T. V. RajanBabu
Chemistry, 730 Autumn 1998
Overview of topics to be covered
Introduction
Expectations for the course
Challenges in organic chemistry
Efficiency and selectivity (chemo-, regio-, and stereo-) in organic synthesis
Stereochemical Principles
Constitution, configuration and conformation
Specifying stereochemistry - CIP notation, Fischer convention
Chirality as a property of matter
Enantiomeric relationships Enantiomeric excess (ee), optical activity - how to determine it
Origin of chirality - asymmetric carbon atom, asymmetric heteroatom with lone-pairs,
chiral molecules without asymmetric centers - how to specify configuration in axially chiral
molecules
Diastereomeric relationships- definitions, specifying diastereomers
Threo and erythro vs syn and anti (threo/erythro R. I. P.)
Consequences of diastereomerism- resolution of enantiomers and limitations- ananlytical methods based
on diastereomerism for the determination of ee’s: GC, HPLC, X-ray, NMR
Diastereoselective synthesis: e. g., Evan’s oxazolidinones for alkylation (more later)
Kinetic resolution - principles, stoichiometric, catalytic - organometallic and enzymatic, with examples
Asymmetric catalysis - diastereomerism in transient intermediates - principles, examples - hydrogenation
Stereochemistry of dynamic processes
Stereoselective and stereospecific reactions (definitions, examples, common mistakes)
Racemization process
Prochiral relationships (Prochiral groups - pro-R, pro-S groups and how to identify them)
Prochiral faces (re and si, how to identify them)
Enantioselective enzymatic processes, how to use them in synthesis,
Asymmetric synthesis: Stoichiometric and catalytic use of reagents
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Examples of the latter: Sharpless epoxidation, Rh-catalyzed hydrogenation, ketone reductions;
Itsuno-Corey reductions, Ru-catalyzed hydrogenations ( for illustration only, details to be
covered
in next course)
Diastereotopic relationships - pro-R, pro-S
Enantiotopic vs diastereotopic groups - how to distinguish between them - in naming, by NMR
Diastereotopic faces - consequences for stereoselective synthesis - Cram’s rule ( no details yet!)
Conformational, Steric and Stereoelectronic Effects
Conformation of ethane, Pitzer strain
Conformation of butane and van der Waals and gauche interactions
Conformations of CH3XHn, ethers, amines, alcohols
Conformations of terminal alkenes, carbonyl compounds (aldehydes and ketones)
Conformations of dienes, enals and enones
Conformations of esters
Conformations of amides - Relationship between K and free energy difference between Z and E amides
- How to calculate K from Go ( also see later under A values)
Conformational analysis of cyclic compounds - cyclohexanes, chair, boat, twist conformations - proof
Substituted cyclohexanes - ‘A’ values of various groups - how to determine ‘A’ values
Conformational effects on reactivity - oxidation of axial vs equatorial alcohols, hydrolysis of axial vs
equatorial esters
haloketone conformations
allylic strain, cyclohexenes
six-membered heterocycles
4, 5, 7, 8 -membered cycloalkanes
Curtin-Hammett principle: mathematical derivation and examples (conformational or diastereomeric
equilibria); examples of Rh-catalyzed hydrogenation of acetamidocinnamates
amine-oxide pyrolysis
Conformation of decalins and perhydrophenanthrenes
Strain in rings - 3-11 membered rings, propallanes, Bredt’s rule, effect on reactivity
Tetrahedrane, [1.1.1]-propallane, Cubane,dodecahedrane and C60
synthesis and reactivity of Bredt olefins
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Anomeric effect in sugars and in other compounds, difference between- and - glycosides- oxidation,
reaction with ozone, radical generation
Other stereoelectronic effects: SN2 reaction, E2-elimination, Fürst-Plattner rule with examples from
steroids
Reactions of isomeric 1,2-bromohydrins from cyclohexenes (elimination vs ring contraction etc.)
SN2’ reactions
Ring expansions, fragmentation reaction of 1,2-hydroxytosylates
Ring contractions, Fragmentation reactions - stereochemistry, reaction conditions
Solvolytic fragmentation reactions
Reductive cyclopropane opening - applications
Tortional starin and stereoelectronic effects -Reduction of cyclic ketones, solvolysis of cyclic tosylates,
Axial vs equatorial approach to cyclic carbonyl compounds by nucleophiles
Klein / Cieplak models
Tortional interactions in bicyclic systems
Ring closure and ring size (Baldwin’s rules) - enthalpy and entropy of activation
Bürgi-Dunitz angle, Radical cyclization reactions under kinetic vs thermodynamic conditions as an
illustration of limits of Baldwin’s rules, also symmetry controlled reactions
Kinetic vs thermodynamic control, Hammond postulate, use of energy level diagrams - examples
Nucleophilic addition to carbonyl compounds
Cram’s rule and variations - Original Cram’s rule, the chelate model, Cornforth modification and the
Felkin-Anh model - Where these are applicable, where not - examples.
Carbon acids, enolates and enamines: alkylation
Acidity and basicity of organic compounds
Kinetic and thermodynamic acidities
Generation and use of alkyl lithiums, lithium amides
Structures of alkyl lithiums, amides
Carbanions stabilized by other functional groups
Malontes, acetoacetates, nitrocompounds etc.
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Enolates - kinetic vs thermodynamic - regiochemistry in unsymmetrical ketone enolates - how to prepare
regiochemically pure enolates
Other carbanions in synthesis - dithianes and corresponding sulfoxides, nitrocompound, cyanoalkanes
Acidites of phosphonium and sulfonium compounds and ylides (for chemistry see later)
Enols, enamines and metalloenamines in synthesis
Mechanism of acid and base catalyzed enolization, kinetic vs thermodynamic control
Detailed mechanism of -substitution of a carbonyl compound (e. g., bromination)
Carbanions as nucleophiles
Enolate structure - X-ray structures of enolates, effect of aggregation, how to control reactivity
C vs O-alkylation: Solvent effects, HMPA, counter ion effects, effect of alkylating agents
Hard and soft acid-base principle
Generation and regioselective alkylation of enolates: silyl enol ethers, enolacetates, Li /amine reductions,
cuprate additions, -in bicyclic systems- stereochemistry
Alkylation of malonates : synthesizing substituted acetic caids
Alkylation of acetoacetates: synthesizing acetone derivatives
Alkylation of aldehydes, esters, amides and nitriles
Generation and reactions of dianions: How to substitute at the more basic -position
Generation and alkylation of chiral enolates - making optically active -substituted acid and alcohol
derivatives (Evans’ auxiliaries)
Lewis-acid mediated alkylation of silyl enol ethers (Mukaiyama reaction) - especially for SN1 -active
substrates
Nitrogen analogs of enols and enolates - enamines and metallaenamines
Synthesis of enamines
Reactivity, alkylation, alkylating -position of aldehydes
Making optically pure -alkylated ketones (Meyers’ auxiliary)
Alkylation of hydrazone anions (A1,3- strain, models), Enders’ N-amino-2-methoxymethylpyrrolidine
Hydrazone cuprates - acetaldehyde anion equivalent
Application of enamines - acylation: synthesis of 1,5-dicarbonyl compounds, stereoelectronic effects
Michael reaction - stabilized enolates- malonates, acetoacetates, nitronates
Michael reaction of kinetic enolates -special acceptors
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Use of ketene silyl acetals as surrogates of enolates
Ketene silyl acetals in Lewis acid, fluoride, thermal additions to enones
Michael reactions with enamines
Robinson annulation
Umpolung - dithianes and analogs, cyanohydrin anions - (Acyl anion synthons)
Metallated enol ethers including cuprates
Nagata cyanation
Reactions of carbon nucleophiles with carbonyl compounds
Aldol condensation - acid/base catalyzed, mechanism, differences
Directed aldol - how?
Enolate regiochemistry, stereochemistry
Examples of directed aldols (Scheme 2.3) - Li, Si, B, Zn
Mukaiyama conditions
Definitions of syn/anti, lk, ul
Zimmerman-Traxler transition states- dependence of size of substituents
Enolate generation (Z and E): Ireland model
Examples of substituent, solvent, counter ion, base effects on enolate stereochemistry
Boron enolates, including limitations
Break down of Z-T transition states: two cases (explain with the aid of models):
Aldol reactions of silyl enol ethers with Lewis acids
Use of TAS+ Me3SiF2– in aldol reactions, counter ion effects
Generation and use of other metal enolates: Zr, Si, Ti, Mg (-> E), Ti (–> E), Ti (–>Z), Sn (–>Z)
Enantiomerically pure aldols
Masamune, Evans auxiliaries and models
Chelated and unchelated transition state models to make all four aldol stereoisomers using diffrent
metals
Asymmetric catalysis in aldol synthesis : Mukaiyama, Carreira, Evans and others
Ito’s gold-catalyzed aldol reactions (a Knoevenagel-type reaction, see later) of -isocyanoacetates
Aldol reactions of ester enolates (how to make E- enolates better)
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Carbanions from esters, acids, amides and nitriles (CS B, Scheme 2.4)
Intramolecular aldols including Robinson annulation (see earlier)
The Hojos and Parrish reaction
Mannich reaction
Knoevenagel condensation
Acylation of nucleophilic carbon by esters (Claisen condensation: inter- and intra- molecular)
Reactive acylating agents: Anhydrides, acid chlorides, ethoxymagnesium malonates, N-acylimidazoles,
methoxymagnesium carbonate, ethyl cyanoformate
Acylation of enamines, equivalent for enolate acylation
Acylation of -ketosulfoxides
Wittig and Related reactions
Stabilized vs unstabilized- mechanism and stereochemistry: making Z and E- olefins
Salt- free Wittig reagents, Schlosser modification
Synthetic applications (scheme CS B 2.12, 2.13)
Stabilized ylides
Wardsworth-Emmons modification and alternatives
Limitations
Horner-Wittig reaction
Silicon equivalent of Wittig reaction, Peterson olefination; How to make Z and E olefins
Sulfonium and sulfoxonium ylides (differences, applications)
Tebbe and related reactions; carbene complexes of transition metals
Functional group interconversions
Alcohols to alkylating agents
Mitsunobu reaction
Mechanistic considerations of SN2 reactions
Useful SN2 reactions for C-heteroatom bond formation
Phase transfer catalysis
Alkylation of amines and amides
Oxygen nucleophiles, protection/deprotection of alcohols
Making esters, epoxides
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S, Se, N, P nucleophiles
Activation of carboxylic acids, macrolactonization
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