Stereospecific Reaction Research Articles

An expedient synthesis of C3-arylidene-oxindole derivatives using calcite nanoflowers as an efficient heterogeneous catalyst

α-β unsaturated heterocyclic compounds such as C3-arylidene-oxindoles, with five-member rings containing nitrogen, have an important role in the realm of medicine. This study aims to synthesize the C3-arylindene-oxindoles derivative compounds using calcite nanoflowers (CaCO3 NFs) as a heterogeneous catalyst for the first time. These CaCO3 NFs prepared by the thermal decomposition method, which is an active and reusable catalyst for stereospecific Knoevenagel condensation reaction between 2-oxindole and aromatic aldehyde under different solvent conditions like water, ethyl alcohol, and 50% aqueous ethyl alcohol. This catalytic method is employed with a wide range of aromatic aldehydes to produce high yields of C3-arylidene-oxindoles (93-99%), with stereo-specifically E-isomers (100%) for 50% alcohol and alcohol as a solvent.

Synthesis of aza-S(VI) motifs

Sulfoximines and sulfonimidamides are of interest as design options for medicinal chemists. This article describes the development of methods for the synthesis of sulfoximines by metal-free NH-transfer to sulfoxides, and NH/O transfer to sulfides, using convenient sources of ammonia and hypervalent iodine reagents. Similarly, sulfonimidamides are prepared from sulfenamides. Methods for the preparation of enantioenriched sulfonimidoyl fluorides are also described, as are their stereospecific reactions with amines and Grignard reagents. This work was presented at the 29th International Symposium on the Organic Chemistry of Sulfur (Guelph, July 2022).

A general approach to stereospecific Pd-catalyzed cross-coupling reactions of benzylic stereocenters.

We have developed a general process for the formation of enantioenriched benzylic stereocenters via stereospecific Pd-catalyzed cross-coupling reactions of enantioenriched benzylic tricyclohexyltin nucleophiles. This process proceeds with excellent stereospecificity for a remarkably broad scope of electrophilic coupling partners including aryl and heteroaryl halides and triflates, acid chlorides, thioesters, chloroformates, and carbamoyl chlorides. Thus, enantioenriched 1,1-diarylalkanes as well as formal products of asymmetric enolate arylation are readily accessed using this approach. We additionally provide the first demonstration of a Sn-selective cross-coupling reaction using a vicinal alkylborylstannane nucleophile. In these reactions, the presence of cyclohexyl spectator ligands on tin is essential to ensure selective transfer of the secondary benzylic unit from tin to palladium.

Samarium-Mediated Asymmetric Synthesis

Samarium is an efficient reducing agent, a radical generator in cyclization and a cascade addition reaction. Interestingly, samarium metal has crucial impact on numerous C-C and C-X (X = hetero atom) bond forming transformations. It has been established as an exceptional chemo-selective and stereoselective reagent. The reactivity of the samarium catalyst/reagent is remarkably enhanced in the presence of various additives, ligands and solvents through effective coordination and an increase in reduction potential. It has inherent character to act as electron donor for a wide range of transformations including the asymmetric version of various reactions. This review accentuates the developments in samarium-mediated/catalyzed asymmetric organic synthesis over the past 12 years, where the chirality has been induced from ligand, a nearby asymmetric center within the substrate or through coordination directed stereospecific reactions.

Enantioselective Total Syntheses of Preussomerins: Control of Spiroacetal Stereogenicity by Photochemical Reaction of a Naphthoquinone through 1,6‐Hydrogen Atom Transfer

AbstractWe report the enantioselective total syntheses of preussomerins EG1, EG2, and EG3. The key transformation is a stereospecific photochemical reaction involving 1,6‐hydrogen atom transfer to achieve retentive replacement of a C−H with a C−O bond, enabling otherwise‐difficult control of the spiroacetal stereogenic center.

Enantioselective Total Syntheses of Preussomerins: Control of Spiroacetal Stereogenicity by Photochemical Reaction of a Naphthoquinone through 1,6-Hydrogen Atom Transfer.

We report the enantioselective total syntheses of preussomerins EG1 , EG2 , and EG3 . The key transformation is a stereospecific photochemical reaction involving 1,6-hydrogen atom transfer to achieve retentive replacement of a C-H with a C-O bond, enabling otherwise-difficult control of the spiroacetal stereogenic center.

DFT Studies on the Molecular Structure, Regioisomerism, Ground and Excited state Charge Transfer Properties of Spiro‐heterocycles

AbstractThe electronic structure, stereochemical aspects and charge transfer properties of the spiro compound (5S,8S) spiro‐{6‐phenyl‐1‐aza‐3‐oxa‐7‐thia‐bicyclo[3,3,0]‐octene‐8,3’(2’H)‐indol}‐2’‐one (spiro bicyclo adduct) synthesized using the multi‐component reaction via 1,3‐dipolar cycloaddition of isatin and thioproline with the dipolarophile phenylacetylene have been studied. The two lowest energy regio‐isomers of the spiro heterocycle formed from the stereospecific dipolar reaction have been analysed along with the electron‐withdrawing and releasing substituents using DFT method at the CAM‐B3LYP/6‐311++G(d,p) level of theory. The atomic charges and the stabilization energy due to the intramolecular charge delocalization process calculated using the natural orbitals at the different molecular sites reveal the different donor‐acceptor interactions occurring in the system. The intramolecular electronic transitions (specifically n to π* and π to π*) is found to occur from the localized donor end component to the acceptor end components in the multi‐component system. The hole produced by the ionization of the entities is found to migrate from the thioproline component to the phenyl acetylene part in a time scale of around 4 fs. The electron‐withdrawing and donating substituents on the spirobicyclo adduct have been proven to tune the excited and ground state charge transfer properties uniquely. The results can shed light on how multi‐component reactions can be directed to produce spiro adducts with versatile applications.

Structural Basis for (2R,3R)-Taxifolin Binding and Reaction Products to the Bacterial Chalcone Isomerase of Eubacterium ramulus.

The bacterial chalcone isomerase (CHI) from Eubacterium ramulus catalyses the first step in a flavanone-degradation pathway by a reverse Michael addition. The overall fold and the constitution of the active site of the enzyme completely differ from the well-characterised chalcone isomerase of plants. For (+)-taxifolin, CHI catalyses the intramolecular ring contraction to alphitonin. In this study, Fwe perform crystal structure analyses of CHI and its active site mutant His33Ala in the presence of the substrate taxifolin at 2.15 and 2.8 Å resolution, respectively. The inactive enzyme binds the substrate (+)-taxifolin as well defined, whereas the electron density maps of the native CHI show a superposition of substrate, product alphitonin, and most probably also the reaction intermediate taxifolin chalcone. Evidently, His33 mediates the stereospecific acid-base reaction by abstracting a proton from the flavonoid scaffold. The stereospecificity of the product is discussed.

O-Quinodimethane Atropisomers: Enantioselective Synthesis and Stereospecific Transformation.

o-Quinodimethanes have remarkable utility as reactive intermediates in Diels-Alder reactions, enabling significantly accelerated routes to complex polycyclic compounds. The discovery of different discrete precursors to thermally generate o-quinodimethanes thereby greatly augmented their availability and versatility. However, due to the required high temperatures and the immense reactivity of o-quinodimethanes, stereoselectivity to afford isomerically defined products still constitutes a critical challenge. Herein, we describe the accessibility of atropisomeric o-quinodimethanes, the enantioselective synthesis of their precursors, their remarkable configurational stability and the stereospecific transformation by the benzannulation of dienophiles. A catalyst-stereocontrolled [2+2+2] cycloaddition, the generation of o-quinodimethane atropisomers and ensuing stereospecific Diels-Alder reactions enabled enantioselectivities through these transient intermediates with of up to 96 : 4 e.r.

Stabilization of α-ZrP ceramic nanosheets adsorbing quaternary ammonium ions in organic solvents and their application as a stable solid support for lipase catalyzing stereospecific synthetic reactions

ABSTRACT Herein, the effect of immobilizing lipase onto layered α-zirconium phosphate ceramic nanosheets (α-ZrP NS) on the enzymatic transesterification of allylic alcohols was investigated in organic solvents. α-ZrP NS modified with quaternary ammonium ions show a excellent dispersion stability in n-hexane. Lipase immobilized on α-ZrP NS enables the improved synthesis of chiral allylic alcohols and esters, with significantly reduced reaction times compared to reactions performed in the absence of α-ZrP NS. The coexistence of α-ZrP NS also results in more efficient steric inversion of the resulting allyl ester, suggesting the utility of α-ZrP NS as a support for lipase-induced stereospecific reactions. The present manuscript discusses on mechanisms of high dispersion stability of α-ZrP NS and their preferable immobilizing effect for the lipase inducing the steric inversion in detail.

Insight into the methylene C–H bond cleavage of ethylbenzene during ethylbenzene hydroxylation using EBDH as a catalyst, a DFT study

The hydroxylation of ethylbenzene to ( S)-1-phenylethanol with the help of ethylbenzene dehydrogenase (EBDH) is a stereospecific catalytic reaction. This hydroxylation process involves the C–H bond cleavage of methylene part of ethylbenzene and transfer of its hydrogen to the oxygen atom attached with the metal at the active site of EBDH as a first step, which leads to the formation of an intermediate. The second step involves the transfer of OH from the active-site metal back to the carbon of intermediate, resulting in the formation of ( S)-1-phenylethanol. This C–H bond cleavage could be homolytic or heterolytic and directly affect the reaction mechanism of ethylbenzene hydroxylation. In this article, density functional theory studies were performed on the ethylbenzene-bound EBDH active-site model complexes to investigate the impact of the C–H bond cleavage of methylene part of ethylbenzene on the reaction mechanism of ethylbenzene hydroxylation. For this, different protonation states and participation of amino acid residues near the Mo center of EBDH were considered. Models with protonation of His192, Lys450, and Asp223 and model without protonation were investigated for comparison. Computed relative energies indicate that the overall lowest energy barrier pathway results when ionic (heterolytic) and radical (homolytic) pathways are combined.

Chelation-Controlled Stereospecific Cross-Coupling Reaction between Alkenes for Atroposelective Synthesis of Axially Chiral Conjugated Dienes.

In this protocol, an efficient palladium-catalyzed asymmetric synthesis of axially chiral conjugated dienes via alkenyl C-H olefination is reported. The corresponding atropisomeric styrenes containing a conjugated diene scaffold were obtained in good yields with good enantioselectivities. This synthetic strategy features an easy operation, mild reaction conditions, a wide functionality tolerance, and high efficiency.

History of the Woodward-Hoffmann Rules. The No-Mechanism Puzzle.

This is Paper 2 in the 27-paper series on the history of the development of the Woodward-Hoffmann rules. Paper 2 takes the reader back to the 1950s and early 1960s, before the publication of the first Woodward-Hoffmann paper in January 1965. The scope of the pericyclic no-mechanism problem is described along with many of the key "hints" or "clues" to orbital symmetry control that were available in the literature prior to 1965. A chronology of reactions with alternating stereospecificities is provided. A second chronology of alternating theoretical hints is provided, e. g., 4n+2 versus 4n. Another chronology is provided, that of the development of frontier molecular orbital theory, with and without phases and nodes. A tabulation is provided of 36 instances in which the MOs of 1,3-butadiene were reported in the literature. A knowledge of the MOs of 1,3-butadiene, plus a knowledge of some of the alternating stereospecific reactions, could have led many chemists to the solution of the pericyclic no-mechanism problem before Woodward and Hoffmann.

Initial Steps to Engineer Coproheme Decarboxylase to Obtain Stereospecific Monovinyl, Monopropionyl Deuterohemes.

The oxidative decarboxylation of coproheme to form heme b by coproheme decarboxylase is a stereospecific two-step reaction. In the first step, the propionate at position two (p2) is cleaved off the pyrrole ring A to form a vinyl group at this position. Subsequently, the propionate at position four (p4) on pyrrole ring B is cleaved off and heme b is formed. In this study, we attempted to engineer coproheme decarboxylase from Corynebacterium diphtheriae to alter the stereospecificity of this reaction. By introducing a tyrosine residue in proximity to the propionate at position 4, we were able to create a new radical center in the active site. However, the artificial Tyr183• radical could not be shown to catalyze any decarboxylation.

Stereospecific reaction of sulfonimidoyl fluorides with Grignard reagents for the synthesis of enantioenriched sulfoximines.

Sulfonimidoyl halides have previously shown poor stability and selectivity in reaction with organometallic reagents. Here we report the preparation of enantioenriched sulfonimidoyl fluorides and their stereospecific reaction at sulfur with Grignard reagents. Notably the first enantioenriched alkyl sulfonimidoyl fluorides are prepared, including methyl. The nature of the N-group is important to the success of the stereocontrolled sequence to sulfoximines.

Production and structural characterization of the cytochrome P450 enzymes in carotene ring hydroxylation.

The superfamily of cytochrome P450 (CYP) enzymes participate in diverse metabolic reactions. Although structural characterization of prokaryotic CYPs has been performed extensively, structural studies for eukaryotic, especially plant, CYPs remain scanty. Members of CYP family 97 are hydroxylases devoted to carotene ring hydroxylation. Specifically, members of the CYP97A and CYP97C subfamilies work synergistically to hydroxylate the β- and ɛ-rings of α-carotene to form lutein. The stereospecific reactions introduce an R-chiral center at the C-3 position of each cyclohexene ring. The Arabidopsis thaliana genome encodes CYP97A3, CYP97B3, and CYP97C1. Recently, we determined crystal structures of CYP97A3 in unliganded and retinaldehyde-bound forms and of CYP97C1 in complex with detergent octylthioglucoside. These structures showed how the active site favors pro-R-hydroxylation. This chapter summarizes the steps for production of CYP97A3, CYP97B3, and CYP97C1. The in vitro assays to test hydroxylase activity and ligand binding affinity are also described, including the steps for production of the redox partner. We also review the details for crystallization and structural determination of CYP97A3 and CYP97C1. Characterization of the active site by high-resolution structure analysis provides clues to substrate channeling, which awaits further investigation.

Enantiospecific Total Synthesis and Absolute Configuration Assignment of Chabrolobenzoquinone H.

Chabrolobenzoquinone H (1), a meroditerpene metabolite with cytotoxic activity, is synthesized via a stereoselective Julia-Kocienski olefination between a chiral pool derived aliphatic PT-sulfone and a benzoquinone aldehyde partner. The latter was obtained via consecutive chain extension steps involving a Stille coupling and a stereospecific olefin cross-metathesis reaction followed by malonic ester synthesis and a Krapcho decarboxylation. Furthermore, this total synthesis securely determined the absolute configuration of the targeted natural product.

Catalyst-Controlled Stereoselective Barton-Kellogg Olefination.

Overcrowded alkenes are expeditiously prepared by the versatile Barton–Kellogg olefination and have remarkable applications as functional molecules owing to their unique stereochemical features. The induced stereodynamics thereby enable the controlled motion of molecular switches and motors, while the high configurational stability prevents undesired isomeric scrambling. Bistricyclic aromatic enes are prototypical overcrowded alkenes with outstanding stereochemical properties, but their stereocontrolled preparation was thus far only feasible in stereospecific reactions and with chiral auxiliaries. Herein we report that direct catalyst control is achieved by a stereoselective Barton–Kellogg olefination with enantio‐ and diastereocontrol for various bistricyclic aromatic enes. Using Rh2(S‐PTAD)4 as catalyst, several diazo compounds were selectively coupled with a thioketone to give one of the four anti‐folded overcrowded alkene stereoisomers upon reduction. Complete stereodivergence was reached by catalyst control in combination with distinct thiirane reductions to provide all four stereoisomers with e.r. values of up to 99:1. We envision that this strategy will enable the synthesis of topologically unique overcrowded alkenes for functional materials, catalysis, energy‐ and electron transfer, and bioactive compounds.

Enantiomerically Enriched α-Borylzinc Reagents by Nickel-Catalyzed Carbozincation of Vinylboronic Esters.

In this paper is described a synthesis of enantiomerically enriched, configurationally stable organozinc reagents by catalytic enantioselective carbozincation of a vinylboronic ester. This process furnishes enantiomerically enriched α-borylzinc intermediates that are shown to undergo stereospecific reactions, producing enantioenriched secondary boronic ester products. The properties of the intermediate α-borylzinc reagent are probed and the synthetic utility of the products is demonstrated by application to the synthesis of (-)-aphanorphine and (-)-enterolactone.

Copper-Catalyzed Ring-Opening/Borylation of Cyclopropenes

Copper-Catalyzed Ring-Opening/Borylation of Cyclopropenes