Enantioenriched Compounds Research Articles

Enantioselective synthesis of dialkylated N-heterocycles by palladium-catalyzed allylic alkylation.

The enantioselective synthesis of α-disubstituted N-heterocyclic carbonyl compounds has been accomplished using palladium-catalyzed allylic alkylation. These catalytic conditions enable access to various heterocycles, such as morpholinone, thiomorpholinone, oxazolidin-4-one, 1,2-oxazepan-3-one, 1,3-oxazinan-4-one, and structurally related lactams, all bearing fully substituted α-positions. Broad functional group tolerance was explored at the α-position in the morpholinone series. We demonstrate the utility of this method by performing various transformations on our useful products to readily access a number of enantioenriched compounds.

ProPhenol-catalyzed asymmetric additions by spontaneously assembled dinuclear main group metal complexes.

ConspectusThe development of catalytic enantioselective transformations has been the focus of many research groups over the past half century and is of paramount importance to the pharmaceutical and agrochemical industries. Since the award of the Nobel Prize in 2001, the field of enantioselective transition metal catalysis has soared to new heights, with the development of more efficient catalysts and new catalytic transformations at increasing frequency. Furthermore, catalytic reactions that allow higher levels of redox- and step-economy are being developed. Thus, alternatives to asymmetric alkene dihydroxylation and the enantioselective reduction of α,β-unsaturated ketones can invoke more strategic C–C bond forming reactions, such as asymmetric aldol reactions of an aldehyde with α-hydroxyketone donors or enantioselective alkynylation of an aldehyde, respectively. To facilitate catalytic enantioselective addition reactions, including the aforementioned aldol and alkynylation reactions, our lab has developed the ProPhenol ligand.In this Account, we describe the development and application of the ProPhenol ligand for asymmetric additions of both carbon- and heteroatom-based nucleophiles to various electrophiles. The ProPhenol ligand spontaneously forms chiral dinuclear metal complexes when treated with an alkyl metal reagent, such as Et2Zn or Bu2Mg. The resulting complex contains both a Lewis acidic site to activate an electrophile and a Brønsted basic site to deprotonate a pronucleophile. Initially, our research focused on the use of Zn-ProPhenol complexes to facilitate the direct aldol reaction. Fine tuning of the reaction through ligand modification and the use of additives enabled the direct aldol reaction to proceed in high yields and stereoselectivities with a broad range of donor substrates, including acetophenones, methyl ynones, methyl vinyl ketone, acetone, α-hydroxy carbonyl compounds, and glycine Schiff bases. Additionally, an analogous magnesium ProPhenol complex was used to facilitate enantioselective diazoacetate aldol reactions with aryl, α,β-unsaturated, and aliphatic aldehydes.The utility of bimetallic ProPhenol catalysts was extended to asymmetric additions with a wide range of substrate combinations. Effective pronucleophiles include oxazolones, 2-furanone, nitroalkanes, pyrroles, 3-hydroxyoxindoles, alkynes, meso-1,3-diols, and dialkyl phosphine oxides. These substrates were found to be effective with a number of electrophiles, including aldehydes, imines, nitroalkenes, acyl silanes, vinyl benzoates, and α,β-unsaturated carbonyls. A truly diverse range of enantioenriched compounds have been prepared using the ProPhenol ligand, and the commercial availability of both ligand enantiomers makes it ideally suited for the synthesis of complex molecules. To date, enantioselective ProPhenol-catalyzed reactions have been used in the synthesis of more than 20 natural products.

Back Cover: Fluxionally Chiral DMAP Catalysts: Kinetic Resolution of Axially Chiral Biaryl Compounds (Angew. Chem. Int. Ed. 44/2014)

Place a pair of enantiomers in a box, wave a magic wand (a chiral catalyst), and two enantioenriched compounds pop out because of their differential interaction with the catalyst. In their Communication on page 11818 ff., M. P. Sibi et al. demonstrate that a novel 4-dimethylaminopyridine catalyst with fluxional chirality is efficient in promoting acylative kinetic resolution of axially chiral biaryl compounds with selectivities of up to 51:1.

Continuous Flow Enantioselective Three-Componentanti-Mannich Reactions Catalyzed by a Polymer-Supported Threonine Derivative

A series of primary amino acid-derived polystyrene-supported organocatalysts was tested in anti-selective Mannich reactions. The polystyrene-immobilized threonine derivative showed the best performance in three-component (hydroxyacetone, anilines, and aldehydes) Mannich reactions to provide anti-β-amino-α-hydroxycarbonyl compounds (11 examples; up to 95% ee), and its use could be extended to dihydroxyacetone and protected hydroxyacetones (7 examples; up to 90% ee). The high activity depicted by the catalyst has allowed its implementation in continuous flow. Under this operation mode, the supported threonine catalyst produces anti-Mannich adducts with generally higher diastereo- and enantioselectivity than in batch. A family of five different enantioenriched anti-Mannich adducts has been sequentially prepared in flow by passing different combinations of anilines and aromatic aldehydes over the same sample of catalyst. This confirms the suitability of this methodology for the rapid access to small libraries of enantioenriched compounds.

Chiral Phase Transfer Catalysts for the Synthesis of Chiral N‐Heterocycles viaAsymmetric Cascade Reactions

The effectiveness of a series of chiral phase transfer catalysts in cascade reactions of active methylene compounds with 2‐cyanobenzaldehyde leading to chiral 3‐substituted isoindolinones and fused benzoindolizidinones has been investigated. High yields and moderate enantiomeric excesses (e.e.s) were achieved employing a chiral phase‐transfer catalyst derived from bifunctional urea–quinine. Moreover, an efficient process of heterochiral crystallization, performed on moderately enantioenriched compounds, led to an impressive increase of the enantiopurity up to 93% e.e.s.

Correction to (DHQ)2AQN-Catalyzed Asymmetric Substitution of Isatin-Derived Hydrazones with O-Boc-Protected Morita–Baylis–Hillman Adducts: A Strategy for Synthesizing Enantioenriched Azo Compounds Incorporating an Oxindole Scaffold

Correction to (DHQ)₂AQN-Catalyzed Asymmetric Substitution of Isatin-Derived Hydrazones with O-Boc-Protected Morita–Baylis–Hillman Adducts: A Strategy for Synthesizing Enantioenriched Azo Compounds Incorporating an Oxindole Scaffold

ChemInform Abstract: Asymmetric Organocatalytic Protonation of Silyl Enolates Catalyzed by Simple and Original Betaines Derived from Cinchona Alkaloids.

The asymmetric protonation of silyl enolates derived from tetralone, benzosuberone, and cyclohexanone has been successfully achieved by using simple and original betaine catalysts derived from Cinchona alkaloids (quinine and quinidine series) to afford the desired α-substituted ketones in high yields and moderate enantioselectivities. The ease of implementation of this approach along with the easy accessibility of the betaine catalyst (four steps from cheap and commercially available quinine or quinidine) make this approach very appealing for the preparation of enantioenriched α-monosubstituted carbonyl compounds.

ChemInform Abstract: Enantioselective One‐Pot Catalytic Synthesis of 4,5‐Epoxy‐3‐alkanols and 1‐Phenyl‐2,3‐epoxy‐1‐alkanols from α,β‐Unsaturated Aldehydes.

AbstractOne‐pot asymmetric ethylation/epoxidation, and an unprecedented arylation/epoxidation of wide range of trisubstituted α,β‐unsaturated aldehydes is presented obtaining the title products including new enantioenriched compounds.

Enantio-, Diastereo-, and Regioselective Iridium-Catalyzed Asymmetric Allylic Alkylation of Acyclic β-Ketoesters

The first regio-, diastereo-, and enantioselective allylic alkylation of acyclic β-ketoesters to form vicinal tertiary and all-carbon quaternary stereocenters is reported. Critical to the successful development of this method was the employment of iridium catalysis in concert with N-aryl-phosphoramidite ligands. Broad functional group tolerance is observed at the keto-, ester-, and α-positions of the nucleophile. Various transformations demonstrating the utility of this method for rapidly accessing complex enantioenriched compounds are reported.

Catalytic Asymmetric Allylic Alkylation of 3‐Arylated Piperidin‐2‐ones

AbstractThe preparation of optically active lactams from 3‐aryl‐2‐piperidinone is reported. The quaternary carbon stereocentres were formed using palladium‐catalysed asymmetric allylic alkylation reactions. The resulting enantioenriched compounds are useful intermediates for the synthesis and development of neurokinin antagonists.

ChemInform Abstract: Catalytic Enantioselective Transformations of Borylated Substrates: Preparation and Synthetic Applications of Chiral Alkylboronates

Organoboronic acid derivatives are well-established intermediates for the prepara- tion of alcohols and amines, and in the formation of C-C bonds via different reactions, including homologations, carbonyl allylboration, or transition-metal-catalyzed cross-cou- pling chemistry. In the past decade, there has been great interest in the development of cat- alytic enantioselective methods for the preparation of chiral, optically enriched organoboronates as precursors of enantioenriched compounds. While the mainstream strat- egy remains the late-stage borylation of organic functional groups, our group has focused on an alternate strategy focused on modification of boron-containing substrates. In this way, acyclic and cyclic secondary alkyl - and allyl-boronates were prepared through catalytic enantio selective processes such as (4 + 2) cycloadditions, isomerizations, allylic substitu- tions, and conjugate additions. The resulting optically enriched boronates have been suc- cessfully utilized in the syntheses of complex natural products and drugs. One remaining challenge in the chemistry of secondary alkylboronate derivatives is their cross-coupling, especially with control of stereoselectivity. In this regard, our recent approach featured the conjugate asymmetric borylation of β-boronyl acrylates, providing the first enantioselective preparation of highly optically enriched 1,1-diboronyl derivatives. The chirality of these geminal diboron compounds is conferred through the use of two distinct boronate adducts, which can be coupled chemo- and stereoselectively with a variety of aryl and alkenyl halides under palladium catalysis.

ChemInform Abstract: Chirality Transfer and Memory of Chirality in Gold‐Catalyzed Reactions

AbstractReview: 38 refs.

ChemInform Abstract: Cooperative Bimetallic Catalysis in Asymmetric Transformations

AbstractReview: 80 refs.

Catalytic enantioselective transformations of borylated substrates: Preparation and synthetic applications of chiral alkylboronates

Organoboronic acid derivatives are well-established intermediates for the preparation of alcohols and amines, and in the formation of C–C bonds via different reactions, including homologations, carbonyl allylboration, or transition-metal-catalyzed cross-coupling chemistry. In the past decade, there has been great interest in the development of catalytic enantioselective methods for the preparation of chiral, optically enriched organoboronates as precursors of enantioenriched compounds. While the mainstream strategy remains the late-stage borylation of organic functional groups, our group has focused on an alternate strategy focused on modification of boron-containing substrates. In this way, acyclic and cyclic secondary alkyl- and allyl-boronates were prepared through catalytic enantioselective processes such as [4 + 2] cycloadditions, isomerizations, allylic substitutions, and conjugate additions. The resulting optically enriched boronates have been successfully utilized in the syntheses of complex natural products and drugs. One remaining challenge in the chemistry of secondary alkylboronate derivatives is their cross-coupling, especially with control of stereoselectivity. In this regard, our recent approach featured the conjugate asymmetric borylation of β-boronyl acrylates, providing the first enantioselective preparation of highly optically enriched 1,1-diboronyl derivatives. The chirality of these geminal diboron compounds is conferred through the use of two distinct boronate adducts, which can be coupled chemo- and stereoselectively with a variety of aryl and alkenyl halides under palladium catalysis.

Chirality Transfer and Memory of Chirality in Gold‐Catalyzed Reactions

Over the last few years, gold-catalyzed reactions that involved chirality transfer and memory of chirality (MOC) have emerged as a powerful tool in enantioselective synthesis. This technique has allowed for the single-step synthesis of enantioenriched compounds from readily available starting materials. This Focus Review discusses this emerging field with an emphasis on mechanistic aspects and their applications in synthetic organic chemistry.

Obtaining Enriched Compounds via a Tandem Enantioselective Reaction and Kinetic Resolution Polishing Sequence

Herein we describe a tandem method of coupling an enantioselective reaction with a nonenzymatic kinetic resolution to prepare highly enantioenriched compounds. The procedure employs a moderately selective enantioselective reaction on a ketone or aldehyde to form an enriched alcohol followed by a kinetic resolution of the alcohol to generate ee's of >99% in yields greater than what is possible with a kinetic resolution. This method highlights an avenue to quickly acquire highly enriched compounds without developing and optimizing a new methodology.

Cooperative bimetallic catalysis in asymmetric transformations

The efficient synthesis of enantioenriched compounds is becoming increasingly important in modern organic, pharmaceutical, and materials chemistry. Recently, chiral cooperative bimetallic catalysts have emerged as a powerful tool to achieve high efficiency and selectivity in asymmetric transformations. This tutorial review highlights strategies and recent advances in cooperative bimetallic catalysts which have been developed for a variety of asymmetric transformations.

ChemInform Abstract: Chiral N-Acyl-tert-butanesulfinamides: The “Safety-Catch” Principle Applied to Diastereoselective Enolate Alkylations.

Diastereoselective enolate alkylation reactions of N-acylsulfinamides and conversion of the alkylation products to a variety of enantiopure products are reported. Several sulfinamides were prepared in solution followed by acylation to provide N-acylsulfinamides. The N-acylsulfinamides were then evaluated in diastereoselective enolate alkylation reactions. Of the sulfinamides evaluated, tert-butanesulfinamide provided the highest diastereoselectivity. To establish the potential utility of sulfinamides as versatile auxiliaries, methods were developed for (1) the racemization-free acylation of tert-butanesulfinamide to prepare optically pure N-acyl-tert-butanesulfinamides, (2) the diastereoselective C-alkylation of N-acyl-tert-butanesulfinamides, (3) the conversion of the N-acyl-tert-butanesulfinamides to the active ester equivalent by N-alkylation and S-oxidation, and (4) the cleavage of the N-alkyl-N-acyl-tert-butanesulfonamides to give chiral alcohol, ester, amide, and carboxylic acid target compounds. These studies provide the groundwork for the development of sulfinamides as dual chiral auxiliaries and linkers for the multistep solid-phase synthesis of enantioenriched compounds.

Biocatalysed concurrent production of enantioenriched compounds through parallel interconnected kinetic asymmetric transformations

Parallel interconnected kinetic asymmetric transformations were performed in order to obtain enantioenriched derivatives starting from a set of racemic or prochiral compounds. Thus, in a one-pot reaction using two redox biocatalysts (a BVMO and an ADH) and a catalytic amount of cofactor that acts as a mediator, enantioenriched ketones, sulfoxides, and sec-alcohols were concurrently obtained in a strict parallel way, minimising the quantity of reagents employed. By selecting the appropriate biocatalysts, this methodology represents a potential tool for performing stereodivergent transformations.

Attempts to explain the self-disproportionation observed in the partial sublimation of enantiomerically enriched carboxylic acids

The partial sublimation of two carboxylic acids, the mandelic acid and ibuprofen has been studied. Many ( RS) + ( S) samples with various enantiomeric excesses ( ee) have been slowly and partially sublimed at a low temperature and the sublimates have been condensed before analysis. About 1% of the starting material was sublimed in each experiment. The results are reproducible showing that the sublimation is under control. The ee of sublimates are comparable to the ee of the eutectic but also to those obtained by mixing the sublimates of two apparatuses used to sublime separately the racemate and the enantiomer. Thus, the sublimations of both carboxylic acids could be controlled by the saturated vapor pressure of the components (( RS) and ( S)) or, as usually proposed, by the formation of a gas phase with a eutectic composition. In the case of mandelic acid, a definitive answer has been given by the partial sublimation of ( S) + ( R) solid mixtures where sublimates with a eutectic composition have been obtained and without any indication of the sublimation of a “kinetic conglomerate”. This study paves the way for future investigations on the slow and partial sublimation of enantioenriched compounds to determine how this latter occurs.