Stereoselective Access Research Articles

Stereocontrolled Synthesis of 1,4-Dicarbonyls via [3,3]-Sulfonium Rearrangement and Application to the Synthesis of Heterocycles

Due to an inherent polarity mismatch of the corresponding retrosynthetic synthons, 1,4-dicarbonyl synthesis through polar pathways requires a retrosynthetic rethink. While Umpolung-based approaches exist, efficient control of both the absolute and relative configuration of newly formed stereogenic centres within this motif has long proven particularly challenging. In this Synpacts, we highlight our work on the stereodivergent synthesis of 1,4-dicarbonyl compounds through an unusual transformation that relies on vinyl sulfoxides and ynamides as reactants. This method allows stereoselective access to each and every one out of the four possible stereoisomers of a generic 1,4-dicarbonyl target in a process where enantio- and diastereoselectivity are “dialled into” the vinyl sulfoxide partner. Recent studies show that the thus formed 1,4-dicarbonyls serve as excellent linchpins for structural diversification into highly substituted heterocycles, including those found in natural products. 1. Introduction 2. Synthesis of 1,4-dicarbonyl compounds under acid catalysis 3. Cyclisation towards γ-lactones and γ-lactams 4. Application in total synthesis 5. Conclusion

Stereoselective Access to Spiro-isoindolinone Scaffolds via Catalytic Asymmetric aza-Piancatelli Rearrangement.

A chiral Brønsted acid catalyzed asymmetric aza-Piancatelli rearrangement of 3-furyl-3-hydroxyisoindolinones with anilines has been developed, enabling the divergent construction of chiral spiro-cyclopentenone-isoindolinones in high yields with excellent diastereo- and enantioselectivities even under a low catalyst loading of 0.5 mol%.

Stereoselective Access to Diverse Alkaloid-Like Scaffolds via an Oxidation/Double-Mannich Reaction Sequence.

Sequential oxidative cleavage and double-Mannich reactions enable the stereoselective conversion of simple norbornenes into complex alkaloid-like structures. The products undergo a wide range of derivatization reactions, including regioselective enol triflate formation/cross-coupling sequences and highly efficient conversion to an unusual tricyclic 8,5,5-fused lactam. Overall, the process represents a formal one-atom aza-ring expansion with concomitant bridging annulation, making it of interest for the broader derivatization of alkene feedstocks.

Chemo-, regio- and stereoselective access to polysubstituted 1,3-dienes via Nickel-catalyzed four-component reactions

1,2-Difunctionalization of alkynes offers a straightforward approach to access polysubstituted alkenes. However, simultaneous multi-component cascade transformations including difunctionalization of two alkynes with both syn- and anti-selectivity in one catalyst system is undeveloped and proves to be a significant challenge. Herein, we report a Nickel-catalyzed four-component reaction to access polysubstituted 1,3-dienes using two terminal alkynes, aryl boroxines, and perfluoroalkyl iodides, wherein the reaction forms three new C-C bonds in a single vessel and serve as a modular strategy to access polysubstituted 1,3-dienes with excellent chemoselectivity, good regioselectivity and exclusive stereoselectivity. Control experiments reveal the plausible reaction mechanism and DFT calculations explain the cause for the formation of this unusual four-component reaction. Furthermore, we successfully incorporate two biologically active units into 1,2,3,4-tetrasubstituted 1,3-dienes, which greatly increases the diversity of molecular scaffolds and brings more potential values to medicinal chemistry, the synthetic utility of our protocol is further demonstrated by the late-stage transformations.

Regio- and stereoselective access to highly substituted vinylphosphine oxides via metal-free electrophilic phosphonoiodination of alkynes

In general, the P-centered ring-opening of quaternary phosphirenium salts (QPrS) predominantly leads to hydrophosphorylated products, while the C-centered ring-opening is primarily confined to intramolecular nucleophilic reactions, resulting in the formation of phosphorus-containing cyclization products instead of difunctionalized products generated through intermolecular nucleophilic processes. Here, through the promotion of ring-opening of three-member rings by iodine anions and the quenching of electronegative carbon atoms by iodine cations, we successfully synthesize β-functionalized vinylphosphine oxides by the P-addition of QPrS intermediates generated in situ. Multiple β-iodo-substituted vinylphosphine oxides can be obtained with exceptional regio- and stereo-selectivity by reacting secondary phosphine oxides with unactivated alkynes. In addition, a variety of β-functionalized vinylphosphine oxides converted from C-I bonds, especially the rapid construction of benzo[b]phospholes oxides, demonstrates the significance of this strategy.

A Domino Dearomative ipso-Annulation/Desymmetrization Approach: Stereoselective Access to Tricyclic Alkaloid Skeletons.

Herein, we reveal an unprecedented domino annulation of N-benzyl-acrylamides with 1,3-dicarbonyls for the assembly of fused tricyclic alkaloid frameworks incorporating a spirocycle via an alkylation/dearomative ipso-annulation/Michael addition (desymmetrization) sequence. This conversion involves three carbon-carbon bond formations, generating four chiral carbons, including three quaternary carbon centers, in a single diastereomer in one pot under identical reaction conditions. The synthetic potential of this atom-economic method is illustrated by modifications of the functional groups present in the products obtained.

Stereoselective Access to β‐gem‐Difluorinated Alcohols Through Enzymatic Reduction

AbstractWe report here a mild process to access diversely functionalized enantioenriched β‐gem‐difluorinated (S)‐alcohols by using biocatalytic reduction in >99% yield and enantiomeric excesses ranging from 96% to >99%. This novel approach involves enzymatic reduction of α‐gem‐difluorinated heterocyclic and carbocyclic ketone derivatives as well as an acyclic gem‐difluorinated β‐ketosulfone and proceeds under mild conditions at 30 °C under aqueous conditions to produce a range of high added value enantioenriched difluorinated alcohols including 3,3‐difluorochromanol, 3,3‐difluorothiochromanol, 3,3‐difluoro‐dihydroquinolinol, and α‐difluorinated β‐hydroxysulfone derivatives. A comparative study between enzymatic reduction and metal‐catalyzed asymmetric transfer hydrogenation was carried out as well.

Selective Synthesis of Functionalized 3(2H)‐Furanones via Tandem Michael Addition/Rearrangement/Cyclization Reaction of Aliphatic Alkynones: A Combined Experimental and Theoretical Study

AbstractA novel catalyst‐ and solvent‐controlled dimerization of aliphatic alkynones through tandem Michael addition/rearrangement/cyclization sequence has been developed. The elaborated protocol provides a convenient chemo‐, regio‐ and stereoselective access to rare 3(2H)‐furanones decorated with 2‐exo‐methylene and 4‐ethenyl functionalities. A comprehensive density functional theory (DFT) study of possible reaction mechanism including ab initio molecular dynamics (AIMD) simulations and quantum theory of atoms in molecules (QTAIM) analysis of various substrate/catalyst/solvent complexes has revealed the Janus‐like behavior of the employed sodium tert‐butoxide/toluene system that is responsible both for the chemoselectivity of the initial addition step and the inhibition of the final cyclization step.

Kinetic resolution of 1-(1-alkynyl)cyclopropyl ketones via gold-catalyzed divergent (4 + 4) cycloadditions: stereoselective access to furan fused eight-membered heterocycles.

Chiral eight-membered heterocycles comprise a diverse array of natural products and bioactive compounds, yet accessing them poses significant challenges. Here we report a gold-catalyzed stereoselective (4 + 4) cycloaddition as a reliable and divergent strategy, enabling readily accessible precursors (anthranils and ortho-quinone methides) to be intercepted by in situ generated gold-furyl 1,4-dipoles, delivering previously inaccessible chiral furan/pyrrole-containing eight-membered heterocycles with good results (56 examples, all >20 : 1 dr, up to 99% ee). Moreover, we achieve a remarkably efficient kinetic resolution (KR) process (s factor up to 747). The scale-up synthesis and diversified transformations of cycloadducts highlight the synthetic potential of this protocol. Computational calculations provide an in-depth understanding of the stereoselective cycloaddition process.

Mild ketyl radical generation and coupling with alkynes enabled by Cr catalysis: stereoselective access to E-exocyclic allyl alcohols.

The mild catalytic generation of ketyl radicals for organic transformations remains an unsolved issue, although it facilitates the discovery of metal-catalyzed reactions with the features of high functional group tolerance. Here, we report the generation of the ketyl radicals and coupling with alkynes that was enabled by cost-effective chromium catalysis, allowing for the formation of valuable E-exocyclic allyl alcohols with high stereo- and chemoselectivity. A broad range of synthetically useful functional groups that are sensitive to strong reductants are compatible with the catalytic system, providing access to diverse substituted E-exocyclic allyl alcohols under mild conditions. Appended hydroxyl groups in products are facilely late-stage functionalized in accessing numerous derivatives, as well as the enantio-enrichment of exocyclic allyl alcohol using chiral ligands. Mechanistic studies suggest that bipyridine-ligated Cr(ii) complex serves as a reactive catalyst enabling the generation of the ketyl radical for coupling, giving vinyl radical, followed by the combination of Cr and transmetalation with Cp2ZrCl moiety in affording oxazirconiumacycle. This reaction provides a new opportunity for the mild formation of transient ketyl radicals from widely accessible aliphatic aldehydes for coupling with Earth-abundant metal catalysis.

Synthesis of (E)-vinyl sulfides via copper-catalyzed hydrothiolation of internal alkynes with thiosulfonates and silanes

A copper-catalyzed syn-hydrothiolation of internal alkynes with thiosulfonates and silanes has been disclosed, which offers regio- and stereoselective access to (E)-vinyl sulfides.

Tandem (4 + 3)-Annulation of Aziridines: Stereoselective Access to Fused Azepinoindoles.

A stereoselective tandem (4 + 3)-coupling of aziridines with 4-alkylidene indole malonates has been disclosed under Cu-catalysis involving a base-promoted annulation. The methodology serves as a potential approach toward the facile construction of fused azepinoindoles with good yields and diastereoselectivities. Late-stage natural product and drug modification as well as preliminary investigations for the enantioselective (4 + 3)-annulation are important practical features.

Nickel-catalyzed direct stereoselective α-allylation of ketones with non-conjugated dienes

The development of efficient and sustainable methods for the construction of carbon-carbon bonds with the simultaneous stereoselective generation of vicinal stereogenic centers is a longstanding goal in organic chemistry. Low-valent nickel(0) complexes which promote α-functionalization of carbonyls leveraging its pro-nucleophilic character in conjunction with suitable olefin acceptors are scarce. We report a Ni(0)NHC catalyst which selectively converts ketones and non-conjugated dienes to synthetically highly valuable α-allylated products. The catalyst directly activates the α-hydrogen atom of the carbonyl substrate transferring it to the olefin acceptor. The transformation creates adjacent quaternary and tertiary stereogenic centers in a highly diastereoselective and enantioselective manner. Computational studies indicate the ability of the Ni(0)NHC catalyst to trigger a ligand-to-ligand hydrogen transfer process from the ketone α-hydrogen atom to the olefin substrate, setting the selectivity of the process. The shown selective functionalization of the α-C-H bond of carbonyl groups by the Ni(0)NHC catalyst opens up new opportunities to exploit sustainable 3d-metal catalysis for a stereoselective access to valuable chiral building blocks.

Nickel-Catalyzed Migratory Cross-Coupling Reactions: New Opportunities for Selective C-H Functionalization.

ConspectusMigratory cross-coupling via metal migration is a process of significant academic and industrial interest. It provides an attractive alternative for the selective installation of a functional group at remote C-H positions from simple precursors, thus enabling the direct synthesis of challenging structures not accessible with traditional cross-coupling. In particular, with the merger of 1,n-Ni/H shift and cross-coupling of nickel, the Ni-catalyzed migratory functionalization of simple precursors has undergone particularly intense development and emerged as a valuable field of research in the past few years. This Account will outline the recent progress made in this arena in terms of migration-functionalization modes, diverse functionalizations, and strategies for regio- and stereocontrol. Mechanistic studies and synthetic applications are also discussed.In detail, we systematically categorize our work into two parts based on the migration modes. In the first part, a platform is created for Ni-catalyzed migratory sp3 C-H functionalization of alkenes or alkyl halides via iterative 1,2-Ni/H shift-selective cross-coupling. The key reactive Ni(II)H species for chain-walking could be generated in situ either in a polarity-reversed fashion relying on stoichiometric reductants (X-Ni(II)-H) or in a redox-neutral fashion with the participation of nucleophilic coupling partners (FG-Ni(II)-H). One significant advantage associated with the polarity-reversed NiH system is the use of relatively stable, abundant, and safe olefin surrogates or alkyl halides instead of the sensitive organometallics required in traditional cross-coupling reactions. Another advantage is that diverse functionalizations, including carbonation and more challenging amination and thiolation could be smoothly achieved with suitable electrophiles or their precursors. Finally, to address the challenging multifaceted selectivity and reactivity issues in asymmetric migratory cross-coupling reactions, we have developed a feasible ligand relay catalytic strategy. In this dynamic ligand exchange process, one ligand promotes rapid migration while the other promotes highly regio- and stereoselective coupling. This innovative strategy overcomes the formidable challenge stemming from the difficulty of designing a single ligand to efficiently promote both steps of chain-walking and asymmetric coupling. In the second part, a new platform for Ni-catalyzed migratory sp2 C-H functionalization via 1,4-Ni/H shift-selective cross-coupling has been reported. Starting from readily available aryl or vinyl coupling partners, the in situ-generated aryl- or vinylnickel(II) species could undergo a rapid and reversible 1,4-Ni/H shift along an sp2 backbone, and subsequent selective coupling with various coupling partners would allow regio- and stereoselective access to diverse 1,4-migratory functionalization products. The key to success was the discovery of an appropriate ligand to efficiently promote both migration and subsequent selective cross-coupling. A vinyl-to-aryl 1,4-Ni/H shift successfully enables the modular ipso/ortho difunctionalization of aryl coupling partners, while an aryl-to-vinyl 1,4-Ni/H shift enables regio- and stereoselective access to functionalized trisubstituted alkenes.We hope that this Account will inspire broad interest and future development of migratory cross-coupling reactions. We strongly believe that continued efforts in this fascinating field will overcome many of the remaining challenges, including cutting-edge ligand/catalyst design to enhance reactivity and selectivity, conceptually new migration modes for additional transformations, and in-depth mechanistic studies for rational reaction design.

Stereoselective Construction of β-chiral Homoallyl Functionalities by Substrate- and Reagent-Controlled Iterative 1,2-Metallate Rearrangements.

Homoallylic alcohols possessing chiral β-centers are considered highly valuable in the synthesis of polyketide-based natural products. Therefore, there is a significant demand for new methods that allow for their stereoselective access. In pursuit of this objective, we have successfully combined our substrate-controlled protocol of Hoppe-Matteson-Aggarwal chemistry with iterative 1,2-metallate rearrangements. Notably, this approach has proven effective in introducing not only primary alcohols but also other functional groups such as alkynes and protected amines.

Palladium-Catalyzed Intermolecular Dearomatization Annulation Cascade Reaction of Furans for Stereoselective Access to 2,5-Dihydrofurans.

A novel palladium-catalyzed intermolecular dearomatization of furans with alkynes via a three-component formal [3 + 2] spiroannulation/allylic substitution cascade reaction has been successfully developed for the stereoselective assembly of spiro 2,5-dihydrofuran frameworks. High step economy and efficacy as well as excellent stereoselectivity were achieved for a broad substrate scope. Two new C-C bonds and one new C-O bond were generated sequentially in a one-pot manipulation. The yielded spiro 2,5-dihydrofuran skeleton bearing a tetrasubstituted carbon center constitutes the core structure for plenty of useful natural products or corresponding analogues. This work represents a significant advancement in the dearomatization strategy for furan heterocycles and provides a practical methodology for expedited access to complex spiro dihydrofuran scaffolds.

Catalytic Alkyne Allylboration: A Quest for Selectivity.

Catalytic methodologies that enable the synthesis of complex organic molecules from simple and readily available starting materials represent a goal in modern synthetic chemistry. In particular, multicomponent carboboration reactions that provide stereoselective access to densely functionalized building blocks are particularly valuable to achieve molecular diversity. This Perspective covers the developments in the area of catalytic allylboration of alkynes and highlights the key features that have allowed for the control of the regio-, diastereo-, and enantioselectivity in these transformations.

Hydroalkoxylation-Initiated Cascade on Sulfone-Tethered Aryl Alkynols Gives Cyclic and Spiro-Heterocyclic β-Ketosulfones.

Serendipitous formation of cyclic β-ketosulfones is observed when sulfone-tethered arylalkynols are reacted with base. The reaction involves a base-promoted propargyl sulfone to the allene isomerization/intramolecular hydroalkoxylation/retro-oxa-Michael/6-endo-trig Michael addition cascade. Sulfone-tethered alkynyl acrylates gave stereoselective access to a diverse array of spirocyclic β-ketosulfone benzofuran/isochroman/indolines and sulfone-tethered bridged bicyclo[3.3.1]nonane. These cyclic β-ketosulfones could be readily elaborated into benzofuran-fused cyclic sulfones and tetracyclic spiroindoline.

Stereoselective Synthesis of β-glycosyl Esters via 1-Hydroxybenzotriazole Mediated Acylation of Glycosyl Hemiacetals.

Highly stereoselective access to β-glycosyl esters was disclosed, employing 1-hydroxybenzotriazole (HOBt) mediated esterification of glycosyl hemiacetals in the presence of EDCI and 1,4-diazabicyclo[2.2.2]octane (DABCO). Mechanistic studies indicated a dynamic kinetic acylation pathway. In addition, a stereoretentive esterification of glycosyl hemiacetals with tert-butyloxycarbonyl ortho-hexynylbenzoate and DMAP was also reported.

Functionalization of Olefinic C−H Bonds by an Aryl‐to‐Vinyl 1,4‐Nickel Migration/Reductive Coupling Sequence

AbstractAn attractive approach to selective functionalization of remote C−H bonds is a metal/hydride shift/cross‐coupling reaction sequence. Complimentary to the heavily exploited 1,2‐nickel/hydride shift along an sp3 chain, a chain‐walking process, the 1,4‐nickel/hydride shift along an sp2 chain is more complex. Here we report an unprecedented aryl‐to‐vinyl 1,4‐nickel/hydride shift reaction, in which the migratory alkenylnickel species generated in situ is selectively trapped by one of various coupling partners, such as isocyanates, alkyl bromides, aryl chlorides or alkynyl bromides, allowing regio‐ and stereoselective access to trisubstituted alkenes. In contrast to the well‐reported ipso‐aryl coupling reactions, this strategy provides remote alkenyl C−H functionalized products with good yield and with excellent chemo‐, regio‐ and E/Z‐selectivity.