All-carbon Quaternary Stereogenic Center Research Articles

Stereoselective Synthesis of trans-Decalin-Based Spirocarbocycles via Photocyclization of 1,2-Diketones.

Diastereoselective synthesis of the trans-decalin-based α-hydroxyl butanone spirocarbocycles bearing all-carbon quaternary stereogenic centers has been achieved via Norrish–Yang photocyclization of trans-decalin-substituted-2,3-butanediones using daylight. Density functional theory (DFT) calculations suggest that this diastereoselective reaction is affected by both substrate conformation and intramolecular hydrogen bonds. The developed chemistry could be applied to synthesizing the derivatives of the trans-decalin-based biologically important natural products.

Rh(III)-catalyzed selective C7-H functionalization of indolines with 1,3-enynes enables access to six-membered 1,7-fused indolines

We described herein a Rh(III)-catalyzed C7-selective CH activation/annulation of indolines with 1,3-enynes to efficiently access various privileged 1,7-fused indolines bearing an all-carbon quaternary stereogenic carbon center. Notably, the resulting products can be readily transformed into 1,7-fused indoles, further widening the C-7 derivatization of indoles and highlighting the synthetic utility of this methodology.

Enantioselective Total Synthesis of (+)-Stephadiamine through Bioinspired Aza-Benzilic Acid Type Rearrangement.

We report the first enantioselective total syntheses of the hasubanan alkaloid (-)-metaphanine and the norhasubanan alkaloid (+)-stephadiamine. Key features of these syntheses include diastereoselective oxidative phenolic coupling reaction and subsequent regioselective intramolecular aza-Michael reaction, which efficiently construct the hasubanan skeleton with the all-carbon quaternary stereogenic center at C13. Based on our hypothesis regarding the biosynthetic pathway of (+)-stephadiamine, we found that (-)-metaphanine is easily converted to (+)-stephadiamine via aza-benzilic acid type rearrangement reaction.

A versatile approach to functionalized cyclic ketones bearing quaternary carbon stereocenters via organocatalytic asymmetric conjugate addition of nitroalkanes to cyclic β-substituted α,β-Enones

Abstract A versatile organocatalytic asymmetric conjugate addition of nitroalkanes to β-substituted cyclic α,β-enones to yield cyclic ketones bearing all-carbon quaternary stereogenic centers at β-C has been developed. This is an extension of the method that we developed during the total synthesis of (−)-haliclonin A, which features the employment of structurally relatively simple, cheap and easily available primary amine-thiourea derived from (R,R)-1,2-diaminocyclohexane as the chiral catalyst. The method shows wide substrate scope, good functional group tolerance, which allows a quick access to multi-functionalized chiral compounds. The synthetic potential of the method was demonstrated by one-step transformations of the nitro-ketone adducts to four other classes of compounds. The absolute configurations of adducts were determined by comparison of both the retention time of chiral HPLC analysis and sense of specific optical rotation with those of a known compound. The enantioselective control mechanism was rationalized based on the DFT computational studies.

Total Synthesis of (+)-Haperforin G.

A concise chemical synthesis of (+)-haperforin G in 20 steps from commercially available starting materials is achieved with the integration of the Co-catalyzed intramolecular Pauson-Khand reaction for the stereoselective construction of cyclopentanone bearing an all-carbon quaternary stereogenic center at the bridge-head position and the light-initiated photocatalysis for convergent and asymmetric cross-coupling of the unstabilized C(sp3)-radical with an enone. The developed chemistry paves the way to synthesizing structurally diverse analogs of haperforin G (6).

Forming All-Carbon Quaternary Stereocenters by Organocatalytic Aminomethylation: Concise Access to β2,2 -Amino Acids.

The asymmetric synthesis of β2,2 -amino acids remains a formidable challenge in organic synthesis. Here a novel organocatalytic enantioselective aminomethylation of ketenes with stable and readily available N,O-acetals is reported, providing β2,2 -amino esters bearing an all-carbon quaternary stereogenic center in high enantiomeric ratios with a catalytic amount of chiral phosphoric acid. Typically, this transformation probably proceeds through an asymmetric counter-anion-directed catalysis. As a result, a concise, practical, and atom-economic protocol toward rapidly access to β2,2 -amino acids has been developed.

Enantioselective synthesis of mixed 3,3′-bisindoles via a phosphine-catalyzed umpolung γ-addition of 3′-indolyl-3-oxindoles to allenoates

An enantioselective umpolung γ-addition reaction of 3′-indolyl-3-oxindoles to allenoates catalyzed by amino acid-derived bifunctional phosphine catalysts has been developed. A wide range of chiral mixed 3,3′-bisindole scaffolds containing an all-carbon quaternary stereogenic center were obtained in high yields and with excellent enantioselectivities. 3,3′-Bisindoles are valuable synthetic intermediates, the employment of which led to formal total syntheses of (+)-Chimonanthine, (+)-Folicanthine and (−)-Calycanthine, as well as facile creation of useful pyrrolidinoindoline core structure.

New entry to the enantioselective formation of substituted cyclohexenes bearing an all-carbon quaternary stereogenic center.

Enantioselective formation of cyclohexene derivatives bearing an all-carbon quaternary stereogenic center is described. The racemic cyclohexenes are readily transformed to chiral substituted cyclohexenes in good yield with excellent enantioselectivity and diastereoselectivity by a palladium-mediated deracemization. The resulting products are promising synthetic intermediates of biologically active natural products. This protocol provides us with a new entry to the concise and scalable synthesis of multifunctionalized compounds.

Palladium(II)-catalyzed asymmetric C-H carbonylation to diverse isoquinoline derivatives bearing all-carbon quaternary stereocenters.

Enantioselective synthesis of tetrahydroisoquinolines bearing an all-carbon quaternary stereogenic center, was achieved via asymmetric C-H activation with high enantioselectivities (up to 93% ee). Fair substrate tolerance was indicated throughout the scope investigation and no evident loss of enantioselectivity was exhibited in late-stage derivatization. This study provides incentives for the construction of diverse chiral isoquinoline derivatives, which are prevalent among pharmaceuticals, natural products, etc.

Enantioselective Desymmetrization of Prochiral Cyclopentene-1,3-diones Triggered by Remote C(sp2)-N Bond Formation.

The enantioselective desymmetrization via remote C(sp2)-H amidation of the prochiral 2,2-disubstituted cyclopentene-1,3-dione with N-methoxybenzamide has been developed. The overall process was catalyzed by a chiral bifunctional thiourea catalyst through a sequential conjugate-addition-elimination-tautomerization. This strategy provides rapid access to highly functionalized five-membered carbocycles, bearing an all-carbon quaternary stereogenic center through remote stereocontrol in high yields with moderate to excellent enantioselectivities.

Enantioselective Dearomatization of Indoles by an Azoalkene-Enabled (3+2) Reaction: Access to Pyrroloindolines.

The enantioselective dearomatization of indoles by an organocatalytic (3+2) reaction has been established. The reaction makes use of simple indole derivatives as substrates, and employs azoalkenes reaction partners. A wide range of pyrroloindolines containing an all-carbon quaternary stereogenic center were readily prepared in high yields and with excellent enantioselectivities.

Chiral N-Heterocyclic-Carbene-Catalyzed Cascade Asymmetric Desymmetrization of Cyclopentenediones with Enals: Access to Optically Active 1,3-Indandione Derivatives.

A chiral N-heterocyclic-carbene-catalyzed cascade asymmetric desymmetrization reaction of cyclopentenediones with enals has been successfully initiated, followed with tandem aldol annulation, aromatization, as well as sequential methylation. The reactions proceeded well under mild reaction conditions, with broad substrate scope and good functional group tolerance, providing a rapid access to highly functionalized chiral 2,2-disubstituted 1,3-indandione derivatives containing an all-carbon quaternary stereogenic center in moderate to good yields with high enantioselectivities.

Cp*Co(III)-Catalyzed Dearomative [3 + 2] Spiroannulation of 2-Alkenylphenols with Ynamides via C-H Activation.

An oxidative [3 + 2] C-H spiroannulation reaction of 2-alkenylphenols with ynamides has been developed toward the synthesis of spiro[4,5]decane derivatives. This dearomative reaction employs earth-abundant cobalt as the metal catalyst and occurs under rather mild reaction conditions (room temperature). The use of ynamides confers unique reactivity and exclusive regioselectivity. The products bearing an all-carbon quaternary stereogenic center were constructed in generally good yields with good functional group tolerance being observed. Experimental mechanistic studies were conducted, and a possible reaction mechanism is proposed.

Enantioselective Organocatalytic Desymmetrization of Cyclopentene-1,3-diones through Formal C(sp2)-H Amidation.

An enantioselective organocatalytic desymmetrization of 2,2-disubstituted cyclopentene-1,3-diones via a formal C(sp2)-H amidation is reported. The reaction was carried out with N-methoxy amide as the nitrogen source and commercially available cinchonidine as the catalyst under mild reaction conditions, releasing methanol as the only byproduct. It provides an efficient way to synthesize enantioenriched chiral cyclopentenyl amines bearing an all-carbon quaternary stereogenic carbon center.

Access to Chiral GABA Analogues Bearing a Trifluoromethylated All-Carbon Quaternary Stereogenic Center through Water-Promoted Organocatalytic Michael Reactions.

Water enables the highly challenging enantioselective Michael addition of sterically congested β-trifluoromethyl-β-aryl- or -alkyl-substituted nitroolefins with dithiomalonates. Under on-water conditions, the reaction rates were remarkably accelerated as a result of enforced hydrophobic interactions between catalysts and reactants. Takemoto-type thiourea catalysts are very effective for this transformation, affording highly enantioenriched Michael adducts that provide simple access to chiral γ-aminobutyric acid (GABA) analogues with a β-trifluoromethylated quaternary stereocenter.

Gold-catalyzed chemoselective formal (3+2)-Annulation reaction between β-naphthols and methyl aryldiazoacetate

A chemoselective domino annulation reaction of β-naphthols with methyl aryldiazoacetate is described. The gold catalyst promoted C–H functionalization of β-naphthols, whereas a rhodium or copper complex led to O–H insertion reactions. Consecutive intramolecular lactonization occurred after site-selective alkylation at the 1-position of β-naphthol, providing functionalized naphthofuranone derivatives. The product was transformed into a chiral molecule bearing an all-carbon quaternary stereogenic center with high enantioselectivity.

Enantioselective Addition Reaction of Azlactones with Styrene Derivatives Catalyzed by Strong Chiral Brønsted Acids.

An enantioselective intermolecular addition reaction of azlactones, as carbon nucleophiles, with styrene derivatives, as simple olefins, was demonstrated using a newly developed chiral Brønsted acid catalyst, namely, F10 BINOL-derived N-triflyl phosphoramide. Addition products having vicinal tetrasubstituted carbon centers, one of which is an all-carbon quaternary stereogenic center, were formed in good yields with moderate to high stereoselectivities. Extremely high acidity of the new chiral Brønsted acid was confirmed by its calculated pKa value based on DFT studies and is the key to accomplishing not only high catalytic activity but also efficient stereocontrol in the intermolecular addition.

Phosphine-Catalyzed (3+2) Annulation of Isoindigos with Allenes: Enantioselective Formation of Two Vicinal Quaternary Stereogenic Centers.

Construction of contiguous all-carbon quaternary stereogenic centers is a long-standing challenge in synthetic organic chemistry. In this report, a phosphine-catalyzed enantioselective (3+2) annulation reaction between allenes and isoindigos, containing either two identical or different oxindole moieties, is introduced as a powerful strategy for the construction of spirocyclic bisindoline alkaloid core structures. The reported reactions feature high chemical yields, excellent enantioselectivities, and very good regioselectivities, and are highly useful for creating structurally challenging bisindoline natural products.

Sequential Phosphine-Catalyzed [4 + 2] Annulation of β'-Acetoxy Allenoates: Enantioselective Synthesis of 3-Ethynyl-Substituted Tetrahydroquinolines.

The first enantioselective sequential phosphine-catalyzed (SPC as abbreviation) mode for the formation of tetrahydroquinolines with an ethynyl-substituted all-carbon quaternary stereogenic center is reported. In this SPC process, a novel [4 + 2] annulation process was devised employing α-substituted allenoates as C2 synthons (α-β', 1,2-dipole) for the first time. 3-Ethynyl-substituted tetrahydroquinolines were readily prepared in good yields and high enantioselectivities.

Palladium(0)-Catalyzed Intermolecular Asymmetric Cascade Dearomatization Reaction of Indoles with Propargyl Carbonate.

An intermolecular asymmetric cascade dearomatization reaction of indole derivatives with propargyl carbonate was developed. The challenges associated with both the chemoselectivity between the carbon and nitrogen nucleophile and the enantioselective control during the formation of an all-carbon quaternary stereogenic center were well addressed by a Pd catalytic system derived from the Feringa ligand. A series of enantioenriched multiply substituted fused indolenines were provided in good yields (71-86 %) with excellent enantioselectivity (91-96 % ee) and chemoselectivity (3/4>19:1 in most cases).