Major Diastereomer Research Articles

Fluorene and Fluorenone Unnatural Amino Acid Motifs via Diastereoselective Pd(II)‐Catalyzed sp3C−H Functionalization

AbstractThis paper reports the construction of racemic and enantiopure (D‐ and L‐) fluorene and fluorenone‐based novel unnatural amino acid derivatives. The Pd(II)‐catalyzed bidentate directing group‐aided arylation of prochiral β‐C(sp3)‐H bonds in racemic, enantiopure carboxamides of amino acids with iodofluorenes was reported. The construction of novel examples of fluorene and fluorenone motifs containing amino acids comprising of norvaline, leucine, phenylalanine, norleucine, 2‐aminooctanoic acid derivatives having the anti‐stereochemistry (with good enantiopurity) was accomplished. The construction of bis fluorenyl alanine scaffolds and fluorenyl motif‐containing non‐α‐amino acid (aminoalkanoic acid) derivatives was also reported. Examples of removal of the directing group (8‐aminoquinoline) and phthalimide‐protecting group present in the fluorenyl‐based unnatural amino acid derivatives have been shown. Accordingly, fluorene motif‐based amino acid esters and free amino group‐containing unnatural amino acid derivatives were synthesized. The stereochemistry of the major (anti) diastereomers obtained via the prochiral β‐C(sp3)‐H arylation of norvaline, leucine, phenylalanine, norleucine, 2‐aminooctanoic acid derivatives was ascertained from the X‐ray structure of a representative compound. Fluorene‐ and fluorenone‐based motifs are vital skeletons in materials and medicinal chemistry research. Accordingly, this work is a contribution towards enriching the library of fluorene and fluorenone unnatural amino acid scaffolds.

Construction of C5‐Indole Unnatural Amino Acid Motifs via Diastereoselective Pd(II)‐Catalyzed β‐C(sp3)‐H Functionalization

We report the construction of C5‐indole unnatural amino acid derivatives via the diastereoselective Pd(II)‐catalyzed prochiral β‐C(sp3)‐H arylation of racemic (DL), and enantiopure L‐ and D‐carboxamides of amino acids with 5‐iodoindoles. Independently, indole‐based compounds and amino acid motifs are important small molecules in organic synthesis and drug discovery research. This report aimed to contribute to enriching the library of indole‐based unnatural amino acid derivatives. The synthesis of examples of C5‐indole motif‐installed amino acid derivatives comprising norvaline, phenylalanine, leucine, norleucine, 2‐aminooctanoic acid having anti‐stereochemistry was accomplished. The synthesis of the C5‐indole motif‐containing non‐α‐amino acid (aminoalkanoic acid) derivatives was also reported. The C‐H arylation reactions of racemic and enantiopure carboxamides with 5‐iodoindoles afforded the corresponding indole unnatural amino acid derivatives with good diastereoselectivity (anti, dr >95:5 and enantiopurity (er up to 99:1). Removal of the directing group (8‐aminoquinoline), phthalimide group and preparation of indole amino acid esters and free amino group‐containing indole unnatural amino acid motifs were also shown. The utility of the methodology was shown by synthesizing indole motif‐containing pyrrolidone and peptide molecules. The stereochemistry of the major (anti) diastereomers was ascertained from the X‐ray structure of a representative compound.

The Michael addition of thiols to 13-oxo-octadecadienoate (13-oxo-ODE) with implications for LC-MS analysis of glutathione conjugation

Unsaturated fatty acid ketones with αβ,γδ conjugation are susceptible to Michael addition of thiols, with unresolved issues on the site of adduction and precise structures of the conjugates. Herein we reacted 13-keto-octadecadienoic acid (13-oxo-ODE or 13-KODE) with glutathione (GSH), N-acetyl-cysteine, and β-mercaptoethanol and identified the adducts. HPLC-UV analyses indicated none of the products exhibit a conjugated enone UV chromophore, a result that conflicts with the literature and relevant to mass spectral interpretation of 1,4 versus 1,6 thiol adduction. Aided by development of an HPLC solvent system that separates the GSH diastereomers and thus avoids overlap of signals in proton NMR experiments, we established the two major conjugates are formed by 1,6 addition of GSH at the 9-carbon of 13-oxo-ODE with the remaining double bond α to the thiol in the 10,11 position. N-acetyl cysteine reacts similarly, while β-mercaptoethanol gives equal amounts of 1,4 and 1,6 addition products. Equine glutathione transferase catalyzed 1,6 addition of GSH to the two major diastereomers in 44:56 proportions. LC-MS in positive ion mode gives a product ion interpreted before as evidence of 1,4-thiol adduction, whereas here we find this ion using the authentic 1,6 adduct. LC-MS with negative ion APCI gave a fragment selective for 1,4 adduction. These results clarify the structures of thiol conjugates of a prototypical unsaturated keto fatty acid and have relevance to the application of LC-MS for the structural analysis of keto-fatty acid glutathione conjugation.

Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole Esters

In pursuit of unsymmetrical precursors for the novel series of anthracenyl-isoxazole amide (AIM) antitumor agents, a series of substituted anthracenes were subjected to bromination and re-aromatization in our study, during which we solved four single crystal X-ray diffractometry (Sc-xrd) structures which we report herein. The C-9 nitrile oxide, after its reaction with bromine, was isolated, but when subjected to re-aromatization, it returned to the starting 10-bromo nitrile oxide 1, which did provide an accurate crystal structure, with R = 0.018. The 10-halogenated 3-(9’-anthryl)-isoxazole esters were subjected to bromination and re-aromatization. Surprisingly, the yields obtained in the presence of the isoxazole were reasonably good (62–68% isolated yields), and the major diastereomers allowed for the characterization using Sc-xrd. The penta bromo product 2 showed a trans, trans, cis relationship for the four bromines on the A-ring of the anthracene, and we observed that for the unit cell, the atropisomers displayed a 1:1 ratio at the chiral axis between the isoxazole and anthrancene rings. Similarly, the 10-chloro 3 indicated a ratio of 1:1 at the chiral axis in the crystal structure. A base-induced re-aromatization afforded 3,10-dihalogenated analogues selectively in very good yields (X = Cl, 89%; X = Br 92%), of which the dibromo 4 was characterized using Sc-xrd. The improved yields of the unique diastereomeric bromination products suggested the consideration of a novel electrophilic aromatic substitution mechanism driven by the stereo-electronic environment, imposed by the isoxazole ester substituent. The promise of the application of this chemistry in the future development of AIM antitumor agents is suggested.

An Access to Chiral Phthalides: Enantioselective Synthesis of Escitalopram

AbstractA method for the asymmetric synthesis of phthalides containing a stereogenic γ‐carbon has been described. The protocol, based on the arylogous Michael addition to chiral alkenoyl oxazolidinones catalyzed by a crown ether under phase‐transfer conditions does not require anhydrous conditions and uses commercially available materials. A complete syn‐stereocontrol is achieved and facial diastereoselectivities are moderate to excellent (62:38 to 99:1 dr). Purification of the major diastereomer by chromatography and selective cleavage of the chiral auxiliary affords enantiopure Michael products. The protocol has been applied to the formal synthesis of escitalopram.

Diastereoselective synthesis of cis‐1,2‐limonene oxide using dimeric Salen‐Mn (III) complexes as reusable catalysts

Diastereoselective epoxidation of R‐(+)‐limonene using achiral and racemic dimeric Salen‐Mn (III) complexes as catalysts ((1a) and (1b)) and in situ generated dimethyldioxirane (DMDO) as an oxidizing agent was explored. The best reaction parameters were: (i) KHSO5/R‐(+)‐limonene molar ratio = 0.25; (ii) R‐(+)‐limonene, catalyst molar ratio = 20, (iii) absence of nitrogenous bases (axial ligands), (iv) ambient temperature (20°C), (v) racemic dimeric catalyst, and (vi) low amount of acetone (4 mL). Under these reaction conditions isolated yield to 1,2‐(+)‐limonene oxide and diastereomeric excess (d.e), and diastereomeric yield excess (d.y.e) to major diastereomer (cis‐epoxide) was 96%, 77%, and 72%, respectively. Moreover, the catalyst was segregated into a solid phase, while products remained in the liquid phase, allowing the easy separation of the catalyst and reaction products. Consequently, the catalyst could be recycled up to three times without appreciable loss of its initial catalytic activity.

Endo-fenchyl acetate rich essential oil of Strobilanthes sessilis Nees inflorescence and its characterisation using GC, GC-MS, and NMR techniques

Strobilanthes Blume is a genus in the family Acanthaceae, with many species endemic to the Indian subcontinent. Strobilanthes sessilis Nees is endemic to the southern Western Ghats of India. The essential oil of dried inflorescence of S. sessilis was extracted using hydrodistillation method and the chemical composition was determined using GC and GC-MS techniques, which revealed the major compound to be endo-fenchyl acetate (89.33%). Other minor compounds like endo-fenchol (3.74%), (E)-caryophyllene (1.07%), and limonene and β-phellandrene (0.55%) were also observed. The major diastereomer of fenchyl acetate was determined using 2D-NMR techniques like HSQC, HMBC, and ROESY to confirm the endo configuration. The optical rotation of the oil in different solvents deduced that the laevorotatory enantiomer of endo-fenchyl acetate as the major or single compound. S. sessilis could be further explored as a major source of endo-fenchyl acetate, which has high importance in flavouring and other biological applications.

Enantioselective Syntheses of Multiply Functionalized Six‐Membered Carbocycles from Nitroalkenes and γ,δ‐Unsaturated ß‐Ketoesters using Chiral Catalysts Derived from Cobalt(III) and 1,2‐Diphenylethylenediamine

AbstractCondensations of the title educts R4CH=CH(C=O)CH2CO2Et and R6CH=CHNO2 in the presence of NEt3 and the catalyst Λ‐[Co((S,S)‐dpen)3]3+2Cl−B(C6F5)4− (both 10 mol%, 0 °C; dpen=1,2‐diphenylethylenediamine) afford R6CHCH(NO2)CH(R4)CH2C(OH)CCO2Et, with three contiguous carbon stereocenters, as >99:1 to 85:15 mixtures of diastereomers (ten examples). The major diastereomers are isolated in 81–63% yields and 97–76% ee. When R4 and R6 are both aryl groups, additions of 1,1,3,3‐tetramethylquanidine/CH3CN epimerize the CHNO2 moieties, affording 78:22 to 67:33 mixtures of the new/old diastereomers (2 h, RT). Alternatively, epimerization to >99:1 mixtures occurs spontaneously over 4 weeks in hexanes/isopropanol. These transformations entail two consecutive Michael additions, and two crystal structures confirm the relative and absolute product configurations. These assignments are supported by NMR data in solution and literature studies of similar compounds. Overall, catalyst Λ‐[Co((S,S)‐dpen)3]3+2Cl−B(C6F5)4− affords superior yields and enantio‐ or diastereoselectivities compared to those previously reported for the title reaction.

Studies Pertaining to the Emerging Cannabinoid Hexahydrocannabinol (HHC).

We report studies pertaining to two isomeric hexahydrocannabinols (HHCs), (9R)-HHC and (9S)-HHC, which are derivatives of the psychoactive cannabinoids Δ9- and Δ8-THC. HHCs have been known since the 1940s, but have become increasingly available to the public in the United States and are typically sold as a mixture of isomers. We show that (9R)-HHC and (9S)-HHC can be prepared using hydrogen-atom transfer reduction, with (9R)-HHC being accessed as the major diastereomer. In addition, we report the results of cannabinoid receptor studies for (9R)-HHC and (9S)-HHC. The binding affinity and activity of isomer (9R)-HHC are similar to that of Δ9-THC, whereas (9S)-HHC binds strongly in cannabinoid receptor studies but displays diminished activity in functional assays. This is notable, as our examination of the certificates of analysis for >60 commercially available HHC products show wide variability in HHC isomer ratios (from 0.2:1 to 2.4:1 of (9R)-HHC to (9S)-HHC). These studies suggest the need for greater research and systematic testing of new cannabinoids. Such efforts would help inform cannabis-based policies, ensure the safety of cannabinoids, and potentially lead to the discovery of new medicines.

Investigation of a novel approach to the core of stemofoline: enantioselective construction of a bicyclic intermediate with three contiguous chiral centers

<p indent="0mm">The enantioselective synthesis of a bicyclic intermediate containing three contiguous chiral centers for a novel approach to the core of stemofoline is described. A (<italic>S</italic>)-malimide derivative developed in this laboratory was used as the chiral building block. The latter was converted in three steps (<italic>N</italic>-deprotection, a Mitsunobu reaction, and a cross-olefin metathesis) into another malimide with the <italic>N</italic>-substituent bearing a nucleophilic allylic silane moiety. The Grignard reagent addition took place regioselectively at the C-2 carbonyl to yield a hemiaminal. The key intramolecular aza-Sakurai reaction was promoted by trifluoroboron etherate, which led to the desired cyclization in good to excellent combined yields. Four diastereomers were formed from this reaction, whose stereochemistries were determined by NOESY technique. The latter revealed that the major diastereomer (obtained in 35% yield) possessed the correct stereochemistries required for the total synthesis of natural enantiomer of stemofoline. A regioselective Wacker oxidation resulted in the formation of the title compound along with a minor regioisomer (an aldehyde) in a ratio of 18: 1 (combined yield: 50%).

Mechanochemical Felkin-Anh Model: Achieving Forbidden Reaction Outcomes with Mechanical Force.

Anti-Felkin-Anh diastereoselectivity can be achieved for nucleophilic additions to α-chiral ketones upon stretching the ketone with a mechanical pulling force. Herein, a mechanochemical Felkin-Anh model is proposed for predicting the outcome of a nucleophilic addition to an α-chiral ketone. Essentially, the fully stretched chiral ketone has one substituent shielding each side of the carbonyl, in contrast to the Felkin-Anh model, in which free rotation around a bond is required to achieve the two rotamers of the ketone. Depending on the pulling scenario, either Felkin-Anh or anti-Felkin-Anh diastereoselectivity is obtained. The model is entirely based on the distance between the pulling points, which is maximized in the anti-periplanar arrangement. The major diastereomer is associated with the approach with the least steric interactions. The intuitive model is validated by means of mechanochemical density functional theory calculations. Importantly, the ketone is fully stretched in the sub 1 nN force regime, thus minimizing the risk of undesired homolytic bond rupture. Moreover, the mechanical force is not used for lowering the reaction barriers associated with the nucleophilic addition; instead, it is solely applied for locking the conformation of a molecule and provoking otherwise inaccessible reaction pathways on the force-modified potential energy surface.

Nickel-Catalyzed Formation of α-Substituted γ-Amino Ketones via Alkene Carboacylation.

Herein, we report Ni-catalyzed intramolecular carboacylation of imides containing a tethered alkene and tetraarylborate nucleophiles. Using a nickel-phosphine catalyst system, α-substituted, γ-amino ketones are generated in up to 92% yield with site selectivity. Deprotection and cyclization of the γ-amino ketone product afforded a cyclic imine in 71% yield, and a stereoselective reduction formed the β-substituted, δ-amino alcohol in 66% yield with 2.3:1 d.r. and 94% ee (major diastereomer).

Chiral Lewis Acid-Catalyzed Norrish Type II Cyclization to Synthesize α-Oxazolidinones via Enantioselective Protonation

Chiral Lewis Acid-Catalyzed Norrish Type II Cyclization to Synthesize α-Oxazolidinones via Enantioselective Protonation

Diastereomeric Resolution Yields Highly Potent Inhibitor of SARS-CoV-2 Main Protease.

SARS-CoV-2 is the causative agent behind the COVID-19 pandemic. The main protease (Mpro, 3CLpro) of SARS-CoV-2 is a key enzyme that processes polyproteins translated from the viral RNA. Mpro is therefore an attractive target for the design of inhibitors that block viral replication. We report the diastereomeric resolution of the previously designed SARS-CoV-2 Mpro α-ketoamide inhibitor 13b. The pure (S,S,S)-diastereomer, 13b-K, displays an IC50 of 120 nM against the Mpro and EC50 values of 0.8–3.4 μM for antiviral activity in different cell types. Crystal structures have been elucidated for the Mpro complexes with each of the major diastereomers, the active (S,S,S)-13b (13b-K), and the nearly inactive (R,S,S)-13b (13b-H); results for the latter reveal a novel binding mode. Pharmacokinetic studies show good levels of 13b-K after inhalative as well as after peroral administration. The active inhibitor (13b-K) is a promising candidate for further development as an antiviral treatment for COVID-19.

Heterogeneous asymmetric β-C-H functionalization of aldehydes under O2 catalyzed by hydroxide-layered Fe(III) sites synergistic with confined interlayer amine

Asymmetric functionalization of inert β-C-H is one of the most powerful strategies in organic synthesis, but of great challenge in the efficient β-C-H activation and the enantioselective C-heteroatom formation. Here, this work proposes an elegant strategy for one-pot asymmetric β-C-H functionalization of aldehyde under O2 catalyzed by hydroxide-layered Fe(III) sites synergistic with confined interlayer amine through a cascade oxidation-addition process on L-proline intercalated Fe-containing layered double hydroxides (LDHs), in which the direct β-H elimination of aldehyde on hydroxide-layered Fe(III) sites with the two-electron abstraction promoted by the Fe(III):N coordination as the key step to efficiently oxidize the enamine. The major β-functionalized diastereomer in the asymmetric nitromethylation of 3-phenylpropanal has been afforded in a regioselectivity of up to >99%, a stereoselectivity of 90%, and a yield of 65% on L-proline intercalated Mg3.00Al0.47Fe0.45-LDHs.

Anti-Inflammatory, Analgesic and Antioxidant Potential of New (2S,3S)-2-(4-isopropylbenzyl)-2-methyl-4-nitro-3-phenylbutanals and Their Corresponding Carboxylic Acids through In Vitro, In Silico and In Vivo Studies.

In the current study, a series of new (2S,3S)-2-(4-isopropylbenzyl)-2-methyl-4-nitro-3-phenylbutanals (FM1-6) with their corresponding carboxylic acid analogues (FM7-12) has been synthesized. Initially, the aldehydic derivatives were isolated in the diastereomeric form, and the structures were confirmed with NMR, MS and elemental analysis. Based on the encouraging results in in vitro COX 1/2, 5-LOX and antioxidant assays, we oxidized the compounds and obtained the pure single (major) diastereomer for activities. Among all the compounds, FM4, FM10 and FM12 were the leading compounds based on their potent IC50 values. The IC50 values of compounds FM4, FM10 and FM12 were 0.74, 0.69 and 0.18 µM, respectively, in COX-2 assay. Similarly, the IC50 values of these three compounds were also dominant in COX-1 assay. In 5-LOX assay, the majority of our compounds were potent inhibitors of the enzyme. Based on the potency and safety profiles, FM10 and FM12 were subjected to the in vivo experiments. The compounds FM10 and FM12 were observed with encouraging results in in vivo analgesic and anti-inflammatory models. The molecular docking studies of the selected compounds show binding interactions in the minimized pocked of the target proteins. It is obvious from the overall results that FM10 and FM12 are potent analgesic and anti-inflammatory agents.

Inherently Chiral 6,7-Diphenyldibenzo[ e,g ][1,4]diazocine: Enantioselective Synthesis and Application as a Ligand Platform

Inherently Chiral 6,7-Diphenyldibenzo[ <i>e,g</i> ][1,4]diazocine: Enantioselective Synthesis and Application as a Ligand Platform

Diastereoselective ring cleavage of azetidines with cyanogen bromide

N-alkyl azetidines bearing a chiral substituent at the nitrogen atom, and a variable substituent at C-3 as a prochiral centre, react readily with cyanogen bromide even at low temperatures to produce the corresponding 3-bromo-N-cyanamides as diastereoisomeric mixtures via ring opening. This reaction was found to be diastereoselective (up to 80:20 dr). In one case, the major diastereomer could be isolated by recrystallization, and the configuration of the newly created stereocentre was determined by X-ray crystallography.

Stereoselective Cyclopropanation of Boron Dipyrromethene (BODIPY) Derivatives by an Organocascade Reaction

AbstractThe synthesis of enantiopure chiral boron dipyrromethenes (BODIPYs) is of importance due the intrinsic properties of BODIPYs as fluorophores that could be used as probes for molecular sensing. The present study reports an asymmetric organocatalytic cascade reaction of meso‐chloromethyl BODIPY derivatives with α,β‐unsaturated aldehydes catalyzed by a chiral secondary amine. The corresponding BODIPY‐derived cyclopropanes were produced in isolated yields 66–98%, and with diastereomeric ratios 3/2–&gt;20/1, and 92–99% ee for major diastereomer. The synthetic utility of the protocol was exemplified on a set of additional transformations of the corresponding optically pure compounds. In addition, a study explaining the reaction mechanism (DFT computations) and photophysical characterization of all enantioenriched products were accomplished.magnified image

Pseudo-Five-Component Reaction for Diastereoselective Synthesis of Butterfly Shaped Bispiro[Oxindole-Pyrrolidine]s.

A pseudo-five-component reaction involving double decarboxylative 1,3-dipolar cycloaddition of azomethine ylides with olefinic oxindoles for the diastereoselective synthesis of bispiro[oxindole-pyrrolidine]s is developed. The major diastereomers are unique butterfly shaped compounds with a plane of symmetry. Recyclable zeolite HY acid catalyst is used to promote the reaction, and only CO2 and H2O are generated as byproducts.