chem3115 synthetic medicinal chemistry - university of...

CHEM3115

Synthetic Medicinal

Chemistry

Lecture 1

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

Selectivity

•Enantioselectivity

•Diastereoselecivity

•Chemoselectivity

•Regioselectivity

When building molecules there are selectivity issues that we need to be aware of .

Selectivity

Recall that enantiomers are non-superimposable

mirror images •Enantioselectivity

Nobel prize 2001

e.g. Sharpless Asymmetric Epoxidation

(SAE)

K. Barry Sharpless


•Diastereoselectivity

Selectivity

Diastereomers: stereoisomers that are NOT enantiomers

e.g. Mukaiyama aldol reaction



•Chemoselectivity

Selectivity

One functional group reacts preferentially

“Chemoselectivity: the mother of invention in total synthesis”

–Phil S. Baran, 2009.



•Chemoselectivity

•Regioselectivity

Selectivity

One functional group can react in different ways,

but reacts one way preferentially.



•Chemoselectivity

•Regioselectivity

Selectivity vs Specificity

These involve a preference for one outcome over a another outcome,

i.e. the other products can be generated.

Contrast the above examples with an SN2

substitution reaction

This reaction is stereospecific; nucleophile must

attack from back side. Therefore it is the

stereochemistry of the starting material that dictates the

stereochemistry of the product.

Why is Selectivity important?

C129H223N3O54

Mol. Wt. = 2680

LD50 = 25 10-9 g/Kg

64 stereogenic centres (R or S)

7 geometric isomers (E or Z)

Therefore: 271 possible

stereoisomers (2.36 1021).

You would need to make 10.5 g to ensure

that 2 molecules are the same.

Yoshito Kishi

Palytoxin

Why is Selectivity important?

Yoshito Kishi

Marketed by Eisai Co. as „Halaven‟.

Anti-cancer drug of last resort

For metastatic breast cancer that has resisted

other treatments.

Therefore: 219 possible stereoisomers

(i.e. 524,288 isomers).

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

Hydride reducing agents

Lithium aluminium

hydride

LiAlH4

Lithium

borohydride

LiBH4

Sodium

borohydride

NaBH4

Diisobutyl aluminium

hydride

DiBAl-H ®

DiBAl

A hydride source;

H-

Lewis acid:

Electron pair

acceptor

Remember that curly arrows show electron movement.

You already know that nucleophile will attack

the carbon atom of the carbonyl.

So the reactivity of reducing

agents is governed by the

stability (nucleophilicity) of

hydride reagent and the

electrophilicity of carbonyl

group.

Hydride reducing agents: chemoselectivity

Hydride reducing agents: chemoselectivity

Aldehyde reacts fast whereas ester reacts very slowly chemoselective reduction.

Hydride reducing agents:

mechanistic considerations

Aldehyde Primary alcohol

Primary alcohol

Ester C=O bond strength

720 kJ mol-1

C-O bond strength

350 kJ mol-1



Amide

Primary amine

Has to be a powerful

reducing agent i.e. LiAlH4

Primary alcohol

Acid

Has to be a powerful

reducing agent i.e. LiAlH4

Hydride reducing agents: diastereoselectivity

•Nucleophiles attack the carbon atom of the carbonyl group at an angle of 107o which

maximises bonding interactions whilst minimising anti-bonding and undesirable electrostatic

interactions.

•This is called the Burgi-Dunitz trajectory.

Diastereoselective reductions of some cyclic compounds:

For 6 membered rings: small nucleophiles approach from axial position

(large nucleophiles approach from equatorial position).

H – is the smallest nucleophile there is.

Cyclohexanone has

two conformations


•Nucleophiles attack the carbon atom of the carbonyl group at an angle of 107o which

maximises bonding interactions whilst minimising anti-bonding and undesirable electrostatic

interactions.

•This is called the Burgi-Dunitz trajectory.

Diastereoselective reductions of some cyclic compounds:

For 6 membered rings: small nucleophiles approach from axial position (large

nucleophiles approach from equatorial position).

H – is the smallest nucleophile there is.


A 5-membered ring has an „envelope‟ conformation.

The ring is rapidly ring flipping. Substituents can be in pseudoaxial or pseudoequatorial positions or on

the point position.

The result is a very flexible system that gives moderately stereoselective reactions.

The Me-susbstituent prefers a pseudoequatorial position and the two faces of the ketone are very

similar. The small reducing reagent prefers pseudoaxial attack.

(Large nucleophiles will approach from the least hindered face and give the expected cis-alcohol

product.)


Diastereoselective reductions of bridged cyclic compounds:


Diastereoselective reductions of bridged cyclic compounds:

For bridged compounds, nucleophiles

approach from the least hindered face.

Diastereoselectivity

It is easy to control the level of diastereoselectivity of reactions that occur on

cyclic substrates.

If you want good stereocontrol during a total synthesis…..try to make a ring.

R. B. Woodward

Nobel prize 1965


Diastereoselective reductions of acyclic compounds:

N.B. this ketone has an α-stereogenic centre.

Although the starting ketone has an infinite number of accessible conformations at the reaction temperature,

one leads to a lower energy transition state.

A guiding principle is that features which stabilise the starting material may stabilise the transition state as

well (recall the Hammond postulate).

What is most stable ground state conformation?

Felkin-Anh model

Least steric interaction, hence

proceeds through the lowest

energy transition state.

This is the favoured

conformation.

Nucleophile has to approach over

the top of the methyl group,

therefore large steric interaction.

Unfavoured



Felkin Anh Model.

If there is a stereogenic centre a to the carbonyl then:

•Draw the Newman projection with the stereogenic centre at the rear of the diagram;

•Rotate the group at the rear so that the large group is perpendicular to the carbonyl group

(there will be two possible conformations);

•The nucleophile will approach at the Burgi-Dunitz trajectory (107o) over the small group

(i.e. one conformation will react preferentially);

•Draw the product Newman projection;

•Draw the product in the standard fashion along the longest carbon chain.

Steric clash; unfavoured Steric clash; unfavoured


Predict the stereochemical outcome of the following reduction:


N.B. This is the kind of answer that will be

expected on an exam paper.

Next time

•Other nucleophiles

•Regioselectivity


•Caveat to Felkin-Anh model

chem3115 synthetic medicinal chemistry - university of...

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