Han Yong Bae

Hydrogen bonding mediated enantioselective organocatalysis in brine: significant rate acceleration and enhanced stereoselectivity in enantioselective Michael addition reactions of 1,3-dicarbonyls to β-nitroolefins

Brine provides remarkable rate acceleration and a higher level of stereoselectivity over organic solvents, due to the hydrophobic hydration effect, in the enantioselective Michael addition reactions of 1,3-dicarbonyls to β-nitroolefins using chiral H-donors as organocatalysts.

Organocatalytic Enantioselective Decarboxylative Aldol Reaction of Malonic Acid Half Thioesters with Aldehydes

The direct asymmetric aldol reaction is one of the most powerful and fundamental tools for forming new carbon– carbon bonds and chiral hydroxy functional groups simultaneously. Inspired by nature, the development of prefunctionalized metal enolates and metal Lewis acids to mimic type II aldolases have provided a general solution to accessing enantioenriched b-hydroxy carbonyl compounds in cooperation with chiral auxiliaries and metal complexes. Specifically, the Mukaiyama aldol reaction is general in scope and is practical for controlling chemo-, stereo-, and enantioselectivity with a pregenerated silyl enol ether. However, to gain access to a variety of aldol products with defined stereochemistry, it is necessary to develop a reaction with a distinct catalytic reaction mode. Since 2000, primary and secondary amine organocatalysts have shown excellent performance, compared to chiral metal Lewis acids, for direct aldol reactions and Mukaiyama-type reactions by forming an enamine intermediate with a carbonyl compound. Recent studies by us and others using malonic acid half thioesters (2, MAHTs) as ester enolate equivalents with various electrophiles were compelling for the application of organocatalytic aldol reactions to mimic polyketide synthases. Moreover, the desired b-hydroxy thioesters 3 could readily be transformed into various functional groups. In addition, such a reaction generates only CO2 as a sole by-product. Recently, Shair et al. investigated the aldol reaction with methyl-substituted MAHT (MeMAHT) using a chiral Cu/ bis(oxazoline) catalyst. Aliphatic aldehydes underwent the aldol reaction to afford the a-methyl substituted aldol products with excellent diatereoand enantioselectivity [Eq. (1)]. However, aromatic and a,b-unsaturated aldehydes were shown to be poor substrates. Herein, we report the first organocatalytic asymmetric aldol reaction of methylsubstituted and unsubstituted MAHTs (2) with a variety of aromatic and aliphatic aldehydes to afford enantioenriched bhydroxythioesters (3) by employing a sulfonamide-based organocatalyst [Eq. (2)]. To the best of our knowledge, this is the first example of metal-free enantioselective organocatalytic aldol reaction of MAHTs (2) with aldehydes (1), as a polyketide synthase mimic, to provide b-hydroxy thioesters (3).

Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin.

In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona-based-squaramide-catalyzed enantioselective Mannich reactions of diverse imines or α-amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl α-amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling-reagent-free synthesis of the antidiabetic drug (-)-(R)-sitagliptin.

Triflimide: An Overlooked High-Performance Catalyst of the Mukaiyama Aldol Reaction of Silyl Ketene Acetals with Ketones

The Mukaiyama aldol reaction is a widely applied carbon-carbon bond forming reaction. However, despite numerous well-established methods using aldehydes as acceptors, only few examples exist with ketones. Here we report a highly practical catalytic approach to this transformation, namely, the triflimide catalyzed Mukaiyama aldol reaction of silyl ketene acetals with ketones. This method exhibits a broad substrate scope, is very rapid, tolerates functionalized substrates, and requires only parts-per-million catalyst loadings with preparative scale reactions up to hundreds of grams in excellent purity (>99 %).

Can a Ketone Be More Reactive than an Aldehyde? Catalytic Asymmetric Synthesis of Substituted Tetrahydrofurans

O-heterocycles bearing tetrasubstituted stereogenic centers are prepared via catalytic chemo- and enantioselective nucleophilic additions to ketoaldehydes, in which the ketone reacts preferentially over the aldehyde. Five- and six-membered rings with both aromatic and aliphatic substituents, as well as an alkynyl substituent, are obtained. Moreover, 2,2,5-trisubstituted and 2,2,5,5-tetrasubstituted tetrahydrofurans are synthesized with excellent stereoselectivities. Additionally, the synthetic utility of the described method is demonstrated with a three-step synthesis of the side chain of anhydroharringtonine.