史壮志 | 教授

南京大学化学系

个人简介

史壮志，理学博士，1983年生于江苏南通，中共党员，现任南京大学化学化工学院配位化学国家重点实验室教授，博士生导师，学科主任。

获奖及荣誉：

2020 国家杰出青年科学基金
2018 中国化学会青年化学奖
2018 江苏省杰出青年
2017 江苏省“双创团队”
2016 江苏省“双创人才”
2014 中组部第五批“青年千人”计划
2014 第五批“江苏省特聘教授”
2011.08-2013.10 德国洪堡奖学金

研究方向
合作产品
工作经历
学术成果

惰性化学键的精准活化、硼化学、自由基化学以及不对称催化等。

专利膦配体甲基氘代化试剂

高效d₃-甲基化试剂——DMTT

研究背景

甲基作为最简单的取代基，不仅在有机合成与药物化学中具有重要作用，还在DNA复制、蛋白修饰、脂质合成等生物代谢过程中扮演核心角色。近年来，人们针对甲基化发展了如MeZnCl、TEMPO-Me等诸多甲基化试剂，然而，氘代甲基化(CD₃)试剂的开发还较少。

氘原子常作为示踪原子来阐释药物化学中的生物代谢路径。除此以外，由于C-D键能高于C-H键能，氘原子的引入常显著地提高药物在组织中的吸收、分布和代谢情况^[1]。主流的氘代策略主要包括氢氘交换和金属、碱或自由基介导的脱卤氘化等。近十年间，大量的氘代候选药物被推向临床，如Austedo、AVP-786、CTP-518等^[2]。从合成的角度来看，氘代甲基化是最理想地向诸多分子的亲核位点处引入氘原子的方法。然而，氘代甲基化的位点选择性是一个重大挑战，传统的氘代甲基化试剂如CD₃I、(CD₃)₂SO₄等化学选择性差，容易上多个甲基，并存在挥发性、腐蚀性、毒性或致癌风险。因此，反应温和、环境友好的选择性氘代甲基化试剂亟待开发。

氘代药物结构图示

DMTT的合成及反应性研究

DMTT的合成

毕得医药与史壮志教授课题组合作的专利产品d₃-甲基化试剂DMTT，室温下即可稳定储存。

d3-甲基化试剂 DMTT (BD01388897)

DMTT反应条件优化及反应性探索

以化合物1a与2a作为研究底物，文献总结出DMTT进行反应需要碱的参与，且K₂CO₃最适宜。在反应性中，芳基羧基的选择性显著优于芳基二甲胺，且在等当量氘代甲基化中表现出优越的羧基反应性偏好；作为对比，其它d₃-甲基供体的反应性和选择性均不理想。

DMTT的适应底物扩展

在常规S_N2条件下，反应底物以羧基为反应官能团，在酰胺、氨基和醇羟基等存在下表现出良好的反应兼容性。当以酚羟基为反应官能团，也可兼容酰胺、醇羟基等基团。芳基或脂肪硫醇、磺酰胺、二酰亚胺也可在该条件下氘代甲基化，并表现出氨基、羟基兼容性。

底物扩展 1

在镍催化条件下，两倍当量的DMTT可对伯胺进行双甲基化，无论芳香胺或脂肪胺，该反应均可控制不生成季铵盐，并表现出羟基、酰胺等活性基团的兼容性。

底物扩展 2

在过渡金属催化下，DMTT可对C-H键活化，得到偶联的C-CD₃产物。活化的C-H键需以邻位的吡啶或乙酰胺作为导向基团。

底物扩展 3

在强碱条件下，DMTT将发生去质子化并进一步生成氘代卡宾中间体，该中间体可被三氟甲基取代的烯烃反应为氘代环丙烷。

底物扩展 4

购买渠道：毕得独家出售

CAS: 2251781-83-4
货号：BD01388897

毕得可提供定制的部分含有CD₃的热门结构

操作步骤可参照原文：Wang et al., Sci Adv. 2020 May 8;6(19):eaba0946.
DOI: 10.1126/sciadv.aba0946

参考文献：
[1] Y. Zhu, J. Zhou, B. Jiao, Deuterated clopidogrel analogues as a new generation of antiplatelet agents. ACS Med. Chem. Lett., 4, 349–352 (2013)
[2] C. Schmidt, First deuterated drug approved. Nat. Biotechnol., 35, 493–494 (2017)

近期代表性成果：

B. Prabagar, Youqing Yang, and Zhangzhi Shi,* Site-Selective C-H Functionalization to Access the Arene Backbone of Indoles and Quinolines. Chem. Soc. Rev., 2021, 50, 11249.
Cheng Chen, Minyan Wang, Hongjian Lu,* Binlin Zhao, and Zhuangzhi Shi,* Enabling Alkyl Thianthrenium Salts in Cross-Couplings by Copper Catalysis. Angew. Chem. Int. Ed., 2021, 60, 21756.
Binlin Zhao, B. Prabagar, and Zhuangzhi Shi,* Modern Strategies for C‒H Functionalization of Heteroarenes with Alternative Coupling Partners. Chem, 2021, 7, 2585.
Cheng Chen, Zheng-Jun Wang, Hongjian Lu,* Yue Zhao, and Zhuangzhi Shi,* Generation of Non-Stabilized Alkyl Radicals from Thianthrenium Salts for C–B and C–C Bond Formation. Nat. Commun., 2021, 12, 4526.
Binlin Zhao, Torben Rogge, Lutz Ackermann,* and Zhangzhi Shi,* Metal-Catalysed C−Het (F, O, S, N) and C−C Bond Arylation. Chem. Soc. Rev., 2021, 50, 8903.
Jian Wen, and Zhuangzhi Shi,* From C4 to C7: Innovative Strategies for Site-Selective Functionalization of Indole C–H Bonds. Acc. Chem. Res., 2021, 54, 1723.
Zheng-Jun Wang, Xiangyang Chen, Lei Wu, Jonathan J. Wong, Yong Liang, Yue Zhao, Kendall. N. Houk,* and Zhuangzhi Shi,* Metal-Free Directed C–H Borylation of Pyrroles. Angew. Chem. Int. Ed., 2021, 60, 8500.
Yandong Wang, Jingyi Bai, Youqing Yang, Wenxuan Zhao, Yong Liang*, Di Wang, Yue Zhao, and Zhuangzhi Shi,* Rhodium-Catalysed Selective C−C Bond Activation and Borylation of Cyclopropanes. Chem. Sci., 2021, 12, 3599.
Dingyi Wang, Mingjie Li, Xiangyang Chen, Minyan Wang,* Yong Liang, Yue Zhao, Kendall. N. Houk, and Zhuangzhi Shi,* Palladium-Catalyzed Silacyclization of (Hetero)Arenes with ODCS Reagent through Twofold C–H Activation. Angew. Chem. Int. Ed., 2021, 60, 7066.
Dingyi Wang, Xiangyang Chen, Jonathan J. Wong, Liqun Jin, Mingjie Li, Yue Zhao, K. N. Houk,* and Zhuangzhi Shi,* Phosphorus(III)-Assisted Regioselective C–H Silylation of Heteroarenes. Nat. Commun., 2021, 12, 524.
Zexian Li, Minyan Wang and Zhuangzhi Shi,* Radical Addition Enables 1,2-Aryl Migration from Vinyl-Substituted All-Carbon Quaternary Center, Angew. Chem. Int. Ed., 2021, 60, 186.
Ben Dong, Jiasheng Qian, Mingjie Li, Zheng-Jun Wang, Minyan Wang, Dingyi Wang, Chengkai Yuan, Ying Han, Yue Zhao, and Zhuangzhi Shi,* External Oxidant-Compatible Phosphorus(III)-Directed Site-Selective C–H Carbonylation. Sci. Adv., 2020, 6, eabd1378.
Minyan Wang, and Zhuangzhi Shi,* Methodologies and Strategies for Selective Borylation of C-Het and C-C Bonds, Chem. Rev., 2020, 120, 7348.
Jian Wen, Ben Dong, Jinjun Zhu, Yue Zhao, and Zhuangzhi Shi,* Revealing Silylation of Csp2 /sp3 -H Bonds in Arylphosphines by Ruthenium Catalysis, Angew. Chem. Int. Ed., 2020, 59, 10909.
Minyan Wang, Yunfei Zhao, Yue Zhao, and Zhuangzhi Shi,* Bioinspired Design of a Robust d3-Methylating Agent (DMTT), Sci. Adv., 2020, 6, aba0946.
Jiahang Lv, Binlin Zhao, Yu Yuan, Ying Han, and Zhuangzhi Shi,* Boron-Media ted Directed Aromatic C–H Hydroxylation, Nat. Commun., 2020, 11, 1316.
Jiahang Lv, Xiangyang Chen, Xiao-Song Xue, Binlin Zhao, Yong Liang, Minyan Wang, Liqun Jin, Yu Yuan, Ying Han, Yue Zhao, Yi Lu, Jing Zhao, Wei-Yin Sun, Kendall. N. Houk* and Zhuangzhi Shi,* Metal-Free Directed sp²-C–H Borylation, Nature, 2019, 575, 336.
Jian Wen, Dingyi Wang, Jiasheng Qian, Di Wang, Chendan Zhu, Yue Zhao and Zhuangzhi Shi,* Rhodium-Catalyzed P^III-Directed ortho-C-H Borylation of Arylphosphines, Angew. Chem. Int. Ed., 2019, 58, 2078.
Dingyi Wang, Ben Dong, Yandong Wang, Jiasheng Qian, Jinjun Zhu, Yue Zhao and Zhuangzhi Shi,* Rhodium-Catalysed Direct Hydroarylation of Alkenes and Alkynes with Phosphines through Phosphorous-Assisted C-H Activation, Nat. Commun., 2019, 10, 3539.
Dingyi Wang, Yunfei Zhao, Chengkai Yuan, Jian Wen, Yue Zhao and Zhuangzhi Shi,* Rhodium(II)-Catalyzed Dehydrogenative Silylation of Biaryl-Type Monophosphines with Hydrosilanes, Angew. Chem. Int. Ed., 2019, 58, 12529.
Binlin Zhao, Zexian Li, Yixiao Wu, Yandong Wang, Jiasheng Qian, Yu Yuan and Zhuangzhi Shi,* An Olefinic 1,2-Boryl-Migration Enabled by Radical Addition: Construction of gem-Bis(boryl)alkanes, Angew. Chem. Int. Ed., 2019, 58, 9448.
Xiaodong Qiu, Panpan Wang, Dingyi Wang, Minyan Wang, Yu Yuan and Zhuangzhi Shi,* P^III-Chelation-Assisted Indole C7-Arylation, Olefination, Methylation, and Acylation with Carboxylic Acids/Anhydrides by Rhodium Catalysis, Angew. Chem. Int. Ed., 2019, 58, 1504.
Xiaodong Qiu, Hong Deng, Yue Zhao and Zhuangzhi Shi,* Rhodium-catalyzed, P-directed selective C7 arylation of indoles, Sci. Adv., 2018, 4, aau6468.
Jiefeng Hu, Guoqiang Wang, Shuhua Li* and Zhuangzhi Shi,* Lewis Base Promoted Selective C-N Borylation of Alkyl Amines, Angew. Chem. Int. Ed., 2018, 57, 15227.
Di Wang, Xiao-Song Xue, Kendall N. Houk* and Zhuangzhi Shi,* Mild Ring-Opening 1,3-Hydroborations of Non-Activated Cyclopropanes, Angew. Chem. Int. Ed., 2018, 57, 16861.
Jiefeng Hu, Yue Zhao and Zhuangzhi Shi,* Highly Tuneable Multi-Borylation of gem-Difluoroalkenes via Copper Catalysis, Nat. Catal., 2018, 1, 860.
Pan Gao, Chengkai Yuan, Yue Zhao and Zhuangzhi Shi,* Copper-Catalyzed Asymmetric Defluoroborylation of 1-(Trifluoromethyl)Alkenes, Chem, 2018, 4, 2201.
Minyan Wang, Xinghui Pu, Yunfei Zhao, Panpan Wang, Zexian Li, Chendan Zhu and Zhuangzhi Shi,* Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylboronate-Activated Alkyl Grignard Reagents, J. Am. Chem. Soc., 2018, 140, 9061.
Arun Jyoti Borah and Zhuangzhi Shi,* Rhodium-Catalyzed, Remote Terminal Hydroarylation of Activated Olefins through a Long-Range Deconjugative Isomerization, J. Am. Chem. Soc., 2018, 140, 6062.
Chendan Zhu, Di Wang, Dingyi Wang, Yue Zhao, Wei-Yin Sun and Zhuangzhi Shi,* Bottom-up Construction of π-Extended Arenes by a Palladium-Catalyzed Annulative Dimerization of o-Iodobiaryl Compounds, Angew. Chem. Int. Ed., 2018, 53, 8848.
Chendan Zhu, Dingyi Wang, Yue Zhao, Wei-Yin Sun, and Zhuangzhi Shi,* Enantioselective Palladium-Catalyzed Intramolecular α-Arylative Desymmetrization of 1,3-Diketones, J. Am. Chem. Soc., 2017, 139, 16486.
Jiefeng Hu, Xiaowei Han, Yu Yuan, and Zhuangzhi Shi,* Stereoselective Synthesis of Z-Fluoroalkenes by Copper-Catalyzed Hydrodefluorination of gem-Difluoroalkenes with Water, Angew. Chem. Int. Ed., 2017, 56, 13342.
Binlin Zhao, Zhuangzhi Shi,* Copper-Catalyzed Intermolecular Heck-Like Coupling of Cyclobutanone Oximes Initiated by Selective C-C Bond Cleavage, Angew. Chem. Int. Ed., 2017, 56, 12727.
Xiaodong Qiu, Minyan Wang, Yue Zhao, Zhuangzhi Shi,* Rhodium(I)-Catalyzed Tertiary Phosphine Directed C-H Arylation: Rapid Construction of Ligand Libraries, Angew. Chem. Int. Ed., 2017, 56, 7233.
Youqing Yang, Pan Gao, Yue Zhao, and Zhuangzhi Shi,* Regiocontrolled Direct C-H Arylation of Indoles at the C4 and C5 Positions, Angew. Chem. Int. Ed., 2017, 56, 3966. ( Both authors contributed equally)
Jiefeng Hu, Minyan Wang, Xinghui Pu, and Zhuangzhi Shi,* Nickel-Catalyzed Retro-Hydroamidocarbonylation of Aliphatic Amides to Olefins, Nat. Commun., 2017, 8, 14993.
Xinghui Pu, Jiefeng Hu, Yue Zhao, and Zhuangzhi Shi,* Nickel-Catalyzed Decarbonylative Borylation and Silylation of Esters, ACS Catal., 2016, 6, 6692.
Youqing Yang, Ruirui Li, Yue Zhao, Dongbing Zhao, and Zhuangzhi Shi,* Cu-Catalyzed Direct C6-Arylation of Indoles, J. Am. Chem. Soc., 2016, 138, 8734.
Jiefeng Hu, Yue Zhao, Jingjing Liu, Yemin Zhang, and Zhuangzhi Shi,* Nickel-Catalyzed Decarbonylative Borylation of Amides: Evidence for Acyl C-N Bond Activation, Angew. Chem. Int. Ed., 2016, 55, 8718.
Youqing Yang, Xiaodong Qiu, Yue Zhao, Yucheng Mu, and Zhuangzhi Shi,* Palladium-Catalyzed C–H Arylation of Indoles at the C7-Position, J. Am. Chem. Soc., 2016, 138, 495.
Pan Gao, Wei Guo, Jingjing Xue, Yue Zhao, Yu Yuan, Yuanzhi Xia,* and Zhuangzhi Shi,* Iridium(III)-Catalyzed Direct Arylation of C-H Bonds with Diaryliodonium Salts, J. Am. Chem. Soc., 2015, 137, 12231.
Chendan Zhu, Yong Liang, Xin Hong, Heqing Sun, Wei-Yin Sun, K. N. Houk,* and Zhuangzhi Shi,* Iodoarene-Catalyzed Stereospecific Intramolecular sp³ C-H Amination: Reaction Development and Mechanistic Insights, J. Am. Chem. Soc., 2015, 137, 7564.