Quaternary Stereocenters Research Articles

Copper‐Catalyzed Radical Silylarylation of Activated Alkenes: Preparation of β‐Silyl Amide‐Pharmaceutical Hybrids

AbstractCopper‐catalyzed silylarylation of N‐(arylsulfonyl)acrylamides via a tandem silyl radical addition/1,4‐aryl migration/desulfonylation sequence has been developed. This method employs silanes as the precursor of silyl radical and di‐tert‐butyl peroxide (DTBP) as the initiator. By using this cascade procedure, a series of β‐silyl amide‐pharmaceutical hybrids which contain an α‐all‐carbon quaternary stereocenter were facilely synthesized.

How achiral Brønsted acid is involved in co-catalyst model with chiral phosphoric acid for construction of quaternary carbon stereocenter

How achiral Brønsted acid is involved in co-catalyst model with chiral phosphoric acid for construction of quaternary carbon stereocenter

Enantioselective Ir-Catalyzed Allyl Alkylation/Semipinacol Rearrangement.

The semipinacol rearrangement is a powerful and versatile method for constructing all-carbon quaternary stereocenters. The development of catalytic asymmetric semipinacol rearrangements using multifunctionalizable electrophiles remains highly sought-after in organic synthesis. In this study, a catalytic enantioselective allylic cation-induced semipinacol rearrangement reaction was presented that enables the simultaneous construction of two skipped chiral carbon centers. Chiral Ir(I)-(P,olefin) and Sc(OTf)3 catalysts cooperatively initiate the asymmetric allylic alkylation of alkenyl cyclobutanols with allylic alcohols, triggering ring expansion of the cyclobutanol moiety through a stereoselective 1,2-alkyl migration. The reaction afforded a range of cyclopentanones bearing an α-quaternary carbon that is adjacent to a chiral allyl scaffold. The products were applied to synthesize enantioenriched fused tricyclopentanoids bearing four stereogenic carbon centers.

Catalytic enantioselective reductive Eschenmoser-Claisen rearrangements.

An important challenge in enantioselective catalysis is developing strategies for the precise synthesis of neighboring congested all-carbon quaternary stereocenters. The well-defined transition states of [3,3]-sigmatropic rearrangements and their underlying stereospecificity render them powerful tools for the synthesis of such arrays. However, this type of pericyclic reaction remains notoriously difficult to catalyze, especially in an enantioselective fashion. Herein, we describe an enantioselective reductive Eschenmoser-Claisen rearrangement catalyzed by chiral 1,3,2-diazaphospholene-hydrides. This developed transformation enables full control of the two newly formed acyclic stereogenic centers, leading to amides with vicinal all-carbon quaternary-tertiary or quaternary-quaternary carbon atoms.

Chromium(III)-Catalyzed Desymmetrization of meso-Epoxides via Remote Stereocontrol: Synthesis of Chiral Fluorenes Bearing All-Carbon Quaternary Stereocenters.

An asymmetric desymmetrization of fluorene-derived meso-epoxides is disclosed for the construction of chiral fluorenes bearing an all-carbon quaternary stereocenter at C9. This desymmetrization is catalyzed by a chiral (salen)CrIII complex via remote stereocontrol, producing diverse chiral fluorenes with excellent yields and stereoselectivity. The practicality of this protocol was demonstrated through the transformation of the obtained products to some intriguing enantioenriched polymerizable monomers.

Rhodium-catalyzed enantioselective in situ C(sp3)−H heteroarylation by a desymmetrization approach

A rhodium-catalyzed desymmetrization reaction for enantioselective methyl C−H arylation is achieved by utilizing an in situ arylating reagent via nucleophilic cyclization of o-aminoaryl alkyne. The reaction results in chiral indoles containing all-carbon quaternary stereocenters under atmospheric conditions, with a wide range of substrates exhibiting good enantioselectivity (44 examples). Mechnism and DFT studies show that the stereocontrol is reasonably achieved through the collaborative control of a large silicon substituted chiral ligand and C−H···π, LP···π interactions between aryl rings of the carboxylate group and the substrate. Control experiments demonstrate that Rh-aryl bond formation via in situ nucleophilic cyclization is more critical for reaction efficiency than via C−H activation of the nucleophilic cyclization byproduct.

Stereoselective Construction of Vicinal Quaternary Stereocenters via the 1,6-Conjugate Addition of β,β-Disubstituted N-Sulfinyl Metalloenamines to Isatin-Derived para-Quinone Methides

AbstractA 1,6-conjugate addition reaction of β,β-disubstituted N-tert-butanesulfinyl metalloenamines, generated via stereospecific α-deprotonation of enantioenriched α,α-disubstituted ketimines or deprotonation of the NH in geometry-defined enesulfinamides, with isatin-derived para-quinone methides is developed to build vicinal quaternary stereocenters with high stereocontrol. The resulting 3,3-disubstituted oxindoles contain a less-accessible acyclic quaternary stereogenic carbon substituted with two sterically and electronically similar groups at the α-position of the imino group. This protocol constitutes a rare example of the stereoselective construction of vicinal quaternary stereocenters via the conjugate addition of acyclic enolates/aza-enolates bearing two similar β-substituents.

Regio- and enantioselective synthesis of acyclic quaternary carbons via organocatalytic addition of organoborates to (Z)-Enediketones

The chemical synthesis of molecules with closely packed atoms having their bond coordination saturated is a challenge to synthetic chemists, especially when three-dimensional control is required. The organocatalyzed asymmetric synthesis of acyclic alkenylated, alkynylated and heteroarylated quaternary carbon stereocenters via 1,4-conjugate addition is here catalyzed by 3,3´-bisperfluorotoluyl-BINOL. The highly useful products (31 examples) are produced in up to 99% yield and 97:3 er using enediketone substrates and potassium trifluoroorganoborate nucleophiles. In addition, mechanistic experiments show that the (Z)–isomer is the reactive form, ketone rotation at the site of bond formation is needed for enantioselectivity, and quaternary carbon formation is favored over tertiary. Density functional theory-based calculations show that reactivity and selectivity depend on a key n→π* donation by the unbound ketone’s oxygen lone pair to the boronate-coordinated ketone in a 5-exo-trig cyclic ouroboros transition state. Transformations of the conjugate addition products to key quaternary carbon-bearing synthetic building blocks proceed in good yield.

Navigating Excess Complexity: Total Synthesis of Daphenylline.

Retrosynthetic analysis is a framework for designing synthetic routes to complex molecules that generally prioritizes disconnections which reduce molecular complexity. However, strict adherence to this principle can overlook pathways involving highly complex intermediates that can be easily prepared through powerful bond-forming transformations. Herein, we demonstrate this tactic of generating excess complexity, followed by strategic bond-cleavage, as a highly effective approach for the 11-step total synthesis of the Daphniphyllum alkaloid daphenylline. To implement this strategy, we accessed a bicyclo[4.1.0]heptane core through a dearomative Buchner cycloaddition, which enabled construction of the seven-membered ring after C-C bond cleavage. Installation of the synthetically challenging quaternary stereocenter methyl group was achieved through a thia-Paternò-Büchi [2 + 2] photocycloaddition followed by stereospecific thietane reduction, further illustrating how building excess complexity can enable desired synthetic outcomes after strategic bond-breaking events. This strategy leveraging bond cleavage transformations should serve as a complement to traditional bond-forming, complexity-generating synthetic strategies.

Ni‐Catalyzed Enantioselective Difunctionalization of Alkynes to Azepine Derivatives Bearing a Quaternary Center and an Unprotected Imine†

Comprehensive SummaryThe azepine ring is a prominent structural scaffold in biologically significant molecules. In this study, we present a Ni(II)‐catalyzed asymmetric difunctionalization of alkynes, involving intermolecular regioselective arylation and intramolecular nitrile addition, enabling the synthesis of enantioenriched azepine derivatives. This reaction simultaneously installs an all‐carbon quaternary stereocenter and introduces an unprotected imine functionality, showing great promise for subsequent transformations. The reaction exhibits good tolerance toward various functional groups, resulting in high yields and enantioselectivities. The synthetic utility of this methodology is further demonstrated through gram‐scale synthesis and product derivatization. This research offers an efficient approach to the synthesis of seven‐membered nitrogen heterocycles.

Catalytic Enantioselective Primary C-H Borylation for Acyclic All-Carbon Quaternary Stereocenters.

Creating a perfect catalyst to operate enzyme-like chiral recognition has been a long-sought aim. A challenging example in this context is constructing acyclic all-carbon quaternary stereogenic centers by transition metal-catalyzed enantioselective C-H activation. We now report highly enantioselective iridium-catalyzed primary C-H borylation of α-all-carbon substituted 2,2-dimethyl amides enabled by a tailor-made chiral bidentate boryl ligand (CBL). The success of the current transformation is attributed to the CBL/iridium catalyst, which has a confined chiral pocket. This protocol provides a diverse array of acyclic all-carbon quaternary stereocenters with excellent enantiocontrol and distinct structural features. Computational study reveals that steric hindrance of CBL could regulate the type of dominant orbital interaction between the catalyst and substrate, which is crucial to conferring high chiral induction.

Development of a Scalable Synthesis toward a KRAS G12C Inhibitor Building Block Bearing an All-Carbon Quaternary Stereocenter, Part 2: Asymmetric Synthesis via Shi Epoxidation

Development of a Scalable Synthesis toward a KRAS G12C Inhibitor Building Block Bearing an All-Carbon Quaternary Stereocenter, Part 2: Asymmetric Synthesis via Shi Epoxidation

Development of a Scalable Synthesis toward a KRAS G12C Inhibitor Building Block Bearing an All-Carbon Quaternary Stereocenter, Part 1: From Discovery Route to Kilogram-Scale Production

Development of a Scalable Synthesis toward a KRAS G12C Inhibitor Building Block Bearing an All-Carbon Quaternary Stereocenter, Part 1: From Discovery Route to Kilogram-Scale Production

Dual-Catalyzed Stereodivergent Electrooxidative Homocoupling of Benzoxazolyl Acetate.

The development of a reliable strategy for stereodivergent radical reactions that allows convenient access to all stereoisomers of homocoupling adducts with multiple stereogenic centers remains an unmet goal in organic synthesis. Herein, we describe a dual-catalyzed electrooxidative C(sp3)-H/C(sp3)-H homocoupling with complete absolute and relative stereocontrol for the synthesis of molecules with contiguous quaternary stereocenters in a general and predictable manner. The stereodivergent electrooxidative homocoupling reaction is achieved by synergistically utilizing two distinct chiral catalysts that convert identical racemic substrates into inherently distinctive reactive chiral intermediates, dictate enantioselective radical addition, and allow access to the full complement of stereoisomeric products via simple catalyst permutation. The successful execution of the dual-electrocatalytic strategy programmed via electrooxidative activation provides a significant conceptual advantage and will serve as a useful foundation for further research into cooperative stereocontrolled radical transformations and diversity-oriented synthesis.

Total Synthesis of Acanthodoral Using a Rearrangement Strategy.

We present the second total synthesis of (±)-acanthodoral, a sesquiterpenoid derived from the marine nudibranch Acanthodoris nanaimoensis. Our approach involves a concise three-step transformation from a previously reported compound, resulting in the formation of a less strained precursor of the bicyclo[3.1.1]heptane core and both all-carbon quaternary stereocenters characteristic of the natural product. Notably, this synthetic route incorporates two pivotal steps: a Sm(II)-induced 1,2-rearrangement and a semipinacol rearrangement.

Organocatalytic enantioselective assembly of dispiro-bisoxindoles with vicinal stereocenters.

Notwithstanding the rapid development achieved in enantioselective transformations, accessing contiguous quaternary and tertiary stereocenters ubiquitous in natural products and biologically active compounds has been an important and challenging task for synthetic chemists in modern organic chemistry. Drawing inspiration from the huge significance of spirooxindoles featuring a unique spatial structure and incredible medicinal activities, the search for these fascinating compounds in nature and developing new synthetic routes for installing multiple stereocenters remain core areas for synthetic chemists. This mini-review article demonstrates a transitory overview of the organocatalytic enantioselective strategies developed for assembling broad-spectrum dispiro-bisoxindole scaffolds comprising vicinal quaternary and tertiary stereocenters. While addressing the notable advancement accomplished in this intriguing field, we have also discussed the drawbacks and challenges associated with the reaction findings to support more research.

Synthesis of labionin and avionin precursors via a nitrogen-centred-radical-triggered 1,5-HAT reaction of Tris derivatives.

Labionin and avionin are non-proteinogenic amino acids containing 2,4-diamino-2-(mercaptomethyl)pentanedioic acid that forms the core structures of spirocyclic peptides including labyrinthopeptin A2 and microvionin, respectively. We have developed a diastereoselective synthetic route to labionin and avionin precursors. This route highlights the formation of the quaternary carbon stereocenter of an α,α-disubstituted amino acid via a regioselective 1,5-HAT reaction of a Tris derivative.

Ag(I)-catalyzed asymmetric (2+4) annulation reaction of 5-alkenyl thiazolones: synthesis of enantioenriched spiro[cyclohexenamines-thiazolones

The first metal-catalyzed (2+4) annulation of 5-alkenyl thiazolones and α,α-dicyanoalkylidenes has been developed via vinylogous Michael/cyclization/isomerization reaction. This (2+4) annulation reaction is catalyzed by a chiral Ag-(R)-DTBM-SEGPHOS catalyst, delivering enantioenriched spiro[cyclohexenamines-thiazolone] having contiguous quaternary and tertiary stereocenters in good to excellent yield (up to 80%) and excellent stereoselectivities (up to 97% ee and >20 : 1 dr). This methodology has high functional group tolerance and produces a broad range of enantioenriched products under mild reaction conditions.

Recent advances in stereoselective construction of fluorinated quaternary carbon centers from fluorinated compounds.

There are many fluorinated quaternary carbon structural units in pharmaceuticals and bioactive compounds. Organic chemists are interested in the stereoselective synthesis of fluorinated quaternary carbon structural units. Constructing a fluorinated quaternary carbon stereocenter can be achieved directly and efficiently by the asymmetric catalytic reaction of fluorinated compounds as substrates. This approach aims to construct fluorinated quaternary carbon stereocenters while diversifying the types of fluorinated compounds. This review introduces a series of reactions for synthesizing fluorinated quaternary carbon chiral centers through asymmetric organic catalysis and transition metal catalysis, including alkylation, arylation, Mannich, Michael addition, and allylation reactions. This work will contribute to the development of the synthesis of fluorinated quaternary carbon chiral center-containing compounds in the future.

Access to Chiral Sulfones with An All-Carbon Quaternary Stereocenter from Sulfur Dioxide

Sulfur dioxide (SO2), as an atmospheric pollutant, has been increasingly attracting the interest of scientists regarding its chemical utilization. Vicinal sulfonyl-functionalization of alkenes through SO2 insertion offers an innovative method...