High Stereoselectivity Research Articles

Cu-catalyzed cascade difluoroalkylation/5-endo cyclization/β-fluorine cleavage of ynones.

A copper-catalyzed, redox-neutral cascade difluoroalkylation/5-endo annulation/β-fluorine cleavage of ynones is developed, providing a direct and stereoselective method to access synthetically important α-monofluoroalkenyl cyclopentanones. Mechanistic studies suggest an unprecedented CuII-assisted β-fluorine fragmentation, which may be valuable for the challenging but important C-F bond activation. Moreover, the in situ generated difluorocarbene was found to serve as an effective reductant for the regeneration of copper(I) catalyst, thus avoiding the addition of external reductants.

Enhancing the asymmetric reduction activity of ene-reductases for the synthesis of a brivaracetam precursor

Brivaracetam is an effective third-generation antiepileptic drug, and its two chiral centers are a major challenge for designing an inexpensive large-scale synthesis process. Enzymatic asymmetric reduction offers an alternative biotransformation method for reducing 2-(5H)-furanone-4-propyl (3a) to (R)-4-propyldihydrofuran-2(3 H)-one (3b), which is a key intermediate in synthesizing brivaracetam. However, no enzymes have been reported to catalyze this reaction with both high activity and stereoselectivity. In this study, fourteen ene-reductases were compared, and the old yellow enzyme OYE2 was identified as having strict stereoselectivity but unsatisfactory activity. Through evaluations with structurally similar substrates and alanine-screening methods, two key residues were identified, T37 and Y82, playing critical roles in catalytic activity. The hydrogenation activity of mutants Y82W and T37C increased by 2.97 and 7.13 times, respectively. Molecular dynamics simulation indicates that mutant Y82W might shorten the distance between the electron acceptor and donor, while T37A might decrease the redox potential of FMN and then accelerate hydrogen transfer. These results indicate that tuning the redox potential properties of FMN is an important consideration for engineering FMN-dependent oxidoreductases. During the gram-scale synthesis of 3b, T37C exhibited excellent stereoselectivity (>99 % ee) and conversion (>99 %), laying a foundation for a simple one-step route in producing the chiral precursor brivaracetam.

Engineered Myoglobin Catalysts for Asymmetric Intermolecular Cyclopropanation Reactions.

Biocatalysis has covered an increasingly important role in the synthesis and manufacturing of pharmaceuticals and other high value compounds. In the interest of expanding the range of synthetically useful reactions accessible via biocatalysts, our group has explored the potential and application of engineered myoglobins for 'abiological' carbene transfer catalysis. These transformations provide a direct route for the construction of new carbon-carbon and carbon-heteroatom bonds, including the synthesis of cyclopropane rings, which are key motifs and pharmacophores in many drugs and bioactive natural products. In this award article, we survey the progress made by our group toward the development of myoglobin-based catalysts for asymmetric intermolecular cyclopropanation reactions. The high stereoselectivity exhibited by these biocatalysts in these reactions, combined with their broad substrate scope, scalability, and robustness to high substrate loading and organic co-solvents, contribute to make these systems particularly useful for chemical synthesis and biocatalysis at the preparative scale. Extension of the scope of biocatalytic carbene transfer reactions to include different classes of carbene donor reagents has created new opportunities for the asymmetric synthesis of functionalized cyclopropanes. Furthermore, the integration of myoglobin-catalyzed stereoselective cyclopropanations with chemical diversification of the enzymatic products has furnished attractive chemoenzymatic strategies to access a diverse range of optically active cyclopropane scaffolds of high value for drug discovery, medicinal chemistry, and the synthesis of natural products.

Protein synergistic action-based development and application of a molecularly imprinted chiral sensor for highly stereoselective recognition of S-fluoxetine

In order to improve the recognition performance of MIPs sensors in chiral drug enantiomers, a novel a highly selective molecular recognition method based on protein-assisted immobilization of chiral molecular conformation was developed. S-fluoxetine (S-FLX) as the target chiral molecule, human serum albumin (HSA), which has a high affinity and strong interactions with S-FLX, was screened from 11 proteins to serve as an auxiliary recognition unit for the fixation of chiral conformation. By incorporating HSA into the preparation of molecularly imprinted polymers (MIPs), the natural chirality and high stereoselectivity of the protein were leveraged for the induction and fixation of the stereo conformation of S-FLX, refinement of internal structures of the imprinted cavities. The sensor exhibited excellent chiral recognition ability and high detection sensitivity. The changes of probe signal intensity of the MIPs/HSA sensor were positively correlated with the logarithmic concentration of S-FLX in the range of 1.0 × 10−16–1.0 × 10−11 mol L−1, where a detection limit of 6.43 × 10−17 mol L−1 was achieved (DL = 3δb/K). The selectivity of MIPs/HSA sensor in recognizing S-FLX was increased by 18.5 times and the sensitivity was increased by 2.6 times after the incorporation of HSA. The developed sensor was successfully used for the analysis of S-FLX in fluoxetine hydrochloride capsules.

Enantioselective Single and Dual α-C-H Bond Functionalization of Cyclic Amines via Enzymatic Carbene Transfer.

Cyclic amines are ubiquitous structural motifs found in pharmaceuticals and biologically active natural products, making methods for their elaboration via direct C-H functionalization of considerable synthetic value. Herein, we report the development of an iron-based biocatalytic strategy for enantioselective α-C-H functionalization of pyrrolidines and other saturated N-heterocycles via a carbene transfer reaction with diazoacetone. Currently unreported for organometallic catalysts, this transformation can be accomplished in high yields, high catalytic activity, and high stereoselectivity (up to 99:1 e.r. and 20,350 TON) using engineered variants of cytochrome P450 CYP119 from Sulfolobus solfataricus. This methodology was further extended to enable enantioselective α-C-H functionalization in the presence of ethyl diazoacetate as carbene donor (up to 96:4 e.r. and 18,270 TON), and the two strategies were combined to achieve a one-pot as well as a tandem dual C-H functionalization of a cyclic amine substrate with enzyme-controlled diastereo- and enantiodivergent selectivity. This biocatalytic approach is amenable to gram-scale synthesis and can be applied to drug scaffolds for late-stage C-H functionalization. This work provides an efficient and tunable method for direct asymmetric α-C-H functionalization of saturated N-heterocycles, which should offer new opportunities for the synthesis, discovery, and optimization of bioactive molecules.

Lewis Acid Promoted Stereoselective Synthesis of Polysubstituted 1,3‐Dienes via a Dual 1,3‐Sulfur Rearrangement

Abstract1,3‐Dienes are prevalent substructures in biologically active molecules and versatile building blocks in synthetic chemistry. Herein, using Lewis acids promoted dual 1,3‐sulfur rearrangements, we developed an approach for the direct synthesis of 1,3‐dithianyl substituted dienes. This method enabled the synthesis of tri‐ and tetra‐substituted 1,3‐dienes with high stereoselectivity and good yield under mild reaction conditions.magnified image

Stereodivergent Assembly of 2,6-cis- and -trans-Tetrahydropyrans via Base-Mediated Oxa-Michael Cyclization: The Key Role of the TMEDA Additive.

The stereodivergent synthesis of cis- and trans-2,6-disubstituted tetrahydropyrans (THPs) via sodium hexamethyldisilazide-promoted oxa-Michael cyclization of (E)-ζ-hydroxy α,β-unsaturated esters is presented. The cyclization affords the kinetically favored trans-THPs with high stereoselectivity (dr up to 93:7) at a low temperature (-78 °C), while the room-temperature reaction does not produce the thermodynamically preferred cis-THPs as major products and occurs with poor stereocontrol. The addition of tetramethylethylenediamine (TMEDA) significantly improves the stereochemical outcome of the room-temperature cyclization and allows attaining high cis-selectivity (dr up to 99:1). The remarkable effect of TMEDA indicates that the sodium cation plays an important role in controlling the stereoselectivity of the thermodynamically driven process, that is, complexation of the cation with the cyclization products results in diminished selectivity. DFT calculations support this conclusion, indicating a greater difference in Gibbs energies of sodium-free cis- and trans-enolates compared to the respective sodium chelate complexes. The synthetic utility of the method has been demonstrated by the formal syntheses of (+)-Neopeltolide and (-)-Diospongin B and the total synthesis of (-)-Diospongin A.

Taming Chiral Quaternary Stereocenters via Remote H-Bonding Stereoinduction in Palladium-Catalyzed (3+2) Cycloadditions.

Ring-opening transformations of donor-acceptor (D-A) cyclopropanes enable the rapid assembly of complex molecules. However, the enantioselective formation of chiral quaternary stereocenters using substrates bearing two different acceptors remains a challenge. Herein, we describe the first palladium-catalyzed highly diastereo- and enantioselective (3+2) cycloaddition of vinyl cyclopropanes bearing two different electron-withdrawing groups, a subset of D-A cyclopropanes. The key to the success of this reaction is the remote stereoinduction through hydrogen bond from chiral ligands, which thereby addressed the aforementioned challenge. A variety of chiral five-membered heterocycles were produced in good yields and with high stereoselectivity (up to 99 % yields, 99 : 1 er and >19 : 1 dr). In-depth mechanistic investigations, including control experiments and theoretical calculations, revealed the origin of the stereoselectivity and the importance of H-bonding in stereocontrol.

Taming Chiral Quaternary Stereocenters via Remote H‐Bonding Stereoinduction in Palladium‐Catalyzed (3+2) Cycloadditions

AbstractRing‐opening transformations of donor‐acceptor (D‐A) cyclopropanes enable the rapid assembly of complex molecules. However, the enantioselective formation of chiral quaternary stereocenters using substrates bearing two different acceptors remains a challenge. Herein, we describe the first palladium‐catalyzed highly diastereo‐ and enantioselective (3+2) cycloaddition of vinyl cyclopropanes bearing two different electron‐withdrawing groups, a subset of D‐A cyclopropanes. The key to the success of this reaction is the remote stereoinduction through hydrogen bond from chiral ligands, which thereby addressed the aforementioned challenge. A variety of chiral five‐membered heterocycles were produced in good yields and with high stereoselectivity (up to 99 % yields, 99 : 1 er and >19 : 1 dr). In‐depth mechanistic investigations, including control experiments and theoretical calculations, revealed the origin of the stereoselectivity and the importance of H‐bonding in stereocontrol.

High-Level Data Fusion Enables the Chemoinformatically Guided Discovery of Chiral Disulfonimide Catalysts for Atropselective Iodination of 2-Amino-6-arylpyridines.

The atropselective iodination of 2-amino-6-arylpyridines catalyzed by chiral disulfonimides (DSIs) is described. Key to the development of this transformation was the use of a chemoinformatically guided workflow for the curation of a structurally diverse training set of DSI catalysts. Utilization of this catalyst training set in the atropselective iodination across a variety 2-aminopyridine substrates allowed for the recommendation of statistically higher-performing DSIs for this reaction. Data Fusion techniques were implemented to successfully predict the performance of catalysts when classical linear regression analysis failed to provide suitable models. This effort identified a privileged class of 3,3'-alkynyl-DSI catalysts which were effective in catalyzing the iodination of a variety of 2-amino-6-arylpyridines with high stereoselectivity and generality. Subsequent preparative-scale demonstrations highlighted the utility of this reaction by providing iodinated pyridines >90:10 er and in good chemical yield.

Stereoselective Synthesis of Structurally Diverse (S)‐Lactams via an Engineered Amine Dehydrogenase

AbstractOptically pure lactams have a wide diversity of applications, one of which is serving as important intermediates in the synthesis of agricultural bioactive compounds or pharmaceuticals. Efficient stereoselective synthesis of chiral lactams with low‐cost amine donors under mild conditions is desired for manufacturing of these important chemicals. Herein, a two‐step chemo‐enzymatic strategy has been designed to produce (S)‐lactams by engineering a natural amine dehydrogenase from Thermoanaerobacter thermohydrosulfuricus (TtherAmDH). TtherAmDH was subjected to eight cycles of directed evolution to enhance its reductive amination activity toward keto acid substrates. The variants showed improved specific activity toward 6 tested substrates and gave high stereoselectivities of up to 99% in the asymmetric synthesis of γ‐ and δ‐ lactams. In particular, TtherAmDHV8 showed a 237‐fold higher specific activity toward the model substrate levulinic acid and gave (S)‐5‐methyl‐2‐pyrrolidone in 99% ee with a space‐time yield of 75.3 g L−1 d−1. These results indicate that the engineered amine dehydrogenase TtherAmDH can serve as an efficient biocatalyst for the manufacture of highly valued chiral lactams.magnified image

Cascade Ring-Opening/Cyclization Reaction of Spiro(nitrocyclopropane)oxindoles with Huisgen Zwitterions and Synthesis of Pyrazolo[3,4-b]indoles.

Herein, we report a ring-opening/cyclization cascade reaction of spiro(nitrocyclopropane)oxindoles with in situ generated Huisgen zwitterions (HZs) from PPh3 and azodicarboxylates. This reaction provides an array of polyfunctionalized pyrazolo[3,4-b]indole derivatives in moderate-to-excellent yields and generally high stereoselectivities with a broad substrate scope. The annulation products obtained from di-tert-butyl azodicarboxylates can be readily transformed into aromatic-substituted pyrazolo[3,4-b]indoles in moderate yields upon treatment with trifluoroacetic acid, thus providing a new entry to this fused heterocycle skeleton. In terms of nitro-substituted donor-acceptor cyclopropane, this work significantly broadens the substrate scope for the annulation reaction of nitrocyclopropanes and HZs. The dual roles of the oxindole moiety in the ring opening of cyclopropane and a plausible mechanism for the cascade reaction are also discussed.

Enantioselective resolution of (R,S)-DMPM to prepare (R)-DMPM by an adsorbed-covalent crosslinked esterase PAE07 from Pseudochrobactrum asaccharolyticum WZZ003.

(R)-N-(2,6-dimethylphenyl) aminopropionic acid methyl ester ((R)-DMPM) is an important chiral intermediate of the fungicide N-(2,6-Dimethylphenyl)-N-(methoxyacetyl)-alanine methyl ester ((R)-Metalaxyl). In this study, (1) D3520 (macroporous acrylic anion resin), selected from the ten resins, was used to immobilize the esterase from Pseudochrobactrum asaccharolyticum WZZ003 (PAE07) for resoluting the (R,S)-DMPM to obtain (R)-DMPM. (2) Up to 20g/L PAE07 could be immobilized onto D3520 with a high enzymatic activity of 32.4 U/g. Moreover, the Km and Vmax values of 19.1mM and 2.8mM/min for D3520-immobilized PAE07 indicated its high activity and stereoselectivity. (3) The optimal temperature and pH for the immobilized PAE07 were 40 ℃ and 8.0, and substrate concentration was up to 0.35M. After 15h reaction, the conversion rate from (R,S)-DMPM to (R)-DMPM was 48.0% and the e.e.p and E values were 99.5% and 1393.0, respectively. In scale-up resolution, 200g/L substrate and 12.5g immobilized esterase PAE07 condition, a conversion rate from substrate to product of 48.1% and a product e.e.p of 98% were obtained within 12h, with the activity of immobilized PAE07 retained 80.2% after 5 cycles of reactions. These results indicated that the D3520-immobilized esterase PAE07 had great potential for enzymatic resolution of (R,S)-DMPM to prepare (R)-Metalaxyl.

Expeditious and Stereoselective Synthesis of (1S)‐Spiro[pyran‐4‐quinolines

AbstractSpiro[pyran‐4‐quinolines] were synthesized in two steps from exo‐glycals. The first step involved the double additions of aniline (or substituted anilines) to produce C,N‐glycosides. The next step was to eliminate the anomeric N‐aryl group by formation of benzophenone‐derived imine, followed by in situ intramolecular Friedel−Crafts alkylation. The resulting (1S)‐spiro[pyran‐4‐quinolines] were obtained in 60–72 % overall yields with exclusive (from the reactions of exo‐galactals) or high stereoselectivity (from those of exo‐glucals with m‐substituted anilines), respectively. Additionally, exo‐galactals were found suitable to perform the two steps consecutively in one‐pot at 75 °C.

Enantio- and Diastereoselective Michael Addition of Cyclic Ketones/Aldehydes to Nitroolefins in Water as Catalyzed by Proline-Derived Bifunctional Organocatalysts.

New l-proline-derived bifunctional secondary amine organocatalysts were synthesized for enantioselective Michael reactions in water as a solvent. Application of these catalysts in Michael additions provided high yield (up to 97%) with high stereoselectivity (dr up to 99:1 and ee up to 99%). The effect of phenyl group at (R)-C6 in the catalyst was investigated and played a key role in successful catalysis by density functional theory computational calculations. The synthetic utility of this reaction was demonstrated by the formal synthesis of Sch 50971, which is a novel histamine H3 receptor agonist.

Recoverable PEG-supported amino alcohol ligand for copper-catalyzed Enantio- and syn-selective henry reaction with nitroethanol: Sustainable and straightforward access to chiral syn-2-nitro-1,3-Diols

A poly(ethylene glycol) (PEG) supported amino alcohol has been developed as a chiral ligand to promote the copper-catalyzed asymmetric nitrolaldol reaction (Henry Reaction) with nitroethanol. The catalyst provides direct access to various syn-2-nitro-1,3-diols with high yields and stereoselectivities. The solubility of PEG moiety allows facile purification and recycling of the catalyst. The utility of the catalyst was further demonstrated by the gram-scale preparations of the key intermediates for florfenicol and reboxetine.

Atroposelective Synthesis of Triaryl α‐Pyranones with 1,2‐Diaxes by N‐Heterocyclic Carbene Organocatalysis

AbstractAtropisomers bearing multiple stereogenic axes are of increasing importance to the field of material science, pharmaceuticals, and catalysis. However, the atroposelective construction of multi‐axis atropisomers remains rare and challenging, due to the intrinsical difficulties in the stereo‐control of the multiple stereogenic axes. Herein, we demonstrate a single‐step construction of a new class of 1,2‐diaxially chiral triaryl α‐pyranones by an N‐heterocyclic carbene organocatalytic asymmetric [3+3] annulation of well‐designed alkynyl acylazolium precursors and enolizable sterically hindered 2‐aryl ketones. The protocol features broad substrate scope (>50 examples), excellent stereo‐control (most cases >20 : 1 dr, up to 99.5 : 0.5 er), and potentially useful synthetic applications. The success of this reaction relies on the rational design of structurally matched reaction partners and the careful selection of the asymmetric catalytic system. DFT calculations have also been performed to discover and rationalize the origin of the high stereoselectivity of this reaction.

Atroposelective Synthesis of Triaryl α-Pyranones with 1,2-Diaxes by N-Heterocyclic Carbene Organocatalysis.

Atropisomers bearing multiple stereogenic axes are of increasing importance to the field of material science, pharmaceuticals, and catalysis. However, the atroposelective construction of multi-axis atropisomers remains rare and challenging, due to the intrinsical difficulties in the stereo-control of the multiple stereogenic axes. Herein, we demonstrate a single-step construction of a new class of 1,2-diaxially chiral triaryl α-pyranones by an N-heterocyclic carbene organocatalytic asymmetric [3+3] annulation of well-designed alkynyl acylazolium precursors and enolizable sterically hindered 2-aryl ketones. The protocol features broad substrate scope (>50 examples), excellent stereo-control (most cases >20 : 1 dr, up to 99.5 : 0.5 er), and potentially useful synthetic applications. The success of this reaction relies on the rational design of structurally matched reaction partners and the careful selection of the asymmetric catalytic system. DFT calculations have also been performed to discover and rationalize the origin of the high stereoselectivity of this reaction.

Nickel‐Catalyzed Enantioconvergent Carboxylation Enabled by a Chiral 2,2′‐Bipyridine Ligand

AbstractIn contrast to previous approaches to chiral α‐aryl carboxylic acids that based on reactions using hazardous gases, pressurized setup and mostly noble metal catalysts, in this work, a nickel‐catalyzed general, efficient and highly enantioselective carboxylation reaction of racemic benzylic (pseudo)halides under mild conditions using atmospheric CO2 has been developed. A unique chiral 2,2′‐bipyridine ligand named Me‐SBpy featuring compact polycyclic skeleton enabled both high reactivity and stereoselectivity. The utility of this method has been demonstrated by synthesis of various chiral α‐aryl carboxylic acids (30 examples, up to 95 % yield and 99 : 1 er), including profen family anti‐inflammatory drugs and transformations using the acids as key intermediates. Based on mechanistic experimental results, a plausible catalytic cycle involving Ni‐complex/radical equilibrium and Lewis acid‐assisted CO2 activation has been proposed.

Nickel-Catalyzed Enantioconvergent Carboxylation Enabled by a Chiral 2,2'-Bipyridine Ligand.

In contrast to previous approaches to chiral α-aryl carboxylic acids that based on reactions using hazardous gases, pressurized setup and mostly noble metal catalysts, in this work, a nickel-catalyzed general, efficient and highly enantioselective carboxylation reaction of racemic benzylic (pseudo)halides under mild conditions using atmospheric CO2 has been developed. A unique chiral 2,2'-bipyridine ligand named Me-SBpy featuring compact polycyclic skeleton enabled both high reactivity and stereoselectivity. The utility of this method has been demonstrated by synthesis of various chiral α-aryl carboxylic acids (30 examples, up to 95 % yield and 99 : 1 er), including profen family anti-inflammatory drugs and transformations using the acids as key intermediates. Based on mechanistic experimental results, a plausible catalytic cycle involving Ni-complex/radical equilibrium and Lewis acid-assisted CO2 activation has been proposed.