© Georg Thieme Verlag Stuttgart • New York – Synform 2019/09, A141–A143 • Published online: August 20, 2019 • DOI: 10.1055/s-0037-1612190

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Isocyanide-based multicomponent reactions (IMCRs), which enable the diversity- and complexity-oriented synthesis of collections of compounds taking advantage of the unique reactivity of the isocyanide functionality, have attracted great interest in the past several decades. In particular, the Passerini and Ugi reactions, and their variants, provide facile and power ful methods for the rapid construction of α-acyloxy carboxamides and α-acetamido carboxamides, as well as many heterocycles. Professor Xiaoming Feng at Sichuan Uni-versity (P. R. of China) pointed out that enantioselective ver-sions of these types of reactions, which are seemingly simple and yet challenging, have been recently achieved by several research groups after extensive studies.1 “Mechanistically, the stereochemistry-determining step involved in Passerini and Ugi reactions is a nucleophilic addition of isocyanides to C=X bonds (X = O, or NR′). Based on this working hypothesis, it is reason able to postulate that a similar zwitterionic intermedi-ate could be readily generated through the enantioselective

addition of simple isocyanides to a C=C bond and subsequent-ly could be trapped by an intra- or intermolecular nucleophile to afford cyclic or acyclic chiral compounds (Scheme 1),” ex-plained Professor Feng, who added: “Moreover, the nucleo-philic addition of isocyanides to C=X or C=C bonds results in the generation of zwitterionic intermediates I, which are po-tentially used as 1,3-dipoles in cycloaddition reactions. To the best of our knowledge, only sporadic racemic syntheses were reported, and asymmetric IMCRs triggered by the addition of simple isocyanides to a C=C bond remain elusive.”

A chiral C2-symmetric N,N′-dioxide-based Lewis acid catal-yst, designed and developed by the group of Professor Feng, exhibited excellent efficiency and selectivity in a number of organic transformations.2 Professor Feng remarked: “Based on our previous work regarding functionalized isocyanides, Qian Xiong, a first-year graduate student in my group, approached this challenge. Initially, the reaction of dimethyl 2-(cyclo-hexylmethylene) malonate, 2-naphthyl isocyanide and TMSN3

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Asymmetric Synthesis of Tetrazole and Dihydroisoquinoline Derivatives by Isocyanide-Based Multicomponent Reactions

Nat. Commun. 2019, 10, 2116

Scheme 1 Strategies to achieve the asymmetric synthesis of tetrazole and dihydroisoquinoline derivatives by IMCRs

© Georg Thieme Verlag Stuttgart • New York – Synform 2019/09, A141–A143 • Published online: August 20, 2019 • DOI: 10.1055/s-0037-1612190

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was conducted in the presence of chiral N,N′-dioxide–metal complex. Surprisingly, the central metal played a vital role and only Mg(OTf)2 afforded the desired product. At the same time, tetrazoles arising from a four-component reaction were isolated as the major products. How to control the chemo-selectivity of this reaction was the next objective. As I often say, organic transformations are easy and the key to them is whether you can find a proper point (conditions) to work!” Professor Feng revealed that it took Qian Xiong several months to find this point. Eventually, with an excess amount of metal salt (MgII/L-RaPr2 = 1.4:1.0) and at 30 °C, the process afforded the four-component tetrazole as the only product. “Compa-ratively lower temperature and an excessive amount of ligand (MgII/L-RaPr2 = 1.0:1.5) is of benefit to the three-component pathway,” said Professor Feng.

Another important issue to be elucidated concerned the exact structure of the four-component product. Initially, the authors thought a mixture of diastereomers of four-compon-ent products was formed in the process, based on primary analysis of 1H NMR spectra. “However, several phenomena suggested that this hypothesis may have not been correct, for example the fact that only two peaks were clearly identifiable by CSP-HPLC analysis of this hypothetic diastereomeric mix-ture,” explained Professor Feng. He continued: “Further more, the diastereomeric ratio of the four-component reaction products did not change after recrystallization. These were among the observations that suggested to us that there might instead be an equilibrium between these two compounds. Therefore, variable-temperature and solvent NMR studies, as well as careful analysis of 2D NMR, were carried out and the outcomes obtained collectively supported the conclusion that rotamers existed in our system.” The utility of the current synthetic strategy was further highlighted by using the key zwitterionic intermediate I as a 1,3-dipole in the first example of enantioselective dearomative [3+2] annulation reaction of isoquinolines. Chiral fused polycyclic 1,2-dihydroisoquino-line-based amidine derivatives were obtained with good to excellent results. “Although isoquinoline is the only substrate to participate in the reaction so far, we believe that other sub-strates may also be capable of capturing such active interme-diates to construct important chiral molecules,” said Professor Feng confidently. As Prof. Michael P. Doyle (University of Texas at San Antonio, USA) commented: “This manuscript has used the authors’ well-known catalysts, the increasingly common concept of multicomponent reactions, and mildly reactive and easily handled materials to formulate complex chemical pro-cesses that are intrinsically dependent on the alkylidene ma-lonate, the isocyanide, and the catalyst as the foundation for new chemical syntheses. The feature of this manuscript that is

most significant is the potential of the isocyanide–alkyl idine adduct for transformations beyond those reported in this ma-nuscript, and with the discovery that the magnesium(II)–N,N′-dioxide ligand is appropriate for high enantiocontrol, this ma-nuscript can be expected to stimulate further research in the area. I can envision successful outcomes from reactions with indole, with diazo compounds, including cycloaddition reac-tions, and, perhaps, even with vinyl ether.”

Professor Feng concluded: “All in all, the attractive features of IMCRs along with the unique reactivity of the isocyanide functionality will offer huge potential in discovering new, concise and efficient methods for the synthesis of highly valu-able chiral compounds. We hope that the current research can stimulate other researchers to join us in exploring the under-developed area together.”

RefeRenCeS

(1) (a) Q. Wang, D.-X. Wang, M.-X. Wang, J. Zhu Acc. Chem. Res. 2018, 51, 1290–1300. (b) J. Zhang, P. Yu, S.-Y. Li, H. Sun, S.-H. Xiang, J. Wang, K. N. Houk, B. Tan Science 2018, 361, eaas8707.(2) (a) X. H. Liu, L. L. Lin, X. M. Feng Acc. Chem. Res. 2011, 44, 574–587. (b) X. H. Liu, L. L. Lin, X. M. Feng Org. Chem. Front. 2014, 1, 298–302. (c) X. H. Liu, H. F. Zheng, Y. Xia, L. L. Lin, X. M. Feng Acc. Chem. Res. 2017, 50, 2621–2631.

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© Georg Thieme Verlag Stuttgart • New York – Synform 2019/09, A141–A143 • Published online: August 20, 2019 • DOI: 10.1055/s-0037-1612190

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Qian Xiong received his BS from Sichuan University (P. R. of China) in 2016. He is currently a PhD student in the College of Chemistry, Sichuan University, under the supervision of Prof. Xiaoming Feng. His focus is on asymmetric isocyanide-based multi-component reactions.

Shunxi Dong received his BS (2008) and PhD (2013) from Sichuan Univer-sity (P. R. of China). He joined RWTH Aachen University (Germany) as a Humboldt postdoctoral fellow with Prof. Carsten Bolm in 2013. After postdoctoral studies (2016–2017) at the University of Münster (Germany) with Prof. Gerhard Erker, he joined the faculty of Prof. Feng’s group at Sichuan University. His interests in-clude the design of chiral catalysts and their utility in new asymmetric transformations.

Yushuang Chen received her BS from Sichuan University (P. R. of China) in 2015. Now, she is a PhD student in the College of Chemistry, Sichuan University, under the supervision of Prof. Xiaoming Feng. Her research in-terests focus on asymmetric reactions involving bimetallic relay catalysis.

Xiaohua Liu received her BS (2000) from Hubei Normal University (P. R. of China) and her MS (2003) and PhD (2006) from Sichuan University (P. R. of China). She joined the faculty of Prof. Feng’s group at Sichuan Univer-sity where she was appointed a Pro-fessor in 2010. Her current research interests include the asymmetric catalysis of chiral guanidines and or-ganic synthesis.

Xiaoming feng received his BS (1985) and MS (1988) from Lanzhou University (P. R. of China). Then he worked at Southwest Normal Uni-versity (P. R. of China, 1988–1993) and became an Associate Professor in 1991. In 1996, he received his PhD from the Institute of Chemistry, Chi-nese Academy of Sciences (CAS) un-der the supervision of Prof. Zhitang Huang and Prof. Yaozhong Jiang. He went to the Chengdu Institute of

Organic Chemistry, CAS (P. R. of China, 1996–2000) and was appointed a Professor in 1997. He did postdoctoral research at Colorado State University (USA, 1998–1999) with Prof. Yian Shi. In 2000, he moved to Sichuan University (P. R. of China). He was selected as an Academician of the Chinese Academy of Sciences in 2013. He focuses on the design of chiral catalysts, the development of new synthetic methods and the synthesis of bioactive compounds.

About the authors

Q. Xiong Prof. X. Liu

Prof. X. FengDr. S. Dong

Y. Chen