NHC-catalyzed covalent activation of heteroatoms for enantioselective reactions

Covalent activation of heteroatoms enabled by N-heterocyclic carbene (NHC) organic catalysts for enantioselective reactions is evaluated and summarized in this review. To date, sulfur, oxygen, and nitrogen atoms can be activated in this manner to react with another substrate to construct chiral carbon–heteroatom bonds with high optical enantioselectivities. The activation starts with addition of an NHC catalyst to the carbonyl moiety (aldehyde or imine) of substrates that contain heteroatoms. The key in this approach is the formation of intermediates covalently bound to the NHC catalyst, in which the heteroatom of the substrate is activated as a nucleophilic reactive site.


Introduction
Heteroatoms are essential to life of all kinds and ubiquitous in nearly all functional molecules with medicinal uses. Asymmetric construction of carbon-heteroatom (C-X) bonds has therefore been an active research topic in chemical synthesis. In the last two decades, catalysis enabled by N-heterocyclic carbenes (NHCs) has been developed as a versatile approach to prepare both carbon-carbon and carbon-heteroatom bonds in highly enantioselective manners. 1 In the subdomain of NHC-catalyzed asymmetric C-X bond formation, the dominant approach is to activate carbon atoms to react with heteroatoms or substrates containing heteroatoms such as amines, ureas and thioureas (Fig. 1a). The carbon atoms can be activated as electrophilic reaction centres via NHC-derived (unsaturated) acyl azolium intermediates or their analogues to react with nucleophilic heteroatoms. 2 Alternatively, the carbon atoms are activated as nucleophilic reaction centers (via acyl anion and enolate intermediate or their analogues). The NHC-derived nucleophilic intermediates then react with heteroatoms (in their oxidized states) or heteroatom-containing substrates (such as imines) as the electrophiles. 3 Fig. 1b shows representative substrates with carbon atoms activated by NHC catalysts as the reactive centres. The heteroatoms involved in these reactions, at least by designing, are not activated by NHC catalysts. These types of reactions have now been covered in many review articles concerning NHC catalysis from different perspectives. A much less-developed approach is to activate heteroatoms through addition of NHC catalysts to the respective substrates for enantioselective reactions. The basic design, as illustrated in Fig. 1c, is to increase the reactivity of heteroatoms by forming covalent bonds between NHC catalysts and substrates. This review is to summarize the development of this direction that is still at its infant stage.

Runjiang
It is worth noting that activation of heteroatoms for asymmetric reactions via non-covalent interactions using azolium salts (precursor of N-heterocyclic carbene), pioneered by Huang and co-workers, is not covered in this article. 4 It is also important to note that in those reactions designed via NHC-catalyzed activation of carbon atoms as the key step, heteroatoms in the substrates or intermediates may also be activated as a result of catalyst-substrate bonding. These studies are also not discussed in this article.
With the scope dened, this review article will discuss NHCcatalyzed activation of oxygen and nitrogen atoms for enantioselective reactions. The use of NHC catalysts to cleave the N-S or C-S bond to release nucleophilic sulfur atoms for asymmetric reactions will also be described.

Covalent activation of oxygen atoms of phenols
Aromatic aldehydes are routinely activated by NHC catalysts and participate in Benzoin condensations, Stetter reactions and acylation reactions. In 2013, the Chi lab found that the benzylic C(sp 3 )-H bond of an indole aldehyde can be activated by NHC catalysts under oxidative conditions through the formation of an o-QDM intermediate. 5 This study suggests that the activating power of NHC catalysts can go across the conjugated aromatic ring system.
Encouraged by this discovery, the Chi group moved to explore the activation of heteroatoms attached to aromatic scaffolds. In 2017, they disclosed that phenol OH can be enantioselectively functionalized through activation of salicylaldehyde by NHC organic catalysts (Fig. 2). 6 In a model reaction using salicylaldehyde (1) and triuoroacetophenone (2) as substrates, the use of A as the NHC pre-catalyst (5 mol%) in the presence of I as an additive (20 mol%) and an oxidant gave the chiral acetal product (3) in 99% yield, 94 : 6 er. The urea additive was critical and behaved as a co-catalyst. The product er dropped to 73 : 27 in the absence of the urea additive. The reaction appears to be general with good functional group tolerance, as shown in 28 examples. The NHC catalyst loading can be decreased in 1 mol% for gram scale synthesis. The authors also  Jean Frechet, he started his independent career at Nanyang Technological University and was quickly promoted to full professor. His current research, supported by students and researchers from Nanyang Technological University and Guizhou University, focuses on the development of new basic activation modes and reactions mediated by organic catalysts, efficient transformations for rapid construction of sophisticated molecules, selective modication of Chinese medicines and biomacromolecules, green reactions and processes for industrial applications, and functional molecules for applications in medicines, agricultural chemicals, and materials.
found that several of their enantiomerically enriched products showed encouraging antifungal activities against Eggplant Verticillium, Phytophthora infestans and Fusarium oxysporum.
Based on experimental observations and DFT calculations, the reaction was believed to proceed through a pathway as illustrated in Fig. 3. Addition of the NHC catalyst to salicylaldehyde 1 gives the Breslow intermediate 4, which can be oxidized to produce the acylazolium intermediate 5. Deprotonation of 5 under basic conditions leads to the formation of the zwitter ionic phenoxide 6, which is stabilized through resonance structures including the o-QMs 6 0 . The asymmetric oxa-[4 + 2] reaction between 6 (6 0 ) and 2 gives the chiral acetal product 3 and releases the free NHC catalyst for additional catalytic cycles.

Covalent activation of nitrogen atoms
The oxygen atom in phenols above can in principle be replaced by other heteroatoms such as nitrogen and sulphur atoms for NHC-catalyzed enantioselective reactions. An elegant design in this direction was disclosed by Scheidt and co-workers in 2019 (Fig. 4). 7 Addition of a carbene catalyst (B) to an N-methylisatoic anhydride (7)  Nitrogen atoms that are part of the aromatic scaffold can also be activated by NHC catalysts for enantioselective reactions. In 2020, Chi and Jin disclosed that the aromatic N atoms of the 2-carbaldehyde derivatives of indole or pyrrole structures can be effectively activated via the formation of an unprecedented NHC-bounded aza-fulvene intermediate 10 (Fig. 5). 8 The N atoms of the indole or pyrrole molecules are selectively activated to react with various ketone substrates through nucleophilic addition reactions.
Up to 75 enantiomerically enriched N,O-acetal compounds have been efficiently prepared through this protocol under the catalysis of several chiral NHC organic catalysts (Fig. 6a). For example, with chiral NHC C used as the reaction catalyst, spiro-   cyclic compounds 11 can be obtained in moderate to excellent yields with excellent optical purities. Switching the NHC catalyst to D, a-ketoesters can be applied as suitable electrophiles to react with substituted indole-2-carbaldehydes (12). Pyrrole-2carbaldehydes bearing different substituents can also work well in this process, although a urea co-catalyst II is needed for better enantioselectivity control over the NHC-catalyzed [3 + 2] cycloaddition reaction (13).
It is worth noting that several of these spiro-cyclic compounds have shown promising anti-microbial activities (Fig. 6b). For instance, compounds 11a-1 and 11a-2 exhibit much better anti-bacterial activities against Ralstonia solanacearum (abbreviated as Rs) than the commercial agrichemicals thiodiazole-copper and bismerthiazol.
A short time later, Biju, 9 Hui 10 and co-workers independently reported similar transformations to this protocol. DFT studies towards the NHC-catalyzed aromatic N activation mechanism and additional electrophile investigations are provided in their studies.
When the aldehyde group was installed on the 7-position of the indole structure, the aromatic N atom can also be functionalized through covalent activations with NHC organic catalysts (Fig. 7). 11 In this case, various electron-decient ketone substrates can be used as electrophiles. With the catalysis of NHC E or F, a variety of chiral [1,3]oxazino [5,4,3-hi]indole derivatives 14 can be afforded in good to excellent yields and enantioselectivities.
Very recently, the groups of Chi 12 and Fu 13 independently found that the remote N atom of the guanidine-derived aldimine 15 can be activated by NHC catalyst G under oxidative conditions to react with isatin 16 and gave spiocyclic product 17 in an excellent yield and enantioselectivity (Fig. 8). Addition of   Another interesting study in this direction is activation of the nitrogen atoms of azirines (Fig. 9). 14 In this study, formyl azirine 22 was successfully activated by the NHC catalyst and a novel azolium aza-dienolate intermediate 23 was generated. Aza-[4 + 2] cycloaddition between 23 and the electron-decient ketone 24 gave the oxazinone product 25 in moderate to excellent yields. Although a wide range of substrates with various substitution patterns worked well in this process, the asymmetric version of this transformation remains undisclosed.

NHC-catalyzed C-S and N-S bond cleavage to release sulphur atoms for enantioselective reactions
The N-S bond in aldehyde-derived sulfonimide (26) was cleavable as a result of NHC-catalyzed activation, as disclosed by Hou and co-workers in 2008. 15 This N-S bond cleavage releases nucleophilic sulnic anions that can react with other electrophiles. In these reactions, since the NHC catalyst is not bound to the sulnic anions, enantioselectivity control cannot be induced by chiral NHC catalysts. In 2013, Chi and co-workers introduced a multi-catalytic approach combining NHC and a thiourea/tertiary amine multifunctional catalyst to achieve enantioselective transformations (Fig. 10a). 16 Aromatic enone substrates 27 worked well in this cooperative catalytic process, with the b-sulnic ketone 28 afforded in moderate to good yields and good to excellent enantioselectivities (Fig. 10b, right part). NHC pre-catalyst H and the chiral amino-thiourea II were used as the co-operative catalysts for this asymmetric transformation. b-Alkyl substituted enones 29 were also promising substrates for this reaction, although the yields and er values of the nal products 30 were only moderate even aer additional condition optimization investigations (Fig. 10b, le part).
The NHC catalyst is believed to rst attack the sulfonimide 26 through nucleophilic addition and give the aza-Breslow intermediate 31. The aza-Breslow intermediate 31 readily cracks into the sulnic anion 32 and the azolium cation 33. Thio-Michael addition reactions of 32 and enones (27 or 29) and intermolecular proton transfer lead to the formation of the b-sulnic ketone products (28 or 30) together with the sideproduct benzonitrile 34. The free NHC catalyst is regenerated during this process and can participate in further catalytic cycles (Fig. 10c).
The NHC-catalyzed N-S bond cleavage strategy has recently been used in the late-stage functionalization of bio-active complex sulfonamides. 17 The key intermediate of the sulfonimide can be formed in situ from benzaldehyde and the corresponding sulfonamide. Therefore, various sulfonamide substrates can be de-aminated and transformed to other sulfone-containing functional molecules through a one-pot  The C-S bond of thioesters derived from thiophenols can be broken to release thiophenol with the sulphur atom reacting as a nucleophile, as reported by Xu and co-workers (Fig. 11). 18 In this reaction, the enantioselectivity is controlled by the other reacting partner (a,b-unsaturated acyl azolium ester intermediate) connected with the NHC catalyst.
Nucleophilic attack of the thioester 35 by the NHC catalyst generates the zwitter ion 37, which can be broken up to give the a,b-unsaturated acylazolium intermediate 38 and the thio anion 39. A stereoselective cascade thio-Michael addition/Michael addition/lacton formation process between the ionic intermediates 38 and 39 nally affords the chiral product 36 and liberates the free NHC catalyst for additional catalytic cycles (Fig. 11b).

Summary and outlook
NHC organic catalysis has been proven to be a versatile strategy in asymmetric synthesis. The extraordinary development in the past two decades, on the other hand, has mainly focused on activation of carbon atoms for enantioselective reactions. Activation of heteroatoms by NHCs for asymmetric reactions is less explored. This review highlights the impressive yet still very limited studies in this direction. Specically, oxygen, nitrogen, and sulphur atoms in relevant substrates have been activated by NHCs as nucleophiles for a number of highly enantioselective reactions. These reactions involve previously unexplored NHCbound intermediates and present interesting reactivities. It is expected that this new approach will allow for quick construction of functional molecules, especially those bearing multiple heteroatoms, in a much simpler manner that is not achievable with the more matured approach of carbon atom activation. At present, the potential in activating heteroatoms by NHCs does not seem to be realized to any considerable level. We hope that this short review will encourage further development in this arena.

Conflicts of interest
There are no conicts to declare.