chem3115 synthetic medicinal chemistrysydney.edu.au/science/chemistry/~mcerlean/lecture...

CHEM3115

Synthetic Medicinal

Chemistry

Lecture 2

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

Reminder

In lecture 1 we discussed selectivity.

•Chemoselectivity in the hydride reduction of carbonyls;

•Different hydride sources have different levels of reactivity

Lithium aluminium

hydride

LiAlH4

Lithium

borohydride

LiBH4

Sodium

borohydride

NaBH4

Diisobutyl aluminium

hydride

DiBAl-H ®

DiBAl

Reminder

In lecture 1 we discussed selectivity.

•Chemoselectivity in the hydride reduction of carbonyls;

•Different hydride sources have different levels of reactivity

•Diastereoselectivity in hydride reduction of carbonyls;

•Nucleophiles approach at 107o (Burgi-Dunitz angle);

•Small nucleophiles approach 5 and 6 membered rings from the axial direction,

(large nucleophiles approach from the equatorial direction);

•Nucleophiles approach bridged bicyclic compounds from the least hindered face;

•Diastereomeric outcome of nucleophilic attack on acyclic carbonyls bearing an a stereogenic centre

can be predicted using the Felkin-Anh model.

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.

Reminder

Organometallics: introduction

Other nucleophiles are capable of reacting with carbonyl groups, i.e. organometallic species.

RMgX R2CuLi RLi

Organomagnesium

„Grignard‟ reagents

Reactivity is determined by nature of organometallic species;

Both carbanion and metal parts contribute to reactivity.

Organocuprate

„Gilman‟ reagents

Organolithium

reagents

Organometallics: carbanion part

For organometallics with the same metal component, reactivity increases with decreasing “s” character.

If the orbital containing the lone pair (negative charge) has a lot of “s” character, then the

negative charge is held closer to the positively charged nucleus and is thus stabilised.

Alkyne: sp hybridized

50% “s” character

pKa ~ 26 pKa ~ 50

Alkane: sp3 hybridized

25% “s” character


Reactivity can mean:

Acting as a nucleophile

Or act as a base

Because alkyl groups are slightly electron donating (hyperconjugation)

they destabilise the carbanion; therefore they increase reactivity.

N.B. this is why tert-butyllithium is a stronger base than n-butyllithium


Electron withdrawing groups help to stabilise the negative charge therefore decrease reactivity.


Organometallics: metal part

Reactivity is determined by

nature of organometallic

species;

Both carbanion and metal parts

contribute to reactivity.

The larger the difference in

electronegativity between

the metal and the organic

parts, then the less

covalent (more ionic) is the

bond and the greater the

reactivity.

Order these organometallic species from most reactive to least reactive.

Order these organometallic species from most reactive to least reactive.

Organometallics: metal part

Organometallics: Formation

There are four main ways to make organometallics:

•Reductive replacement – e.g. Grignard synthesis

(Oxidative addition of the metal)

There are four main ways to make

organometallics:

•Reductive replacement – e.g. Grignard

synthesis


•Metal – hydrogen exchange (deprotonation;

because lots of organometallics are

commercially available)


Chelating/ directing group

ortho lithiation


organometallics:


synthesis





•Metal – halogen exchange



organometallics:


synthesis





•Metal – halogen exchange

•Metal – metal exchange


Organometallics: Regioselectivity

Organometallics: Regioselectivity

Resiniferatoxin

(Potent analgesic)

Paul Wender

Stanford University

Organometallics: Diastereoselectivity

Diastereoselective nucleophilic additions to some cyclic compounds:

Most organometallics can be

regarded as large

nucleophiles, therefore they

approach carbonyl on six

membered rings from the

equatorial direction

Large nucleophiles approach

carbonyl on five membered

rings from the pseudo-

equatorial direction, but

selectivity is bad to due

flexibility of ring.

Due to steric clash,

nucleophiles must approach

bridged bicyclic compounds

from the least hindered face.

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.


The effect of electronegative atoms.

The electronegative NBn2 group appears to be acting as the L substituent


There is more than sterics operative here (notice the dr is very high).

Conformations of a-chiral carbonyl compounds that place an electronegative atom perpendicular to

the C=O bond will be more reactive.

This is an electronic effect


•Acyclic carbonyl with an a-stereogenic centre:

Felkin Anh

•Atom at the a position is an electronegative element:

It must be considered as the large group.


Chelation can reverse selectivity

In this example the selectivity

follows normal Felkin-Anh control (justify

it to yourself)

If the counter ion is changed to one that can

interact with sulfur we get the alternative

daistereoisomer.

Two things are needed for chelation to occur.

- A heteroatom with lone pairs available for coordination to a metal

- A metal atom that prefers to coordinate to more than one heteroatom at once.

These are mainly more highly charged ions.

- Usually only 5- or 6-membered chelates are formed.


Other pertinent examples

Note a higher diastereoselectivity with chelation control versus Felkin Anh control.

Chelation controlled diastereoselectivity is higher due to a cyclic transition state.

As the size of R increases, chelation is more difficult. Thus diastereoselectivity is affected and the rate of

the addition reaction becomes slower. Chelation increases the rate of reaction at the carbonyl group.


Explain why two different reducing agents give diastereomeric products.



Al3+ can chelate;

6-membered ring.

Explain why two different reducing agents give diastereomeric products.

Under Felkin-Anh control

Under chelation control


Summary

Organometallics:

•Relative reactivities as a consequence of carbanion and metal fragment.

•Carbanion : sp3 > sp2 > sp

•sp3 carbanions : more electron donating groups increase reactivity, more electron

withdrawing groups decrease reactivity.

•Metal : reactivity Li > Mg > Cu due to electronegativity differences.

•Regioselectivity as a consequence of nature of the carbon-metal bond.

•organocuprates react in a 1,4-manner.

•Organomagnesium and organolithitiums react in a 1,2- manner.

•Diastereoselectivity on cyclic and acyclic systems:

•Equatorial attack of nucleophile on 5 and 6 membered rings.

•Attack form least hindered face on bridged bicyclic compounds.

•Felkin-Anh control on acyclic systems.

•Felkin-Anh model expanded to cover electronegative elements at the a-position and

chelation control

Next time

The exciting world of enolate chemistry

chem3115 synthetic medicinal chemistrysydney.edu.au/science/chemistry/~mcerlean/lecture...

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