Quaternary Carbon Stereogenic Centers Research Articles

Tao-Phos-controlled desymmetrization of succinimide-based bisalkynes via asymmetric copper-catalyzed Huisgen alkyne–azide click cycloaddition: substrate scope and mechanism

It was found that the catalytic Huisgen cycloaddition reaction of succinimide-derived bisalkynes with azides resulted in useful succinimide-derived triazoles bearing quaternary carbon-stereogenic centers with good to excellent yields as well as good chemoselectivity and moderate to high enantioselectivities (up to 97% ee), in which the CuF2/Tao-Phos complex was proved to be an effective bimetallic catalyst in the presence of triethylamine. The mechanistic studies based on the effect of reaction parameters on stereoselectivity as well as ESI-MS analysis suggested that our ligand (Tao-Phos) and related binuclear copper centers play a crucial role in this asymmetric click chemistry because of the strong catalyst–substrate interaction with the aid of a possibly in situ formed binuclear or multinuclear copper-based transition state. This work not only provides a new example of a Cu(II)-mediated asymmetric AAC reaction involving chelating base and azides, but also suggests the significance of binuclear copper species in catalytic asymmetric click reactions with two copper center-involved enantioselective inductions.

ChemInform Abstract: High Pressure Organic Chemistry. Part 40. Enantioselective Synthesis of Quaternary Carbon Stereogenic Centers Through the Primary Amine‐Catalyzed Michael Addition Reaction of α‐Substituted Cyclic Ketones at High Pressure.

AbstractCompounds bearing a quaternary carbon stereogenic center at the α‐position of cyclic ketones are obtained by an efficient new method involving the enantioselective Michael addition of cyclic ketones with acrylates using simple chiral 1‐phenylethylamine as catalyst under high pressure.

Enantioselective Total Synthesis of Secalonic Acid E.

The first enantioselective synthesis of a secalonic acid containing a dimeric tetrahydroxanthenone skeleton is described, using a Wacker-type cyclization of a methoxyphenolic compound to form a chiral chroman with a quaternary carbon stereogenic center with >99% ee. Further steps are a Sharpless dihydroxylation and a Dieckmann condensation to give a tetrahydroxanthenone. A late-stage one-pot palladium-catalyzed Suzuki-dimerization reaction leads to the 2,2'-biphenol linkage to complete the enantioselective total synthesis of secalonic acid E in 18 steps with 8% overall yield.

ChemInform Abstract: Copper‐Catalyzed Intermolecular Asymmetric Propargylic Dearomatization of Indoles.

The first copper-catalyzed intermolecular dearomatization of indoles by an asymmetric propargylic substitution reaction was developed. This method provides a highly efficient synthesis of versatile furoindoline and pyrroloindoline derivatives containing a quaternary carbon stereogenic center and a terminal alkyne moiety with up to 86 % yield and 98 % ee.

ChemInform Abstract: Enantioselective Rhodium‐Catalyzed Allylic Substitution with a Nitrile Anion: Construction of Acyclic Quaternary Carbon Stereogenic Centers.

AbstractThe scalable title reaction represents the first example of an asymmetric alkylation of α‐substituted benzylic nitrile anions with nitrile malonates for the preparation of acyclic quaternary carbon stereogenic centers.

Total Synthesis of (+)-Chimonanthine, (+)-Folicanthine, and (-)-Calycanthine.

Facile, straightforward, and asymmetric total syntheses of (+)-chimonanthine (1), (+)-folicanthine (2), and (-)-calycanthine (3) were accomplished in four to five steps from commercially available tryptamine. The synthesis features copper-mediated asymmetric cyclodimerization of chiral tryptamine derivative, which established a new entry into constructing the sterically hindered vicinal quaternary stereogenic carbon centers of dimeric hexahydropyrroloindole alkaloids in one procedure. An unprecedented base-induced isomerization from the chimonanthine skeleton to the calycanthine skeleton was observed and facilitated the synthesis of (-)-calycanthine (3).

Asymmetric Michael Addition Reaction of α-Aryl-Substituted Lactams Catalyzed by Chiral Quaternary Ammonium Salts Derived from Cinchona Alkaloids: A New Short Synthesis of (+)-Mesembrine

The enantioselective Michael addition reaction of α-aryl-substituted lactams with electron-deficient olefins was efficiently catalyzed using chiral quaternary ammonium salts derived from cinchona alkaloids. This method was highly useful for the construction of an all-carbon-substituted quaternary carbon stereogenic center at the α-position of lactams in good to high yields and with good enantiomeric excess and could be applied to the short synthesis of (+)-mesembrine.

ChemInform Abstract: N‐Substituted Tertiary and O‐Substituted Quaternary Carbon Stereogenic Centers by Site‐, Diastereo‐ and Enantioselective Vinylogous Mannich Reactions.

AbstractThe triphenylphosphine derived amino‐acid containing catalyst (PCA) is applied in the Ag‐catalyzed condensation of imines (I) and (VII) with siloxypyrroles to afford lactams (III) and (IX) in good stereoselectivity.

Diastereoselective Addition of Metal α-Fluoroenolates of Carboxylate Esters to N-tert-Butylsulfinyl Imines: Synthesis of α-Fluoro-β-amino Acids.

We report a diastereoselective addition reaction of fluoroacetate and α-alkylated fluoroacetate to N-tert-butylsulfinyl imines. This method provides a concise route to α-fluoro-β-amino acids containing fluorinated quaternary stereogenic carbon centers with very good yields and high diastereoselectivities. This protocol has the benefit of using abundant and readily accessible starting materials and is operationally simple. Additionally, the stereochemical outcome of the present reaction was different from that of the previously known addition of comparable nonfluorinated, brominated, and chlorinated enolates to N-sulfinyl imines, suggesting that an open transition state (rather than a closed one) is involved in the current fluoroalkylation reaction.

N-Heterocyclic Carbene-Copper-Catalyzed Group-, Site-, and Enantioselective Allylic Substitution with a Readily Accessible Propargyl(pinacolato)boron Reagent: Utility in Stereoselective Synthesis and Mechanistic Attributes.

The first instances of catalytic allylic substitution reactions involving a propargylic nucleophilic component are presented; reactions are facilitated by 5.0 mol % of a catalyst derived from a chiral N-heterocyclic carbene (NHC) and a copper chloride salt. A silyl-containing propargylic organoboron compound, easily prepared in multigram quantities, serves as the reagent. Aryl- and heteroaryl-substituted disubstituted alkenes within allylic phosphates and those with an alkyl or a silyl group can be used. Functional groups typically sensitive to hard nucleophilic reagents are tolerated, particularly in the additions to disubstituted alkenes. Reactions may be performed on the corresponding trisubstituted alkenes, affording quaternary carbon stereogenic centers. Incorporation of the propargylic group is generally favored (vs allenyl addition; 89:11 to >98:2 selectivity); 1,5-enynes can be isolated in 75-90% yield, 87:13 to >98:2 SN2'/SN2 (branched/linear) selectivity and 83:17-99:1 enantiomeric ratio. Utility is showcased by conversion of the alkynyl group to other useful functional units (e.g., homoallenyl and Z-homoalkenyl iodide), direct access to which by other enantioselective protocols would otherwise entail longer routes. Application to stereoselective synthesis of the acyclic portion of antifungal agent plakinic acid A, containing two remotely positioned stereogenic centers, by sequential use of two different NHC-Cu-catalyzed enantioselective allylic substitution (EAS) reactions further highlights utility. Mechanistic investigations (density functional theory calculations and deuterium labeling) point to a bridging function for an alkali metal cation connecting the sulfonate anion and a substrate's phosphate group to form the branched propargyl addition products as the dominant isomers via Cu(III) π-allyl intermediate complexes.

ChemInform Abstract: Asymmetric Synthesis of Chiral 3,3‐Disubstituted Oxindoles Using Isatin as Starting Material

AbstractReview: 137 refs.

ChemInform Abstract: Enantioselective Copper‐Catalyzed Azide‐Alkyne Click Cycloaddition to Desymmetrization of Maleimide‐Based Bis(alkynes).

A copper catalyst system derived from TaoPhos and CuF2 was used successfully for catalytic asymmetric Huisgen [3+2] cycloaddition of azides and alkynes to give optically pure products containing succinimide- and triazole-substituted quaternary carbon stereogenic centers. The desired products were obtained in good yields (60-80 %) and 85:15 to >99:1 enantiomeric ratio (e.r.) in this click cycloaddition reaction.

Copper-catalyzed enantioselective allylic cross-coupling with alkylboranes

We have presented full details of our work on alkylboranes, which we have introduced as new reagents for copper-catalyzed SN2′-type enantioselective allylic substitutions. The copper catalysis delivered enantioenriched chiral products containing tertiary or quaternary carbon stereogenic centers branched with functionalized sp3-alkyl groups. The wide availability of alkylboranes via the established alkene hydroboration reaction is an attractive feature of these transformations. Various functional groups are tolerated in the substrates. A reaction pathway involving addition–elimination of a neutral alkylcopper(I) species with the allyl chloride substrate is proposed.

ChemInform Abstract: Central—Axial—Central Chirality Transfer: Asymmetric Synthesis of Highly Substituted Indenes Bearing a Stereogenic Quaternary Carbon Center from Optically Active Propargyl Alcohols.

AbstractA new, convenient, and environmentally benign route to synthesize a variety of highly substituted indene derivatives bearing a quaternary stereogenic carbon center is reported.

Copper‐Catalyzed Intermolecular Asymmetric Propargylic Dearomatization of Indoles

AbstractThe first copper‐catalyzed intermolecular dearomatization of indoles by an asymmetric propargylic substitution reaction was developed. This method provides a highly efficient synthesis of versatile furoindoline and pyrroloindoline derivatives containing a quaternary carbon stereogenic center and a terminal alkyne moiety with up to 86 % yield and 98 % ee.

Copper-catalyzed intermolecular asymmetric propargylic dearomatization of indoles.

The first copper-catalyzed intermolecular dearomatization of indoles by an asymmetric propargylic substitution reaction was developed. This method provides a highly efficient synthesis of versatile furoindoline and pyrroloindoline derivatives containing a quaternary carbon stereogenic center and a terminal alkyne moiety with up to 86 % yield and 98 % ee.

Enantioselective rhodium-catalyzed allylic substitution with a nitrile anion: construction of acyclic quaternary carbon stereogenic centers.

A direct and highly enantioselective rhodium-catalyzed allylic alkylation of allyl benzoate with α-substituted benzyl nitrile pronucleophiles is described. This simple protocol provides a new approach toward the synthesis of acyclic quaternary carbon stereogenic centers and provides the first example of the direct asymmetric alkylation of a nitrile anion. The synthetic utility of the nitrile products is amply demonstrated through conversion to various functional groups and the synthesis of a bioactive aryl piperazine in an expeditious four-step sequence.

N-Substituted tertiary and O-substituted quaternary carbon stereogenic centers by site-, diastereo- and enantioselective vinylogous Mannich reactions

A readily accessible small-molecule phosphine, derived from commercially available starting materials such as an enantiomerically pure amino acid, serves as the precursor to a Ag-based chiral complex that can be prepared and used in situ to promote a variety of enantioselective vinylogous Mannich (EVM) reactions that involve siloxypyrroles as reaction partners. Transformations with unsubstituted nucleophilic components proceed efficiently and with exceptional site- (γ vs α-addition), diastereo- and enantioselectivity [up to 98% yield, generally >98:2 γ/α and diastereomeric ratio (dr) and up to 99:1 enantiomeric ratio (er)]. The first examples of efficient, diastereo- and enantioselective vinylogous Mannich additions with 5-methyl-substituted siloxyfuran, resulting in the formation of O-substituted quaternary carbon stereogenic centers are presented as well. Appreciable efficiency and diastereo- and enantioselectivity (up to >98:2dr and >99:1er) is accompanied by formation of α-addition products that can be oxidatively removed.

Central-axial-central chirality transfer: asymmetric synthesis of highly substituted indenes bearing a stereogenic quaternary carbon center from optically active propargyl alcohols.

An asymmetric synthesis of highly substituted indenes 3, bearing a quaternary stereogenic carbon center, has been developed via the central-axial-central chirality transfer from optically active propargyl alcohols 1. This transformation involves the addition/rearrangement of 1 and ynamides 2 to give tetra-substituted allenes 4 and further cyclization of 4.

ChemInform Abstract: Enantioselective Aldol Reactions of α,β‐Unsaturated Ketones with Trifluoroacetophenone Catalyzed by a Chiral Primary Amine.

Abstract Chiral primary amine catalyzed direct asymmetric aldol reactions of ketones with trifluoroacetophenone, afforded trifluoromethylated β-hydroxycarbonyl aldol products bearing a quaternary carbon stereogenic center in high yields (up to 93% yield) and with high to excellent enantioselectivities of up to 99% ee.