Homoenolate Equivalents Research Articles

Organocatalytic enantio- and diastereoselective assembly of cyclopropane-incorporated polycyclic molecules via isobenzopyrylium ions.

A highly enantio- and diastereoselective organocatalytic formation of cyclopropanes embedded in a complex bridged polycyclic architecture is disclosed. In the presence of a chiral phosphoric acid catalyst, this reaction generates four new stereogenic centers and three new C-C bonds efficiently from isochromene acetals and vinylboronic acids under mild conditions. Different from conventional asymmetric cyclopropanation strategies, this process does not involve carbenes or carbenoids. The complex products can serve as precursors to useful homoenolate equivalents. Mechanistically, DFT studies provided insights into the key transition states of the enantiodetermining [4 + 2] cycloaddition, in which the enantioselectivity is induced by the chiral phosphate counter anion of the isobenzopyrylium intermediate.

Lewis Base/3d Transition-Metal Cooperatively Catalyzed Asymmetric Reactions

AbstractLewis base/transition-metal cooperatively catalyzed asymmetric transformations have attracted extensive attention as they offer complementary catalytic systems within the realm of cooperative catalysis. Recently, the synergistic use of Lewis bases in combination with earth-abundant 3d metals has emerged as a fascinating prospect, presenting an opportunity to move away from the reliance on noble metals and to explore novel catalytic processes. In this Account, we highlight our recent achievements regarding the chemistry and synthetic utility of isothiourea (ITU) activated C1-ammonium enolates and N-heterocyclic carbene (NHC)-bound homoenolate equivalents in conjunction with 3d transition-metal activated electrophiles. The remarkable success in the stereoselective construction of carbon–carbon and carbon–heteroatom bonds has led to significant contributions to stereodivergent synthesis.1 Introduction2 ITU/Copper Cooperative Catalysis3 NHC/Copper Cooperative Catalysis4 NHC/Nickel Cooperative Catalysis5 Conclusion

β‐Functionalized and α,β‐Difunctionalized Ketones from 1‐Arylallylic Alcohols via Dipotassio α,β‐Dianion Intermediates

This study reports the synthesis of diverse β-functionalized ketones from readily available 1-arylallylic alcohols in the presence of (trimethylsilyl)methylpotassium (TMSCH2K). The reaction proceeded via the formation of the highly nucleophilic dipotassio α,β-dianion as the key intermediate, which served as a metal homoenolate equivalent. This protocol also allowed the one-pot synthesis of α,β-difunctionalized ketones using two different electrophiles, thus demonstrating its synthetic advantages over other protocols involving metal homoenolates.

Palladium-Catalyzed Siloxycyclopropanation of Alkenes Using Acylsilanes.

Currently, catalytically transferable carbenes are limited to electron-deficient and neutral derivatives, and electron-rich carbenes bearing an alkoxy group (i.e., Fischer-type carbenes) cannot be used in catalytic cyclopropanation because of the lack of appropriate carbene precursors. We report herein that acylsilanes can serve as a source of electron-rich carbenes under palladium catalysis, enabling cyclopropanation of a range of alkenes. This reactivity profile is in sharp contrast to that of metal-free siloxycarbenes, which are unreactive toward normal alkenes. The resulting siloxycyclopropanes serve as valuable homoenolate equivalents, allowing rapid access to elaborate β-functionalized ketones.

Copper-Catalyzed Ring-Opening Defluorinative Alkylation of Siloxydifluorocyclopropanes: Synthesis of γ-Fluoro-δ-Ketoesters and γ,δ-Diketonitriles.

In view of the importance of both fluorinated synthons and homoenolate equivalents, synthetic application of difluorocyclopropanols is desired but remains challenging due to their thermodynamic instability. Herein, we use siloxydifluorocyclopropanes as difluorocyclopropanol precursors to carry out new Cu-catalyzed ring-opening defluorinative alkylation. With α-bromo carboxylic esters as coupling partners, the reaction affords γ-fluoro-δ-ketoesters via a CuI/CuII catalytic cycle. Interestingly, by the use of α-bromoamides, the ring-opening defluorinative alkylation is followed by an additional intramolecular C-N oxidative coupling to deliver a lactam intermediate, which further undergoes defluorination, hydrolysis, ring opening, and dehydration cascade via a CuI/CuII/CuIII catalytic pathway, leading to γ,δ-diketonitriles as the final products.

Imines as acceptors and donors in N-heterocyclic carbene (NHC) organocatalysis.

The synthetic potential of imines as electrophiles or as a source of nucleophilic coupling partner in N-heterocyclic carbene (NHC) catalysis for the synthesis of various nitrogen heterocycles and functionalized amines is highlighted in this Feature Article. Electrophilic imines are suitable candidates for intercepting the NHC-derived acyl anions, homoenolate equivalents, and (di)enolates for the synthesis of α-amino ketones and a variety of lactam derivatives. Moreover, enamines generated from imines bearing α-hydrogen could be trapped with α,β-unsaturated acylazoliums for the synthesis of functionalized dihydropyridinones. NHCs are also useful for the umpolung of imines for the generation of aza-Breslow intermediates thus leading to the synthesis of indoles, quinolines, dihydroquinoxalines etc. A concise account of the diverse reactivity of imines in NHC catalysis has been presented.

N-Heterocyclic Carbene-Catalyzed 1,6-Addition of Homoenolate Equivalent Intermediates: Asymmetric Synthesis of Nonspirocyclic Quaternary Oxindoles

Although there is a growing interest in developing asymmetric 1,6-addition reactions of carbon nucleophiles to Michael acceptors, the corresponding 1,6-addition of homoenolates remains an unsolved ...

Enantioselective Rhodium-Catalyzed Allylic Alkylation of β,γ-Unsaturated α-Amino Nitriles: Synthetic Homoenolate Equivalents.

An enantioselective rhodium-catalyzed allylic alkylation of β,γ-unsaturated α-amino nitriles is described. This protocol provides a novel approach for the construction of β-stereogenic carbonyl derivatives via the catalytic asymmetric alkylation of a homoenolate equivalent. The particularly challenging nature of this transformation is highlighted by the fact that three modes of selectivity must be manipulated, namely regio- and enantioselectivity, in addition to geometrical control. The γ-stereogenic cyanoenamine products can be readily hydrolyzed in situ to afford the β-substituted carboxylic acids, which in turn provide expedient access to a number of related carbonyl derivatives. Additionally, control experiments indicate that the chiral rhodium-allyl intermediate facilitates the selective formation of the E-cyanoenamine products, which is critical since the Z-isomer affords significantly lower enantiocontrol.

Enantioselective Rhodium‐Catalyzed Allylic Alkylation of β,γ‐Unsaturated α‐Amino Nitriles: Synthetic Homoenolate Equivalents

AbstractAn enantioselective rhodium‐catalyzed allylic alkylation of β,γ‐unsaturated α‐amino nitriles is described. This protocol provides a novel approach for the construction of β‐stereogenic carbonyl derivatives via the catalytic asymmetric alkylation of a homoenolate equivalent. The particularly challenging nature of this transformation is highlighted by the fact that three modes of selectivity must be manipulated, namely regio‐ and enantioselectivity, in addition to geometrical control. The γ‐stereogenic cyanoenamine products can be readily hydrolyzed in situ to afford the β‐substituted carboxylic acids, which in turn provide expedient access to a number of related carbonyl derivatives. Additionally, control experiments indicate that the chiral rhodium‐allyl intermediate facilitates the selective formation of the E‐cyanoenamine products, which is critical since the Z‐isomer affords significantly lower enantiocontrol.

Modern Developments in the Chemistry of Homoenolates

Homoenolates are unique synthetic intermediates which display umpolung reactivity. Homoenolates and homoenolate equivalents like cyclopropanols have seen a recent surge in popularity due to their particular utility for accessing β‐functionalized carbonyl derivatives. This popularity has been enabled by the development of protocols for facile access to cyclopropanols and homoenolates from a variety of readily available starting materials. This microreview will highlight common strategies for generating cyclopropanols and metal homoenolates, as well as procedures for homoenolate functionalization, with a particular emphasis on protocols that have appeared after 2003. As an amphoteric molecule, two main reactivity modes have been established: the homoenolate reacts as a carbon nucleophile for β‐functionalization reactions and/or as a carbonyl electrophile, a strategy which has only emerged in the past few years. This microreview will highlight the use of homoenolates as convenient intermediates for accessing especially challenging motifs. The use of homoenolate chemistry in the context of natural product and pharmaceutical synthesis will also be presented.

N-Heterocyclic Carbene Catalysis via Azolium Dienolates: An Efficient Strategy for Remote Enantioselective Functionalizations.

N-heterocyclic carbene (NHC) catalysis has emerged as a powerful strategy in organic synthesis. In recent years a number of reviews have been published on NHC-catalyzed transformations involving Breslow intermediates, acyl azoliums, α,β-unsaturated acyl azoliums, homoenolate equivalents, and azolium enolates. However, the azolium dienolate intermediates generated by NHCs have been employed in asymmetric synthesis only very recently, especially in cycloadditions dealing with remote functionalization. This Minireview highlights all the developments and the new advances in NHC-catalyzed asymmetric cycloaddition reactions involving azolium dienolate intermediates.

Generation and Application of Homoenolate Equivalents Utilizing [1,2]-Phospha-Brook Rearrangement under Brønsted Base Catalysis.

A new method for catalytic generation of a homoenolate equivalent and its application to carbon-carbon bond formation was developed by utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis. The α-oxygenated allyl anions, which can serve as homoenolate equivalents, were catalytically generated in situ by treating readily available chalcones with diethyl phosphite or the pre-formed 1,2-adducts of diethyl phosphite with chalcones in the presence of a catalytic amount of a phosphazene base, P2-tBu. The resulting allyl anions were subsequently trapped by various electrophiles, including Michael acceptors, imines, and aldehydes, providing the corresponding adducts in good yields with moderate to good diastereoselectivities.

N-Heterocyclic Carbene-Catalyzed Reaction of Chalcone and Cinnamaldehyde To Give 1,3,4-Triphenylcyclopentene Using Organocatalysis To Form a Homoenolate Equivalent

In this experiment, students carry out a modern organocatalytic reaction using IMes·HCl and NaOH to catalyze the formation of 1,3,4-triphenylcyclopentene from cinnamaldehyde and chalcone in water. Deprotonation of IMes·HCl with NaOH forms the N-heterocyclic carbene IMes that reacts with cinnamaldehyde to form a homoenolate equivalent of cinnamate, which undergoes a conjugate addition to chalcone followed by an intramolecular aldol reaction to form a cyclopentane. Formation of a β-lactone and decarboxylation leads to 1,3,4-triphenylcyclopentene. This reaction introduces students to both organocatalysis and the use of carbonyl anion and homoenolate equivalents in synthesis. This novel and interesting chemistry was first reported in 2006, and the reaction was modified to be carried out in water under an air atmosphere in 2013. The very nonpolar product is easily purified chromatographically. The aliphatic protons form a somewhat complex pattern due to allylic and homoallylic coupling, but with no overlap, so...

A Dual Lewis Base Activation Strategy for Enantioselective Carbene-Catalyzed Annulations

A dual activation strategy integrating N-heterocyclic carbene (NHC) catalysis and a second Lewis base has been developed. NHC-bound homoenolate equivalents derived from α,β-unsaturated aldehydes combine with transient reactive o-quinone methides in an enantioselective formal [4 + 3] fashion to access 2-benzoxopinones. The overall approach provides a general blueprint for the integration of carbene catalysis with additional Lewis base activation modes.

Controlled β-protonation and [4+2] cycloaddition of enals and chalconesvia N-heterocyclic carbene/acid catalysis: toward substrate independent reaction control

A substrate-independent selective generation of enolates over homoenolate equivalents in NHC-catalyzed reactions of enals and chalcones is disclosed. Acid co-catalysts play vital roles in control of the reaction pathways, allowing for individual access to diverse products from identical substrates.

ChemInform Abstract: Lewis Acid Activated Synthesis of Highly Substituted Cyclopentanes by the N‐Heterocyclic Carbene Catalyzed Addition of Homoenolate Equivalents to Unsaturated Ketoesters.

AbstractThe use of Ti(O‐Pr)4 as a mild Lewis acid in combination with NHC catalysis is essential for the activation of α,β‐unsaturated aldehydes and promotion of the conjugate addition to ketoesters.

NHC-Catalyzed Addition of Homoenolate Equivalents to Unsaturated Keto Esters

A N-heterocyclic carbene catalyzed addition of homoenolate equivalents derived from enals 1 to unsaturated β,γ-unsaturated α-keto ­esters 2 has been reported. Lewis acidic Ti(Oi-Pr)4 was compatible with NHC catalysis and crucial for the formation of the desired products. N-heterocyclic carbene precatalyst 3 delivered substituted cyclopentanes 4 possessing four contiguous stereocenters in moderate to good yields with high diastereoselectivity and excellent enantio­selectivity.

Inside Cover: Lewis Acid Activated Synthesis of Highly Substituted Cyclopentanes by the N-Heterocyclic Carbene Catalyzed Addition of Homoenolate Equivalents to Unsaturated Ketoesters (Angew. Chem. Int. Ed. 7/2011)

Inside Cover: Lewis Acid Activated Synthesis of Highly Substituted Cyclopentanes by the N-Heterocyclic Carbene Catalyzed Addition of Homoenolate Equivalents to Unsaturated Ketoesters (Angew. Chem. Int. Ed. 7/2011)

Innentitelbild: Lewis Acid Activated Synthesis of Highly Substituted Cyclopentanes by the N‐Heterocyclic Carbene Catalyzed Addition of Homoenolate Equivalents to Unsaturated Ketoesters (Angew. Chem. 7/2011)

Innentitelbild: Lewis Acid Activated Synthesis of Highly Substituted Cyclopentanes by the N‐Heterocyclic Carbene Catalyzed Addition of Homoenolate Equivalents to Unsaturated Ketoesters (Angew. Chem. 7/2011)

Lewis acid activated synthesis of highly substituted cyclopentanes by the N-heterocyclic carbene catalyzed addition of homoenolate equivalents to unsaturated ketoesters.

Lewis acid activated synthesis of highly substituted cyclopentanes by the N-heterocyclic carbene catalyzed addition of homoenolate equivalents to unsaturated ketoesters.