Efficient intramolecular cyclizations of phenoxyethynyl diols into multisubstituted α,β-unsaturated lactones

Article abstract of DOI:10.1021/ol401824v

AgOTf-catalyzed intramolecular cyclization of phenoxyethynyl diols proceeded under mild conditions to afford the multisubstituted α,β-unsaturated-γ-lactones in 55-98% yields. This method was also applicable to the synthesis of α,β-unsaturated-δ-lactones. A similar cyclization proceeded when AgOTf was replaced with a stoichiometric amount of N-bromosuccinimide to furnish the α-bromo-substituted α,β-unsaturated lactones.

Full text of DOI:10.1021/ol401824v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Efficient Intramolecular Cyclizations
of Phenoxyethynyl Diols into
Multisubstituted r,β-Unsaturated
Lactones
Masahiro Egi,* Yuya Ota, Yuka Nishimura, Kaori Shimizu, Kenji Azechi, and
Shuji Akai*,†
School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku,
Shizuoka, Shizuoka 422-8526, Japan
egi@u-shizuoka-ken.ac.jp
Received June 28, 2013
ABSTRACT
AgOTf-catalyzed intramolecular cyclization of phenoxyethynyl diols proceeded under mild conditions to afford the multisubstituted R,β-unsaturated-
γ-lactones in 55ꢀ98% yields. This method was also applicable to the synthesis of R,β-unsaturated-δ-lactones. A similar cyclization proceeded when
AgOTf was replaced with a stoichiometric amount of N-bromosuccinimide to furnish the R-bromo-substituted R,β-unsaturated lactones.
R,β-Unsaturated-γ-lactones are constituents of a wide
variety of naturally occurring compounds that exhibit a
range of biological activities with medicinal and agricultural
applicability.1 The potential importance of such com-
pounds has stimulated the development of a number of
synthetic methodologies, especially by employing various
transition metals, for developing environmentally benign
processes.2 Recently, considerable attention has been
devoted to developing a reliable and efficient γ,γ-disubstituted
R,β-unsaturated-γ-lactone preparation protocol, as this
scaffold forms part of the structure of the natural bio-
active compounds.3 Some typical examples of transition-
metal-catalyzed intramolecular lactone generation methods
are summarized in Figure 1: (a) the ring-closing meta-
thesis of A using ruthenium catalysts to generate an alkene
moiety,4 (b) the intramolecular cyclization of allenic acids
(2) For reviews, see: (a) Ugurchieva, T. M.; Veselovsky, V. V. Russ.
Chem. Rev. 2009, 78, 337–373. (b) Carter, N. B.; Nadany, A. E.;
Sweeney, J. B. J. Chem. Soc., Perkin Trans. 1 2002, 2324–2342. For
some recent examples, see: (c) Li, S.; Miao, B.; Yuan, W.; Ma, S. Org.
Lett. 2013, 15, 977–979. (d) Matsuo, K.; Shindo, M. Org. Lett. 2010, 12,
5346–5349. (e) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2009, 74, 6295–6298. (f) Casiraghi, G.; Zanardi, F.; Battistini, L.;
Rassu, G. Synlett 2009, 1525–1542. (g) Villalobos, M. N.; Wood, J. L.;
Jeong, S.; Benson, C. L.; Zeman, S. M.; McCarty, C.; Weiss, M. M.;
Salcedo, A.; Jenkins, J. Tetrahedron 2009, 65, 8091–8098. (h) Cacchi, S.;
Fabrizi, G.; Goggiamani, A.; Sferrazza, A. Synlett 2009, 1277–1280.
(i) Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129, 778–779.
(j) Kang, J.-E.; Lee, E.-S.; Park, S.-I.; Shin, S. Tetrahedron Lett. 2005, 46,
7431–7433. (k) Fuji, K.; Morimoto, T.; Tsutsumi, K.; Kakiuchi, K.
Chem. Commun. 2005, 3295–3297. (l) Brown, S. P.; Goodwin, N. C.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192–1194. (m)
Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2003, 42, 2892–2895. (n) Ma, S.; Yu, Z. Angew. Chem.,
Int. Ed. 2003, 42, 1955–1957.
† Present address: Graduate School of Pharmaceutical Sciences, Osaka
University, 1-6, Yamadaoka, Suita, Osaka 565-0871, Japan.
(1) (a) Pilli, R. A.; Rosso, G. B.; de Oliveira, M. C. F. Nat. Prod. Rep.
2010, 27, 1908–1937. (b) Aoyagi, Y.; Yamazaki, A.; Nakatsugawa, C.;
Fukaya, H.; Takeya, K.; Kawauchi, S.; Izumi, H. Org. Lett. 2008, 10,
4429–4432. (c) Xie, X.; Yoneyama, K.; Kusumoto, D.; Yamada, Y.;
Takeuchi, Y.; Sugimoto, Y.; Yoneyama, K. Tetrahedron Lett. 2008, 49,
2066–2068. (d) Flematti, G. R.; Ghisalberti, E. L.; Dixon, K. W.;
Trengove, R. D. Science 2004, 305, 977. (e) Murakami, T.; Morikawa,
Y.; Hashimoto, M.; Okuno, T.; Harada, Y. Org. Lett. 2004, 6, 157–160. (f)
Alali, F. Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504–540.
(3) For a review, see: Bartoli, A.; Rodier, F.; Commeiras, L.; Parrain,
J.-L.; Chouraqui, G. Nat. Prod. Rep. 2011, 28, 763–782.
(4) (a) Albrecht, U.; Langer, P. Tetrahedron 2007, 63, 4648–4654.
(b) D’Annibale, A.; Ciaralli, L.; Bassetti, M.; Pasquini, C. J. Org. Chem.
2007, 72, 6067–6074. (c) Marco, J. A.; Carda, M.; Rodrı
´
guez, S.;
Castillo, E.; Kneeteman, M. N. Tetrahedron 2003, 59, 4085–4101.
r
10.1021/ol401824v
XXXX American Chemical Society

and their esters B that proceed in the presence of copper and
palladium catalysts to furnish quaternary carbon centers,5
and (c) the construction of oxygenꢀacyl bonds through
the gold-catalyzed cyclization of (Z)-enynols C1 followed
by the oxidative cleavage of the exomethylene moiety,6 and
also through the palladium- or rhodium-catalyzed addition
of organoboron compounds to 4-hydroxy-2-alkynoates C2
followed by lactonization.7 In addition, the cyclization of
homopropargyl alcohols C3 having a silyl or bromo group
at the acetylene terminus has been successfully executed
using palladium, mercury, and gold catalysts, although with
the production of R,β-saturated-γ-lactones.8
group at the acetylene terminus undergo rearrangement
more rapidly than those with alkyl and aryl groups. This is
attributed to the inherent high reactivity of the phenoxy-
ethynyl moiety, which accelerates the 1,3-shift of the
hydroxyl groups to the adjacent position of the phenoxy
group.12 It was anticipated that the use of phenoxyethynyl
groups would render the alkyne susceptible to attack even
by bulky nucleophiles in the intramolecular cyclization.
Herein, we report the highly efficient AgOTf-catalyzed
intramolecular cyclization of phenoxyethynyl diols 3
having tertiary alcohol moieties under mild conditions to
afford γ,γ-disubstituted R,β-unsaturated-γ-lactones 4 in
good to excellent yields. Additionally, N-bromosuccinimide
(NBS) promoted a similar cyclization of 3 to give the
corresponding R-bromo derivatives 9.
Table 1. Screening of Reaction Conditions for the Cyclization of
3a to 4a
Figure 1. Reported Transition-Metal-Catalyzed Intramolecular
Lactone Formation.
yield of
4a (%)b
entry
catalyst
time (h)
1a
2
none
6
74
79
(Ph3P)AuCl, AgOTf
(0.5 mol % each)
2.5
Intermolecular lactonizations have also utilized the
ruthenium- or palladium-catalyzed cycloaddition of alle-
nyl alcohols and ketones with carbon monoxide.9 The
palladium-catalyzed γ-arylation of R-angelicalactone has
also been reported.10 However, owing to their inherent
steric hindrance, the application of these methods to the
syntheses of γ,γ-disubstituted R,β-unsaturated-γ-lactones
frequently requires a high catalyst loading, furnishes mod-
erate yields, has a narrow substrate scope, and calls for
harsh reaction conditions involving elevated temperatures
or a prolonged reaction time.
3
4
5
6
7
8
9
AgOTf (0.5 mol %)
AgNTf2 (0.5 mol %)
Ag3PO4 (0.5 mol %)
CF3CO2H (10 mol %)
CF3SO3H (10 mol %)
Me3SiOTf (10 mol %)
PhOH (10 mol %)
0.5
1
93
90
4.5
2
45
78
34
1.5
2.5
3
52
no reaction
a The reaction was conducted under reflux. b Isolated yield.
Our ongoing research has focused on the transition-
metal-catalyzed rearrangements of propargyl alcohols into
R,β-unsaturated carbonyl compounds.11 These studies
have revealed that propargyl alcohols having a phenoxy
Lithium phenoxyacetylide, generated in situ from
dichlorovinyl phenyl ether 213 and n-BuLi, reacted with
the hydroxyketone 1a in Et2O to afford the corresponding
diol 3a in 93% yield. Using 3a as a substrate, the reaction
conditionsfor the lactonization were evaluatedasshown in
Table 1. MaGee et al. reported that the intramolecular
lactonization of similar substrates, i.e., ethoxyethynyl
diols, required a temperature of 150 °C, which suggested
(5) (a) Ma, S.; Yu, Z. Angew. Chem., Int. Ed. 2002, 41, 1775–1778.
(b) Ma, S.; Wu, S. Tetrahedron Lett. 2001, 42, 4075–4077.
(6) Liu, Y.; Song, F.; Guo, S. J. Am. Chem. Soc. 2006, 128, 11332–
11333.
(7) (a) Alfonsi, M.; Arcadi, A.; Chiarini, M.; Marinelli, F. J. Org.
Chem. 2007, 72, 9510–9517. (b) Oh, C. H.; Park, S. J.; Ryu, J. H.; Gupta,
A. K. Tetrahedron Lett. 2004, 45, 7039–7042.
(12) (a) Hashmi, A. S. K.; Rudolph, M.; Huck, J.; Frey, W.; Bats,
ꢀ
J. W.; Hamzic, M. Angew. Chem., Int. Ed. 2009, 48, 5848–5852. For
(8) (a) Reddy, M. S.; Kumar, Y. K.; Thirupathi, N. Org. Lett. 2012,
other examples of efficient conversions with alkynyl ethers or ynamides
in transition metal catalysis, see: (b) Rettenmeier, E.; Schuster, A. M.;
Rudolph, M.; Rominger, F.; Gade, C. A.; Hashmi, A. S. K. Angew.
Chem., Int. Ed. 2013, 52, 5880–5884. (c) Hashmi, A. S. K.; Rudolph, M.;
Bats, J. W.; Frey, W.; Rominger, F.; Oeser, T. Chem.;Eur. J. 2008, 14,
6672–6678. (d) Istrate, F. M.; Buzas, A. K.; Jurberg, I. D.; Odabachian,
Y.; Gagosz, F. Org. Lett. 2008, 10, 925–928. (e) Hashmi, A. S. K.;
ꢀ
ꢁ
14, 824–827. (b) Compain, P.; Gore, J.; Vatele, J.-M. Tetrahedron 1996,
52, 10405–10416.
(9) (a) Kang, S.-K.; Kim, K.-J.; Hong, Y.-T. Angew. Chem., Int. Ed.
2002, 41, 1584–1586. (b) Yoneda, E.; Kaneko, T.; Zhang, S.-W.;
Onitsuka, K.; Takahashi, S. Org. Lett. 2000, 2, 441–443. (c) Cowell,
A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193–4198.
(10) Hyde, A. M.; Buchwald, S. L. Org. Lett. 2009, 11, 2663–2666.
(11) (a) Egi, M.; Umemura, M.; Kawai, T.; Akai, S. Angew. Chem.,
Int. Ed. 2011, 50, 12197–12200. (b) Egi, M.; Yamaguchi, Y.; Fujiwara,
N.; Akai, S. Org. Lett. 2008, 10, 1867–1870.
ꢀ
Salathe, R.; Frey, W. Synlett 2007, 1763–1766. (f) Couty, S.; Meyer, C.;
Cossy, J. Angew. Chem., Int. Ed. 2006, 45, 6726–6730. (g) Zhang, L.;
Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 11806–11807.
(13) Geary, L. M.; Hultin, P. G. Eur. J. Org. Chem. 2010, 5563–5573.
B
Org. Lett., Vol. XX, No. XX, XXXX

the formation of a ketene intermediate as an initial step.14
In contrast, the intramolecular cyclization of 3a proceeded
gradually in refluxing toluene (at slightly lower temp-
erature) to give 4a in 74% yield, along with the same
quantityof phenol (entry 1), which suggestedthatthe latter
cyclization went on via a different pathway. In order to
achieve a milder cyclization temperature, a cationic gold
species15,16 generated from (Ph3P)AuCl and AgOTf
was examined because of its highly alkynophilic nature
(entry 2). The reaction was achieved at room temperature
with an extremely low catalyst loading of 0.5 mol % each.
Moreover, the use of silver catalysts17 was responsible
for the rapid completion of the reaction (entries 3ꢀ5). In
particular, comparable effects were achieved by using AgOTf
or AgNTf2 as the catalyst, although AgOTf was slightly
superior. The treatment of 3a with either protic or Lewis
acids enabled the intramolecular cyclization; however,
10 mol % of the acids was required and the yields of 4a
were moderate (entries 6ꢀ8). It was found that the released
PhOH, which is acidic, did not function as a catalyst
(entry 9). Thus, AgOTf was consideredas the most suitable
catalyst for the intramolecular cyclization of 3a.
Table 2. AgOTf-Catalyzed Intramolecular Cyclization of 3bꢀi
into 4bꢀi
Next, the reactivity of diverse phenoxyethynyl diols 3
was examined using 0.5 mol % of AgOTf in toluene at
room temperature (Table 2). The intramolecular cycliza-
tions of 3bꢀf18 proceeded smoothly within 60 min to give
the R,β-unsaturated-γ-lactones 4bꢀf in 50ꢀ98% yields
(entries 1ꢀ6), which included the products (4b, 4dꢀf) with
alkyl and styryl groups at the β-position, as well as 4c
with no substituent at the β-position. The formation of
the sterically hindered spiro compounds 4b and 4c in high
yields isanother advantageof thismethod (entries 1 and 2).
Interestingly, the diastereomers (cis- and trans-3e) were
found to have different reactivities (entries 4 and 5). In
the case of 3f, the combined catalyst of (Ph3P)AuCl and
AgOTf exhibited better performance than AgOTf alone to
give 4f in 79% yield. Moreover, AgOTf-catalyzed intra-
molecular cyclizations could be extended to the syntheses
of R,β-unsaturated-δ-lactones 4gꢀi (entries 7ꢀ9).
a Isolated yield. b Using (Ph3P)AuClꢀAgOTf (0.5 mol % each)
instead of AgOTf.
A plausible mechanism for AgOTf-catalyzed intra-
molecular cyclization of 3 is proposed in Scheme 1. The
phenoxyethynyl group is an electron-rich moiety, as evi-
dent from its resonance form 30,12 and readily coordinates
to the silver cation to generate the electrophilic oxonium
intermediate 5, which is susceptible to the nucleophilic
Scheme 1. Plausible Mechanism for AgOTf-Catalyzed
Intramolecular Cyclization of 3
(14) Liang, L.; Ramaseshan, M.; MaGee, D. I. Tetrahedron 1993, 49,
2159–2168.
(15) We discovered the cationic gold(I)-catalyzed intramolecular
cyclization of 3-alkyne-1,2-diols. However, the use of AgOTf alone
did not promote a similar cyclization; see: (a) Egi, M.; Azechi, K.; Akai,
S. Org. Lett. 2009, 11, 5002–5005. For other cyclizations of that type, see:
€
€
(b) Hashmi, A. S. K.; Buhrle, M.; Wolfle, M.; Rudolph, M.; Wieteck,
M.; Rominger, F.; Frey, W. Chem.;Eur. J. 2010, 16, 9846–9854.
(16) For recent reviews on gold catalysis, see: (a) Rudolph, M.;
Hashmi, A. S. K. Chem. Soc. Rev. 2012, 41, 2448–2462. (b) Hashmi,
A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766–1775.
ꢀ
~
(17) For a review on silver catalysis, see: Alvarez-Corral, M.; Munoz-
Dorado, M.; Rodrıguez-Garcıa, I. Chem. Rev. 2008, 108, 3174–3198.
´
´
(18) The reaction of the hydroxycarbonyl compounds 1 (1.0 equiv)
with i-PrMgCl (1.0 equiv) and lithium phenoxyacetylide (1.0 equiv) in
THF provided an efficient alternative route to the synthesis of the
phenoxyethynyl diols 3. See the Supporting Information.
attack by even sterically hindered tertiary alcohol (5f6).
Subsequently, the donation of a lone pair on the ethereal
oxygen atom results in the generation of the transient
Org. Lett., Vol. XX, No. XX, XXXX
C

cyclization of 3a and 3h to provide the R-bromo lactones
9a and 9h in 67% and 43% yields, respectively (Scheme 2);
the bromo group of these compounds should facilitate
further installation of a wide variety of functional groups
at the R-position.
Scheme 2. NBS-Mediated Cyclization of 3 into 9
In conclusion, this study illustrates the feasibility of
phenoxyethynyl diols 3 as useful substrates for intra-
molecular lactonizations. The reactions proceeded in the
presence of 0.5 mol % of AgOTf to afford a variety of
multisubstituted R,β-unsaturated-γ- and δ-lactones 4.21
The advantages of this method include a rapid reaction
(<60 min) at room temperature and good-to-excellent
yields. Moreover, the NBS-mediated cyclization of 3 pro-
vided the R-bromo lactones 9. Further investigation of the
practical extension of this method and elucidation of the
reaction mechanism are in progress in our laboratory.
oxonium cation and water (6f7). Then, 7 reacts with
water to give the intermediate 8 releasing a proton
and finally provides the corresponding lactone 4 along
with the regeneration of the Ag(I) species for further
cyclization.
Based on the above encouraging results, the bromonium-
ion-mediated intramolecular cyclization of phenoxy-
ethynyl diols 3 was also evaluated.19,20 Here, the use of
NBS instead of AgOTf brought about the intramolecular
Acknowledgment. This work was supported by a
Grant-in-Aid for Young Scientists (B) from MEXT
(for M.E.).
Supporting Information Available. Experimentaldetails.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) In the past decade, there has been an explosive increase in
interest in electrophilic heteroatom cyclizations. For reviews, see: (a)
Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Chem.;Eur. J. 2012,
18, 5460–5489. (b) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev.
2011, 111, 2937–2980. (c) Snyder, S. A.; Treitler, D. S.; Brucks, A. P.
Aldrichimica Acta 2011, 44, 27–40.
(20) (a) Reddy, M. S.; Thirupathi, N.; Babu, M. H.; Puri, S. J. Org.
Chem. 2013, 78, 5878–5888. (b) Snyder, S. A.; Treitler, D. S.; Brucks,
A. P. J. Am. Chem. Soc. 2010, 132, 14303–14314. (c) Tang, B.-X.; Yin,
Q.; Tang, R.-Y.; Li, J.-H. J. Org. Chem. 2008, 73, 9008–9011. (d) Zhang,
X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 12230–12231. (e) Fu, C.;
Ma, S. Eur. J. Org. Chem. 2005, 3942–3945.
(21) Typical Experimental Procedure. Under a nitrogen atmosphere,
AgOTf (1.0 mg, 0.0039 mmol) was added to a solution of the phenoxy-
ethynyl diol 3a (217 mg, 0.78 mmol) in toluene (2.0 mL, 0.4 M) at room
temperature. The reaction mixture was stirred for 30 min and then
filtered through a pad of Celite. The filtrate was evaporated in vacuo.
The residue was purified by column chromatography (silica gel,
n-hexane/EtOAc = 5:1) to give the unsaturated lactone 4a (133 mg, 93%).
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX