Quinone methide-conjugated

SCHEME 9.21 Sequence directed alkylation by a quinone methide conjugate. 

SCHEME 9.22 Intramolecular trapping produces a self-adduct of the quinone methide conjugate. 

SCHEME 9.23 An oligodeoxynucleotide-bis(quinone methide) conjugate was designed for cross-linking duplex DNA by initial triplex formation but resulted at best in only monoalkylation of its target. 

SCHEME 9.24 A quinone methide conjugate for cross-linking DNA through recognition of the minor groove primarily formed self-adducts irreversibly. 

Quinone Methides. The reaction between aldehydes and alkylphenols can also be base-cataly2ed. Under mild conditions, 2,6-DTBP reacts with formaldehyde in the presence of a base to produce the methylol derivative (22) which reacts further with base to eliminate a molecule of water and form a reactive intermediate, the quinone methide (23). Quinone methides undergo a broad array of transformations by way of addition reactions. These molecules ate conjugated homologues of vinyl ketones, but are more reactive because of the driving force associated with rearomatization after addition. An example of this type of addition is between the quinone methide and methanol to produce the substituted ben2yl methyl ether (24). 

Awad, H. M. Boersma, M. G. Boeren, S. van Bladeren, P. J. Vervoort, J. Rietjens, I. M. C. M. Quenching of quercetin quinone/quinone methides by different thiolate scavengers stability and reversibility of conjugate formation. Chem. Res. Toxicol. 2003,16, 822-831. 

SCHEME 2.7 Generation of conjugated /j-quinone methide structures by 5,6-dihydroxyin-dole oxidation. 

Selected Substituent-Stabilized Tocopherols and Conjugatively Stabilized Ortho-Quinone Methides... 

FIGURE 6.46 Oxidation chemistry of 5-(4-methylphenyl)- y-tocopherol (76), establishing a reaction system phenylogous to a-tocopherol (1), with quinone methide 77 and benzyl bromide 78 being the conjugatively stabilized, phenylogous counterparts of o-QM 3 and 5a-bromo-a-tocopherol (46), respectively. 

SCHEME 9.17 DNA cross-linking by a quinone methide-acridine conjugate. 

Kumar, D. Veldhuyzen, W. F. Zhou, Q. Rokita, S. E. Conjugation of a hairpin pyrrole-imidazole polyamide to a quinone methide for control of DNA cross-linking. Bioconjug. Chem. 2004, 15, 915-922. 

Bolton, J. L. Comeau, E. Vukomanovic, V. The influence of 4-alkyl substituents on the formation and reactivity of 2-methoxy-quinone methides evidence that extended ji-conjugation dramatically stabilizes the quinone methide formed from eugenol. Chem.-Biol. Interact. 1995, 95, 279-290. 

Boersma, M.G. et al., Regioselectivity and reversibility of the glutathione conjugation of quercetin quinone methide, Chem. Res. Toxicol., 13, 185, 2000. 

The neutral 1,4- and 1,2-quinone methides react as Michael acceptors. However, the reactivity of these quinone methides is substantially different from that of simple Michael acceptors. The 1,6-addition of protonated nucleophiles NuH to simple Michael acceptors results in a small decrease in the stabilization of product by the two conjugated 7T-orbitals, compared to the more extended three conjugated 7T-orbitals of reactant. However, the favorable ketonization of the initial enol product (Scheme 1) confers a substantial thermodynamic driving force to nucleophile addition. By comparison, the 1,6-addition of NuH to a 1,4-quinone methide results in a large increase in the -stabilization energy due to the formation of a fully aromatic ring (Scheme 2A). This aromatic stabilization is present to a smaller extent at the reactant quinone methide, where it is represented as the contributing zwitterionic valence bond structure for the 4-0 -substituted benzyl carbocation (Scheme 1). The ketonization of the product phenol (Scheme 2B) is unfavorable by ca. 19 kcal/mol.1,2... 

One interesting property of quinone methide 63 is that the terminal carbon of the extended conjugated system lies in both an extended quinone methide (carbons marked by +) and an extended enol (carbons marked by ). This carbon reacts as both a base in undergoing protonation to form a quinone (upper pathway, Scheme 30A) and a Lewis acid in undergoing addition of nucleophilic... 

Given the role of the ferrocene moiety as an intramolecular hole-reservoir, the conjugated 7i-system and the basic action of pyridine, the mechanism given in Scheme 2 for the generation of quinone methide species was proposed. The ferrocene moiety is oxidised, and the electron may be to a small extent delocalized... 

The quinone methides can also react by elimination of formaldehyde or hydrogen ion at the /3-carbon atom, especially when the formation of conjugated diaryl structures is possible. Examples of this type of reactions are the formation of stilbenes from phenyl coumarans or 1,2-diarylpropane struc-... 

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