Recent Developments in Homogeneous Gold Catalysis

Recent Developments in Homogeneous Gold Catalysis David A. Nagib

MacMillan Group Literature Meeting

03.17.2010

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

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

>

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.


heterofunctionalizationheterocyclization

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

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

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

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

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

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

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

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

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)

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


Au

Nu

Au

Nu E

Nu Au

E

Nu

Au

Nu E

E



H

Nu



trans-addition










Non-Canonical Reactivity

Compared with nucleophilic activation provided by canonical metal catalysis, gold offers orthogonal electrophilic activation

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


Au

Nu

Au

Nu E

Nu Au

E

Nu

Au

Nu E



E



H

Nu





trans-addition






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

Enyne Cycloisomerizations Revisited


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


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

Enyne Cycloisomerizations Revisited


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


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 …

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

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

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

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

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]

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

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�'

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]


R R�'

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]


R R�'

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]


- MoO2

+ H2O1% MoO2

R R'

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


R R'

OO

9 examples56-78% yield

+ H2O

[O]

OOAuIII

OO

AuIII

OAuIII

OOR R'

R R' R R'R R'

- AuI

reductiveelimination

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


R R'

OAr

15 examples45-71% yield

[O]

OAuIII

Ar

R R'R R'

- AuI

reductiveelimination

OAuIII

R R'

ArB(OH)2

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]


E

R'R

ONu

R'R

E+

Nu[O]

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

Recent Developments in Homogeneous Gold Catalysis

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