Catalytic Asymmetric Addition of Meldrum’s Acid,Malononitrile, and 1,3‐Dicarbonyls to ortho‐Quinone Methides Generated In Situ Under Basic Conditions

A new approach to the utilization of highly reactive and unstable ortho‐quinone methides (o‐QMs) in catalytic asymmetric settings is presented. The enantioselective reactions are catalysed by bifunctional organocatalysts, and the o‐QM intermediates are formed in situ from 2‐sulfonylalkyl phenols through base‐promoted elimination of sulfinic acid. The use of mild Brønsted basic conditions for transiently generating o‐QMs in catalytic asymmetric processes is unprecedented, and allows engaging productively in the reactions nucleophiles such as Meldrum’s acid, malononitrile and 1,3‐dicarbonyls. The catalytic transformations give new and general entries to 3,4‐dihydrocoumarins, 4H‐chromenes and xanthenones. These frameworks are recurring structures in natural product and medicinal chemistry, as testified by the formal syntheses of (R)‐tolterodine and (S)‐4‐methoxydalbergione from the catalytic adducts.     

Substituent Effects on Oxidation‐Induced Formation of Quinone Methides from Arylboronic Ester Precursors

A series of arylboronic esters containing different aromatic substituents and various benzylic leaving groups (Br or N⁺Me₃Br^?) have been synthesized. The substituent effects on their reactivity with H₂O₂ and formation of quinone methide (QM) have been investigated. NMR spectroscopy and ethyl vinyl ether (EVE) trapping experiments were used to determine the reaction mechanism and QM formation, respectively. QMs were not generated during oxidative cleavage of the boronic esters but by subsequent transformation of the phenol products under physiological conditions. The oxidative deboronation is facilitated by electron‐withdrawing substituents, such as aromatic F, NO₂, or benzylic N⁺Me₃Br^?, whereas electron‐donating substituents or a better leaving group favor QM generation. Compounds containing an aromatic CH₃ or OMe group, or a good leaving group (Br), efficiently generate QMs under physiological conditions. Finally, a quantitative relationship between the structure and activity has been established for the arylboronic esters by using a Hammett plot. The reactivity of the arylboronic acids/esters and the inhibition or facilitation of QM formation can now be predictably adjusted. This adjustment is important as some applications may benefit and others may be limited by QM generation.     

Ferrocenyl Quinone Methide–Thiol Adducts as New Antiproliferative Agents: Synthesis,Metabolic Formation from Ferrociphenols,and Oxidative Transformation

Ferrociphenols ( FCs ) and their oxidized, electrophilic quinone methide metabolites ( FC‐QMs ) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC‐QMs toward cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FC‐SR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of the FC‐SR adducts exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either revert to their FC‐QM precursors or transform into new quinone methides (QMs) containing the SR moiety, FC‐SR‐QM . These results provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs , and also open the way to a new series of organometallic antitumor compounds.     

Ferrocenyl Quinone Methide–Thiol Adducts as New Antiproliferative Agents: Synthesis,Metabolic Formation from Ferrociphenols,and Oxidative Transformation

Ferrociphenols ( FCs ) and their oxidized, electrophilic quinone methide metabolites ( FC‐QMs ) are organometallic compounds related to tamoxifen that exhibit strong antiproliferative properties. To evaluate the reactivity of FC‐QMs toward cellular nucleophiles, we studied their reaction with selected thiols. A series of new compounds resulting from the addition of these nucleophiles, the FC‐SR adducts, were thus synthesized and completely characterized. Such conjugates are formed upon metabolism of FCs by liver microsomes in the presence of NADPH and thiols. Some of the FC‐SR adducts exhibit antiproliferative properties comparable to those of their FC precursors. Under oxidizing conditions they either revert to their FC‐QM precursors or transform into new quinone methides (QMs) containing the SR moiety, FC‐SR‐QM . These results provide interesting data about the reactivity and mechanism of antiproliferative effects of FCs , and also open the way to a new series of organometallic antitumor compounds.     

Catalytic Asymmetric 1,6‐Conjugate Addition of para‐Quinone Methides: Formation of All‐Carbon Quaternary Stereocenters

Described herein is a general and mild catalytic asymmetric 1,6‐conjugate addition of para‐quinone methides (p‐QMs), a class of challenging reactions with previous limited success. Benefiting from chiral Brønsted acid catalysis, which allows in situ formation of p‐QMs, our reaction expands the scope to general p‐QMs with various substitution patterns. It also enables efficient intermolecular formation of all‐carbon quaternary stereocenters with high enantioselectivity.     

Synthesis,X‐ray characterization and density functional theory studies of N6‐benzyl‐N6‐methyladenine–M(II) complexes (M = Zn,Cd): The prominent role of π–π, C–H···π and anion–π interactions

We report the synthesis and X‐ray characterization of the N⁶‐benzyl‐N⁶‐methyladenine ligand (L) and three metal complexes, namely [Zn(HL)Cl₃]·H₂O ( 1 ), [Cd(HL)₂Cl₄] ( 2 ) and [H₂L]₂[Cd₃(μ‐L)₂(μ‐Cl)₄Cl₆]·3H₂O ( 3 ). Complex 1 consists of the 7H‐adenine tautomer protonated at N3 and coordinated to a tetrahedral Zn(II) metal centre through N9. The octahedral Cd(II) in complex 2 is N⁹‐coordinated to two N⁶‐benzyl‐N⁶‐methyladeninium ligands (7H‐tautomer protonated at N3) that occupy apical positions and four chlorido ligands form the basal plane. Compound 3 corresponds to a trinuclear Cd(II) complex, where the central Cd atom is six‐coordinated to two bridging μ‐L and four bridging μ‐Cl ligands. The other two Cd atoms are six‐coordinated to three terminal chlorido ligands, to two bridging μ‐Cl ligands and to the bridging μ‐L through N3. Essentially, the coordination patterns, degree of protonation and tautomeric forms of the nucleobase dominate the solid‐state architectures of 1 – 3 . Additionally, the hydrogen‐bonding interactions produced by the endocyclic N atoms and NH groups stabilize high‐dimensional‐order supramolecular assemblies. Moreover, energetically strong anion–π and lone pair (lp)–π interactions are important in constructing the final solid‐state architectures in 1 – 3 . We have studied the non‐covalent interactions energetically using density functional theory calculations and rationalized the interactions using molecular electrostatic potential surfaces and Bader's theory of atoms in molecules. We have particularly analysed cooperative lp–π and anion–π interactions in 1 and π⁺–π⁺ interactions in 3 .     

Chiral N,N′‐Dioxide–Scandium(III) Complex‐Catalyzed Asymmetric Friedel–Crafts Alkylation Reaction of ortho‐Hydroxybenzyl Alcohols with C3‐Substituted N‐Protected Indoles

The first Lewis acid catalyzed asymmetric Friedel–Crafts alkylation reaction of ortho‐hydroxybenzyl alcohols with C3‐substituted indoles is described. A chiral N,N′‐dioxide Sc(OTf)₃ complex served not only to promote formation of ortho‐quinone methides (o‐QMs) in situ but also induced the asymmetry of the reaction. This methodology enables a novel activation of ortho‐hydroxybenzyl alcohols, thus affording the desired chiral diarylindol‐2‐ylmethanes in up to 99 % yield and 99 % ee. A range of functional groups were also tolerated under the mild reaction conditions. Moreover, this strategy gives concise access to enantioenriched indole‐fused benzoxocines.     

Theoretical Study on Cooperativity Effects between Anion–π and Halogen‐Bonding Interactions

This article analyzes the interplay between lone pair–π (lp–π) or anion–π interactions and halogen‐bonding interactions. Interesting cooperativity effects are observed when lp/anion–π and halogen‐bonding interactions coexist in the same complex, and they are found even in systems in which the distance between the anion and halogen‐bond donor molecule is longer than 9 Å. These effects are studied theoretically in terms of energetic and geometric features of the complexes, which are computed by ab initio methods. Bader′s theory of “atoms in molecules” is used to characterize the interactions and to analyze their strengthening or weakening depending upon the variation of charge density at critical points. The physical nature of the interactions and cooperativity effects are studied by means of molecular interaction potential with polarization partition scheme. By taking advantage of all aforementioned computational methods, the present study examines how these interactions mutually influence each other. Additionally, experimental evidence for such interactions is obtained from the Cambridge Structural Database (CSD).     

Formal Asymmetric Catalytic Thiolation with a Bifunctional Catalyst at a Water–Oil Interface: Synthesis of Benzyl Thiols

The enantioselective conjugated addition of tritylthiol to in situ generated ortho‐quinone methides (o‐QMs) is catalyzed by an acid–base bifunctional squaramide organocatalyst. The transformation proceeds with high yield (up to 99 %) and stereoselectivity (up to 97:3 e.r.) using water as solvent under mild conditions. The catalyst system provides a new strategy for the synthesis of optically active benzyl mercaptans. Control experiments suggested that o‐QMs are generated by the tertiary amine moiety of the squaramide organocatalyst and that the water–oil biphase is crucial for achieving high reactivity and stereoselectivity.     

On the Importance of Anion–π Interactions in the Mechanism of Sulfide:Quinone Oxidoreductase

Sulfide:quinone oxidoreductase (SQR) is a flavin‐dependent enzyme that plays a physiological role in two important processes. First, it is responsible for sulfide detoxification by oxidizing sulfide ions (S^2? and HS^?) to elementary sulfur and the electrons are first transferred to flavin adenine dinucleotide (FAD), which in turn passes them to the quinone pool in the membrane. Second, in sulfidotrophic bacteria, SQRs play a key role in the sulfide‐dependent respiration and anaerobic photosynthesis, deriving energy for their growth from reduced sulfur. Two mechanisms of action for SQR have been proposed: first, nucleophilic attack of a Cys residue on the C4 of FAD, and second, an alternate anionic radical mechanism by direct electron transfer from Cys to the isoalloxazine ring of FAD. Both mechanisms involve a common anionic intermediate that it is stabilized by a relevant anion–π interaction and its previous formation (from HS^? and Cys‐S‐S‐Cys) is also facilitated by reducing the transition‐state barrier, owing to an interaction that involves the π system of FAD. By analyzing the X‐ray structures of SQRs available in the Protein Data Bank (PDB) and using DFT calculations, we demonstrate the relevance of the anion–π interaction in the enzymatic mechanism.     

PI by NMR: Probing CH–π Interactions in Protein–Ligand Complexes by NMR Spectroscopy

While CH–π interactions with target proteins are crucial determinants for the affinity of arguably every drug molecule, no method exists to directly measure the strength of individual CH–π interactions in drug–protein complexes. Herein, we present a fast and reliable methodology called PI (π interactions) by NMR, which can differentiate the strength of protein–ligand CH–π interactions in solution. By combining selective amino‐acid side‐chain labeling with ¹H‐¹³C NMR, we are able to identify specific protein protons of side‐chains engaged in CH–π interactions with aromatic ring systems of a ligand, based solely on ¹H chemical‐shift values of the interacting protein aromatic ring protons. The information encoded in the chemical shifts induced by such interactions serves as a proxy for the strength of each individual CH–π interaction. PI by NMR changes the paradigm by which chemists can optimize the potency of drug candidates: direct determination of individual π interactions rather than averaged measures of all interactions.     

CH–π and CF–π Interactions Lead to Structural Changes of N‐Heterocyclic Carbene Palladium Complexes

The role of CH–π and CF–π interactions in determining the structure of N‐heterocyclic carbene (NHC) palladium complexes were studied using ¹H NMR spectroscopy, X‐ray crystallography, and DFT calculations. The CH–π interactions led to the formation of the cis‐anti isomers in 1‐aryl‐3‐isopropylimidazol‐2‐ylidene‐based [(NHC)₂PdX₂] complexes, while CF–π interactions led to the exclusive formation of the cis‐syn isomer of diiodobis(3‐isopropyl‐1‐pentafluorophenylimidazol‐2‐ylidene) palladium(II).     

Carbene‐Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones

A direct decarboxylative strategy for the generation of aza‐o‐quinone methides (aza‐o‐QMs) by N‐heterocyclic carbene (NHC) catalysis has been discovered and explored. This process requires no stoichiometric additives in contrast with current approaches. Aza‐o‐QMs react with trifluoromethyl ketones through a formal [4+2] manifold to access highly enantioenriched dihydrobenzoxazin‐4‐one products, which can be converted to dihydroquinolones through an interesting stereoretentive aza‐Petasis–Ferrier rearrangement sequence. Complementary dispersion‐corrected density functional theory (DFT) studies provided an accurate prediction of the reaction enantioselectivity and lend further insight to the origins of stereocontrol. Additionally, a computed potential energy surface around the major transition structure suggests a concerted asynchronous mechanism for the formal annulation.     

Ortho‐Quinone Methides as Reactive Intermediates in Asymmetric Brønsted Acid Catalyzed Cycloadditions with Unactivated Alkenes by Exclusive Activation of the Electrophile

An efficient method for the highly enantioselective synthesis of chiral chromanes bearing multiple stereogenic centers was developed. A chiral BINOL‐based N‐triflylphosphoramide proved to be an effective catalyst for the in situ generation of ortho‐quinone methides (o‐QMs) and their subsequent cycloaddition reaction with unactivated alkenes provided chromanes with excellent diastereo‐ and enantioselectivity.     

Enantioselective Reactions of 2‐Sulfonylalkyl Phenols with Allenic Esters: Dynamic Kinetic Resolution and [4+2] Cycloaddition Involving ortho‐Quinone Methide Intermediates

We report herein a dynamic kinetic resolution (DKR) involving ortho ‐quinone methide (o ‐QM) intermediates. In the presence of Et₃N and the cinchonine‐derived nucleophilic catalyst D , the DKR of 2‐sulfonylalkyl phenols with allenic esters afforded chiral benzylic sulfones in 57–79 % yield with good to excellent enantioselectivity (85–95 % ee ). Furthermore, with 2‐(tosylmethyl)sesamols or 2‐(tosylmethyl)naphthols, from which stable o ‐QM substrates can be generated, a formal [4+2] cycloaddition delivered 4‐aryl‐ or alkyl‐substituted chromans with excellent enantioselectivity (88–97 % ee ).     

Asymmetric Synthesis of Enantioenriched 2‐Aryl‐2,3‐Dihydrobenzofurans by a Lewis Acid Catalyzed Cyclopropanation/Intramolecular Rearrangement Sequence

A cyclopropanation/intramolecular rearrangement initiated by the Michael addition of in situ generated ortho‐quinone methides (o‐QMs) has been developed for the enantioselective synthesis of 2‐aryl‐2,3‐dihydrobenzofurans containing two consecutive stereogenic centers, including a quaternary carbon atom. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction proceeded in excellent yields (up to 95 %) with excellent stereoselectivity (up to >99 ee, up to >20:1 d.r.).     

11‐Hydro­xy‐3,3‐di­methyl‐7,12‐dioxo‐3,4,6,6a,7,12,12a,12b‐octa­hydro­benz­[a]­anthracen‐1‐yl acetate

The Diels–Alder reaction between 5‐hydroxy‐1,4‐naphtho­quinone and 5,5‐di­methyl‐3‐vinyl‐1,2‐cyclo­hexa­dienyl acetate by endo addition gives the title compound, C₂₂H₂₂O₅, in 68% yield. This racemic diastereoisomer has the opposite regiochemistry to ochromycinone analogues produced previously and may allow access to a new type of anticancer‐active saqua­yamycin analogue.     

Oxidation‐Responsive Aliphatic Polycarbonates from N‐Substituted Eight‐Membered Cyclic Carbonate: Synthesis and Degradation Study

Oxidation‐responsive aliphatic polycarbonates represent a promising branch of functional biodegradable polymers. This paper reports the synthesis and ring‐opening polymerization (ROP) of an eight‐membered cyclic carbonate possessing phenylboronic pinacol ester ( C3 ) and the H₂O₂‐triggered degradation of its polymer ( PC3 ). C3 is prepared from the inexpensive and readily available diethanolamine with a moderate yield and undergoes the well‐controlled anionic ROP with a living character under catalysis of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene. It can also be copolymerized with l ‐lactide, trimethylene carbonate, and 5‐ter‐butyloxycarbonylamino trimethylene carbonate, affording the copolymers with a varied distribution of the repeating units. To clearly demonstrate the oxidative degradation mechanism of PC3 , this paper first investigates the H₂O₂‐induced decomposition of small‐molecule model compounds by proton nuclear magnetic resonance (¹H NMR). It is found that the adduct products formed by the in‐situ‐generated secondary amines and p‐quinone methide (QM) are thermodynamically unstable and can decompose slowly back to QM and the amines. On this basis, this paper further studies the H₂O₂‐accelerated degradation of PC3 nanoparticles that are prepared by the o/w emulsion method. A sequential process of oxidation of the phenylboronic ester, 1,6‐elimination of the in‐situ‐generated phenol, releasing CO₂ and intramolecular cyclization or isomerization is proposed as the degradation mechanism of PC3 .     

Catalytic Oxo/Imido Heterometathesis by a Well‐Defined Silica‐Supported Titanium Imido Complex

Grafting Ti(=NtBu)(Me₂Pyr)₂(py)₂ (Me₂Pyr= 2,5‐dimethylpyrrolyl, py=pyridine) onto the surface of silica partially dehydroxylated at 700 °C gives the well‐defined silica‐supported Ti imido complex (≡SiO)Ti(=NtBu)(Me₂Pyr)(py)₂, which is fully characterized by IR and solid‐state NMR spectroscopy as well as elemental and mass balance analyses. While stoichiometric imido‐transfer reactivity is typical for Ti imides, the obtained surface complex is unique in that it enables catalytic transformations involving Ti imido and oxo intermediates. In particular, it efficiently catalyzes imidation of carbonyl compounds with N‐sulfinylamines by oxo/imido heterometathesis.