Tetrasubstituted Stereogenic Center Research Articles

Catalytic Enantioselective Synthesis of N,C(α),C(α)-Trisubstituted α-Amino Acid Derivatives Using 1H-Imidazol-4(5H)-ones as Key Templates.

1H-Imidazol-4(5H)-ones are introduced as novel nucleophilic α-amino acid equivalents in asymmetric synthesis. These compounds not only allow highly efficient construction of tetrasubstituted stereogenic centers, but unlike hitherto known templates, provide direct access to N-substituted (alkyl, allyl, aryl) α-amino acid derivatives.

Catalytic Enantioselective Synthesis of N,Cα,Cα‐Trisubstituted α‐Amino Acid Derivatives Using 1H‐Imidazol‐4(5H)‐ones as Key Templates

Abstract1H‐Imidazol‐4(5H)‐ones are introduced as novel nucleophilic α‐amino acid equivalents in asymmetric synthesis. These compounds not only allow highly efficient construction of tetrasubstituted stereogenic centers, but unlike hitherto known templates, provide direct access to N‐substituted (alkyl, allyl, aryl) α‐amino acid derivatives.

Enantioselective assembly of spirocyclic oxindole-dihydropyranones through NHC-catalyzed cascade reaction of isatins with N-hydroxybenzotriazole esters of α,β-unsaturated carboxylic acid.

An NHC-catalyzed formal [4 + 2] reaction of isatins with N-hydroxybenzotriazole ester of α,β-unsaturated carboxylic acids bearing γ-H to construct spirocyclic oxindole-dihydropyranones featuring a chiral tetrasubstituted carbon stereogenic center was developed. The high enantioselectivity, the ready availability of the raw materials, the facile assembly, and the potential biological significance of the final products make this protocol an attractive alternative for the synthesis of spirocyclic heterocycles.

Synthesis of EFdA via a Diastereoselective Aldol Reaction of a Protected 3-Keto Furanose

An efficient enantioselective total synthesis of EFdA, a remarkably potent anti-HIV nucleoside analogue with various favorable pharmacological profiles, has been achieved in 37% overall yield from diacetone-D-glucose by a 14-step sequence that features a highly diastereoselective installation of the tetrasubstituted stereogenic center at the C4' position, direct oxidative cleavage of an acetonide-protected diol derivative to an aldehyde, and one-pot 2'-deoxygenation of a ribonucleoside intermediate.

Recent Advances in Catalytic Asymmetric C–C Bond-Forming Reactions to Ketimines Promoted by Metal-Based Catalysts

Abstract Recent progress (post-2010) in the field of metal-catalyzed asymmetric C–C bond-forming reactions using ketimines as electrophiles is reviewed. Compared with the corresponding aldimines, ketimines generally display less inherent reactivity and the two substituents on the imine carbon hamper prochiral-face-selection for enantioselective reactions. Recent advances with newly developed catalytic systems have resulted in several solutions to these long-standing problems. The construction of tetrasubstituted stereogenic centers is a crucial topic of asymmetric catalysis in the 21st century, and it is becoming increasingly clear that reactions using ketimines as electrophiles become one of the most important routes to access such chemical entities.

ChemInform Abstract: Enantioselective Organocatalyzed Formal [4 + 2] Cycloaddition of Ketimines with Allenoates: Easy Access to a Tetrahydropyridine Framework with a Chiral Tetrasubstituted Stereogenic Carbon Center.

Enantioselective organocatalytic synthesis of tetrahydropyridines bearing a chiral tetrasubstituted carbon stereogenic center has been achieved. The spiro-type monoaryl phosphine catalyst, (R)-SITCP, was found to promote the formal [4+2] cycloaddition of saccharin-derived ketimines and α-methyl allenoate to afford the corresponding six-membered N-heterocycles in high yields and excellent regioselectivities with up to 93% ee.

ChemInform Abstract: An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents; Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia).

A new synthetic route, the shortest reported to date, to access a key intermediate for the synthesis of various triazole antifungal agents was developed. The elusive tetrasubstituted stereogenic center that is essential in advanced triazole antifungal agents was constructed via the catalytic asymmetric cyanosilylation of a ketone. The subsequent transformations were performed in two one-pot operations, enhancing the overall synthetic efficiency toward the intermediate. This streamlined synthetic approach was successfully applied to efficient enantioselective syntheses of efinaconazole (Jublia) and ravuconazole.

Diastereo- and enantioselective construction of a bispirooxindole scaffold containing a tetrahydro-β-carboline moiety through an organocatalytic asymmetric cascade reaction.

The first catalytic asymmetric construction of a new class of bispirooxindole scaffold-containing tetrahydro-β-carboline moiety has been established through chiral phosphoric acid-catalyzed three-component cascade Michael/Pictet-Spengler reactions of isatin-derived 3-indolylmethanols, isatins, and amino-ester, which afforded structurally complex and diverse bispirooxindoles with one quaternary and one tetrasubstituted stereogenic centers in excellent stereoselectivities (all >95:5 diastereomeric ratio (d.r.), up to 98:2 enantiomeric ratio (e.r.)). This intriguing class of chiral bispirooxindoles integrated the two important structures of tetrahydro-β-carboline and bispirooxindole, both of them possessing significant bioactivities. This approach also combined the merits of asymmetric organocatalysis and multicomponent tandem reaction, which provided a unique strategy for the preparation of structurally rigid bispiro-architectures with concomitant creation of multiple quaternary stereogenic centers.

Direct catalytic asymmetric vinylogous conjugate addition of unsaturated butyrolactones to α,β-unsaturated thioamides.

Soft Lewis acid/Brønsted base cooperative catalysts have enabled direct catalytic asymmetric vinylogous conjugate addition of α,β- and β,γ-unsaturated butyrolactones to α,β-unsaturated thioamides with perfect atom economy. When using α-angelica lactone and its derivatives as pronucleophiles, as little as 0.5 mol% catalyst loading was sufficient to complete the reaction necessary to construct consecutive tri- and tetrasubstituted stereogenic centers in a highly diastereo- and enantioselective fashion.

Direct Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated Butyrolactones to α,β‐Unsaturated Thioamides

AbstractSoft Lewis acid/Brønsted base cooperative catalysts have enabled direct catalytic asymmetric vinylogous conjugate addition of α,β‐ and β,γ‐unsaturated butyrolactones to α,β‐unsaturated thioamides with perfect atom economy. When using α‐angelica lactone and its derivatives as pronucleophiles, as little as 0.5 mol % catalyst loading was sufficient to complete the reaction necessary to construct consecutive tri‐ and tetrasubstituted stereogenic centers in a highly diastereo‐ and enantioselective fashion.

An Enantioselective Synthesis of the Key Intermediate for Triazole Antifungal Agents; Application to the Catalytic Asymmetric Synthesis of Efinaconazole (Jublia)

A new synthetic route, the shortest reported to date, to access a key intermediate for the synthesis of various triazole antifungal agents was developed. The elusive tetrasubstituted stereogenic center that is essential in advanced triazole antifungal agents was constructed via the catalytic asymmetric cyanosilylation of a ketone. The subsequent transformations were performed in two one-pot operations, enhancing the overall synthetic efficiency toward the intermediate. This streamlined synthetic approach was successfully applied to efficient enantioselective syntheses of efinaconazole (Jublia) and ravuconazole.

Enantioselective Organocatalyzed Formal [4+2] Cycloaddition of Ketimines with Allenoates: Easy Access to a Tetrahydropyridine Framework with a Chiral Tetrasubstituted Stereogenic Carbon Center

AbstractEnantioselective organocatalytic synthesis of tetrahydropyridines bearing a chiral tetrasubstituted carbon stereogenic center has been achieved. The spiro‐type monoaryl phosphine catalyst, (R)‐SITCP, was found to promote the formal [4+2] cycloaddition of saccharin‐derived ketimines and α‐methyl allenoate to afford the corresponding six‐membered N‐heterocycles in high yields and excellent regioselectivities with up to 93% ee.

酸-塩基型不斉有機分子触媒を用いるエナンチオ選択的aza-森田-Baylis-Hillman型ドミノ反応の開発

The aza-Morita-Baylis-Hillman (aza-MBH) reaction is a C-C bond-formation between enones and imines mediated by a nucleophilic Lewis base catalyst. The aza-MBH products are highly functionalized allylic amines which are proved to be valuable building blocks for pharmaceutical compounds. Organocatalyzed domino reactions are an attractive methodology because of its ability to construct complex chiral molecules from readily available substrates under mild reaction conditions in two or more steps in a single operation without using any toxic metals. However, a few reports on the domino reaction based on the MBH have been made due to the complicated MBH process involving Michael/Mannich/H-transfer/retro-Michael sequence. Herein, we report an enantioselective domino reaction based on the aza-MBH process using chiral acid-base organocatalysts. The acid-base functionalities activate the substrates and promote the complicated MBH sequence by their synergistic cooperation. The designed enantioselective MBH-type domino reactions provided highly functionalized heterocycles in up to 98% ee, some of which have a tetrasubstituted carbon stereogenic center.

Organocatalyzed Formal [2 + 2] Cycloaddition of Ketimines with Allenoates: Facile Access to Azetidines with a Chiral Tetrasubstituted Carbon Stereogenic Center

An enantioselective organocatalyzed aza-MBH-type reaction of ketimines and allenoates has been developed. The present formal [2 + 2] cycloaddition produces highly functionalized azetidines with a chiral tetrasubstituted carbon stereogenic center in good to excellent yields and high enantioselectivities.

Organocatalytic, Asymmetric Synthesis of 3‐Sulfenylated N‐Boc‐Protected Oxindoles

Sulfenylated oxindoles: The first asymmetric sulfenylation of N-Boc-protected oxindoles has been developed to provide products containing a tetrasubstituted stereogenic center in high to excellent yields (86-98 %) and, in most cases, excellent enantioselectivities (up to 96 % ee; see scheme).

Copper Carbenoid, Reactant and Catalyst for One‐Pot Diazo Ester Coupling Cascade Rearrangement of Enediynes: Formation of Two Contiguous Tetrasubstituted Stereocenters

AbstractThe copper‐catalyzed reaction of enediynes with diazo esters leads to cyclic amino esters bearing two contiguous tetrasubstituted stereogenic centers through a one‐pot, five‐step cascade. Copper iodide catalyzes the formation of an intermediate 3‐alkynoate and copper carbenoid promotes its reversible isomerization to the corresponding allenoate. The alkynoate‐allenoate equilibrium is completely shifted to the right by the rapid consumption of the allenoate by Myers–Saito cyclization. This is followed by 1,5‐H atom transfer and recombination of the resulting biradical. Memory of chirality phenomenon explains the high enantioselectivity.

ChemInform Abstract: Organocatalytic Asymmetric α‐Amination of Unprotected 3‐Aryl and 3‐Aliphatic Substituted Oxindoles Using Di‐tert‐butyl Azodicarboxylate.

The bifunctional quinine-derived thiourea catalyst 14 was found to catalyze the direct amination of unprotected 3-aryl and aliphatic substituted oxindoles with di-tert-butyl azodicarboxylate (DBAD) to construct a tetrasubstituted stereogenic carbon center at the C-3 position of oxindoles in good to excellent yield and enantioselectivity.

Organocatalytic Asymmetric α‐Amination of Unprotected 3‐Aryl and 3‐Aliphatic Substituted Oxindoles using Di‐tert‐butyl Azodicarboxylate

AbstractThe bifunctional quinine‐derived thiourea catalyst 14 was found to catalyze the direct amination of unprotected 3‐aryl and aliphatic substituted oxindoles with di‐tert‐butyl azodicarboxylate (DBAD) to construct a tetrasubstituted stereogenic carbon center at the C‐3 position of oxindoles in good to excellent yield and enantioselectivity.

Corrigendum: Chiral Neutral Zirconium Amidate Complexes for the Asymmetric Hydroamination of Alkenes

The authors would like to thank Prof. Kai Hultzsch of Rutgers University for alerting them to their erroneous illustration of the tetrasubstituted stereogenic center in the Mosher amide derivatives as S in the Supporting Information. The authors have verified, with the assistance of Prof. Hultzsch, that the method and NMR data presented in the Supporting Information gives the correct configuration of 2-methyl-4,4-diphenylpyrrolidine as indicated.1 While the illustrated and assigned configuration of the pyrrolidine products in both the manuscript and Supporting Information are correct,1 because of the Cahn–Ingold–Prelog priorities in assigning configuration there is a change from S to R upon amide synthesis. Thus, the use of (S)-Mosher acid chloride gives the (R)-Mosher amide products. To ensure that this error is not propagated in the literature, a revised version of the Supporting Information has been filed with all of the corrected illustrations included on the spectra. The sentence at the bottom of the first column on page 356 should be corrected to read “Reported ee values were determined by integration of 1H and/or 19F NMR spectra of the (S)-Mosher acid chloride derivatives of at least two independent experiments.” The authors regret any confusion that may have arisen from their erroneous illustration. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.