TSRI Press. 1999. - 486 p.
The notes have been used as the introductory section of a course on Mode Organic Synthesis that composes 6 weeks or a little more than one-half of a quarter course at The Scripps Research Institute, Department of Chemistry. Consequently, an exhaustive treatment of the individual topics is beyond the scope of this portion of the course. The remaining 4 weeks of the quarter delve into more detail on various topics and introduce concepts in multistep organic synthesis (E. Sorensen). For our students, this is accompanied by a full quarter course in physical organic chemistry and is followed by a full quarter course on state of the art natural products total synthesis (K. C. Nicolaou, E. Sorensen) and a quarter elective course on transition metal chemistry. Complementary to these synthetic and mechanistic courses, two quarter courses on bioorganic chemsitry and an elective course on the principles of molecular biology and immunology are available to our students. Efforts have been made to not duplicate the content of these courses. For those who might examine or use the notes. The original notes were not assembled with special attention to this detail, but rather for the basic content and the ‘nuts and bolts’ laboratory elements of organic synthesis.
Table of Contents
I. Conformational Analysis
A. Acyclic sp–sp Systems
B. Cyclohexane and Substituted Cyclohexanes, A Values (?G°)
C. Cyclohexene
D. Decalins
E. Acyclic sp3–sp3 Systems
F. Anomeric Effect
G. Strain
H. pKa of Common Organic Acids
II. Kinetics and Thermodynamics of Organic Reactions
A. Free Energy Relationships
B. Transition State Theory
C. Intramolecular Versus Intermolecular Reactions
D. Kinetic and Thermodynamic Control
E. Hammond Postulate
F. Principle of Microscopic Reversibility
III. Reaction Mechanisms and Conformational Effects on Reactivity
A. Ester Hydrolysis
B. Alcohol Oxidations
C. SN Reactions
D. Elimination Reactions
E. Epoxidation by Intramolecular Closure of Halohydrins
F. Epoxide Openings (SN)
G. Electrophilic Additions to Olefins
H. Rearrangement Reactions
I. Pericyclic Reactions
J. Subtle Conformational and Stereoelectronic Effects on Reactivity
K. Methods for the Synthesis of Optically Active Materials
IV. Oxidation Reactions
A. Epoxidation Reactions
B. Additional Methods for Epoxidation of Olefins
C. Catalytic Asymmetric Epoxidation
D. Stoichiometric Asymmetric Epoxidation
E. Baeyer–Villiger and Related Reactions
F. Beckmann Rearrangement and Related Reactions
G. Olefin Dihydroxylation
H. Catalytic and Stoichiometric Asymmetric Dihydroxylation
I. Catalytic Asymmetric Aminohydroxylation
J. Ozonolysis
V. Oxidation of Alcohols
A. Chromium-based Oxidation Reagents
B. Manganese-based Oxidation Reagents
C. Other Oxidation Reagents
D. Swe Oxidation and Related Oxidation Reactions
VI. Reductions Reactions
A. Conformational Effects on Carbonyl Reactivity
B. Reactions of Carbonyl Groups
C. Reversible Reduction Reactions: Stereochemistry
D. Irreversible Reduction Reactions: Stereochemistry of Hydride Reduction Reactions and Other Nucleophilic Additions to Carbonyl Compounds
E. Aluminum Hydride Reducing Agents
F. Borohydride Reducing Agents
G. Hydride Reductions of Functional Groups
H. Characteristics of Hydride Reducing Agents
I. Asymmetric Carbonyl Reductions
J. Catalytic Hydrogenation
K. Dissolving Metal Reductions
L. Amalgam-derived Reducing Agents
M. Other Reduction Methods
VII. Hydroboration–Oxidation
A. Mechanism
B. Regioselectivity
C. Diastereoselectivity
D. Metal-catalyzed Hydroboration
E. Directed Hydroboration
F. Asymmetric Hydroboration
VIII. Enolate Chemistry
A. Acidic Methylene Compounds
B. Enolate Structure
C. Enolate Alkylations
D. Enolate Generation
E. Alkylation Reactions: Stereochemistry
F. Asymmetric Alkylations
G. Aldol Addition (Condensation)
H. Aldol Equivalents
I. Enolate-imine Addition Reactions
J. Claisen Condensation
K. Dieckmann Condensation
L. Enolate Dianions
M. Metalloimines, Enamines and Related Enolate Equivalents
N. Alkylation of Extended Enolates
IX. Metalation Reactions
A. Directed Metalation
B. Organolithium Compounds by Metal–Halogen Exchnage
C. Organolithium Compounds by Metal–Metal Exchange (Transmetalation)
D. Organolithium Compounds from the Shapiro Reaction
E. Key Organometallic Reactions Enlisting Metalation or Transmetalation Reactions
X. Key Ring Forming Reactions
A. Diels–Alder Reaction
B. Robinson Annulation
C. Birch Reduction
D. Dieckmann Condensation
E. Intramolecular Nucleophilic Alkylation
F. Intramolecular Aldol Condensation
G. Intramolecular Michael Reaction
H. Cation–Olefin Cyclizations
I. Free Radical Cyclizations
J. Anionic Cyclizations
K. 1,3-Dipolar Cycloadditions
L. [1,3]-Sigmatropic Rearrangements
M. Electrocyclic Reactions
N. Nazarov Cyclization
O. Divinylcyclopropane Rearrangement
P. Carbene Cycloaddition to Alkenes
Q. [2 + 3] Cycloadditions for -Membered Ring Formation
R. Cyclopropenone Ketal Cycloaddition Reactions
S. [2 + 2] Cycloadditions
T. Arene–Olefin Photoadditions
U. Intramolecular Ene Reaction
V. Oxy–Ene Reaction: Conia Reaction
W. Cyclopentenone Annulation Methodology
X. Pauson–Khand Reaction
Y. Carbonylation Cyclizations
Z. Olefin Ring Closing Metathesis
XI. Olefin Synthesis
A. Wittig Reaction
B. Wadsworth–Hoer–Emmons Reaction
C. Peterson Olefination
D. Tebbe Reaction and Related Titanium-stabilized Methylenations
E. Other Methods for Terminal Methylene Formation
F. Olefin Inversion Reactions
G. [3,3]-Sigmatropic Rearrangements: Claisen and Cope Rearrangements
H. [2,3]-Sigmatropic Rearrangements
I. Olefin Synthesis Illustrated with Juvenile Hormone
XII. Conjugate Additions: Organocuprate ,-Additions
XIII. Synthetic Analysis and Design
A. Classifications
B. Retrosynthetic Analysis
C. Strategic Bond Analysis
D. Total Synthesis Exemplified with Longifolene
XIV. Combinatorial Chemistry
The notes have been used as the introductory section of a course on Mode Organic Synthesis that composes 6 weeks or a little more than one-half of a quarter course at The Scripps Research Institute, Department of Chemistry. Consequently, an exhaustive treatment of the individual topics is beyond the scope of this portion of the course. The remaining 4 weeks of the quarter delve into more detail on various topics and introduce concepts in multistep organic synthesis (E. Sorensen). For our students, this is accompanied by a full quarter course in physical organic chemistry and is followed by a full quarter course on state of the art natural products total synthesis (K. C. Nicolaou, E. Sorensen) and a quarter elective course on transition metal chemistry. Complementary to these synthetic and mechanistic courses, two quarter courses on bioorganic chemsitry and an elective course on the principles of molecular biology and immunology are available to our students. Efforts have been made to not duplicate the content of these courses. For those who might examine or use the notes. The original notes were not assembled with special attention to this detail, but rather for the basic content and the ‘nuts and bolts’ laboratory elements of organic synthesis.
Table of Contents
I. Conformational Analysis
A. Acyclic sp–sp Systems
B. Cyclohexane and Substituted Cyclohexanes, A Values (?G°)
C. Cyclohexene
D. Decalins
E. Acyclic sp3–sp3 Systems
F. Anomeric Effect
G. Strain
H. pKa of Common Organic Acids
II. Kinetics and Thermodynamics of Organic Reactions
A. Free Energy Relationships
B. Transition State Theory
C. Intramolecular Versus Intermolecular Reactions
D. Kinetic and Thermodynamic Control
E. Hammond Postulate
F. Principle of Microscopic Reversibility
III. Reaction Mechanisms and Conformational Effects on Reactivity
A. Ester Hydrolysis
B. Alcohol Oxidations
C. SN Reactions
D. Elimination Reactions
E. Epoxidation by Intramolecular Closure of Halohydrins
F. Epoxide Openings (SN)
G. Electrophilic Additions to Olefins
H. Rearrangement Reactions
I. Pericyclic Reactions
J. Subtle Conformational and Stereoelectronic Effects on Reactivity
K. Methods for the Synthesis of Optically Active Materials
IV. Oxidation Reactions
A. Epoxidation Reactions
B. Additional Methods for Epoxidation of Olefins
C. Catalytic Asymmetric Epoxidation
D. Stoichiometric Asymmetric Epoxidation
E. Baeyer–Villiger and Related Reactions
F. Beckmann Rearrangement and Related Reactions
G. Olefin Dihydroxylation
H. Catalytic and Stoichiometric Asymmetric Dihydroxylation
I. Catalytic Asymmetric Aminohydroxylation
J. Ozonolysis
V. Oxidation of Alcohols
A. Chromium-based Oxidation Reagents
B. Manganese-based Oxidation Reagents
C. Other Oxidation Reagents
D. Swe Oxidation and Related Oxidation Reactions
VI. Reductions Reactions
A. Conformational Effects on Carbonyl Reactivity
B. Reactions of Carbonyl Groups
C. Reversible Reduction Reactions: Stereochemistry
D. Irreversible Reduction Reactions: Stereochemistry of Hydride Reduction Reactions and Other Nucleophilic Additions to Carbonyl Compounds
E. Aluminum Hydride Reducing Agents
F. Borohydride Reducing Agents
G. Hydride Reductions of Functional Groups
H. Characteristics of Hydride Reducing Agents
I. Asymmetric Carbonyl Reductions
J. Catalytic Hydrogenation
K. Dissolving Metal Reductions
L. Amalgam-derived Reducing Agents
M. Other Reduction Methods
VII. Hydroboration–Oxidation
A. Mechanism
B. Regioselectivity
C. Diastereoselectivity
D. Metal-catalyzed Hydroboration
E. Directed Hydroboration
F. Asymmetric Hydroboration
VIII. Enolate Chemistry
A. Acidic Methylene Compounds
B. Enolate Structure
C. Enolate Alkylations
D. Enolate Generation
E. Alkylation Reactions: Stereochemistry
F. Asymmetric Alkylations
G. Aldol Addition (Condensation)
H. Aldol Equivalents
I. Enolate-imine Addition Reactions
J. Claisen Condensation
K. Dieckmann Condensation
L. Enolate Dianions
M. Metalloimines, Enamines and Related Enolate Equivalents
N. Alkylation of Extended Enolates
IX. Metalation Reactions
A. Directed Metalation
B. Organolithium Compounds by Metal–Halogen Exchnage
C. Organolithium Compounds by Metal–Metal Exchange (Transmetalation)
D. Organolithium Compounds from the Shapiro Reaction
E. Key Organometallic Reactions Enlisting Metalation or Transmetalation Reactions
X. Key Ring Forming Reactions
A. Diels–Alder Reaction
B. Robinson Annulation
C. Birch Reduction
D. Dieckmann Condensation
E. Intramolecular Nucleophilic Alkylation
F. Intramolecular Aldol Condensation
G. Intramolecular Michael Reaction
H. Cation–Olefin Cyclizations
I. Free Radical Cyclizations
J. Anionic Cyclizations
K. 1,3-Dipolar Cycloadditions
L. [1,3]-Sigmatropic Rearrangements
M. Electrocyclic Reactions
N. Nazarov Cyclization
O. Divinylcyclopropane Rearrangement
P. Carbene Cycloaddition to Alkenes
Q. [2 + 3] Cycloadditions for -Membered Ring Formation
R. Cyclopropenone Ketal Cycloaddition Reactions
S. [2 + 2] Cycloadditions
T. Arene–Olefin Photoadditions
U. Intramolecular Ene Reaction
V. Oxy–Ene Reaction: Conia Reaction
W. Cyclopentenone Annulation Methodology
X. Pauson–Khand Reaction
Y. Carbonylation Cyclizations
Z. Olefin Ring Closing Metathesis
XI. Olefin Synthesis
A. Wittig Reaction
B. Wadsworth–Hoer–Emmons Reaction
C. Peterson Olefination
D. Tebbe Reaction and Related Titanium-stabilized Methylenations
E. Other Methods for Terminal Methylene Formation
F. Olefin Inversion Reactions
G. [3,3]-Sigmatropic Rearrangements: Claisen and Cope Rearrangements
H. [2,3]-Sigmatropic Rearrangements
I. Olefin Synthesis Illustrated with Juvenile Hormone
XII. Conjugate Additions: Organocuprate ,-Additions
XIII. Synthetic Analysis and Design
A. Classifications
B. Retrosynthetic Analysis
C. Strategic Bond Analysis
D. Total Synthesis Exemplified with Longifolene
XIV. Combinatorial Chemistry