QUINONE METHIDES -- CONTENTS -- Preface to Series -- Introduction -- Contributors -- 1 Photochemical Generation and Characterization of Quinone Methides -- 1.1 Introduction -- 1.2 Quinone Methides from Benzylic Photoelimination -- 1.2.1 Photoelimination of Fluoride -- 1.2.2 Photodehydration -- 1.2.3 Photoelimination of Quaternary Ammonium Salts -- 1.2.4 Photoelimination of Alcohols and Esters -- 1.3 Quinone Methides from ESIPT to Unsaturated Systems -- 1.3.1 Quinone Methides from ESIPT to Carbonyls -- 1.3.2 Quinone Methides from ESIPT to Alkenes and Alkynes -- 1.3.3 Quinone Methides from ESIPT to Aromatic Carbon -- 1.4 Other Photochemical Routes to Quinone Methides -- 1.5 Conclusions and Outlook -- References -- 2 Modeling Properties and Reactivity of Quinone Methides by DFT Calculations -- 2.1 Introduction -- 2.2 QM Reactivity as Alkylating Agents -- 2.2.1 Computational Models -- 2.2.1.1 Basis Set Choice -- 2.2.1.2 Energetics of the Benzylation by o-QM in the Gas Phase and in Aqueous Solution -- 2.2.2 H-Bonding and Solvent Effects in the Benzylation of Purine and Pyrimidine Bases -- 2.2.2.1 Cytosine Benzylation under Kinetic Control -- 2.2.2.2 Stability/Reactivity of the QM-Cytosine Conjugates -- 2.2.2.3 Purine Bases Benzylation: Kinetic and Thermodynamic Aspects -- 2.3 Reactivity as Heterodiene -- 2.4 Tautomerizations Involving Quinones and Quinone Methides -- 2.4.1 QM Versus Quinone Stability: Substituent Effects -- 2.5 o-Quinone Methide Metal Complexes -- 2.5.1 Geometries and Reactivity as Function of the Metal and the Structural Features -- 2.6 Generation of o-QM -- 2.6.1 Generation of o-QM Tethered to Naphthalene Diimides by Mild Activation -- 2.6.2 Thermal Generation of o-QM in Oxidative Processes in the Gas Phase -- 2.7 Thermal Decomposition of o-QM in the Gas Phase -- 2.8 QM Generation in Lignin Formation.

2.9 Conclusion and Perspective -- References -- 3 Quinone Methide Stabilization by Metal Complexation -- 3.1 Introduction -- 3.2 QM-Based Pincer Complexes -- 3.2.1 Formation -- 3.2.2 Reactivity and Modifications -- 3.2.3 Os-Based, p-QM Complexes -- 3.3 One-Site Coordinated QM Complexes -- 3.3.1 η(2)-ortho-QM Complexes -- 3.3.1.1 Formation -- 3.3.1.2 Release and Reactivity of η(2)-o-QMs -- 3.3.2 η(2)-p-QM Complexes -- 3.3.2.1 Formation -- 3.3.2.2 Controlled Release and Modification of η(2)-p-QMs -- 3.4 η(4)-Coordinated QM Complexes -- 3.4.1 Formation of η(4)-Coordinated QM Complexes -- 3.4.2 Reactivity of η(4)-Coordinated QM Complexes -- 3.4.3 η(4)-Coordinated QM Complexes of Mn -- 3.5 Characterization of QM Complexes -- 3.5.1 IR -- 3.5.2 (1)H and (13)C {(1)H} NMR -- 3.5.3 X-Ray -- 3.6 Conclusion and Future Applications -- Acknowledgments -- References -- 4 Intermolecular Applications of o-Quinone Methides (o-QMs) Anionically Generated at Low Temperatures: Kinetic Conditions -- 4.1 Introduction to o-QMs -- 4.2 Thermal Generation Conditions -- 4.3 Low-Temperature Kinetic Generation of o-QMs -- 4.3.1 Formation of the o-QMs Triggered by Fluoride Ion -- 4.3.2 Stepwise Formation of o-QMs -- 4.3.3 Kinetically Controlled Cycloadditions -- 4.4 Mechanistic Investigations -- 4.5 Long-Term Prospects -- References -- 5 Self-Immolative Dendrimers Based on Quinone Methides -- 5.1 Introduction -- 5.2 Substituent-Dependent Disassembly of Dendrimers -- 5.3 Elimination-Based AB(3) Self-Immolative Dendritic Amplifier -- 5.4 Controlled Self-Assembly of Peptide Nanotubes -- 5.5 AB(6) Self-Immolative Dendritic Amplifier -- 5.6 Enzymatic Activation of Second-Generation Self-Immolative Dendrimers -- 5.7 Dual Output Molecular Probe for Enzymatic Activity -- 5.8 Cleavage Signal Conduction in Self-Immolative Dendrimers -- 5.9 Future Prospects -- References.

6 Ortho-Quinone Methides in Tocopherol Chemistry -- 6.1 Introduction -- 6.2 α-Tocopherol and Its Derived o-QM: General Aspects -- 6.3 Chemo- and Regioselectivity in the o-QM Formation from Tocopherol -- 6.3.1 o-QM Versus "5a-Chromanolmethyl" Radicals -- 6.3.2 Regioselectivity in the Oxidation of α-Tocopherol: Up-o-QMs Versus Down-o-QMs -- 6.3.3 Detailed Formation Pathway and Stabilization of the Tocopherol-Derived o-QM 3 and Other o-QMs -- 6.4 Reactions of the "Common" Tocopherol-Derived Ortho-Quinone Methide 3 -- 6.4.1 Self-Reaction of the o-QM: Spiro Dimers and Spiro Trimers -- 6.4.2 Spiro Oligomerization/Spiro Polymerization of Tocopherol Derivatives -- 6.4.3 Bromination of α-Tocopherol and Further Reactions of 5a-Bromo-α-Tocopherol and Other 5a-Substituted Tocopherols -- 6.4.4 Cyclization of para-Tocopherylquinone 7 into o-QM 3 -- 6.4.5 Synthesis via o-QM 3 and Reaction Behavior of 3-(5-Tocopheryl)propionic Acid -- 6.5 Formation of Tocopherol-Derived o-QMs Involving Other Positions Than C-5A -- 6.5.1 5-(γ-Tocopheryl)acetic Acid -- 6.5.2 4-Oxo-α-Tocopherol -- 6.5.3 3-Oxa-Chromanols -- 6.5.4 Selected Substituent-Stabilized Tocopherols and Conjugatively Stabilized Ortho-Quinone Methides -- 6.6 Future Prospects -- Acknowledgments -- References -- 7 Characterizing Quinone Methides by Spectral Global Fitting and (13)C Labeling -- 7.1 Introduction -- 7.2 Studying the Transient Quinone Methide Intermediate -- 7.2.1 Using Spectral Global Fitting to Study Transient Quinone Methides -- 7.2.2 Enriched (13)C NMR Spectroscopy -- 7.3 New Insights into Methide Chemistry -- 7.3.1 Novel Methide Polymerization Reactions -- 7.3.2 Products of Dithionite Reductive Activation -- 7.3.3 Probing DNA Adduct Structures with (13)C-Labeled Methides -- 7.3.4 Design of a "Cyclopropyl Quinone Methide" -- 7.3.5 Kinetic Studies of the Mitosene Quinone Methide.

7.3.6 Cyclopent[b]indole-Based Quinone Methides -- 7.3.7 Prekinamycin-Based Quinone Methides -- 7.4 Conclusions and Future Prospects -- 7.4.1 Quinone Methide O-Protonation -- 7.4.2 Antitumor Agent Design -- 7.4.3 Enriched (13)C NMR Monitoring of Methide Reactions -- 7.4.4 Future Prospects -- References -- 8 Natural Diterpene and Triterpene Quinone Methides: Structures, Synthesis, and Biological Potentials -- 8.1 Introduction -- 8.2 Natural Diterpene QMs -- 8.2.1 Chemical Structures and Biological Activity of Natural Diterpene QMs -- 8.2.2 Dimers of Natural Diterpene QMs -- 8.3 Total Synthesis of Diterpene QMs -- 8.3.1 Stepwise Synthesis of Diterpene QMs -- 8.3.2 Diel-Alder Approach in the Diterpene QM Synthesis -- 8.3.3 Polyene Cyclization as a Mimic of Biosynthesis in Plants -- 8.4 Natural Triterpene QMs -- 8.4.1 Cytotoxicity of Natural Triterpene QMs Against Cancer Cell Lines -- 8.4.2 Anti-Inflammatory Effects of Natural Triterpene QMs -- 8.4.3 Other Biological Activities of Natural Triterpene QMs -- 8.4.4 Biosynthesis of Natural Triterpene QMs -- 8.5 Terpene QMs and Reactive Oxygen Species -- 8.6 Conclusion and Future Prospects -- References -- 9 Reversible Alkylation of DNA by Quinone Methides -- 9.1 Introduction -- 9.1.1 Reversible Alkylation of DNA -- 9.1.2 Initial Reports of Reversible Alkylation by Quinone Methides -- 9.2 Reversible Alkylation of Deoxynucleosides by a Simple Quinone Methide -- 9.2.1 Quinone Methide Regeneration is Required for Isomerization between Its N1 and 6-Amino Adducts of dA -- 9.2.2 Kinetic and Thermodynamic Adducts Formed by Quinone Methides -- 9.2.3 The Structure of Quinone Methides and Their Precursors Modulate the Reversibility of Reaction -- 9.3 Reversible Alkylation of DNA by Quinone Methide Bioconjugates -- 9.3.1 The Reversibility of Quinone Methide Reaction Does Not Preclude Its Use in Forming DNA Cross-Links.

9.3.2 Repetitive Capture and Release of a Quinone Methide Extends Its Effective Lifetime -- 9.3.3 Intramolecular Capture and Release of a Quinone Methide Provides a Method for Directing Alkylation to a Chosen Sequence of DNA -- 9.4. Conclusions and Future Prospects -- Acknowledgments -- References -- 10 Formation and Reactions of Xenobiotic Quinone Methides in Biology -- 10.1 Introduction -- 10.2 Formation of QMs -- 10.3 Alkylphenols -- 10.3.1 BHT and Related Alkylphenols: Historical Overview -- 10.3.2 Relationships of QM Structure to Reactivity and Toxicity -- 10.3.2.1 Effects of Alkyl Substitution -- 10.3.2.2 Hepatotoxicity -- 10.3.2.3 Lung Damage -- 10.3.3 Mechanisms of BHT Toxicity: Identification of Intracellular Targets -- 10.3.3.1 Gene Induction -- 10.3.3.2 Reactivities of QMs with Cellular Nucleophiles -- 10.3.3.3 Detection of QM-Protein Adducts Formed In Vitro -- 10.3.3.4 Glutathione S-Transferase P1 (GSTP1) Adduct -- 10.3.3.5 Protein Adducts Formed In Vivo -- 10.3.3.6 ortho-Alkylphenols -- 10.4 Methoxyphenols and Catechols -- 10.4.1 Methoxyphenols -- 10.4.2 Catechols -- 10.5 Quinone Methides from SERMs -- 10.6 Quinone Methides from Estrogens -- 10.7 Nonclassical Quinone Methides -- 10.8 Conclusions and Future Prospects -- Acknowledgments -- References -- 11 Quinone Methides and Aza-Quinone Methides as Latent Alkylating Species in the Design of Mechanism-Based Inhibitors of Serine Proteases and β-Lactamases -- 11.1 Introduction -- 11.1.1 Mechanism-Based Inhibitors/Suicide Substrates -- 11.1.2 Reactivity of Quinone Methides -- 11.2 Serine Proteases: Minimal Schemes -- Catalytic Mechanisms -- Suicide Inhibition -- 11.2.1 Linear Versus Cyclized Suicide Substrates -- 11.3 Inhibitor Synthesis -- 11.4 Proteases: Neutral Dihydrocoumarins -- 11.4.1 Proteases: Coumarincarboxylates -- 11.5 Aza-Quinone Methides/Quinonimine Methides.

11.5.1 α-Chymotrypsin: Inactivity of Five- and Six-Membered Lactams.