Published online: 2021-02-25 245 Organic Materials S.-C. Yu et al. Short Review Asymmetric Organocatalysis with Chiral Covalent Organic Frameworks Song-Chen Yua,b Liang Cheng*a,b,c Li Liu*a,b a Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China b University of Chinese Academy of Sciences, Beijing 100049, China c Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Hangzhou 310024, China [email protected]; [email protected] Dedicated to Prof. emeritus Dong Wang on the occasion of his 80th birthday. 4–6 Received: 14.12.2020 sis is envisioned as an ideal pathway in which a small Accepted after revision: 24.02.2021 amount of a well-designed chiral catalyst, as low as ppm DOI: 10.1055/a-1400-5581; Art ID: om-20-0043sr quantity, is capable of transforming achiral starting materials License terms: into enantiomeric molecules stereoselectively. The last two © 2021. The Author(s). This is an open access article published by Thieme under the decades has witnessed the blossom of asymmetric catalysis terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, – permitting copying and reproduction so long as the original work is given appropriate prompted by metal chiral ligand complexes and organo- credit. Contents may not be used for commercial purposes, or adapted, remixed, catalysts, which have found wide application from laboratory transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) synthesis of mini-gram scale to industrial manufacture of tonsofchemicals.At thesametime,their immobilizationonto Abstract Inspired by Mother Nature, the use of chiral covalent organic frameworks as heterogeneous asymmetric organocatalysts has arisen inorganic or organic supports has received considerable over the last decade as a new method in enantioselective synthesis. In attention.7 These supported versions of active metal-/ this Short Review, sophisticated design of these polymeric materials and organocatalysts exhibited several distinct advantages in their application in asymmetric organocatalysis will be discussed. terms of their practical use and easy-to-recovery compared Key words chiral covalent organic frameworks, post-modification, with their homogeneous analogues. However, considering asymmetric organocatalysis, enantioselective synthesis the unequal microenvironments of each active site, some- times inferior asymmetric inductions were observed. The chemistry behind covalent organic frameworks (COFs), a unique class of crystalline organic polymers with perpetual porosity and extremely well-organized struc- Introduction tures, has aroused great interest among chemists in the last decade from diverse fields.8–17 With the continuous Chirality is a universal property of asymmetry that is discovery of new COFs, their applications have significantly essential in most branches of science.1,2 Most biological expanded from gas adsorption and separation to macromolecules like nucleic acids, proteins, and saccha- energy-storage devices, optoelectronics, sensing to drug rides are presented in only one chiral form. For example, delivery, and catalysis.18–22 Instead of preparing chiral DNA is composed with four D-deoxyriboses while around 20 polymers containing several repeating catalytic units, the L-amino acids make up thousands of different proteins. use of organized and chiral frameworks in enantioselective Different enantiomers of exogenous small organic mole- catalysis is beginning to be investigated.23–31 These cules may bind inversely (or even absolutely not) to their materials, either with post-modified chiral motifs or target receptors. It is reasonable that one of the enantiomers inherent asymmetric backbones, fulfilled asymmetric exhibits preferred properties while the other(s) may cause organocatalysis in a confined microenvironment that serious and/or undesired side effects, or occasionally mimics polymeric enzymes or ribozymes and thus may another effects.3 Therefore, the design, preparation, and contribute to the efficiency and selectivity improvement separation of designated enantiomer have a special attrac- during the catalytic process. Besides, they also possess the tion to chemists, especially in pharmaceutical industry, advantages of polymeric catalysts in terms of stability in where chiral drugs predominate. aqueous solutions, strong acids, and bases, which make Among the vast majority of methodologies for the them a better catalyst than natural enzymes. In this Short generation of enantiopure compounds, asymmetric cataly- Review, this emerging field will be introduced.32 © 2021. The Author(s). Organic Materials 2021, 3, 245–253 Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany ! ~ 246 Organic Materials S.-C. Yu et al. Short Review Biosketches Song-Chen Yu received his BS degree Sciences. In 2018, he joined Dr. Li focuses his research interest on from Nankai University in 2017. Liu’s research group at Institute of synthesis and catalytic application Currently, he is a graduate student Chemistry, Chinese Academy of Sci- of chiral covalent organic in University of Chinese Academy of ences to pursue a PhD degree. He frameworks. Prof. Cheng received his B.Sc degree scientist at the Department of Chem- molecules. He has been awarded the from Beijing Normal University in istry, Columbia University in 2011. He Young Elite Scientist Sponsorship 2004, and PhD from Institute of returned to Institute of Chemistry, Program by China Association for Chemistry, Chinese Academy of Sci- Chinese Academy of Sciences in 2015 Science and Technology, the Excel- ences in 2009. After 2 years in as an Associate Professor. His re- lent Young Scientists Fund of Natural pharmaceutical industry, he joined search focuses on the development Science Foundation of China, and the the laboratory of Prof. Ronald Bre- of biorthogonal transformations and Thieme Chemistry Journals Award. slow as a postdoctoral research chemical modulation of biomacro- ducted postdoctoral research at the Associate Professor and Professor at Prof. Liu received her PhD from Institute of Chemistry, Chinese Department of Organic Chemistry, Institute of Chemistry, Chinese Acad- Academy of Sciences in 1994. University of Ghent, Belgium (1999–- emy of Sciences. Her research inter- Then she spent 5 years as a lecturer 2001) and University of Washington est focuses on the development of at Graduate School of Chinese at Seattle (2002–2003). From 2003 efficient organic reactions in aqueous Academy of Sciences. She con- up to now, she has served as an media. Most COFs reported in literature were achiral, meaning that they are superimposable with their mirror images. There are three types of synthesis methods for the construction of chiral COFs: the chirality-induced post- modification of achiral COF (Figure 1, path a), construction with chiral monomers (path b),33 and the use of achiral monomers under asymmetric conditions (path c).34 We have chosen not to distinguish between these chirality induction pathways in the preparation of chiral COFs and the influence of post-modification onto the structure of COFs. Instead, a conceptual style will be adopted, focusing on the diverse strategy and modifying approaches that have been proposed and utilized in asymmetric catalysis with chiral COFs. Hopefully this Short Review may inspire more synthetic chemists and materials scientists to devote themselves to this fast-developing field and create more chiral COF materials with interesting properties. Figure 1 Three pathways for the construction of chiral COFs. © 2021. The Author(s). Organic Materials 2021, 3, 245–253 ! ~ 247 Organic Materials S.-C. Yu et al. Short Review Asymmetric Organocatalysis with Chiral COFs Enamine catalysis has been proven as a generic activation mode of carbonyl-containing compounds from its seminal application in the Mannich addition in 2000.35,36 Since then, a tremendous amount of efforts has been devoted towards the identification of new types of chiral enamine catalysts. The general mechanism of the typical secondary amine-containing catalyst was that they rapidly interact with an aldehyde/ketone substrate to form an enamine intermediate, which functions as an active nucleophile to engage with another electrophile to generate the adduct (Figure 2). Chiral pyrrolidine is regarded as one of the best enamine catalysts. The simplest and natural L-proline and its derivatives have shown promising efficiency and enantioselectivity in a variety of transformations like the Aldol addition, Michael addition, Mannich addition, amination, etc.37–40 The 2-substituted group either functions as a steric hindrance substituent that controls the addition direction (as shown in Figure 2), or forms hydrogen bonding with the electrophiles to fulfill the dual-activation. Generally, a larger substituent always gives a better stereoselectivity. However, sometimes simply increasing the steric group would not benefit the efficiency. The Michael addition of aldehydes/ketones to nitro- alkenes is one of the most-studied C–C bond formation reactions, which was regarded as a useful method to obtain γ-nitro carbonyls.41 A diverse range of enantioselective organocatalysts based on pyrrolidines has been developed for this transformation. Luo et al. applied click chemistry into the construction of triazole-based