Choon Wee Kee

Graphene oxide and Rose Bengal: oxidative C–H functionalisation of tertiary amines using visible light

Visible light induced oxidative C–H functionalisation of tertiary amines catalysed by the combination of graphene oxide and Rose Bengal was developed. This reaction avoids the use of stoichiometric amounts of peroxy compounds as terminal oxidants. This reaction is useful for tri-alkyl amines including chiral tertiary amines. Both cyanide and trifluoromethyl nucleophiles were shown to participate in this reaction, providing α-cyano- and α-trifluoromethylated tertiary amines.

Dehydrogenative coupling reactions catalysed by Rose Bengal using visible light irradiation

Rose Bengal, an organic dye, was demonstrated to be a photoredox catalyst for dehydrogenative coupling reactions using visible light irradiation. α-Functionalised tertiary amines were obtained with good to excellent yields. Air is essential for this reaction and acts as the terminal oxidant. This is an environmentally friendly C–H functionalisation methodology that avoids the use of metal catalysts and stoichiometric amount of peroxo-compounds.

Organic dye photocatalyzed α-oxyamination through irradiation with visible light

Rose Bengal, an organic dye, was used as a visible light photocatalyst to investigate novel α-oxyamination reactions between 1,3-dicarbonyl compounds and a free radical (TEMPO). Compounds that are difficult to obtain such as quaternary fluorinated compounds were synthesized using this method. This visible light photocatalytic reaction can also be performed in water.

Pentanidium-Catalyzed Enantioselective Phase-Transfer Conjugate Addition Reactions

A new chiral entity, pentanidium, has been shown to be an excellent chiral phase-transfer catalyst. The enantioselective Michael addition reactions of tert-butyl glycinate-benzophenone Schiff base with various α,β-unsaturated acceptors provide adducts with high enantioselectivities. A successful gram-scale experiment at a low catalyst loading of 0.05 mol % indicates the potential for practical applications of this methodology. Phosphoglycine ester analogues can also be utilized as the Michael donor, affording enantioenriched α-aminophosphonic acid derivatives and phosphonic analogues of (S)-proline.

Expanding the Utility of Brønsted Base Catalysis: Biomimetic Enantioselective Decarboxylative Reactions

As a result of the low reactivity of simple esters, the use of them as nucleophiles in direct asymmetric transformations is a long-standing challenge in synthetic organic chemistry. Nature approaches this difficulty through a decarboxylative mechanism, which is used for polyketide synthesis. Inspired by nature, we report guanidine-catalyzed biomimetic decarboxylative C-C and C-N bond-formation reactions. These highly enantioselective decarboxylative Mannich and amination reactions utilized malonic acid half thioesters as simple ester surrogates. It is proposed that nucleophilic addition precedes decarboxylation in the mechanism, which has been investigated in detail through the identification of intermediates by using electrospray ionization (ESI) mass-spectrometric analysis and DFT calculations.

Enantiodivergent and γ‐Selective Asymmetric Allylic Amination

There are many readily available methods for the preparation of enantiopure carbonyl compounds containing aand bchiral centers. However, the selective functionalization of the g position has been met with more difficulties and less progress. Asymmetric vinylogous aldol reactions, Michael reactions, and phosphine-catalyzed nucleophilic addition to alkynes and allenes [Eq. (1)] are some of the successful attempts made to address this difficult problem. In particular, the asymmetric vinylogous reactions seem to be most promising at delivering the desired results, despite the fact that the high electron density at the a position makes it kinetically favorable relative to the g position. A cinchonaalkaloid-catalyzed direct enantioselective g amination was reported using activated alkylidene cyanoacetates and malononitriles [Eq. (2); EWG = electron-withdrawing group]. Proline derivatives were also employed to catalyze the direct asymmetric g functionalization of a,b-unsaturated aldehydes by transforming the electron-poor alkene into an electron-rich one [Eq. (3)].

Mechanistic Insights into Bicyclic Guanidine-Catalyzed Reactions from Microscopic and Macroscopic Perspectives

Chiral bicyclic guanidine can act as an efficient chiral Brønsted base catalyst in enantioselective reactions, delivering good yields with high enantioselectivities. There is interest in understanding the detailed mechanisms of these guanidine-catalyzed reactions. Herein, we performed a detailed kinetic study of three different types of chiral bicyclic guanidine-catalyzed reactions, determining the bifunctionality of our guanidine catalyst. Although these three reactions share a similar catalytic cycle, their intrinsic kinetic behaviors are significantly different from each other because of the difference in the rate-determining step. The calculated theoretical rate expression for each reaction, as a result of the mechanism elucidated with density functional theory calculations, agrees well with the respective experimentally observed rate equation.

In Silico Design of Halogen-Bonding-Based Organocatalyst for Diels–Alder Reaction, Claisen Rearrangement, and Cope-Type Hydroamination

Using DFT calculations, we investigated the use of halogen bonding (XB) interactions to accelerate and control organic reactions, namely Diels-Alder reaction, Claisen rearrangement, and Cope-type hydroamination. Our designed triarylbenzene tripodal organocatalyst is characterized by three halogen bond donors, perfluoro-iodophenyl groups. The calculated transition states unravel multiple halogen bonds between the iodine atoms and various types of halogen bond acceptors (lone pair, π and σ bonds). These cooperative noncovalent interactions provide efficient binding between the catalyst and substrate (∼15 kcal/mol binding energy) and are the key factors for transition-state stabilization and molecular recognition. On the basis of our DFT calculations and calculated turnover frequencies, the XB-catalyzed reactions are found to be competitive with the corresponding hydrogen bonding catalysis reported in literature.

18F-Trifluoromethylation of Unmodified Peptides with 5-18F-(Trifluoromethyl)dibenzothiophenium Trifluoromethanesulfonate

The 18F-labeling of 5-(trifluoromethyl)-dibenzothiophenium trifluoromethanesulfonate, commonly referred to as the Umemoto reagent, has been accomplished applying a halogen exchange 18F-fluorination with 18F-fluoride, followed by oxidative cyclization with Oxone and trifluoromethanesulfonic anhydride. This new 18F-reagent allows for the direct chemoselective 18F-labeling of unmodified peptides at the thiol cysteine residue.

Pentanidium- and Bisguanidinium-Catalyzed Enantioselective Alkylations Using Silylamide as Brønsted Probase.

Most asymmetric phase transfer reactions are Brønsted base reactions, and the inorganic bases used greatly influenced the profile of the reaction. Alkoxide salts are able to activate substrates with high pKa values, but background reactions are often unavoidable. On the other hand, carbonate and phosphate salts are milder, but their low basicity limits the scope of their reactions. This presents a difficult situation whereby fragile substrates such as lactone will be hydrolyzed by a stronger base but will not be activated with a weaker one. Thus, a Brønsted probase strategy is devised, in which a strong base can be generated in situ from silylamide (probase) through the use of fluoride. In this approach, the strong base produced will be transient and not be in excess, thus reducing background and side reactions. We demonstrate this strategy using pentanidinium and bisguanidinium as catalysts; highly enantioselective phase transfer alkylation of several types of substrates including dihydrocoumarin (lactone) can be achieved. We found that the probase also acts as a silylation reagent, generating silyl enol ether or silyl ketene acetal, which are key intermediates in the reaction. We further propose that hypervalent silicates form ion-pairs with pentanidinium and bisguanidinium as intermediates in the reaction, and it is through these ion-pairs that the selective enantiofacial approach of the electrophile is determined.