Synthesis of highly substituted γ-butyrolactones by a gold-catalyzed cascade reaction of benzyl esters

Article abstract of DOI:10.1002/chem.201402524

Easily accessible benzylic esters of 3-butynoic acids in a gold-catalyzed cyclization/rearrangement cascade reaction provided 3-propargyl γ-butyrolactones with the alkene and the carbonyl group not being conjugated. Crossover experiments showed that the formation of the new C-C bond is an intermolecular process. Initially propargylic-benzylic esters were used, but alkyl-substituted benzylic esters worked equally well. In the case of the propargylic- benzylic products, a simple treatment of the products with aluminum oxide initiated a twofold tautomerization to the allenyl-substituted g-butyrolactones with conjugation of the carbonyl group, the olefin, and the allene. The synthetic sequence can be conducted stepwise or as a one-pot cascade reaction with similar yields. Even in the presence of the gold catalyst the new allene remains intact.

Full text of DOI:10.1002/chem.201402524

DOI: 10.1002/chem.201402524
Full Paper
&
Synthetic Methods |Hot Paper|
Synthesis of Highly Substituted g-Butyrolactones by a Gold-
Catalyzed Cascade Reaction of Benzyl Esters
Maria Camila Blanco Jaimes,[a] Alexander Ahrens,[a] Daniel Pflꢀsterer,[a] Matthias Rudolph,[a]
and A. Stephen K. Hashmi*[a, b]
Abstract: Easily accessible benzylic esters of 3-butynoic
acids in a gold-catalyzed cyclization/rearrangement cascade
reaction provided 3-propargyl g-butyrolactones with the
alkene and the carbonyl group not being conjugated. Cross-
benzylic products, a simple treatment of the products with
aluminum oxide initiated a twofold tautomerization to the
allenyl-substituted g-butyrolactones with conjugation of the
carbonyl group, the olefin, and the allene. The synthetic se-
over experiments showed that the formation of the new CÀ quence can be conducted stepwise or as a one-pot cascade
C bond is an intermolecular process. Initially propargylic–
benzylic esters were used, but alkyl-substituted benzylic
esters worked equally well. In the case of the propargylic–
reaction with similar yields. Even in the presence of the gold
catalyst the new allene remains intact.
Introduction
Gold has emerged as a powerful tool in the field of organic
chemistry, becoming one of the main areas of catalysis re-
search.[1] The last 14 years have witnessed an increasing
number of publications illustrating the great potential of gold
catalysts in the synthesis of complex organic molecules. Most
of the reactions are highly selective, atom economic, and can
be performed under mild conditions.[1]
g-Butyrolactones are very common structural units in many
biologically active compounds and natural products.[2] Figure 1
depicts some representative molecules containing a g-butyro-
lactone substructure, which possess cytotoxic, antibiotic, and
antimicrobial activities.[2]
Figure 1. Bioactive molecules containing a butyrolactone core.
Different strategies have been reported for the synthesis of
g-butyrolactones.[3] including metathesis[4] and organocataly-
sis,[5] as well as, palladium,[6] molybdenum,[7] ruthenium,[8] rho-
dium,[9] and gold catalysis.[10] Among the examples of gold-cat-
alyzed syntheses of g-butyrolactone scaffolds, the reports of
Hammond and co-workers,[10a] Gouverneur and co-workers,[10b]
and Blum and co-workers[10c] are of particular interest for this
investigation.
Hammond and coworkers reported on the stoichiometric re-
action of allenoate 1 with cationic gold complexes. Stable vinyl
gold(I) complexes 2 could be successfully isolated, revealing
their role as intermediates in further cascade reactions. In par-
ticular, the trapping of these species with electrophiles such as
iodine, which furnished iodo-substituted butenolides
3
(Scheme 1a) was demonstrated.[10a] Gouverneur and coworkers
used a similar approach for the formation of vinyl gold com-
plexes starting from allenoate 1. These authors were the first
to describe gold-catalyzed cyclization followed by an oxidative
cross-coupling process with alkynes promoted by Selectfluor
as external oxidant[10b] (Scheme 1b). Blum and coworkers also
used organogold(I) complexes 2 as key intermediates for their
investigations on the formation of butenolides 5. These au-
thors used allenoates 1 bearing an allylic moiety as cationic
leaving group. To induce deallylation, palladium complexes
were used for the formation of p-allyl Pd complex 6. Subse-
quent transmetalation between gold complex 2 and Pd com-
[a] M. C. Blanco Jaimes, A. Ahrens, D. Pflꢀsterer, Dr. M. Rudolph,
Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)711-685-4205
E-mail: hashmi@hashmi.de
[b] Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University
Jeddah 21589 (Saudi Arabia)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402524.
Chem. Eur. J. 2014, 20, 1 – 8
1
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
num oxide (Al2O3), a different product was observed. This
product corresponded to allene 11, the product of an isomeri-
zation reaction promoted by the basic sites of Al2O3.[13]
The internal double bond of 10 was proven by the absence
1
of vinylic protons in the H NMR spectrum, and the absence of
internal alkyne was proven by signals at d=80 and 77 ppm in
the 13C NMR spectrum. The propargylic–allylic proton had a typ-
1
ical signal at d=4.55 ppm in the H NMR spectrum. This signal
changed significantly after the rearrangement to 11; a vinylic
proton at approximately d=5.65 ppm indicated the presence
of a trisubstituted double bond and the typical allene signal at
d=208 ppm was visible in the 13C NMR spectrum.
This preliminary result indicated the potential of this meth-
odology for the synthesis of diverse highly substituted lactones
10 and 11, bearing an alkyne or allene moiety, which could be
further functionalized. It also motivated us to study the reac-
tion mechanism and to investigate the scope and limitations
of this transformation in detail.
Scheme 1. Transformations of aurated butyrolactone intermediate 2. dba=-
dibenzylideneacetone.
plex 6, followed by CÀC bond formation by reductive elimina-
tion afforded butenolides 5 (Scheme 1c).[10c]
Herein, we present an alternative pathway towards g-butyro-
lactones by using alkynes as precursors and showing a subse-
quent twofold tautomerization to allenyl-substituted g-butyro-
lactones.
The first stage of this investigation corresponds to the syn-
thesis of substituted propargylic esters 16. These compounds
were obtained in moderate-to-high yields (53–94%) by means
of a three-step synthetic procedure starting from readily avail-
able primary alcohols 12 and aldehydes 13. Primary alcohols
12 were submitted to Jones oxidation conditions, leading to
carboxylic acids 14 in moderate yields (64–75%), whereas alde-
hydes 13 gave rise to secondary alcohols 15 in moderate-to-
high yields (55–98%) after nucleophilic addition of suitable
Grignard compounds. Finally, a Steglich esterification[14] be-
tween the previously obtained carboxylic acids 14 and secon-
dary alcohols 15 led to propargylic esters 16 in moderate-to-
high yield (Scheme 3).
Results and Discussion
Initially, butyrolactone 10 was unexpectedly obtained as the
product of a cascade reaction starting from substituted propar-
gylic ester 7. The expectation had been that this propargylic
ester, bearing a tethered alkyne, would undergo a carbene-
transfer cascade reaction related to the recent reports on gold
carbene transfers over pendant alkynes (Scheme 2).[11] Curious-
ly, with propargylic ester 7 no such migration was observed.
Butyrolactone 10 was obtained as the only product. Instead of
the expected 5-exo-dig cyclization at the terminal alkyne (to in-
itiate the carbenoid pathway), a 5-endo-dig cyclization at the
non-terminal alkyne had taken place, followed by intermolecu-
lar CÀC coupling between vinyl gold species 8 and carbocation
9. This process is proposed to take place in a similar fashion to
that reported by Blum and coworkers;[10c] but in the case re-
ported herein, no palladium is necessary (Scheme 2).[12] Fur-
thermore, when the reaction product was treated with alumi-
Scheme 3. Synthesis of propargylic esters 16. DCC=N,N-dicyclohexylcarbo-
diimide; DMAP=4-dimethylaminopyridine.
An initial screening of reaction
conditions was performed with
substrate 16a. The precatalysts,
silver salts, and solvents were
screened to find the best condi-
tions to promote the formation
of lactones 17 in high yields.
Firstly, different ligands at the
gold catalysts were screened,
AgSbF6 was used as the counter
ion and dichloromethane as sol-
vent (Table 1).
Scheme 2. Gold-catalyzed cascade reaction of propargylic ester 7.
&
&
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
2
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
Table 1. Screening of gold precatalysts for substrate 16a.[a]
Table 2. Screening of silver salts and solvents.[b]
[Ag]
Solvent
t
[h]
Conversion
[%][b]
Yield [%][b]
17a:18
[Au][b]
t
[h]
Conversion
[%][e]
Yield [%][e]
17a:18
1
2
3
4
5
6
7
AgSbF6
AgNTf2
AgOTf
AgSbF6
AgSbF6
AgSbF6
AgSbF6
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
acetone
toluene
benzene
3
4
4
4
4
4
4
100
74
86
64
76
99
97
91:4
62:4
65:7
1
2
3
4
5
Ph3PAuCl
SPHOSAuCl
XPHOSAuCl
IPrAuCl
4
4
4
3
12
57
80
100
100
77
40:4
58:8
76:3
91:4
70:5
45:7
45:26
68:18
29:64
IPrAuCl[c]
[a] The reactions were carried out in an NMR tube using 0.1 mol of the
6
4
100
68:11
substrate and 500 mL of the corresponding deuterated solvent. [b] Deter-
1
mined by H NMR spectroscopy using dioxane as an internal standard.
7
8
9
phosphiteAuCl
–
p-TsOH
4
5
5
100
50
66
81:2
0:42
0:56
[d]
conversion was only observed with AgSbF6 (entry 1). Although
AgNTf2 (entry 2) and AgOTf (entry 3) achieved good yields (up
to 65%), AgSbF6 was the best counterion for this transforma-
tion, providing 91% yield. For the screening of solvents the
combination IPrAuCl/AgSbF6 was used.
[a] The reactions were carried out in a NMR tube by using 0.1 mol of the
substrate and 500 mL of the corresponding deuterated solvent.
[b] SPHOS=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl; XPHOS=
2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl;
IPr=1,3-bis(diiso-
propylphenyl)imidazol-2-ylidene; Phosphite=tris(2,4-di-tert-butylphenyl)-
phosphite; Ts=Tosyl. [c] 2 mol% of gold and silver were used. [d] Only
AgSbF6 was used. [e] Determined by 1H NMR spectroscopy using dioxane
as an internal standard.
In chloroform, only 64% conversion and 45% yield was
reached after 4 h (entry 4). By the same manner, although tolu-
ene and benzene achieved almost full conversion, yields of
only 68 and 29%, respectively, were detected (entries 6 and 7).
Therefore, the optimized conditions for the transformation
of propargylic esters 16 into highly substituted lactones 17 by
5-endo-dig cyclization/CÀC coupling are 3 mol% IPrAuCl/
AgSbF6 in dichloromethane at room temperature.
Triphenylphosphine gold chloride showed only moderate
conversion and yield for the formation of lactone 17a (Table 1,
entry 1). A change in the electronic properties of the ligand
showed improvements in the conversion and yield of the reac-
tion. That is, Buchwald-type ligands SPHOS and XPHOS ach-
ieved high conversions and yields up to 76% (entries 2 and 3).
Pleasingly, carbene-type ligand IPrAuCl achieved full conver-
sion and 91% yield in only three hours at room temperature
(entry 4). Based on this result, it was decided to decrease the
catalyst loading to 2 mol%. Unfortunately, only 77% conver-
sion and 70% yield could be reached after 12 h at room tem-
perature (entry 5). NAC–gold chloride (NAC=nitrogen acyclic
carbene) 19 also showed full conversion after 4 h, achieving
68% yield (entry 6). Similar results were observed with phos-
phite–gold chloride, reaching full conversion and 81% yield
(entry 7). Nevertheless, among the catalysts screened, IPrAuCl
provided the best yield in the shortest reaction time. Finally,
control experiments without gold catalysts were carried out. In
the presence of only silver salt, no formation of the expected
lactone 17a was observed; instead, 42% yield of compound
18 was formed (entry 8). This product is a result of the proto-
deauration of the vinyl gold(I) intermediate that participates in
the reaction. A similar result was obtained with p-toluenesul-
fonic acid (entry 9). These results indicate that the cascade cyc-
lization/CÀC coupling is only promoted by gold catalysts.
With the best ligand in hand, different counter ions and sol-
vents were screened (Table 2). Of the silver salts employed, full
Under the optimized conditions the scope of the gold-cata-
lyzed reaction was next investigated. Table 3 summarizes the
results obtained with various propargylic esters 16. In most
cases, lactones 17 could be obtained in moderate-to-high
yields. To understand the factors that control the gold-cata-
lyzed reaction, different functionalities at the three variable po-
sitions were investigated.
Initial variations at the acetylenic position (R1) of ester 16
showed no remarkable differences in terms of reaction yields.
Lactones 17a, 17b, and 17c were successfully obtained in
high yields (Table 3, entries 1–3). However, the reaction exhibits
significant changes in the reaction time. Thus, when a phenyl
moiety was used, the reaction time was increased up to 12 h
(entry 3), four times longer than the 3 h needed with long-
and short-chained alkyl groups (entries 1 and 2). This outcome
is not surprising when the rigidity and larger steric hindrance
of the phenyl substituent is taken into account.
Next, the migrating fragment (R2ÀCÀR3) was investigated. To
understand the mechanism of the reaction in terms of the CÀC
coupling between the vinyl gold species and the migrating
carbocation, we performed a series of experiments varying the
stability of this fragment. To accomplish this, initially only R2
was varied and R3 was allowed to remain constant as an inter-
nal alkyne. As expected, the results showed a strong depend-
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
3
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Table 3. Reaction scope.
Table 3. (Continued)
Starting
material
t
[h]
Product
Yield
of 17
[%]
[d]
12
3
–
–
–
Starting
material
t
[h]
Product
Yield
of 17
[%]
[e]
13[b]
24
–
17a
(75)
1
2
3
3
17j
(45)
14
15
0.25
17b
(70)
17k
(76)
3
17c
(75)
3
12
17l
(24)
16[f]
3
3
17d
(50)
4[a]
3
17m
(89)
17
[c]
5
6
24
3
–
–
–
17n
(88)
18
19
20
3
3
[d,e]
–
17o
(46)
17e
(55)
7
8
9
3
3
17p
(65)
24
17 f
(61)
17q
(47)
21[a]
24
17g
(65)
[d,e]
22[a]
24
24
–
–
–
0.5
[e]
23[a,b]
–
17h
(51)
10
3
3
[a] 5 mol% of catalyst was used. [b] The reaction was carried out at 408C.
[c] Protodeauration product was formed. [d] Decomposition was detected.
[e] No reaction was observed. [f] A 3:7 mixture of propargylester/allenyl
ester was employed as starting material.
17i
(62)
11
&
&
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
4
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
ency on the electron density of the substituent group (R2).
Thus, when aryl groups bearing electron-donating groups
(EDG) were used as substituents in R2, the corresponding lac-
tones were obtained in moderate-to-high yields in short reac-
tion times (entries 4, and 7–10). Although 5 mol% of gold was
used for the transformation of propargylic ester 16d (entry 4),
its conversion achieved the lowest yield among these exam-
ples. Lactone 17d bears only a methyl group at the aryl ring,
thus lacking of the mesomeric effect present in the other ex-
amples owing to the methoxy groups. By the same manner,
lactone 17g, bearing three methoxy groups at the aryl group,
was obtained in 65% yield after only 30 min of reaction
(entry 9). On the other hand, when aryl groups bearing elec-
tron-withdrawing groups (EWG), or without substituents, were
used, the formation of lactones 17 was not accomplished (en-
tries 5 and 6). In those cases, only decomposition and/or un-
substituted lactones (i.e. 18) were observed. These results indi-
cate that for these systems the carbocation formed is not
stable enough to enable the CÀC coupling with the vinyl gold
species, which instead undergoes simple protodeauration. The
formation of 17o and 17p (entries 19 and 20) was slower
(24 h). Different to the allylic ester in entry 19, the homoallylic
ester is not activated by the olefin, in the case of the cycloprop-
yl group there is also no kinetic benefit for the conversion.
Entry 23 shows a tertiary alcohol, in this case no reaction of
the substrate was detected and the starting material could be
reisolated. Because the preparation of such tertiary esters is
quite difficult, this lack of reactivity is no serious synthetic re-
striction.
Heteroaryl groups at the R2 position were also examined.
For this purpose, only p-excessive heterocycles, such as thio-
phene, were used. Thus, derivate 17i, bearing a methylthio-
phene substituent, could be obtained after 3 h in 62% yield
(entry 11). On the other hand furan did not convert (entry 12).
A vinyl group was also investigated as a substituent R2—no
conversion was observed even after 24 h at 408C (entry 13).
The fact that formation of the unsubstituted lactone (product
of the protodeauration of vinyl gold intermediate)
was not observed could be explained by considering
an extremely high activation energy related to a re-
markably lower stability of the migrating carbocation.
Therefore, it is possible to conclude that the forma-
tion of any product, in this case, is inhibited by a sig-
nificant increase in the activation energy needed to
form both intermediates; the vinyl gold species and
the migrating carbocation. This indicates that the for-
mation of these two species is strictly linked to the
stability of the carbocation. With these results in
mind, in the next experiments the R2 fragment was
kept constant, as an aryl group bearing a methoxy
substituent, and R3 was varied by using different al-
kynyl, alkenyl, and alkyl groups (entries 14–20). Deri-
vates 17j and 17k, possessing a terminal and an in-
ternal alkyne at the R3 position, respectively, were ob-
extra stabilization to the carbocation. Lactone 17n, possessing
an alkyl chain, could also be obtained in high yield after 3 h of
reaction (88%, entry 18). When a vinyl group was employed as
substituent, the initially formed carbocation has the possibility
to migrate into the allylic system. In this case, the product cor-
responding to the CÀC coupling between the vinyl gold spe-
cies and the less hindered carbocation was observed in 46%
yield (entry 19). No formation of the branched product was de-
tected. An allylic moiety at the R3 position avoids this problem
and still offers the stabilization needed to perform the reaction.
Thus, derivate 17p was obtained in 65% after 24 h of reaction
(entry 20). Finally, taking into account the high stability of cy-
clopropyl carbonium ions,[15] stabilization coming from cyclo-
propyl rings was investigated. Derivate 17q, bearing a phenyl
group and a cyclopropyl ring, was satisfactorily obtained in
47% yield after 24 h (entry 21). This result corroborates the
higher stabilization coming from the cyclopropyl ring, as prop-
argylic ester 16e, bearing also a phenyl ring, but instead of
the cyclopropyl ring an alkyne moiety, could not be trans-
formed into the desired lactone (entry 5). When two cycloprop-
yl rings were used as substituents only decomposition was ob-
served (entry 22).
These results indicate that the high stabilizing effect from an
aromatic substituent is needed to diminish the activation
energy, allowing the formation of the migrating carbocation
and the vinyl-gold-species intermediate. It is possible to con-
clude, that when an aromatic ring bearing EDGs is present at
the R2 position, the synthesis of highly substituted lactones
bearing terminal and internal alkynyl, alkenyl, alkyl, cycloalkyl
groups, and aromatic moieties takes place in moderate-to-high
yields.
As mentioned before, an isomerization of lactones 17 bear-
ing an alkyne moiety was observed when the gold-catalyzed
reaction was purified by chromatography using Al2O3 instead
of silica gel. This type of isomerization has been reported by
Larock and co-workers and Hashmi and co-workers in the syn-
thesis of allenyl ketones.[13] Figure 2 depicts the allenyl-substi-
Figure 2. Isomerization of lactones 17 to allenyl-substituted lactones 20. [a] Yield in pa-
rentheses refers to the one-pot gold-catalyzed reaction and isomerization starting from
propargylic esters 16 (conditions: column chromatography on aluminum oxide using
tained in moderate-to-high yield (entries 14 and 15).
The best yield was achieved with derivate 17m bear-
ing a phenyl group (89%, entry 17), which offers hexane/ethyl acetate).
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
5
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
tuted lactones 20 obtained from the Al2O3-promoted
twofold tautomerization of the corresponding lac-
tones 17.
For each case, the yields corresponding to the cas-
cade gold-catalyzed reaction/isomerization from
propargylic esters 16, as well as the yields of the iso-
merization from isolated lactones 17, are given.
Allenyl-substituted lactones 20 were satisfactorily
obtained in high yields (76–86%) after the Al2O3-pro-
moted isomerization of previously isolated lactones
17. No significant variations in the performance of
this transformation were observed, demonstrating
the broad scope and wide applicability of this
method. On the other hand, moderate yields (40–
62%) were obtained starting from propargylic esters
16. As expected, there is a dependency on the elec-
tron density of the substituents, and the overall
yields are, therefore, strongly related to those ob-
Scheme 4. Crossover experiment of propargylic esters 16a and 16q.
tained for the gold-catalyzed synthesis of lactones 17. In most
cases, allenyl-substituted lactones 20 were obtained as a mix-
ture of two diastereomers as a result of the axial chirality of
the trisubstituted allene moiety.
In conclusion, lactones 17 and allenyl-substituted lactones
20 are easily accessible from properly functionalized propargyl-
ic esters 16. The reaction only takes place when carbocation-
stabilizing substituents are present in the structure, allowing
the formation of the vinyl-gold species and the carbocation in-
termediates. To corroborate those observations and to propose
a more precise reaction mechanism, a crossover experiment
with derivates 16a and 16q was carried out. The aim of the
crossover experiment was to unequivocally verify whether the
CÀC coupling of the vinyl gold species with the carbocation
indeed takes place in an intermolecular fashion, or if the carbo-
cation is not properly formed and the coupling takes place in
an intramolecular fashion. Scheme 4 depicts the results, which
Scheme 5. Proposed reaction mechanism.
1
were monitored by H NMR spectroscopy, GC-MS and HRMS.
The experiment gave the expected lactones 17a and 17m,
but also the cross-coupled products 17b and 21 (Scheme 4).
The fact that the yields obtained for the expected lactones
(25–33%) are higher than those for the cross-coupling prod-
ucts (10–12%) indicates that although the reaction follows an
intermolecular pathway, the CÀC coupling of the two species
formed from the same molecule must be rapid and close-ion
pairs might dominate. Furthermore, the higher yields obtained
for derivates containing two phenyl rings, 17m and 21, are in
accordance with the greater stabilization of the carbocation
that should be formed. This outcome demonstrates that the
gold-catalyzed formation of substituted lactones 17 indeed
takes place by formation of stabilized carbocations that react
in an intermolecular fashion with the vinyl gold intermediates.
According to the results obtained, Scheme 5 shows the cata-
lytic cycle for the gold-catalyzed cascade cyclization/CÀC cou-
pling of propargylic esters 16. The first stage implies p activa-
tion of propargylic esters 16 by the gold species, forming com-
plex A. This activation allows nucleophilic attack of the oxygen
atom through 5-endo-dig cyclization, leading to the oxonium
intermediate B, which in turn generates the stabilized carbo-
cation C and the vinyl gold(I) intermediate D. CÀC coupling be-
tween the electrophile and the vinyl gold species gives rise to
the highly substituted lactones 17 under liberation of the cata-
lyst, which closes the catalytic cycle. Final isomerization, pro-
moted by basic Al2O3, of properly functionalized lactones 17
generates the allenyl-substituted lactones 20.
Conclusion
This methodology is based on the gold(I)-catalyzed 5-endo-dig
cyclization of propargylesters 16, followed by trapping of vinyl
gold(I) intermediates with stable carbocations, leading to
highly substituted lactones. The reaction performs satisfactorily
when propargylic esters bearing terminal and internal alkynyl,
alkenyl, alkyl, cycloalkyl groups, and aromatic moieties are
used. The presence of an aromatic ring with EDGs is needed to
stabilize the carbocation. Novel highly substituted lactones
were synthesized in high-to-moderate yields and with high
atom economy. In some cases, these new lactones possess an
&
&
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
6
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
[6] a) S. Ma, Z. Yu, Chem. Eur. J. 2004, 10, 2078–2087; b) S. H. Kim, K. H.
Kim, H. J. Lee, J. N. Kim, Tetrahedron Lett. 2013, 54, 329–334.
[7] J. Adrio, J. C. Carretero, J. Am. Chem. Soc. 2007, 129, 778–779.
[8] E. L. McInturff, J. Mowat, A. R. Waldeck, M. J. Krische, J. Am. Chem. Soc.
2013, 135, 17230–17235.
exocyclic alkyne or allene moiety, which could enable further
functionalizations towards more complex targets.
Acknowledgements
[9] C. Zhang, J. Yun, Org. Lett. 2013, 15, 3416–3419.
[10] a) L.-P. Liu, B. Xu, M. S. Mashuta, G. B. Hammond, J. Am. Chem. Soc.
2008, 130, 17642–17643; b) V. Gouverneur, M. N. Hopkinson, J. E. Ross,
G. T. Giuffredi, A. D. Gee, Org. Lett. 2010, 12, 4904–4907; c) S. A. Blum, Y.
Shi, K. E. Roth, S. D. Ramgren, J. Am. Chem. Soc. 2009, 131, 8732; d) J.-E.
Kang, E.-S. Lee, S.-I. Park, S. Shin, Tetrahedron Lett. 2005, 46, 7431–7433.
[11] a) C. A. Witham, P. Mauleon, N. D. Shapiro, B. D. Sherry, F. D. Toste, J. Am.
Chem. Soc. 2007, 129, 5838–5839; b) W. Rao, M. J. Koh, D. Li, H. Hirao,
P. W. Chan, J. Am. Chem. Soc. 2013, 135, 7926–7932; c) C. H. Oh, J. H.
Kim, L. Piao, J. Yu, S. Y. Kim, Chem. Eur. J. 2013, 19, 10501–10505; d) T.
Lauterbach, S. Gatzweiler, P. Nçsel, M. Rudolph, F. Rominger, A. S. K.
Hashmi, Adv. Synth. Catal. 2013, 355, 2481–2487; e) P. Nçsel, L. N. dos
Santos Comprido, T. Lauterbach, M. Rudolph, F. Rominger, A. S. K.
Hashmi, J. Am. Chem. Soc. 2013, 135, 15662–15666.
[12] For studies concerning Au/Pd systems, see also: a) A. S. K. Hashmi, C.
Lothschütz, R. Dçpp, M. Ackermann, J. De Buck Becker, M. Rudolph, C.
Scholz, F. Rominger, Adv. Synth. Catal. 2012, 354, 133–147; b) A. S. K.
Hashmi, M. Ghanbari, M. Rudolph, F. Rominger, Chem. Eur. J. 2012, 18,
8113–8119; c) A. S. K. Hashmi, R. Dçpp, C. Lothschütz, M. Rudolph, D.
Riedel, F. Rominger, Adv. Synth. Catal. 2010, 352, 1307–1314; d) A. S. K.
Hashmi, C. Lothschütz, R. Dçpp, M. Rudolph, T. D. Ramamurthi, F. Ro-
minger, Angew. Chem. 2009, 121, 8392–8395; Angew. Chem. Int. Ed.
2009, 48, 8243–8246.
M.C.B.J. is grateful to the DAAD for a fellowship. Gold salts
were generously donated by Umicore AG & Co. KG.
Keywords: alkynes · allenes · furans · gold · lactones
[1] For recent general reviews on gold catalysis, see: a) N. Krause, C.
Winter, Chem. Rev. 2011, 111, 1994–2009; b) A. S. K. Hashmi, M. Ru-
dolph, Chem. Commun. 2011, 47, 6536–6544; c) A. S. K. Hashmi, Angew.
Chem. 2010, 122, 5360–5369; Angew. Chem. Int. Ed. 2010, 49, 5232–
5241; d) D. J. Gorin, B. D. Sherry, F. D. Toste, Chem. Rev. 2008, 108, 3351–
3378; e) E. Jimꢂnez-Nfflnez, A. M. Echavarren, Chem. Commun. 2007, 4,
333–346; f) A. Fürstner, P. W. Davies, Angew. Chem. 2007, 119, 3478–
3519; Angew. Chem. Int. Ed. 2007, 46, 3410–3449; g) A. S. K. Hashmi,
G. J. Hutchings, Angew. Chem. 2006, 118, 8064–8105; Angew. Chem. Int.
Ed. 2006, 45, 7896–7936.
[2] a) A. Kar, S. Gogoi, N. P. Argade, Tetrahedron Lett. 2005, 61, 5297–5302;
b) R. Bandichhor, B. Nosse, O. Reiser, Top. Curr. Chem. 2005, 243, 43–72;
c) C. J. Duncan, M. Cuendet, F. R. Fronczek, J. M. Pezzuto, R. G. Mehta,
M. T. Hamann, S. A. Ross, J. Nat. Prod. 2003, 66, 103–107; d) H. Miyabe,
K. Fujji, T. Goto, O. Naito, Org. Lett. 2000, 2, 4071–4074; e) Z.-H. Peng,
K. A. Woerpel, Org. Lett. 2001, 3, 675–678; f) X. Yang, Y. Shimizu, J. R.
Steiner, J. Clardy, Tetrahedron Lett. 1993, 34, 761–764; g) B. Davidson,
C. M. Ireland, J. Nat. Prod. 1990, 53, 1036–1038.
[13] a) R. C. Larock, M.-S. Chow, S. J. Smith, J. Org. Chem. 1986, 51, 2623–
2624; b) A. S. K. Hashmi, J. W. Bats, J.-H. Choi, L. Schwarz, Tetrahedron
Lett. 1998, 39, 8969–8972; c) A. S. K. Hashmi, T. L. Ruppert, T. Knçfel,
J. W. Bats, J. Org. Chem. 1997, 62, 7295–7304; d) A. S. K. Hashmi, L.
Schwarz, M. Bolte, Eur. J. Org. Chem. 2004, 1923–1935.
[14] B. Neises, W. Steglich, Angew. Chem. 1978, 90, 556–557; Angew. Chem.
Int. Ed. Engl. 1978, 17, 522–524.
[15] C. U. Pittman Jr., G. Olah, J. Am. Chem. Soc. 1965, 87, 5123–5132.
[3] a) M. G. Edwards, M. N. Kenworthy, R. R. A. Kitson, M. S. Scott, R. J. K.
Taylor, Angew. Chem. 2008, 120, 1961–1963; Angew. Chem. Int. Ed.
2008, 47, 1935–1937; b) P. Langer, Synlett 2006, 20, 3369–3381; c) Y.
Wei, G.-N. Ma, M. Shi, Eur. J. Org. Chem. 2011, 5146–5155.
[4] M. Billamboz, J. C. Legeay, F. Hapiot, E. Monflier, C. Len, Synthesis 2012,
44, 137–143.
[5] J. Qi, X. Xie, R. Han, D. Ma, J. Yang, X. She, Chem. Eur. J. 2013, 19, 4146–
4150.
Received: March 9, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
7
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Synthetic Methods
M. C. Blanco Jaimes, A. Ahrens,
D. Pflꢀsterer, M. Rudolph, A. S. K. Hashmi*
&& – &&
Synthesis of Highly Substituted g-
Butyrolactones by a Gold-Catalyzed
Cascade Reaction of Benzyl Esters
Six is the magic number: In the gold-
catalyzed rearrangements of simple
diyne substrates with an ester bridge six
bonds are cleaved and six new bonds
are formed in a one-pot conversion (see
scheme).
&
&
Chem. Eur. J. 2014, 20, 1 – 8
www.chemeurj.org
8
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!