2012 chem3115lecture3.pdf

CHEM3115

Synthetic Medicinal

Chemistry

Lecture 3

Dr Chris McErlean

Rm 518a

[email protected]

Lecture 19 Carbonyl Chemistry. Reducing reagents: Chemo and diatseteroselectivity;

Introduction to Felkin-Anh model.

Lecture 20 Carbonyl Chemistry. Organometallics: formation and reactivity; 1,2 vs 1,4

addition; Felkin-Anh vs Chelation control

Lecture 21 Carbonyl Chemistry. Enolates: formation, regioselectivity; silylenol ethers:

thermodynamic vs kinetic control; enolate geometry with LDA

Lecture 22 Carbonyl Chemistry. Enolates: Aldol reactions; diastereoselectivity via

Zimmerman Traxler transition states. Auxillary approach to enantioselectivity.

Lecture 23 Chemistry of other sp2 centres. Alkenes: synthesis via Wittig, Julia and

Metathesis (RCM and cross metathesis).

Lecture 24 Chemistry of other sp2 centres. Palladium in Contemporary Synthesis:

general mechanism, Suzuki, Stille, Negeshi, Sonogashira and Heck reactions.

Lecture 25 Workshop problems; Recap and review.

Lecture outline

Enolates: introduction

We have seen examples of hydride and organometallic reagents as nucleophiles.

Another set of nucleophiles are enolates.

Reminder:

Hydrogen atoms a to a carbonyl are acidic.

pKa ~ 20 pKa ~ 25 pKa ~ 32

Enolates: regioselectivity

Enolates can react at carbon or oxygen, i.e. they are ambident nucleophiles

So can we predict which site they will react at, i.e. regioselectivity ?

Enolates: regioselectivity

Almost all electrophiles react at carbon atom Silyl reagents are hard electrophiles.

Hard nucleophiles react fastest with hard electrophiles.

Silyl reagents react at oxygen atom.

Enolates: reactions

Enolates react with a large range of electrophiles, e.g.:

alkylations

acylation

Claisen ester

condensation

Aldol reaction

Enolates: reactions

Remember, silyl reagents are

hard reagents; they react at

oxygen.

Note: this is not an SN2 reaction.

Enolates: formation

The three commonly used ways to form enolates are:

•Deprotonation.

•Metallation of silyl enol ethers.

•Addition to a,b-unsaturated carbonyls

Deprotonation:

As we have already seen, hydrogen atoms a to a carbonyl are

acidic and can be removed with a base.

Enolates: formation

Deprotonation of cyclohexanones:

Axial protons are more acidic and therefore

are deprotonated first.

During deprotonation, the developing p

orbital is parallel with the C=O bond and

can therefore form the enolate

It is the conjugation of the p orbital

with the pi bond of the carbonyl that

provides the resonance stabilisation

of the enolate

Enolates: formation

Thermodynamic vs kinetic enolate formation.

Thermodynamic product Kinetic product

tetra-substituted alkene;

thermodynamically more

stable product

No methyl group; less crowded

therefore less steric hinderance;

likely to be deprotonated first.

Enolates: formation

If reaction is reversible, then difference in energy of the products determines product ratio.

If reaction is irreversible, then difference in activation energies determines product ratio.

Thermodynamic reactions

Reactions are reversible and reach an equilibrium state

Difference in free energy between the products dictates selectivity

ΔG = -RT lnK (K is the equilibrium constant, or ratio of two products)

Note activation energy does not control the position of the equilibrium, but does control the rate

at which equilibrium is reached

lowest energy (most stable) product is the major product

Enolates: formation

Kinetic reactions

are irreversible (reverse reaction is very slow)

major product is not necessarily the most stable (although it can be)

activation energy of competing reactions is the controlling factor

lowest energy pathway leads to major product

- ratio of products = k major/k minor = eΔEact/RT

Enolates: formation


To generate this enolate, we need thermodynamic control.

Reversible reaction, i.e. set up an equilibrium.

Use an alkoxide base, e.g. KOt-Bu or NaOt-Bu.


To generate this enolate, we need kinetic control.

Irreversible reaction

Use a strong, irreversible base, e.g. n-BuLi, LDA, NaH

Enolates: formation

An even better way to ensure that this enolate

is formed is to make the silyl enol ether and

then perform a silicon metal exchange.

TMSCl acts as a Lewis acid and

activates the ketone.

This allows for a very bulky

base to be used which

enhances kinetic control.

Enolates: formation

How could we make this enolate?

Direct deprotonation will lead to a mixture as there is little difference between the enolate

But which organometallic reagent

adds to the alkene of an enone?

Enolates: formation

organocuprates

Enolates: diastereoselectivity

Alkylations of enolates, enamines and silyl enol ethers of cyclohexanone prefer axial attack.

Attack from the apparently more hindered bottom face makes the trigonal carbon atom turn

tetrahedral by forming a vertical bond to the electrophile downwards. The ring goes directly to a

chair conformation with the electrophile in the axial position. This is the least energy pathway

(kinetic control).

The transition state leading to the higher energy twist boat conformation is of higher

energy than the transition state leading to the chair conformation.

Cyclohexanones

Axial attack also dominates in conjugate addition to 6-membered rings.


Norzoanthamine

(anti-osteoporotic)

Masaaki Miyahita (2004 and 2009)


Diastereoselectivity on smaller ring systems.

Essentially one diastereoisomer is formed. The alkylation is irreversible and as such is under ‘kinetic

control’.

Note we are not concerned with enantiomers here. The i-Pr group is the only group out of the plane of

the 4-membred ring enolate. We have arbitrarily drawn it ‘down’ in the diagram to show the

electrophile approaches from the opposite side to this sterically bulky group.

The product is racemic, but essentially one diastereoisomer.


When there are 2 or 3 trigonal carbons in the ring, the ring is flatter and diastereoselective reactions on

the whole obey simple steric control.

Eg. Conjugate addition.

The newly formed stereocentre can dictate the reaction of electrophiles with the

enolate intermediate….


Enolates: formation acyclic systems

The discussion to this point has dealt with cyclic systems….what about acyclic systems?

The outcome of enolate forming reactions on acyclic substrates can be predicted with good

accuracy if the reaction proceeds via a cyclic transition state.

NB cis or trans in this

case refers to the O-metal

group e.g.

LDA deprotonation of acyclic substrates can proceed via a cyclic transition state


normally this severe 1,3-diaxial

interaction between one of the iso-propyl

ligands on N and R dictates the formation

of a trans enolate

If X is very large this 1,2

interaction dominates the

reactive conformation and

gives the cis enolate


Large steric clash

between

t-butyl group and

ethyl group

Lesser steric clash

between

isopropyl group on LDA

and ethyl group

Favoured

Summary

Enolates:

•Mostly react at carbon atom (except for silicon reagents)

•Can be formed by deprotonation, silicon-metal exchange, 1,4-addition to enones

•On six membered rings:

•Electrophiles approach from the axial direction

•(conjugate addition also takes place from the axial direction)

•On smaller rings

•Electrophiles approach from the least hindered face

•(conjugate addition also takes place from the least hindered face).

•For acyclic systems, enolate geometry can be predicted if a cyclic transition state is involved

e.g. LDA deprotonations

•Discussed the differences between thermodynamic and kinetic control

Next time

Aldol reactions

2012 chem3115lecture3.pdf

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