Facial Selectivity Research Articles

π-Facial Stereoselectivity in Acyl Nitroso Cycloadditions to 5,5-Unsymmetrically Substituted Cyclopentadienes: Computational Exploration of Origins of Selectivity and the Role of Substituent Conformations on Selectivity.

The π-facial selectivity of Diels-Alder cycloadditions of 5-monosubstituted cyclopentadienes is known experimentally and has been extensively studied computationally. Previous studies on 5-monosubstituted cyclopentadienes by the Burnell and Houk groups showed that facial selectivity arises principally from hyperconjugative aromaticity or antiaromaticity of polar groups that cause distortion of the cyclopentadiene; steric effects of nonpolar groups can also be important. We have now explored the stereoselective cycloaddition of 5,5-unsymmetrically substituted cyclopentadienes to an acyl nitroso dienophile reported by Kan and co-workers. Computational studies with M06-2X/6-311+G(d,p) indicate that the stereoselectivity in the cycloadditions of 5,5-unsymmetrically substituted cyclopentadienes is not just a simple combination of effects found for monosubstituted counterparts. Substituent conformations and diene-dienophile steric and electronic interaction effects all influence stereoselectivity. Predictions are made about several as-yet-unstudied cyclopentadiene cycloadditions.

Enantioselective Synthesis of Nitriles Containing a Quaternary Carbon Center by Michael Reactions of Silyl Ketene Imines with 1-Acrylpyrazoles

The enantioselective construction of quaternary carbon centers is a marked challenge in asymmetric catalysis research. It is extremely difficult when a chiral catalyst can not distinguish the facial selectivity of the substrate through bond interactions. Here we realized an enantioselective Michael reaction of silyl ketene imines to 1-acrylpyrazoles using a chiral N,N'-dioxide-Co(II) complex. The protocol is highly efficient for the construction of nitrile-, aryl-, and dialkyl-bearing carbon centers and has been successful applied in the divergent synthesis of pharmaceuticals and natural products. The through-space dispersion interactions between unbound silyl ketene imines and the 1-acrylpyrazole-bonded catalyst play a key role in facilitating the reactivity and the enantioselectivity of this process.

Unveiling the Substituent Effects in the Stereochemistry of [3+2] Cycloaddition Reactions of Aryl‐ and Alkyldiazomethylphosphonates with Norbornadiene within a MEDT Perspective

AbstractThe [3+2] cycloaddition (32CA) reactions of norbornadiene with aryl and alkyl substituted diazomethylphosphonates (SDAPs) have been studied within the molecular electron density theory (MEDT). Electron localization function (ELF) shows the presence of apseudoradicalC3 center at the alkyl SDAPs, classifying them aspseudo(mono)radicalspecies, while the aryl SDAP is classified as a zwitterionic one, owing to the delocalization of the C3 electron density on the C3‐P bond. These 32CA reactions present high activation enthalpies in dichloromethane, between 17.3 and 21.6 kcal mol−1, being strongly exothermic by more than 33.8 kcal mol−1. While these 32CA reactions present a totalsynfacial selectivity, theendo/exostereoselectivity depends on the steric hindrance caused by the bulk substituents present in these SDAPs along the approach to norbornadiene. Interestingly the phenyl group provokes a lesser hindrance than that of the small methyl group, justifying the 95 % ofexostereoselectivity experimentally observed. ELF and the AIM (Atoms‐in‐Molecules) analyses account for the bonding changes along these 32CA reactions. The energy cost for the rupture of the norbornadiene C−C and that of the SDAPs N−N double bonds are the major contributors to the activation energies of these non‐polar 32CA reactions.

Aldol Reactions of Conformationally Stable Axially Chiral Thiohydantoin Derivatives.

Two novel axially chiral ortho-trifluoromethylphenyl thiohydantoin derivatives have been prepared atroposelectively from the reaction of R and S alanine methyl ester HCl salts with ortho-trifluoromethylphenyl isothiocyanate in the presence of triethyl amine. It was found that after purification of the crude product by simple recrystallization, the R amino acid esters yielded thiohydantoins having solely M axial chirality whereas the S ones returned the P isomers only. This result prompted us to perform sterically controlled aldol reactions on M and P thiohydantoin atropisomers. It was found that during the aldol reaction of 3-o-trifluoromethyl-5-methylthiohydantoins, the o-trifluoromethyl group of the M isomers efficiently shielded the Si face of the intermediate and in this way, enabled the selective formation of only the R configured aldol products at C5 of the heterocyclic ring. The P thiohydantoins, on the other hand, yielded only the S C5 configured aldol products as a result of the Re face shielding of the ortho-trifluoromethyl group of intermediate enolates. A noteworthy face selectivity of the benzaldehyde molecule was not observed (anti/syn only 3/2) during the aldolization of trifluoromethylphenyl derivatives of thiohydantoins. Aldol reactions were also done using the previously synthesized axially chiral thiohydantoins with ortho-Cl, Br, and I phenyl substituents which had predominantly P conformations (P/M ratios > 95%), and the stereochemical outcomes were compared with those of the ortho-trifluoromethyl substituted ones. 80–90% face selectivity of the benzaldehyde molecule was observed for the axially chiral o-halophenyl substituted thiohydantoins. The syntheses done with axially chiral 3-ortho-trifluoromethylphenyl- and 3-ortho-iodophenyl-5-methyl thiohydantoins enabled stereoselective formation of quaternized chiral carbon centers at C5 of the thiohydantoin ring.

Do developmental prosopagnosics with high vs. low levels of autism traits differ in how they process faces?

Developmental prosopagnosia (DP) studies have routinely excluded individuals with high autism traits, assuming that DPs with high levels of autism traits have qualitatively different mechanisms of face recognition impairment, e.g., caused by social motivational factors. Indeed, autism spectrum disorders (ASD) are associated with face recognition memory and face emotion processing deficits but largely unimpaired face perception and holistic face processing abilities, whereas DPs without ASD have shown face perception and holistic processing deficits in addition to face memory deficits. To investigate the relationship between autism traits and face processing in DP, we administered a large behavioral battery and a face/scene/object/body fMRI localizer to 43 DPs with a wide range of Autism Quotient (AQ) scores as well as 27 healthy controls. When comparing the high (n=15; met broader autism phenotype classification) and low (n=28) AQ DP groups (AQ: 28.33 vs. 14.50; p<.001), we found a similar pattern across face processing tasks, with no differences in face matching (Cambridge Face Perception Test; p=.617), holistic face processing (Inversion effect: p=.644; Part-whole effect: p=.170), featural processing (Eyes: p=.643; Mouth: p=.984), or face memory (Cambridge Face Memory Test; p=.598). Both DP groups performed significantly worse on the face processing tasks compared to the control group (p’s<.05), with the exception of the mouth composite. As expected, the higher AQ group showed significantly decreased face emotion recognition compared to the low AQ group (p=.028). During the fMRI localizer task, both DP groups showed similarly reduced face selectivity in the left occipital and fusiform face areas compared to controls. Notably, the higher AQ DPs also showed decreased face selectivity in the bilateral posterior superior temporal sulcus compared to the lower AQ DPs. These results suggest that high autism traits do not result in qualitatively different face processing in DPs, but are associated with greater face emotion recognition impairments.

Recent Advances in Transition-Metal-Catalyzed C–H Functionalization Reactions Involving Aza/Oxabicyclic Alkenes

AbstractBicyclic alkenes, including oxa- and azabicyclic alkenes, readily undergo activation with facial selectivity in the presence of transition-metal complexes. This is due to the intrinsic angle strain on the carbon–carbon double bonds in such unsymmetrical bicyclic systems. During the past decades considerable progress has been made in the area of ring opening of bicyclic strained rings by employing the concept of C–H activation. This short review comprehensively compiles the various C–H bond activation assisted reactions of oxa- and azabicyclic alkenes, viz., ring-opening reactions, hydroarylation, and annulation reactions.1 Introduction2 Reactions of Heterobicyclic Ring Systems2.1 Ring-Opening Reactions of Oxa- and Azabenzonorbornadienes2.1.1 Reactions Using 7-Oxabenzonorbornadienes2.1.2 Reactions Using 7-Azabenzonorbornadienes2.2 Hydroarylation Reactions2.3 Annulation Reactions2.4 Other Reactions3 Conclusion

Separate and Shared Neural Basis of Face Memory and Face Perception in Developmental Prosopagnosia.

Developmental prosopagnosia (DP), also known as face blindness, is a cognitive disorder with a severe deficit in recognizing faces. However, the heterogeneous nature of DP leads to a longstanding debate on which stages the deficit occurs, face perception (e.g., matching two consecutively presented faces) or face memory (e.g., matching a face to memorized faces). Here, we used the individual difference approach with functional magnetic resonance imaging to explore the neural substrates of DPs’ face perception and face memory that may illuminate DPs’ heterogeneity. Specifically, we measured the behavioral performance of face perception and face memory in a large sample of individuals suffering DP (N = 64) and then associated the behavioral performance with their face-selective neural responses in the core face network (CFN) and the extended face network (EFN), respectively. Behaviorally, we found that DP individuals were impaired in both face perception and face memory; however, there was only a weak correlation between the performances of two tasks. Consistent with this observation, the neural correlate of DPs’ performance in face memory task was localized in the bilateral fusiform face area, whereas DPs’ performance in face perception task was correlated with the face selectivity in the right posterior superior temporal sulcus, suggesting that the neural substrates in the CFN for face memory and face perception were separate in DP. In contrast, shared neural substrates of deficits in face perception and face memory tasks were identified in the EFN, including the right precuneus and the right orbitofrontal cortex. In summary, our study provides one of the first empirical evidence that the separate and shared neural substrates of face perception and face memory were identified in the CFN and EFN, respectively, which may help illuminating DP’s heterogeneous nature.

Cortical recycling in high-level visual cortex during childhood development.

Human ventral temporal cortex (VTC) contains category-selective regions that respond preferentially to ecologically-relevant categories such as faces, bodies, places, and words, which are causally involved in the perception of these categories. How do these regions develop during childhood? We used functional MRI to measure longitudinal development of category-selectivity in school-age children over 1 to 5 years. We discovered that from young childhood to the teens, face- and word-selective regions in VTC expand and become more category-selective, but limb-selective regions shrink and lose their preference for limbs. Critically, as a child develops, increases in face- and word-selectivity are directly linked to decreases in limb-selectivity, revealing that during childhood limb-selectivity in VTC is repurposed into word- and face-selectivity. These data provide evidence for cortical recycling during childhood development. This has important implications for understanding typical as well as atypical brain development and necessitates a rethinking of how cortical function develops during childhood.

Scaffold‐Directed Face Selectivity Machine‐Learned from Vectors of Non‐covalent Interactions

AbstractThis work describes a method to vectorize and Machine‐Learn, ML, non‐covalent interactions responsible for scaffold‐directed reactions important in synthetic chemistry. Models trained on this representation predict correct face of approach in ca. 90 % of Michael additions or Diels–Alder cycloadditions. These accuracies are significantly higher than those based on traditional ML descriptors, energetic calculations, or intuition of experienced synthetic chemists. Our results also emphasize the importance of ML models being provided with relevant mechanistic knowledge; without such knowledge, these models cannot easily “transfer‐learn” and extrapolate to previously unseen reaction mechanisms.

Scaffold-Directed Face Selectivity Machine-Learned from Vectors of Non-covalent Interactions.

This work describes a method to vectorize and Machine-Learn, ML, non-covalent interactions responsible for scaffold-directed reactions important in synthetic chemistry. Models trained on this representation predict correct face of approach in ca. 90 % of Michael additions or Diels-Alder cycloadditions. These accuracies are significantly higher than those based on traditional ML descriptors, energetic calculations, or intuition of experienced synthetic chemists. Our results also emphasize the importance of ML models being provided with relevant mechanistic knowledge; without such knowledge, these models cannot easily "transfer-learn" and extrapolate to previously unseen reaction mechanisms.

Control of the Organocatalytic Enantioselective α-Alkylation of Vinylogous Carbonyl Enolates for the Synthesis of Tetrahydropyran Derivatives and Beyond.

The organocatalytic α-alkylation of vinylogous carbonyl compounds to hydroxynitroolefins for the synthesis of hemiacetals was realized with excellent enantioselectivities and in high yields. High diastereoselectivity (up to >20:1) has been accomplished with the addition of Et3N. The α- and γ-alkylation of vinylogous ketone against nitroolefins displayed high but opposite facial selectivities. Transformation of the hemiacetal products to other polycyclic compounds, including the euroticin B analog, has been demonstrated.

Robust, Enantioselective Construction of Challenging, Biologically Relevant Tertiary Ether Stereocenters.

A robust, catalytic enantioselective method to construct challenging, biologically relevant, tertiary ether stereocenters has been developed. The process capitalizes on readily accessible bis(oxazoline) ligands to control the facial selectivity of the addition of copper acetylides to benzopyrylium triflates, reactive species generated in situ. Up to 99% enantiomeric excesses are achieved with a broad substrate scope. Using density functional theory (DFT) calculations, the origin of the experimentally observed enantiocontrol was attributed to additional non-covalent interactions observed in the transition state leading to the major enantiomer, such as π-stacking. The resultant substrates have direct applications in the synthesis of naturally occurring bioactive chromanones and tetrahydroxanthones.

Molecular-level understanding of gibbsite particle aggregation in water

Using molecular dynamics simulations, we investigate the molecular scale origin of crystal face selectivity when one gibbsite particle attaches to another in water. A comparison of the free energy per unit surface area of particle–particle attachment indicates that particle attachment through edge surfaces, where the edge surfaces are either (1 0 0) or (1 1 0) crystal faces, is more energetically favorable compared to attachment between two basal surfaces (i.e., (0 0 1) crystal faces) or between the basal surface of one particle and the edge surface of another. This result suggests that gibbsite crystals with low basal/edge surface area ratio will preferentially attach through edge surfaces, potentially helping the crystals grow laterally. However, for larger gibbsite particles (high basal/edge surface area ratio) the total free energy, not normalized by surface area, of particle attachment through the basal surfaces is lower (more negative) than attachment through the edge surfaces, indicating that larger gibbsite particles will preferentially aggregate through basal surface attachments. The short-range electrostatic interactions including the interparticle hydrogen bonds from surface –OH groups drive particle attachment, and the dominant contribution to the free energy minimum is enthalpic rather than entropic. However, the enthalpy of basal-edge attachment is significantly offset by the entropy leading to a higher free energy (less negative) compared to that of basal-basal attachment. Study of the free energy for a few imperfect attachments of two particles indicates a higher free energy (i.e., less negative, less stable), compared to a perfect attachment

Rapid Enantioselective and Diastereoconvergent Hybrid Organic/Biocatalytic Entry into the Oseltamivir Core.

A formal synthesis of the antiviral drug (-)-oseltamivir (Tamiflu) has been accomplished starting from m-anisic acid via a dissolving metal or electrochemical Birch reduction. The correct absolute stereochemistry is efficiently set through enzyme-catalyzed carbonyl reduction on the resultant racemic α,β-unsaturated ketone. A screen of a broad ketoreductase (KRED) library identified several that deliver the desired allylic alcohol with nearly perfect facial selectivity at the new center for each antipodal substrate, indicating that the enzyme also is able to completely override inherent diastereomeric bias in the substrate. Conversion is complete, with d-glucose serving as the terminal hydride donor (glucose dehydrogenase). For each resulting diastereomeric secondary alcohol, O/N-interconversion is then efficiently effected either by synfacial [3,3]-sigmatropic allylic imidate rearrangement or by direct, stereoinverting N-Mitsunobu chemistry. Both stereochemical outcomes have been confirmed crystallographically. The α,β-unsaturation is then introduced via an α-phenylselenylation/oxidation/pyrolysis sequence to yield the targeted (S)-N-acyl-protected 5-amino-1,3-cyclohexadiene carboxylates, key advanced intermediates for oseltamivir pioneered by Corey (N-Boc) and Trost (N-phthalamido), respectively.

Stereoselective [4+2] Cycloaddition of Singlet Oxygen to Naphthalenes Controlled by Carbohydrates.

Stereoselective reactions of singlet oxygen are of current interest. Since enantioselective photooxygenations have not been realized efficiently, auxiliary control is an attractive alternative. However, the obtained peroxides are often too labile for isolation or further transformations into enantiomerically pure products. Herein, we describe the oxidation of naphthalenes by singlet oxygen, where the face selectivity is controlled by carbohydrates for the first time. The synthesis of the precursors is easily achieved starting from naphthoquinone and a protected glucose derivative in only two steps. Photooxygenations proceed smoothly at low temperature, and we detected the corresponding endoperoxides as sole products by NMR. They are labile and can thermally react back to the parent naphthalenes and singlet oxygen. However, we could isolate and characterize two enantiomerically pure peroxides, which are sufficiently stable at room temperature. An interesting influence of substituents on the stereoselectivities of the photooxygenations has been found, ranging from 51:49 to up to 91:9 dr (diastereomeric ratio). We explain this by a hindered rotation of the carbohydrate substituents, substantiated by a combination of NOESY measurements and theoretical calculations. Finally, we could transfer the chiral information from a pure endoperoxide to an epoxide, which was isolated after cleavage of the sugar chiral auxiliary in enantiomerically pure form.

A robust and stereocomplementary panel of ene-reductase variants for gram-scale asymmetric hydrogenation

We report an engineered panel of ene-reductases (ERs) from Thermus scotoductus SA-01 (TsER) that combines control over facial selectivity in the reduction of electron deficient CC double bonds with thermostability (up to 70 °C), organic solvent tolerance (up to 40 % v/v) and a broad substrate scope (23 compounds, three new to literature). Substrate acceptance and facial selectivity of 3-methylcyclohexenone was rationalized by crystallisation of TsER C25D/I67T and in silico docking. The TsER variant panel shows excellent enantiomeric excess (ee) and yields during bi-phasic preparative scale synthesis, with isolated yield of up to 93 % for 2R,5S-dihydrocarvone (3.6 g). Turnover frequencies (TOF) of approximately 40 000 h−1 were achieved, which are comparable to rates in hetero- and homogeneous metal catalysed hydrogenations. Preliminary batch reactions also demonstrated the reusability of the reaction system by consecutively removing the organic phase (n-pentane) for product removal and replacing with fresh substrate. Four consecutive batches yielded ca. 27 g L−1 R-levodione from a 45 mL aqueous reaction, containing less than 17 mg (10 μM) enzyme and the reaction only stopping because of acidification. The TsER variant panel provides a robust, highly active and stereocomplementary base for further exploitation as a tool in preparative organic synthesis.

Chemistry of Unsymmetrical C1-Substituted Oxabenzonorbornadienes.

Oxabenzonorbornadiene (OBD) is a useful synthetic intermediate, which can be readily activated by transition metal complexes with great face selectivity due to its dual-faced nature and intrinsic angle strain on the alkene. To date, the understanding of transition-metal catalyzed reactions of OBD itself has burgeoned; however, this has not been the case for unsymmetrical OBDs. Throughout the development of these reactions, the nature of C1-substituent has proven to have a profound effect on both the reactivity and selectivity of the outcome of the reaction. Upon substitution, different modes of reactivity arise, contributing to the possibility of multiple stereo-, regio-, and in extreme cases, constitutional isomers, which can provide unique means of constructing a variety of synthetically useful cyclic frameworks. To maximize selectivity, an understanding of bridgehead substituent effects is crucial. To that end, this review outlines hitherto reported examples of bridgehead substituent effects on the chemistry of unsymmetrical C1-substituted OBDs.

Anatomical correlates of face patches in macaque inferotemporal cortex

Primate brains typically have regions within the ventral visual stream that are selectively responsive to faces. In macaques, these face patches are located in similar parts of inferotemporal cortex across individuals although correspondence with particular anatomical features has not been reported previously. Here, using high-resolution functional and anatomical imaging, we show that small "bumps," or buried gyri, along the lower bank of the superior temporal sulcus are predictive of the location of face-selective regions. Recordings from implanted multielectrode arrays verified that these bumps contain face-selective neurons. These bumps were present in monkeys raised without seeing faces and that lack face patches, indicating that these anatomical landmarks are predictive of, but not sufficient for, the presence of face selectivity. These bumps are found across primate species that span taxonomy lines, indicating common evolutionary developmental mechanisms. The bumps emerge during fetal development in macaques, indicating that they arise from general developmental mechanisms that result in the regularity of cortical folding of the entire brain.

Multipoint Recognition of Molecular Conformations with Organocatalysts for Asymmetric Synthetic Reactions

Abstract Organocatalysts activate substrates through mild noncovalent and covalent interactions, and their cooperative actions at multiple catalytic sites are essential even in intrinsically rapid organic reactions such as intramolecular cyclizations. The enzyme-like catalytic system is effective for recognizing specific molecular conformations of substrates, which continually change under reaction conditions, through multipoint interactions, thereby leading to high stereoselectivity. On the basis of this concept, we developed a range of organocatalytic asymmetric synthetic reactions, which are challenging using other categories of catalysts. The proposed catalysis was applied to various manners of asymmetric induction including those accompanied by not only facial selectivity but also by kinetic resolution (KR), dynamic kinetic resolution (DKR), desymmetrization, and dynamic kinetic asymmetric transformation (DYKAT). They enabled various asymmetric transformations through intramolecular hetero-Michael addition, construction of axial chirality, and α,β-unsaturated acylammonium catalysis, which advanced the methods for asymmetric heterocycle synthesis, construction of tetrasubstituted chiral carbons, enantioselective synthesis of axially chiral compounds, and asymmetric library synthesis of pharmaceutically potential compounds. This study also expanded the chemistry of bifunctional organocatalysis. This review provides a comprehensive account of our achievements regarding multipoint recognition of molecular conformations with organocatalysts for asymmetric synthetic reactions.

Synthesis of Constrained C‐Glycosyl Amino Acid Derivatives Involving 1,3‐Dipolar Cycloaddition of Cyclic Nitrone as Key Step

An efficient two‐step strategy for the synthesis of constrained C‐glycosyl amino acid derivatives from C‐vinylglycosides involving a 1,3‐dipolar cycloaddition using l‐(–)‐menthone‐derived nitrone as the key step is described. After optimization of 1,3‐dipolar cycloaddition conditions, various C‐vinylglycosides were tested leading exclusively to one diastereoisomer of the corresponding cycloadduct in good to excellent yields. The total facial selectivity observed was also studied by DFT calculations. Original conformationally restricted C‐glycosyl amino acid derivatives (8 examples) were isolated after simple cleavage of the chiral auxiliary.