Rauhut-Currier Research Articles

Phosphine-Catalyzed Asymmetric Organic Reactions.

Asymmetric phosphine catalysis showcasing remarkable progress over the past two decades has emerged as a key synthetic platform for the creation of molecular frameworks encountered in medicinal chemistry and materials science. Different types of novel chiral phosphine catalysts have been developed and employed in cornucopias of organic transformations, such as annulation, addition, Morita-Baylis-Hillman, and Rauhut-Currier reactions, among others. This review summarizes all of the literature examples from late 1990s to the end of 2017, alongside their mechanistic insights whenever possible, with a very aim to trigger more intensive research in the future to render asymmetric phosphine catalysis one of the most common and reliable tools to organic chemists.

Enantioselective Construction of Bicyclic Pyran and Hydrindane Scaffolds via Intramolecular Rauhut–Currier Reactions Catalyzed by Thiourea-Phosphines

Highly enantioselective intramolecular RC reactions via desymmetrization of cyclohexadienones have been developed. By employing cyclohexadienones with a flexible ether or alkyl group linked internal enone moiety, optically enriched bicyclic pyran and hydrindane skeletons were constructed. Bifunctional phosphine catalysts bearing a thiourea moiety were found to effectively promote the reaction, and preliminary studies suggest that the hydrogen-bonding interaction between thiourea and carbonyl group is crucial and facilitates the otherwise flexible backbones to undergo the desired cyclization.

Organocatalytic Enantioselective Cross-Vinylogous Rauhut-Currier Reaction of Methyl Coumalate with Enals.

The organocatalytic enantioselective intermolecular cross-vinylogous Rauhut-Currier (RC) reaction of methyl coumalate with α,β-unsaturated aldehydes is reported, and the enals are activated by iminium catalysis to serve as the Michael acceptors and methyl coumalate is used as an activated diene to generate a latent enolate. The excellent selectivity is driven by the aromaticity of methyl coumalate, and the post transformation of this heterocyclic structure into other electron-deficient arenes and heterocycles have addressed, in part, the challenging selectivity issues of the intermolecular cross-RC reactions and the limited scope of iminium catalysis.

Organocatalytic Enantioselective Cross‐Vinylogous Rauhut–Currier Reaction of Methyl Coumalate with Enals

AbstractThe organocatalytic enantioselective intermolecular cross‐vinylogous Rauhut–Currier (RC) reaction of methyl coumalate with α,β‐unsaturated aldehydes is reported, and the enals are activated by iminium catalysis to serve as the Michael acceptors and methyl coumalate is used as an activated diene to generate a latent enolate. The excellent selectivity is driven by the aromaticity of methyl coumalate, and the post transformation of this heterocyclic structure into other electron‐deficient arenes and heterocycles have addressed, in part, the challenging selectivity issues of the intermolecular cross‐RC reactions and the limited scope of iminium catalysis.

Recent Advances in Amino Acid-Based Phosphine Catalysts and Their Applications in Asymmetric Reactions

Amino acid-based catalysts have been intensively researched in recent years. Amino acid-derived phosphines possess high nucleophilicity and exhibit unique catalytic activities in asymmetric synthesis. L-Threonine and valine are most utilized natural amino acids in the preparation of chiral phosphines. The efficient and versatile chiral phosphine catalysts are applied in a wide range of reactions such as MBH reaction, Rauhut–Currier reaction, Michael addition, [4 + 2]-annulation, [3 + 2]-annulation, 1,4-dipolar cycloaddition. They are also widely used in the construction of core structures of natural products. Amino acid-based phosphine catalysts and their applications in asymmetric synthesis are summarized.

DMAP catalysed vinylogous Rauhut–Currier reaction of allenoates with para-quinone methides

The hitherto unknown, organocatalysed (DMAP) vinylogous Rauhut-Currier reaction of 2,3-butadienoates with para-quinone methides has been achieved. The products, diarylmethane substituted allenoates, are formed in high to excellent yields under mild reaction conditions.

Primary Aminothiourea-Catalyzed Enantioselective Synthesis of Rauhut-Currier Adducts of 3-Arylcyclohexenone with a Tethered Enone on the Aryl Moiety at the Ortho-Position.

An enantioselective synthesis of Rauhut-Currier (RC) adducts from 3-aryl cyclohexenone with a tethered enone moiety at the ortho-position on the aryl group is accomplished. This method provides a wide range of valuable synthetic building blocks having a unique [6-5-6] all-carbon-fused tricyclic skeleton. A primary amine-containing thiourea, a bifunctional organocatalyst, was found to be an efficient catalyst for this transformation. The primary amine counterpart of the catalyst possibly activates the aliphatic enone via dienamine formation (HOMO activation), whereas the thiourea counterpart activates the tethered enone (LUMO activation). Considering the difficulty in achieving an RC reaction of β,β-disubstituted (alkyl and aryl) enones, this method would be significantly rewarding.

Bis(amino)cyclopropenylidene Catalyzed Rauhut-Currier Reaction between α,β-Unsaturated Carbonyl Compounds and para-Quinone Methides.

An intermolecular Rauhut-Currier reaction between α,β-unsaturated carbonyl compounds and p-quinone methides has been developed by employing bis(amino)cyclopropenylidene as a catalyst. This protocol allows access to a variety of vinyl diarylmethane derivatives in moderate to good yields.

α-Functionalization of 2-Vinylpyridines via a Chiral Phosphine Catalyzed Enantioselective Cross Rauhut-Currier Reaction.

Herein, 2-vinylpyridines as a new type of electron-poor system for the asymmetric cross Rauhut-Currier reaction are reported. 2-Vinylpyridines are chemo- and enantioselectively activated by a newly designed chiral phosphine catalyst. The new reaction provides a powerful synthetic tool for accessing structurally diverse, highly valued chiral pyridine building blocks in good yields and with high enantioselectivities. Preliminary mechanistic studies reveal that two NH protons in the catalyst are critical for the synergistic activation of the substrates and governing the stereoselectivity of this reaction.

Optically active helical polyisocyanides bearing chiral phosphine pendants: Facile synthesis and application in enantioselective Rauhut-Currier reaction

Three novel enantiopure phenyl isocyanide monomers with BH3-protected phosphine functional group were designed and synthesized. Polymerization of these monomers using a alkyne-Pd(II) complex as a catalyst led to the formation of respective helical polyisocyanides in high yields with controlled molecular weights (Mns) and narrow molecular weight distributions (Mw/Mns). Removing the protecting BH3 groups afforded helical poly(phenyl isocyanide)s bearing phosphine pendants. Thanks to the chiral induction of monomer, the isolated helical polyisocyanides showed high optical activity, as revealed by circular dichroism (CD) and absorption spectroscopies and polarimetry. The helical structures of these polymers were quite stable in various organic solvents with different polarities and in a wide temperature range. Moreover, these helical polymers could be used as organocatalysts and showed good performance in enantioselective cross Rauhut-Currier reaction. The enantiomeric excess (ee) values of the isolated products of cross Rauhut-Currier reaction could be up to 90%. The polymer organocatalysts could be easily recovered from the reaction mixtures and reused at least five times in the reaction without significant loss of their enantioselectivities and catalytic activities.

Phosphine‐Catalyzed Asymmetric Intermolecular Cross Rauhut–Currier Reaction of β‐Perfluoroalkyl‐Substituted Enones and Vinyl Ketones

AbstractThe highly enantioselective N‐acylaminophosphine‐catalyzed challenging asymmetric intermolecular cross Rauhut–Currier reaction of vinyl ketones with β‐perfluoroalkyl enones is described, which provides a facile access to chiral multifunctional compounds bearing a perfluoroalkyl‐substituted stereocenter in good yields and ees.magnified image

Photoinduced Carboborative Ring Contraction Enables Regio- and Stereoselective Synthesis of Multiply Substituted Five-Membered Carbocycles and Heterocycles.

We report herein a photoinduced carboborative ring contraction of monounsaturated six-membered carbocycles and heterocycles. The reaction produces substituted five-membered ring systems stereoselectively and on preparative scales. The products feature multiple stereocenters, including contiguous quaternary carbons. We show that the reaction can serve as a synthetic platform for ring system alteration of natural products. The reaction can also be used in natural product synthesis. A concise total synthesis of artalbic acid has been enabled by a sequence of photoinduced carboborative ring contraction, Rauhut-Currier reaction, and nitrilase-catalyzed hydrolysis. The synthetic utility of the reaction has been further demonstrated by converting the intermediate organoboranes to alcohols, amines, and alkenes.

Acrylamide in Rauhut-Currier reaction; intramolecular isomerization of activated alkenes for quinolone synthesis

Acrylamides are fundamental Michael acceptors which have been used profoundly in synthetic, medicinal and polymer chemistry. However, due to their lower reactivity they have been least used in Morita-Baylis-Hillman (MBH) reaction and have been out of its vinylogus version Rauhut Currier (RC) reaction. Herein, use of acrylamide in RC reaction is being presented. Intramolecular RC reaction followed by [1,3]-H shift led to the synthesis of quinolone moiety. DABCO catalyzed IRC reaction of acrylamide at 80 °C in presence of water, was found to work on a number of precursors. En route chemo selective, gram scale method for ambiphilic, versatile precursor 2-amino chalcone is also reported. Chemoselective and economical conversion of 2-nitro chalcone to 2-aryl quinoline has also been developed.

Enantioselective Synthesis of Functionalized 4-Aryl Hydrocoumarins and 4-Aryl Hydroquinolin-2-ones via Intramolecular Vinylogous Rauhut-Currier Reaction of para-Quinone Methides.

A novel strategy for the asymmetric construction of functionalized 4-aryl-3,4-dihydrocoumarins and 4-aryl-3,4-dihydroquinolin-2-ones via an intramolecular vinylogous Rauhut-Currier reaction of para-quinone methides (p-QMs) under the bifunctional catalysis of chiral amine-phosphine is described. This intramolecular mode for the catalytic enantioselective 1,6-conjugate addition of p-QMs has been explored for the first time, delivering two types of synthetically important heterocycles in high yields and enantioselectivites.

An Accelerated Intermolecular Rauhut-Currier Reaction Enables the Total Synthesis of (-)-Flueggenine C.

The first total synthesis of dimeric securinega alkaloid (-)-flueggenine C is completed via an accelerated intermolecular Rauhut-Currier (RC) reaction. Despite the numerous reports on the total synthesis of monomeric securinegas, the synthesis of dimeric securinegas whose monomeric units are connected by a putative enzymatic RC reaction has not been reported to date. We have found that installation of a nucleophilic functional group at the γ-position of an enone greatly accelerates the rate of the diastereoselective intermolecular RC reaction. This discovery enabled an efficient and selective formation of the dimeric intermediate which was further transformed to (-)-flueggenine C.

Mechanisms and stereoselectivities of phosphine-catalyzed Rauhut-Currier reaction between N-phenylmaleimide and 2-benzoyl acrylate: A computational investigation

With the aid of density functional theory (DFT) calculations, we have studied the mechanisms and stereoselectivities in PPh3-catalyzed intermolecular Rauhut-Currier reaction of N-phenylmaleimide (R1) and 2-benzoyl acrylate (R2). Various reaction pathways in the absence and presence of benzoic acid (PhCO2H) were investigated. Comparing the overall reaction barriers based on mechanism A (in the absence of PhCO2H) and mechanism B (in the presence of PhCO2H), we were able to understand the critical role of PhCO2H. The preferred mechanism (mechanism B) initiates nucleophilic conjugated addition of PPh3 to R1 to form a zwitterionic intermediate B_1 (first step). It then reacts with R2 to generate intermediate B_2 (second step). The following intramolecular proton transfer is shown to occur via two successive H-shift processes with the assistance of PhCO2H: the C5 atom of B_2 first abstracts a proton from PhCO2H to generate B_3, then the H atom transfers from C3 to the PhCOO− group completes the intramolecular proton transfer and produces B_4 (third step). Finally, the catalyst PPh3 releases from B_4 affording the cross-coupling product (fourth step). On the basis of our calculation results, path D leading to the S-configuration product P(S) is the most energy favorable pathway among the eight possible stereoselective pathways. The second step is found to be the rate- and stereoselectivity-determining step with an overall free energy barrier of 21.3kcal/mol. Our DFT results are in good agreement with experimental observations. The present study should be valuable for understanding this kind of reaction.

Chiral Organocatalyzed Intermolecular Rauhut-Currier Reaction of Nitroalkenes with Ethyl Allenoate.

An enantioselective intermolecular Rauhut-Currier (RC) reaction of nitroalkenes with ethyl allenoate has been established with quinidine-derived β-isocupreidine. The present RC reaction afforded α-functionalized allenoates 3 in up to 94% yield with 59% enantiomeric excess (ee).

Mechanisms and stereoselectivities of the DABCO-catalyzed Rauhut–Currier reaction of α,β-unsaturated ketones and aryl acrylates: a computational investigation

Mechanism of the RC reaction in the absence and presence of PhOH.

Phosphine-catalyzed intramolecular Rauhut-Currier reaction: enantioselective synthesis of hydro-2H-indole derivatives.

A highly enantioselective intramolecular Rauhut-Currier reaction catalyzed by a multifunctional chiral aminophosphine catalyst was reported. A series of hydro-2H-indole derivatives that bear an all-carbon quaternary center were obtained in high yields (up to 94%), and excellent diastereo- and enantioselectivities (up to >20 : 1 dr and >99% ee). And this reaction could be performed on a gram scale using 2 mol% catalyst loading.

Tail-to-tail dimerization and Rauhut-Currier reaction of disubstituted Michael acceptors catalyzed by N-heterocyclic carbene

The N-heterocyclic carbene (NHC)-catalyzed dimerizations of a variety of disubstituted Michael acceptors have been investigated. In addition to the tail-to-tail dimerization of methacrylates reported previously, the scope of vinylidene substrates expands to γ-methyl-α-methylene-γ-butyrolactone, dimethyl 2-methylenepentanedioate, dimethyl itaconate, methacrylamides, and 2-isopropenylbenzoxazole, none of which have been dimerized by metal-catalyzed counterparts. In contrast, vinylene substrates, such as crotononitrile, methyl crotonate, and 2-cyclohexen-1-one, do not undergo the dimerization probably due to the steric hindrance of the β-substituent. Instead, the Rauhut-Currier (RC) reaction of these was found to proceed. The stoichiometric reaction of crotononitrile with NHC indicates that this RC reaction also involves the deoxy-Breslow intermediate and the reversible proton transfer.