Efficient synthesis of γ-lactones via gold-catalyzed tandem cycloisomerization/oxidation

Article abstract of DOI:10.1021/ol302323a

A novel Au-catalyzed tandem cycloisomerization/oxidation of homopropargyl alcohols was developed. Various γ-lactones can be accessed readily by utilizing this strategy. Notably, the mechanism of this reaction is distinctively different from the related Ru-catalyzed reactions where the ruthenium vinylidene intermediate was proposed.

Full text of DOI:10.1021/ol302323a

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4958–4961
Efficient Synthesis of γ‑Lactones via
Gold-Catalyzed Tandem
Cycloisomerization/Oxidation
Chao Shu, Meng-Qi Liu, Yu-Zhe Sun, and Long-Wu Ye*
Department of Chemistry, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005, Fujian, P. R. China
longwuye@xmu.edu.cn
Received August 21, 2012
ABSTRACT
A novel Au-catalyzed tandem cycloisomerization/oxidation of homopropargyl alcohols was developed. Various γ-lactones can be accessed
readily by utilizing this strategy. Notably, the mechanism of this reaction is distinctively different from the related Ru-catalyzed reactions where the
ruthenium vinylidene intermediate was proposed.
Homogeneous gold catalysis is still undergoing rapid
growth, and more fascinating facets of gold chemistry have
been revealed.1 It is surprising, however, that few examples
have been reported about gold vinylidenes as reactive
intermediates.2 In 1999, Trost and co-workers demon-
strated an elegant protocol for the Ru-catalyzed oxidative
cyclization of homopropargyl alcohol,3 and the ruthenium
vinylidene intermediate was proposed in this catalytic
cycle. This cyclization reaction provides a novel access to
γ-lactone synthesis from readily available homopropargyl
alcohol, but the reaction demands high temperature(95°C)
and the yields are generally moderate. Very recently,
Zhang’s group reported a gold-catalyzed cycloisomerization
of benzene-1,2-diynes, where a gold vinylidene intermediate
is most likely involved on the basis of both mechanistic
studies and theoretical calculations.4 This result inspired us
to further explore gold vinylidene chemistry, which might
serve as a complementary method for Trost’s lactone
synthesis. We envisioned that the gold vinylidene inter-
mediate I might be generated by reacting homopropargyl
alcohol 1 with a gold complex. Then, this highly reactive
gold complex I could be trapped quickly by an intramolec-
ular OꢀH insertion to form oxacarbene species II, which
would be further oxidized to γ-lactone 2 (eq 1).
(1) For selected reviews for gold catalysis, see: (a) Rudolph, M.;
Hashmi, A. S. K. Chem. Soc. Rev. 2012, 41, 2448. (b) Corma, A.; Leyva-
To implement this design, the critical issue is to find a
suitable oxidant to minimize the side reaction caused by
gold-catalyzed intermolecular oxidations of alkynes via an
R-oxo gold carbene route.5,6 We recently found that when
simple m-CPBA was used as the oxidant,7 gold could also
catalyze such an oxidative cyclization reaction even at
ꢀ
€
Perez, A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657. (c) Furstner, A.
Chem. Soc. Rev. 2009, 38, 3208. (d) Sohel, S. M. A.; Liu, R.-S. Chem.
Soc. Rev. 2009, 38, 2269. (e) Patil, N. T.; Yamamoto, Y. Chem. Rev.
2008, 108, 3395. (f) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev.
ꢀ
ꢀ~
2008, 108, 3351. (g) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev.
2008, 108, 3326. (h) Arcadi, A. Chem. Rev. 2008, 108, 3266. (i) Li, Z.;
Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (j) Bongers, N.; Krause,
N. Angew., Chem., Int. Ed. 2008, 47, 2178.
(2) (a) Xia, Y.; Dudnik, A. S.; Li, Y.; Gevorgyan, V. Org. Lett. 2010,
12, 5538. (b) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Tetrahedron
2008, 64, 6876. (c) Lavallo, V.; Frey, G. D.; Kousar, S.; Donnadieu, B.;
Bertrand, G. Proc. Nat. Acad. Sci. U.S.A. 2007, 104, 13569. (d) Seregin,
I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 12050. (e) Soriano, E.;
Marco-Contelles, J. Organometallics 2006, 25, 4542. (f) Mamane, V.;
(4) (a)Ye, L.; Wang, Y.; Aue, D. H.; Zhang, L. J. Am. Chem. Soc. 2012,
134, 31. During the course of our study, three more recent examples about
gold vinylidenes were reported by Hashmi: (b) Hashmi, A. S. K.; Braun, I.;
€
€
Nosel, P.; Schadlich, J.; Wieteck, M.; Rudolph, M.; Rominger, F. Angew.
Chem., Int. Ed. 2012, 51, 4456. (c)Hashmi, A. S. K.; Wieteck, M.; Braun, I.;
€
Hannen, P.; Furstner, A. Chem.;Eur. J. 2004, 10, 4556.
€
Nosel, P.; Jongbloed, L.; Rudolph, M.; Rominger, F. Adv. Synth. Catal.
(3) (a) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 1999, 121, 11680.
(b) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 2528.
2012, 354, 555. (d) Hashmi, A. S. K.; Braun, I.; Rudolph, M.; Rominger, F.
Organometallics 2012, 31, 644.
r
10.1021/ol302323a
Published on Web 08/29/2012
2012 American Chemical Society

room temperature in good to excellent yields, providing
a very efficient and practical method for the preparation
of γ-lactone derivatives. However, mechanism studies
revealed that this catalytic cyclization reaction did not pro-
ceed via the gold vinylidene intermediate according to our
initial assumption. Instead, it occurred presumably through a
tandem Au-catalyzed oxycyclization, followed by an acid-
accelerated oxidation sequence, which behaved distinctively
different from the related Ru-catalyzed reactions, where the
intermediacy of ruthenium vinylidene was proposed.3a In this
paper, we report these preliminary results.
Homopropargyl alcohol 1a was chosen as the model
substrate for our initial study. Considering that strong
nucleophilic oxidants such as quinoline/pyridine N-oxides
would lead to the formation of dihydrofuran-3-ones5f via an
R-oxo gold carbene intermediate, we initially examined the
reaction by using the oxidants which worked well in the Ru-
catalyzed oxidative cyclization.3a However, all (maleimide,
N-hydroxysuccinimide, and N-hydroxyphthalimide)
failed to furnish the desired lactone. To our delight, it
was found that the corresponding γ-lactone 2a could be
obtained in 50% yield by using m-CPBA as the oxidant
(Table 1, entry 1). Among the different gold catalysts
examined (entries 2ꢀ8), (4-CF3C6H4)3PAuNTf2 gave a
slightly improved yield (entry 7). We were pleased to find
that the addition of acids substantially improved the
reaction (entries 9ꢀ12), and an excellent yield (90%) could
be achieved in the presence of 1.0 equiv of MsOH (entry
11). The use of other acids failed to improve the yield
(entries 13 and 14). Of note, without using any gold cata-
lyst, noγ-lactone2awas observedunder the acidicreaction
conditions, and PtCl2 and AgNTf2 were not effective in
promoting this reaction (entries 15 and 16).
Table 1. Optimization of Reaction Conditionsa
entry
gold catalyst
Ph3PAuNTf2
acid (equiv)
yieldb (%)
1
50
26
27
8
2
Cy-JohnPhosAuNTf2
XPhosAuNTf2
3
4
BrettPhosAuNTf2
Et3PAuNTf2
5
24
8
6
IPrAuNTf2
7
(4-CF3C6H4)3PAuNTf2
(C6F5)3PAuNTf2
(4-CF3C6H4)3PAuNTf2
(4-CF3C6H4)3PAuNTf2
(4-CF3C6H4)3PAuNTf2
(4-CF3C6H4)3PAuNTf2
(4-CF3C6H4)3PAuNTf2
(4-CF3C6H4)3PAuNTf2
PtCl2
53
25
61
72
90c
81
77
16
16
<5e
8
9
MsOH (0.2)
MsOH (0.5)
MsOH (1.0)
MsOH (1.3)
CF3CO2H (1.0)
HNTf2 (1.0)
MsOH (1.0)
MsOH (1.0)
10
11
12
13
14
15d
16
AgNTf2
a Reaction conditions: [1a] = 0.05 M; DCE: 1, 2-dichloroethane.
b Estimated by 1H NMR using diethyl phthalate as internal reference. c Yield
of isolated 2a was 86%. d Toluene, 80 °C. e Most 1a remained unreacted.
were readily allowed (entries 9ꢀ13). Moreover, tertiary
homopropargylic alcohols were suitable substrates for this
reaction to furnish the corresponding γ-lactones (entries
14ꢀ18). Notably, substrates 1t and 1u could also
undergo smooth tandem cycloisomerization to afford
the strained 5,6-cis-fused 2t and 2u, highlighting the syn-
thetic utility of this methodology (entries 19 and 20). To
test the practicality of the current catalytic system, the
reaction was carried out on a gram scale in the presence of
2.5 mol % of gold catalyst, and the desired product 2a was
afforded in 85% yield (entry 21). Finally, it should be
pointed out that a number of the γ-lactones in Table 2 are
of significant interest, including 2a, a food additive;8 2g, an
intermediate as an antituberculosis agent;9 2o, known for
anticonvulsant activity;10 2p, a commercial liqorice root
extract;11 and 2r, a perfuming agent.12
Under the optimal reaction conditions, various homo-
propargyl alcohols were tested to examine the generality of
the current reaction. As shown in Table 2, this reaction
proceeded smoothly with various substrates, and the yields
ranged from 56% to 92%. A range of functional groups
were tolerated, including bromo (entry 4), azido (entry 5),
protected amino (entry 6), and hydroxy (entries 7 and 8).
In addition, aromatic substrates also gave the correspond-
ing γ-lactones in moderate to good yields, and sub-
stitutions on the aromatic ring at different positions
The utility of this chemistry was further demonstrated
in the concise and efficient synthesis of steroidal spiro-γ-
lactone 2v (Scheme 1), which showed efficient inhibitory
activity for enzyme 17β-hydroxysteroid dehydrogenase
(17β-HSD).13 Starting from estrone, the formation of the
spiro-γ-lactone 2v was achieved in a respectable 58% yield.
(5) (a) Wang, Y.; Ji, K.; Lan, S.; Zhang, L. Angew. Chem., Int. Ed.
2012, 51, 1915. (b) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 133,
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2011, 133, 15372. (e) Vasu, D.; Hung, H.-H.; Bhunia, S.; Gawade, S. A.;
Das, A.; Liu, R.-S. Angew. Chem., Int. Ed. 2011, 50, 6911. (f) Qian, D.;
Zhang, J. Chem. Commun. 2011, 11152. (g) Davies, P. W.; Cremonesi,
A.; Martin, N. Chem. Commun. 2011, 379.
(7) For relaying “O” from m-CPBA to a tethered CꢀC triple bond via
gold catalysis, see: (a) Cui, L.; Peng, Y.; Zhang, L. J. Am. Chem. Soc.
2009, 131, 8394. (b) Cui, L.; Zhang, G.; Peng, Y.; Zhang, L. Org. Lett.
2009, 11, 1225. For pioneering work in the acid-accelerated oxidation of
protected lactols into lactones using m-CPBA, see: (c) Grieco, P. A.;
Oguri, T.; Yokoyama, Y. Tetrahedron Lett. 1978, 19, 419.
(8) Delort, E.; Velluz, A.; Frerot, E.; Rubin, M.; Jaquier, A.; Linder,
S.; Eidman, K. F.; MacDougall, B. S. J. Agric. Food Chem. 2011, 59,
11752.
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Kozikowski, A. P. Bioorg. Med. Chem. Lett. 2008, 18, 5311.
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Farm. 1974, 5, 85.
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Org. Lett., Vol. 14, No. 18, 2012
4959

further oxidized to (þ)-harzialactone A,16 an antitumor
marine metabolite.
Table 2. Reaction Scope for the Formation of γ-Lactonesa
To probe the mechanism of this reaction, we first monitored
the cyclization reaction of 1a by 1H NMR and detected two
unknown intermediates 4a-1 and 4a-2, which could be con-
verted to the γ-lactone 2a after 5 h (Figure 1, see the
Supporting Information). However, trying to establish their
structures by using ES-MS or isolate these active species failed.
To elucidate these structures, we then prepared hemiacetal
substate 3a and treated it with m-CPBA (eq 3). Gratifyingly, in
the presence of 1.0 equiv of MsOH, γ-lactone 2a was formed in
90% yield. Importantly, we indeed observed the same inter-
mediates (10%) which were detected in the above 1H NMR
experiments, suggesting that the unknown intermediates 4a-1
and 4a-2 should be the peroxide 4a. Without the additional
MsOH, however, the conversion of this reaction was very low,
and only 17% γ-lactone 2a was obtained after 5 h. This study
also explained well the role of acid in this reaction.
In addition, we also synthesized the dihydrofuran sub-
strate 5a to further investigate the reaction (eq 4). It was
found that almost no lactone 2a and peroxide intermediate
4a were formed under the previously optimized reaction
conditions. However, in the presence of 5 equiv of H2O, the
reaction did afford the desired lactone 2a, and the inter-
mediate 4a was also observed from the 1H NMR spectrum.
Of note, neither lactone 2a nor peroxide 4a formation was
observed without using the gold catalyst. We also per-
formed the reaction by slow addition of dihydrofuran 5a
using the syringe pump to try to mimic the slow formation of
the intermediate during gold catalysis. To our delight, the
reaction proceeded very well to afford the desired lactone 2a
in 90% yield. It is noteworthy that in this case, lactone 2a
could be formed in similar efficiency in the absence of gold.
These results strongly supported that the reaction presum-
ably involves a 5-endo-dig cyclization of homopropargyl
alcohol, followed by the acid-accelerated oxidation.
a Reactions run in vials; [1] = 0.05 M; isolated yields are reported.
b 10 mmol scale, 2.5 mol % gold catalyst was used, 7 h.
It is noteworthy that, starting from the same estrone,
compound 2v typically demands rather lengthy synthesis,
including the additional necessary protection and depro-
tection stages of the sequence.13a
Scheme 1. Synthesis of Spiro-γ-lactone 2v
Since chiral homopropargyl alcohols were readily
available,14 this chemistry provided easy access to chiral
γ-lactones, which are important classes of bioactive het-
erocycles that are difficult to construct.15 For example, the
enantiomerically enriched alcohol ent-1d, obtained easily
from L-phenylalanine,14f was converted into correspond-
ingγ-lactone ent-2dwith the ee maintained during this gold
catalysis (eq 2). Of note, chiral γ-lactone ent-2d could be
(14) For recent selected examples, see: (a) Jain, P.; Wang, H.; Houk,
K. N.; Antilla, J. C. Angew. Chem., Int. Ed. 2012, 51, 1391. (b) Trost, B. M.;
Ngai, M.-Y.; Dong, G. Org. Lett. 2011, 13, 1900. (c) Barnett, D. S.; Schaus,
S. E. Org. Lett. 2011, 13, 4020. (d) Shi, S.-L.; Xu, L.-W.; Oisaki, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 6638. (e) Usanov, D. L.;
Yamamoto, H. Angew. Chem., Int. Ed. 2010, 49, 8345. (f) Montagnat, O. D.;
Lessene, G.; Hughes, A. B. J. Org. Chem. 2010, 75, 390.
(15) (a) Ghosh, M. Tetrahedron 2007, 63, 11710. (b) Shibata, C.; Mori,
K. Eur. J. Org. Chem. 2004, 1083. (c) Khim, S.-K.; Schultz, A. G. J. Org.
ꢀ
Chem. 2004, 69, 7734. (d) James, D. G.; Petroski, R. J.; Cosse, A. A.;
However, in treatment of the substrate 1a with
5 mol % gold catalyst in the absence of m-CPBA, neither
Zilkowski, B. W.; Bartelt, R. J. J. Chem. Ecol. 2003, 29, 2189. (e) Mereyala,
H. B.; Gadikota, R. R. Tetrahedron: Asymmetry 1999, 10, 2305.
4960
Org. Lett., Vol. 14, No. 18, 2012

proposed (Scheme 2). The reaction may initially involve
the formation of π complex through coordination of
the gold catalyst to the triple bond of homopropargyl
alcohol 10. Next, 5-endo-dig cyclization formed vinyl gold
intermediate A, which would be transformed into the
oxocarbenium intermediate C in the presence of acid.18
The intermediate dihydrofuran 50, once generated, should
be rapidly protonated to intermediate C in order to avoid
the epoxidation of its electron-rich CꢀC double bond by
m-CPBA. Finally, the nucleophilic attack by the m-CPBA
ought to liberate the product 2 via the formation of the
peroxide intermediate D. In this process, the role of H2O
(from 85% m-CPBA) is likely to access the hemiacetal 30
via hydration of dihydrofuran intermediate50, whichcould
finally undergo an acid-accelerated oxidation to deliver the
final lactone 2.7c The decrease of deuterium of the com-
pound 4a0 from 91% to 61% was probably due to the fact
that some of intermediate A was converted to intermediate
F during the reaction.
Scheme 2. Plausible Mechanism for This Catalytic Cyclization
dihydrofuran 5a nor lactone 2a was formed, with only the
formation of trace hemiacetal compound 3a (∼3% 1HNMR
yield). These results suggested that the dihydrofuran 5a was
actually not fully generated in the reaction system. In another
words, once generated, it should be protonated into
oxocarbenium intermediate very quickly. This study
also exhibits well the advantage of such a tandem
cycloisomerization/oxidation sequence.
Finally, we performed deuterium labeling studies. It was
found that when substrate 1a0 (91% D) was treated under
the optimized reaction conditions, almost no deuter-
ium incorporation into the lactone 2a was observed
(eq 5). Importantly, we detected 61% deuterium incor-
poration into peroxide 4a by 1H NMR, indicating that
the gold vinylidene pathway was less likely.17
In summary, we have developed a flexible and general
solution for the synthesis of various γ-lactones via a
tandem gold-catalyzed cycloisomerization and in situ
regioselective m-CPBA oxidation sequence, which is dis-
tinctively different from the related ruthenium catalysis.
Notably, with this newly established methodology, enan-
tiospecific synthesis of γ-lactones could be easily achieved
in a highly efficient and concise manner, and its application
has further been demonstrated by a formal synthesis of
harzialactone A. The use of readily available substrates,
a simple procedure, and mild reaction conditions and, in
particular, no need to exclude moisture or air (“open flask”)
render these methods potentially useful in organic synthesis.
Acknowledgment. We are grateful for financial sup-
port from the National Natural Science Foundation of
China (No. 21102119), NFFTBS (No. J1030415), and
Xiamen University. We also thank Professor Dr. Liming
Zhang (University of California Santa Barbara) for
valuable discussions and amendments on this paper
and Professor Yuan-Ping Ruan for HPLC analysis.
Special gratitude goes to Professor Dr. Yong Tang
(Shanghai Institute of Organic Chemistry) for his long-
term support.
On the basis of these experimental observations, a
plausible mechanism for this catalytic cyclization is
(16) For enantioselective synthesis of harzialactone A, see: (a) Kumar,
D. N.; Reddy, C. R.; Das, B. Synthesis 2011, 3190. (b) Kotkar, S. P.;
Suryavanshi, G. S.; Sudalai, A. Tetrahedron: Asymmetry 2007, 18, 1795. (c)
Jian, Y.-J.; Wu, Y.; Li, L.; Lu, J. Tetrahedron: Asymmetry 2005, 16, 2649. (d)
Mereyala, H. B.; Joe, M.; Gadikota, R. R. Tetrahedron: Asymmetry 2000, 11,
4071. (e) Mereyala, H. B.; Gadikota, R. R. Tetrahedron: Asymmetry 1999,10,
2305.
(17) If the D in 4a is from m-CPBA via gold carbene insertion, the
deuterium incorporation into intermediate 4a should be much less than
50% (the active H/D in the reaction system was from OH, MsOH, D,
m-CPBA).
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(18) (a) Belting, V.; Krause, N. Org. Lett. 2006, 8, 4489. (b) Alcaide,
´
B.; Almendros, P.; Martınez del Campo, T.; Carrascosa, R. Eur. J. Org.
Chem. 2010, 4912.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
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