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Born in Singapore in May 1971, Professor Tan Choon-hong graduated with first class honours from the National University of Singapore with a Bachelor of Science degree in 1995, from the University of Cambridge in 1999 with a Ph.D. in Science from Professor Andrew B. Holmes, and then joined the Yoshito Kishi Research Group at Harvard University from 2000 to 2002 as a postdoctoral fellow From 2002 to 2003, he joined the Robert R. Rando Research Group of Harvard Medical School as an associate researcher, and began independent research in May 2003, committed to the development and application of chiral guanidine, and was awarded the title of tenured professor in 2010. He then developed a series of asymmetric phase transfer catalysts based on guanidine as a chiral base, and was promoted to full professor in 2016 and elected president of the Singapore National Institution of Chemistry (SINC) the following year.
Professor Tan Choon-hong. Image source: Nanyang Technological University
In recent years, Professor Chen Junfeng has mainly devoted himself to the study of Pentanidinium (hereinafter referred to as PN) and Bisguanidinium (hereinafter referred to as BG), two types of SP2 hybrid nitrogen center, guanidine as the backbone of the ion pair catalyst. This article will feature 4 articles summarized in accounts of Chemical Research (Acc. Chem. Representative work on Res., 2017, 50, 842) and 1 latest work of the same series of 2018 (J. Am. Chem. Soc., 2018, 140, 1952) for a brief introduction.
(a) Asymmetric Michael addition reaction catalyzed by PN
PN is the earliest generation of asymmetric phase transfer catalyst derived from guanidine, first published in J. Kelly in 2011. Am. Chem. Soc.（J. Am. Chem. Soc., 2011, 133, 2828) reported. The synthesis idea of PN is very concise, through the inexpensive chiral diamine alkylation after cyclization to form imidazoline chloride and guanidine two parts, and finally under the action of triethylamine to eliminate hydrochloric acid to obtain coupling products.
Figure 1. PN's design idea. Image source: Acc. Chem. Res.
As we all know, phase transfer catalysts have the advantages of extremely low loading and easy pilot amplification in the industry, and PN successfully completed the gram scale reaction in 24 hours with a catalyst dosage of 5/10,000, and maintained high yield and stereoselectivity.
Figure 2. Application of PN in asymmetric Michael addition reactions. Image source: Acc. Chem. Res.
(2) BG-catalyzed dihydroxylation and carbonyl hydroxylation reactions
In 2015, the biguanide catalyst BG was first reported in J. Am. Chem. Soc. (J. Am. Chem. Soc., 2015, 137, 10677), this is a modified and successful second-generation guanidine-derived asymmetric phase transfer catalyst. Compared with the previous generation of catalysts, BG only needs to obtain imidazoline chloride salt and mix it with piperazine 3:1 to obtain under the same conditions. Compared to the previous generation, BG contains two cationic centers of sp2 heterozyrene, which is a divalent salt.
Figure 3. BG's design idea. Image source: Acc. Chem. Res.
This time, BG combined with the stoichiometric potassium permanganate oxidizer, successfully formed two chiral centers of pinacol on the dismodeled alkene ester and a 2-hydroxy-3-carbonyl carboxylate with a chiral center on the tristituted alkenyl ester. In this reaction, the permanganate first oxidizes the 3 positions, and then triggers the formation of enyl alcohols from the ester carbonyl group, so that the 2 positions are oxidized. According to calculations, the intermediate energy obtained after the Si-face attack is lower, which explains the origin of high enantioselectivity.
Figure 4. BG carries the oxidation reaction of stoichiometric potassium permanganate. Image source: Acc. Chem. Res.
(3) BG catalytic oxidation of chiral sulfoxide
Following the success of stoichiometry metal ion oxidants, Professor Chen Junfeng's research group turned to the study of catalytic metal oxidation systems. The catalytic amount of metal high-valent acid roots combined with chiral cations to form an ion-pair catalyst, after oxidizing the substrate, the reduced metal acid is once again oxidized by the clean terminal oxidant hydrogen peroxide. Based on the characteristics of metal acid ions soluble in water, combined with chiral cations and easily soluble in organic solvents, acid ions can be flexibly drilled between the two phases, using hydrogen peroxide to achieve the purpose of recycling.
Figure 5. Oxidation of BG with a catalytic amount of compound molybdenum acid. Image source: Acc. Chem. Res.
This strategy has been successfully applied to the oxidation of thioethers to form a corresponding chiral sulfoxide, which is an important functional group in many drugs. Nature Communications (Nat. Commun., 2016, 7, 13455) reports that molybdenum hydrochlorides of sulfuric acid ligands are mainly carboxylate sulfide-based substrates that are eventually applied to the synthesis of chiral ammodafene.
Figure 6. Synthesis of chiral amodamine. Image source: Acc. Chem. Res.
(4) Asymmetric alkylation reactions catalyzed by PN and BG
In 2016, the authors reported that the chiral ion pair catalyst combined with a weak nucleophilic strong alkaline latent base (probase), against the asymmetric SN1 reaction in the homogeneous reaction that is not resistant to high-solubility strong bases, successfully breaking the reaction barrier. The article (J. Am. Chem. Soc., 2016, 138, 9935) Alkylation of two types of substrates was completed simultaneously by using two catalysts, demonstrating the spectral utility of the potential alkali strategy. The first reaction applied halogen-containing PN, and the yield of up to 95% and the enantiosel selectivity of 96% could be obtained for the substrate of dihydrocoumarins; the second reaction applied BG, and the yield of up to 99% and the enantioselectivity of 99% for the benzyl-substituted 1-indanone substrate was obtained.
Figure 7. Application of potential bases in alkylation reactions. Image source: Acc. Chem. Res.
In this method, cesium fluoride and potential alkali react at the phase interface to generate high-valent silicon salts, and then pair with chiral cations to form a catalyst into the organic phase, with good substrate universality and high stereoselectivity.
Figure 8. BG carries high-priced silicon to complete the mechanism of chiral alkylation. Image credit: J. Am. Chem. Soc.
(5) BG-catalyzed Bruker rearrangement reaction
Based on the understanding of high-valent silicon intermediates, in 2017, Professor Chen Junfeng's research group reported the Brooke rearrangement reaction of 1,2-aryl migration (J. Am. Chem. Soc., 2018, 140, 1952）。 Under the trigger of cesium fluoride, the alkyl group on the high-valent silicon migrates to the adjacent carbonyl carbon to form an oxygen anion, and then brook rearrangement causes the silicon group to migrate to oxygen, and finally the chiral alcohol is formed under the protonation of triisopropyl silanol. Cesium fluoride is introduced into the organic phase by BG, and after reacting with the substrate, BG always forms an ion pair control with intermediates at all levels of the reaction, thus ensuring excellent stereoselectivity.
Figure 9. BG rearranges within molecules with high-priced silicon action. Image credit: J. Am. Chem. Soc.
So far, the author has briefly introduced the five works of Professor Chen Junfeng in recent years. After reading through, you can feel the systematic nature of Professor Chen's work, he is committed to the development of ion pair catalysts, the applicable reaction types are also very diverse, each article has in-depth research and unique insights on the mechanism of reaction.
Research group website
http://www.ntu.edu.sg/home/choonhong/