gold-catalyzed formation of heterocycles – an enabling new...

TECHNOLOGIES

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Gold-catalyzed formation ofheterocycles – an enabling newtechnology for medicinal chemistryHong C. Shen1,*, Thomas H. Graham2

1Department of Medicinal Chemistry, Roche R&D Center (China) Ltd., Shanghai 201203, China2Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ 07065-0900, USA

Drug Discovery Today: Technologies Vol. 10, No. 1 2013

Editors-in-Chief

Kelvin Lam – Simplex Pharma Advisors, Inc., Arlington, MA, USA

Henk Timmerman – Vrije Universiteit, The Netherlands

New synthetic chemistry for medicinal chemistry

Gold-catalyzed transformations allow efficient access

to a wide scope of heterocyclic structures that serve as

building blocks and pharmacophores in medicinal

chemistry. Compared with other transition metal

and Lewis acid catalysis, gold catalysis presents

mechanistic divergence, excellent functional group tol-

erance and/or operational advantages. Emergent appli-

cations of gold catalysis have played a key role in the

synthesis of biologically active molecules including a

drug candidate.

Introduction

Heterocycles have been extensively utilized in medicinal

chemistry resulting in their incorporation into numerous

small molecule drugs. While the most straightforward strat-

egy to introduce heterocycles into drugs is to use commer-

cially available heterocyclic building blocks, it is common for

discovery and process chemists to construct heterocycles by

either traditional condensation approaches, or more

recently, transition metal catalysis [1].

Despite the use of gold and gold salts in heterogeneous

catalysis since the 1960s, [2] the era of homogeneous gold

catalysis did not start until the end of the 20th century [3].

Since then, numerous methods involving gold catalysis have

emerged to construct heterocycles in a novel, convenient and

selective fashion.

*Corresponding author.: H.C. Shen ([email protected])

1740-6749/$ � 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ddtec.2012

Section editor:Floris P.J.T. Rutjes – Institute for Molecules and Materials,Radboud University Nijmegen, Nijmegen, The Netherlands.

Advantages of gold catalysis

The advantages of gold catalysis can be viewed by comparison

to the traditional modes of activation including Lewis and

Brønsted acids as well as other transition metals (Table 1). In

contrast to the traditional modes of activation, the vast

majority of gold-catalyzed reactions rely on the selective

coordination to alkynes, alkenes or allenes as a consequence

of the exceptional p-acidity of gold catalysts [3b]. The affinity

for p-bonded systems makes gold similar to its periodic

neighbors, mercury and platinum; however, gold lacks the

toxicity of mercury and is less expensive than platinum [4].

Gold catalysts can also be viewed as a traceless halide by

mediating reactions that are traditionally mediated by the p-

acidity of electrophilic halides such as diatomic iodine [5].

Oxygen- and nitrogen-containing groups are less prone to

coordination with gold and, as a result, water and alcohols are

often well tolerated in gold catalysis [6,7]. Gold catalysts also

tolerate aerobic conditions because of the high oxidation

potential of converting Au(I) to Au(III). Other transition

metals and Lewis acids can be less selective toward p-nucleo-

philes and often require aprotic and anaerobic conditions.

Brønsted acids are tolerant of moisture, but functional group

compatibility can be a drawback. The compatibility with air

and moisture as well as diverse functional groups allows gold-

catalyzed transformations to efficiently access structures of

.10.014 e3

http://dx.doi.org/10.1016/j.ddtec.2012.10.014


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Drug Discovery Today: Technologies | New synthetic chemistry for medicinal chemistry Vol. 10, No. 1 2013

Table 1. A general comparison of gold catalysis with traditional modes of activationa

Gold Other transition metals Lewis acid Brønsted acid

Compatible with moisture/protic solvents U � � U

Compatible with oxygen U � U/� U

Functional group compatibility U U � U/�

Potential for tandem and multi-component catalysis U U U/� U

a Exceptions can be found in all categories.

immense diversity and complexity from much simpler start-

ing materials. Furthermore, distinct from classical carboca-

tions generated with Lewis and Brønsted acids, non-classical

carbocation/carbenoid intermediates often lead to well-con-

trolled chemo-, regio-, diastereo- and enantioselective trans-

formations. The unique non-classical carbocation/carbenoid

intermediates also allow for tandem catalysis and multi-

component reactions in a similar manner to other transition

metals such as platinum and palladium. However, gold does

not normally cycle between the Au(I) and Au(III) oxidation

states like other late transition metals for which oxidative

addition and reductive eliminations are common modes of

reactivity [8]. The lack of redox-cycling makes gold more like

traditional Lewis acids but with a distinct affinity for p-

bonded systems.

General modes of reactivity

The most common examples of heterocycle formation with

gold catalysis involve intramolecular cyclizations. The excep-

tionally selective p-acidity of gold catalysts defines the pre-

dominant reactivity of gold catalysts and, as a result, p-

donating groups such as alkynes, alkenes and allenes are

typical reactants. The complexation of the gold catalyst with

the reactant p-system activates the p-system toward attack by

a pendant nucleophile. The proposed mechanism involves

addition of the heteronucleophile in a trans configuration

from the complexed gold followed by a subsequent proto-

deauration that releases the gold catalyst (Scheme 1).

Depending on the nature of the substrates, both exo- and

endo-cyclizations and various ring sizes are possible. Nucleo-

philes are typically carbon, nitrogen, oxygen or sulfur.

In the cases where R2X is the nucleophile and X is a

divalent oxygen or sulfur, the formation of the trivalent X

cation often leads to a subsequent rearrangement (Scheme 2).

For example, allyl sulfide 1 cyclizes onto the ortho-alkyne and

then rearranges to afford the 3-allyl benzothiophene 3 [9].

The reaction presumably proceeds via the zwitterionic gold

species 2.

When X is sp2 hybridized, particularly in the cases of

ketones, aldehydes and imines, the addition of X to the

gold-activated p-bond forms a putative zwitterionic species,

that is, susceptible to intramolecular rearrangements or

additional bond-forming steps. (Scheme 3). For example,

e4 www.drugdiscoverytoday.com

endo-cyclization of cyclohexanol 4 affords the putative zwit-

terionic intermediate 5, which undergoes a 1,2-alkyl shift to

afford the spirocyclic furanone 6 in 95% yield. Alternatively,

cyclization of the structurally similar cyclohexenone 7

affords the oxonium 8, which traps exogenous methanol

to afford furan 9. The examples shown in Scheme 3 demon-

strate the power of gold catalysis to afford diverse molecular

architectures from structurally similar reactants [10].

The third reaction mode involves a nucleophile that also

bears a leaving group thus setting the stage to generate a

putative gold carbenoid (Scheme 4). For example, cyclization

of the aryl azide 10 with release of dinitrogen affords the gold

carbenoid intermediate 11. Protodeauration and tautomer-

ization then affords pyrrole 12. In a similar manner, exogen-

ous nucleophiles such as quinoline N-oxides and pyridine-N-

aminides can also be used to access gold carbenoids from

alkynes (Scheme 4). Zhang and coworkers demonstrated the

gold-catalyzed addition of quinoline N-oxide (13) to alkyne

14 to afford oxocarbenoid 15 [11]. Condensation with a

nitrile and subsequent cyclization afforded 2,5-disubstituted

oxazole 16. While many of the examples use the nitrile as

solvent, the authors note that only a 3-fold excess of the

nitrile is required for reasonable yields to be attained. Davies

and coworkers recently described a similar strategy to prepare

4-aminooxazoles (19) from ynamides (17) and pyridine-N-

aminides (18) [12]. The transformation is formally a gold-

catalyzed [3 + 2]-cycloaddition route to trisubstituted oxa-

zoles.

While often denoted and referred to as carbenoids, inter-

mediates can be represented as cationic organogold species

(20) or as gold carbenoids (21) (Scheme 5). However, the true

nature, either non-classical cationic or carbenoid, of organo-

gold intermediates has been the subject of numerous primary

research reports and reviews [3h,13]. In general, organogold

intermediates can be viewed as existing somewhere on the

continuum between non-classical cations and carbenoids

[14].

Selected examples of heterocycles generated with

gold catalysis

Despite the recent emergence, the scope of heterocycle for-

mation via gold catalysis has been rapidly expanded. Sum-

marized in Table 2 are selected examples highlighting the

Vol. 10, No. 1 2013 Drug Discovery Today: Technologies | New synthetic chemistry for medicinal chemistry

[AuL]X

XHa

b

aX

H

b

[AuL]

XXHa

b

aX

b

R R

R

[AuL]XXHa

b

aX

H

b

RR

R

N Ph

F

TsClNH

FF

Ph

Ts

Cl

AuCl3 (1 0 mol% )

Org. Lett. 2009,11, 2920

Org. Lett. 2006, 8, 325

O

Me

C5H11 C5H11

C4H9C4H9

PPh3AuCl (1 mol% )

TFA (10 mo l% )

aceton e

90%OMe

MeCN, rt, 15 min

69%

NH

Ph Ph

PMPH N

O

N

Ph Ph

PMPHN

O

MeN N

AuCl

i-Pr

i-Pr (5 mol%)

i-Pr

i-Pr

AgOTf (5 mol %)dio xane, rt, 15 h

100%

Org. Lett. 2006, 8, 5303

HHR

R H

R H

Drug Discovery Today: Technologies

Scheme 1.

diversity of structures that are readily available via gold

catalysis. Almost all common saturated and unsaturated het-

erocycles are included, and some of the examples show that

densely decorated heterocycles can be efficiently assembled.

It is conceivable that certain novel heterocyclic core struc-

tures may serve as a key pharmacophore/scaffold for drug-like

molecules.

Examples of gold catalysis for preparing targets with

attractive biological activities

As a well-known class of antibiotics and covalent enzyme

modulators, b-lactams are attractive targets in medicinal

chemistry. They are in general prone to decomposition in

the presence of strong nucleophiles and bases. As such,

organic reactions involving b-lactams should be carefully

controlled. Gold catalysis is compatible with the b-lactam

functionality due to the mild reaction conditions under

neutral pH. Both allene and alkyne cyclizations can provide

a variety of b-lactam scaffolds [15]. For example, starting with

the allenyl substrate 23, a convenient 5-endo-trig cyclization

afforded fused-bicyclic 24 in 65–85% yields (Scheme 6) [16].

The transformation was highly regiospecific toward 5-endo-

trig cyclization. Interestingly, structurally similar substrates

underwent other modes of cyclization onto the allene to

furnish spiro-, or fused-bicyclic, or bis-heterocyclic scaffolds

[17]. As such, gold catalysis became a powerful method to

generate numerous structural variations containing the b-

lactam motif, which is precisely what medicinal chemists are

www.drugdiscoverytoday.com e5


O+

OH

Ph

AuCl2

AuCl2

OPh

OMe

MeOH

O+ Ph

OOH

Ph O

O

Ph

CH2Cl 2

MeOH, CH2Cl 2

[AuL]+

+E

[AuL]

O Ph

AuCl3 (5 mol%)

AuCl3 (1mol%)

95%

Angew.Chem.Int.Ed. 2006, 45, 5878

NuNu

Heterocycles

88%

J.Am.Chem.Soc. 2004, 126, 11164

64

5

7

8

9

Cl-

Cl-


Scheme 3.

R2XR2X

[AuL][AuL]

rearrangementHeterocycles

S

Ph

SPh

SPh

AuCl-

AuCl (2 mol%)

tolue ne, 25 °C93%

Ange w. Chem. Int. Ed. 2006, 45, 4473

31

2


Scheme 2.



AuLNu

AuL

NuLGLG

Heterocycles

N3

n-Bu

CH2Cl 2, 35 °C, 30 min82%

J.Am.Chem.Soc. 2005, 127,11260

J.Am.Chem.Soc. 2011, 133,8482

Angew.Chem.Int.Ed. 2011, 50 ,8931

N

AuLAuL+

Ph

CH3CN, 60 °C, 3 h91%

N

OPh MeN+

Me O-

AuL+

Ph

O

AuL+Ph

O

AuL

N+MeCH3CN

NPh N

O

AuL+

Ms

N+NH

Ph

O

NPh

Ms

N+N Ph

O

AuL

NPh

MsN O

Ph

AuL+

N

Ph

PhMs

Ph

Ph Ph

toluene, 90 °C, 4 h96%

Ph

N AuO

O

Cl Cl

(5 mol%)

10

11

12

14

13

15

16

17 18 19

n-Bu

n-Bu n-Bun-Bu n-Bu

NH

n-Bun-Bu

(dppm)Au2Cl2 (2.5 mol%)AgSbF6 (5 mol%)

Ph3PAuNTf2 (5 mol%)

N2+

N

AuL+H


Scheme 4.

non-classicalcation

20

AuL AuL

C5H11 C5H11C5H11

••

N NN

+

+

21 22carbenoid carbene


Scheme 5.



Table 2. Selected examples of heterocycles derived from gold-catalyzed transformations

NO

Ph

O

Ph

NO

isoxazole

J. Am. Chem. Soc.1993, 115, 4401

ON Ph

i-Pr

Org. Lett.2011, 13, 2746

NN

R3

R1

F

R2

NN

pyrazole

Org. Lett.2011, 13, 4220

N

O

N

O R2R1

J. Am. Chem. Soc. 2011, 133, 8482Chem. Eur. J. 2010, 16, 956

Org. Lett. 2004, 6, 4391

HN

NPh

Ph

Angew. Chem. Int. Ed.2011, 50, 5560

NH

NH

Ar2

Ar1


N

Ph

n-Pr

Ot-Bu

Org. Lett.2006, 8, 289

N

O

CO2Me

N

n-PrH

O

NN

Ph


NNR1

MeR2

O

R3

Tetrahedron: Asymmetry2001, 12, 2715

N Ar/HAr

F

SO2Ph

Org. Lett.2009, 11, 2920

Beilstein J. Org. Chem.2011, 7, 1379

N

N

F

Org. Lett.2011, 13, 3458

Tetrahedron2009, 65, 1809

N R2

R3H

R1

O

N

O R2R1


N

NR

Heterocycles1987, 25, 297

J. Am. Chem. Soc.2011, 133, 3517

NH

i-Pr

Me

OBnN

O

Me

OTBS

H

H Me

Beilstein J. Org. Chem.2011, 7, 622

Org. Lett.2004, 6, 4121

NH

Science2007, 317, 496

N

Ph

ArMe

Me

H H

J. Am. Chem. Soc.2011, 133, 5500

N

Me

Ts

MeH

J. Org. Chem.2010, 75, 4542

N

Ar

O

J. Org. Chem.2010, 75, 6031

N

i-Pr

Me

OPhHNOrg. Lett.

2006, 8, 5303

N Ph

MeO2C

Me

MeO

O

NMe

Me

Me

Me

J. Am. Chem. Soc.2006, 128, 1798

N R2

R1Me

Me

J. Am. Chem. Soc.2007, 129, 2452

NPh

Org. Lett.2006, 8, 4043

NMe O

Bn

EtO

Me

J. Am. Chem. Soc.2007, 129, 5828

( )n

X=N,On=1,2

NX

BOC

Me

Me( )n


NO O

Pht-Bu

Org. Lett.2010, 12, 2453

AN

SiMe3

OTBS

NSiMe3

OTBSS

J. Am. Chem. Soc. 2006, 128, 12050Org. Lett. 2010, 12, 5538

oxazole

indole

pyrrole

dihydropyrrole

N

O

Org. Biomol. Chem.2011, 9, 4017

NHBOC

RBr

O

J. Org. Chem.2010, 75, 3274

pyrrolidine

NH

Ph

J. Am. Chem. Soc.2005, 127, 11260

TsTs

Ts

TsTsSO2Mes

Ts Ts Ts

A= C,N

NMs

R3

( )n

A = N,O

A N

MeO

N

NHPhO

Org. Lett.2010, 12, 1900



N

NBn

NO

Org. Lett.2011, 13, 3458

J. Org. Chem.2003, 68, 6959

N R1

R2

Org. Lett.2008, 10, 2629

N R1

R3 O

R2

N

OEtO

H

MePh

OEt

Org. Lett.2007, 9, 3191

N

O

NBn O

N Ts

Me

Tetrahedron2010, 66, 1496

O

N NH

O

MeMe

J. Am. Chem. Soc.2007, 129, 12070

N

Ph

N

CO2Et

Ph

N

N

CO2Et

Org. Lett.2011, 13, 4184

N

OMe

MeO

MeO

Chem. Eur. J.2005, 11, 3155

N

BzO Ph

Et

i-Bu

HNCBZ

Ph

OMe

J. Am. Chem. Soc.2009, 131, 14660

NMe

O

n-Pr

OH

J. Org. Chem.2007, 72, 7359

Nn-Bu

OBz

BOC

Org. Biomol. Chem.2010, 8, 2697

MeN

Org. Lett.2011, 13, 1334

NH

n-Hept

O

Me

Chem. Eur. J.2011, 17, 1433

N

OBr

Synlett2007, 1759

N NH

PhTMS

O

MeOOrg. Lett.

2011, 13, 4228

N

NH Me

Ph

ACS Comb. Sci.2011, 13, 209

NH

N

O

Ph

Org. Lett.2010, 12, 1900

N

O

R2R1

BOC

Org. Lett.2011, 13, 4371

NBOC

OTBSOTBS

Tetrahedron Lett.2011, 52, 2969

O

HN

Synthesis2011, 127

J. Am. Chem. Soc.2011, 133, 15248

J. Org. Chem.2012, 77, 801

pyridine

piperidine

2H/4H-pyridine

morpholine Ts

Ts

Ts

Ts

Ts

Ns Bn

R



O

O

O

OMe

CO2Et

n-BuMe

Me

Org. Lett.2006, 8, 4485

J. Org. Chem.2007, 72, 7359

O

OBr


OPhPh

Org. Lett.2006, 8, 1953

O O

Pht-Bu

J. Org. Chem.2004, 69, 3669

OR5 R1

R4 R2R3

Org. Lett.2010, 12, 3468

OPh

O

Me

Chem. Eur. J.2011, 17, 1433

OO ( )n

O OR O O

CO2MePh

( )n


J. Am. Chem. Soc.2006, 128, 3112

OOMe

Ph Ph

F

J. Am. Chem. Soc.2006, 128, 11332

Me

Me OH

O

Science2007, 317, 496

OBn O


O

MeO2C

MeMe

O

Org. Lett.2007, 9, 2235

O

O

R1R2

pyran

lactone

Org. Lett.2011, 13, 2834

OH

O O C8H17

J. Am. Chem. Soc.2005, 127, 10500

O Me

OMe

J. Org. Chem.2010, 75, 6300

O

O

EtO

R OPh

BnO

OO

(1 : 3.7)

O

O+

Org. Lett.2006, 8, 4489

Tetrahedron Lett.2007, 48, 1439 Org. Lett. 2006, 8, 4907

OH

Science2007, 317, 496

OMe CO2Et

t-Bu HMe

Org. Lett.2001, 3, 2537

OPh

n-Pent

Org. Lett.2010, 12, 4724

furan

OMe Ph

NOPhPh

Ph


tetrahydrofuran

OPh

Me


O Me

O

Me


Br



N

O

N

OMe

J. Org. Chem. 2011, 76, 1239

SS

R2

R1

Angew. Chem. Int. Ed. 2006, 45, 4473

N

OO N O

O

Bn

J. Org. Chem. 2006, 71, 5023

N O

O

Bn

MeMe

ISynlett

2006, 2727

NO

O

Synlett2006, 3309

( )n

Si-Pr

Me

OMe

Angew. Chem. Int. Ed. 2006, 45, 1897

S

R O

MeO

J. Am. Chem. Soc. 2007, 129, 4160

X( )n

N

O

O

OEt

J. Am. Chem. Soc. 2011, 133, 1769

NMe

O

Org. Lett. 2009, 11, 1225

NH

N

MeO2C DNBS

NH

N

CO2MeDNBS

Angew. Chem. Int. Ed. 2006, 45, 1105

OMe

Ph

Me

Angew. Chem. Int. Ed. 2011, 50, 9076

thiophenethiopyran

medium rings

oxazolidinone

NBzO

MePh

Me

Me

Ph

J. Am. Chem. Soc. 2008, 130, 9244

N MeMeTs

Beilstein J. Org. Chem. 2011, 7, 951

N

NMe

O

Me

S

Adv. Synth. Catal. 2012, 354, 1273

N

O

OTBS

TBSChem. Eur. J. 2006, 12, 5376

Bs

Ts

looking for when they build diverse scaffolds to explore

structure–activity relationships.

Englerins A (27) is a natural product that exhibits 1–2

orders of magnitude higher potency than taxol against cer-

tain cancer cell lines. The Echavarren group took advantage

of the gold-catalyzed [2 + 2 + 2] alkyne/alkene/carbonyl

cycloaddition of 1,6-enyne 25 to form two C–C and one

C–O bonds in a domino fashion (Scheme 7) [18]. Remarkably,

the propargylic stereogenic center imposes excellent control

of stereochemistry leading to virtually a single diastereomer

(26) in 58% yield. It should be noted that the allylic alcohol

in the substrate did not need to be protected, and this process

can be routinely performed at 0.5–1 g scale. The facile stereo-

selective formation of the bicyclic scaffold from a structurally

less complex linear substrate highlighted the utility of this

powerful gold-catalyzed transformation.

NHO

Me

OTBS

H

HR

•CH2Cl 2 N

O

Me

OTBS

H

H R

2423

AuCl3(5 mol%)

65-85%


Scheme 6.

Indole alkaloid flinderoles B and C (29) were identified as

antimalarial natural products. The Toste group envisioned

the use of a gold-catalyzed allene hydroarylation to assemble

the tricyclic core of the natural product (28) (Scheme 8) [19].

The choice of ligand was crucial to the success of the reaction

– while triphenylphosphinegold (I) failed to induce the cycli-

zation, the more electropositive N-heterocyclic carbene gold

afforded the desired tricyclic intermediate as a single diaster-

eomer in excellent yield.

GlaxoSmithKline developed a selective 5-HT4 receptor

agonist (34) as a potential treatment for disorders of the

gastrointestinal tract (Scheme 9). The synthesis relied on a

key dihydrobenzopyran intermediate (31). The initial synth-

esis involved accessing 31 by way of a thermal Claisen

rearrangement; however, significant investments were made

to control the purity and safety issues of this route including

attempts to develop a continuous flow reaction [20]. Addi-

tional studies explored the use of the transition metal-cata-

lyzed aromatic Claisen rearrangement [21]. Platinum, silver

and gold salts were explored. Silver afforded a low mass

balance due to the formation of by-products that were also

observed in the thermal Claisen rearrangement. Platinum

afforded improved results, but a major portion of the mass

balance was the des-propargyl phenol 32 and a minor by-

product was the ketone 33, probably a consequence of adven-

titious water. Gold catalysts, however, afforded greatly

improved yields of 31 with minimal formation of 32 and



H OHMe

MeTESO

H

AuL

O Me

+

MeTESO

H

O

MeOH

AuLMe

Me+

Me OTES Me

[AuL]+ –[AuL]+

OH O

Me

Me

MeTESO

H

O

Me OH

Me

Me

OMe

H

O

MeOH

MeMe

Ph

H

O[IPrAuNCPh]SbF6(3 mol%)

CH2Cl2, rt, 5 h58%

Englerin A (27)

2625


Scheme 7.

N

OTBDPS

MeO2C MeO2C

Me

Me

• N

Me

Me

OTBDPSNH

NMe2

N

Me

NMe2

Me MeIPrAuCl (5 mol%)AgSbF6 (5 mol%)

1,2-dichloroe thane45 ºC88%

Flinderole B and C (29)

28


Scheme 8.

O

NH

O OMe

O

R

O

NH

O OMe

O

R

O

NH

O OMe

O

R

O

OH

NH

O OMe

O

R

30, R= (C H3)3C31 (8 0%) 3332

O

NH2

Br

OHN

N

O

5-HT4 recepto r agon ist (34 )

(Ph3P)AuNT f2 (0. 1 mol%)

toluene, 85 º C


Scheme 9.



O

t-BuOt-BuO2CMe

Me Me

N

S

PAu

Au

•2 TFA

P = PPh2

PPP

NH

Me

NN

S

CO2Me

CO2Me

hepatitis Cantiviralagents

Et3N, toluene0 ˚C, 3 d92% yield99% ee


Scheme 10.

33. With only 0.1 mol% (Ph3P)AuNTf2 at 858C the desired

product 31 was isolated in 80% yield with the by-product

formation held at under 3%. The authors note that the low

catalyst loading and the ease of synthesis made the gold-

catalyzed route superior to the thermal route when total cost

and operational convenience were considered.

The Najera group demonstrated the synthesis of hepatitis C

antiviral agents with a gold-catalyzed 1,3-dipolar cycloaddi-

tion of azomethine ylides with electron deficient olefins

(Scheme 10) [22]. A chiral BINAP-gold(I) trifluoroacetate

complex mediated the 1,3-dipolar cycloaddition between t-

butyl acrylate and an azomethine ylide at ambient tempera-

ture and afforded the cycloaddition product in greater than

92% yield and 99% enantiomeric excess. The authors suggest

that the trifluoroacetate counterion acts as a Brønsted base

while the gold complex acts as a Lewis acid. The transforma-

tion is also feasible on more sterically congested substrates

[23].

Conclusions and prospects

Heterocycle-containing molecules constitute especially

important targets in the pharmaceutical industry. Homoge-

neous gold catalysis represents a new frontier to access a wide

range of heterocycles. These reactions are based upon the

activation of alkynes, allenes and sometimes alkenes by the

gold species, or cycloisomerizations with tethered heteroa-

toms. The gold-catalyzed transformations are convenient,

and often accomplished under remarkably mild conditions.

In addition to excellent control of chemo-, regio- and dia-

stereoselectivity in many reactions, highly enantioselective

gold catalysis has also emerged. Further developments in the

areas of catalytic multi-component or tandem reactions [24],

oxidative coupling [25] and cycloaddition [26] reactions will

provide additional methods for the rapid construction of

complex molecules from simple and commercially available

feedstocks. Finally, the broad substrate scope and diverse

product scaffolds that are obtained from gold-catalyzed reac-

tions will undoubtedly increase the impact of these transfor-

mations on medicinal chemistry. Numerous applications of

gold catalysis in the synthesis of biologically active com-

pounds have validated the emerging utility of these synthetic

methods.

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