Stereoselective Route Research Articles

Photocontrolled Cobalt Catalysis for Selective Hydroboration of α,β‐Unsaturated Ketones

AbstractSelectivity between 1,2 and 1,4 addition of a nucleophile to an α,β‐unsaturated carbonyl compound has classically been modified by the addition of stoichiometric additives to the substrate or reagent to increase their “hard” or “soft” character. Here, we demonstrate a conceptually distinct approach that instead relies on controlling the coordination sphere of a catalyst with visible light. In this way, we bias the reaction down two divergent pathways, giving contrasting products in the catalytic hydroboration of α,β‐unsaturated ketones. This includes direct access to previously elusive cyclic enolborates, via 1,4‐selective hydroboration, providing a straightforward and stereoselective route to rare syn‐aldol products in one‐pot. DFT calculations and mechanistic experiments confirm two different mechanisms are operative, underpinning this unusual photocontrolled selectivity switch.

Photocontrolled Cobalt Catalysis for Selective Hydroboration of α,β-Unsaturated Ketones.

Selectivity between 1,2 and 1,4 addition of a nucleophile to an α,β‐unsaturated carbonyl compound has classically been modified by the addition of stoichiometric additives to the substrate or reagent to increase their “hard” or “soft” character. Here, we demonstrate a conceptually distinct approach that instead relies on controlling the coordination sphere of a catalyst with visible light. In this way, we bias the reaction down two divergent pathways, giving contrasting products in the catalytic hydroboration of α,β‐unsaturated ketones. This includes direct access to previously elusive cyclic enolborates, via 1,4‐selective hydroboration, providing a straightforward and stereoselective route to rare syn‐aldol products in one‐pot. DFT calculations and mechanistic experiments confirm two different mechanisms are operative, underpinning this unusual photocontrolled selectivity switch.

Stereoselective syntheses of 3-dehydroxynaltrexamines and N-methyl-3-dehydroxynaltrexamines

Methodology is presented for the synthesis of 6α/β-3-dehydroxynaltrexamines and 6α/β-N-methyl-3-dehydroxynaltrexamines. A stereoselective route is provided for each target compound while a novel one-pot method for the synthesis of 6α/β-N-methyl-3-dehydroxynaltrexamines is also explored. These results enable the versatile and efficient preparation of key epoxymorphinan intermediates to facilitate future selective opioid ligand discovery and development.

Evolution of a Cycloaddition–Rearrangement Approach to the Squalestatins: A Quarter-Century Odyssey

The highs, lows, and diversions of a journey leading to two syntheses of 6,7-dideoxysqualestatin H5 is described. Both syntheses relied on highly diastereoselective n-alkylations of a tartrate acetonide enolate and subsequent oxidation–hydrolysis to provide an asymmetric entry to β-hydroxy-α-ketoester motifs. The latter were differentially elaborated to diazoketones which underwent stereo- and regioselective Rh(II)-catalysed cyclic carbonyl ylide formation–cycloaddition and then acid-catalysed transketalisation to generate the 2,8-dioxabicyclo[3.2.1]octane core of the squalestatins/zaragozic acids at the correct tricarboxylate oxidation level. The unsaturated side chain was either protected with a bromide substituent during the transketalisation or introduced afterwards by a stereoretentive Ni-catalyzed Csp3–Csp2 cross-electrophile coupling.1 Introduction 2 Racemic Model Studies to the Squalestatin/Zaragozic Acid Core3 Asymmetric Model Studies to a Keto α-Diazoester3.1 Dialkyl Squarate Desymmetrisation3.2 Tartrate Alkylation3.2.1 Further Studies on Seebach’s Alkylation Chemistry 4 Failure at the Penultimate Step to DDSQ 5 Second-Generation Approach to DDSQ: A Bromide Substituent Strategy 5.1 Stereoselective Routes to E-Alkenyl Halides via β-Oxido Phosphonium Ylides 5.2 Back to DDSQ Synthesis6 An Alternative Strategy to DDSQ: By Cross-Electrophile Coupling7 Alkene Ozonolysis in the Presence of Diazo Functionality: Accessing α-Ketoester Intermediates8 Summary

Electrooxidation Enables Selective Dehydrogenative [4+2] Annulation between Indole Derivatives

AbstractDearomative annulation of indoles has emerged as a powerful tool for the preparation of polycyclic indoline‐based alkaloids. Compared with well‐established methods towards five‐membered‐ring‐fused indolines, the six‐membered‐ring‐fused indolines are rarely accessed under thermal conditions. Herein, a dearomative [4+2] annulation between different indoles is developed through an electrochemical pathway. This transformation offers a remarkably regio‐ and stereoselective route to highly functionalized pyrimido[5,4‐b]indoles under oxidant‐ and metal‐free conditions. Notably, this electrochemical approach maintains excellent functional‐group tolerance and can be extended as a modification tactic for pharmaceutical research. Preliminary mechanism studies indicate that the electrooxidation annulation proceeds through radical–radical cross‐coupling between an indole radical cation and an N‐centered radical generated in situ.

Electrooxidation Enables Selective Dehydrogenative [4+2] Annulation between Indole Derivatives.

Dearomative annulation of indoles has emerged as a powerful tool for the preparation of polycyclic indoline-based alkaloids. Compared with well-established methods towards five-membered-ring-fused indolines, the six-membered-ring-fused indolines are rarely accessed under thermal conditions. Herein, a dearomative [4+2] annulation between different indoles is developed through an electrochemical pathway. This transformation offers a remarkably regio- and stereoselective route to highly functionalized pyrimido[5,4-b]indoles under oxidant- and metal-free conditions. Notably, this electrochemical approach maintains excellent functional-group tolerance and can be extended as a modification tactic for pharmaceutical research. Preliminary mechanism studies indicate that the electrooxidation annulation proceeds through radical-radical cross-coupling between an indole radical cation and an N-centered radical generated in situ.

Intermolecular Addition of Carbon-Centered Radicals to Ynamides. A Regio- and Stereoselective Route to Persubstituted α-Iodo-enamides.

Rather surprisingly, C-C bond formation through "intermolecular" radical addition to internal ynamides has never been reported. Actually, ynamides are excellent acceptors for "electrophilic" carbon-centered radicals. These processes enable the introduction of functionalized alkyl chains at Cβ, groups that have not yet been introduced via the addition of organometallics. Radical carboiodination affords persubstituted α-iodo-enamides in moderate to high yield. The addition is totally stereoselective. Theoretical support to the mechanism and the scope and limitation of the reaction are discussed.

A Stereoconvergent Tsuji-Trost Reaction in the Synthesis of Cyclohexenyl Nucleosides.

A highly regio- and stereoselective route to d- and l-cyclohexenyl nucleosides has been devised, using the Tsuji-Trost reaction as the key step. Contrarily to the widely accepted mechanism (involving a net retention of configuration), the reaction proceeded in a highly stereoconvergent manner, providing cis nucleosides regardless of the relative configuration of the starting materials. DFT calculations confirmed the experimental data while suggesting the origin of the stereochemical reaction outcome.

Continuous-Flow Biocatalytic Process for the Synthesis of the Best Stereoisomers of the Commercial Fragrances Leather Cyclohexanol (4-Isopropylcyclohexanol) and Woody Acetate (4-(Tert-Butyl)Cyclohexyl Acetate)

Leather cyclohexanol (4-(isopropyl)cyclohexanol) and woody acetate (4-(tert-butyl)cyclohexyl acetate) are commercialized for functional perfumery applications as mixtures of cis- and trans-isomers. The cis-isomers are more potent odorants than the corresponding trans counterparts, but they are the less favoured products in most of the classical synthetic routes. Known stereoselective routes to cis-4-alkylcyclohexanols are characterized by a high environmental burden and/or troublesome reaction work-up. In this work, we examine the use of commercial alcohol dehydrogenases (ADHs) to produce cis-4-alkylcyclohexanols, including the two derivatives with isopropyl and tert-butyl substituents, by the stereoselective reduction of the corresponding ketones. High conversions and diastereoisomeric excess values were achieved with five of the eighteen tested ADHs. To complete the synthetic approach to woody acetate, Candida antarctica A (CALA) was employed as a catalyst for the enzymatic acetylation of cis-4-(tert-butyl)cyclohexanol. In order to provide a technological upgrade to the production of the most odorous isomers of the two commercial fragrances, we designed a continuous-flow process based on the combination of in-line enzymatic steps with in-line work-up, effectively providing samples of cis-leather cyclohexanol and cis-woody acetate with high diastereoisomeric purity.

Engineering imine reductases for industrial applications

Imine reductases are promising catalysts, facilitating a direct stereoselective route to secondary amines. Now, protein engineering has created stable and efficient variants that allow their application in kilogram-scale synthesis.

Convergent Stereoselective Synthesis of the C16-C37 Subunit of Sorangicin A.

A convergent stereoselective route to the C16-C37 fragment of sorangicin A is disclosed using an α-chloro sulfide for C-C bond formation. The key intermediate, an α,β-unsaturated ketone, is revealed by a [2,3] sigmatropic rearrangement of a propargylic sulfoxide. Three disparate approaches are detailed to create the C25 carbinol stereocenter. The cis-2,6-disubstitution of the THP ring is secured by ionic hydrogenation. A cross-metathesis reaction and Julia-Kocienski olefination furnish the C16-C37 fragment of sorangicin A.

Chemoenzymatic Synthesis of an Odanacatib Precursor through a Suzuki‐Miyaura Cross‐Coupling and Bioreduction Sequence

AbstractA series of 1‐aryl‐2,2,2‐trifluoroethanones has been chemically synthesized to later study their bioreduction using stereocomplementary alcohol dehydrogenases (ADHs). Satisfyingly, (R)‐alcohols were obtained in high conversions and selectivities using the ADH from Ralstonia species and the one from Rhodococcus ruber, while the (S)‐enantiomers were independently produced using the ADH from Lactobacillus brevis and the commercially available evo‐1.1.200. In the search for a stereoselective route towards the Odanacatib, an orally bioavailable and selective inhibitor of Cathepsin K, the development of a sequential methodology combining a palladium‐catalyzed cross coupling between 1‐(4‐bromophenyl)‐2,2,2‐trifluoroethanone and 4‐(methylsulfonyl)phenylboronic acid in aqueous medium with the bioreduction of the resulting 2,2,2‐trifluoro‐1‐(4′‐(methylsulfonyl)‐[1,1′‐biphenyl]‐4‐yl)ethanone has been extensively studied. Finally, the desired (R)‐2,2,2‐trifluoro‐1‐(4′‐(methylsulfonyl)‐[1,1′‐biphenyl]‐4‐yl)ethanol was obtained in enantiomerically pure form and 85 % yield with a 128 g L−1 d−1 productivity following a sequential approach.

Synthetic, Zwitterionic Sp1 Oligosaccharides Adopt a Helical Structure Crucial for Antibody Interaction.

The zwitterionic Streptococcus pneumoniae serotype 1 polysaccharide (Sp1) is an important anchor point for our immune system to act against streptococcal infections. Antibodies can recognize Sp1 saccharides, and it has been postulated that Sp1 can elicit a T-cell-dependent immune reaction as it can be presented by MHC-II molecules. To unravel the molecular mode of action of this unique polysaccharide we here describe the chemical synthesis of a set of Sp1 fragments, ranging from 3 to 12 monosaccharides in length. We outline a unique synthetic approach to overcome the major synthetic challenges associated with the complex Sp1 structure and provide a stereoselective route of synthesis for the oligosaccharide backbone as well as a strategy to introduce the carboxylic acid functions. Molecular dynamics (MD) simulations together with NMR spectroscopy studies reveal that the oligosaccharides take up helical structures with the nona- and dodecasaccharide completing a full helical turn. The 3D structure of the oligosaccharides coincides with the topology required for good interaction with anti-Sp1 antibodies, which has been mapped in detail using STD-NMR. Our study has revealed the Sp1 nona- and dodecasaccharides as promising synthetic antigens, displaying all (3D) structural elements required to mimic the natural polysaccharide and required to unravel the molecular mode of action of these unique zwitterionic polysaccharides.

Stereoselective Synthesis of the C1-C22 Carbon Framework of (-)-Amphidinolide K.

Two stereoselective routes to the C7-C22 subunit of amphidinolide K are disclosed. Jacobsen's hydrolytic kinetic resolution and Sharpless' asymmetric dihydroxylation reactions have been employed for the construction of the tetrahydrofuran ring. The C10-C11, C16-C17, C9-O, and C18-O bonds have been created using α-chloro sulfide intermediates and [2,3] sigmatropic rearrangement. Marshall's propargylation protocol is utilized to create the C4 stereogenic center, and regioselective hydrozirconation/iodine quench afforded an alkenyl iodide which is employed in the NHK coupling with the C7-C22 subunit. Oxonia-Cope rearrangement resulted in the creation of the C18 carbinol stereogenic center and chain elongation.

Biocatalytic Strategy for Highly Diastereo- and Enantioselective Synthesis of 2,3-Dihydrobenzofuran-Based Tricyclic Scaffolds.

2,3-Dihydrobenzofurans are key pharmacophores in many natural and synthetic bioactive molecules. A biocatalytic strategy is reported here for the highly diastereo- and enantioselective construction of stereochemically rich 2,3-dihydrobenzofurans in high enantiopurity (>99.9% de and ee), high yields, and on a preparative scale via benzofuran cyclopropanation with engineered myoglobins. Computational and structure-reactivity studies provide insights into the mechanism of this reaction, enabling the elaboration of a stereochemical model that can rationalize the high stereoselectivity of the biocatalyst. This information was leveraged to implement a highly stereoselective route to a drug molecule and a tricyclic scaffold featuring five stereogenic centers via a single-enzyme transformation. This work expands the biocatalytic toolbox for asymmetric C-C bond transformations and should prove useful for further development of metalloprotein catalysts for abiotic carbene transfer reactions.

Biocatalytic Strategy for Highly Diastereo‐ and Enantioselective Synthesis of 2,3‐Dihydrobenzofuran‐Based Tricyclic Scaffolds

Abstract2,3‐Dihydrobenzofurans are key pharmacophores in many natural and synthetic bioactive molecules. A biocatalytic strategy is reported here for the highly diastereo‐ and enantioselective construction of stereochemically rich 2,3‐dihydrobenzofurans in high enantiopurity (>99.9% de and ee), high yields, and on a preparative scale via benzofuran cyclopropanation with engineered myoglobins. Computational and structure‐reactivity studies provide insights into the mechanism of this reaction, enabling the elaboration of a stereochemical model that can rationalize the high stereoselectivity of the biocatalyst. This information was leveraged to implement a highly stereoselective route to a drug molecule and a tricyclic scaffold featuring five stereogenic centers via a single‐enzyme transformation. This work expands the biocatalytic toolbox for asymmetric C–C bond transformations and should prove useful for further development of metalloprotein catalysts for abiotic carbene transfer reactions.

Hydrogenation of (Hetero)aryl Boronate Esters with a Cyclic (Alkyl)(amino)carbene-Rhodium Complex: Direct Access to cis-Substituted Borylated Cycloalkanes and Saturated Heterocycles.

We herein report the hydrogenation of substituted aryl- and heteroaryl boronate esters for the selective synthesis of cis-substituted borylated cycloalkanes and saturated heterocycles. A cyclic (alkyl)(amino)carbene-ligated rhodium complex with two dimethyl groups at the ortho-alkyl scaffold of the carbene showed high reactivity in promoting the hydrogenation, thereby enabling the hydrogenation of (hetero)arenes with retention of the synthetically valuable boronate group. This process constitutes a clean, atom-economic, as well as chemo- and stereoselective route for the generation of cis-configured, diversely substituted borylated cycloalkanes and saturated heterocycles that are usually elusive and difficult to prepare.

Hydrogenation of (Hetero)aryl Boronate Esters with a Cyclic (Alkyl)(amino)carbene–Rhodium Complex: Direct Access to cis‐Substituted Borylated Cycloalkanes and Saturated Heterocycles

AbstractWe herein report the hydrogenation of substituted aryl‐ and heteroaryl boronate esters for the selective synthesis of cis‐substituted borylated cycloalkanes and saturated heterocycles. A cyclic (alkyl)(amino)carbene‐ligated rhodium complex with two dimethyl groups at the ortho‐alkyl scaffold of the carbene showed high reactivity in promoting the hydrogenation, thereby enabling the hydrogenation of (hetero)arenes with retention of the synthetically valuable boronate group. This process constitutes a clean, atom‐economic, as well as chemo‐ and stereoselective route for the generation of cis‐configured, diversely substituted borylated cycloalkanes and saturated heterocycles that are usually elusive and difficult to prepare.

A Concise Stereoselective Route to C‐ and P‐ Chirogenic Hydroxypropyl Phosphines by Ring‐Opening of Optically Active Oxaphospholane‐2‐oxide

AbstractA facile, stereoselective method for the synthesis of both carbon‐ and P‐chirogenic phosphine oxides and phosphines bearing a hydroxyl chelating arm was developed. A carefully designed oxaphospholane was constructed via tandem Arbuzov‐ intramolecular cyclization reaction, using commercially available compounds. Regioselective ring opening alkylation/arylation provided optically active phosphine oxides within two synthetic steps. An additional step of stereospecific deoxygenation produced P‐chirogenic tertiary phosphines in high dr.

Synthesis and biological activity of diastereoisomeric octahydro-1H-indole-5,6,7-triols, analogues of castanospermine

A straightforward stereoselective route towards (3aR,5R,6S,7R,7aR)- and (3aR,5R,6S,7R,7aR)-octahydro-1H-indole-5,6,7-triol, analogues of castanospermine, starting from the corresponding shikimic acid derivatives is described. The key transformations of this approach are the Overman rearrangement and ring-closing metathesis to form the diastereoisomeric cis-fused (5R,6S,7R)-octahydro-1H-indole-5,6,7-triols in good overall yields. Evaluation for in vitro cytotoxicity revealed for some prepared compounds significant antiproliferative activity and weak glycosidase inhibition.