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Overview of the Topics to Be Covered in CHEM Overview of the Topics to be Covered in CHEM 330 Table of Contents A. Introduction 2 B. General Principles for the Construction of 1,3- Dioxygenated Assemblies 6 C. Construction of 1,3-Dicarbonyl Systems 12 D. Preparation and Alkylation of Carbonyl Enolates 29 E. Conjugate Addition Chemistry 64 F. Construction of β-Hydroxycarbonyl Assemblies 82 G. Construction of 1,3-Diol Systems 114 H. Pericyclic Reactions: Diels-Alder Chemistry 116 CHEM 330 p.2 A. INTRODUCTION Course objective: to learn modern technology for the stereocontrolled assembly of molecules of current biomedical relevance Importance of complex molecules in the biopharmaceutical industry of the 21st century Evolution of the complexity of pharmaceutical molecules during the past century: The first 100 years HO H H OAc S N O COOH COO NH2 Aspirin - Bayer, ca. 1880 Thienamycin - Merck, ca. 1980 N OH H OH N N N COOH O Indinavir - Merck, ca. 1995 The future OH OH O O OH O O NH2 OH Discodermolide - Novartis, 2004 CHEM 330 p.3 H H H H O O OH OH H O O H O O O O O O H H H H H H OH H O H O O O O H Halichondrine H O H H Me OH O H H H N O O 3 O O H H H H MsO O O H O O H Eribulin mesylate O (Eisai, 2010) Ubiquitous presence of the 1,3-dioxygenated functionality in molecules of biomedical interest Three types of such 1,3-dioxygenated functionality: 1,3-dicarbonyl, 1,3-hydroxycarbonyl, 1,3-dihydroxy: O O OH O OH OH R1 R3 R1 R3 R1 R3 R2 R2 R2 1,3-dicarbonyl 1,3-hydoxycarbonyl 1,3-dihydroxy (= β-dicarbonyl) (= β-hydroxycarbonyl) "type A" "type B" "type C" The 1,3-dioxygenated functionality as a logical starting point for the exploration of modern synthetic methodology. Principle: only a particular configuration of the various stereocenters endows a molecule with the desired bioactivity. Consequently, technology for the assembly of 1,3- dioxygenated functionalities must be: – diastereocontrolled (it must produce largely / only a given diastereomer of the requisite subunit), and – enantiocontrolled (it must produce largely / only a given enantiomer of the above diastereomer) CHEM 330 p.4 Stereochemical aspects of 1,3-dioxygenated structures: "Type A" structures possess a single stereogenic carbon; therefore, they may exist as a pair of stereoisomers that are enantiomers: O O O O O O or R1 R3 may mean: R1 R3 R1 R3 R2 R2 R2 enantiomers Chemical properties of 1,3-dicarbonyl structures: Low pKa (10-14, average ≈ 12) of 1,3-dicarbonyl functionalities Facile interconversion of the enantiomers of a 1,3-dicarbonyl structure through: (i) reversible deprotonation: enolate protonation from above: formation of enantiomeric structure B H O O easy, O O O R1 1 3 O R R 1 3 B H 2 H fast R R R R3 R2 R2 geometric plane B : symmetrical, planar structure enolate protonation from below: return to original structure (ii) keto-enol tautomerism: enol protonation from above: formation of enantiomeric structure O O easy, O OH 1 O R OH 1 3 H 2 R R fast R1 R3 R R3 H 2 geometric R R2 plane symmetrical, planar structure enol protonation from below: return to original structure Racemization: the interconversion of two enantiomers leading to a statistical, 50:50 mixture of the two. The configuration of a 1,3-dicarbonyl structure is not controllable. The preparation of 1,3-dicarbonyl structures presents no stereochemical issues, due to facile racemization. CHEM 330 p.5 "Type B" structures incorporate a pair of stereogenic carbons; therefore, they may exist as a four possible stereoisomers: O OH O OH O OH or or R1 R3 may mean: R1 R3 R1 R3 R2 R2 1 R2 2 Note: structures 1 and 3 and O OH O OH structures 2 and 4 are enantiomers; or structures 1 and 2, 1 and 4, 2 and 3, R1 R3 R1 R3 and 3 and 4 are diastereomers. R2 R2 3 4 the creation of 1,3-hydroxycarbonyl units presents significant stereochemical issues. "Type C" structures incorporate three stereogenic carbons; therefore, they may exist as a eight possible stereoisomers (pairs of which may be enantiomers or diastereomers): • a molecule containing n stereogenic centers can exist OH OH in 2n stereoisomeric forms * * R1 * R3 • a 1,3-dihydroxy unit contains three stereogenic centers 2 (starred C atoms) R 3 • 2 = 8 stereoisomers are possible the preparation of 1,3-dihydroxy structures also comports major stereochemical issues. Because the creation of 1,3-dicarbonyl compounds poses fewer / no stereochemical problems relative to the preparation of 1,3-hydroxycarbonyl or 1,3-dihydroxy structures, it is an ideal starting point to study the synthesis of 1,3-dioxygenated functionalities. CHEM 330 p.6 B. General Principles for the Construction of 1,3-Dioxygenated Assemblies Principle: bonds between atoms, in particular carbon atoms, are created by causing atoms of opposite polarity (+ / -) to interact. Synthons: hypothetical, often electrically charged fragments needed in bond-forming operations "Real" molecules that behave as carriers of individual synthons: reagents Example of a reagent that carries a C atom possessing (+) character: CH3–I Example of a reagent that carries a C atom possessing (–) character: CH3–Li. Principle: the polarity of an atom is determined by the substituent(s) attached to it Importance of the analysis of atomic polarity in charting a synthesis (selection of + and – synthons) A substituent induces alternating polarity along a carbon chain, e.g.: O (+) (+) (+) (-) (-) (-) Principle: the precise oxidation state of a carbon atom bearing a heteroratomic substituent has no influence on polarization: what counts is the nature of the heteroatom. Consequently, systems 1 and 2 below are equivalent in terms of polarity: O OH (+) (+) (+) (+) (+) (+) (-) (-) (-) (-) 1 2 Principle: in carbon chains incorporating multiple heteroatomic substituents, each substituent polarizes individual carbon atoms independently of other substituents. The two O functionalities of a 1,3-dioxygenated system induce matching atomic polarity in the C atoms: O O (+) (-) (+) (+) (-)(+) Mismatched atomic polarity in, e.g., a 1,4 dioxygenated system: CHEM 330 p.7 O (-) (+) (-) (+) (+) (-)(+) (-) O Principle: the construction of a polarity-matched system is easier than the assembly of a polarity-mismatched structure. Principle: in order to build a polarity-mismatched system, one must reverse the natural polarity of an atom. Reversal of polarity or Umpolung Synthons required for the construction of a 1,3-dicarbonyl system: O O O O 1 3 R R R1 R3 2 R 2 R O Derivatives of carboxylic acids (acid chlorides, esters, etc.) as carriers of 1 R O Carbonyl enolates as carriers of R3 R2 Possible construction of a 1,3-hydroxycarbonyl system ("type B" structure): OH O OH O 1 3 R R R1 R3 2 R 2 R OH Aldehydes as carriers of Construction of a 1,3-diol system ("type C" structure): a special case of 1,3- hydroxycarbonyl construction, because a C=O group may be reduced to an OH with appropriate reagents: OH OH OH O R1 R3 R1 R3 R2 R2 Importance of carbonyl-based transformations in organic synthesis CHEM 330 p.8 C. Construction of 1,3-Dicarbonyl Systems Carbonyl-based reactions as ideal starting points to explore modern synthetic methodology Acid chlorides and anhydrides as generally unsuitable reagents (with a few exceptions and for reasons to be addressed later) for the synthesis of 1,3-dicarbonyl systems Formation of 1,3-dicarbonyl (=β-dicarbonyl) structures by reaction of carbonyl enolates with esters: the Claisen condensation O O O O O O R1 OEt R3 R1 R3 R1 R3 R2 EtO R2 R2 Claisen condensation of ethyl acetate: 2 CH -COOEt —[base]à CH -CO-CH -COOEt + EtOH 3 3 2 ethyl acetate ethyl acetoacetate Approximate pKa's of representative organic molecules: H–CH2-COOEt H–CH2-CO-CH3 EtO–H pKa ≈ 25 pKa ≈ 20 pKa ≈ 17 Detailed step-by-step mechanism of the Claisen condensation of EtOAc promoted by EtONa Use of pKa differences to estimate the position of the equilibrium in a proton transfer reaction Example: the deprotonation of CH3-COOEt with EtONa: Na Na EtO H–CH2-COOEt EtO–H + CH2-COOEt pKa ≈ 25 pKa ≈ 17 –8 pkeq ≈ 25 – 17 = 8 Keq ≈ 10 Principle: equilibrium constants / pKa differences provide an approximate measure of the extent of deprotonation. CHEM 330 p.9 —8 Example: for the above reaction, Keq ≈ 10 . Suppose also that the initial concentrations of EtOAc and base are identical and equal to 1 M. The extent of deprotonation of EtOAc under these conditions is roughly equal to the square root of Keq, i.e.: –8 –4 [ CH2-COOEt ] ≈ Keq = 10 = 10 meaning that approximately 1 part in 10,000 of the quantity of EtOAc will be present as the enolate under these conditions (consult the handouts on pKa's posted on the course website for details of the calculation). Principle: generally, acceptable reaction rates require an instant concentration of reactive intermediates (enolates, etc.) greater than about 10–5-10–6 M. Relationship between equilibrium constants and ΔG: the Gibbs equation: ΔG = –n RT ln K eq where n = number of moles, R = gas constant (=1.98•10–3 kcal/°K mol) Principle: because changes in pKa are associated with ΔG's, one may use ΔpKa's to estimate whether a reaction step involving basic agents will be thermodynamically favorable or unfavorable: Reminder: A step that produces a weaker base at the expenses of a stronger base is thermodynamically favorable (because ΔG < 0) A step that produces a stronger base at the expenses of a weaker base is thermodynamically unfavorable (because ΔG > 0) Thermodynamically unfavorable deprotonation of ethyl acetate with NaOEt and consequent reversibility of the process The condensation of two molecules of ethyl acetate to form ethyl acetoacetate as a themodynamically unfavorable process 2 CH3-COOEt à CH3-CO-CH2-COOEt + EtOH ΔG > 0 Principle: mixing one equivalent of pure ethyl acetoacetate with one equivalent of pure ethanol in the presence of a catalytic amount of EtONa would induce a reverse Claisen condensation that will convert the starting components into two molecules of ethyl acetate (the thermodynamically more favorable state of the system): – CH3-CO-CH2-COOEt + EtOH —[ cat.
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