High Enantio Research Articles

Enantio- and Diastereoselective Desymmetrization of 1,1'-Biaryl-2,6-Dicarbaldehydes by Copper-Catalyzed 1,2-Addition of Silicon Nucleophiles.

A desymmetrizing 1,2-addition of silicon nucleophiles to biaryl derivatives containing an 2,6-dicarbaldehyde-1-yl unit is reported. The reaction is catalyzed by copper with a triazolium-ion-derived N-heterocyclic carbene as the chiral ligand and makes use of an Si-B reagent as the silicon pronucleophile. The practical methodology furnishes axially chiral aromatic carbaldehydes decorated with a centrally chiral α-hydroxysilane moiety in moderate to good yields and with high enantio- as well as excellent diastereoselectivities. The silicon nucleophile always attacks at the diastereotopic face of either carbonyl group away from the ortho substituent on the phenyl ring at C1 of the 2,6-dicarbaldehyde-1-yl fragment. The resulting axially and centrally chiral products can be further converted into valuable biaryl compounds with hardly any erosion of the enantiomeric excess.

Catalytic, Enantioselective Cycloaddition of Pyrrole-2-methides with Aldehydes toward a Synthesis of 2,3-Dihydro-1H-pyrrolizin-3-ols.

An organocatalytic, highly enantioselective [6 + 2]-cycloaddition of 2-methide-2H-pyrroles with aryl acetaldehydes represents a novel and straightforward route toward densely substituted 2,3-dihydro-1H-pyrrolizin-3-ols, which were generated with good yields and high enantio- and diastereoselectivity. This one-step process involves a BINOL-phosphoric acid catalyzed reaction of 1H-pyrrole-2-carbinols with aryl acetaldehydes via the corresponding hydrogen-bonded, chiral 2-methide-2H-pyrroles.

Synthesis of Chiral Endocyclic Allenes and Alkynes via Pd-Catalyzed Asymmetric Higher-Order Dipolar Cycloaddition.

A Pd-catalyzed asymmetric higher-order dipolar cycloaddition between allenyl carbonates and azadienes is achieved by exploiting novel alkylidene-π-allyl-Pd dipoles. This research provides a modular platform for the synthesis of challenging chiral endocyclic allenes bearing a medium-sized heterocyclic motif and a centrally chiral stereocenter in good yields with high enantio- and diastereoselectivities (29 examples, up to 97% yield, 97:3 er and >19:1 dr). Experimental and computational studies elucidate the possible reaction mechanism and the observed stereochemical results. Based on the mechanistic understanding, a new π-propargyl-Pd dipole was designed to further extend the success of the higher order dipolar cycloaddition strategy to the synthesis of 10-membered endocyclic alkynes from propargyl carbonates and azadienes (13 examples, up to 98% yield and 94.5:5.5 er).

One-Pot Access to Functionalised Malamides via Organocatalytic Enantioselective Formation of Spirocyclic β-Lactone-Oxindoles and Double Ring-Opening.

Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein, an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic β-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the β-lactone and oxindole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereo-selectivity (up to >95:5 dr and >99:1 er).

Enzymatic Synthesis of Unprotected α,β-Diamino Acids via Direct Asymmetric Mannich Reactions.

α,β-Diamino acids are important structural motifs and building blocks for numerous bioactive natural products, peptidomimetics, and pharmaceuticals, yet efficient asymmetric synthesis to access these stereoarrays remains a challenge. Herein, we report the development of a pyridoxal 5'-phosphate (PLP)-dependent enzyme that is engineered to catalyze stereoselective Mannich-type reactions between free α-amino acids and enolizable cyclic imines. This biocatalyst enabled one-step asymmetric enzymatic synthesis of the unusual pyrrolidine-containing amino acid L-tambroline at gram-scale with high enantio- and diastereocontrol. Furthermore, this enzymatic platform is capable of utilizing a diverse range of α-amino acids as the Mannich donor and various cyclic imines as the acceptor. By coupling with different imine-generating enzymes, we established versatile biocatalytic cascades and demonstrated a general, concise, versatile, and atom-economic approach to access unprotected α,β-diamino acids, including structurally complex α,α-disubstituted α,β-diamino acids with contiguous stereocenters.

Copper-Catalyzed Asymmetric Kinugasa/Michael Addition Cascade Reactions for the Synthesis of Chiral Spiro β-Lactams.

A mild copper-catalyzed asymmetric Kinugasa/Michael addition cascade process is developed. The reaction of α, β-unsaturated ester-tethered propiolamides with nitrones provides an efficient protocol for the construction of functionalized chiral 2,6-diazaspiro[3.4]octane-1,5-dione products in satisfactory yields and with high enantio- and diastereoselectivities.

α-Alkylation and Asymmetric Transfer Hydrogenation of Tetralone via Hydrogen Borrowing and Dynamic Kinetic Resolution Strategy Using a Single Iridium(III) Complex.

Here we present a novel strategy for the synthesis of enantiomerically enriched tetrahydronaphthalen-1-ols. The reaction proceeds via an alkylation (via hydrogen borrowing) and ammonium formate-mediated asymmetric transfer hydrogenation (via dynamic kinetic resolution), giving alkylated tetralols in high yields and good enantio- and diastereoselectivity across a diverse range of both alcohol and tetralone substrates. Additionally, these products were successfully derivatized to several complex molecules, demonstrating the utility of the tetrahydronaphthalen-1-ol.

Synthesis of S(IV)-Stereogenic Chiral Thio-Oxazolidinones via Palladium-Catalyzed Asymmetric [3+2] Annulations.

Organic molecules bearing chiral sulfur stereocenters exert a great impact on asymmetric catalysis and synthesis, chiral drugs, and chiral materials. Compared with acyclic ones, the catalytic asymmetric synthesis of thio-heterocycles has largely lagged behind due to the lack of efficient synthetic strategies. Here we establish the first modular platform to access chiral thio-oxazolidinones via Pd-catalyzed asymmetric [3+2] annulations of vinylethylene carbonates with sulfinylanilines. This protocol is featured by readily available starting materials, and high enantio- and diastereoselectivity. In particular, an unusual effect of a non-chiral supporting ligand on the diastereoselectivity was observed. Possible reaction mechanisms and stereocontrol models were proposed.

Incorporation of Chiral Frustrated Lewis Pair into Metal-Organic Framework with Tailored Microenvironment for Heterogeneous Enantio- and Chemoselective Hydrogenation.

The development of efficient heterogeneous catalysts with multiselectivity (e.g., enantio- and chemoselectivity) has long been sought after but with limited progress being made so far. To achieve enantio- and chemoselectivity in a heterogeneous system, as inspired by enzymes, we illustrate herein an approach of creating an enzyme-mimic region (EMR) within the nanospace of a metal-organic framework (MOF) as exemplified in the context of incorporating a chiral frustrated Lewis pair (CFLP) into a MOF with a tailored pore environment. Due to the high density of the EMR featuring the active site of CFLP and auxiliary sites of the hydroxyl group/open metal site within the vicinity of CFLP, the resultant EMR@MOF demonstrated excellent catalysis performance in heterogeneous hydrogenation of α,β-unsaturated imines to afford chiral β-unsaturated amines with high yields and high enantio- and chemoselectivity. The role of the hydroxyl group/open metal site in regulating chemoselectivity was proved by the observation of a catalyst-substrate interaction experimentally, which was also rationalized by computational results. This work not only contributes a MOF as a new platform for multiselective catalysis but also opens a promising avenue to develop heterogeneous catalysts with multiselectivity for challenging yet important transformations.

Discovery and Development of the Enantioselective Minisci Reaction.

ConspectusThe class of reactions now known as Minisci reactions is broadly defined as the addition of nucleophilic carbon-based radicals to basic heteroarenes with subsequent rearomatization to form a new carbon-carbon bond. Since the pioneering work of Minisci in the 1960s and 1970s, these reactions are now widely used in medicinal chemistry due to the ubiquity of basic heterocycles in druglike molecules. One of the long-standing challenges of Minisci chemistry has been that of regioselectivity due to the mixtures of positional isomers commonly obtained on many substrates if there is a choice between similarly activated sites. At the outset of the work described herein, we hypothesized that it may be possible to tackle this using a catalytic strategy whereby a bifunctional Brønsted acid catalyst simultaneously activates the heteroarene and engages attractive non-covalent interactions with the incoming nucleophile, resulting in a proximal attack. Using chiral BINOL-derived phosphoric acids, we not only were able to achieve this goal of regiocontrol but also discovered that we could control the absolute stereochemistry at the new stereocenter formed when prochiral α-amino radicals were employed. At the time, this discovery was unprecedented in the context of Minisci reactions.This Account details the discovery of this protocol and the further development, expansion, and investigations into the mechanism that we have carried out since then, several in collaboration with other research groups. Collaborative efforts have involved an expansion of the scope to diazines guided by multivariate statistical analysis through the development of a predictive model (collaboration with Sigman). Also, a mechanistic study involving detailed DFT analysis (collaboration with Goodman and Ermanis) unveiled the selectivity-determining step as being the deprotonation of a key cationic radical intermediate by the associated chiral phosphate anion. We have additionally carried out a number of synthetic developments of the protocol such as removing the need to prefunctionalize the radical nucleophile; hydrogen-atom transfer can be used to enable a formal coupling of two C-H bonds to form a C-C bond while retaining high enantio- and regioselectivity. Most recently, we have been able to expand the protocol so that α-hydroxy radicals can be used: until this point, all examples had concerned α-amino radicals. Again, HAT was used to generate the α-hydroxy radicals, and DFT studies carried out in collaboration (Ermanis) provided mechanistic insights.Since our original report, there have appeared a number of exciting developments from other research groups whereby the protocol has been applied to new substrates or using different precursors to generate the requisite α-amino radical. There have also been several examples in which alternative photocatalyst systems have been used to reduce the redox-active esters in the original enantioselective Minisci protocol. While primarily an Account, these contributions from other research groups will be covered briefly for context toward the end of the article.

Three-Component Approach to Densely Functionalized Trifluoromethyl Allenols by Asymmetric Organocatalysis.

We have developed a new three-component catalytic coupling reaction of alkynyl boronates, diazomethanes, and aliphatic/aromatic ketones in the presence of BINOL derivatives. The reaction proceeds with a remarkably high enantio- and diastereoselectivity (up to three contiguous stereocenters) affording tertiary CF3-allenols in a single operational step. The reaction proceeds under mild, neutral, metal-free conditions, which leads to a high level of functional group tolerance.

Construction of Acyclic All-Carbon Quaternary Stereocenters and 1,3-Nonadjacent Stereoelements via Organo/Metal Dual Catalyzed Asymmetric Allenylic Substitution of Aldehydes.

A method for the asymmetric construction of functionalized acyclic all-carbon quaternary stereocenters and 1,3-nonadjacent stereoelements has been developed via organo/metal dual catalyzed asymmetric allenylic substitution of branched and linear aldehydes, by developing an unknown acyclic secondary-secondary diamine as the enabling organocatalyst. Although it is believed that secondary-secondary diamines are difficult to be used as the organocatalysts in organo/metal dual catalysis, this study demonstrates that such diamines can be successfully combined with a metal catalyst in organo/metal dual catalysis. Our study enables the asymmetric construction of two important classes of motifs which were previously difficult to access, axially chiral allene-containing acyclic all-carbon quaternary stereocenters and 1,3-nonadjacent stereoelements bearing allenyl axial chirality and central chirality, in good yields with high enantio- and diastereoselectivity.

Cooperative Asymmetric Dual Catalysis Involving a Chiral N-Heterocyclic Carbene Organocatalyst and Palladium in an Annulation Reaction: Mechanism and Origin of Stereoselectivity

The increasing number of examples on cooperative dual catalysis involving organocatalysts and transition metal catalysts indicate their wider acceptance and utility in synthetic applications. In such reactions, the concurrent activation of substrates is likely to present mechanistic complexities. In one of the studies, designed for intermolecular annulation aimed at making a biologically important class of benzazepines, chiral N-heterocyclic carbenes engage an enal in the form of a Breslow intermediate (nucleophilic partner) and Pd(0) activates rac-vinyl benzoxazinanone as a Pd-π-allyl intermediate (electrophile). Given the current importance and the lack of molecular insights on the origin of high enantio-/diastereoselectivities and cooperativity in such dual catalytic reactions, we have undertaken a detailed computational investigation using density functional theory. The kinetically most accessible Pd-π-allyl intermediate from the (S)- and (R)-vinyl benzoxazinanone is found to be Cre and Csi (where re and si denote the open prochiral faces through which the nucleophile can add), respectively. An energetically favorable change in configuration from Csi to Cre, via a PPh3-induced π–σ–π isomerization, suggests that an enantioconvergent mechanism was responsible for the enrichment of the desired Cre Pd-π-allyl species. Ready availability of Cre and the higher energy transition state (TS) for the alternative nucleophilic addition to the Csi is responsible for the high ee (computed >99%, experimental 99%). Improved shape complementarity between the chiral electrophile and nucleophile in the most preferred C–C bond formation TS as well as the noncovalent interactions (C–H··· π, π···π, and H-bonding) therein dictates the diastereoselectivity. An intramolecular C–N bond formation to the final annulated product is the turnover-determining TS. Molecular insights and energetic features, as obtained through our computations, are found to be in concert with several experimental observations, even beyond the sense and extent of stereoselectivities.

Cobalt-catalyzed enantioselective C-H/N-H annulation of aryl sulfonamides with allenes or alkynes: facile access to C-N axially chiral sultams.

Herein we report a cobalt-catalyzed enantioselective C-H/N-H annulation of aryl sulfonamides with allenes and alkynes, using either chemical or electrochemical oxidation. By using O2 as the oxidant, the annulation with allenes proceeds efficiently with a low catalyst/ligand loading of 5 mol% and tolerates a wide range of allenes, including 2,3-butadienoate, allenylphosphonate, and phenylallene, resulting in C-N axially chiral sultams with high enantio-, regio-, and position selectivities. The annulation with alkynes also exhibits excellent enantiocontrol (up to >99% ee) with a variety of functional aryl sulfonamides, and internal and terminal alkynes. Furthermore, electrochemical oxidative C-H/N-H annulation with alkynes is achieved in a simple undivided cell, demonstrating the versatility and robustness of the cobalt/Salox system. The gram-scale synthesis and asymmetric catalysis further highlight the practical utility of this method.

Stereodivergent Construction of Csp3 -Csp3 Bonds Bearing Vicinal Stereocenters by Synergistic Palladium and Phase-Transfer Catalysis.

Synergistic catalysis has emerged as one of the most powerful tools for stereodivergent formation of Csp3 -Csp3 bonds bearing vicinal stereocenters. Despite the many successes that have been achieved in this field, stereodivergent Csp3 -Csp3 coupling reactions involving stabilized nucleophiles remain challenging because of the competing single-catalysis pathway. Herein, we report a synergistic palladium/phase-transfer catalyst system that enables diastereodivergent Csp3 -Csp3 coupling reactions of 1,3-dienes with stabilized nucleophile oxindoles. Both the syn and anti coupling products, bearing quaternary and tertiary vicinal stereocenters, could be selectively produced in good yields with high enantio- and diastereoselectivities. Non-covalent activation of the stabilized nucleophile via chiral ion pair in a biphasic system is a crucial success factor in achieving diastereodivergence.

Asymmetric Synthesis of Isotopic Atropisomers based on ortho-CH3/CD3 Discrimination and Their Structural Properties.

N-C axially chiral 3-(2-trideuteriomethyl-4,6-dimethylphenyl)-2-ethylquinazolin-4-ones and 3-(2-trideuteriomethyl-4,6-dimethylphenyl)-2-(1-phenylpropan-2-yl)quinazolin-4-ones were prepared in high enantio- and diastereomeric purities (98% ee). These quinazolinone derivatives are isotopic atropisomers based on ortho-CH3/CD3 discrimination and were revealed to possess a slight optical rotation and high rotational stability.

Cooperative Pd/Cu-catalyzed diastereodivergent coupling of allenamides and aldimine esters to access the Mannich-type motifs

Mannich reaction is a significant transformation to prepare chiral amines from imine; however, vinylimines are still unaddressed substrates in this transformation due to the inherent competition between the Mannich and Michael addition. Herein we report a cooperative Pd/Cu-catalyzed enantioselective coupling of allenamides with aldimine esters for expeditious access to Mannich-type motifs α,β-diamino esters. The reaction has excellent regioselectivity, and by selecting the combinations of Pd and Cu catalysts with appropriate chiralities, both the syn- and anti- coupling products could be selectively prepared with high enantio-, diastereoselectivities. This work represents a rare example of employing cooperative catalysis for achieving diastereodivergent Mannich-type coupling reaction and would inspire further studies in this field. • Formal Mannich reaction of vinylimines • Cooperative palladium/copper catalysis-enabled stereodivergent coupling • Access all four stereoisomers of α,β-diamino esters Mannich reaction is among the most useful methods in preparing chiral amine compounds. Despite the huge success in catalytic enantioselective Mannich reaction, diastereodivergent preparing both syn- and anti- Mannich products from the same set of substrates is still underdeveloped. On the other hand, due to the inherent regioselectivity issue (Mannich versus Michael addition), vinylimines are still less-solved challenging substrates in Mannich reaction. We report a cooperative Pd/Cu-catalyzed enantioselective coupling of allenamides with aldimine esters for access to Mannich-type motifs α,β-diamino esters. By choosing the appropriate combination of chiralities of Pd and Cu catalysts, diastereodivergent access to both the syn - and anti -coupling products could be achieved with good regio-, diastereo-, and enantioselectivities. This work sheds light on using cooperative catalysis to achieve Mannich-type motifs in a diastereodivergent manner. Zi et al. describe a cooperative Pd/Cu catalyst system for diastereodivergent coupling of allenamides with aldimine esters, which provides a formal Mannich-type reaction of vinylimines. By choosing the appropriate combination of chiralities of Pd and Cu catalysts, all four stereoisomers of α,β-diamino esters could be selectively achieved with high enantio- and diastereoselectivities.

Catalytic Desymmetric Dicarbofunctionalization of Unactivated Alkenes.

The construction of multi-stereocenters by a transition metal-catalyzed cross-coupling reaction is a major challenge. The catalytic desymmetric functionalization of unactivated alkenes remains largely unexplored. Herein, we disclose -a desymmetric dicarbofunctionalization of 1,6-dienes via a nickel-catalyzed reductive cross-coupling reaction. The leverage of the underdeveloped chiral 8-Quinox enables the Ni-catalyzed desymmetric carbamoylalkylation of both unactivated mono- and disubstituted alkenes to form pyrrolidinone bearing two nonadjacent stereogenic centers in high enantio- and stereoselectivitives with broad functional-group tolerance. The synthetic application of pyrrolidinones allows the rapid access to complex chiral fused-heterocycles.

Differentiating Catalysis in the Dearomative [4 + 2]-Cycloaddition Involving Enals and Heteroaromatic Aldehydes.

In this paper, the application of differentiating catalysis in the [4 + 2]-cycloaddition between 2-alkyl-3-formylheteroarenes and α,β-unsaturated aldehydes is described. Within the developed approach, the same aminocatalyst is employed for the independent activation of both starting materials, differentiating their properties via LUMO-lowering and HOMO-rising principles. By the combination of dearomative dienamine activation with iminium ion chemistry high enantio- and diastereoselectivity of the doubly asymmetric process was accomplished. Selected transformations of products were also demonstrated.

Organo-catalysis as emerging tools in organic synthesis: aldol and Michael reactions

Abstract Organocatalysis has occupied sustainable position in organic synthesis as a powerful tool for the synthesis of enantiomeric-rich compounds with multiple stereogenic centers. Among the various organic molecules for organocatalysis, the formation of carbon–carbon is viewed as a challenging issue in organic synthesis. The asymmetric aldol and Michael addition reactions are the most significant methods for C–C bond forming reactions. These protocols deliver a valuable path to access chiral molecules, which are useful synthetic hybrids in biologically potent candidates and desirable versatile pharmaceutical intermediates. This work highlighted the impact of organocatalytic aldol and Michael addition reactions in abundant solvent media. It focused on the crucial methods to construct valuable molecules with high enantio- and diastereo-selectivity.