Tertiary Stereogenic Centers Research Articles

Catalytic Asymmetric Domino Michael/Annulation Reaction of Bifunctional Chromone Synthons with β,γ-Unsaturated α-Keto Esters: Rapid Access to Polysubstituted Spirocyclic Hexahydroxanthones

A thiourea-catalyzed asymmetric domino Michael/annulation process was devised employing bifunctional oxindole-chromones as C4 synthons and β,γ-unsaturated α-keto esters as C2 synthons. This reaction enables the highly diastereo- and enantioselective synthesis of a range of biologically relevant spirocyclic hexahydroxanthones with one quaternary and four tertiary stereogenic centers, also featuring an intriguing combination of two privileged motifs, including hexahydroxanthone and oxindole substructures, in good yields (up to 76%) and excellent stereoselectivities (up to >99% ee and >20:1 dr). Moreover, using β,γ-unsaturated α-keto esters as the C2 building blocks, which are different from enone substrates such as chalcone and benzalacetone, with the reversible Michael reaction further expanded the scope of the method. In addition, scale-up also demonstrated the applicability of this protocol.

Desymmetrization of difluoromethylene groups by C-F bond activation.

Tertiary stereogenic centres containing one fluorine atom are valuable for medicinal chemistry because they mimic common tertiary stereogenic centres containing one hydrogen atom, but they possess distinct charge distribution, lipophilicity, conformation and metabolic stability1-3. Although tertiary stereogenic centres containing one hydrogen atom are often set by enantioselective desymmetrization reactions at one of the two carbon-hydrogen (C-H) bonds of a methylene group, tertiary stereocentres containing fluorine have not yet been constructed by the analogous desymmetrization reaction at one of the two carbon-fluorine (C-F) bonds of a difluoromethylene group3. Fluorine atoms are similar in size to hydrogen atoms but have distinct electronic properties, causing C-F bonds to be exceptionally strong and geminal C-F bonds to strengthen one another4. Thus, exhaustive defluorination typically dominates over the selective replacement of a single C-F bond, hindering the development of the enantioselective substitution of one fluorine atom to form a stereogenic centre5,6. Here we report the catalytic, enantioselective activation of a single C-F bond in an allylic difluoromethylene group to provide a broad range of products containing a monofluorinated tertiary stereogenic centre. By combining a tailored chiral iridium phosphoramidite catalyst, which controls regioselectivity, chemoselectivity and enantioselectivity, with a fluorophilic activator, which assists the oxidative addition of the C-F bond, these reactions occur in high yield and selectivity. The design principles proposed in this work extend to palladium-catalysed benzylic substitution, demonstrating the generality of the approach.

Catalytic Asymmetric [3 + 2] Annulation via Indolyl Copper-Allenylidene Intermediates: Diastereo- and Enantioselective Assembly of Pyrrolo[1,2-a]indoles.

A catalytic asymmetric decarboxylative [3 + 2] annulation via indolyl copper-allenylidene amphiphilic intermediates has been developed. This protocol offers a straightforward method for the synthesis of biologically important pyrrolo[1,2-a]indoles bearing contiguous quaternary and tertiary stereogenic centers with excellent diastereo- and enantioselectivities (up to >20:1 dr and >99% ee). In addition, the diversity-oriented synthesis of pyrrolo[1,2-a]indoles was achieved via versatile transformations of the alkyne-containing cycloadducts.

Cooperative Catalysis for the Highly Diastereo- and Enantioselective [4+3]-Cycloannulation of ortho-Quinone Methides and Carbonyl Ylides.

We describe herein a highly diastereo‐ and enantioselective [4+3]‐cycloannulation of ortho‐quinone methides and carbonyl ylides to furnish functionalized oxa‐bridged dibenzooxacines with excellent yields and stereoselectivity in a single synthetic step. The combination of rhodium and chiral phosphoric acid catalysis working in concert to generate both transient intermediates in situ provides direct access to complex bicyclic products with two quaternary and one tertiary stereogenic centers. The products may be further functionalized into valuable and enantiomerically highly enriched building blocks.

Pd-Catalyzed Asymmetric Hydroalkylation of 1,3-Dienes: Access to Unnatural α-Amino Acid Derivatives Containing Vicinal Quaternary and Tertiary Stereogenic Centers.

Pd-phosphinooxazoline (Pd-PHOX)-catalyzed asymmetric hydroalkylation of 1,3-dienes with azlactones was successfully developed for the first time, affording various enantioenriched α-quaternary α-amino acid derivatives bearing contiguous quaternary and tertiary stereogenic centers in good yields with exclusive regioselectivity and excellent stereoselective control (up to 92% yield, >20:1 dr, and >99% ee). The scale-up catalytic asymmetric hydroalkylation was performed well without loss of reactivity and stereoselectivities, which exhibited great potential application. The synthetic utility of the current methodology was demonstrated through product transformations to access other biologically important compounds such as chiral β-amino alcohol and α-quaternary cyclic α-amino acid derivatives.

L-Isoleucine-catalyzed Michael Synthesis of N-Alkylsuccinimide Derivatives and Their Antioxidant Activity Assessment

N-Substituted succinimides having different alkyl groups were prepared by the reaction of N-substituted maleimide with aldehydes. A two-component catalyst system composed of an amino acid (l-isoleucine) and a base (KOH) was used to facilitate reaction of the α-hydrogen-containing aldehyde with N-substituted maleimide. With 20 mol % catalyst/cocatalyst, good results in term of the reaction time and yield (892-99%) of products containing contiguous quaternary and tertiary stereogenic centers were obtained. The CHN elemental analyses of N-substituted succinimides indicated appreciable purity. Structural assessment of the synthesized N-substituted succinimides was carried out by 1H and 13C NMR spectroscopy. The products exhibited excellent antioxidant and mild antimicrobial activities.

Synthesis of Enantioenriched Vicinal Tertiary and Quaternary Carbon Stereogenic Centers within an Acyclic Chain.

Overcoming the inherent difficulty to prepare quaternary carbon stereogenic centers, the diastereo- and enantioselective preparation of acyclic carbon backbones possessing vicinal quaternary and tertiary stereogenic centers (i.e. in a 1,2-relationship) causes distorted geometries and represents a very acute problem in organic synthesis. Several approaches are discussed in this minireview underlining the challenges illustrated by the rather limited number of approaches available to practitioners.

Base‐free Enantioselective C(1)‐Ammonium Enolate Catalysis Exploiting Aryloxides: A Synthetic and Mechanistic Study

AbstractAn isothiourea‐catalyzed enantioselective Michael addition of aryl ester pronucleophiles to vinyl bis‐sulfones via C(1)‐ammonium enolate intermediates has been developed. This operationally simple method allows the base‐free functionalization of aryl esters to form α‐functionalized products containing two contiguous tertiary stereogenic centres in excellent yield and stereoselectivity (all ≥99:1 er). Key to the success of this methodology is the multifunctional role of the aryloxide, which operates as a leaving group, Brønsted base, Brønsted acid and Lewis base within the catalytic cycle. Comprehensive mechanistic studies, including variable time normalization analysis (VTNA) and isotopologue competition experiments, have been carried out. These studies have identified (i) orders of all reactants; (ii) a turnover‐limiting Michael addition step, (iii) product inhibition, (iv) the catalyst resting state and (v) catalyst deactivation through protonation.

Base-free Enantioselective C(1)-Ammonium Enolate Catalysis Exploiting Aryloxides: A Synthetic and Mechanistic Study.

An isothiourea-catalyzed enantioselective Michael addition of aryl ester pronucleophiles to vinyl bis-sulfones via C(1)-ammonium enolate intermediates has been developed. This operationally simple method allows the base-free functionalization of aryl esters to form α-functionalized products containing two contiguous tertiary stereogenic centres in excellent yield and stereoselectivity (all ≥99:1 er). Key to the success of this methodology is the multifunctional role of the aryloxide, which operates as a leaving group, Brønsted base, Brønsted acid and Lewis base within the catalytic cycle. Comprehensive mechanistic studies, including variable time normalization analysis (VTNA) and isotopologue competition experiments, have been carried out. These studies have identified (i) orders of all reactants; (ii) a turnover-limiting Michael addition step, (iii) product inhibition, (iv) the catalyst resting state and (v) catalyst deactivation through protonation.

BINOL Phosphoric Acid-Catalyzed Asymmetric Mannich Reaction of Cyclic N-Acyl Ketimines with Cyclic Enones.

A highly enantio- and diastereoselective Mannich reaction of cyclic N-acyl ketimines generated in situ from 3-hydroxyisoindolin-1-ones with cyclic enones has been accomplished using a chiral phosphoric acid catalyst to afford the chiral isoindalinone derivatives in high yields with excellent enantioselectivities (upto 97 % ee). This is the first report on the synthesis of chiral isoindolin-1-ones bearing adjacent quaternary and tertiary stereogenic centers.

Organocatalyzed Annulation Cascade toward Asymmetric Functionalization of Dibenzoxazepines and Dibenzothiazepines with Vicinal Tertiary Stereogenic Centers

AbstractAn efficient organocatalyzed annulation cascade has been established for the stereoselective functionalization of dibenzoxazepine and dibenzothiazepine scaffolds. The protocol used ready‐stock proline as a catalyst and a variety biologically important oxa/thiazepine based polycyclic frameworks featuring congested chiral vicinal tertiary centers were obtained in high yields and excellent diastereoselectivities (>20:1 dr) and enantioselectivities (>96:4 er). Synthetic utility was showcased through the gram‐scale reaction and diverse derivatization sequences.

Preparation of a Chiral Building Block by an Organocatalytic Asymmetric Intramolecular Michael Reaction

AbstractThe preparation of a chiral building block, including a stereodiad consisting of two tertiary stereogenic centers, by a highly enantioselective organocatalytic intramolecular Michael reaction is described. The use of a chiral secondary‐amine‐bearing thiourea substituted with a para‐nitrophenyl group in the presence of benzoic acid is key to preparing the chiral building block in high yield and excellent enantioselectivity. The prepared chiral building block has both aldehyde and nitro groups, allowing a variety of functional‐group transformations necessary for the total synthesis of atisane‐type terpenoids.

Enantioselective synthesis of pyrano[2,3-c]pyrrole via an organocatalytic [4 + 2] cyclization reaction of dioxopyrrolidines and azlactones.

An enantioselective [4 + 2] cyclization reaction of dioxopyrrolidines and azlactones has been successfully developed through a squaramide catalysis strategy. This protocol provides an efficient and mild access to obtain pyrano[2,3-c]pyrrole scaffolds containing contiguous quaternary and tertiary stereogenic centers in excellent yields (up to 99%) with high levels of diastereo- and enantioselectivities (up to 99% ee). Two possible pathways were proposed to explain the observed stereoselectivity.

Palladium‐Catalyzed Enantioselective Addition of Chiral Metal Enolates to In Situ Generated ortho‐Quinone Methides

AbstractWe describe herein a conceptually novel, cooperative Brønsted acid/base catalyzed process for the conjugate addition of cyclic β‐keto esters to ortho‐quinone methides both generated in situ. Upon hemiacetalization, densely functionalized chiral chromans with two adjacent quaternary and additionally a tertiary stereogenic center were obtained with very good diastereoselectivity (up to >95:5 d.r.) and typically excellent enantioselectivity (up to >99 % ee). The striking feature and key to success is the dual catalytic activation of both nucleophile and electrophile in two separate cycles with a single chiral catalyst.

Palladium-Catalyzed Enantioselective Addition of Chiral Metal Enolates to In Situ Generated ortho-Quinone Methides.

We describe herein a conceptually novel, cooperative Brønsted acid/base catalyzed process for the conjugate addition of cyclic β-keto esters to ortho-quinone methides both generated in situ. Upon hemiacetalization, densely functionalized chiral chromans with two adjacent quaternary and additionally a tertiary stereogenic center were obtained with very good diastereoselectivity (up to >95:5 d.r.) and typically excellent enantioselectivity (up to >99 % ee). The striking feature and key to success is the dual catalytic activation of both nucleophile and electrophile in two separate cycles with a single chiral catalyst.

Enantioselective Synthesis of Tertiary Allylic Fluorides by Iridium‐Catalyzed Allylic Fluoroalkylation

AbstractFew allylic electrophiles containing two different substituents at a single allyl terminus and none in which one of the two substituents is a heteroatom, have been shown previously to react with iridium catalysts to form substitution products. We report that iridium‐catalysts are uniquely suited to form tertiary allylic fluorides enantioselectively by the addition of a diverse range of carbon‐centered nucleophiles at the fluorine‐containing terminus of 3‐fluoro‐substituted allylic esters. The products contain tertiary stereogenic centers bearing a single fluorine, which are isosteric with common tertiary stereocenters containing a single hydrogen. Computational studies reveal the principal steric interactions influencing the stability of endo and exo π‐allyl intermediates formed from 3,3‐disubstituted allylic electrophiles.

Asymmetric Rh(I)-Catalyzed Functionalization of the 3-C( sp3)-H Bond of Benzofuranones with α-Diazoesters.

An asymmetric Rh(I)-catalyzed functionalization of the 3-C( sp3)-H bond of benzofuranones with α-diazoesters has been developed, providing a new strategy for the stereoselective 3-alkylation of benzofuranones. With low catalyst loadings (low to 0.02 mol % Rh), a number of benzofuranones bearing consecutive quaternary and tertiary stereogenic centers have been synthesized (up to 94% yield, 95:5 dr, and >99% ee). The synthetic utilities of this methodology have been demonstrated by elaborating the model product 3aa to a series of enantiopure compounds with similarities to natural products and drug candidates.

Copper-catalyzed Enantioselective Intramolecular Alkylboron Allylic Alkylation

A reductive C–C-bond-forming cyclization of vinyl-terminated allyl chlorides via alkene hydroboration with 9-BBN-H followed by Cu-catalyzed asymmetric intramolecular allylic alkylation with a new chiral phosphoramidite ligand produced six-membered ring compounds with a tertiary or quaternary stereogenic center in the ring with high enantioselectivity.

Copper-Catalyzed Enantioselective Coupling between Allyl­boronates and Phosphates Using a Phenol–Carbene Chiral Ligand: Asymmetric Synthesis of Chiral Branched 1,5-Dienes

Details of the Cu-catalyzed enantioselective allyl–allyl coupling reaction between allylboronates and (Z)-allylic phosphates using a new chiral N-heterocyclic carbene (NHC) ligand containing a phenolic hydroxy group are presented. The copper catalysis delivers enantio­enriched chiral 1,5-dienes with a tertiary stereogenic center. Compatibility with various functional groups and the use of earth-abundant and relatively low-toxicity copper as a metal are attractive features of this protocol. The utility of the chiral phenol–NHC ligand for enantioselective copper catalysis with organoboron compounds is demonstrated and enantiodiscrimination models are discussed.

A facile and highly diastereoselective synthesis of carbocyclic spiro-pyrazolones via DABCO catalyzed Michael-Michael domino reaction

An efficient domino Michael-Michael reaction of ω- and δ-nitro α,β-unsaturated esters with alkylidenepyrazolones has been accomplished using DABCO as the organocatalyst under mild reaction conditions. Under the present organocatalytic method, a wide range of carbocyclic spiro-pyrazolones with three tertiary stereogenic centers and a quaternary stereocenter has been prepared in high yields and excellent diastereoselectivities. An ester and nitro groups present in the spiro-pyrazolones have been utilized for further structural transformations.