Decarboxylative Asymmetric Allylic Alkylation Research Articles

Asymmetric Synthesis of Quaternary α-Aryl Stereocentres in Benzofuran-3(2H)-Ones Using Decarboxylative Asymmetric Allylic Alkylation.

The Pd-catalysed decarboxylative asymmetric allylic alkylation (DAAA) has been applied to the enantioselective synthesis of sterically hindered benzofuran-3(2H)-one-derived α-aryl-β-keto esters employing the (R,R)-ANDEN phenyl Trost ligand. A range of substrates were synthesised, employing previously developed aryllead triacetate methodology to install various aryl groups. The resulting α-aryl-α-allyl benzofuran-3(2H)-one DAAA products were obtained in moderate to high yields and in enantioselectivities of up to 96 % ee, with the best results observed for substrates containing a di-ortho-substitution pattern on the aryl ring as well as naphthyl-containing substrates.

Enantioselective Synthesis of Sterically Hindered α‐Allyl‐α‐Aryl Lactams via Palladium‐Catalysed Decarboxylative Asymmetric Allylic Alkylation

AbstractThe Pd‐catalysed decarboxylative asymmetric allylic alkylation (DAAA) of sterically hindered α‐aryl,β‐amido allyl ester lactams has been developed. The key step in the synthesis of a range of α‐aryl lactam substrates for catalysis was a Pb‐mediated α‐arylation of a β‐amido allyl ester affording 14 novel examples of α‐aryl‐β‐amido allyl ester lactams in good yields (up to 80 %). The Pd‐catalysed DAAA was optimised with the 2,4,6‐trimethoxyphenyl‐containing substrate. Using (S,S)‐DACH‐phenyl Trost as the optimal chiral ligand, enantioselectivities of up to 82 % ee were obtained. A substrate scope of 11 examples of α‐aryl‐β‐amido allyl ester lactams showed that products containing the di‐ortho‐methoxy‐substituted phenyls and naphthyl groups gave rise to the highest ees, whereas products not bearing this substitution pattern showed lower enantioselectivities (<60 % ee). Transition states to rationalise the observed stereochemical outcome are proposed.

Catalytic Decarboxylative Asymmetric Allylic Alkylation for the Synthesis of Axially Chiral Biaryls

AbstractHerein, we report a palladium‐catalyzed atroposelective decarboxylative asymmetric allylic alkylation. A chiral palladium complex with a phosphoramidite ligand effectively desymmetrizes biaryls containing cinnamyl carbonate with excellent enantioselectivities. The addition of a catalytic amount of base accelerates the reaction process without loss of enantioselectivity. Cross‐over experiment provides mechanistic insight, suggesting that allyl palladium complex primarily dissociates from the original biaryl substrate and deliver allyl species intermolecularly. Analysis of product distribution at various time points indicates that secondary kinetic resolution plays a crucial role in achieving remarkable atroposelectivity.

Decarboxylative Asymmetric Allylic Alkylation for the Synthesis of α‑Difunctionalized Cyclic Sulfones

Decarboxylative Asymmetric Allylic Alkylation for the Synthesis of α‑Difunctionalized Cyclic Sulfones

Catalytic Enantioselective Synthesis of α-Difunctionalized Cyclic Sulfones.

As saturated heterocyclic building blocks become increasingly popular in medicinal chemistry and drug discovery programs, expansion of the synthetic toolkit to novel stereofunctionalized heterocycles is a priority. Herein, we report the development of a palladium-catalyzed decarboxylative asymmetric allylic alkylation reaction to access a broad range of enantioenriched α-difunctionalized 5- and 6-membered sulfones from easily accessible racemic starting materials. The allylic alkylation step was found to occur with high levels of enantioselectivity as a result of a palladium-mediated dynamic kinetic resolution of E/Z enolate intermediates. This methodology paves the way to hitherto unexplored stereodefined cyclic sulfones for medicinal chemistry applications.

Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Thietane 1,1-Dioxides.

A palladium-catalyzed decarboxylative asymmetric allylic alkylation of thietane 1,1-dioxides via linear enolate intermediates from racemic starting materials has been developed. This process installs an α-sulfonyl tetrasubstituted stereogenic center with high enantioselectivity. The potential to transform the alkylated products to novel types of enantioenriched spirocycles for medicinal chemistry applications has also been demonstrated.

Synthesis of Enantioenriched gem-Disubstituted 4-Imidazolidinones by Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation.

A variety of enantioenriched gem-disubstituted 4-imidazolidinones were prepared in up to >99% yield and 95% ee by the Pd-catalyzed decarboxylative asymmetric allylic alkylation of imidazolidinone-derived β-amidoesters. In the process of preparing these substrates, a rapid synthetic route to 4-imidazolidinone derivatives was developed, beginning from 2-thiohydantoin. The orthogonality of the benzoyl imide and tert-butyl carbamate groups used to protect these nitrogen-rich products was demonstrated, enabling potential applications in drug design.

Recent Advances in the Construction of Quaternary Stereocenters via Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation

AbstractPalladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) provides an efficient and powerful strategy to construct quaternary stereocenters, which are widely present in biologically active natural products and approved drugs. In this short review, we summarize recent developments (since 2018) in the facile synthesis of quaternary stereocenters via DAAA methods. Several representative examples of the use of DAAA strategies for the total synthesis of complex natural products further demonstrate its synthetic potential in the realm of organic and medicinal chemistry.1 Introduction2 Construction of Quaternary Stereocenters via Palladium Catalyzed DAAA3 Construction of Quaternary Stereocenters via Pd-Catalyzed Interceptive DAAA4 Application of DAAA in Natural Product Synthesis5 Conclusion

Reaction Mechanism, Origins of Enantioselectivity, and Reactivity Trends in Asymmetric Allylic Alkylation: A Comprehensive Quantum Mechanics Investigation of a C(sp3)-C(sp3) Cross-Coupling.

We utilize quantum mechanics to evaluate a variety of plausible mechanistic pathways for the entirety of the catalytic cycle for asymmetric decarboxylative allylic alkylation of allyl β-ketoesters. We present a mechanistic picture that unites all current experimental observations, including enantioinduction, reaction rate, catalyst resting state, enolate crossover experiments, water tolerance, and the effects of solvation on inner- and outer-sphere mechanisms. Experiments designed to evaluate the fidelity and predictive power of the computational models reveal the methods employed herein to be highly effective in elucidating the reactivity of the catalytic system. On the basis of these findings, we highlight a computational framework from which chemically accurate results are obtained and address the current limitations of the decarboxylative asymmetric allylic alkylation reaction.

Probing Trends in Enantioinduction via Substrate Design: Palladium-Catalyzed Decarboxylative Allylic Alkylation of α-Enaminones

Herein, we report the palladium-catalyzed decarboxylative asymmetric allylic alkylation of α-enaminones. In addition to serving as valuable synthetic building blocks, we exploit the α-enaminone scaffold and its derivatives as probes to highlight structural and electronic factors that govern enantioselectivity in this asymmetric alkylation reaction. Utilizing the (S)-t-BuPHOX ligand in a variety of nonpolar solvents, the alkylated products are obtained in up to 99% yield and 99% enantiomeric excess.

Development of Chemo‐ and Enantioselective Palladium‐Catalyzed Decarboxylative Asymmetric Allylic Alkylation of α‐Nitroesters

AbstractWe describe the development of a Pd‐catalyzed decarboxylative asymmetric allylic alkylation of α‐nitro allyl esters to afford acyclic tetrasubstituted nitroalkanes. Optimization of the reaction parameters revealed unique ligand and solvent combinations crucial for achieving chemo‐ and enantioselective C‐alkylation of electronically challenging benzylic nitronates and sterically encumbered 2‐allyl esters. Substrates were efficiently accessed in a combinatorial fashion by a cross‐Claisen/ α‐arylation sequence. The method provides functional group orthogonality that complements nucleophilic imine allylation strategies for α‐tertiary amine synthesis.

Development of Chemo- and Enantioselective Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of α-Nitroesters.

We describe the development of a Pd-catalyzed decarboxylative asymmetric allylic alkylation of α-nitro allyl esters to afford acyclic tetrasubstituted nitroalkanes. Optimization of the reaction parameters revealed unique ligand and solvent combinations crucial for achieving chemo- and enantioselective C-alkylation of electronically challenging benzylic nitronates and sterically encumbered 2-allyl esters. Substrates were efficiently accessed in a combinatorial fashion by a cross-Claisen/ α-arylation sequence. The method provides functional group orthogonality that complements nucleophilic imine allylation strategies for α-tertiary amine synthesis.

Palladium‐Catalyzed Decarboxylative Asymmetric Allylic Alkylation: Development, Mechanistic Understanding and Recent Advances

AbstractThe palladium‐catalyzed decarboxylative asymmetric allylic alkylation (DAAA) is comprehensively reviewed, from its original development to recent advances in terms of substrate scope, reactivity, regio‐ and enantioselectivity. The current understanding of the mechanistic details, based on a combination of experimental and computational studies, is described. Selected examples of the application of this asymmetric synthetic methodology in natural product synthesis are given. The exploration of Pd‐catalyzed decarboxylative asymmetric catalysis, in particular, the related interceptive decarboxylative asymmetric allylic alkylation, has become a focus in recent years and this is also summarized.magnified image

Cycloadditions of Oxacyclic Allenes and a Catalytic Asymmetric Entryway to Enantioenriched Cyclic Allenes

AbstractThe chemistry of strained cyclic alkynes has undergone a renaissance over the past two decades. However, a related species, strained cyclic allenes, especially heterocyclic derivatives, have only recently resurfaced and represent another class of valuable intermediates. We report a mild and facile means to generate the parent 3,4‐oxacyclic allene from a readily accessible silyl triflate precursor, and then trap it in (4+2), (3+2), and (2+2) reactions to provide a variety of cycloadducts. In addition, we describe a catalytic, decarboxylative asymmetric allylic alkylation performed on an α‐silylated substrate, to ultimately permit access to an enantioenriched allene. Generation and trapping of the enantioenriched cyclic allene occurs with complete transfer of stereochemical information in a Diels–Alder cycloaddition through a point‐chirality, axial‐chirality, point‐chirality transfer process.

Cycloadditions of Oxacyclic Allenes and a Catalytic Asymmetric Entryway to Enantioenriched Cyclic Allenes.

The chemistry of strained cyclic alkynes has undergone a renaissance over the past two decades. However, a related species, strained cyclic allenes, especially heterocyclic derivatives, have only recently resurfaced and represent another class of valuable intermediates. We report a mild and facile means to generate the parent 3,4-oxacyclic allene from a readily accessible silyl triflate precursor, and then trap it in (4+2), (3+2), and (2+2) reactions to provide a variety of cycloadducts. In addition, we describe a catalytic, decarboxylative asymmetric allylic alkylation performed on an α-silylated substrate, to ultimately permit access to an enantioenriched allene. Generation and trapping of the enantioenriched cyclic allene occurs with complete transfer of stereochemical information in a Diels-Alder cycloaddition through a point-chirality, axial-chirality, point-chirality transfer process.

Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Dihydroquinolinones.

A palladium-catalyzed decarboxylative asymmetric allylic alkylation (Pd-DAAA) of benzo-fused and non-benzo-fused δ-valerolactams is disclosed. This methodology gives access to chiral lactams bearing C3-quaternary stereocenters, which are central to many natural products and biologically active compounds. The reaction proceeds via palladium-catalyzed ionization of an allyl ester, followed by carbon dioxide extrusion and recombination of the electrophilic Pd-π-allyl complex with the in situ generated lactam enolate. This final step converts racemic allylic ester starting materials into enantiomerically enriched substituted lactams with high yield and enantiomeric excess.

Synthesis of Chiral Nonracemic α-Difluoromethylthio Compounds with Tetrasubstituted Stereogenic Centers via a Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation.

The synthesis of chiral, nonracemic difluoromethylthio (SCF2H) compounds that contain a tetrasubstituted stereogenic center is reported. Racemic α-SCF2H-β-ketoallylesters 5 were initially prepared by an electrophilic difluoromethylthiolation of β-ketoallylesters 6, followed by a Pd-catalyzed Tsuji decarboxylative asymmetric allylic alkylation (DAAA) to provide a wide variety of chiral, nonracemic α-allyl-α-SCF2H-ketones (4) with high enantiopurity. This strategy can be extended to the enantioselective synthesis of chiral, nonracemic α-allyl-α-trifluoromethylthio(SCF3)-ketones (7).

Quaternary Substituted Oxindoles through Decarboxylative Asymmetric Allylation

Key words decarboxylative asymmetric allylic alkylation - oxindoles - quaternary centers - palladium catalysis

Highly Enantioselective Construction of Sterically Hindered α-Allyl-α-Aryl Lactones via Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation

Pd-catalyzed decarboxylative asymmetric allylic alkylation has been developed for sterically hindered α-aryl, β-oxo-allyl ester lactone substrates. Pb-mediated α-arylation of the β-oxo-allyl ester was used as the key step to synthesize the substrates for catalysis in moderate to high yields. Optimization studies for decarboxylative asymmetric allylic alkylations (DAAA) were conducted using δ-valerolactone-derived α-aryl β-oxo-allyl ester with 2,4,6-trimethoxyphenyl as the aryl substituent. Using (R,R)-ANDEN-phenyl Trost as the chiral ligand, enantioselectivities of up to >99% ee and 98% ee were achieved with the six-membered and five-membered lactone substrates, respectively. Bulky aryl groups containing di-ortho substitutions and naphthyl groups gave the highest enantioselectivities. This synthetic route allows for the simple modification of aryl groups, giving highly enantioselective access to important structural motifs.

Enantioselective synthesis of sterically hindered α-allyl-α-aryl oxindoles via palladium-catalysed decarboxylative asymmetric allylic alkylation.

The highly enantioselective synthesis of sterically hindered α-allyl-α-aryl oxindoles possessing an all-carbon quaternary stereocenter at the oxindole 3-position has been developed. The key step in the synthetic route employed was a novel one-pot, two-step synthesis of α-aryl-β-amido allyl ester substituted oxindoles in good yields of 41-75% (13 examples) by interception of an unstable allyl ester intermediate through reaction with aryllead triacetate reagents. Pd-Catalyzed decarboxylative asymmetric allylic alkylation (DAAA) was optimized with 2,4,6-trimethoxyphenyl as the aryl-containing substrate. A screen of chiral P,N- and P,P-based ligands showed that the ANDEN-phenyl Trost ligand was the most effective, affording the corresponding α-allyl-α-aryl oxindole product in 96% yield and 99% ee. A substrate scope of a further 12 α-aryl-β-amido allyl ester substituted oxindoles showed that products containing bulky di-ortho-methoxy substituted arenes and naphthyl groups were formed in very high ee's (94-98%), whereas those lacking this substitution pattern were formed in more moderate levels of enantioselectivities (56-63% ee). Surprisingly, the 2,6-dimethylphenyl-substituted substrate afforded the O-allylated product in contrast to the expected C-allylated product. A crystal structure was obtained of the 2,4,6-trimethoxyphenyl-substituted α-allyl-α-aryl oxindole product which enabled us to identify the absolute stereochemistry of the quaternary stereocenter formed. A plausible explanation to rationalise the sense of enantioselection observed in these DAAA transformations is also proposed.