TECHNOLOGIES
DRUG DISCOVERY
TODAY
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
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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
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Drug Discovery Today: Technologies | New synthetic chemistry for medicinal chemistry Vol. 10, No. 1 2013
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-
Drug Discovery Today: Technologies
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
Drug Discovery Today: Technologies
Scheme 2.
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Vol. 10, No. 1 2013 Drug Discovery Today: Technologies | New synthetic chemistry for medicinal chemistry
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
Drug Discovery Today: Technologies
Scheme 4.
non-classicalcation
20
AuL AuL
C5H11 C5H11C5H11
••
N NN
+
+
21 22carbenoid carbene
Drug Discovery Today: Technologies
Scheme 5.
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Drug Discovery Today: Technologies | New synthetic chemistry for medicinal chemistry Vol. 10, No. 1 2013
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
Angew. Chem. Int. Ed.2011, 50, 8358
N
Ph
n-Pr
Ot-Bu
Org. Lett.2006, 8, 289
N
O
CO2Me
N
n-PrH
O
NN
Ph
Angew. Chem. Int. Ed.2011, 50, 4450
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
Angew. Chem. Int. Ed.2011, 50, 8931
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
Angew. Chem. Int. Ed.2010, 49, 598
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
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Vol. 10, No. 1 2013 Drug Discovery Today: Technologies | New synthetic chemistry for medicinal chemistry
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
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Drug Discovery Today: Technologies | New synthetic chemistry for medicinal chemistry Vol. 10, No. 1 2013
O
O
O
OMe
CO2Et
n-BuMe
Me
Org. Lett.2006, 8, 4485
J. Org. Chem.2007, 72, 7359
O
OBr
Angew. Chem. Int. Ed.2007, 46, 1117
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
Tetrahedron Lett.2006, 47, 6273
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
Tetrahedron Lett.2005, 46, 7431
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
Angew. Chem. Int. Ed.2010, 49, 6669
tetrahydrofuran
OPh
Me
Angew. Chem. Int. Ed.2011, 50, 5762
O Me
O
Me
Angew. Chem. Int. Ed.2000, 39, 2285
Br
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Vol. 10, No. 1 2013 Drug Discovery Today: Technologies | New synthetic chemistry for medicinal chemistry
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%
Drug Discovery Today: Technologies
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
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Drug Discovery Today: Technologies | New synthetic chemistry for medicinal chemistry Vol. 10, No. 1 2013
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
Drug Discovery Today: Technologies
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
Drug Discovery Today: Technologies
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
Drug Discovery Today: Technologies
Scheme 9.
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Vol. 10, No. 1 2013 Drug Discovery Today: Technologies | New synthetic chemistry for medicinal chemistry
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
Drug Discovery Today: Technologies
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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