chem3115 synthetic medicinal chemistry - …sydney.edu.au/science/chemistry/~mcerlean/lecture...

CHEM3115

Synthetic Medicinal

Chemistry

Lecture 6

Dr Chris McErlean

Rm 518a

Ext. 13970

http://www.chem.uysd.edu.au/~mcerlean/

[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

Palladium chemistry

Why bother with palladium?

What possible relevance can a metal have to a synthetic medicinal chemistry course?

Getting a drug to market costs $1.8 billion

„Big Pharma” spends $50 billion per year on R&D

So…they make a lots of compounds...and do a lot of reactions

Angew. Chem. Int. Ed. (2010) 49, 8082.

Reactions carried out at GSK

Palladium(0) is a Nucleophile !

Pd(0), whether as an atom, or ligated with 1 or 2 phosphine ligands behaves as a super-

nucleophile. It readily inserts into C-X bonds (X = Br, I, OTf). In a reaction called oxidative

addition.

Pd(0), is a very ‘soft’ Lewis acid it only readily binds phosphines (PR3) or alkenes or alkynes.

Nitrogen and oxygen ligands are not favoured for coordination

Therefore Pd(0) will insert fastest into C-I

bonds, then C-Br, and then C-Cl.

Palladium chemistry

Sources of Palladium(0) Reactive vs. Stabilised

Density Function Theory (DFT) calculations indicate the following order of reactivity in the

Oxidative Addition. The most active catalysts, unfortunately, have almost no „lifetime‟.

X is halide, OTf, etc…..

Palladium chemistry

Ligands for Palladium(0)

The number of ligands coordinated to the palladium affects the reactivity. Choice of an

appropriate ligand is empirical but some general trends can be noted….

Favoured by..

Favoured by..

Commercially

available with

R = Ph; BUT

must to loose

two PR3 to

become reactive

Palladium chemistry

Palladium chemistry

Field of ligand design dominated by Stephen Buchwald (MIT)

A. Start from Pd(0): Two common commercial precursors are available Pd(PPh3)4 and Pd(dba)2.

B. Reduce Pd(OAc)2: Two common in situ methods are shown.

C. Use PdX2L2 + 2 MR: The organometallic reagent (M-R) is often the carbanion in the C-C coupling

reaction (present in excess).

Most Pd-catalysed C-C couplings require the initial presence of Pd(0) to start the catalytic cycle!

The are several ways to attain this.

Palladium chemistry

We know how to generate Pd(0) and how it reacts, but what about Pd(II)?

Palladium chemistry

(II)

LnPd

X

R1

MR2

Pd-X bond ~70 kcal mol-1

Pd-C bond ~55 kcal mol-1

- MX

Driving force ! >120 kcal mol-1

(II)LnPd

R2

R1M = ZnX, SnBu3, B(OH)3, etc..

A. Transmetallation: Exchange of a Pd-X bond (X = halide) for an organo group.

B. Reductive Elimination: A very common catalysis termination step in catalytic

C-C coupling. NOTE only Pd-C or Pd-H bonds participate easily (favourable bond energetics).

Pd-X bond >70 kcal mol-1

(II)

LnPd

R2

R1R2 R1

Facile

- LnPd(0)

C-C bond ~90 kcal mol-1Pd-C bond ~55 kcal mol-1

(II)

LnPd

X

X

X X

Neverhappens !

- LnPd(0)

X-X bond <60 kcal mol-1

X = Cl, Br, OAc

C. b Elimination and Insertion: See the next two slides.

Palladium chemistry

• A free coordination site on palladium is required.

• The palladium is not oxidised or reduced in this process.

• It is a syn elimination and stereospecific (i.e. in the species below only Ha is eliminated)

• It is the reverse of alkene insertion.

• Repetitive b elimination followed by insertion can promote

isomerisation of the double position in some products.

• It prevents the use of sp3 RX electrophiles in Pd chemistry.

Pd

H

bR1

R2

L L

(II)Pd

L L

(II) HH2C

R1

R2b elimination

insertion

An empty orbital on electrophilic Pd(II) „reaches out‟ and captures the electron density in a C-H

bond on an sp3 centre „two atoms out‟ from the palladium.

Pd

Ph

HdHb

Ha

Hc

(II)

LnOnly this hydrogen is syn (in the same plane) as the palladium

Palladium chemistry

• Only Pd-C bonds participate in this reaction (the energetics for Pd-X insertions are unfavourable).

• The palladium is not oxidised or reduced in this process.

• It is a syn addition and stereospecific (i.e. the Pd and organogroup add to the same alkene face)

• Unlike the hydride case, the reverse of Pd-C insertion does not readily occur.

• Attack at the least substituted end of the double bond is the normal regiochemistry (steric factors).

• It generates a free coordination site at palladium

Pd

Ar

L X

(II)Pd

L X

(II) Ar

insertion

H

R

HH

n

R

n

H

H

H

An organogroup (typically an aryl or vinyl group arising from a previous oxidative addition)

migrates to a coordinated cis alkene by populating the p* antibonding orbital on the alkene.

RO

Pd

Ar

and

R2N

Pd

ArCARE! regiochemistry reversed in alkenes

with p donor substituents (electronic control)

Palladium chemistry

The Heck reaction couples an unsaturated

halide or triflate ( X = OTf) with an alkene in a

basic solution. The reaction product is a more

substituted alkene. The reaction is performed

in the presence of a palladium catalyst. The

halide or triflate is an sp2 compound (aryl,or

vinyl compound) and the alkene contains at

least one proton. The catalyst can be

Pd(PPh3)4 or an easily reduced Pd(II)

precursor, such as Pd(OAc)2. The base is

usually NEt3, K2CO3, NaOAc or Ag3PO4.

The Heck Reaction

This coupling reaction is stereoselective with a

propensity for trans coupling as the palladium halide

group and the bulky organic residue move away from

each other in the reaction sequence in a rotation step.

The Heck reaction is applied industrially in the

production of naproxen and the sunscreen component

octyl methoxycinnamate.

Nobel Prize 2010

The mechanism can be

broken down into a number of

Key steps:

I Pd(0) formation [A to B]

(see earlier slides)

II Oxidative Addition [B to C]

The palladium(0) catalyst [B]

(nucleophile) becomes Pd(II)

III Alkene coordination [C to D]

As Pd(II) species are electrophic

IV Cis ligand migration [D to E]

Regio chemistry is sterically

controlled. A syn addition!

VI b elimination [F to G]

Another syn process.

V Alkyl rotation [E to F]

Relieves steric strain of previous

syn addition

VII Product dissociation [G to H]

Pd(II)-to-alkene interactions weak

VIII Reductive elimination [C to D]

Added base removes HX

The Heck Reaction

Org. Lett., 2002, 4, 4399-4401. “Ligandless” approach

PEG is….

Note: acetal survives the Heck

And is „unmasked‟ with the HCl

At the end to an aldehyde.

Org. Lett., 2003, 5, 777-780.

Note: reverse of „normal‟ regio

chemistry due to presence of an

heteroatom (NHR in this case)

J. Org. Chem., 2005, 70, 5997-6003.

oo

n

The Heck Reaction

(II)

LnPd

X

R1

MR2

Pd-X bond ~70 kcal mol-1

Pd-C bond ~55 kcal mol-1

- MX

Driving force ! >120 kcal mol-1

(II)LnPd

R2

R1M = ZnX, SnBu3, B(OH)3, etc..

A. Transmetallation: Exchange of a Pd-X bond (X = halide) for an organo group.

B. Reductive Elimination: A very common catalysis termination step in catalytic

C-C coupling. NOTE only Pd-C or Pd-H bonds participate easily (favourable bond energetics).

Pd-X bond >70 kcal mol-1

(II)

LnPd

R2

R1R2 R1

Facile

- LnPd(0)

C-C bond ~90 kcal mol-1Pd-C bond ~55 kcal mol-1

(II)

LnPd

X

X

X X

Neverhappens !

- LnPd(0)

X-X bond <60 kcal mol-1

X = Cl, Br, OAc

C. b Elimination and Insertion: See the next two slides.

Palladium chemistry

The Stille Reaction

The Stille Coupling is a versatile C-C bond forming reaction between stannanes and halides or

pseudohalides, with very few limitations on the R-groups. Well-elaborated methods allow the preparation

of different products from all of the combinations of halides and stannanes depicted below. The main

drawback is the toxicity of the tin compounds used. Stannanes are often air stable.

Nucleophiles Electrophiles

J. K. Stille

Died in the Sioux City plane crash 1989

Complex unstable

if X = OTf. Therefore

add LiCl to couplings

of ArOTf species

The Stille Reaction

Transmetalation: Use organolithiums or Grignard reagents

(see lecture 2)

RLiMany routesto these

R3SnCl

R SnR3-LiCl

Formation of LiCl is the driving force

R = Me (toxic, but more reactive) Bu (less toxic and less reactive)

The Stille Reaction

So how do we make organostannanes?

Angew. Chem., 2004, 116, 1152-1156.

Tetrahedron, 2003, 59, 3635-3641.

J. Org. Chem, 1990, 55, 3019-3023.

The Stille Reaction

The Stille Reaction

Chloropeptin 1 (anti-HIV agent)

The Negishi Coupling, published in 1977, was the first reaction that allowed the

preparation of unsymmetrical biaryls in good yields. The palladium-catalyzed

coupling of organozinc compounds with various halides (aryl, vinyl, benzyl, or

allyl) has quite broad scope. In some remarkable cases even alkyl halides have

been successfully coupled (but this is still rare).

R1 X R2 ZnX

Pd0Ln

R1 R2+

Advantage - unreactive to all but the most electrophilic FGs

-ZnX2

The Negishi Reaction

Ei-Ichi Negishi

Nobel prize 2010


But how do we make organozinc reagents?

Note: 2-pyridyllithium is unstable so can‟t

Be used directly.

Eur. J. Org. Chem., 2002, 2292-2297.


The scheme above shows the first published Suzuki Coupling, which is the palladium-

catalysed cross coupling between organoboronic acid and halides..

N.B. a promoter (either a OH- [use an aqueous base!] or F- source [use CsF] is required).

The Suzuki Reaction

Akira Suzuki

Nobel prize 2010

Most commonly used Pd coupling in

pharmaceutical industry.

22% of all C-C bond constructions.

Org. Biomol. Chem. (2006) 4, 2337.

A

B

C

An alternative transmetalation step directly from

A to C using ArB(OH)3- has also been proposed

followed by Subsequent hydrolysis of the

XB(OH)3- anion.

See note

F

BAr

OH

OH

Cycle alsoviable from this

nucleophile fromCsF promotion

The Suzuki Reaction

RLiMany routes

to these

B(OMe)3

R B(OMe)2OMe easilyhydrolysed

R B(OH)2

H3O

But how would we make organoboranes?

The Suzuki Reaction

J. Am. Chem. Soc., 2003, 125, 7198-7199. Note sp3 coupling

A unusual variant using tosylates: J. Org. Chem., 2003, 68, 670-673.

Note: KRBF3 nucleophiles don’t need promotion J. Org. Chem., 2002, 67, 8424-8429.

OTf

The Suzuki Reaction

The Suzuki Reaction

This coupling of terminal alkynes with aryl or vinyl halides is performed with a

palladium catalyst, a copper(I) cocatalyst, and an amine base. Typically, the reaction

requires anhydrous and anaerobic conditions, but newer procedures have been

developed where these restrictions are not important. Despite it low pKa the amine

base can deprotonate the alkyne C-H bond as the coordinated copper (I) acts a a very

strong electron withdrawing group.

X

HPd0Ln

+CuI NR3R

R1

R1

R

The Sonogashira Reaction

HR1

pKa >20

No Reaction!

NEt3 HR1

pKa ~9

Facile reaction

NEt3

CuX

CuX

Kenkichi

Sonogashira Nobel prize can only be shared three-ways…

Unluckiest man in the world.

J. Org. Chem., 2005, 70, 391-393. CuX also required in this reaction

Org. Lett., 2003, 5, 1841-1844.

Org. Lett., 2002, 1411-1414.


J. Org. Chem., 2005, 70, 9626 -9628.

Conditions: (a) 3-bromobenzylamine, Et3N, HOBt,

EDC, DCM; (b) i. TFA/DCM, ii. N-Boc-Leu-OH, Et3N,

HOBt, EDC, DCM; (c) i. TFA/DCM, ii. N-Boc-Phe-OH,

Et3N, HOBt, EDC, DCM; (d) i. TFA/DCM, ii. n-

alkynoic acid, Et3N, HOBt, EDC, DCM


R‟-M

MX

In general, palladium

couplings proceed via the

same four steps:

•Oxidative insertion

•Transmetalation

•Tran/cis isomerisation

•Reductive elimination

Only exception if the Heck

reaction which involves a

carbopalladation and then a

beta-hydride elimination.

Catalytic Cycle

Palladium(0) is a Nucleophile !

Pd(0), whether as an atom, or ligated with 1 or 2 phosphine ligands behaves as a super-

nucleophile. It readily inserts into C-X bonds (X = Br, I, OTf). In a reaction called oxidative

addition.

Therefore Pd(0) will insert fastest into C-I

bonds, then C-Br, and then C-Cl.

Palladium chemistry

So why can‟t we just do an oxidative insertion into a C-H bond?

C-H Activation Chemistry

Pd(0) is a super nucleophile… but not good enough to get the job done.

Rather than pushing electron density into C-H bond, lets withdraw it.

Pd(II) is electrophilic …but not enough to get the job done

Let‟s use Pd(IV)….super electrophile.

Jin-Quan Yu

Scripps

Use Pd(II) and an oxidant

C-H Activation Chemistry

Palladium chemistry

Suggest structures for compounds (A) and (B).

Draw mechanistic arrows for first step.

Suggest another organometallic species that could

be used instead of the stannane.

Suggest suitable reagents for both transformations

Draw mechanisms for both transformations.

Palladium chemistry

Summary

Pd (0) is a super nucleophile

In general, palladium couplings proceed via the same four steps:

Oxidative insertion

Transmetalation

Tran/cis isomerisation

Reductive elimination

Transmetallaion step:

Boron – Suzuki Coupling

Zinc – Negishi coupling

Tin – Stille coupling

Copper acetylide – Sonogashira coupling

Only exception if the Heck reaction which involves a carbopalladation

and then a beta-hydride elimination.

C-H Activation

Next time

Workshop / problem session

Tearful farewell

chem3115 synthetic medicinal chemistry - …sydney.edu.au/science/chemistry/~mcerlean/lecture...

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