CHEM3115 Synthetic Medicinal Chemistry - …sydney.edu.au/science/chemistry/~mcerlean/Lecture...
Transcript of CHEM3115 Synthetic Medicinal Chemistry - …sydney.edu.au/science/chemistry/~mcerlean/Lecture...
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CHEM3115
Synthetic Medicinal
Chemistry
Lecture 6
Dr Chris McErlean
Rm 518a
Ext. 13970
http://www.chem.uysd.edu.au/~mcerlean/
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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
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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
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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
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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
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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
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Palladium chemistry
Field of ligand design dominated by Stephen Buchwald (MIT)
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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
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We know how to generate Pd(0) and how it reacts, but what about Pd(II)?
Palladium chemistry
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(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
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• 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
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• 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
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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
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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
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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
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(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
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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
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Complex unstable
if X = OTf. Therefore
add LiCl to couplings
of ArOTf species
The Stille Reaction
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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?
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Angew. Chem., 2004, 116, 1152-1156.
Tetrahedron, 2003, 59, 3635-3641.
J. Org. Chem, 1990, 55, 3019-3023.
The Stille Reaction
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The Stille Reaction
Chloropeptin 1 (anti-HIV agent)
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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
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The Negishi Reaction
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The Negishi Reaction
But how do we make organozinc reagents?
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Note: 2-pyridyllithium is unstable so can‟t
Be used directly.
Eur. J. Org. Chem., 2002, 2292-2297.
The Negishi Reaction
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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.
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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
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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
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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
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The Suzuki Reaction
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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.
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The Sonogashira Reaction
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J. Org. Chem., 2005, 70, 391-393. CuX also required in this reaction
Org. Lett., 2003, 5, 1841-1844.
Org. Lett., 2002, 1411-1414.
The Sonogashira Reaction
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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
The Sonogashira Reaction
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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
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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?
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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
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C-H Activation Chemistry
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C-H Activation Chemistry
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C-H Activation Chemistry
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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.
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Suggest suitable reagents for both transformations
Draw mechanisms for both transformations.
Palladium chemistry
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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
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Next time
Workshop / problem session
Tearful farewell