Quaternary Stereogenic Carbon Research Articles

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

AbstractReview: 137 refs.

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.

Application of asymmetric alkylation of malonic diester with phase-transfer catalysis: synthesis of LFA-1 antagonist BIRT-377

An efficient asymmetric synthesis of LFA-1 antagonist BIRT-377 using enantioselective phase-transfer catalytic alkylation has been developed. The alkylation of α-monosubstituted tert-butyl methyl malonate was catalyzed by a quaternary ammonium salt derived from a cinchona alkaloid to obtain the product with a quaternary stereogenic carbon in high yield and with high enantioselectivity. The chiral α,α-disubstituted product thus obtained was transformed into BIRT-377 through alternating chemoselective deprotection of the two ester groups followed by Curtius rearrangement.

ChemInform Abstract: Enantioselective Construction of Quaternary Stereogenic Carbon Atoms by the Lewis Base Catalyzed Additions of Silyl Ketene Imines to Aldehydes.

AbstractThe presented reaction gives alcohols bearing quaternary stereocenters in high yields and excellent diastereo‐ and enantioselectivities tolerating a broad scope of aliphatic and aromatic substituents on both, the aldehyde and ketene imine.

ChemInform Abstract: One‐Pot Enantioselective Construction of Indoloquinolizidine Derivatives Bearing Five Contiguous Stereocenters Using Aliphatic Aldehydes, Nitroethylenes, and Tryptamine.

An organocatalytic cascade reaction was established for the construction of indoloquinolizidine derivatives bearing five contiguous stereocenters from readily available aliphatic aldehydes, nitroethylenes, and tryptamine. This one-pot process gave 30–55% overall yields with excellent d.r. (>20:1 in all cases) and ee (91–98%). Additionally, quaternary stereogenic carbon center-containing indoloquinolizidines were prepared through NBS-mediated cyclization of one of the intermediates.

Copper-mediated dimerization to access 3a,3a'-bispyrrolidinoindoline: diastereoselective synthesis of (+)-WIN 64821 and (-)-ditryptophenaline.

A copper-mediated cyclization and dimerization of tryptamine or tryptophan was developed to generate a C2-symmetry C3(sp(3))-C3(sp(3)) bridge with two contiguous stereogenic quaternary carbons in one step. Impressively, the ratio between exo and endo cyclization products varies when different protecting groups of Nb are utilized. This dimerization reaction could be conducted in gram scale. With this dimerization method, both endocyclotryptophan (+)-WIN 64821 and exocyclotryptophan (-)-ditryptophenaline were synthesized in 5 steps.

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.

Asymmetric tandem 1,5-hydride shift/ring closure for the synthesis of chiral spirooxindole tetrahydroquinolines.

The direct functionalization of sp(3) C-H bonds through a tandem 1,5-hydride shift/ring closure is described. Various optically active spirooxindole tetrahydroquinoline derivatives bearing contiguous quaternary or tertiary stereogenic carbon centers were readily synthesized. A chiral scandium complex of N,N'-dioxide promoted the reactions in good yields (up to 97%) with excellent diastereoselectivities (>20:1) and enantioselectivities (up to 94% ee). Kinetic isotope effect (KIE) experiments and internal redox reactions of chiral substrates were conducted, and the results provided intriguing information that helped clarify the mechanism of the reaction.

Asymmetric fluorocyclizations of alkenes.

CONSPECTUS: The vicinal fluorofunctionalization of alkenes is an attractive transformation that converts feedstock olefins into valuable cyclic fluorinated molecules for application in the pharmaceutical, agrochemical, medical, and material sectors. The challenges associated with asymmetric fluorocyclizations induced by F(+) reagents are distinct from other types of halocyclizations. Processes initiated by the addition of an F(+) reagent onto an alkene do not involve the reversible formation of bridged fluoronium ions but generate acyclic β-fluorocationic intermediates. This mechanistic feature implies that fluorocyclizations are not stereospecific. A discontinuity exists between the importance of this class of fluorocyclization and the activation modes currently available to implement successful catalysis. Progress toward fluorocyclization has been achieved by investing in neutral and cationic [NF] reagent development. The body of work on asymmetric fluorination using chiral cationic [NF](+) reagents prepared by fluorine transfer from the dicationic [NF](2+) reagent Selectfluor to quinuclidines, inspired the development of asymmetric F(+)-induced fluorocyclizations catalyzed by cinchona alkaloids; for catalysis, the use of N-fluorobenzenesulfonimide, which is less reactive than Selectfluor, ensures that the achiral F(+) source remains unreactive toward the alkene. These organocatalyzed enantioselective fluorocyclizations can be applied to indoles to install the fluorine on a quaternary benzylic stereogenic carbon center and to afford fluorinated analogues of natural products featuring the hexahydropyrrolo[2,3-b]indole or the tetrahydro-2H-furo[2,3-b]indole skeleton. In an alternative approach, the poor solubility of dicationic Selectfluor bis(tetrafluoroborate) in nonpolar solvent was exploited with anionic phase transfer catalysis as the operating activation mode. Exchange of the tetrafluoroborate ions of Selectfluor with bulky lipophilic chiral anions (e.g., TRIP and derivatives) brings into solution the resulting chiral Selectfluor reagent, now capable of asymmetric fluorocyclization. This strategy is best applied to a subset of substrates bearing a nucleophilic pendent group (benzamide is best) capable of hydrogen bonding for association with the chiral phosphate catalyst. These contributions focused on fluoroheterocyclization involving either O- or N-nucleophiles. As for other halocyclizations, alkenes armed with π C-nucleophiles represent the most demanding class of substrates for asymmetric F(+)-induced electrophilic fluorination-cyclization. Successful implementation required the design of new chiral Selectfluor reagents featuring stereogenicity on the DABCO core. These reagents, accessible from chiral vicinal diamines, allowed the synthesis of unusual chiral fluorine-containing tetracyclic compounds, some composed of carbon, hydrogen, and fluorine exclusively. The challenges associated with F(+)-induced fluorocarbocyclizations prompted methodologists to consider chemistry where the Csp(3)-F bond formation event follows a catalyst-controlled cyclization. An exciting development built on in the area of transition metal π-cyclization of polyenes leading to cationic metal-alkyl intermediates. When intercepted by oxidative fluorodemetalation with a F(+) source, the resulting products are complex polycyclic structures emerging from an overall catalytic cascade fluorocarbocyclization. Complementing F(+)-based reactions, examples of fluorocyclizations with fluoride in the presence of an oxidant were reported. Despite some exciting developments, the field of asymmetric fluorocyclizations is in its infancy and undoubtedly requires new activation modes, catalysts, as well as F(+) and F(-) reagents to progress into general retrosynthetic approach toward enantioenriched fluorocycles. Numerous opportunities emerge, not least the use of a latent fluorine source as a means to minimize background fluorination.

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation.

Pd-catalyzed enantioselective alkylation in conjunction with further synthetic elaboration enables the formal total syntheses of a number of “classic” natural product target molecules. This publication highlights recent methods for setting quaternary and tetrasubstituted tertiary carbon stereocenters to address the synthetic hurdles encountered over many decades across multiple compound classes spanning carbohydrate derivatives, terpenes, and alkaloids. These enantioselective methods will impact both academic and industrial settings, where the synthesis of stereogenic quaternary carbons is a continuing challenge.

ChemInform Abstract: Construction of Quaternary Stereogenic Carbon Centers Through Copper‐Catalyzed Enantioselective Allylic Cross‐Coupling with Alkylboranes.

A combination of an in situ generated chiral CuI/DTBM-MeO-BIPHEP catalyst system and EtOK enabled the enantioselective SN2′-type allylic cross-coupling between alkylborane reagents and γ,γ-disubstituted primary allyl chlorides with enantiocontrol at a useful level. The reaction generates a stereogenic quaternary carbon center having three sp3-alkyl groups and a vinyl group. This protocol allowed the use of terminal alkenes as nucleophile precursors, thus representing a formal reductive allylic cross-coupling of terminal alkenes. A reaction pathway involving addition/elimination of a neutral alkylcopper(I) species with the allyl chloride substrate is proposed.

Cover Picture: Silicon Meets Cyclotron: Muon Spin Resonance of Organosilicon Radicals / The Pentamethylcyclopentadienylsilicon(II) Cation: Synthesis, Characterization, and Reactivity / Enantioselective Construction of Quaternary Stereogenic Carbon Atoms by the Lewis Base Catalyzed Additions of Silyl Ketene Imines to Aldehydes / Iron Silicates, Iron‐Modulated Zeolite Catalysts, and Molecular Models Thereof / Ultrathin Silica Films: The Atomic Structure of Two‐Dimensional Crystals and

Cover Picture: Silicon Meets Cyclotron: Muon Spin Resonance of Organosilicon Radicals / The Pentamethylcyclopentadienylsilicon(II) Cation: Synthesis, Characterization, and Reactivity / Enantioselective Construction of Quaternary Stereogenic Carbon Atoms by the Lewis Base Catalyzed Additions of Silyl Ketene Imines to Aldehydes / Iron Silicates, Iron‐Modulated Zeolite Catalysts, and Molecular Models Thereof / Ultrathin Silica Films: The Atomic Structure of Two‐Dimensional Crystals and

Enantioselective construction of quaternary stereogenic carbon atoms by the Lewis base catalyzed additions of silyl ketene imines to aldehydes.

Silyl ketene imines derived from a variety of α-branched nitriles have been developed as highly useful reagents for the construction of quaternary stereogenic centers via the aldol addition reaction. In the presence of SiCl4 and the catalytic action of a chiral phosphoramide, silyl ketene imines undergo extremely rapid and high yielding addition to a wide variety of aromatic aldehydes with excellent diastereo- and enantioselectivity. Of particular note are the high yields and selectivities obtained from electron-rich, electron-poor, and hindered aldehydes. Linear aliphatic aldehydes did react with good diastereo- and enantioselectivity in the presence of nBu4N(+)I(-), but branched aldehydes were much less reactive. Semiempirical calculations provided a rationalization of the observed diastereo- and enantioselectivity via open transitions states.

Construction of Quaternary Stereogenic Carbon Centers through Copper‐Catalyzed Enantioselective Allylic Cross‐Coupling with Alkylboranes

A combination of an in situ generated chiral Cu(I) /DTBM-MeO-BIPHEP catalyst system and EtOK enabled the enantioselective SN 2'-type allylic cross-coupling between alkylborane reagents and γ,γ-disubstituted primary allyl chlorides with enantiocontrol at a useful level. The reaction generates a stereogenic quaternary carbon center having three sp(3) -alkyl groups and a vinyl group. This protocol allowed the use of terminal alkenes as nucleophile precursors, thus representing a formal reductive allylic cross-coupling of terminal alkenes. A reaction pathway involving addition/elimination of a neutral alkylcopper(I) species with the allyl chloride substrate is proposed.

Construction of Quaternary Stereogenic Carbon Centers through Copper‐Catalyzed Enantioselective Allylic Cross‐Coupling with Alkylboranes

AbstractA combination of an in situ generated chiral CuI/DTBM‐MeO‐BIPHEP catalyst system and EtOK enabled the enantioselective SN2′‐type allylic cross‐coupling between alkylborane reagents and γ,γ‐disubstituted primary allyl chlorides with enantiocontrol at a useful level. The reaction generates a stereogenic quaternary carbon center having three sp3‐alkyl groups and a vinyl group. This protocol allowed the use of terminal alkenes as nucleophile precursors, thus representing a formal reductive allylic cross‐coupling of terminal alkenes. A reaction pathway involving addition/elimination of a neutral alkylcopper(I) species with the allyl chloride substrate is proposed.

Ruthenium(II)/Chiral Brønsted Acid Co‐Catalyzed Enantioselective Four‐Component Reaction/Cascade Aza‐Michael Addition for Efficient Construction of 1,3,4‐Tetrasubstituted Tetrahydroisoquinolines

An elegant synergistic catalytic system comprising a ruthenium complex with a chiral Brønsted acid was developed for a four-component Mannich/cascade aza-Michael reaction. The ruthenium-associated ammonium ylides successfully trapped with in situ generated imines indicates a stepwise process of proton transfer in the ruthenium-catalyzed carbenoid N-H insertion reaction. The different decomposition abilities of various ruthenium complexes towards diazo compounds were well explained by the calculated thermodynamic data. The transformation features a mild, rapid, and efficient method for the synthesis of enantiomerically pure 1,3,4-tetrasubstituted tetrahydroquinolines bearing a quaternary stereogenic carbon center from simple starting precursors in moderate yields with high diastereo- and enantioselectivity.

ChemInform Abstract: Diastereoselective Synthesis of Complex cis‐Hexahydroindanes by Reductive Alkylation.

An efficient and operationally simple approach to complex cis-hexahydroindanes is reported. Upon Birch reduction of unprotected, C4-alkylated tetrahydroindanols and electrophilic trapping of the tetrasubstituted enolate, cis-fused products are formed with a new stereogenic quaternary carbon. The reaction is convergent, completely diastereoselective, and shows a broad scope with regard to the electrophile.

ChemInform Abstract: Simple Branched Sulfur—Olefins as Chiral Ligands for Rh‐Catalyzed Asymmetric Arylation of Cyclic Ketimines: Highly Enantioselective Construction of Tetrasubstituted Carbon Stereocenters.

New, simple, sulfinamide-based branched olefin ligands have been developed and successfully used in Rh-catalyzed asymmetric arylations of cyclic ketimines, providing efficient and highly enantioselective access to valuable benzosultams and benzosulfamidates containing a stereogenic quaternary carbon center. This is the first example of applying a sulfur–olefin ligand in catalytic asymmetric addition of imines.

Diastereoselective Synthesis of Complex cis-Hexahydroindanes by Reductive Alkylation

An efficient and operationally simple approach to complex cis-hexahydroindanes is reported. Upon Birch reduction of unprotected, C4-alkylated tetrahydroindanols and electrophilic trapping of the tetrasubstituted enolate, cis-fused products are formed with a new stereogenic quaternary carbon. The reaction is convergent, completely diastereoselective, and shows a broad scope with regard to the electrophile.

ChemInform Abstract: Silyl Ketene Imines: Highly Versatile Nucleophiles for Catalytic, Asymmetric Synthesis

AbstractReview: ca. 100 refs.