Recent Developments in Homogeneous Gold Catalysis · PDF fileRecent Developments in...
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Recent Developments in Homogeneous Gold Catalysis David A. Nagib
MacMillan Group Literature Meeting
03.17.2010
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Relativistic Effects in Gold Catalysis
Relativistic effects – phenomenon resulting from the need to consider velocity as significant relative to the speed of light
m = m°/√1-(v/c)2
Consequences: • Relativistic mass increases as velocity approaches c • Increased mass results in decreased Bohr radius • Contracted 6s orbital better shields (expands) 5d orbital
Relativistic contraction of 6s orbital
• Faster • Heavier • Nearer
Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395-403 Pyykkö, P.; Desclaux, J. P. Acc. Chem. Res. 1979, 12, 276-281
Filled 4f orbital
Filled 5d orbital
79Au
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Relativistic Effects in Gold Catalysis
Relativistic effects – phenomenon resulting from the need to consider velocity as significant relative to the speed of light
m = m°/√1-(v/c)2
Consequences: • Relativistic mass increases as velocity approaches c • Increased mass results in decreased Bohr radius • Contracted 6s orbital better shields (expands) 5d orbital
• Faster • Heavier • Nearer
Au
Increased π-acidity
R
Ag
R>
Increased e− delocalization(i.e. backbonding)
Au Ag
AgAu
>
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Modes of Reactivity in Homogeneous Gold Catalysis
Au
Nu
Au
Nu E
Nu Au
E
Nu
Au
Nu E
E
cationderived products
cation cyclizationrearrangement
H
Nu
carbenoidderived products
C-H insertioncyclopropanation
trans-addition
increased e− delocalization(expanded 5d orbital)
♦ Au backbonding E+ = alkene, ylide, etc.
♦ proto-deauration E+ = H+ (Nu-H)
Lewis acidderived products
ring expansioncycloisomerization
increased π-acidity(contracted 6s orbital)
♦ aprotic nucleophile E+ = alkene, alcohol, etc.
Lewis acidderived products
heterofunctionalizationheterocyclization
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Modes of Reactivity in Homogeneous Gold Catalysis
Au
Nu
Au
Nu E
Nu Au
E
Nu
Au
Nu E
E
cationderived products
cation cyclizationrearrangement
H
Nu
carbenoidderived products
C-H insertioncyclopropanation
trans-addition
increased e− delocalization(expanded 5d orbital)
♦ Au backbonding E+ = alkene, ylide, etc.
♦ proto-deauration E+ = H+ (Nu-H)
Lewis acidderived products
ring expansioncycloisomerization
increased π-acidity(contracted 6s orbital)
♦ aprotic nucleophile E+ = alkene, alcohol, etc.
Lewis acidderived products
heterofunctionalizationheterocyclization
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Activation of π-systems Towards Nucleophiles
Oxygen nucleophiles
Other nucleophiles
Hydration: Fukuda, Y.; Utimoto, K. J. Org. Chem. 1991, 56, 3729-3734 Teles, J.; Brode, S.; Chabanas, M. Angew. Chem. Int. Ed. 1998, 37, 1415-1418
Hydro-amination: Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349-3352
Hydro-fluorination: Akana, J.; Bhattacharyya, K.; Muller, P.; Sadighi, J. J. Am. Chem. Soc. 2007, 129, 7736-7727
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Trostʼs Synthesis of Bryostatin
Trost, B.; Dong, G. Nature 2008, 456, 485-488
Gold-catalyzed 6-endo-dig cyclization provides highly sensitive dihydrofuran C ring under mild conditions
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Employing Carbon Nucleophiles: Hydroarylation
Reetz, M.; Sommer, K. Eur. J. Org. Chem. 2003, 18, 3485-3496
Au(I) & Au(III)-catalysts provide complete regioselectivity in the hydroarylation of terminal alkynes
o/p
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Employing Carbon Nucleophiles: Enolate Alkylation
Kennedy-Smith, J.; Staben, S.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526-4527
A wide range of β-keto esters serve as efficient nucleophiles for the mild and fast hydroalkylation of terminal alkynes
Deuterium studies support trans-addition mechanism and explain limitation towards internal alkynes
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Cyclization of Silyl Enol Ethers
Staben, S.; Kennedy-Smith, J.; Huang, D.; Corkey, B.; LaLonde, R.; Toste, F. D. Angew. Chem. Int. Ed. 2006, 45, 5991-5994
Enol silanes are also suitable nucleophiles for quaternary (& now tertiary) carbon center construction
Water serves as the external proton source for the final proto-deauration
terminal-δ-alkyne
( )n
RTBSO
HR
O R
( )nH
5-exo-dig
6-exo-dig
internal additionfavored
O
AuL
TBS
H2O
H
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Internal vs Terminal Alkynes
Markovnikov addition provides access to variously substituted cyclopentenes depending on alkyne substitution
Staben, S.; Kennedy-Smith, J.; Huang, D.; Corkey, B.; LaLonde, R.; Toste, F. D. Angew. Chem. Int. Ed. 2006, 45, 5991-5994
( )n
RTBSO
H
internal-γ-alkyneR
O R
( )nH
XX
X = Ar, I
5-endo-dig
benzylic/halo additionfavored
O
AuL
X
TBS
terminal-δ-alkyne
( )n
RTBSO
HR
O R
( )nH
5-exo-dig
6-exo-dig
internal additionfavored
O
AuL
TBS
H2O
H
R
O R
( )n
•
R
( )n
RTBSO
H H
terminal-β-allene
5-endo-trig
conformation governsaddition
•
O
AuL
TBS
H
H
H
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Synthetic Applications of Cyclopentenes
The non-ester bearing quaternary cyclopentenes allow rapid synthetic access to a variety of Lycopodium alkaloids.
Staben, S.; Kennedy-Smith, J.; Huang, D.; Corkey, B.; LaLonde, R.; Toste, F. D. Angew. Chem. Int. Ed. 2006, 45, 5991-5994 Linghu, X.; Kennedy-Smith, J.; Toste, F. D. Angew. Chem. Int. Ed. 2007, 46, 7671-7673
For comparison, structurally similar Lycopodium alkaloids synthesized in 22-24 steps: Laemmerhold, K.; Breit, B. Angew. Chem. Int. Ed. 2010, ASAP
( )n
RTBSO
H
internal-γ-alkyneR
O R
( )nH
XX
X = Ar, I
5-endo-dig
benzylic/halo additionfavored
O
AuL
X
TBS
R
O
tBuO
O
Me H
O
1. Organocat.2. H+
3. β-allene add'n4. NIS
8 steps
H
O
MeH
O
Me
BocN
3 steps
BnO
N
(+)-lycopladine A8 steps
(+)-fawcettimine13 steps
Me
N
OHO
H
HO
TFA
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Enantioselective Conia-Ene
A chiral Pd-complex was preferred due to the linear geometry of the ligand and substrates across the Au-catalyst
X-ray structures demonstrate the distance between the ligand framework and the pro-chiral substrate
4.58 Å 3.14 Å
Corkey, B.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168-17169 Shapiro, N.; Toste, F. D. Synlett. 2010, 5, 675-691
Au vs Pd
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Enantioselective Gold Catalysis
Development of a Au(I)-catalyzed asymmetric hydroamination reaction
Coordinating counteranion provides increasing enantioselectivity due to the proposed model below
LaLonde, R.; Sherry, B.; Kang, E.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452-2453
All 3 species observed by 31P NMR of 2:1 L(AuCl)2:AgBF4 "
Coordinating counteranions shift equilibrium to left (higher ee)
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Chiral Counterion Catalysis
Chiral induction still challenging due to the expanse of the linear gold complex
An interesting alternative
Hamilton, G.; Kang, E.; Mba, M.; Toste, F. D. Science. 2007, 317, 496-499 Perspective: Lacour, J.; Linder, D. Science. 2007, 317, 462-463
Chiral ligand strategy
Chiral counterion strategy
Increasing solvent polarity
Nucleophiles also include -NHSO2Ar & -CO2H
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Modes of Reactivity in Homogeneous Gold Catalysis
Au
Nu
Au
Nu E
Nu Au
E
Nu
Au
Nu E
E
cationderived products
cation cyclizationrearrangement
H
Nu
carbenoidderived products
C-H insertioncyclopropanation
trans-addition
increased e− delocalization(expanded 5d orbital)
♦ Au backbonding E+ = alkene, ylide, etc.
♦ proto-deauration E+ = H+ (Nu-H)
Lewis acidderived products
ring expansioncycloisomerization
increased π-acidity(contracted 6s orbital)
♦ aprotic nucleophile E+ = alkene, alcohol, etc.
Lewis acidderived products
heterofunctionalizationheterocyclization
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Non-Canonical Reactivity
Compared with nucleophilic activation provided by canonical metal catalysis, gold offers orthogonal electrophilic activation
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Ring Expansions
Compared with nucleophilic activation provided by canonical metal catalysis, gold offers orthogonal electrophilic activation
Non-canonical nucleophiles that lack metal-coordination sites (i.e. C-C σ-bond) are suitable partners in Au-catalysis
Markham, J.; Staben, S.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 9708-9709 Kleinbeck, F.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 9178-9179
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Modes of Reactivity in Homogeneous Gold Catalysis
Au
Nu
Au
Nu E
Nu Au
E
Nu
Au
Nu E
Lewis acidderived products
ring expansioncycloisomerization
E
cationderived products
cation cyclizationrearrangement
H
Nu
Lewis acidderived products
heterofunctionalizationheterocyclization
carbenoidderived products
C-H insertioncyclopropanation
trans-addition
increased π-acidity(contracted 6s orbital)
increased e− delocalization(expanded 5d orbital)
♦ proto-deauration E+ = H+ (Nu-H)
♦ aprotic nucleophile E+ = alkene, alcohol, etc.
♦ Au backbonding E+ = alkene, ylide, etc.
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Enyne Cycloisomerizations
Simple olefins can also serve as nucleophiles when tethered to a π–activated alkyne (1,6-Enynes)
A series of skeletal rearrangements involving carbenoid and cationic intermediates may be invoked for this transformation
96% yield
2% (PPh3)AuSbF6CH2Cl2, r.t., 10 min
5-exo-dig
MeE
E EE
Me
Nieto-Oberhuber, C.; Muñoz, M.; Buñuel, E.; Nevado, C.; Cárdenas, D.; Echavarren, A. Angew. Chem. Int. Ed. 2004, 43, 2402-2406
Product selectivity is highly dependant on the substitution of the α,ω–enyne starting materials
H
AuL
H
Me
carbene
E
E
H
H
Me
E
E AuL
E
E
MeH
LAu
cation
E
ELAu
cation
HMe
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Enyne Cycloisomerizations Revisited
Simple olefins can also serve as nucleophiles when tethered to a π–activated alkyne (1,5-Enynes)
Mamane, V.; Gress, T.; Krause, H.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 8654-8655 Kleinbeck, F.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 9178-9179
1,5-Enynes (from propargyl alcohols) reliably provide synthetic access to the cis-fused 3,5-ring systems
8 examples> 94% yield
2% (PPh3)AuSbF6CH2Cl2, r.t., 5 min
5-exo-digAuL
RR
R
H
RR
RAuL
RR
R
H
1,2-H shift
98% yield
Bn
OHTMS
5% (dppm)ReOCl35% NH4PF6, MeNO2, 65°C
1% LAuSbF6
CH2Cl2, r.t.BnBn
H
propyl
79% yield
propyl
propyl
Free alcohols can replace the benzyl substituent and provide access to propane-fused cyclopentenone
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Enyne Cycloisomerizations Revisited
Simple olefins can also serve as nucleophiles when tethered to a π–activated alkyne (1,5-Enynes)
Mamane, V.; Gress, T.; Krause, H.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 8654-8655 Kleinbeck, F.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 9178-9179
Propargyl deuterium label is selectively incorporated in the vinyl position of the product
8 examples> 94% yield
2% (PPh3)AuSbF6CH2Cl2, r.t., 5 min
5-exo-digAuL
RR
R
H
RR
RAuL
RR
R
H
1,2-H shift
AuL
carbenoid
AuLAuL
R'R"
R'R"
R'R"
cation hybrid
AuL
R'R"
R R R R
D D D D
R'R"
RD
1,2-Disubstituted olefins underwent cycloisomerization stereospecifically
Further mechanistic considerations
Gold-carbenoid character is strongly suggested by these mechanistic observations …
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Carbene Controversy
Fürstner strongly argues that these gold-catalyzed processes exhibit more non-classical carbocationic features
Fürstner, A.; Morency, L. Angew. Chem., Int. Ed. 2008, 47, 5030-5033 Seidel, G.; Mynott, R.; Fürstner, A. Angew. Chem., Int. Ed. 2009, 48, 2510-2513
Employing a carboxylate trap as a mechanistic probe, Fürstner demonstrated the 1,6-enynes arise from cationic mechanism
R1
R2
OH
OE E
OOH
LAu
E
E R1
R2
R1
R2
OHO
EE
LAu
OO
E
E R1
R2
OO
E
E
R1
R2
if R2 =
Me if R1 = Me
R1 = H R2 = H
R1 = H R2 = MeR1 = Me R2 = H
if R1 = Me if R2 = Me
19% yield 11% yield- 80% yield
82% yield -
cationicmechanism
carbenemechanism
AuPPh3H
O
O
AuPPh3H
O
O
carbene cation
NMR studies strongly suggest that the cation mesomer better represents the complex
Fürstner isolated and characterized a stable alkyl-gold complex that could exist as a carbene
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Carbenes Defended
Toste held that many of their methodologies strongly resembled reactivity associated with carbenic systems
Toste & Goddardʼs bonding model for gold(I) carbene complex involves both σ- and π- bonding, with a bond order ≤ 1
Toste & Goddard refute Fürstnerʼs NMR experiments with bond rotation calculations and measurements of their own
Benitez, D.; Shapiro, N.; Tkatchouk, E.; Wang, Y.; Goddard, W.; Toste, F. D. Nature Chem. 2009, 1, 482-486 Horino, Y.; Yamamoto, T.; Ueda, K.; Kuroda, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2809-2811
[Au]
( )n( )n
( )n
[Au] [Au]+
( )n ( )n
(n = 1-4)
9 examples82-99% yields
12 examples60-86% yields
C-H insertion
(n = 1,2) (n = 3,4)
HH
C-C migration AuPPh3H
O
O
Furstner'snon-carbene
Toste/Goddardcarbene
AuLH
O
O
O
O
Ph Ph
vs
Ph Ph
80% yield
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Carbene Controversy Concluded
An entire literature meeting could be devoted to this subject …
The carbocation-carbenoid continuum best offers a helpful mnemonic to explain and predict many facets of gold catalysis
Carbocationic ONLY
Carbene ONLY
Carbocationic Carbenoid Continuum
Ongoing debate on the cationic and carbene character of gold catalysis suggests a continuum of tunable reactivity
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Methods of Generating Gold Carbenes
Gold carbenes from alkynyl sulfoxides offer an orthogonal approach to reactivity previously associated with diazocarbonyls
Shapiro, N.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 4160-4161 Gorin, D.; Davis, N.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260-11261
Azides are analogous carbene precursors
LG+
[Au]+
Nu
[Au]+
Nu-LG+[Au]+ 5-exo-dig
[Au]
NuLG+
gold carbene
LGNu-
S
[Au]+
O
[Au]+
OSPh
[Au]+ 5-exo-dig
[Au]
OSPh
gold carbene
O
Ph
SPh
S
OC-H insertion
94% yield
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Methods of Generating Gold Carbenes
Gold carbenes from alkynyl sulfoxides offer an orthogonal approach to reactivity previously associated with diazocarbonyls
Shapiro, N.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 4160-4161 Gorin, D.; Davis, N.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260-11261
[Au]+
O
gold carbene
SMe
Me
SMe Me 5% IPrAuCl
5% AgSbF6CH2Cl2, r.t.
C-C σ-bondmigration O
ArS
N2
OSMe
Me
[M]
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Another Method of Generating Gold Carbenes
Propargyl carboxylates allow synthetically facile access to gold carbenes via a 1,2-acyloxy migration
Johansson, M.; Gorin, D.; Staben, S.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002-18003
Modular synthesis of propargyl carboxylates coupled with gold carbene pathways allow for rapid complexity generation
OO
R'R
[Au]+
OOR
R'[Au]+
OO
R'R
[Au]+ 5-exo-dig
1,2-acyloxy migration
[Au]
OO
R R'
gold carbene
70% yield> 20:1 dr, 81% ee
O
O
R
R'
Ph
Ph
L*
O
R'R
OX
ketone
acid derivative
alkyne
2 steps
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Propargyl Carboxylate Reactivity
Substitution patterns dictate formation of vinyl gold versus gold carbene species
Wang, S.; Zhang, G.; Zhang, L. Synlett. 2010, 5, 692-706
OO
R'R
EWGor H
[Au]+
OOR
R'[Au]+
OO
R'R
[Au]+ 5-exo-dig
1,2-acyloxy migration
[Au]
OO
R R'
[Au]+
gold carbene
tBu
[3,3]-rearrangement
[Au]+
OO
R'R
OO
⋅R
OO
R'[Au]
OO
RR'
[Au]
6-endo-dig[Au]
α-carbonylvinyl gold
R R�'
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Vinyl Gold Intermediate
Substitution patterns dictate formation of vinyl gold versus gold carbene species
Wang, S.; Zhang, G.; Zhang, L. Synlett. 2010, 5, 692-706
Vinyl gold species can also be exploited in a variety of rapid complexity generating transformations
OE
R'R
ONu
R'R
or
[3,3]-rearrangement
[Au]+
OO
R'R
OO
⋅R
OO
R'[Au]
OO
RR'
[Au]
6-endo-dig[Au]
α-carbonylvinyl gold
R R�'
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Electrophilic Trapping of Vinyl Gold
Electrophilic trapping by N-halo-succinimides affords α-halo -enones and -enals from propargyl acetates
Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147-2150 Yu, M.; Zhang, G.; Zhang, L. Tetrahedron. 2009, 65, 1846-1855
butyl
OBr
Me
butyl
OI
butyl
or
NBSorNIS85% yield
> 99:1 dr94% yield> 20:1 dr
[3,3]-rearrangement
[Au]+
OO
R'R
OO
⋅R
OO
R'[Au]
OO
RR'
[Au]
6-endo-dig[Au]
α-carbonylvinyl gold
R R�'
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Electrophilic Trapping of Vinyl Gold
Catalytic molybdenum oxide allows for the use of propargyl alcohols in addition to propargyl carboxylates
Yu, M.; Zhang, G.; Zhang, L. Org. Lett. 2007, 9, 2147-2150 Ye, L.; Zhang, L. Org. Lett. 2009, 11, 3646-3649
butyl
OBr
Me
butyl
OI
butyl
or
NBSorNIS85% yield
> 99:1 dr94% yield> 20:1 dr
OH
HMe
butyl
[3,3]-rearrangement
[Au]+
OMo
O
R'R
O
⋅R
OMo
O
R'[Au]
OMo
O
RR'
[Au]
6-endo-dig[Au]
α-carbonylvinyl gold
- MoO2
+ H2O1% MoO2
R R'
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Nucleophilic Trapping of Vinyl Gold
Oxidation of the vinyl gold intermediate allows access to Au(III) oxidation state and corresponding nucleophilic trapping
Peng, Y. Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2009, 131, 5062-5063
A variety of intermolecular nucleophilic functionalizations can be envisioned to access α-substituted enones and enals
[3,3]-rearrangement
[Au]+
OO
R'R
OO
⋅R
OO
R'[Au]
OO
RR'
[Au]
6-endo-digAuI
α-carbonylvinyl gold
R R'
OO
9 examples56-78% yield
+ H2O
[O]
OOAuIII
OO
AuIII
OAuIII
OOR R'
R R' R R'R R'
- AuI
reductiveelimination
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Gold Cross-Coupling
Addition of boronic acids under semi-aqueous conditions readily provides α-aryl enones and enals
Zhang, G.; Peng, Y. Cui, L.; Zhang, L. Angew. Chem. Int. Ed. 2009, 121, 3158-3161 Related transformation for homo-allylic alcohols: Zhang, G.; Cui, L.; Wang, Y.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 1474-1475
[3,3]-rearrangement
[Au]+
OO
R'R
OO
⋅R
OO
R'[Au]
OO
RR'
[Au]
6-endo-digAuI
α-carbonylvinyl gold
R R'
OAr
15 examples45-71% yield
[O]
OAuIII
Ar
R R'R R'
- AuI
reductiveelimination
OAuIII
R R'
ArB(OH)2
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Major Milestones in Homogeneous Gold Catalysis Alkynophilic π–activation toward nucleophiles
Investigating & harnessing carbenoid character
Asymmetric catalysis; counteranion control
Novel propargyl carboxylate reactivity
P−Au+
P−Au−Y*
P−Au+
P−Au+
*
X− X− Y−
mono-cationicspecies
Greater enantiocontrol
di-cationicspecies
Lesser enantiocontrol
coordinatingcounteranion
non-coordinatingcounteranion
Au
RNu-H Nu
HRElectrophile(π) activation
C-C migration
C-H insertion cyclopropanation
proton shift
[Au]
R HR
R R
O
OO[Au]
α-carbonylvinyl gold
E
R'R
ONu
R'R
E+
Nu[O]
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Gold-Catalyzed Organic Reactions Stephen, A.; Hashmi, K.; Chem. Rev. 2007, 7, 3180–3211
Gold-Catalyzed Organic TransformationsLi, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 8, 3239–3265
Chem Rev - Special Issue ʻ08Coinage Metals in Organic Synthesis
Alternative Synthetic Methods through New Developments in Catalysis by GoldArcadi, A. Chem. Rev. 2008, 8, 3266–3325
Gold-Catalyzed Cycloisomerizations of Enynes: A Mechanistic Perspective Jiménez-Núñez, E.; Echavarren, A. Chem. Rev. 2008, 8, 3326–3350
Ligand Effects in Homogeneous Au Catalysis Gorin, D.; Sherry, B.; Toste, F. D. Chem. Rev. 2008, 8, 3351–3378
and many more …
A Reactivity-Driven Approach to the Discovery & Development of Gold-Catalyzed Organic Reactions Shapiro, N. D.; Toste, F. D. Synlett., 2010, 5, 675-691
Gold-Catalyzed Reaction of Propargylic Carboxylates via an Initial 3,3-Rearrangement Wang, S.; Zhang, G.; Zhang, L. Synlett. 2010, 5, 692-706
Synlett ʻ10 Accounts
Recent Reviews on Homogeneous Gold Catalysis
Gold catalysis in total synthesisStephen, A.; Hashmi, K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766-1775
N-Heterocyclic carbenes in Au catalysis Marion, N.; Nolan, S. Chem. Soc. Rev. 2008, 37, 1776-1782
Chem Soc Rev - Special Issue ʻ08 GOLD: CHEMISTRY, MATERIALS & CATALYSIS