Asymmetric Ring Expansion Research Articles

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.

Mechanistic Insights into Sc(III)-Catalyzed Asymmetric Homologation of Ketones with Diazo Compounds: How Trans Influence Assists in Controlling Stereochemistry.

Asymmetric one-carbon homologation or ring expansion of ketones with formal insertion of carbene intermediate, is a challenging but useful strategy to construct a complex skeleton. Sc(III) and chiral ligands have been employed in this regard. However, due to flexible conformations and a variety of stereo models, the origin of stereochemistry remains ambiguous. Density functional theory (DFT) calculations were carried out to explore the interactions that control the stereoselectivity of a Sc(III)-catalyzed asymmetric homologation. The trans influence of counterions was found to affect the coordination mode of ketone to Sc(III), and consequently affect the stereoselectivity.

Benzo‐fused Nitrogen Heterocycles by Asymmetric Ring Expansion and Stereochemically Retentive Re‐contraction of Cyclic Ureas

AbstractBenzo‐fused nitrogen heterocycles are common features of bioactive molecules, and the enantioselective synthesis of their substituted analogues is an important goal. In this paper we demonstrate a practical and mechanistically intriguing approach to the enantioselective synthesis of 1‐arylbenzazepines and their analogues. The reaction sequence starts with an asymmetric migratory ring expansion of indoline, tetrahydroquinoline, or tetrahydrobenzazepine ureas on treatment with a chiral lithium amide base. Treatment of the ring‐expanded ureas with acid triggers a two‐atom ring contraction—an ‘azatropic shift’ in which one urea nitrogen displaces the other—with almost complete retention of stereochemistry. Aminolysis of the urea products provides enantioenriched 1‐aryl‐tetrahydrobenzazepine derivatives and their congeners, including an analogue of an intermediate in the synthesis of the drug solifenacin. Deuteration, in situ IR, and DFT studies provide evidence for the mechanisms of the reaction steps.

Benzo-fused Nitrogen Heterocycles by Asymmetric Ring Expansion and Stereochemically Retentive Re-contraction of Cyclic Ureas.

Benzo-fused nitrogen heterocycles are common features of bioactive molecules, and the enantioselective synthesis of their substituted analogues is an important goal. In this paper we demonstrate a practical and mechanistically intriguing approach to the enantioselective synthesis of 1-arylbenzazepines and their analogues. The reaction sequence starts with an asymmetric migratory ring expansion of indoline, tetrahydroquinoline, or tetrahydrobenzazepine ureas on treatment with a chiral lithium amide base. Treatment of the ring-expanded ureas with acid triggers a two-atom ring contraction-an 'azatropic shift' in which one urea nitrogen displaces the other-with almost complete retention of stereochemistry. Aminolysis of the urea products provides enantioenriched 1-aryl-tetrahydrobenzazepine derivatives and their congeners, including an analogue of an intermediate in the synthesis of the drug solifenacin. Deuteration, in situ IR, and DFT studies provide evidence for the mechanisms of the reaction steps.

Highly Enantioselective Construction of the Polycyclic Piperazin-2-ones via NHC-Catalyzed [12 + 2] Cycloadditions.

NHC-catalyzed diastereoselective and enantioselective [12 + 2] higher-order cycloadditions of 5H-benzo[a]-pyrrolizine-3-carbaldehydes with cyclic sulfonic imines are described. Various optically pure polycyclic piperazin-2-ones were successfully constructed under mild reaction conditions with excellent diastereoselectivities and enantioselectivities. The generated chiral polycyclic piperazin-2-ones could be transformed to planar-chiral nine-membered cyclic amides via squaramide-catalyzed asymmetric ring-expansion reactions.

Rhodium/Ming-Phos-catalyzed asymmetric annulation reaction of silacyclobutanes with terminal alkynes

Asymmetric ring-expansion reactions of silacyclobutanes (SCBs) with alkynes have evolved as one of the powerful protocols for the construction of silicon-stereogenic compounds. However, the achievement of highly enantioselective annulation of SCBs with terminal alkynes remains a challenge. Herein, we report a rhodium-catalyzed asymmetric annulation reaction of SCBs with terminal alkynes, which relies on the newly identified chiral sulfinamide phosphine ligand Ming-Phos. This catalytic system exhibits unique effects under mild conditions, leading to the direct synthesis of structurally diverse chiral silacycles in moderate to good yields with high enantioselectivities (up to 95% ee).

Enantioselective Synthesis of 6/5-Spirosilafluorenes by Asymmetric Ring Expansion of 4/5-Spirosilafluorenes with Alkynes.

A rhodium-catalyzed asymmetric ring expansion of 4/5-spirosilafluorenes with terminal alkynes has been developed using sterically demanding binaphthyl phosphoramidite ligand. The reaction is not only strategically distinct from cyclization or cycloaddition but also showcases the first enantioselective synthesis of axially chiral 6/5-spirosilafluorenes.

Enantioselective Synthesis of Spirosilabicyclohexenes by Asymmetric Dual Ring Expansion of Spirosilabicyclobutane with Alkynes.

Silaspiranes have attracted particular attention due to their chiral spiro-silicon center, which serves as an ideal carbon isostere and can endow spiro-analogs with distinct properties. Distinct from previously reported cyclization or cycloaddition strategies to form 5/5-silaspiranes, we report herein the asymmetric dual ring expansion of spirosilabicyclobutanes with alkynes to synthesize axially chiral spirosilabicyclohexenes bearing a novel 6/6-silaspirane framework. DFT (density functional theory) calculations provide the deep insight into the origin of the high enantioselectivity controlled by the sterically demanding binaphthyl phosphoramidite ligand. Preliminary studies of chiroptical properties indicate that one of the spirosilabicyclohexene analogs exhibit fluorescence emission, Cotton effects and CPL (circularly polarized luminescence) activity.

Enantioselective Synthesis of Spirosilabicyclohexenes by Asymmetric Dual Ring Expansion of Spirosilabicyclobutane with Alkynes

AbstractSilaspiranes have attracted particular attention due to their chiral spiro‐silicon center, which serves as an ideal carbon isostere and can endow spiro‐analogs with distinct properties. Distinct from previously reported cyclization or cycloaddition strategies to form 5/5‐silaspiranes, we report herein the asymmetric dual ring expansion of spirosilabicyclobutanes with alkynes to synthesize axially chiral spirosilabicyclohexenes bearing a novel 6/6‐silaspirane framework. DFT (density functional theory) calculations provide the deep insight into the origin of the high enantioselectivity controlled by the sterically demanding binaphthyl phosphoramidite ligand. Preliminary studies of chiroptical properties indicate that one of the spirosilabicyclohexene analogs exhibit fluorescence emission, Cotton effects and CPL (circularly polarized luminescence) activity.

Asymmetric Rhodium-Catalyzed C–C Activation of Cyclobutanones

Significance: C–C activation is an attractive method to functionalize strained four-membered ring systems. Zhou and Dong demonstrate the utility of allenes as a formal vinyl carbenoid in a rhodium-catalyzed asymmetric intramolecular ring expansion of cyclobutanones. Comment: An impressive substrate scope for this C–C activation protocol is demonstrated. Challenging cyclobutanone substrates such as those that are α-substituted also worked for this methodology, albeit with slightly diminished yields. General reaction: O R1

Rhodium-Catalyzed Asymmetric Ring Expansion of Cyclobutanols

Rhodium-Catalyzed Asymmetric Ring Expansion of Cyclobutanols

ChemInform Abstract: The First Asymmetric Ring‐Expansion Carbonylation of meso‐Epoxides.

AbstractThe first asymmetric ring‐expansion carbonylation of meso‐epoxides (I), (IV) and (VI) is reported.

ChemInform Abstract: A Catalytic Asymmetric Ring‐Expansion Reaction of Isatins and α‐Alkyl‐α‐diazoesters. Highly Efficient Synthesis of Functionalized 2‐Quinolone Derivatives.

Asymmetric expansion: A catalytic asymmetric ring-expansion reaction of the title compounds occurs in the presence of a Sc(OTf)(3) catalyst bearing an N,N'-dioxide-based ligand. Highly functionalized 2-quinolone derivatives containing a chiral C4-quaternary stereocenter were obtained in high yields and high levels of selectivity under mild reaction conditions (see scheme; Tf=trifluoromethanesulfonyl).

A Catalytic Asymmetric Ring‐Expansion Reaction of Isatins and α‐Alkyl‐α‐Diazoesters: Highly Efficient Synthesis of Functionalized 2‐Quinolone Derivatives

Asymmetric expansion: A catalytic asymmetric ring-expansion reaction of the title compounds occurs in the presence of a Sc(OTf)(3) catalyst bearing an N,N'-dioxide-based ligand. Highly functionalized 2-quinolone derivatives containing a chiral C4-quaternary stereocenter were obtained in high yields and high levels of selectivity under mild reaction conditions (see scheme; Tf=trifluoromethanesulfonyl).

The first asymmetric ring-expansion carbonylation of meso-epoxides

The first asymmetric ring-expansion carbonylation of meso-epoxides to β-lactones is reported. Two structurally diverse chiral Cr(III) chloro complexes in conjunction with Co(2)(CO)(8) were shown to be competent catalytic systems for this transformation, displaying significant levels of asymmetric induction of up to 56% ee.

ChemInform Abstract: Desymmetrizing Asymmetric Ring Expansion of Cyclohexanones with α‐Diazoacetates Catalyzed by Chiral Aluminum Lewis Acid.

AbstractThe catalyst controls the process to give seven‐membered rings with an all‐carbon quaternary center.

Desymmetrizing Asymmetric Ring Expansion of Cyclohexanones with α-Diazoacetates Catalyzed by Chiral Aluminum Lewis Acid

Chiral aluminum Lewis acid catalyst composed of Me(3)Al and 3,3'-bis(trimethylsilyl)-BINOL in a 2:1 ratio was found to promote novel catalytic asymmetric ring expansion of cyclohexanone with α-substituted α-diazoacetates to give seven-membered rings with an all-carbon quaternary center. Application of this strategy to 4-substituted cyclohexanones opened up a novel way for the catalytic desymmetrizing asymmetric construction of cycloheptanones bearing remote α,δ-chiral centers.

Organocatalytic Asymmetric Ring Expansion of Cyclobutanones

A secondary amine catalyzed ring expansion of substituted cyclobutanones with ­nitrosobenzene is reported. Surprisingly, none of the expected α-aminoxylation products was isolated and the ring-expanded products were obtained in reasonable yields, diastereo- and enan­tioselectivities. The proposed mechanism involves an enamine formation, followed by a formal nitroso aldol reaction (1). However, intermediate 2 cyclizes, presumably directed by the catalyst, and leads to bicyclic intermediate 3, which undergoes a rearrangement and hydrolysis, thus liberating the ­catalyst and product.

ChemInform Abstract: Desymmetrizing Asymmetric Ring Expansion: Stereoselective Synthesis of 7‐Membered Cyclic β‐Keto Carbonyl Compounds with an α‐Hydrogen.

AbstractRing expansion of symmetrically substituted cyclohexanones with N‐α‐diazoacetyl camphorsultam (II) is devised as a stereoselective approach to functionalized cyclic β‐keto carbonyls having a kinetically stabilized α‐hydrogen.

ChemInform Abstract: A Concise and Enantioselective Approach to Cyclobutanones by Tandem Asymmetric Epoxidation and Enantiospecific Ring Expansion of Cyclopropylidene Alcohols. An Enantiocontrolled Synthesis of (+)- and ( -)-α-Cuparenones.

A tandem Katsuli-Sharpless asymmetric epoxidation and enantiospecific ring expansion of 2-alkyl(or 2-aryl)-2-cyclopropylideneethanols (1a-i) afforded chiral 1-alkyl(or 1-aryl)-1-(hydroxymethyl)cyclobutanones (3a-i) in high yields and high enantiomeric excess. These compounds are potentially valuable synthons for the enantioselective creation of the quaternary carbons. Hence, this enabled us to accomplish a concise and enantioselective total synthesis of both (+)- and (-)-α-cuparenones