Hindered Face Research Articles

DFT studies on the diastereoselectivity and regioselectivity of multicomponent domino Knoevenagel/Diels–Alder reaction

In this study, mechanism and stereochemistry of multicomponent domino Knoevenagel/Diels–Alder reaction were investigated theoretically. Structures of reagents, transition states, intermediates, and products were optimized at M062X/6-31[Formula: see text]G(d,p) level of theory. Although the mechanism of this reaction involved several processes, including bond rotation, isomerization, asymmetric cycloaddition, acid-base, and nucleophile–electrophile competitions, critical processes were studied to provide a clearer picture of the mechanism of this valuable reaction in terms of stereochemistry considerations. According to the results, the ring closure step of reaction performed via a polar Dield-Alder mechanism, having enthalpy at approximately 40[Formula: see text]kcal/mol. The diastereoselectivity of the reaction was controlled by the interaction of dienophile with the less hindered face of diene through a more stable endo transition state ([Formula: see text] and 27.31 in methanol and gas phase, respectively). HSAB criteria could explain the regioselectivity of this reaction by considering the least softness difference ([Formula: see text]) for interacting C-atoms based on Hirshfeld populations. The result was the creation of cis-spiro cyclohexanone under kinetic and thermodynamic controls as a predominant diastereoselective and regioselective product.

Enantioselective Total Synthesis of Macfarlandin C, a Spongian Diterpenoid Harboring a Concave‐Substituted cis‐Dioxabicyclo[3.3.0]octanone Fragment

The enantioselective total synthesis of the rearranged spongian diterpenoid (-)-macfarlandin C is reported. This is the first synthesis of a rearranged spongian diterpenoid in which the bulky hydrocarbon fragment is joined via a quaternary carbon to the highly hindered concave face of the cis-2,8-dioxabicyclo[3.3.0]octan-3-one moiety. The strategy involves a late-stage fragment coupling between a tertiary carbon radical and an electrophilic butenolide resulting in the stereoselective formation of vicinal quaternary and tertiary stereocenters. A stereoselective Mukaiyama hydration that orients a pendant carboxymethyl side chain cis to the bulky octahydronapthalene substituent was pivotal in fashioning the challenging concave-substituted cis-dioxabicyclo[3.3.0]octanone fragment.

Enantioselective Total Synthesis of Macfarlandin C, a Spongian Diterpenoid Harboring a Concave‐Substituted cis‐Dioxabicyclo[3.3.0]octanone Fragment

AbstractThe enantioselective total synthesis of the rearranged spongian diterpenoid (−)‐macfarlandin C is reported. This is the first synthesis of a rearranged spongian diterpenoid in which the bulky hydrocarbon fragment is joined via a quaternary carbon to the highly hindered concave face of the cis‐2,8‐dioxabicyclo[3.3.0]octan‐3‐one moiety. The strategy involves a late‐stage fragment coupling between a tertiary carbon radical and an electrophilic butenolide resulting in the stereoselective formation of vicinal quaternary and tertiary stereocenters. A stereoselective Mukaiyama hydration that orients a pendant carboxymethyl side chain cis to the bulky octahydronapthalene substituent was pivotal in fashioning the challenging concave‐substituted cis‐dioxabicyclo[3.3.0]octanone fragment.

Diastereoselective synthesis of atropisomeric pyrazolyl pyrrolo[3,4-d]isoxazolidines via pyrazolyl nitrone cycloaddition to facially divergent maleimides: intensive NMR and DFT studies.

A pyrazolyl nitrone (2) underwent 1,3-dipolar cycloadditions to afford some N-substituted maleimides (3a–o). An atropisomeric character was introduced into the formed cycloadducts by using maleimides that have a restricted rotation around the C–N bond. Also, facial selectivity of both endo and exo cycloaddition was observed where the major atropisomer was one that is formed by attacking the nitrone from the less hindered face of the dipolarophile. On the other hand, maleimides with free rotation around the C–N bond led to endo and exo cycloadducts without atropisomerism. The presence of atropisomerism in the formed cycloadducts was confirmed by extensive NMR studies and DFT calculations.

Diels‐Alder Reaction of Levoglucosenone with a Protected cis‐Cyclohexadienediol: Structural and Electronic Basis behind the Unexpected Stereoselectivity

AbstractRecently, we found that the Diels–Alder reaction between levoglucosenone and the acetonide of (1S,2R)‐3‐methylcyclohexa‐3,5‐diene‐1,2‐diol occurs through the most hindered face of the diene. This unexpected facial selectivity has no precedent for di‐O‐isopropylidene‐protected dienes, and the reasons behind it remain unclear. Here, we expand on our earlier findings, computationally assessing the structural and electronic factors responsible for this unforeseen stereoselectivity. The B3LYP/6‐31+G(d,p) results identify the three main adducts (β‐endo‐ortho:α‐endo‐meta:α‐exo‐ortho), giving a product ratio (63:9:28) that is in line with the experimental value (64:16:10). The β‐endo attack allows to maximize the electrostatic attraction between the reactants, giving rise to dipolar C−O⋅⋅⋅H−C interactions with the isopropylidene group at the transition state. The endo/exo preference can be rationalized through electrostatic repulsion and steric hindrance between the isopropylidene and methylene fragments. Finally, the non‐classical C=O⋅⋅⋅H−C hydrogen bonding stabilizes the ortho transition structures, making them more polar and asynchronous.

Unexpected Interactions between Alkyl Straps and Pyridine Ligands in Sulfur-Strapped Porphyrin Nanorings

Strapped or “basket-handle” porphyrins have been investigated previously as hemoglobin mimics and catalysts. The facial selectivity of their interactions with axial ligands is a sensitive test for noncovalent bonding. Here the binding of pyridyl ligands to zinc porphyrins with thioester-linked alkyl straps is investigated in solution by NMR spectroscopy and UV–vis titration, and in the solid state by X-ray crystallography. We expected that coordination of the axial ligand would occur on the less hindered face of the porphyrin, away from the strap. Surprisingly, attractive interactions between the strap and the ligand direct axial coordination to the strapped face of the porphyrin, except when the strap is short and tight. The strapped porphyrins were incorporated into π-conjugated cyclic porphyrin hexamers using template-directed synthesis. The strap and the sulfur substituents are located either inside or outside the porphyrin nanoring, depending on the length of the strap. Six-porphyrin nanorings with outwardly pointing sulfur anchors were prepared for exploring quantum interference effects in single-molecule charge transport.

Stereoselective synthesis of enantiopure N-substituted pyrrolidin-2,5-dione derivatives by 1,3-dipolar cycloaddition and assessment of their in vitro antioxidant and antibacterial activities

1,3-Dipolar cycloaddition between a chiral nitrone and N-substituted maleimides afforded unprecedented enantiopure spiro-fused heterocycles in good yields with a high enantio- and diastereoselectivity. The reaction was taking place on the less hindered face of the nitrone. The obtaining heterocycles were screened for their in vitro antioxidant properties and the results revealed that the potent antioxidant activity was generally recorded to compounds (3g) and (3e). The in vitro antibacterial activities of these two compounds were also investigated and the results demonstrated the strongest potential of compound (3g) against all the tested bacteria. Molecular properties were analyzed and showed good oral drug candidate like properties and that could be exploited as a potential antioxidant and antimicrobial agent. Finally, the preliminary results obtained from this investigation attempted to clarify if the structurally different side chains of active compounds interfere with their biological properties.

Synthesis of Gly-ψ[(Z)CF═CH]-Phe, a Fluoroalkene Dipeptide Isostere, and Its Incorporation into a Leu-enkephalin Peptidomimetic.

A new Leu-enkephalin peptidomimetic designed to explore the hydrogen bond acceptor ability of the third peptide bond has been prepared and studied. This new analog is produced by replacing the third amide of Leu-enkephalin with a fluoroalkene. An efficient and innovative synthesis of the corresponding dipeptide surrogate Fmoc-Gly-ψ[(Z)CF═CH]-Phe-OH is described. The key step involves the alkylation of a tin dienolate from the less hindered face of its chiral sulfonamide auxiliary derived from camphor. Once its synthesis was complete, its incorporation into the peptidomimetic sequence was achieved on a solid support with chlorotrityl resin following the Fmoc strategy. The peptidomimetic was characterized using competition binding with [125I]-deltorphin I on membrane extracts of HEK293 cells expressing the mouse delta opioid receptor (DOPr) and based on its abilities to inhibit the electrically induced contractions of the mouse vas deferens and to activate the ERK1/2 signaling pathway in DRGF11/DOPr-GFP cells. Together with our previous observations, our findings strongly suggest that the third amide bond of Leu-enkephalin primarily acts as a hydrogen bond acceptor in DOPr. Consequently, this amide bond can be successfully replaced by an ester, a thioamide, or a fluoroalkene without greatly impacting the binding or biological activity of the corresponding analogs. The lipophilicity (LogD7.4) of the active analog was also measured. It appears that fluoroalkenes are almost as efficient at increasing the lipophilicity as normal alkenes.

Unprecedented 3- O -methyl-3- C -trifluoromethyl- d -ribono- (and l -lyxono)-γ-lactones synthesized by nucleophilic trifluoromethylation of d -hexose-derived cyclic ketones

Abstract 3-O-Methyl-3-C-trifluoromethyl- d -ribono-(and l -lyxono)-γ-lactones have been prepared from protected d -hexoses (gluco, galacto) by multi-step routes from d -glucose. The synthetic strategy includes the following steps: regioselective oxidation, nucleophilic trifluoromethylation with the Ruppert-Prakash reagent of 3-keto hexofuranose derivatives attacked stereoselectively from the less hindered face, protective group manipulations, and regioselective oxidation of a hemiacetalic hydroxyl. Base-catalyzed hydrolysis of two related d -ribonolactones afforded 3-O-Me-3-C-CF3- d -ribonic acid.

(Organic and Biological Electrochemistry Division Manuel M. Baizer Award) Following the Lead of R. B. Woodward and M. M. Baizer: Using Concepts in Physical Organic Chemistry to Shape the Course of Electrochemical Reactions

One of R. B. Woodward’s many contributions to organic chemistry was the way in which he used physical organic chemistry and an understanding of mechanism to shape the development of new synthetic methods. From the use of temporary, conformational constraints to dictate the stereochemistry of a complex target to the interception of a key intermediate to bring about a cis-hydroxylation reaction from the most hindered face of a molecule, the Woodward group beautifully demonstrated that the outcome of a reaction could be predetermined by considering and then controlling its mechanistic features. In a similar manner, Manuel M. Baizer taught us much about how to think about electrochemical reactions. His work helped take the “magic” out of electroorganic processes and demonstrated that electroorganic reactions were indeed organic reactions. They were triggered by electron-transfer processes and had additional parameters that needed to be considered, but to a great extent they could be understood and optimized as synthetic transformations by considering their chemical mechanism. This perspective served to make organic electrochemistry accessible to the larger synthetic community. The combination of lessons learned from these two pioneers laid the foundation for our own studies concerning electrochemical reactions and their use in synthesis. From the oxidation of amides used in the synthesis of peptidomimetics, to the use of oxidative cyclization reactions in synthesis, to the site-selective generation of chemical reagents for the functionalization of microelectrode array surfaces, we have continually relied on the fact that electroorganic reactions are simply organic reactions and can thus be optimized as such. The overall approach has fueled not only our own work, but also that of so many others, far too many to name here. In the talk to be presented, an overview of electrochemical synthetic methods will be presented against a backdrop of the mechanistic insights and findings that enabled and enhanced their development. An emphasis will be placed on the synthetic utility of reactions that take advantage of reactive radical cation intermediates,1 site-selective reactions on conducted on microelectrode arrays,2 and a look toward the future use of paired electrochemical reactions for the on-site generation of chemical reagents.3

Trans-selective rhodium catalysed conjugate addition of organoboron reagents to dihydropyranones.

The selective synthesis of 2,6-trans-tetrahydropyran derivatives employing the rhodium catalysed addition of organoboron reagents to dihydropyranone templates, derived from a zinc-catalysed hetero-Diels-Alder reaction, is reported. The addition of both arylboronic acids and potassium alkenyltrifluoroborates have been accomplished in high yields using commercially-available [Rh(cod)(OH)]2 catalyst. The selective formation of the 2,6-trans-tetrahydropyran stereoisomer is consistent with a mechanism involving alkene association and carbometalation on the less hindered face of the dihydropyranone.

Stereoselective Synthesis of Polyhydroxylated Amines Using (<i>S</i>)-Pyroglutamic Acid Derivatives

Naturally occurring polyhydroxylated amines such as (+)-1-deoxynojirimycin, polyoxamic acid, anisomycin, (-)swainsonine, and alexine stereoisomers, which have interesting biological activities including glucosidase- and mannosidase-inhibitory activity, immunoregulatory activity, and antibacterial effects, were synthesized stereoselectively starting from (S)-pyroglutamic acid derivatives. α,β-Unsaturated lactams ((S)-5-hydroxymethyl-2-oxo-3-pyrroline derivatives), α,β-unsaturated δ-lactone ((S)-4-amino-2-penten-5-olide derivative), and E-olefin ((S,E)-methyl-4-amino-5-hydroxypent-2-enoate derivative) from (S)-pyroglutamic acid derivatives were dihydroxylated using OsO4 in the presence of N-methyl morpholine N-oxide (NMO) to afford various chiral building blocks with different configurations. The stereoselectivity of cis-dihydroxylation for α,β-unsaturated lactams and α,β-unsaturated δ-lactone was very high, while the stereoselectivity was low for E-olefin. Therefore, the double asymmetric induction of E-olefin using K2OsO4 with chiral ligands was successively applied to yield high stereoselectivity. (2R,3S)-2-Hydroxymethyl-3-hydroxypyrrolidine and Gaissman-Weiss lactone, important intermediates for the preparation of pyrrolizidine alkaloids, were synthesized from a (3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-2-pyrrolidinone derivative derived from α,β-unsatulated lactam. (+)-1-Deoxynojirimycin was synthesized from a (2S,3R,4R)-methyl 4-amino-2,3,5-trihydroxypentanoate derivative of E-olefin. (-)-Swainsonine and its stereoisomers were synthesized from (2R,3S,4R)- or (2R,3R,4R)-2-hydroxymethyl-3,4-dihydroxypyrrolidine derivatives of α,β-unsaturated δ-lactone or α,β-unsaturated lactam. The key reaction was diastereoselective allylation of the aldehyde derived from the corresponding 2-hydroxymethylpyrrolidine derivatives with various allylation reagents. The high diastereoselectivity could be explained by cyclic chelate formation between metals and the α-aminocarbonyl group or β-alkoxycarbonyl group, in which the nucleophile approaches from the less hindered face. Four alexine stereoisomers were synthesized from (2R,3R,4S,5R)- and (2R,3R,4S,5S)-2,3-dihydroxymethyl-3,4-dihydroxyl pyrrolidine derivatives of α,β-unsaturated lactam.

Potassium (1R,4R,5S,8S)-4,5,8-trihydroxy-3-oxo-2,6-dioxabicyclo[3.3.0]octane-4-sulfonate dihydrate

The title salt, K+·C6H7O9S−·2H2O, formed by reaction of dehydro-l-ascorbic acid with potassium hydrogen sulfite in water, crystallizes as colourless plates. The potassium ion is coordinated by eight O atoms arising from hy­droxy or sulfonate groups. The sulfonate group is bonded to the C atom neighbouring that of the lactone carbonyl group. As is commonly observed in crystalline l-ascorbic acid derivatives, the O atom of the primary hy­droxy group is linked to the second C atom from the lactone C atom, forming a hemi-acetal function, thereby creating a bicyclic system of two fused five-membered rings, both of which have envelope conformations with one of the shared C atoms as the flap. Addition of the sulfur nucleophile occurs from the less hindered face. One of the two independent lattice water mol­ecules has hydrogen bonds to sulfonate O atoms of two different anions and is the acceptor of bonds from hy­droxy groups of two further anions; the second lattice water mol­ecule donates to the carbonyl and a hy­droxy O atom in different anions, and accepts from a hy­droxy O atom in a further anion. Thus, through K—O coordination and hydrogen bonds, the potassium cations, sulfonate anions and water mol­ecules are linked in a three-dimensional network.

Origins of Stereoselectivities of Dihydroxylations of cis-Bicyclo[3.3.0]octenes

Stereoselectivities of the dihydroxylations of cis-bicyclo[3.3.0]octene intermediates for a projected total synthesis of chromodorolide A have been explored experimentally. The reaction occurs unexpectedly on the apparently more hindered (concave) face; this result has been explained through computational studies using B3LYP and B3LYP-D3 methods. Torsional effects are largely responsible for the stereoselectivity encountered in the chromodorolide A synthesis. Many literature examples have been reported on related cases. QM calculations show that the stereoselectivities of dihydroxylations of fused cyclopentenes are influenced by the conformational rigidity or flexibility of the substrate. Torsional, electrostatic, and steric effects can all influence stereoselectivity, and the rigidity or flexibility of conformations of reactants provides a predictive guide to stereoselectivity.

Enantioselective Addition of Cyclic Enol Silyl Ethers to 2-Alkenoyl-Pyridine-N-Oxides Catalysed by CuII-Bis(oxazoline) Complexes

Asymmetric reactions involving (E)-3-aryl-1-(pyridin-2-yl-N-oxide)prop-2-en-1-ones and cyclic enol silyl ethers show good yields and excellent enantioselectivities (up to 99.9 % ee) when catalysed by bis(oxazoline)-Cu(II) complexes. Different reaction pathways can be followed by different enol silyl ethers: with 2-(trimethylsilyloxy)furan, a Mukaiyama-Michael adduct is obtained, whereas a hetero Diels-Alder cycloadduct was formed by using (1,2-dihydronaphthalen-4-yloxy)trimethylsilane. In the latter reaction, the absolute configuration of the product is consistent with a reagent approach to the less hindered Re face of the coordinated substrate in the reactive complex.

1,3-dipolar cycloadditions of arylnitrile oxides and 2-diazopropane with 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives

Abstract The reactions of arylnitrile oxides 2 and 2-diazopropane 5 with 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives 1 have been studied. 1,3-dipolar cycloaddition of arylnitrile oxides and 2-diazopropane with 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives is taking place regiospecifically. The asymmetric induction expected by the chiral centre of the 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives was very effective, diastereoisomers 3 and 4 were formed in an approximate 90:10 ratio. The stereoselectivity of the 1,3-dipolar cycloaddition of the 2-diazopropane with the 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives are investigated. The attack of the 1,3-dipole occurred from the less hindered face of the dipolarophile, giving the isomer 6 .

Enantioselective Cycloadditions of 2‐Alkenoylpyridine‐N‐oxides Catalysed by a Bis(oxazoline)/CuII Complex: Structure of the Reactive Intermediate

Diels-Alder and 1,3-dipolar cycloadditions involving (E)-3-aryl-1-(pyridin-2-yl-N-oxide)prop-2-en-1-ones as the 2π components are efficiently catalysed by bis(oxazoline)-Cu(II) complexes. The cycloadducts are obtained in quantitative yields with up to 98 % ee; absolute configurations were determined by X-ray analysis. The structure of the reactive complex, determined by X-ray analysis, is fully consistent with the stereochemical outcome of the catalysed process (approach of the diene or nitrone to the less hindered face of the coordinated pyridine-N-oxide derivative).

ChemInform Abstract: Development of a Synthesis of Lankacidins: Stereoselective Synthesis of the δ-Lactone Fragment.

Electrophiles react at C(3) stereoselectively on the less hindered face of the enolate derived from the 4-substituted azetidinone 5 to give products in which the new substituent is trans to the (tert-butyldimethylsilyloxymethyl) group at C(4). Aldol addition with 3-(tert-butyldimethylsilyloxy)propanal gave the alcohols 27 and 29, ratio 80 : 20, which were separated as mixtures at C(1′). Oxidation, followed by exchange of protecting groups, gave the 3-(1′-oxopropyl)azetidinones 39 and 41 which, on selective monodesilylation, were converted into the δ-lactones 43 and 44. The benzyloxymethyl protected 3-(hydroxyalkyl)azetidinones 40 and 42 were similarly prepared and gave the δ-lactones 43 and 44 on hydrogenolysis. The stereochemistry of the major δ-lactone 43 corresponds to that of the lankacidins at C(2) and C(3). The 3-(1′-oxopropyl)azetidinone 26, which has additional substituents at C(16) and C(17)(Isnkacidin numbering), was similarly prepared.

Transition State Models for Probing Stereoinduction in Evans Chiral Auxiliary-Based Asymmetric Aldol Reactions

The use of chiral auxiliaries is one of the most fundamental protocols employed in asymmetric synthesis. In the present study, stereoselectivity-determining factors in a chiral auxiliary-based asymmetric aldol reaction promoted by TiCl(4) are investigated by using density functional theory methods. The aldol reaction between chiral titanium enolate [derived from Evans propionyl oxazolidinone (1a) and its variants oxazolidinethione (1b) and thiazolidinethione (1c)] and benzaldehyde is examined by using transition-state modeling. Different stereochemical possibilities for the addition of titanium enolates to aldehyde are compared. On the basis of the coordination of the carbonyl/thiocarbonyl group of the chiral auxiliary with titanium, both pathways involving nonchelated and chelated transition states (TSs) are considered. The computed relative energies of the stereoselectivity-determining C-C bond formation TSs in the nonchelated pathway, for both 1a and 1c, indicate a preference toward Evans syn aldol product. The presence of a ring carbonyl or thiocarbonyl group in the chiral auxiliary renders the formation of neutral TiCl(3)-enolate, which otherwise is energetically less favored as compared to the anionic TiCl(4)-enolate. Hence, under suitable conditions, the reaction between titanium enolate and aldehyde is expected to be viable through chelated TSs leading to the selective formation of non-Evans syn aldol product. Experimentally known high stereoselectivity toward Evans syn aldol product is effectively rationalized by using the larger energy differences between the corresponding diastereomeric TSs. In both chelated and nonchelated pathways, the attack by the less hindered face of the enolate on aldehyde through a chair-like TS with an equatorial disposition of the aldehydic substituent is identified as the preferred mode. The steric hindrance offered by the isopropyl group and the possible chelation are identified as the key reasons behind the interesting stereodivergence between Evans and non-Evans products normally reported for the title reaction. The application of an activation strain model on the critical TSs has been effective toward rationalizing the origin of stereoselectivity. Improved interaction energy between the reactants is found to be the key stabilizing factor for the lowest energy TS in both chelated and nonchelated pathways. The present study provides newer insights on the role of titanium(IV) toward modulating stereoselectivity in aldol reactions.

機能性ニトロンを用いたアミノ酸型天然物の合成研究

(5R)- [and (5S)]-5,6-Dihydro-5-phenyl-2H-1,4-oxazin-2-one N-oxides were designed and synthesized as chiral (E)-geometry-fixed α-alkoxycarbonylnitrones that exist as equilibrating mixture of (E)- and (Z)-isomers. The cyclic nitrone reacted with olefins under mild conditions to afford the main cycloadducts via the least sterically demanding exo modes. The nitrone also reacted with an allyl alcohol in the presence of magnesium bromide from the less hindered face via exo-mode to afford exclusively cycloadduct as a single stereoisomer. These reactions were applied to the syntheses of carbocyclic polyoxin C, anti-β-substituted aspartic acid, clavalanine, monatin, lycoperdic acid, neodysiherbaine A, and maremycins A and D1.