Quaternary Stereocenters Research Articles

Chiral Biaryl N-Heterocyclic Carbene-Palladium Catalysts with Anagostic C-H···Pd Interaction for Enantioselective Desymmetric C-N Cross-Coupling.

Novel chiral biaryl imidazo[1,5-a]pyridine carbene-palladium complexes (ImPy-Pd) featuring an anagostic C-H···Pd interaction and a C5-aryl substituent have been developed and successfully applied to the Pd-catalyzed enantioselective desymmetric C-N cross-coupling of malonamide derivatives, providing chiral 3,4-dihydroquinoline-2-ones with quaternary stereocenters in high yields (≤99%) and enantioselectivities (≤97:3 er). The chiral catalyst exerts stereocontrol by restricting the rotation of substituents around the metal center through anagostic interactions with sterically bulky substituents.

Asymmetric Synthesis of Polycyclic Heterocyclic Compounds via Friedel-Crafts Reaction/Cyclization Reaction Catalyzed by Nickel Catalyst.

The first highly enantioselective asymmetric Friedel-Crafts reaction/cyclization reaction of 5-aminopyrazoles with 3-alkenyloxindoles to afford polycyclic heterocyclic compounds bearing an all-carbon quaternary stereocenter catalyzed by a complex of NiII with the C2-symmetric bipyridine-N,N'-dioxide ligand L12 has been developed. The relevant products with a wide range of substrates and good functional tolerance were obtained in 89-98% yield with 56-99% ee in the presence of 10 mol % Ni(OTf)2 and 11 mol % L12 in DCM at 25 °C. Moreover, an experiment on scaling up the process along with the transformations of the cycloadducts further emphasized the practical application of the synthesis.

Rhodium‐Catalyzed Asymmetric Cyclopropanation of Indoles with N‐Triftosylhydrazones

AbstractHerein we report a general rhodium‐catalyzed asymmetric intermolecular dearomative cyclopropanation of indoles using trifluoromethyl N‐triftosylhydrazones as carbene precursors. The reaction enables the rapid construction of diverse cyclopropane‐fused indolines bearing a trifluoromethylated quaternary stereocenter with high enantioselectivity (up to 99 % ee). This mild method exhibits broad substrate scope, tolerating various functional groups, and can even be utilized for the late‐stage diversification of complex bioactive molecules. DFT calculations suggest that the formation of a key zwitterionic intermediate is responsible for the chiral induction. Overall, this approach opens up new possibilities for asymmetric cyclopropanation of challenging aromatic heterocyclic compounds.

6π 1,5-Diaza-electrocyclization of Isatin, α-Ketoester Derived Hydrazones with α,β-Unsaturated Ketoesters, Ketones, and Aldehydes Enables Functionalized Pyrazoles.

A novel and efficient 6π 1,5-diaza-electrocyclization of readily available isatin, α-ketoester derived hydrazones with α,β-unsaturated ketoesters, ketones, and aldehydes has been developed. A series of functionalized pyrazoles bearing an oxindole unit were easily afforded by this tool with good yields and high functional group tolerance under mild conditions. Importantly, the obtained pyrazole could be further converted to 3-pyrazolecarboxylic acid with a quaternary carbon stereocenter.

A Base Promoted [3+2] Cycloaddition of Benzothiazolium Salts with Isoindigos to Synthesis N, S‐polyheterocyclic 3, 3′ Bispirooxindoles

A base promoted [3+2] cycloaddition of benzothiazolium salts with isoindigos has been developed, and a series of nove N, S‐polyheterocyclic 3, 3′ bispirooxindoles with four contiguous cycles and two spiro quaternary stereocenters have been successfully and effectively prepared in good to excellent yields (up to 99%) under mild conditions.

Pentafluorosulfanylation of Acrylamides: The Synthesis of SF5-Containing Isoquinolinediones with SF5Cl.

We disclose herein an efficient and facile method for the synthesis of SF5-containing isoquinolinediones with an all-carbon quaternary stereocenter via intramolecular pentafluorosulfanylation of acrylamides using SF5Cl as a pentafluorosulfanylation reagent. The protocol proceeds under mild reaction conditions and enjoys a broad substrate scope, wide functional group compatibility, and high atom- and step-economy. A radical mechanism involving the SF5 radical cascade addition/cyclization of acrylamides is proposed.

Construction of Dihydropyrano[2,3‐c]pyrazolone via Photo‐induced Wolff Rearrangement/Chiral Isothiourea Catalyzed [4+2] Cyclization Reaction

AbstractA photoinduced Wolff rearrangement/chiral isothiourea catalyzed [4+2] cycloaddition reaction of pyrazolone derivatives and α‐diazoketones was developed, affording the corresponding dihydropyrano[2,3‐c]pyrazolone derivatives in moderate to good yields (50–94 %) with satisfactory to excellent diastereoselectivities (>20 : 1 dr, in almost all cases) and enantioselectivities of 31–99 %. This protocol features readily available substrates, mild reaction conditions, and effective construction of vicinal tertiary and quaternary carbon stereocenters.

Asymmetric Synthesis of Benzofuranones with a C3 Quaternary Center via an Addition/Cyclization Cascade Using Noncovalent N-Heterocyclic Carbene Catalysis.

An asymmetric addition/cyclization cascade of amidoesters and iminoquinones is developed using noncovalent N-heterocyclic carbene (NHC) catalysis. The process enables access to various functionalized benzofuranones with an all-carbon quaternary stereocenter with high yields and ee values. The reaction displays a broad substrate scope. Via product modifications, enantioenriched synthesis of biologically relevant spirocyclic lactones and lactams is achieved. Substrate activation via noncovalent interaction with NHC is suggested for the process.

Stereoselective Construction of Less-Accessible Acyclic Quaternary Carbon Stereocenters via Rhodium-Catalyzed Allylic Alkylation of β,β-Disubstituted Enesulfinamides.

In the presence of Wilkinson's catalyst, the N-sulfinyl metalloenamines derived from NH-deprotonation of β,β-disubstituted enesulfinamides undergo nucleophilic allylic substitution with allyl carbonate, affording α-allylated ketimines with high stereoselectivity. These allylation products possess challenging acyclic quaternary stereocenters containing one allyl group and two alkyl groups that are both sterically and electronically similar (e.g., Me and Et). By utilizing appropriate stereoisomers of enesulfinamides, it becomes feasible to selectively access each of the four potential stereoisomers of the allylation products, thereby facilitating the selective synthesis of stereoisomers of α-tertiary chiral amines featuring a β-quaternary stereocenter through imino nucleophilic addition.

--Steric Activation in the Nazarov Cyclization of Fully Substituted Divinyl Ketones.

Fully substituted divinyl ketones (fsDVKs) have long been regarded as resistant to Nazarov cyclization (NC) unless they contain strategically positioned electronically-activating substituents. Here, however, we show that fsDVKs bearing only electronically neutral alkyl or aryl groups actually undergo facile NC due to steric-crowding in the pentadienyl cation intermediate, which raises its energy and reduces the barrier height to cyclization. Strongly ionizing and suitably bulky acid moieties further increase the energy of this intermediate cation, favoring cyclization. These features enable NCs of fsDVKs to be employed in the ready construction of multiple contiguous all-carbon quaternary stereocenters under mild conditions, in the absence of electronically activating groups.

Asymmetric one-carbon ring expansion of diverse N-heterocycles via copper-catalyzed diyne cyclization.

One-carbon ring expansion reaction of N-heterocycles has gained particular attention in the past decade because this method allows for the conversion of readily available N-heterocycles into potentially useful complex ring-expanded N-heterocycles, which are inaccessible by traditional methods. However, the catalytic asymmetric variant of this reaction has been rarely reported to date. Herein, we disclose an enantioselective one-carbon ring expansion reaction through chiral copper-catalyzed diyne cyclization, leading to the practical, atom-economic and divergent assembly of an array of valuable chiral N-heterocycles bearing a quaternary stereocenter in generally good to excellent yields with excellent enantioselectivities (up to >99% ee). This protocol represents the first example of asymmetric one-carbon ring expansion reaction of N-heterocycles based on alkynes.

New Synthetic Approaches for the Construction of Enantioenriched Molecules Bearing Quaternary Stereocenters

AbstractOptically active molecule architectures stand as an important class of organic compounds and occupy a key role in academic and industrial communities. Particularly, the molecules bearing quaternary carbon are of vital importance because of its favorable conformation and valuable three‐dimensional molecules, which frequently play a key role in a broad spectrum of functional materials, pharmaceutical relevant natural molecules, and agrochemicals. Over the past few decades, a large number of synthetic strategies for the enantioselective construction of compounds with chiral quaternary carbon centers have been the focus of a number of research initiatives. In this review, the state‐of‐the‐art toward the synthesis of enantioenriched molecules bearing quaternary stereocenters are summarized, which could be segmented into four categories: 1) Construction of optically active quaternary carbon centers by addition to prochiral sp2 carbon; 2) Construction of optically active all‐carbon quaternary stereocenters via substitution at non‐chiral tetra‐substituted carbon; 3) Construction of optically active all‐carbon quaternary stereocenters via kinetic resolution; 4) Construction of optically active all‐carbon quaternary stereocenters via desymmetrization reactions.

Total Synthesis of the Humulene‐Derived Sesquiterpenoid (‐)‐Integrifolian‐1,5‐dione

AbstractThe oxygenated sesquiterpenoid (‐)‐integrifolian‐1,5‐dione, which originates from a plant that finds widespread use in South American traditional medicine, is distinguished by a rigid bicyclic framework consisting of a cyclopropane that is cis‐annulated to a cyclodecane ring. The first total synthesis of this demanding target is described, which relies on a highly selective cyclopropanation reaction of an α‐stannylated‐α‐diazoester catalyzed by a heteroleptic dirhodium paddlewheel complex, followed by an unprecedented Stille‐type cross coupling of the resulting stannylated cyclopropane with methyl iodide as the electrophilic partner to form the all‐carbon quaternary stereocenter at one of the bridgehead positions. Equally decisive was the bicyclization strategy based on lactonization/ring expansion that ultimately allowed the strained ten‐membered carbocycle to be forged.

Conjugate Addition of 3‐Aryl Oxindoles to in situ generated o‐ Quinone Methides Without Essential Electronic or Steric Groups

Herein an efficient method for in situ generated o‐quinone methides without essential electronic or steric groups at the exocyclic methylene or on six‐membered ring was established. The method relies on acetylation of salicylylols and subsequently base promoted 1,4‐elimination. The in situ generated o‐quinone methides could be undergoing conjugate addition with 3‐aryl oxindoles in one‐pot reaction system, which provided 3,3‐disubstituted oxindoles bearing a quaternary stereocenter in good yields (up to 99%).

Rhodium-Catalyzed Asymmetric Cyclopropanation of Indoles with N-Triftosylhydrazones.

Here we report a general rhodium-catalyzed asymmetric intermolecular dearomative cyclopropanation of indoles using trifluoromethyl N-triftosylhydrazones as carbene precursors. The reaction enables the rapid construction of diverse cyclopropane fused indolines bearing a trifluoromethylated quaternary stereocenter in high enantioselectivities (up to 99% ee). This mild method exhibits a broad substrate scope, is compatible with various functional groups, and can even be utilized for the late-stage diversification of complex bioactive molecules. DFT calculations suggest that the formation of a key zwitterionic intermediate is responsible for the chiral induction. Overall, this approach opens up new possibilities for asymmetric cyclopropanation of challenging aromatic heterocyclic compounds.

Diastereoselective Stereo-Divergent Synthesis of Spiroindolines via Ligand-Controlled Silver(I)-Catalyzed Asymmetric [3 + 2] cycloadditions

A series of spirocyclic pyrrolidine derivatives with quaternary stereocenters was constructed via asymmetric [3 + 2] cycloaddition reactions between imino esters and 2-oxindole. By ingenious use of ligands on the silver catalyst allows stereoselectivity to either endo-isomers (ee up to 98 %, yields up to 96 %) with (R, Rp)-Ph-Phosferrox or exo-isomers (ee up to 99 %, yields up to 87 %) with (R)-BINAP. This work is notable for its high yields, broad substrate adaptability and excellent enantioselectivity.

Evolution of the Short Enantioselective Total Synthesis of the Unique Marine Myxobacteria Polyketide Salimabromide

Comprehensive SummarySalimabromide, a unique and scarce marine tetracyclic polyketide, was synthesized in both racemic and optically active forms. A novel carboxylic acid‐directed method for tandem oxidative difunctionalization of olefins was developed, whereby the formation of bridged butyrolactone and enone moieties occurs concurrently. Density functional theory (DFT) calculations indicate that this reaction follows a [3+2] process rather than the [2+2] process. In the meantime, the distinctive benzo‐fused [4.3.1] carbon skeleton and highly hindered vicinal quaternary stereocenters were simultaneously constructed through a challenging intramolecular Giese‐Baran radical cyclization. Furthermore, deuterium kinetic isotopic effects were utilized to enhance the efficacy of this pivotal step. This represents a new illustration of the application of kinetic isotope effects in natural product synthesis. Then, the short asymmetric synthesis of (+)‐salimabromide (13 or 15 steps) was accomplished by combing this method with rhodium‐catalyzed enantioselective hydrogenation of a cycloheptenone derivative (97% ee) or conjugate addition of an aryl boronic acid with 2‐cyclohepten‐1‐one (> 99% ee).

Sulfone as traceless activating group: Divergent synthesis of α-fluoroamides with C–F quaternary stereocenters

A novel approach to α-fluoroamides bearing a C–F quaternary stereocenter is reported herein. With sulfone installed as the activating group, an alkyl group as well as a fluorine atom was introduced successively under mild conditions. Subsequently, heterolytic fission of the C–S bond occurred smoothly under photoredox conditions to afford a tertiary radical, which then engaged in varied intramolecular cyclizations depending on substrate structure and condition applied, rendering sulfone an overall traceless activating group.

Asymmetric Intermolecular Conjugate Addition of 3-Substituted 2-Benzofuranones to Maleimides via Noncovalent NHC Catalysis

AbstractAn efficient N-heterocyclic carbene (NHC)-catalyzed asymmetric conjugate addition reaction to afford synthetically challenging benzofuranone derivatives having vicinal all-carbon quaternary and tertiary stereocenters is presented. The reaction operates solely through noncovalent interaction between a newly designed NHC and the substrates, providing access to a series of functionalized benzofuranones in good yields and with high ee values. The protocol applies to preparative-scale synthesis. A catalytic cycle involving a noncovalent substrate–NHC interaction is implicated in the process, based on a mechanistic control study.

Quaternary Chiral Phthalides Enabled by Dirhodium(II)/Phosphine Catalyzed Asymmetric Carbonyl Addition Cascade.

The catalytic asymmetric synthesis of chiral phthalides has garnered considerable interest. However, the construction of phthalides with a chiral quaternary carbon stereocenter still remains challenging. In this study, we developed a new strategy toward catalytic asymmetric synthesis of chiral 3,3-disubstituted phthalides via a dirhodium(II)/phosphine-catalyzed carbonyl addition cascade, yielding phthalides with up to 97% ee values. The reaction proceeded through dirhodium(II)/phosphine-catalyzed asymmetric carbonyl addition of arylboronic acids to isoquinoline-1,3,4(2H)-triones, followed by base-mediated ring contraction.