Synthesis of Furo[2,3-b]pyran-2-ones through Ag(I)- or Ag(I)-Au(I)-Catalyzed Cascade Annulation of Alkynols and α-Ketoesters

Article abstract of DOI:10.1021/acs.orglett.7b04027

Ag(I)- or Ag(I)-Au(I)-catalyzed cascade annulation of alkynols (5-hexyn-1-ol systems) with α-ketoesters involving a dual activation process (π and σ) has been developed for the first time. This reaction proceeds through cycloisomerization of alkynol to give the 6-endo-enol ether followed by annulation with an α-ketoester to furnish furo[2,3-b]pyran-2-ones in good yields. Chemical structures of all products were rigorously confirmed by single crystal X-ray analysis and analogy.

Full text of DOI:10.1021/acs.orglett.7b04027

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Furo[2,3‑b]pyran-2-ones through Ag(I)- or Ag(I)−Au(I)-
Catalyzed Cascade Annulation of Alkynols and α‑Ketoesters
Sagar S. Thorat,†,‡ Priyanka Kataria,†,‡ and Ravindar Kontham*,†,‡
†Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune-411008, India
‡Academy of Scientific and Innovative Research (AcSIR), New Delhi, India
S
* Supporting Information
ABSTRACT: Ag(I)- or Ag(I)−Au(I)-catalyzed cascade annulation of alkynols (5-hexyn-1-ol systems) with α-ketoesters
involving a dual activation process (π and σ) has been developed for the first time. This reaction proceeds through
cycloisomerization of alkynol to give the 6-endo-enol ether followed by annulation with an α-ketoester to furnish furo[2,3-
b]pyran-2-ones in good yields. Chemical structures of all products were rigorously confirmed by single crystal X-ray analysis and
analogy.
trimethylsilyl)-ethyl pyruvate, which results in perhydro[2,3-
b]pyran derivatives, while Schmidt condensed 3,4-dihydro-2H-
pyran with oxalyl chloride, to give the 2-chloro variant in MeOH
at an elevated temperature of 120 °C in 42% yield.9 However,
these two reports were limited to a single example in each case.
In light of the emerging importance of cascade and domino
reactions in the construction of complex organic molecules from
structurally simple building blocks,10 recently, we reported a
novel protocol for the synthesis of unsaturated γ-spiroketal-γ-
lactones 3 (1,6-dioxaspiro[4.4]non-3-en-2-ones) using Bi(III)-
catalyzed annulation of alkynol 1 (4-pentyn-1-ol) with α-
ketoester 2. In this transformation, alkynol 1 underwent a 5-
exo-dig mode of cyclization to afford the enol ether T1, followed
by condensation with the α-ketoester 2 to produce the
spirolactone 3.11 In this connection, we hypothesized that
treating 5-hexyn-1ol 4 with suitable the π-acid catalyst could
furnish the thermodynamically favored endo-enol ether M1 via
initial 6-exo-dig mode of cyclization to give M2 followed by
inward isomerization. The subsequent reaction of M1 with σ-
activated α-ketoester 2 would furnish the desired furo[2,3-
b]pyran-2-one 5 instead of oxaspirolactone 6 (Scheme 1).
To test our hypothesis, alkynol 4a (1 equiv) and ethyl pyruvate
2a (1 equiv) were reacted using the well-known dual activating
(π and σ) catalyst AgOTf12 (10 mol %) in dichloroethane at
room temperature, which was a very slow reaction. To our
delight, when we raised the reaction temperature to 80 °C, the
expected furo[2,3-b]pyran-2-one 5aa was isolated in an excellent
atural products are an exceptional source of small molecule
Ndrug leads and a continuous inspiration for the design of
libraries for drug discovery.1 In this context, furo[2,3-b]pyrans
have been found to be key structural units in many biologically
active and structurally diverse natural products, for instance,
alboatrin (phytotoxic metabolite),2 xyloketals A−D and H
(calcium channel blockers),3 myxostiolide (plant growth
regulator),4 hyperaspidinol (hepatitis, depression, antivenom
activities),5 spicatolide-C (anti-inflammatory),6 and guaianolide
(inhibitor of nitric oxide production)7 (Figure 1).
Despite potential biological properties, only two synthetic
methods have been documented in the literature to construct
furo[2,3-b]pyran scaffolds. Flower et al. reported a protocol8 of
TiCl4 mediated addition of 3,4-dihydro-2H-pyran to (2-
Received: December 28, 2017
Figure 1. Natural products containing furo[2,3-b]pyran scaffold.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b04027
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Concept of the Cascade Annulation of Alkynols
Table 1. Optimization of Reaction Conditions
and α-Ketoseters Using a π- and σ-Acidic Catalyst
b
entry
1
catalyst
AgOTf
solvent
yield (%)
(CH2)2Cl2
(CH2)2Cl2
CH2Cl2
toluene
THF
60
85
62
58
−
83
80
72
86
81
−
c
2
AgOTf
3
4
5
AgOTf
AgOTf
AgOTf
d
6
AgOTf
PhF
e
7
AgOTf
PhF
f
8
AgOTf
PhF
g
9
Ph3PAuCl/AgOTf
AuCl/AgOTf
AuCl/JohnPhos
Ph3PAuCl
Pd(PPh3)2Cl2
PdCl2/Na2CO3
TfOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
g
10
g
11
12
13
14
−
−
−
−
CH2CN
CH2Cl2
h
15
yield of 85% in 4 h. The structure of 5aa was unambiguously
confirmed by 1H, 13C NMR, mass spectrometry and single crystal
X-ray crystallography (Scheme 2).
a
Reaction conditions unless otherwise specified: 4a (1 equiv), 2a (1
equiv), and catalyst (10 mol %) in the indicated solvent (anhydrous)
b
c
d
at rt for 12 h. Isolated yields of 5aa. 80 °C, 4 h. 10 mol % of
AgOTf, 80 °C, 45 min. 5 mol % of AgOTf, 80 °C, 2 h. 10 mol % of
AgOTf, rt, 12 h. Each 5 mol % of catalyst is used. Control
e
f
g
h
Scheme 2. Initial Synthesis of the Furo[2,3-b]pyran-2-one
experiments. rt = room temperature, Tf = triflate (CF3SO2).
were found to be the best conditions for this transformation
(Scheme 2). Further altering the reaction parameters such as
catalyst loading and the molar ratios of reactants did not lead to a
considerable change in the outcome (Table 1).
With the optimized conditions established, initially, we tested
the substrate scope using alkynols possessing primary and
secondary hydroxyl functionality with a range of diverse α-
ketoesters. Annulation of cyclohexane fused alkynol14 with ethyl
pyruvate, ethyl phenylglyoxylate, ethyl anisylglyoxylate, and ethyl
4-nitrophenylglyoxylate furnished the corresponding adducts
5aa−ad in good yields. A cyclohexane fused internal alkynol with
ethyl pyruvate provided 5ba in a good yield of 59%. A
cyclopentane fused terminal alkynol participated well in the
reaction with ethyl pyruvate and an indole-derived α-ketoester to
give 5ca and 5cg in good yields. Commercially available 5-hexyn-
1-ol also proved to be a good substrate in this process delivering
various adducts 5da−dd, along with very interesting indole and
thiophene derived analogs 5dg and 5dh in good yields. Very
interestingly, the reaction of 5-hexyn-1-ol with β,γ-unsaturated-
α-ketoester provided furo[2,3-b]pyran-2-one 5df instead of a
possible [4 + 2]-cycloaddition product. This result is in contrast
to the reports of Xu15 and Feng16 (inverse electron demand
hetero-Diels−Alder (IED hetero-DA) reaction). The phenyl
acetylene derived α-ketoester was also a good substrate for this
transformation and afforded 5de in 54% yield. Propargylic ether
derived alkynol was also well tolerated and gave the desired
adduct 5ea in a moderate yield of 38%. This compromised yield
here could be due to the instability of the product under the
current reaction conditions. The reaction of a secondary alkynol
with ethyl pyruvate gave the desired product 5fa as a single
diastereomer in good yield, with the relative stereochemistry
being confirmed by NOE analysis.14 Electron-releasing sub-
stituents (p-OMe) in the ethyl arylglyoxylates facilitated the
good outcome of the reaction (5ac and 5dc) compared to
electron-withdrawing substituents (p-NO2) (5ad and 5dd). To
Encouraged by these results, we continued to further verify the
effect of other catalytic systems and reaction conditions using 4a
and 2a as reactants (Table 1). The reaction with AgOTf in
(CH2)2Cl2 and CH2Cl2 at room temperature provided 5aa in
moderate yields of 60% and 62% respectively (entries 1 and 3).
The reaction in toluene gave 5aa in 58% yield, whereas THF
failed to give the desired product (entries 4 and 5).
Fluorobenzene is found to be the best solvent, which provided
the products in good yields in a short reaction time and at
ambient temperature (entries 6−8). The well established
cooperative catalytic system13 of Au(I) and AgOTf (each 5
mol %) in CH2Cl2 furnished the desired product in good yields
(entries 9 and 10). Au(I)-catalysts alone did not furnish the
desired product (entries 11 and 12). Palladium(II) catalysts
(entries 13 and 14) and other Lewis acid catalysts (Hg(OTf)2,
Bi(OTf)3, In(OTf)3, Cu(OTf)2, and Sc(OTf)3) were tested in
this reaction, but only some of them were found to be moderately
active.14 Next, Bi(OTf)3 in combinations with BF3OEt2 and TFA
were tested, which gave 5aa in moderate yields.14 No conversion
was observed with TfOH, a usual contaminant in the AgOTf
catalyst (entry 15). To our delight, the initially identified
conditions of AgOTf (10 mol %) in (CH2)2Cl2 at 80 °C for 4 h
B
DOI: 10.1021/acs.orglett.7b04027
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
exemplify the practical applicability of this protocol, a 500 mg
scale reaction under the standard conditions was conducted to
obtain 5da in 77% yield. Annulation with ethyl aryl-glyoxylates
was slightly slower compared to ethyl pyruvate (Scheme 3).14
Geminal disubstituted alkynols gave the best yields compared to
unsubstituted analogs, which is attributed to the Thorpe−Ingold
effect.17
Scheme 4. Synthesis of Furo[2,3-b]pyran-2-ones Using
Tertiary Alkynols
Scheme 3. Synthesis of Furo[2,3-b]pyran-2-ones Using
a
Primary and Secondary Alkynols
A plausible reaction pathway based on these experiments and
other earlier reports is presented in Scheme 5.11,19 Ag(I)
Scheme 5. Plausible Reaction Pathway
a
Reaction time is 4 h, unless otherwise specified. All yields mentioned
above are isolated yields.
After successful synthesis of several furo[2,3-b]pyran-2-one
analogues involving primary and secondary alkynols (Scheme 3),
we intended to check the reactivity of alkynols having tertiary
hydroxyl functionality. Hence, alkynol 4g was treated with ethyl
pyruvate (2a) under the optimized conditions of AgOTf (10 mol
%) in (CH2)2Cl2 at 80 °C for 4 h, but we observed
decomposition. Instead, PPh3AuCl in CH2Cl2 at rt afforded
10% of desired product 5ga and hydroxy-ketone 7 in 75% yield.
After a few experiments, we were delighted to find that one of the
initially identified conditions involving PPh3AuCl and AgOTf
mediated cooperative catalysis in anhydrous CH2Cl2 was quite
efficient in catalyzing this transformation, it furnishing the
desired adduct 5ga in a good yield of 56% via the hydroxy-ketone
intermediate 7 (eq 1). Intermediate 718 was isolated and
characterized and was successfully converted to 5ga in 50% yield
using AgOTf alone in CH2Cl2 at rt (eq 2). Utilizing these
optimized reaction conditions (eq 1), furo[2,3-b]pyran-2-ones
5gc and 5gh were prepared from ethyl anisylglyoxylate and ethyl
thiophenylglyoxylate respectively (Scheme 4).14
mediated π-activation of alkynol 4 would facilitate the cyclo-
isomerization via A (6-exo-dig cyclization) to give initial exo-enol
ether B, which immediately would undergo inward isomerization
to give the more favored endo-enol ether C. Immediate attack of
the intermediate C onto the σ-activated α-ketoester 2 could then
give the oxocarbenium ion intermediate D. Intramolecular
addition of the ester oxygen to the oxocarbenium ion D could
then provide E. AgOTf mediated removal of water from E to
provide F, followed by addition of in situ released water onto
intermediate F would give the hemiacetal G. Expulsion of EtOH
from G delivers the furo[2,3-b]pyran-2-one 5 (Scheme 5).
To gain insights into the reaction mechanism, we conducted a
few supporting experiments (Scheme 5). The reaction of 5-
hexyn-1-ol (4d) with ethyl pyruvate (2a) in the absence of
AgOTf failed to deliver the desired product 5da (eq 3). As we
observed in our earlier work,11 in situ released water was trapped
using activated MS-4 Å, which arrested the formation of 5da (eq
4). Cycloisomerization of 4d to generate endo-enol ether C and
release of EtOH as a byproduct were established using real-time
C
DOI: 10.1021/acs.orglett.7b04027
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1H NMR experiments (eq 5).14 These observations are in
agreement with earlier reports.20
Notes
The authors declare no competing financial interest.
Finally, further diversification of furo[2,3-b]pyran-2-one 5da
was studied through a couple of fundamental transformations
(Scheme 6). Pd/C Mediated hydrogenation gave the saturated
ACKNOWLEDGMENTS
■
We are thankful to the SERB (Science & Engineering Research
Board), New Delhi, India for financial support (Grant No. YSS/
2015/000725). S.S.T. thanks CSIR-India for the award of a
Junior Research Fellowship (JRF), and P.K. thanks UGC-India
for the award of a Junior Research Fellowship (JRF).
Scheme 6. Diversification of Furo[2,3-b]pyran-2-one
REFERENCES
■
(1) Harvey, A. L.; Edrada-Ebel, R. A.; Quinn, R. J. Nat. Rev. Drug
Discovery 2015, 14, 111−129 and references cited therein.
(2) (a) Biswas, B.; Sarkar, D.; Venkateswaran, R. V. Tetrahedron 2008,
64, 3212−3216. (b) Ichihara, A.; Nonaka, M.; Sakamura, S.; Sato, R.;
Tajimi, A. Chem. Lett. 1988, 17, 27−30.
(3) Xu, Z.; Li, Y.; Xiang, Q.; Pei, Z.; Liu, X.; Lu, B.; Chen, L.; Wang, G.;
Pang, J.; Lin, Y. J. Med. Chem. 2010, 53, 4642−4653.
(4) Kimura, Y.; Shimada, A.; Kusano, M.; Yoshii, K.; Morita, A.;
Nishibe, M.; Fujioka, S.; Kawano, T. J. Nat. Prod. 2002, 65, 621−623.
(5) Paterson, L. D.; Barker, D. Beilstein J. Org. Chem. 2015, 11, 265−
270.
(6) Issa, H. H.; Chang, S. M.; Yang, Y. L.; Wu, Y. C. Chem. Pharm. Bull.
2006, 54, 1599−1601.
analog 8 as a single diastereomer. Dihydroxylation using OsO4
and NMO furnished the diol 9 with excellent diastereoselectivity.
In these two cases, attack of reagents from the sterically free
convex face of 5da would be the probable reason for the observed
diastereoselectivity (according to the X-ray structure of 5aa,
Scheme 2). The relative stereochemistry of 8 and 9 was assigned
based on NOE analysis. Very interestingly, saponification of 5da
using methanolic NaOH led to the formation of 4-hydroxy-2-
butenolide scaffold 10, which is related to secoprostaglandins21
in an unprecedented way.22
In conclusion, we have described the first catalytic protocol for
the synthesis of furo[2,3-b]pyran-2-ones using AgOTf or AgOTf
and PPh3PAuCl catalyzed cascade annulation of alkynols and α-
ketoesters in a step and atom economic way. Diverse furo[2,3-
b]pyran-2-ones were prepared, and their synthetic utility is also
well demonstrated. This cascade annulation strategy should find
applications in the synthesis of biologically interesting natural
products and also provides a platform for diversity-oriented
synthesis in medicinal chemistry.
(7) Phan, M. G.; Tran, T. T. N.; Phan, T. S.; Matsunami, K. Phytochem.
Lett. 2014, 9, 137−140.
(8) Willis, M. C.; Flower, S. E. Synlett 2003, 10, 1491−1493.
(9) Schmidt, B.; Werner, F.; Kelling, A.; Schilde, S. J. Het. Chem. 2010,
47, 1171−1175.
(10) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int.
Ed. 2006, 45, 7134−7186.
(11) Kambale, D. A.; Thorat, S. S.; Pratapure, M. S.; Gonnade, R. G.;
Kontham, R. Chem. Commun. 2017, 53, 6641−6644.
(12) Fang, G.; Bi, X. Chem. Soc. Rev. 2015, 44, 8124−8173 and
references cited therein.
(13) Inamdar, S. M.; Shinde, V. S.; Patil, N. T. Org. Biomol. Chem. 2015,
13, 8116−162 and references cited therein.
(14) See Supporting Information for details.
(15) (a) Zhang, S.; Xu, Z.; Jia, J.; Tung, C.-H.; Xu, Z. Chem. Commun.
2014, 50, 12084−12087. (b) Wang, X.; Dong, S.; Yao, Z.; Feng, L.;
Daka, P.; Wang, H.; Xu, Z. Org. Lett. 2014, 16, 22−25. (c) Wang, X.;
Yao, Z.; Dong, S.; Wei, F.; Wang, H.; Xu, Z. Org. Lett. 2013, 15, 2234−
2237.
(16) Li, J.; Lin, L.; Hu, B.; Lian, X.; Wang, G.; Liu, X.; Feng, X. Angew.
Chem., Int. Ed. 2016, 55, 6075−6078.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b04027.
■
(17) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans.
1915, 107, 1080−1106.
S
(18) (a) Davies, P. W.; Detty-Mambo, C. Org. Biomol. Chem. 2010, 8,
2918−2922. (b) Hydration products of alkynes commonly observed in
gold catalysis, even when anhydrous solvents and inert atmospheres are
used.
Experimental procedures, spectroscopic data, and copies
of NMR spectra for all new compounds (PDF)
́
(19) (a) Barluenga, J.; Mendoza, A.; Rodríguez, F.; Fananas, F. J.
̃
Angew. Chem., Int. Ed. 2009, 48, 1644−1647 and references cited
therein. (b) Zhou, Q.-L. Angew. Chem., Int. Ed. 2016, 55, 5352−5353.
(c) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817−7831. (d) Aponick, A.;
Li, C.-Y.; Palmes, J. A. Org. Lett. 2009, 11, 121−124.
Accession Codes
CCDC 1811177 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
(20) (a) Zhdanko, A.; Maier, M. E. Chem. - Eur. J. 2014, 20, 1918−
1930. (b) Seo, S.-Y.; Yu, X.; Marks, T. J. J. Am. Chem. Soc. 2009, 131,
263−276 and references cited therein.
(21) (a) Cheng, Y.-S.; Yu, W.; Xu, Y.; Salomon, R. G. J. Nat. Prod. 2017,
80, 488−498. (b) Yuste, F.; Shchez-Obregbn, R. J. Org. Chem. 1982, 47,
3665−3668.
AUTHOR INFORMATION
■
(22) See Supporting Information for proposed reaction mechanism.
Corresponding Author
*E-mail: k.ravindar@ncl.res.in.
ORCID
Ravindar Kontham: 0000-0002-5837-2777
D
DOI: 10.1021/acs.orglett.7b04027
Org. Lett. XXXX, XXX, XXX−XXX