Recent Developments in Homogeneous Gold Catalysis

Recent Developments in Homogeneous Gold Catalysis

David A. Nagib

MacMillan Group

Literature Meeting

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. Nature2007, 446, 395-403

Pyykkö, P.; Desclaux, J. P. Acc. Chem. Res.1979, 12, 276-281 Filled

4f orbital

Filled

5d orbital

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 Ag Au

>

Modes of Reactivity in Homogeneous Gold Catalysis

Au Nu Au Nu E Nu _Au E Nu Au Nu E E

cation

derived products

cation cyclization

rearrangement

H Nu

carbenoid

derived products

C-H insertion

cyclopropanation

trans-addition

increased e

−

_{delocalization}

(expanded 5d orbital)

♦

Au backbonding

E

+

= alkene, ylide, etc.

♦

proto-deauration

E

+

= H

+

(Nu-

H

)

Lewis acid

derived products

ring expansion

cycloisomerization

increased

π

-acidity

(contracted 6s orbital)

♦

aprotic nucleophile

E

+

= alkene, alcohol, etc.

Lewis acid

derived products

heterofunctionalization

Modes of Reactivity in Homogeneous Gold Catalysis

Au Nu Au Nu E Nu _Au E Nu Au Nu E E

cation

derived products

cation cyclization

rearrangement

H Nu

carbenoid

derived products

C-H insertion

cyclopropanation

trans-addition

increased e

−

_{delocalization}

(expanded 5d orbital)

♦

Au backbonding

E

+

= alkene, ylide, etc.

♦

proto-deauration

E

+

= H

+

(Nu-

H

)

Lewis acid

derived products

ring expansion

cycloisomerization

increased

π

-acidity

(contracted 6s orbital)

♦

aprotic nucleophile

E

+

= alkene, alcohol, etc.

Lewis acid

derived products

heterofunctionalization

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.

Trost

ʼ

s Synthesis of Bryostatin

Trost, B.; Dong, G. Nature2008, 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

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

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 R TBSO H R O _R ( )_n H 5-exo-dig 6-exo-dig internal addition favored 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 R TBSO H internal-γ-alkyne R O _R ( )_n H X X X = Ar, I 5-endo-dig benzylic/halo addition favored O AuL X TBS terminal-δ-alkyne ( )_n R TBSO H R O _R ( )_n H 5-exo-dig 6-exo-dig internal addition favored O AuL TBS H2O H R O _R ( )_n • R ( )n R TBSO H H terminal-β-allene 5-endo-trig conformation governs addition • 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 R TBSO H internal-γ-alkyne R O _R ( )_n H X X X = Ar, I 5-endo-dig benzylic/halo addition favored O AuL X TBS R O t_BuO O Me H O 1. Organocat. 2. H+ 3. β-allene add'n 4. NIS 8 steps H O Me H O Me BocN 3 steps BnO N (+)-lycopladine A 8 steps (+)-fawcettimine 13 steps Me N O HO H H O 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 31_{P 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

Modes of Reactivity in Homogeneous Gold Catalysis

Au Nu Au Nu E Nu _Au E Nu Au Nu E E

cation

derived products

cation cyclization

rearrangement

H Nu

carbenoid

derived products

C-H insertion

cyclopropanation

trans-addition

increased e

−

_{delocalization}

(expanded 5d orbital)

♦ Au backbonding

E

+

= alkene, ylide, etc.

♦

proto-deauration

E

+

= H

+

(Nu-

H

)

Lewis acid

derived products

ring expansion

cycloisomerization

increased

π

-acidity

(contracted 6s orbital)

♦

aprotic nucleophile

E

+

= alkene, alcohol, etc.

Lewis acid

derived products

heterofunctionalization

Non-Canonical Reactivity

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

Modes of Reactivity in Homogeneous Gold Catalysis

Au Nu Au Nu E Nu _Au E Nu Au Nu E

Lewis acid

derived products

ring expansion

cycloisomerization

E

cation

derived products

cation cyclization

rearrangement

H Nu

Lewis acid

derived products

heterofunctionalization

heterocyclization

carbenoid

derived products

C-H insertion

cyclopropanation

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

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)AuSbF₆ CH₂Cl₂, r.t., 10 min 5-exo-dig Me E E E E 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 Me H LAu cation E E LAu cation H Me

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)AuSbF6 CH2Cl2, r.t., 5 min 5-exo-dig AuL R R R H R R R AuL R R R H 1,2-H shift 98% yield Bn OH TMS 5% (dppm)ReOCl₃ 5% NH4PF6, MeNO2, 65°C 1% LAuSbF₆ CH2Cl2, r.t. Bn Bn H propyl 79% yield propyl propyl

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)AuSbF6 CH2Cl2, r.t., 5 min 5-exo-dig AuL R R R H R R R AuL R R R H 1,2-H shift AuL carbenoid AuL AuL R' R" R' R" R' R" cation hybrid AuL R' R" R R _R R D D _D D R' R" R D  1,2-Disubstituted olefins underwent cycloisomerization stereospecifically

 Further mechanistic considerations

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 O E E O OH LAu E E R1 R2 R1 R2 OH O E E LAu O O E E R1 R2 O O E E R1 R2 if R2 = M e if R1 = Me R₁ = H R₂ = H R₁ = H R₂ = Me R₁ = Me R₂ = H if R₁ = Me _{if R} 2 ₌ M e 19% yield 11% yield - 80% yield 82% yield -cationic mechanism carbene mechanism AuPPh3 H O O AuPPh3 H 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 examples

82-99% yields 12 examples60-86% yields C-H insertion (n = 1,2) (n = 3,4) H H C-C migration H AuPPh3 O O Furstner's

non-carbene Toste/Goddardcarbene

AuL H 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

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] Nu LG+ gold carbene LG Nu -S [Au]+ O [Au]+ O S Ph [Au]+ _5-exo-dig [Au] O S Ph gold carbene O Ph SPh S O C-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 S Me Me S Me Me _{5% IPrAuCl} 5% AgSbF6 CH₂Cl₂, r.t. C-C σ-bond migration O ArS N2 O S Me 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

O O R' R [Au]+ O O R R' [Au]+ O O R' R

[Au]+ 5-exo-dig

1,2-acyloxy migration [Au] O O R _R' gold carbene 70% yield > 20:1 dr, 81% ee O O R R' Ph Ph L* O R' R O X 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 O O R' R EWG or H [Au]+ O O R R' [Au]+ O O R' R

[Au]+ 5-exo-dig

1,2-acyloxy migration [Au] O O R _R' [Au]+ gold carbene t_Bu [3,3]-rearrangement [Au]+ O O R' R O O

⋅

R O O R' [Au] O O R R' [Au] 6-endo-dig [Au] α-carbonyl vinyl 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

O E R' R O Nu R' R or [3,3]-rearrangement [Au]+ O O R' R O O

⋅

R O O R' [Au] O O R R' [Au] 6-endo-dig [Au] α-carbonyl vinyl gold 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 O Br Me butyl O I butyl or NBS or NIS 85% yield > 99:1 dr 94% yield> 20:1 dr [3,3]-rearrangement [Au]+ O O R' R O O

⋅

R O O R' [Au] O O R R' [Au] 6-endo-dig [Au] α-carbonyl vinyl gold 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 O Br Me butyl O I butyl or NBS or NIS 85% yield > 99:1 dr 94% yield> 20:1 dr OH H Me butyl [3,3]-rearrangement [Au]+ O Mo O R' R O

⋅

R O Mo O R' [Au] O Mo O R R' [Au] 6-endo-dig [Au] α-carbonyl vinyl gold - MoO2 + H₂O 1% 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]+ O O R' R O O

⋅

R O O R' [Au] O O R R' [Au] 6-endo-dig AuI α-carbonyl vinyl gold R R' O O 9 examples 56-78% yield + H₂O [O] O O AuIII O O AuIII O AuIII O O R R' R R' R R' R R' - AuI reductive elimination

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]+ O O R' R O O

⋅

R O O R' [Au] O O R R' [Au] 6-endo-dig AuI α-carbonyl vinyl gold R R' O Ar 15 examples 45-71% yield [O] O AuIII Ar R R' R R' - AuI reductive elimination O AuIII 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-cationic species Greater enantiocontrol di-cationic species Lesser enantiocontrol coordinating

counteranion non-coordinating_counteranion

Au R Nu-H Nu H R Electrophile (π) activation C-C migration C-H insertion cyclopropanation proton shift [Au] R H R R R O O O [Au] α-carbonyl vinyl gold E R' R O Nu R' R E+ Nu [O]

Gold-Catalyzed Organic Reactions

Stephen, A.; Hashmi, K.;

Chem. Rev. 2007, 7, 3180–3211

Gold-Catalyzed Organic Transformations


Li, Z.; Brouwer, C.; He, C.

Chem. Rev. 2008, 8, 3239–3265

Chem Rev - Special Issue ʻ08


Coinage Metals in Organic Synthesis

Alternative Synthetic Methods through New Developments

in Catalysis by Gold


Arcadi, 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 synthesis


Stephen, 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