2CH(CH3)(CH2CH3)、-CH2CH(CH2CH3)2、-CH2C(CH3)3、-CH2C(CH2CH3)3、-CH(CH3)CH(CH3)(CH2CH3)、-CH2CH2CH(CH3)2、-CH2CH2CH(CH3)(CH2CH3)、-CH2CH2CH(CH2CH3)2、-CH2CH2C(CH3)3、-CH2CH2C(CH2CH3)3、-CH(CH3)CH2CH(CH3)2、-CH(CH3)CH(CH3)CH(CH3)2等。因此,烷基包括伯烷基、仲烷基和叔烷基。
“Boc”是指具有式(CH3)3C-O-C(=O)-的叔丁氧基羰基。
“Bn”是指具有式-CH2-苯基的苄基。
术语“卤素”、“卤化物”和“卤代”中的每一者是指-F或氟、-Cl或氯、-Br或溴、或者-I或碘。
术语“烷氧基”是指具有指定碳原子数的-O-烷基。例如,(C1-C6)-烷氧基包括-O-甲基、-O-乙基、-O-丙基、-O-异丙基、-O-丁基、-O-仲丁基、-O-叔丁基、-O-戊基、-O-异戊基、-O-新戊基、-O-己基、-O-异己基和-O-新己基。
术语“环烷基”是指饱和的单环、双环、三环或多环的3元至14元环体系,例如C3-C8-环烷基。环烷基可以经由任何原子连接。环烷基的代表性实例包括但不限于环丙基、环丁基、环戊基和环己基。在某些实施方案中,式(L)的配体中的环烷基除了具有如所示的-NHAc和-CO2H取代基之外,还取代有选自卤素、C1-C6-烷基、C1-C6-烷氧基和C6-C10-芳基中的1至2个取代基。
“芳基”在单独使用或者作为另外的术语的一部分使用时意指无论是否稠合都具有指定的碳原子数或者如果未指定数目则具有多至14个碳原子的碳环芳族基团,例如C6-C10-芳基或C6-C14-芳基。芳基的实例包括苯基、萘基、联苯基、菲基、并四苯基等(参见例如Lang’s Handbook of Chemistry(Dean,J.A.编辑)第13版.表7-2[1985])。示例性芳基为苯基。芳基可以为未经取代的或任选地经一个或更多个如本文描述的取代基取代的。
术语“任选地取代”是指经指定的取代基任选地取代(即,未经取代或经取代)。
本文描述的化合物可以以多种异构体形式存在,包括构型异构体、几何异构体和构象异构体,包括例如顺式或反式构象。化合物也可以以一种或更多种互变异构体形式存在,包括单一互变异构体以及互变异构体的混合物二者。术语“异构体”旨在涵盖本公开内容的化合物的所有异构体形式,包括化合物的互变异构体形式。本公开内容的化合物也可以以开链或环化形式存在。在一些情况下,环化形式中的一者或更多者可以由失水产生。开链和环化形式的具体组成可以取决于如何分离、储存或施用化合物。例如,化合物在酸性条件下可能主要以开链形式存在,而在中性条件下可能环化。所有形式都包括在本公开内容中。
本文所描述的一些化合物可以具有不对称中心,并因此以不同的对映体和非对映体形式存在。如本文描述的化合物可以呈光学异构体或非对映体的形式。因此,本公开内容涵盖了如本文描述的呈其光学异构体、非对映异构体及其混合物(包括外消旋混合物)形式的化合物及其用途。本公开内容的化合物的光学异构体可以通过已知技术例如不对称合成、手性色谱法、模拟移动床技术获得,或者经由通过采用光学活性拆分剂对立体异构体进行的化学分离获得。
除非另有说明,否则术语“立体异构体”意指化合物的一种立体异构体,其基本上不含该化合物的其他立体异构体。因此,具有一个手性中心的立体异构纯化合物将基本上不含该化合物的相反对映体。具有两个手性中心的立体异构纯化合物将基本上不含该化合物的其他非对映体。典型的立体异构纯化合物包含多于约80重量%的该化合物的一种立体异构体和少于约20重量%的该化合物的其他立体异构体,例如多于约90重量%的该化合物的一种立体异构体和少于约10重量%的该化合物的其他立体异构体,或者多于约95重量%的该化合物的一种立体异构体和少于约5重量%的该化合物的其他立体异构体,或者多于约97重量%的该化合物的一种立体异构体和少于约3重量%的该化合物的其他立体异构体,或者多于约99重量%的该化合物的一种立体异构体和少于约1重量%的该化合物的其他立体异构体。如上所述的立体异构体可以被视为包含以本文中所述的其各自的重量百分比存在的两种立体异构体的组合物。
如果所描绘的结构与该结构的给定名称之间存在差异,则以描绘的结构为准。此外,如果结构或结构的一部分的立体化学未用例如粗线或虚线表示,则该结构或该结构的一部分解释为涵盖其所有立体异构体。然而,在一些情况下,当存在多于一个手性中心时,结构和名称可以表示为单一对映体,以帮助描述相对立体化学。有机合成领域的技术人员将由用于制备化合物的方法知道化合物是否制备为单一对映体。
在本文描述的方法的一些实施方案中,X为CH2。在另一些实施方案中,X为O。
在多个实施方案中,n为0,而在另一些实施方案中n为1。在说明性实施方案中,式(2)的化合物为选自表1中的一者:
表1.示例性式(2)的化合物.
在式(L)的配体中,根据多个实施方案,z为1。在另一些实施方案中,z为0或2。
在多个实施方案中,x和y中的一者为0而另一者为1。在另外的实施方案中,R4和R5与它们所结合的碳原子一起形成5元至6元环烷基,其中环烷基除了具有如所示的-NHAc和-CO2H取代基之外还任选地取代有选自卤素、C1-C6-烷基、C1-C6-烷氧基和C6-C10-芳基中的1至2个取代基。例如,根据一个实施方案,R4和R5与它们所结合的碳原子一起形成5元环烷基,其中环烷基除了具有如所示的-NHAc和-CO2H取代基之外还任选地取代有选自卤素、C1-C6-烷基、C1-C6-烷氧基和C6-C10-芳基中的1至2个取代基。根据另一个实施方案,R4和R5与它们所结合的碳原子一起形成6元环烷基,其中环烷基除了具有如所示的-NHAc和-CO2H取代基之外还任选地取代有选自卤素、C1-C6-烷基、C1-C6-烷氧基和C6-C10-芳基中的1至2个取代基。示例性式(L)的配体为选自表2中的一者。
表2:示例性式(L)的配体.
例如,根据一个实施方案,可用的式(L)的配体为L9:
在多个实施方案中,基于式(2)的化合物的量,式(L)的配体以约1mol%至约15mol%的量存在。例如,该量可以在约7mol%至约12mol%的范围内。在多个实施方案中,配体(L)的量为约1mol%、2mol%、3mol%、4mol%、5mol%、6mol%、7mol%、8mol%、9mol%、10mol%、11mol%、12mol%、13mol%、14mol%或15mol%。在一个说明性实施方案中,该量为约10mol%。
在多个实施方案中,式(1)的化合物为选自表3中的一者。
表3:示例性式(1)的化合物.
在本文所述的方法中,钯催化剂通过经由本领域已知的或市售的试剂引入钯(II)而产生。根据一个实施方案,一种合适的钯(II)源为Pd(OAc)2。在另一个实施方案中,来源为Pd(CH3CN)4(BF4)2。
催化剂负载量可以根据本领域技术人员已知的因素例如整体反应动力学而改变。因此,在多个实施方案中,基于式(2)的化合物的量,钯(II)源以约1mol%至约15mol%的量存在。在另一些实施方案中,该量为约7mol%至约12mol%。示例性量包括1mol%、2mol%、3mol%、4mol%、5mol%、6mol%、7mol%、8mol%、9mol%、10mol%、11mol%、12mol%、13mol%、14mol%和15mol%。在一个实施方案中,该量为10mol%。
本领域中已知的各种氧化剂可用于本公开内容的方法中。如本文更详细描述的,根据一个实施方案,合适的氧化剂为过碳酸钠。
在多个实施方案中,本文所述的方法的接触步骤进一步在LiOAc的存在下发生。在一个实施方案中,其中可用的溶剂为六氟异丙醇。
根据本公开内容的实施方案,本文所述的方法可以在各种温度下进行。例如,温度为约20℃、25℃、30℃、35℃、40℃、45℃、50℃、55℃、60℃、65℃、70℃、75℃或80℃。在一个说明性实施方案中,温度为约60℃。
在多个实施方案中,式(L)的配体为以约10mol%的量存在的(L9):
o和m之和为1或2;钯(II)源是量为约10mol%的Pd(OAc)2;以及氧化剂为过碳酸钠。
脂族羧酸是普遍存在且综合用途广泛的模体,并且在有机化学中通常是便宜的试剂;因此,它们是用于C-H活化反应的优先底物。根据本公开内容的一个实施方案,10遵循使用叔丁基过氧化氢(TBHP)作为唯一氧化剂对游离羧酸进行β-C(sp3)-H内酯化10i和酰氧基化10j的最新公开内容,通过选择TBHP作为旁观氧化剂(bystanding oxidant)并选择脂族酸1a作为模型底物,开始研究环化C(sp3)-H/C(sp2)-H偶联反应。在前述β-酰氧基化反应10j的最佳条件下,得到50%1H NMR产率的期望产物2a而不形成竞争性还原消除产物,例如β-内酯或β-羟基酸。对旁观氧化剂和基底的进一步研究揭示,在多个实施方案中,Na2CO3·1.5H2O2和LiOAc的组合将产率提高至57%(参见实施例)。在一些实施方案中,使用过碳酸钠(最便宜且最容易处理的氧化剂之一)11是使所述方法实用且可扩展的一个优势。
鉴于配体促进的Pd(II)催化的C-H活化的最新进展,12接下来寻找可以显著提高催化剂的反应性的配体。由单-N-保护的氨基酸(MPAA)配体实现的游离羧酸的C(sp3)-H活化反应所指导10c,d,g,i,j,测试了一系列市售的MPAA配体(L1至L4):β-氨基酸配体L4相对于α-氨基酸配体L1至L3表现出优异的反应性(57%相对于19%至45%),这也在经由Pd(II)/Pd(IV)催化循环的游离酸的其他C(sp3)-H官能化反应中观察到10d,i,j。通过对β-氨基酸配体的骨架的系统性修饰(L5至L10;参见图2),出乎意料地发现,在一个实施方案中,基于顺式-环戊烷的配体L9得到最佳反应性(78%分离产率)。不受任何特定理论的束缚,L9的优异反应性可以归因于由环戊烷键实现的更刚性的构象。对照实验表明,在不存在配体的情况下或在存在γ-氨基酸配体(L11)的情况下,产率低(分别为23%或20%)。
此外,环化C(sp3)-H/C(sp2)-H偶联反应的范围通过多个实施方案进行评估(图3)。宽范围的带有单个α-甲基(1a至1e和1h)或α-偕二甲基(1f和1g)的叔脂族酸全部是相容的,从而得到中等至良好产率(52%至78%)的四氢化萘产物。较低反应性的包含α-氢(1i至1l)的游离羧酸也以综合有用的产率(35%至65%)反应。其中,芳基环上的各种官能团例如甲基(2b)、甲氧基(2j和2k)、氟(2c、2g和2l)、和氯(2d)以及萘基(2e)是可接受的,其中卤素部分(2d)用作对于后续衍生化有用的合成柄。
本公开内容的方法还可用于合成生物学上重要的色原烷产物。例如,根据多个实施方案,包含α-偕二甲基(1m至1r)或α-氢(1s,来自Roche酯)的β-苯氧基羧酸全部是反应性底物。虽然芳基环上的一系列供电子基团(甲氧基、叔丁基、环己基和苄基)(2s和2n至2p)均很好地被接收以得到良好产率(70%至85%)的期望产物,但包含吸电子基团(溴和三氟甲基)的脂族酸(2q和2r)表现出相对低的反应性(31%和23%),这可能是由于缺电子芳烃的C(sp2)-H活化的缓慢性质。在当前条件下,羧酸1t未能提供四氢异喹啉(THIQ)产物2t。这种环化的C-H/C-H偶联反应也适于合成二氢化茚母核(2u至2w)。例如,在一个实施方案中,[F+]氧化剂3g,13(1-氟-2,4,6-三甲基吡啶四氟硼酸盐)对包含α-偕二甲基的叔脂族酸表现出优异的反应性(2v和2w)。
另外的实施方案示出了本公开内容的涉及伊鲁烷型倍半萜的方法,其包括一大类天然产物:它们的典型特征在于带有具有挑战性的全碳季中心的二氢化茚核(其多种氧化态都是可以的)(图4)。14由于其有前景的生物活性,已经为这些目标的全合成付出了巨大的努力。15,16鉴于这种方法用于构建二氢化茚母核的能力,开始经由多次C-H官能化的(±)-russujaponol F全合成(图5)。报道了第一russujaponol F全合成基于C(sp3)-H芳基化策略分别以13步(26%产率)和15步(12%产率)以外消旋和对映选择性形式发生。15从市售的或通过邻C-H甲基化17合成的苯乙酸3开始,通过酯化并随后使用I2和选择性氟试剂对3进行单碘化18以79%的产率制备芳基碘化物4。对新戊酸的C-H芳基化的研究表明,在配体L1210f ,19的情况下,可以以62%的产率获得单芳基化产物5,以及以12%产率获得环化C-H/C-H偶联产物6。在这些条件下6的形成可以归因于在另外的芳基碘化物用作旁观氧化剂的情况下5的第二次芳基化。20然后在标准条件下使用[F+]氧化剂进行环化C-H/C-H偶联从而以41%的产率得到期望产物6。最后,使用LAH对6进行整体还原,以96%的产率纯净地得到(±)-russujaponol F,从而以四步和28%的总产率完成全合成:迄今为止最简短且产率最高的russujaponol F全合成。
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实施例
在以下非限制性实施例中阐述了本公开内容的另外的实施方案。
一般信息。Pd(OAc)2、LiOAc、Ag2CO3和过碳酸钠(Na2CO3·1.5H2O2)购自Sigma-Aldrich。Pd(CH3CN)4(BF4)2购自Strem。1-氟-2,4,6-三甲基吡啶四氟硼酸盐购自TCI。六氟异丙醇(HFIP)购自Oakwood。除非另有说明,否则其他试剂均以最高商业品质购买,并且没有进一步纯化而使用。在0.25mm硅胶60-F254上进行分析型薄层色谱法。用短波UV光或KMnO4以及热作为显影剂进行可视化。在Bruker DRX-600仪器上记录1H NMR谱。参考对于TMS的0.0ppm,化学位移以百万分率(parts per million,ppm)为单位引用。以下缩写(或其组合)用于说明多重性:s=单峰、d=双峰、t=三重峰、q=四重峰、m=多重峰、br=宽峰。以赫兹单位(Hz)报告耦合常数J。在Bruker DRX-600上记录13C NMR谱,并通过宽带质子去耦来充分去耦。参考CDCl3在77.16ppm处的三重峰的中心线,以ppm报告化学位移。使用E.Merck二氧化硅(60,颗粒尺寸为0.043mm至0.063mm)来进行柱色谱法,并在Merck二氧化硅板(60F-254)上进行制备型薄层色谱法(preparative thin layer chromatography,pTLC)。使用ESI-TOF(electrospray ionization-time of flight,电喷雾电离-飞行时间)在Agilent质谱仪上记录高分辨率质谱(high-resolution mass spectra,HRMS)。
脂族酸的准备。脂族羧酸1a至1w从商业来源获得或按照文献步骤合成。1-5
单-N-保护的β-氨基酸配体的准备。配体L5至L11可商购或按照文献步骤合成。6-9
用于环化C-H/C-H偶联反应的一般步骤
一般步骤A:在培养管中,在空气中按顺序称重Pd(OAc)2(10mol%,2.2mg)、配体L9(10mol%,1.7mg)、LiOAc(1.0当量,6.6mg)、Na2CO3·1.5H2O2(2.0当量,31.4mg)和1(0.1mmol)并放入磁力搅拌棒。然后添加HFIP(1.0mL)。将反应混合物在室温下搅拌3分钟,然后加热至60℃持续12小时(600rpm)。在使其冷却至室温之后,将混合物用HCO2H(0.1mL)处理并在真空中浓缩。将粗混合物通过pTLC纯化(己烷/EA和1%AcOH)以得到产物2。
一般步骤B:在培养管中,在空气中按顺序称重Pd(CH3CN)4(BF4)2(10mol%,4.4mg)、Ag2CO3(1.0当量,27.4mg)、1-氟-2,4,6-三甲基吡啶四氟硼酸盐(2.0当量,45.4mg)、和1(0-1mmol)并放入磁力搅拌棒。然后添加HFIP(1.0mL)。将反应混合物在室温下搅拌3分钟,然后加热至90℃持续12小时(600rpm)。在使其冷却至室温之后,将混合物用HCO2H(0.1mL)处理,用二氯甲烷(DCM)稀释,通过硅藻土塞过滤,并在真空中浓缩。将粗混合物通过pTLC纯化(己烷/EA和1%AcOH)以得到产物2。
实施例1:2-乙基-1,2,3,4-四氢化萘-2-羧酸(2a)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,16.0mg,78%产率)。
1H NMR(600MHz,CDCl3)δ7.14-7.03(m,4H),3.22(d,J=16.5Hz,1H),2.92-2.83(m,1H),2.83-2.75(m,1H),2.67(d,J=16.5Hz,1H),2.20-2.12(m,1H),1.85-1.77(m,1H),1.79-1.69(m,1H),1.70-1.61(m,1H),0.94(t,J=7.5Hz,3H).
13C NMR(150MHz,CDCl3)δ182.5,135.5,134.9,129.3,128.8,126.0,125.9,46.0,36.6,31.1,30.1,26.3,8.9.
对于C13H15O2 -[M-H]-的HRMS(ESI-TOF)计算值:203.1078;实测值:203.1072。
实施例2:2-乙基-7-甲基-1,2,3,4-四氢化萘-2-羧酸(2b)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,16.5mg,76%产率)。
1H NMR(600MHz,CDCl3)δ7.00-6.93(m,1H),6.93-6.85(m,2H),3.17(d,J=16.4Hz,1H),2.87-2.78(m,1H),2.78-2.70(m,1H),2.63(d,J=16.4Hz,1H),2.28(s,3H),2.18-2.08(m,1H),1.84-1.75(m,1H),1.77-1.68(m,1H),1.69-1.59(m,1H),0.93(t,J=7.4Hz,3H).
13C NMR(150MHz,CDCl3)(主要和次要旋转异构体)δ182.8,135.6,135.6,135.5,134.8,132.6,132.0,130.1,129.6,129.4,128.9,127.1,127.0,46.3,46.2,36.8,36.5,31.3,31.3,30.5,30.3,26.4,26.1,21.3,9.1.
对于C14H17O2 -[M-H]-的HRMS(ESI-TOF)计算值:217.1234;实测值:217.1232。
实施例3:2-乙基-7-氟-1,2,3,4-四氢化萘-2-羧酸(2c)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,13.0mg,59%产率)。
1H NMR(600MHz,CDCl3)δ7.06-6.97(m,1H),6.84-6.73(m,2H),3.24-3.12(m,1H),2.90-2.71(m,2H),2.68-2.58(m,1H),2.20-2.11(m,1H),1.83-1.68(m,2H),1.68-1.60(m,1H),0.98-0.90(m,3H).
13C NMR(150MHz,CDCl3)(主要旋转异构体)δ182.2,161.2(d,J=243.4Hz),136.9(d,J=7.2Hz),130.9(d,J=2.8Hz),130.1(d,J=8.2Hz),115.0(d,J=20.4Hz),113.1(d,J=21.3Hz),45.8,36.6,31.3,30.3,25.7,8.9.
13C NMR(150MHz,CDCl3)(次要旋转异构体)δ182.3,161.2(d,J=243.4Hz),137.4(d,J=7.2Hz),130.5(d,J=7.8Hz),130.4(d,J=2.9Hz),115.4(d,J=20.8Hz),115.2(d,J=21,0Hz),46.1,36.0,31.2,29.8,26.5,8.9.
对于C13H14FO2 -[M-H]-的HRMS(ESI-TOF)计算值:221.0983;实测值:221.0990。
实施例4:7-氯-2-乙基-1,2,3,4-四氢化萘-2-羧酸(2d)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,14.5mg,61%产率)。
1H NMR(600MHz,CDCl3)67.15-7.06(m,2H),7.06-6.98(m,1H),3.25-3.15(m,1H),2.90-2.73(m,2H),2.69-2.59(m,1H),2.22-2.13(m,1H),1.85-1.71(m,2H),1.71-1.61(m,1H),0.93(t,J=7.5Hz,3H).
13C NMR(150MHz,CDCl3)(主要和次要旋转异构体)δ182.0,182.0,137.3,136.8,133.9,133.4,131.4,131.4,130.6,130.1,129.0,128.6,126.1,126.1,46.0,45.8,36.4,36.1,31.3,31.3,30.1,29.9,26.3,25.8,8.9.
对于C13H14ClO2 -[M-H]-的HRMS(ESI-TOF)计算值:237.0688;实测值:237.0684。
实施例5:2-乙基-1,2,3,4-四氢菲-2-羧酸(2e)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,13.3mg,52%产率)。
1H NMR(600MHz,CDCl3)δ7.92(d,J=8.4Hz,1H),7.78(d,J=8.1Hz,1H),7.62(d,J=8.4Hz,1H),7.51-7.45(m,1H),7.45-7.40(m,1H),7.20(d,J=8.4Hz,1H),3.35(d,J=16.7Hz,1H),3.23-3.12(m,2H),2.82(d,J=16.7Hz,1H),2.36-2.29(m,1H),1.99-1.91(m,1H),1.83-1.74(m,1H),1.74-1.66(m,1H),0.97(t,J=7.5Hz,3H).
13C NMR(151MHz,CDCl3)δ182.5,132.3,132.2,132.1,130.1,128.6,128.2,126.3,126.1,125.0,123.0,45.7,37.5,30.9,29.8,23.2,9.0.
对于C17H17O2 -[M-H]-的HRMS(ESI-TOF)计算值:253.1234;实测值:253.1230。
实施例6:2-甲基-1,2,3,4-四氢化萘-2-羧酸(2f)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,12.5mg,66%产率)。
1H NMR(600MHz,CDCl3)δ7.17-7.02(m,4H),3.24(d,J=16.4Hz,1H),2.95-2.86(m,1H),287-2.78(m,1H),2.67(d,J=16.4Hz,1H),2.21-2.13(m,1H),1.85-1.75(m,1H),1.32(s,3H).
13C NMR(150MHz,CDCl3)δ182.7,135.1,134.7,129.4,128.9,126.0,126.0,41.6,38.5,31.8,26.2,24.4.
对于C12H13O2 -[M-H]-的HRMS(ESI-TOF)计算值:189.0921;实测值:189.0919。
实施例7:7-氟-2-甲基-1,2,3,4-四氢化萘-2-羧酸(2g)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,11.0mg,53%产率)。
1H NMR(600MHz,CDCl3)δ7.06-6.99(m,1H),6.84-6.74(m,2H),3.26-3.14(m,1H),2.93-2.74(m,2H),2.67-2.57(m,1H),2.22-2.12(m,1H),1.81-1.72(m,1H),1.31(s,3H).
13C NMR(150MHz,CDCl3)(主要旋转异构体)δ183.1,161.2(d,J=243.6Hz),136.7(d,J=7.3Hz),130.5(d,J=1.8Hz),130.2(d,J=7.8Hz),115.4(d,J=20.8Hz),113.2(d,J=21.1Hz),41.5,38.5,31.9,25.6,24.5.
13C NMR(150MHz,CDCl3)(次要旋转异构体)δ183.2,161.2(d,J=243.6Hz),137.0(d,J=7.2Hz),130.6(d,J=6.2Hz),130.2(d,J=3.1Hz),115.0(d,J=20.5Hz),113.1(d,J=21.3Hz),41.7,37.8,31.5,26.5,24.5.
对于C12H12FO2 -[M-H]-的HRMS(ESI-TOF)计算值:207.0827;实测值:207.0825。
实施例8:2-丁基-1,2,3,4-四氢化萘-2-羧酸(2h)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,16.5mg,71%产率)。
1H NMR(600MHz,CDCl3)δ7.13-7.03(m,4H),3.22(d,J=16.4Hz,1H),2.91-2.82(m,1H),2.82-2.74(m,1H),2.69(d,J=16.4Hz,1H),2.20-2.10(m,1H),1.87-1.77(m,1H),1.73-1.63(m,1H),1.63-1.55(m,1H),1.35-1,23(m,4H),0.89(t,J=6.8Hz,3H).
13C NMR(150MHz,CDCl3)δ181.4,135.3,134.7,129.1,128.6,125.7,125.7,45.3,37.9,37.0,30.2,26.5,26.1,23.0,13.9.
对于C15H19O2 -[M-H]-的HRMS(ESI-TOF)计算值:231.1391;实测值:231.1390。
实施例9:1,2,3,4-四氢化萘-2-羧酸(2i)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,11.5mg,65%产率)。
1H NMR(600MHz,CDCl3)δ7.17-7.03(m,4H),3.11-2.97(m,2H),2.95-2.84(m,2H),2.84-2.75(m,1H),2.29-2.20(m,1H),1.96-1.83(m,1H)
13C NMR(150MHz,CDCl3)δ181.7,135.7,134.7,129.2,129.0,126.2,126.0,39.9,31.5,28.5,25.8.
对于C11H11O2 -[M-H]-的HRMS(ESI-TOF)计算值:175.0765;实测值:175.0757。
NMR数据与报道的数据11相符。
实施例10:6-甲氧基-1,2,3,4-四氢化萘-2-羧酸(2j)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,12.0mg,58%产率)。
1H NMR(600MHz,CDCl3)δ7.02(d,J=8.4Hz,1H),6.71(d,J=8.4Hz,1H),6.63(s,1H),3.77(s,3H),3.05-2.93(m,2H),2.91-2.83(m,2H),2.82-2.73(m,1H),2.29-2.19(m,1H),1.94-1.82(m,1H).
13C NMR(150MHz,CDCl3)δ181.2,157.9,136.8,130.1,126.8,113.6,112.4,554,40.1,30.7,28.8,25.7.
对于C12H13O3 -[M-H]-的HRMS(ESI-TOF)计算值:205.0870;实测值:205.0869。
实施例11:5-甲氧基-1,2,3,4-四氢化萘-2-羧酸(2k)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,7.3mg,35%产率)。
1H NMR(600MHz,CDCl3)δ7.10(t,J=7.9Hz,1H),6.72(d,J=7.7Hz,1H),6.67(d,J=8.1Hz,1H),3.82(s,3H),318-3.08(m,1H),2.93-2.80(m,2H),2.79-2.70(m,2H),2.25-2.18(m,1H),1.92-1.78(m,1H).
13C NMR(150MHz,CDCl3)δ179.1,157.5,137.1,126.4,123.7,121.1,107.2,55.4,39.4,28.7,25.6,25.4.
对于C12H13O3 -[M-H]-的HRMS(ESI-TOF)计算值:205.0870;实测值:205.0869。
实施例12:7-氟-1,2,3,4-四氢化萘-2-羧酸(2l)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,10.9mg,56%产率)。
1H NMR(600MHz,CDCl3)δ7.11-7.03(m,1H),691-6.78(m,2H),3.12-2.96(m,2H),2.95-2.88(m,1H),2.87-2.76(m,2H),2.33-2.21(m,1H),1.97-1.87(m,1H).
13CNMR(150MHz,CDCl3)(主要旋转异构体)δ180.7,161.2(d,J=243.7Hz),139.6(d,J=7.4Hz),131.2(d,J=2.7Hz),130.3(d,J=8.2Hz),115.3(d,J=20.6Hz),113.3(d,J=21.4Hz),39.5,31.4,27.8,25.8.
13C NMR(150MHz,CDCl3)(次要旋转异构体)δ180.8,161.3(d,J=244.2Hz),137.6(d,J=73Hz),1305(d,J=7.8Hz),130.2(d,J=2.8Hz),115.1(d,J=20.7Hz),113.2(d,J=21.1Hz),39.7,30.8,28.6,25.4.
对于C11H10FO2 -[M-H]-的HRMS(ESI-TOF)计算值:193.0670;实测值:193.0666。
实施例13:3-甲基色原烷-3-羧酸(2m)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,13.0mg,68%产率)。
1H NMR(600MHz,CDCl3)δ7.15-7.08(m,1H),7.06(d,J=7.4Hz,1H),6.91-6.85(m,1H),6.83(d,J=8.2Hz,1H),4.31(dd,J=10.8,1.4Hz,1H),3.95(d,J=10.8Hz,1H),3.27(d,J=16.4Hz,1H),2.70(d,J=16.4Hz,1H),1.34(s,3H).
13C NMR(150MHz,CDCl3)δ180.7,153.5,130.0,127.7,121.1,120.1,116.8,71.0,40.8,34.5,21.1.
对于C11H11O3 -[M-H]-的HRMS(ESI-TOF)计算值:191.0714;实测值:191.0713。
NMR数据与报道的数据12相符。
实施例14:7-(叔丁基)-3-甲基色原烷-3-羧酸(2n)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,20.0mg,80%产率,2n/2n’=3/1)。
1H NMR(600MHz,CDCl3)δ6.99(d,J=8.0Hz,1H),6.92(dd,J=8.0,2.0Hz,1H),6.86(d,J=2.0Hz,1H),4.29(dd,J=10.8,1.4Hz,1H),3.93(dd,J=10.8,1.4Hz,1H),3.24(d,J=16.3Hz,1H),2.66(d,J=16.3Hz,1H),1.34(s,3H),1.28(s,9H).
13C NMR(150MHz,CDCl3)δ180.8,153.0,151.2,129.4,118.4,117.0,113.7,71.0,40.9,34.6,34.1,31.4,21.2.
对于C15H19O3 -[M-H]-的HRMS(ESI-TOF)计算值:247.1340;实测值:247.1339。
实施例15:5-(叔丁基)-3-甲基色原烷-3-羧酸(2n’)
1H NMR(600MHz,CDCl3)δ7.05(t,J=7.8Hz,1H),6.99(d,J=7.8Hz,1H),6.73(d,J=7.8Hz,1H),4.37(d,J=10.5Hz,1H),3.91(d,.J=10.5Hz,1H),3.51(d,J=16.0Hz,1H),2.90(d,J=16.0Hz,1H),1.42(s,9H),1.35(s,3H).
13C NMR(150MHz,CDCl3)δ180.9,154.0,149.4,127.1,119.0,118.9,115.6,70.4,40.8,36.2,34.9,31.2,21.5.
对于C15H19O3 -[M-H]-的HRMS(ESI-TOF)计算值:247.1340;实测值:247.1337。
实施例16:3-甲基-3,4,7,8,9,10-六氢-2H-苯并[h]色原烷-3-羧酸(2o)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,21.0mg,85%产率)。
1H NMR(600MHz,CDCl3)δ6.81(d,J=7.8Hz,1H),6.63(d,J=7.8Hz,1H),4.29(d,J=10.8Hz,1H),3.96(d,J=10.8Hz,1H),3.23(d,J=16.3Hz,1H),2.70(t,J=5.8Hz,2H),2.65(d,J=16.3Hz,1H),2.64-2.58(m,2H),1.80-1.69(m,4H),1.33(s,3H).
13C NMR(150MHz,CDCl3)δ181.2,151.1,136.7,126.5,125.4,121.6,116.2,70.9,40.7,34.5,29.6,23.1,23.0,22.9,21.1.
对于C15H17O3 -[M-H]-的HRMS(ESI-TOF)计算值:245.1183;实测值:245.1183。
实施例17:8-苄基-3-甲基色原烷-3-羧酸(2p)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,20.0mg,70%产率)。
1H NMR(600MHz,CDCl3)δ7.27-7.20(m,2H),7.19(d,J=7.5Hz,2H),7.15(t,J=7.3Hz,1H),6.94(d,J=7.5Hz,1H),6.89(d,J=7.4Hz,1H),6.80(t,J=7.5Hz,1H),4.31(d,J=10.7Hz,1H),4.03-3.88(m,3H),3.28(d,J=16.4Hz,1H),2.71(d,J=16.4Hz,1H),1.34(s,3H).
13C NMR(150MHz,CDCl3)δ180.5,151.2,141.1,129.1,129.0,128.5,128.4,128.1,125.9,120.7,119.9,71.0,40.7,35.7,34.7,21.0.
对于C18H17O3 -[M-H]-的HRMS(ESI-TOF)计算值:281.1183;实测值:281.1184。
实施例18:8-溴-3-甲基色原烷-3-羧酸(2q)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,8.5mg,31%产率)。
1H NMR(600MHz,CDCl3)δ7.36(d,J=7.8Hz,1H),7.02(d,J=7.8Hz,1H),6.76(t,J=7.8Hz,1H),4.41(d,J=10.8Hz,1H),4.07(d,J=10.8Hz,1H),3.29(d,J=16.4Hz,1H),2.72(d,J=16.4Hz,1H),1.36(s,3H).
13C NMR(151MHz,CDCl3)δ179.8,150.1,131.5,129.2,121.9,110.9,71.7,40.7,34.6,21.0(1碳信号由于重叠而未被分配).
对于C11H10BrO3 -[M-H]-的HRMS(ESI-TOF)计算值:268.9819;实测值:268.9820。
实施例19:3-甲基-8-(三氟甲基)色原烷-3-羧酸(2r)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,6.0mg,23%产率)。
1H NMR(600MHz,CDCl3)δ7.40(d,J=7.7Hz,1H),7.23(d,J=7.7Hz,1H),6.93(t,J=7.7Hz,1H),4.38(d,J=11.3Hz,1H),4.06(d,J=11.3Hz,1H),3.29(d,J=16.4Hz,1H),273(d,J=16.4Hz,1H),1.35(s,3H).
13C NMR(150MHz,CDCl3)δ179.5,151.6,133.8,125.4(q,J=5.4Hz),123.7(q,J=272.3Hz),121.6,120.2,118.2(q,J=30.9Hz),71.2,40.3,34.3,21.0.
对于C12H10F3O3 -[M-H]-的HRMS(ESI-TOF)计算值:259.0588;实测值:259.0587。
实施例20:(R)-7-甲氧基色原烷-3-羧酸(2s)
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在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,15.0mg,72%产率)。
1H NMR(600MHz,CDCl3)δ6.98(d,J=8.4Hz,1H),6.49(dd,J=8.4,2.6Hz,1H),6.39(d,J=2.6Hz,1H),4.47-4.40(m,1H),4.21-4.14(m,1H),3.75(s,3H),3.10-3.04(m,1H),3.03-2.96(m,2H),
13C NMR(150MHz,CDCl3)δ176.8,159.4,154.8,130.3,112.1,108.1,101.7,66.3,55.5,38.4,26.8.
对于C11H11O4 -[M-H]-的HRMS(ESI-TOF)计算值:207.0663;实测值:207.0660。
实施例21:2-乙基-2,3-二氢-1H-茚-2-羧酸(2u)
在0.1mmol规模上遵循一般步骤A。通过pTLC纯化得到标题化合物(无色油状物,10.0mg,53%产率)。
1H NMR(600MHz,CDCl3)δ7.21-7.16(m,2H),7.16-7.11(m,2H),3.48(d,J=16.2Hz,2H),2.92(d,J=16.2Hz,2H),1.83(q,J=7.2Hz,2H),0.94(t,J=7.2Hz,3H).
13C NMR(150MHz,CDCl3)δ182.3,141.4,126.7,124.6,54.7,41.8,31.5,10.0.
对于C12H13O2 -[M-H]-的HRMS(ESI-TOF)计算值:189.0921;实测值:189.0918。
实施例22:2,4-二甲基-2,3-二氢-1H-茚-2-羧酸(2v)
在0.1mmol规模上遵循一般步骤B。通过pTLC纯化得到标题化合物(无色油状物,11.5mg,61%产率)。
1H NMR(600MHz,CDCl3)δ7.08(t,J=7.4Hz,1H),7.03(d,J=7.4Hz,1H),6.98(d,J=7.4Hz,1H),3.53(d,J=15.9Hz,1H),3.43(d,J=16.0Hz,1H),2.86(d,J=15.9Hz,1H),2.80(d,J=16.0Hz,1H),2.24(s,3H),1.41(s,3H).
13C NMR(150MHz,CDCl3)δ184.2,141.0,140.0,134.2,127.6,127.0,122.1,49.0,44.2,42.8,25.4,19.2.
对于C12H13O2 -[M-H]-的HRMS(ESI-TOF)计算值:189.0921;实测值:189.0915。
实施例23:2-甲基-2,3-二氢-1H-茚-2-羧酸(2w)
在0.1mmol规模上遵循一般步骤B。通过pTLC纯化得到标题化合物(无色油状物,8.0mg,48%产率)。
1H NMR(600MHz,CDCl3)δ7.23-7.18(m,2H),7.18-7.14(m,2H),3.52(d,J=15.8Hz,2H),2.85(d,J=15.8Hz,2H),1.41(s,3H).
13C NMR(150MHz,CDCl3)δ182.5,141.2,126.8,124.8,49.5,44.0,25.0.
对于C11H11O2 -[M-H]-的HRMS(ESI-TOF)计算值:175.0765;实测值:175.0762。
NMR数据与报道的数据13相符。
实施例24:(±)-russujaponol F的全合成
在0℃下向3(1.0mmol,164mg)的EtOH(5.0mL)溶液中添加SOCl2(2.0当量,0.15mL),然后将混合物在回流下搅拌过夜。在使其冷却至室温之后,将混合物在真空下浓缩以得到相应的乙基酯。按照文献步骤10稍作修改,向乙基酯的CH3CN溶液(10.0mL)中添加I2(0.5当量,127mg)和选择性氟试剂(0.5当量,177mg),并将混合物在60℃下搅拌3小时。在使其冷却至室温之后,将混合物用EA稀释,用饱和Na2S2O3洗涤,并在真空中浓缩。将粗混合物通过柱色谱法纯化以得到碘化产物4(250mg,79%产率)。
2-(3-碘-2,6-二甲基苯基)乙酸乙酯(4)
1H NMR(600MHz,CDCl3)δ7.65(d,J=8.1Hz,1H),6.74(d,J=8.1Hz,1H),4.15(q,J=7.1Hz,2H),3.75(s,2H),2.48(s,3H),2.29(s,3H),1.25(t,J=7.1Hz,3H),
13C NMR(150MHz,CDCl3)δ171.0,139.9,138.1,137.8,133.0,1298,99.7,61.1,37.1,26.0,20.5,14.3.
对于C12H16IO2 +[M+H]+的HRMS(ESI-TOF)计算值:319.0189;实测值:319.0196。
在培养管中,在空气中按顺序称重Pd(OAc)2(10mol%,2.2mg)、配体L12(10mol%,2.0mg)、CsOAc(1.0当量,19.2mg)、Ag2CO3(2.0当量,55.1mg)、新戊酸(3.0当量,30.6mg)和4(0.1mmol,31.8mg)并放入磁力搅拌棒。然后添加HFIP(1.0mL)。将反应混合物在室温下搅拌3分钟,然后加热至80℃持续12小时(600rpm)。在使其冷却至室温之后,将混合物用HCO2H(0.1mL)处理,用DCM稀释,通过硅藻土塞过滤,并在真空中浓缩。将粗混合物通过pTLC纯化(己烷/EA)以得到芳基化产物5(18.0mg,62%产率)和产物6(3.5mg,12%产率)。
3-(3-(2-乙氧基-2-氧乙基)-2,4-二甲基苯基)-2,2-二甲基丙酸(5)
1H NMR(600MHz,CDCl3)δ6.99(d,J=7.9Hz,1H)6.96(d,J=7.9Hz,1H),4.14(q,J=7.1Hz,2H),3.70(s,2H),2.99(s,2H),2.30(s,3H),226(s,3H),1.23(t,J=7.1Hz,3H),1.19(s,6H).
13C NMR(150MHz,CDCl3)δ183.1,171.6,136.5,135.7,134.0,132.5,130.1,127.5,60.9,44.1,42.3,36.2,27.3,24.7,20.7,17.0,14.4.
对于C17H23O4 -[M-H]-的HRMS(ESI-TOF)计算值:291.1602;实测值:291.1605。
在培养管中,在空气中按顺序称重Pd(CH3CN)4(BF4)2(10mol%,2.2mg)、Ag2CO3(1.0当量,13.8mg)、1-氟-2,4,6-三甲基吡啶四氟硼酸盐(2.0当量,22.7mg)和5(0.05mmol,14.6mg)并放入磁力搅拌棒。然后添加HFIP(0.5mL)。将反应混合物在室温下搅拌3分钟,然后加热至90℃持续12小时(600rpm)。在使其冷却至室温之后,将混合物用HCO2H(0.05mL)处理,用DCM稀释,通过硅藻土塞过滤,并在真空中浓缩。将粗混合物通过pTLC纯化(己烷/EA)以得到产物6(6.0mg,41%产率)。
5-(2-乙氧基-2-氧乙基)-2,4,6-三甲基-2,3-二氢-1H-茚-2-羧酸(6)
1H NMR(600MHz,CDCl3)δ6.90(s,1H),4.14(q,J=7.0Hz,2H),3.66(s,2H),3.49(d,J=16.0Hz,1H),3.44(d,J=16.0Hz,1H),2.81(d,J=16.0Hz,1H),2.80(d,J=16.0Hz,1H),2.30(s,3H),2.21(s,3H),1.41(s,3H),1.25(t,J=7.1Hz,3H).
13C NMR(150MHz,CDCl3)δ181.9,171.7,139.7,138.3,136.0,133.3,130.0,124.1,60.9,48.8,44.2,43.5,35.4,25.5,20.8,16.5,14.4.
对于C17H21O4 -[M-H]-的HRMS(ESI-TOF)计算值:289.1445;实测值:289.1447。
在培养管中,在0℃下向6(0.02mmol,6.0mg)的THF(1.0mL)溶液中添加LAH(3.0当量,在THF中1.0M,0.06mL)。将反应混合物温热至室温并在室温下搅拌过夜。将混合物用乙醚稀释,用饱和的NH4Cl洗涤,并在真空中浓缩。将粗混合物通过pTLC纯化(己烷/EA)以得到(±)-russujaponol F(4.5mg,96%产率)。NMR数据与报道的数据14,15相符。
1H NMR(600MHz,CDCl3)δ6.87(s,1H),3.74(t,J=7.4Hz,2H),3.52(s,2H),2.95(t,J=7.5Hz,2H),δ2.88(d,J=15.9Hz,1H),2.84(d,J=15.9Hz,1H),2.63(d,J=15.9Hz,1H),2.59(d,J=15.9Hz,1H),2.32(s,3H),2.22(s,3H),1.18(s,3H).
13C NMR(150MHz,CDCl3)δ140.3,139.8,135.4,133.2,132.3,124.4,71.1,62.1,44.3,43.1,42.4,32.9,24.6,20.6,16.3.
对于C15H21O2 -[M-H]-的HRMS(ESI-TOF)计算值:233.1547;实测值:233.1544。
整个以上实施例中编号的参考文献如下:
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2.Shen,P.-x.;Hu,L.;Shao,Q.;Hong,K.;Yu,J.-Q.Pd(II)-catalyzedenantioselective C(sp3)-Harylation of free carboxylicacids.J.Am.Chem.Soc.2018,140,6545-6549.
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Claims (23)
1.一种用于制备式(2)的化合物的方法:
包括在钯(II)源和氧化剂的存在下,使式(1)的化合物:
与式(L)的配体:
接触,由此形成式(2)的化合物,其中:
X为CH2或O;
n为选自0和1的整数;
o和m为独立地选自0、1和2的整数,其中o和m之和不大于4;
x和y为独立地选自0和1的整数;
z为选自0、1和2的整数;
R1选自H和C1-C6-烷基;
各R2和R3独立地选自C1-C6-烷基、C1-C6-烷氧基、卤素、C1-C6-卤代烷基和(C6-C10-芳基)(C1-C6-烷基)-;
或者相邻的R2和R3与它们所结合的碳原子一起形成稠合的C5-C6-环烷基或苯基;以及
各R4和R5独立地选自H、C1-C6-烷基和(C6-C10-芳基)(C1-C6-烷基)-;
或者,当z为1时,则R4和R5与它们所结合的碳原子一起形成5元至6元环烷基,其中所述环烷基除了具有所示的-NHAc和-CO2H取代基之外,还任选地取代有选自卤素、C1-C6-烷基、C1-C6-烷氧基和C6-C10-芳基中的1至2个取代基。
2.根据权利要求1所述的方法,其中X为CH2。
3.根据权利要求1所述的方法,其中X为O。
4.根据权利要求1至3中任一项所述的方法,其中n为0。
5.根据权利要求1至3中任一项所述的方法,其中n为1。
6.根据权利要求1所述的方法,其中所述式(2)的化合物为选自下表中的一者:
7.根据权利要求1至6中任一项所述的方法,其中z为1。
8.根据权利要求1至7中任一项所述的方法,其中x和y中的一者为0,并且另一者为1。
9.根据权利要求1至7中任一项所述的方法,其中R4和R5与它们所结合的碳原子一起形成5元至6元环烷基,其中所述环烷基除了具有所示的-NHAc和-CO2H取代基之外,还任选地取代有选自卤素、C1-C6-烷基、C1-C6-烷氧基和C6-C10-芳基中的1至2个取代基。
10.根据权利要求1至7和9中任一项所述的方法,其中R4和R5与它们所结合的碳原子一起形成5元环烷基,其中所述环烷基除了具有所示的-NHAc和-CO2H取代基之外,还任选地取代有选自卤素、C1-C6-烷基、C1-C6-烷氧基和C6-C10-芳基中的1至2个取代基。
11.根据权利要求1至7中任一项所述的方法,其中所述式(L)的配体为选自下表中的一者:
12.根据权利要求11所述的方法,其中所述式(L)的配体为L9:
13.根据权利要求1至12中任一项所述的方法,其中基于式(2)的化合物的量,所述式(L)的配体以约1mol%至约15mol%的量存在。
14.根据权利要求1至13中任一项所述的方法,其中所述式(L)的配体以约7mol%至约12mol%的量存在。
15.根据权利要求1至14中任一项所述的方法,其中所述式(L)的配体以约10mol%的量存在。
16.根据权利要求1至15中任一项所述的方法,其中所述钯(II)源选自Pd(OAc)2和Pd(CH3CN)4(BF4)2。
17.根据权利要求1至16中任一项所述的方法,其中基于式(2)的化合物的量,所述钯(II)源以约1mol%至约15mol%的量存在。
18.根据权利要求1至17中任一项所述的方法,其中所述钯(II)源以约7mol%至约12mol%的量存在。
19.根据权利要求1至18中任一项所述的方法,其中所述钯(II)源以约10mol%的量存在。
20.根据权利要求1至19中任一项所述的方法,其中所述氧化剂为过碳酸钠。
21.根据权利要求1至20中任一项所述的方法,还包括在LiOAc的存在下进行所述接触。
22.根据权利要求1至21中任一项所述的方法,还包括在六氟异丙醇的存在下进行所述接触。
23.根据权利要求1所述的方法,其中
所述式(L)的配体为以约10mol%的量存在的(L9):
o和m之和为1或2;
所述钯(II)源是量为约10mol%的Pd(OAc)2;以及
所述氧化剂为过碳酸钠。
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