Product Stereoselectivity Research Articles

Organic Stereochemistry. Part 7

AbstractThis review continues a general presentation of the principles of stereochemistry with special emphasis on the biomedicinal sciences. Here, we discuss and illustrate the phenomenon of substrate stereoselectivity in biochemistry (endogenous metabolism) and principally in xenobiochemistry or drug metabolism. The review begins with an overview of the stereoselective processes occurring in the biomedicinal sciences. The general rule is for distinct stereoisomers, be they enantiomers or diastereoisomers, to elicit different pharmacological responses (Part 5), to a lesser extent be transported with different efficacies (Part 5), and to be metabolized at different rates (this Part). In other words, biological environments discriminate between stereoisomers both when acting on them and when being acted upon by them. The concept of substrate stereoselectivity describes this phenomenon in endogenous biochemistry and xenobiotic metabolism, as discussed and illustrated in the present Part. The sister concept of product stereoselectivity will be presented in Part 8.

A versatile route to benzodiazocine and spiropyran derivatives through chalcones

Syntheses of 3-(phenyl)-benzo[b]thiophene [2, 3-d][1,2] benzodiazocine derivatives have been accomplished by the reaction of 3-phenacylidine-2-benzo[b]thiophene-2-ones with o-phenylene diamine. The photolytic reaction with trans-stilbene resulted in the exclusive formation of spiro{2′,5′,6′-triphenyl-2H-pyran-4′,3}-benzo[b]thiophene-2-one derivatives. Theoretical calculations have been performed to study the mechanism and stereoselectivity of products. Good yield and broad scope of usable substrates of industrial relevance are other prominent features of the present methodologies. Syntheses of 3-(phenyl)-benzo[b]thiophene [2, 3-d][1,2] benzodiazocine derivatives by the reaction of 3-phenacylidine-2-benzo[b]thiophene-2-ones with o-phenylene diamine have been accomplished. A [4+2] photocycloaddition has been carried out to obtain spiro{20,50,60-triphenyl-2H-pyran-40,3}-benzo[b] thiophene-2-one derivatives from 3-phenacylidine-2-benzo[b]thiophene-2-ones and trans-stilbene.

Biological Stereoselectivity of Atropisomeric Natural Products and Drugs

Selected examples of natural product and drug atropisomers that exhibit stereoselectivity towards receptor and enzyme targets are reviewed. The atropisomeric preference of the receptors and enzyme binding domains makes these agents attractive molecules for drug development in the treatment of various diseases. Included are commonly recognized atropisomers containing a chiral biaryl axis along with some less common examples of atropisomers without a biaryl axis. The biological targets include: antiapoptotic proteins; bacteria; microtubules; kinases; vasopressin receptors; a G-protein coupled receptor related to obesity; monocarboxylate transporters; tachykinin NK1 -receptors; cyclooxygenase-1 and squalene synthase.

Experimental and theoretical investigation of the oxidative carbonylation of toluene to toluic acid catalyzed by palladium(II) in the presence of vanadium and molecular oxygen

The mechanism and kinetics of the liquid-phase, oxidative carbonylation of toluene to toluic acid over Pd(II) in the presence of trifluoroacetic acid (TFAH), trifluoroacetic anhydride (TFAA), and molecular oxygen were investigated through a combination of experimental and theoretical approaches. The experimental results are consistent with the previously proposed mechanism for the oxidative carbonylation of arenes. The reaction is initiated by coordination of toluene to the Pd(II) complex and activation of a CH bond in the benzene ring. This initial step becomes rate limiting when a sufficiently high (NH4VO3)/Pd ratio is used for the reoxidation of Pd(0) to Pd(II). Both processes are found to be dependent on the electron withdrawing and donating capability of the anionic ligands. Overall catalyst activity peaks for ligands of intermediate basicity, and diminishes for both more and less basic ligands. Theoretical analysis of the coordination of toluene and activation of the CH bond on the benzene ring reveals that the basicity of the ligands affects the two processes in opposite ways. Weakly basic ligands promote the coordination of toluene but have the opposite effect on the activation of the CH bond. The tradeoff in these two effects leads to a maximum in the apparent rate coefficient with pKa of the conjugate acid of the anionic ligands. The absence of significant product stereoselectivity is due to a lack of steric hindrance in the binding of toluene to the Pd(II) complex.

Noncovalent Bifunctional Organocatalysts: Powerful Tools for Contiguous Quaternary‐Tertiary Stereogenic Carbon Formation, Scope, and Origin of Enantioselectivity

Relying on the assembly of commercially available catalyst building blocks, highly stereocontrolled quaternary carbon (all carbon substituted) formation has been achieved with unmatched substrate diversity. For example, the in situ assembly of a tricomponent catalyst system allows α-branched aldehyde addition to nitroalkene or maleimide electrophiles (Michael products), while addition to an α-iminoester affords Mannich reaction products. Very good yields are observed and for fifteen of the eighteen examples 96-99 % ee is observed. Using racemic α-branched aldehydes, two contiguous (quaternary-tertiary) stereogenic centers can be formed in high diastereo- and enantiomeric excess (eight examples) via an efficient in situ dynamic kinetic resolution, solving a known shortcoming for maleimide electrophiles in particular. The method is of practical value, requiring only 1.2 equiv of the aldehyde, a 5.0 mol % loading of each catalyst component, for example, O-tBu-L-threonine (O-tBu-L-Thr), sulfamide, DMAP or O-tBu-L-Thr, KOH, and room temperature reactions. As a highlight, the first demonstration of ethylisovaleraldehyde (7) addition is disclosed, providing the most congested quaternary stereogenic carbon containing succinimide product (8) known to date. Finally, mechanistic insight, via DFT calculations, support a noncovalent assembly of the catalyst components into a bifunctional catalyst, correctly predict two levels of product stereoselectivity, and suggest the origin of the tricomponent catalyst system's exceptionality: an alternative hydrogen bond motif for the donor-acceptor pair than currently suggested for non-assembled catalysts.

Cavity-induced enantioselectivity reversal in a chiral metal–organic framework Brønsted acid catalyst

A pair of highly porous chiral metal–organic frameworks (CMOFs 1 and 2) were constructed from [Cu2(carboxylate)4] secondary building units (SBUs) and chiral 3,3′,6,6′- or 4,4′,6,6′-tetra(benzoate) ligands derived from 1,1′-binaphthyl-2,2′-phosphoric acid. Both 1 and 2 were active catalysts for Friedel–Crafts reactions between indole and imines. Interestingly, the 1-catalyzed asymmetric reactions yielded the major enantiomers of the opposite chirality to those afforded by the corresponding homogeneous catalyst. Structural analyses and QM/MM calculations revealed that the flip of product handedness results from the chiral environment of CMOF-1 cavity, similar to enzymatic catalysis in which the product stereoselectivity is determined by the enzyme pocket.

Confirmation of Chirality in Homogeneous and Heterogeneous Salen‐Based Catalysts

AbstractThe extent to which diastereomeric excess (de) of epoxide products is influenced by the structure of the chiral olefin substrate has been assessed for two enantiomers of limonene and two enantiomers of pinene and using a number of homogeneous and heterogeneous [Mn(salen)]‐based catalysts, based on both chiral and achiral structures. No evidence was obtained to suggest that double asymmetric induction took place, but instead results indicate that the stereoselectivity of the epoxide product was governed wholly by the substrate. Results call into question the use of such substrates alone in drawing conclusions regarding the nature of presumed stereogenic centers in such catalysts.

Computational interpretation of the stereoselectivity for a dirhodium tetracarboxylate-catalyzed amidation reaction

A catalytic cycle of a dirhodium tetracarboxylate (diRh) catalyzed intramolecular amidation reaction was investigated with density functional calculations, and the stereoselectivity of the amidation product was successfully interpreted. The product selectivity was calculated from the free energy of activations for four different reaction pathways. The pathway that forms cis-stereomer on the singlet potential energy surface has the lowest free energy of activation in the four pathways examined. The results may provide deeper insight into transition-metal catalyzed C N bond formation reactions, as well as help synthetic chemists better design/select the catalyst ligands and the reactant substrates for this type of reaction.

Mechanistic Insights into the Substrate‐Controlled Stereochemistry of Glycals in One‐Pot Rhodium‐Catalyzed Aziridination and Aziridine Ring Opening

We carried out a principle study on the reaction mechanism of rhodium-catalyzed intramolecular aziridination and aziridine ring opening at a sugar template. A sulfamate ester group was introduced at different positions of glycal to act as a nitrene source and, moreover, to allow the study of the relative reactivity of the nitrene transfer from different sites of the glycal molecule. The structural optimization of each intermediate along the reaction pathway was extensively done by using BPW91 functional. The crucial step in the reaction is the Rh-catalyzed nitrene transfer to the double bond of the glycal. We found that the reaction could proceed in a stepwise manner, whereby the N atom initially induced a single-bond formation with C1 on the triplet surface or in a single step through intersystem crossing (ISC) of the triplet excited state of the rhodium-nitrene transition state to the singlet ground state of the aziridine complexes. The relative reactivity for the conversion of the nitrene species to the aziridine obtained from the computed potential energy surface (PES) agrees well with the reaction time gained from experimental observation. The aziridine ring opening is a spontaneous process because the energy barrier for the formation of the transition state is very small and disappears in the solution calculations. The regio- and stereoselectivity of the reaction product is controlled by the electronic property of the anomeric carbon as well as the facial preference for the nitrene insertion, and the nucleophilic addition.

Stereoselective Synthesis of Phosphoryl Derivatives

The reaction of dialkylphosphonites with N-(bromomethyl)phthalimide furnishes alkyl phenyl hydrogenphosphinates, dialkyl phenylphosphonates, and N-[(bromomethyl)phthalimido)]-phosphinates. The stereoselectivity of the primary product of the reaction appears to increase with the increasing size of the groups attached to the phosphorus atom.

Physical and chemical quenching rates and their influence on stereoselective photooxygenation of oxazolidinone-functionalized enecarbamates

Physical and chemical quenching rate constants were measured for the reaction of singlet oxygen with oxazolidinone-functionalized enecarbamates to investigate the role of vibrational deactivation in product stereoselectivity.

The Stereochemical Course of 4-Hydroxy-2-nonenal Metabolism by Glutathione S-Transferases

4-Hydroxy-2-nonenal (HNE) is a toxic aldehyde generated during lipid peroxidation and has been implicated in a variety of pathological states associated with oxidative stress. Glutathione S-transferase (GST) A4-4 is recognized as one of the predominant enzymes responsible for the metabolism of HNE. However, substrate and product stereoselectivity remain to be fully explored. The results from a product formation assay indicate that hGSTA4-4 exhibits a modest preference for the biotransformation of S-HNE in the presence of both enantiomers. Liquid chromatography mass spectrometry analyses using the racemic and enantioisomeric HNE substrates explicitly demonstrate that hGSTA4-4 conjugates glutathione to both HNE enantiomers in a completely stereoselective manner that is not maintained in the spontaneous reaction. Compared with other hGST isoforms, hGSTA4-4 shows the highest degree of stereoselectivity. NMR experiments in combination with simulated annealing structure determinations enabled the determination of stereochemical configurations for the GSHNE diastereomers and are consistent with an hGSTA4-4-catalyzed nucleophilic attack that produces only the S-configuration at the site of conjugation, regardless of substrate chirality. In total these results indicate that hGSTA4-4 exhibits an intriguing combination of low substrate stereoselectivity with strict product stereoselectivity. This behavior allows for the detoxification of both HNE enantiomers while generating only a select set of GSHNE diastereomers with potential stereochemical implications concerning their effects and fates in biological tissues.

A thermodynamic study of ketoreductase-catalyzed reactions 5. Reduction of substituted ketones in n-hexane

The equilibrium constants K for the ketoreductase-catalyzed reduction reactions of 1-benzyl-3-pyrrolidinone, ethyl 2-oxo-4-phenylbutyrate, ethyl 4-chloroacetoacetate, 1-benzyl-4-piperidone, and 1-benzyl-3-piperidone were measured in n-hexane at T=298.15K by using gas chromatography. The equilibrium constants for the reaction involving 1-benzyl-4-piperidone were also measured as a function of temperature (288.15 to 308.05)K. The calculated thermodynamic quantities for the reaction (1-benzyl-4-piperidone+2-propanol=1-benzyl-4-hydroxypiperidine+acetone) reaction carried out in n-hexane at T=298.15K are: K=(26.2±1.7); ΔrGm∘=-(8.10±0.16)kJ·mol-1; ΔrHm∘=-(3.44±0.42)kJ·mol-1; and ΔrSm∘=(15.6±1.4)J·K-1·mol-1. The chirality of the hydroxyl products of the reactions (1)–(3) and (5)has also been investigated. The results showed that the stereoselectivity of the hydroxyl products formed can be controlled by the selection of the solvent and enzyme used in these reactions. The thermochemical results for these reactions are compared with the results for reactions that have analogous structural features as well as with the results of quantum chemical calculations.

A computational study on the substituent effects and product stereoselectivity of the intermolecular formal aza-[3+3] cycloaddition reaction between vinylogous amides and α,β-unsaturated imine cations

The substituent effects and product stereoselectivity of the title reaction has been studied using density functional theory (DFT) calculations at the B3LYP/6-31G(d,p) level of theory. It was found that the substituents do not perturb the mechanism of intermolecular formal aza-[3+3] cycloaddition. Our calculations also show that methyl or benzyl groups on the N atom of vinylogous amide favor the addition step, but alkyl substituents on the either N atom or terminal C atom of α,β-unsaturated imine cation have opposite effects. Alkyl substituents on the N atom of α,β-unsaturated imine cation may lower the activation barriers for elimination of amide. The steric interaction between two substituents leads to the formation of major product both thermodynamically and kinetically.

Regio- and Stereoselectivity in the Paterno-Buchi Reaction Between 2,3-Dihydrofuran and Furan with Benzaldehyde

The photochemical coupling reaction between 2,3-dihydrofuran and benzaldehyde was studied by using DFT/B3LYP/6-31G+(d,p) method. The regiochemistry of the attack of the benzaldehyde on the double bond is related to the different stability of the biradical intermediates. The endo stereoselectivity of the product depends on the superposition between HSOMO and LSOMO in the biradical intermediate. The photochemical reaction between furan and benzaldehyde was studied at the same level. The regioselectivity depends on the relative stability of the possible biradical intermediates. The exo stereoselectivity of the coupling product depends on the superposition between the HSOMO and LSOMO of the biradical intermediate.

Synthesis of chiral C/N-functionalized morpholine alcohols: study of their catalytic ability as ligand in asymmetric diethylzinc addition to aldehyde

A broad variety of chiral C/N-functionalized morpholine alcohols sharing a common structural motif in the 3-(hydroxymethyl)morpholine 6 were prepared from enantiomerically pure serine for the purpose of studying their catalytic ligand properties. The asymmetric addition of diethylzinc to benzaldehyde in the presence of 10 mol % of chiral C/N-functionalized morpholine alcohols gave 1-phenyl-1-propanol in 59–81% yield with 10–30% ee. The addition of 10 mol % of n-butyl lithium to the reaction mixture resulted in a significant enhancement of the stereoselectivity in the case of ligands bearing the two geminal phenyl substituents on the backbone. In the presence of n-butyl lithium and using ( S)-3-(hydroxydiphenylmethyl)morpholine ( S)- 19 as the chiral promoter, ( S)-1-phenyl-1-propanol was obtained in 81% yield with 76% ee. The geminal diphenyl-class of morpholine ligands was examined for the diethylzinc addition to four different aldehydes in the presence of n-butyl lithium. ( S)- N-Benzyl-3-(hydroxydiphenylmethyl)morpholine ( S)- 27 was found to be most enantioselective in the case of 4-methoxybenzaldehyde to give ( R)-alcohol in 87% yield with 80% ee. Catalysts ( S)- 19 and its N-methyl derivative ( S)- 26 gave alcohols with an ( S)-absolute configuration while the N-benzylated derivative ( S)- 27 gave the opposite enantiomeric products. The tentative transition state models to account for the observed product stereoselectivity with morpholine ligands holding the geminal diphenyl group on the β-amino alcohol segment are proposed.

Crystal Structure of the Polyketide Cyclase AknH with Bound Substrate and Product Analogue: Implications for Catalytic Mechanism and Product Stereoselectivity

AknH is a small polyketide cyclase that catalyses the closure of the fourth carbon ring in aclacinomycin biosynthesis in Streptomyces galilaeus, converting aklanonic acid methyl ester to aklaviketone. The crystal structure analysis of this enzyme, in complex with substrate and product analogue, showed that it is closely related in fold and mechanism to the polyketide cyclase SnoaL that catalyses the corresponding reaction in the biosynthesis of nogalamycin. Similarity is also apparent at a functional level as AknH can convert nogalonic acid methyl ester, the natural substrate of SnoaL, to auraviketone in vitro and in constructs in vivo. Despite the conserved structural and mechanistic features between these enzymes, the reaction products of AknH and SnoaL are stereochemically distinct. Supplied with the same substrate, AknH yields a C9-R product, like most members of this family of polyketide cyclases, whereas the product of SnoaL has the opposite C9-S stereochemistry. A comparison of high-resolution crystal structures of the two enzymes combined with in vitro mutagenesis studies revealed two critical amino acid substitutions in the active sites, which contribute to product stereoselectivity in AknH. Replacement of residues Tyr15 and Asn51 of AknH, located in the vicinity of the main catalytic residue Asp121, by their SnoaL counter-parts phenylalanine and leucine, respectively, results in a complete loss of product stereoselectivity.

Stereoselective Aldol Additions of Titanium Enolates of N‐Acetyl‐4‐isopropyl‐thiazolidinethione.

Abstract The addition of chlorotitanium enolates of N-acetyl isopropyl thiazolidine-2-thione to aldehydes was investigated. The stereoselectivity of the aldol products was controlled by the number of equivalents of base added. The syn aldol product was obtained preferentially when 2 equiv of Lewis acid and 1 equiv of base were employed. The anti aldol product was obtained preferentially when 1 equiv of Lewis acid and 2 equiv of base were employed for unsaturated aldehydes. Unexpected results were found with hindered aldehydes when 2 equiv of base were employed.

Stereoselective aldol additions of titanium enolates of N-acetyl-4-isopropyl-thiazolidinethione

The addition of chlorotitanium enolates of N-acetyl isopropyl thiazolidine-2-thione to aldehydes was investigated. The stereoselectivity of the aldol products was controlled by the number of equivalents of base added. The syn aldol product was obtained preferentially when 2 equiv of Lewis acid and 1 equiv of base were employed. The anti aldol product was obtained preferentially when 1 equiv of Lewis acid and 2 equiv of base were employed for unsaturated aldehydes. Unexpected results were found with hindered aldehydes when 2 equiv of base were employed.

Rapid, Highly Diastereoselective Addition of Dialkylzinc Reagents to Atropisomeric 2‐Formyl Arylamides.

AbstractFor Abstract see ChemInform Abstract in Full Text.