Niankai Fu

Pushing the Limits of Aminocatalysis: Enantioselective Transformations of α-Branched β-Ketocarbonyls and Vinyl Ketones by Chiral Primary Amines

Enantioselective α-functionalizations of carbonyl compounds are fundamental transformations for the asymmetric synthesis of organic compounds. One of the more recent developments along this line is in aminocatalysis, which leads to the direct α-functionalization of simple aldehydes and ketones. However, most of the advances have been achieved with linear aldehydes and ketones as substrates. Effective aminocatalysis with α-branched carbonyls, particularly α-branched ketones, has remained elusive. The primary difficulty arises from the space-demanding α-substituent, which impedes iminium/enamine formation. In 2005, synthetic organic chemists revived catalysis using primary amines, which brought new attention to these challenges, because of the conformational flexibility of primary amines. On the basis of early biomimetic studies by Hine, in 2007 we developed the bioinspired chiral primary amine catalysts featuring primary-tertiary diamines. This type of catalyst involves enamine/iminium catalysis, and we could apply this chemistry to all of the major types of ketones and aldehydes. In this Account, we present research from our laboratory that significantly expands aminocatalysis to include α-branched ketones such as β-ketocarbonyls and α-substituted vinyl ketones. Our primary amine catalysis methodology, when used alone or in conjunction with metal catalysts, provides convenient access to both enantiopure α-tertiary and quaternary ketones, structures that are not available via other approaches. Our mechanistic studies showed that acidic additives play the critical role in facilitating catalytic turnover, most likely by shuttling protons during the enamine/iminium tautomerizations. These additives are also critical to induce the desired stereochemistry via ammonium N-H hydrogen bonding. Proton transfer by shuttling is also stereoselective, resulting in enantioselective enamine protonation as observed in the reactions of α-substituted vinyl ketones. In addition, we have carried out density functional theory studies that help to delineate the origins of the stereoselectivity in these reactions.

Chiral Primary−Tertiary Diamine−Brønsted Acid Salt Catalyzed Syn-Selective Cross-Aldol Reaction of Aldehydes

Highly syn-selective cross-aldol reaction of aldehydes has remained a challenging subject in the field of aminocatalysis. To achieve this end, chiral primary amines have been explored and the primary-tertiary diamine-Brønsted acid salts are found to promote the cross-aldol reactions of aldehydes with high activity and syn selectivity. Among various vicinal diamines screened, l-phenylalanine derived 2a/TfOH conjugate is identified as the optimal catalyst, showing good catalytic activity (up to 97% yield) and high syn selectivities (syn/anti up to 24:1, 87% ee). The current catalysis works selectively with small aliphatic aldehydes donors such as propionaldehyde and isobutyraldehyde, but not with aliphatic aldehydes bearing larger beta-substitute (>Me). In addition, the use of 2a/TfOH conjugate has also enabled the first syn-selective cross-aldol reactions of glycoaldehyde donors.

Metal-catalyzed electrochemical diazidation of alkenes

A charged approach to forming C–N bonds Adjacent carbon-nitrogen bonds often appear in chemical compounds of pharmaceutical interest. Fu et al. developed a versatile method to form these bonds by pairing manganese catalysis with electrochemical azide oxidation in the presence of olefins. A major advantage of the electrochemical approach is the tunable precision of its oxidizing power, which leaves other sensitive substituents such as alcohols and aldehydes intact. The reaction proceeded over several hours at room temperature, forming hydrogen at the counter electrode as a benign by-product. Science, this issue p. 575 Electrochemical oxidation underlies a broadly applicable method to place nitrogen substituents on two adjacent carbons. Vicinal diamines are a common structural motif in bioactive natural products, therapeutic agents, and molecular catalysts, motivating the continuing development of efficient, selective, and sustainable technologies for their preparation. We report an operationally simple and environmentally friendly protocol that converts alkenes and sodium azide—both readily available feedstocks—to 1,2-diazides. Powered by electricity and catalyzed by Earth-abundant manganese, this transformation proceeds under mild conditions and exhibits exceptional substrate generality and functional group compatibility. Using standard protocols, the resultant 1,2-diazides can be smoothly reduced to vicinal diamines in a single step, with high chemoselectivity. Mechanistic studies are consistent with metal-mediated azidyl radical transfer as the predominant pathway, enabling dual carbon-nitrogen bond formation.

Asymmetric Sulfa-Michael Addition to α-Substituted Vinyl Ketones Catalyzed by Chiral Primary Amine

The first effective example of asymmetric conjugate addition-protonation reactions of thiols to α-substituted vinyl ketones by chiral primary amine catalysis is reported. A simple chiral primary-tertiary diamine catalyst derived from l-phenylalanine was found to promote the sulfa-Michael addition-protonation reactions with good to excellent enantioselectivity.

Catalytic Asymmetric Electrochemical Oxidative Coupling of Tertiary Amines with Simple Ketones

Catalytic asymmetric electrochemical C-H functionalization of simple ketones has been developed. The transformation is realized by the combination of electrochemical oxidation and chiral primary amine catalysis. This metal- and oxidant-free method furnishes diverse C1-alkylated tetrahydroisoquinolines in high yields and with excellent enantioselectivities under very mild conditions.

Chiral primary-amine-catalyzed conjugate addition to α-substituted vinyl ketones/aldehydes: divergent stereocontrol modes on enamine protonation.

Enantioselective protonation with a catalytic enamine intermediate represents a challenging, yet fundamentally important process for the synthesis of α-chiral carbonyls. We describe herein chiral primary-amine-catalyzed conjugate additions of indoles to both α-substituted acroleins and vinyl ketones. These reactions feature enamine protonation as the stereogenic step. A simple primary-tertiary vicinal diamine 1 with trifluoromethanesulfonic acid (TfOH) was found to enable both of the reactions of acroleins and vinyl ketones with good activity and high enantioselectivity. Detailed mechanistic studies reveal that these reactions are rate-limiting in iminium formation and they all involve a uniform H2 O/acid-bridged proton transfer in the stereogenic steps but divergent stereocontrol modes for the protonation stereoselectivity. For the reactions of α-branched acroleins, facial selections on H2 O-bridged protonation determine the enantioselectivity, which is enhanced by an OH⋅⋅⋅π interaction with indole as uncovered by DFT calculations. On the other hand, the stereoselectivity of the reactions with vinyl ketones is controlled according to the Curtin-Hammett principle in the CC bond-formation step, which precedes a highly stereospecific enamine protonation.

Chiral primary amine catalysed asymmetric conjugate addition of azoles to α-substituted vinyl ketones

We report here the first effective example of asymmetric conjugate addition–protonation reactions of azoles to vinyl ketones by chiral primary amine catalysis. High enantioselectivity can be easily achieved by screening different primary amine catalysts, and the Curtin–Hammett control in the C–N bond formation step was verified by DFT calculations to account for the observed stereoselectivity.

Anodically Coupled Electrolysis for the Heterodifunctionalization of Alkenes

The emergence of new catalytic strategies that cleverly adopt concepts and techniques frequently used in areas such as photochemistry and electrochemistry has yielded a myriad of new organic reactions that would be challenging to achieve using orthodox methods. Herein, we discuss the strategic use of anodically coupled electrolysis, an electrochemical process that combines two parallel oxidative events, as a complementary approach to existing methods for redox organic transformations. Specifically, we demonstrate anodically coupled electrolysis in the regio- and chemoselective chlorotrifluoromethylation of alkenes.

Electrocatalytic Radical Dichlorination of Alkenes with Nucleophilic Chlorine Sources

We report a Mn-catalyzed electrochemical dichlorination of alkenes with MgCl2 as the chlorine source. This method provides operationally simple, sustainable, and efficient access to a variety of vicinally dichlorinated compounds. In particular, alkenes with oxidatively labile functional groups, such as alcohols, aldehydes, sulfides, and amines, were transformed into the desired vicinal dichlorides with high chemoselectivity. Mechanistic data are consistent with metal-mediated Cl atom transfer as the predominant pathway enabling dual C-Cl bond formation and contradict an alternative pathway involving electrochemical evolution of chlorine gas followed by Cl2-mediated electrophilic dichlorination.

Chiral primary amine catalyzed asymmetric Michael addition of malononitrile to α-substituted vinyl ketone.

The first efficient and highly enantioselective Michael addition-protonation reaction of malononitriles to α-substituted vinyl ketones has been developed by using a chiral primary amine as the organocatalyst. With a Hantzsch ester as the hydride source, an enantioselective tandem reduction, Michael addition-protonation reaction of benzylidenemalononitrile has also been achieved with good yields and high enantioselectivities.