Regiocontrol in the Heck-Reaction and Fast Fluorous Chemistry
The Heck reactiongjrowlan/stereo2/lecture12.pdf123.702 Organic Chemistry The Heck reaction • The...
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123.702 Organic Chemistry The Heck reaction • The Heck reaction is a versatile method for the coupling sp 2 hybridised centres • Again it is not the purpose of this course to teach organometallics etc 1 R 1 X + R 2 cat. PdX 2 R 3 N [R 3 3 P] R 2 R 1 R 1 = Ar, ArCH 2 , X = Br, I, OTf Br Pd L L Br oxidative addition Pd L Br syn addition R 3 N R 3 NH Br Pd(0) (14e) L Pd L L Pd Br H L Pd H Pd L H Br L Br –L +L Pd(II) (16e) Pd(II) (16e) Pd(II) (16e) β-hydride elimination
Transcript of The Heck reactiongjrowlan/stereo2/lecture12.pdf123.702 Organic Chemistry The Heck reaction • The...
123.702 Organic Chemistry
The Heck reaction
• 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
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R1 X + R2cat. PdX2
R3N[R3
3P]
R2 R1
R1 = Ar, ArCH2,X = Br, I, OTf
Br
PdL
LBr
oxidative addition
PdL
Br
syn addition
R3N
R3NH Br
Pd(0)(14e)
L Pd L
L Pd BrH
L
Pd
H
PdLH
Br
LBr
–L
+L Pd(II)(16e)
Pd(II)(16e)
Pd(II)(16e)
β-hydride elimination
123.702 Organic Chemistry
O
Ph
Pd(I)LnH
O
Ph
PdHI
LO H O
Ph
PdI
L
H
O
Ph
Pd(I)Ln
H
hydro-palladation
Hβ-hydride
eliminationO
PhPd
IL
HO
Pd IL
δ+ δ–
syn addition
O
Pd(I)LnH
HH
Alkene isomerisation
• 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
2
O+
I
O
0.01% Pd(OAc)2R3N
100°C
123.702 Organic Chemistry
Enantioselective Heck reaction
• 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
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O TfO+
Pd(dba)2 (3%), lig (6%)i-Pr2NEt
O
92%>99% ee
N
O
PPh2
t-Buligamino acid derivative
I
TBSO Pd[(R)-BINAP]Cl2AgPO4, CaCO3
NMe
O H
TBSO
78%82% ee
O
O
N
O
I
Me Pd2(dba)3(R)-BINAP
Ag3PO4N,N-dimethylaniline
O
O
NO
Me
71% ee
PPh2PPh2
(R)-BINAP
123.702 Organic Chemistry
Enantioselective Heck reaction in total synthesis
• (+)-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
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OTf
OO
OMe
OMe
Me Pd2(dba)3, (S)-BINAP, PMP, tol, 110°C
82%68%ee O
OMe
OMe O
LnPdMe
OMe
OMe O
Me
O
O
O O
Me
O
xestoquinone
i. H2, Pd/Cii. CAN
123.702 Organic Chemistry
Suzuki-Miyuara reaction
• 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...
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Pd0L L
Pd0L
–Loxidative addition
transmetallation
reductive elimination
PdL
X
B(OH)2
X
PdL
R1
R2
R1
R2
R2
R1R2
123.702 Organic Chemistry
Enantioselective biaryl formation
• 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
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BrP(O)(OMe)2 +
B(OH)2
Me P(O)(OMe)2
Me
95%86% ee
Pd2(dba)3 (0.2%)lig2
PCy2
NMe2
lig2
MeB
O O
+Me
I
(PdClC3H5)2lig1
CsF MeMe
60%85% ee
FePPh2
lig1Me
NMe2H
123.702 Organic Chemistry
Enantioselective Pd catalysed allylic substitution
• Displacement of good leaving group (OAc, OCO2R, halide, epoxide etc.)• Normally by soft nucleophile • Not direct displacement but via a palladium η3 complex
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XLn+1Pd0nuc.... nuc
Ln+1Pd0 LnPd0
XLnPd0
X
PdIIX
LnPdII
LLX
nuc
nucPd0Ln
nuc
need vacant coordination site
oxidative addition
need vacant coordination site
need vacant coordination site
σ-bond species and π-allyl complex in
equilibrium
electron deficient (cation) -
electrophile
123.702 Organic Chemistry
Me
Me
Me
CO2MeMeO2C H
Me
Me
Me
PdL L
MeO2C CO2Me
NaMe SO2Ph
Me
Me
Pd(PPh3)4
Regio- and stereoselectivity
• 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)
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Me Me
OAc
Me
Me
Me
Me
PdL L
MeO2C CO2Me
NaPd(PPh3)4Me
Me
Me
HMeO2C
CO2Me
123.702 Organic Chemistry
O
Me
O
+OAcPd(0), cat.
base
92%75%ee
OO
Me
OAc
MeO2C CO2Me
Na
Pd(0), cat.
81%98%ee
CO2Me
CO2Me
+
LR
R PdL
Enantioselectivity
• 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:
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nuc
Substrate
Nucleophile
NH HN
PPh2 Ph2P
O O
Fe PPh2
PPh2
O
N
O O
N
O
N
Me
MeMe
123.702 Organic Chemistry
NTs OTBSH
ROM–RCM
N
HOH
OH
OH
(–)-swainsonine
O O
NHTs
OO
NHTsmeso
cat. (7.5mol%)Pd2dba3 (2.5mol%)
Et3N
95%97%ee
NTs
O
O
Allylic substitution in total synthesis
• (–)-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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NH HN
PPh2 Ph2P
O O
NTs
OTBS
123.702 Organic Chemistry
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
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N
O
Me
Me
N
O
MeMe
L2 (10mol%), PhH, 22°C, 48h
91%98% ee
NMo THF
OOAr
Ar
i-Pri-Pr
Me
Me
Ph
L2
123.702 Organic Chemistry
Summary of methods for stereoselective synthesis
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Method Advantages Disadvantages Examples
resolution both enantiomers available maximum 50% yield synthesis of (–)-propranolol
chiral pool 100% ee guaranteed often only 1 enantiomer available
synthesis of (R)-sulcatol
chiral auxiliary often excellent ee’s; built in resolving agent
extra steps to introduce and remove auxiliary
oxazolidinones
chiral reagent often excellent ee’s; stereoselectivity can be independent of substrate control
only a few reagents are successful and often only for a few substrates
alpine-borane®, Brown allylation reagents
chiral catalyst economical; only small amounts of recyclable material used
only a few reactions are really successful; frequently a lack of substrate generality
asymmetric hydrogenation; Sharpless epoxidation
• 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...
