Download The Heck reaction

1
The Heck reaction
R1
X
+
cat. PdX2
R2
R3N
[R33P]
R1 = Ar, ArCH2,
X = Br, I, OTf
R1
R2
• The Heck reaction is a versatile method for the coupling sp2 hybridised centres
• Again it is not the purpose of this course to teach organometallics etc
Br
R3NH Br
L Pd L
oxidative
addition
R3N
H
L
L Pd Br
L
+L
H
L
Pd
Br
Pd Br
Pd(0)
(14e)
Pd(II)
(16e)
L
Pd(II)
(16e)
–L
L
Pd(II)
(16e)
Pd Br
H
syn
addition
β-hydride
elimination
Br
Pd
L
123.702 Organic Chemistry
2
Alkene isomerisation
0.01% Pd(OAc)2
R3N
+
O
I
L
Pd I
δ+
O
δ–
O
100°C
syn
addition
Pd(I)Ln
H
H
O
β-hydride
elimination
Ph
O
L
I
Pd
H
hydropalladation
Ph
H
O
Pd(I)Ln
H
H
Ph
Ph
O
O
O
H Pd L
I
H
Ph
H
Pd(I)Ln
O
L
Pd
I
H
• β-Hydride elimination is reversible
• This alkenes can ‘walk’ or migrate to give the most stable alkene
• Only restriction is every step must be syn
123.702 Organic Chemistry
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Enantioselective Heck reaction
Pd(dba)2 (3%), lig (6%)
i-Pr2NEt
+
O
O
O
TfO
PPh2 N
92%
>99% ee
t-Bu
lig
amino acid derivative
• With the use of chiral ligands the Heck reaction can be enantioselective
• Intramolecular variant allows the construction of ring systems
• The silver salt accelerates the reaction and prevents alkene isomerisation
TBSO
TBSO
Pd[(R)-BINAP]Cl2
AgPO4, CaCO3
I
N
Me
O
H
78%
82% ee
O
N
O
I
O
O
Pd2(dba)3
(R)-BINAP
Me
Ag3PO4
N,N-dimethylaniline
PPh2
Me
PPh2
N
(R)-BINAP
O
O
71% ee
123.702 Organic Chemistry
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Enantioselective Heck reaction in total synthesis
OMe
Me
OTf
Pd2(dba)3, (S)-BINAP,
PMP, tol, 110°C
O
LnPd
Me
82%
68%ee
O
OMe
OMe
O
O
OMe
OMe
Me
i. H2, Pd/C
ii. CAN
O
Me
O
O
O
xestoquinone
O
OMe
O
• (+)-Xestoquinone was isolated from the Pacific sponge Xestospongia sapra (not
•
•
•
shown!) and is a potent irreversible inhibitor of both the oncogenic protein tyrosine
kinase pp60V-src encoded by the Rous sarcoma virus & the human epidermal growth
factor kinase (EGF)
The first total synthesis involved two Heck reactions; the first is enantioselective to
give a quaternary centre and the second gives a second 6-ring
Shawn P. Maddaford, Neil G. Andersen, Walter A. Cristofoli & Brian A. Keay, J. Am.
Chem. Soc. 1996, 118, 10766
Review of asymmetric Heck: Chem. Rev. 2003, 103, 2945
123.702 Organic Chemistry
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Suzuki-Miyuara reaction
L Pd0 L
–L
R2
reductive
elimination
L Pd0
oxidative
addition
X
R2
R1
L
Pd
X
R1
L
Pd
R2
R2
transmetallation
R1
B(OH)2
• The Suzuki-Miyuara reaction is (normally) the palladium catalysed coupling of an
•
•
alkenyl or aryl halide with an alkenyl or aryl boronic acid
Normally the components should be sp2 hybridised to avoid β-eliminations
Mechanism etc is (surprise surprise) outside the scope of this course but the
wonderful enantioselective examples are not...
123.702 Organic Chemistry
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Enantioselective biaryl formation
Me
O
B
(PdClC3H5)2
lig1
CsF
+
Me
Me
O
Me
I
PPh2
NMe2
Fe
H
Me
lig1
60%
85% ee
Br
P(O)(OMe)2
+
Pd2(dba)3 (0.2%)
lig2
Me
Me
NMe2
P(O)(OMe)2
PCy2
B(OH)2
95%
86% ee
lig2
• Virtually every (if not every...) reaction we have covered in this course has formed a
•
•
stereogenic centre (central chirality)
These two examples form axially chiral compounds
Please note: both ligands are thought to be mono-dentate (in the active species at
least, although they may be bidentate in ‘resting state’) via the phosphine
123.702 Organic Chemistry
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Enantioselective Pd catalysed allylic substitution
Ln+1Pd0
nuc....
X
nuc
• Displacement of good leaving group (OAc, OCO2R, halide, epoxide etc.)
• Normally by soft nucleophile
• Not direct displacement but via a palladium η3 complex
LnPd0
X
oxidative
addition
X
σ-bond
species and πallyl complex in
equilibrium
need vacant
coordination site
0
Ln+1Pd
Ln
0
LnPd
PdII
nuc
X
L
nuc
nuc
Pd0Ln
PdII
X
L
electron deficient
(cation) electrophile
123.702 Organic Chemistry
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Regio- and stereoselectivity
Me
Me
Pd(PPh3)4
Me
Me
MeO2C
CO2Me
Me
Me
Na
SO2Ph
Me
L
Me
Me
Pd
L
MeO2C
H
CO2Me
• Palladium initially adds to the opposite face to the leaving group
•
•
(although possible equilibrium)
Soft nucleophiles (large, diffuse charge) usually attack from opposite face to PdLn
Normally the nucleophile will add to the least hindered end of the allyl system
(although ligand can can this)
OAc
Me
Pd(PPh3)4
Me
Me
CO2Me
Me
Me
Na
Me
Me
MeO2C
L
Me
Pd
L
H
MeO2C
Me
CO2Me
123.702 Organic Chemistry
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Enantioselectivity
R
R
nuc
Pd
L
L
• Problem with inducing selectivity is that ligand is on opposite side to nucleophile
• Bulky ligands can overcome this problem
• Stereogenic centre can either be on:
Substrate
MeO2C
+
CO2Me
Na
OAc
O
Pd(0), cat.
O
CO2Me
81%
98%ee
NH
CO2Me
HN
PPh2 Ph2P
Nucleophile
O
OAc
+
O
Me
Pd(0), cat.
base
92%
75%ee
O
O
Me
O
Me
Fe
N
PPh2 Me
PPh2
O
N
O
O
N
Me
123.702 Organic Chemistry
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Allylic substitution in total synthesis
O
O
O
NHTs
O
cat. (7.5mol%)
Pd2dba3 (2.5mol%)
Et3N
NHTs
N
O
N
Ts
95%
97%ee
meso
OH
H
OTBS
NTs
O
ROM–
RCM
OH
N
Ts H
OH
OTBS
(–)-swainsonine
O
O
NH
HN
PPh2 Ph2P
• (–)-Swainsonine can be isolated from locoweeds; in cattle it causes symptons similar
to mad cow disease (BSE) - hence plants named after the Spanish for crazy
• In humans it shows anticancer, antiviral, and immunoregulatory properties
• This synthesis is by Nicole Buschmann, Anke Rückert and Siegfried Blechert J. Org.
•
Chem. 2002, 67, 4325
The desymmetrisation is by Barry M. Trost and Daniel E. Patterson J. Org. Chem.
1998, 63, 1339
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Other catalytic enantioselective reactions
• There are now a huge number of enantioselective reactions with more being
invented / developed all the time
• It is highly unlikely that this research in this vast, fascinating field will slow in the
foreseeable future...(well I hope not anyway)
• It should be possible to develop enantioselective variants of most reactions - even
those that do not initially look set-up for such chemistry...
• Below is an example of a chiral variant of the Schrock metathesis catalyst
• The reaction involves desymmetrisation by selective reaction if one disubstituted
alkene
O
O
L2 (10mol%),
PhH, 22°C, 48h
N
Me
N
i-Pr
i-Pr
Ar
Me
Me
Me
91%
98% ee
N
O Mo THF Me
O
Ar
Ph
Me
L2
123.702 Organic Chemistry
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Summary of methods for stereoselective synthesis
Method
Advantages
Disadvantages
resolution
both enantiomers available maximum 50% yield
synthesis of (–)-propranolol
chiral pool
100% ee guaranteed
synthesis of (R)-sulcatol
often only 1 enantiomer
available
Examples
chiral auxiliary often excellent ee’s; built in extra steps to introduce
resolving agent
and remove auxiliary
oxazolidinones
chiral reagent
alpine-borane®, Brown
allylation reagents
often excellent ee’s;
stereoselectivity can be
independent of substrate
control
chiral catalyst economical; only small
amounts of recyclable
material used
only a few reagents are
successful and often only
for a few substrates
only a few reactions are
asymmetric hydrogenation;
really successful; frequently Sharpless epoxidation
a lack of substrate
generality
• Hopefully this course has shown that the area of stereoselective synthesis (or more
particularly, methodology for stereoselective synthesis) is a vast & fascinating topic
• There are many reactions we have not covered (there is already far too much
material in the course)
• I hope you found the course as interesting as I did...
123.702 Organic Chemistry