Nitrile oxide cycloaddition to 4-hydroxy-2-cyclopentenone: Solvent effect and selectivity

Article abstract of DOI:10.1016/j.tetlet.2017.07.056

The facial selectivity in the nitrile oxide cycloaddition reactions of 4-hydroxy-2-cyclopentenone and its bulky t-butyloxy derivative is reported. A quantitative evaluation of the solvent effect on the hydrogen bonding directing ability is given, showing

Full text of DOI:10.1016/j.tetlet.2017.07.056

Accepted Manuscript
Nitrile oxide cycloaddition to 4-hydroxy-2-cyclopentenone: solvent effect and
selectivity
Vera Fassardi, Teresa Basile, Misal Giuseppe Memeo, Paolo Quadrelli
PII:
S0040-4039(17)30911-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.056
TETL 49138
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
8 June 2017
6 July 2017
14 July 2017
Please cite this article as: Fassardi, V., Basile, T., Memeo, M.G., Quadrelli, P., Nitrile oxide cycloaddition to 4-
hydroxy-2-cyclopentenone: solvent effect and selectivity, Tetrahedron Letters (2017), doi: http://dx.doi.org/
1
0.1016/j.tetlet.2017.07.056
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Graphical Abstract
Nitrile oxide cycloaddition to 4-hydroxy-2-
cyclopentenone: solvent effect and selectivity
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Vera Fassardi, Teresa Basile, Misal Giuseppe Memeo, Paolo Quadrelli*

1
Tetrahedron Letters
Nitrile oxide cycloaddition to 4-hydroxy-2-cyclopentenone: solvent effect and
selectivity
Vera Fassardi, Teresa Basile, Misal Giuseppe Memeo and Paolo Quadrelli 
Dipartimento di Chimica, Università degli Studi di Pavia, Viale Taramelli 12, 27100 – Pavia (Italy)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The facial selectivity in the nitrile oxide cycloaddition reactions of 4-hydroxy-2-cyclopentenone
and its bulky t-butyloxy derivative is reported. A quantitative evaluation of the solvent effect on
the hydrogen bonding directing ability is given, showing the presence of some syn-
stereoselectivity even in good H-bond acceptor solvents. The stereoselectivities of the O-t-butyl
derivative may serve as reference data for more complex systems and point to the existence of a
sole steric effect on the directivity; M(II) ions did not significantly improve the selectivity. The
results are also discussed in light of the potential application of these scaffolds in the nucleoside
analogue synthesis.
Available online
Keywords:
Nitrile oxide
4
-Hydroxy-2-cyclopentenone
2
009 Elsevier Ltd. All rights reserved.
Solvent effect
Stereoselectivity
Nucleoside synthesis
1
. Introduction
Racemic 4-oxocyclopent-2-en-1-yl acetate 1 was recently employed in a concise synthesis of nucleoside analogues with
pyrimidine and purine heterobases. The protocol, involving a typical nucleophilic substitution process with uracil, thymine, 6-
chloropurine and some adenines, gave the expected 4-heterosubstituted products 2 along with the isomeric 2-heterosubstituted
compounds 3 as minor components (Scheme 1). Selected products were evaluated for antiviral activity in a primary screening
against a variety of viruses.
O
O
O
NaH
R N
+
2
+
NR2
MeCN
°C, 3.5 h
NR2
0
1
OAc
2
3
+
_
Uracil
R
N O
Thymine
6
-Chloropurine
Adenines
O
R
O N-O Bond
Cleavage
R'
N
HO
O
NR2
NR2
4
5
Scheme 1. Synthesis of nucleoside analogues from 4-oxocyclopent-2-en-1-yl acetate (1) and generic heterobases (NR ).
2
1
One compound, belonging to the class of products 2 and bearing a uracil base, was highly active against HPV.
In the search of new compounds for virus diseases treatment and selective antiviral chemotherapy, which are being actively
pursued in our group, various carbocyclic starting materials have been used to obtain the desired nucleoside analogues in the
minimum synthetic steps. In this view, compounds of type 2 are prone to functionalization with nitrile oxides to furnish
cycloadducts 4 along with their synthetically elaborated derivatives 5 through simple N-O bond cleavage, for application as
potential candidates for antiviral activity testing.
—
——

Corresponding author. Tel.: +39-0382-987315; fax: +39-0382-987323; e-mail: paolo.quadrelli@unipv.it

3
Recently, we reported a quantitative evaluation of the stereoselectivity in the cycloaddition reaction of nitrile oxides with
cyclopent-2-enol and allylic cyclopentenyl amides, with particular attention given to the H-bond (HB) directing effects when
2
different solvents were used. Moreover, the possibility to increase or divert the facial selectivity by tuning the experimental
3
conditions, i.e. temperature effects or the presence of bivalent metal M(II) ions, was also investigated.
Herein, we present preliminary studies regarding the facial selectivity in the nitrile oxide cycloaddition reactions of 4-hydroxy-2-
cyclopentenone (6) and its bulky t-butyloxy derivative to mimic the presence of a heterobase substituent, thus serving as reference
data for more complex systems. A quantitative evaluation of the solvent effect on the HB directing ability in the cycloaddition
reaction of nitrile oxide is given, showing the presence of some syn-stereoselectivity even in good H-bond acceptor solvents. The
stereoselectivities of the O-t-butyl derivative point to the existence of a steric effect on the diastereoselectivity; M(II) ions did not
significantly improve the selectivity.
2
. Results
4
4
-Hydroxy-2-cyclopentenone (6), freshly prepared from the rearrangement of furfuryl alcohol, was submitted to the
cycloaddition reaction with benzonitrile oxide (BNO) in CHCl /EtOH to afford the expected stereoisomeric cycloadducts 7a,b (58%
3
5
,6
and 34% yield, respectively) along with the elimination product 8 (4%) (Scheme 2).
O
Ph3 H
2
N
O
4
Ph
N
O
Ph
N
O
H
H
BNO
5
1O
6
O
O
CHCl /EtOH
r.t., 2 d
3
H
H
H
OH
OH
OH
6
7a (6-syn)
7b (6-anti)
8
N
H
Ph
O
O
O
9
Scheme 2. BNO cycloaddition to 4-hydroxy-2-cyclopentenone (6).
The solvent effect was investigated by performing the reactions in 14 solvents of different polarities and Hydrogen Bond
Acceptor (HBA) abilities, and determining the product distribution by quantitative HPLC analyses. Table 1 gives the reaction yields
7
and stereoisomeric ratios of 7a,b along with the Taft’s  parameter, a descriptor of the solvent HBA ability. The values are the
average results of at least two independent experiments.
Table 1. Reaction yields and stereoisomeric ratios of cycloadducts 7a,b in the cycloaddition reactions of 4-hydroxy-2-
a
cyclopentenone (6) with BNO.
b
Entry
Solvents ()
Cy (0.00)
Yield (%)
7a
76
71
83
74
73
71
32
36
34
32
44
28
16
22
7b
24
29
17
26
27
29
68
64
79
68
56
72
84
78
7a/b
1
2
3
4
5
6
7
8
9
90
89
98
97
95
97
68
94
66
45
74
71
89
64
3.2
2.4
4.9
2.8
2.7
2.4
0.5
0.6
0.4
0.5
0.8
0.4
0.2
0.3
n-Hex (0.00)
CCl
CH Cl
CHCl
4
(0.00)
(0.00)
(0.00)
2
2
3
PhH (0.10)
1,4-Dioxane (0.37)
AcOEt (0.45)
Et O (0.47)
2
Acetone (0.48)
THF (0.55)
MeOH (0.62)
DMF (0.69)
EtOH (0.77)
1
1
1
1
1
0
1
2
3
4
a
b
Reagents and conditions: BNO (63 mg, 0.52 mmol), 4-hydroxy-2-cyclopentenone (1.2 equiv.), solvent (25 mL), 25 °C, 2 d.  values, see ref. 7.
In non-HBA solvents ( = 0.00-0.10; Table 1, entries 1-6), the 6-syn cycloadduct 7a, derived from the HB directed cycloaddition
shown in transition structure (TS) 9 (see inset of Scheme 2), is the major product and amounts to 71-83% of the cycloaddition
products. The best result (Entry 3), both in terms of chemical yield and facial selectivity, was obtained in CCl . In HBA acceptor
4
solvents (Entries 7-14) the HB directing effect decreases due to the competing effect of the solvent for the HB and the amount of

4
cycloadduct 7a steadily drops with the increasing solvent  values. In DMF (Entry 13) the selectivity is reversed with respect to
Entry 3. The 7a/b ratio gives an immediate and clear indication of the reaction behavior in the tested solvents. In non-HBA solvents
the 7a/b ratio was 2.4-3.2 while in HBA solvents it was 0.3-0.8.
Figure 1. Plot and linear regression of the log(7a%) and log(12a%) vs
solvent  values.
A graphical illustration of the solvent effect is given in Figure 1, where the log of the percentage of adduct 6-syn 7a in the
reaction mixtures is plotted against the solvent  values. In non-HBA solvents ( equal or proximal to 0.00), the HB directing effect
is fairly active and constant, with all of the points clustered together. The use of HBA solvents results in a drop of the points along
2
the black line with slope –0.75. The linear regression is acceptable (r = 0.90) and shows that the  parameter satisfactorily accounts
for the solvent effect on the stereoselectivity. This is consistent with the results obtained for the cycloaddition of BNO with
cyclopent-2-enol, and nicely resembles the behavior of cyclopentenyl amides in the same reaction (see ref. 2 for comparison).
CrO /H SO
4
O
OH
3
2
Acetone, 0 °C
6%
t-BuOOH
7
Jones
Oxidation
Cu(OAc) .H O (10 mol%)
AcOH 80%
2
2
1
0 OtBu
11 OtBu
BNO
Benzene
r.t., 2 d
Ph3 H
2
N
O
4
Ph
H
O
Ph
O
H
OtBu
O
5
N
N
1O
6
O
O
H
H
H
O
OtBu
OtBu
Ph
N
13
12a (6-syn)
12b (6-anti)
8
6%
90%
4%
Scheme 3. BNO cycloaddition to 4-t-butoxy-2-cyclopentenone (11).
Conversely, the related BNO cycloaddition to 4-t-butoxy-2-cyclopentenone 11, obtained via the oxidation of alcohol 10 which is
8
derived from the Cu(II)-catalyzed oxidation of cyclopentadiene, does not show any noticeable solvent dependence (Table 2). The
reaction of BNO with 11 in benzene gave the stereoisomeric cycloadducts 12a,b and the elimination product 8 (Scheme 3), which
were separated by column chromatography. The cycloadducts were obtained in good yields, 12a (54%) and 12b (8%), and the
9
structural assignments were determined from their analytical and spectroscopic data.
The solvent effect was investigated by performing the reactions in 14 solvents of different polarities and HBA abilities and
determining the product distribution by quantitative HPLC analyses. Table 2 gives the reaction yields and stereoisomeric ratios of
7
1
2a,b along with the Taft’s  parameter. The values are the average results of at least two independent experiments.
Table 2. Reaction yields and stereoisomeric ratios of cycloadducts 12a,b in the cycloaddition reactions of 4-t-butoxy-2-
a
cyclopentenone (11) with BNO.
b
Entry
Solvents ()
Cy (0.00)
Yield (%)
12a
2
2
12b
98
98
12a/b
0.09
0.09
1
2
74
73
n-Hex (0.00)

5
3
4
5
6
7
8
9
CCl
CH Cl
CHCl
PhH (0.10)
1,4-Dioxane (0.37)
AcOEt (0.45)
Et O (0.47)
2
Acetone (0.48)
THF (0.55)
4
(0.00)
72
60
58
66
50
61
66
51
56
49
48
40
3
13
12
8
5
11
8
10
12
20
8
97
87
88
92
95
89
92
90
88
80
92
89
0.03
0.15
0.14
0.09
0.05
0.12
0.09
0.11
0.14
0.25
0.09
0.12
2
2
(0.00)
(0.00)
3
1
0
1
2
3
4
1
1
1
1
MeOH (0.62)
DMF (0.69)
EtOH (0.77)
11
a
b
Reagents and conditions: BNO (63 mg, 0.52 mmol), 4-t-butoxy -2-cyclopentenone (1.2 equiv.), solvent (25 mL), 25 °C, 2 d.  values, see ref. 7.
As a general comment, the reaction yields are generally lower than those of the previous reported reaction with alcohol 6 as the
dipolarophile. In non-HBA solvents ( = 0.00-0.10; Table 2, entries 1-6), the 6-anti cycloadduct 12b is notably the major product
and amounts to 80-98% of the cycloaddition products. The best result (Entry 1), both in terms of chemical yield and selectivity, was
obtained in cyclohexane. In HBA acceptor solvents (Entries 7-14) the same behavior is observed since no HB directive effect can be
6
considered and steric and electronic effects guide the selectivity. The 12a/b ratios below 0.25 indicate the prevalence for the anti-
orientation of BNO cycloaddition.
In the lower half of Figure 1, the red squares show the random distribution of the 6-syn adduct 12a in the reaction mixtures when
the log percentage values are plotted against the Taft’s  descriptor. In this case the solvent does not appear to be engaging in
hydrogen bonding with the substrate.
Metal-mediated approaches have been proposed for nitrile oxide 1,3-dipolar cycloaddition reactions to acyclic allylic alcohols in
1
0
11
order to improve the regio- and stereocontrol. In accordance with literature observations and our recent results regarding the
2
cycloaddition of nitrile oxides with cyclopent-2-enol, we also studied the reaction of 4-hydroxy-2-cyclopentenone (6) with BNO in
the presence of representative bivalent M(II) salts in CH Cl (Scheme 2).
2
2
2
The solvent choice was based on the necessary comparison with the results obtained in the absence of any metal ion. CH Cl is a
2
2
typical non-HBA solvent (Taft’s parameter  = 0.00) and the directing effect by the dipolarophile (see TS 9 in the inset of Scheme
2
) is solely at work. Moreover, CH Cl displays a good ability to dissolve the inorganic salts under the applied experimental
2 2
conditions.
Table 3 reports the reaction yields as well as stereoisomeric ratios of cycloadducts 7a,b when M(II) salts are present in
equimolecular amounts. The values are the average results of at least two independent experiments.
Table 3. Reaction yields and stereoisomeric ratios of cycloadducts 7a,b in the cycloaddition reactions of 4-hydroxy-2-
a
cyclopentenone (6) with BNO in the presence of M(II) salts in CH Cl .
2
2
Entry
M(II)X
Yield (%)
7a
7b
7a/b
(1.0 equiv.)
Reaction conducted at 25 °C
b
1
2
3
4
5
6
7
8
CH
MgBr
MgTf
ZnBr
ZnTf
Mg(ClO
2
Cl
2
97
74
61
57
71
60
65
64
63
26
39
43
29
40
35
36
37
2.8
1.6
1.3
2.4
1.5
1.9
1.8
1.7
2
75
82
44
55
87
80
76
2
2
2
4
)
2
Ni(ClO
Zn(ClO
4
)
2
4
)
2
Reaction conducted at 0 °C
9
MgBr
MgTf
ZnBr
ZnTf
Mg(ClO
2
84
81
50
60
84
81
77
56
55
70
61
67
65
65
44
45
30
39
33
35
35
1.3
1.2
2.3
1.6
2.0
1.9
1.9
1
1
1
1
1
1
0
1
2
3
4
5
2
2
2
4 2
)
4 2
Ni(ClO )
Zn(ClO )
4 2
a
b
2 2
Reagents and conditions: BNO (63 mg, 0.52 mmol), 4-hydroxy-2-cyclopentenone (1.2 equiv.), CH Cl (25 mL), 25 °C, 2 d. Without salts.
The reaction yields were generally lower with respect to the experiment conducted without salts (compare with the values
reported in Table 1). Independent of the additive used, bivalent Lewis acid-mediated reactions in CH Cl erode the syn-
2
2
stereoselectivity offered by the HB directing effect of the substrates alone. They also appear randomly distributed with respect to the
salts used; therefore it is difficult to make any correlation with the ionic radius of the M(II) element or the counterion and lowering
the reaction temperature does not ameliorate the selectivity outcome.
3
. Discussion
The fair correlation between the percentage of cycloadduct 7a in the reaction mixtures and the Taft’s  parameter support the
idea of HB directivity in these reactions and indicate that the  parameter is the descriptor of choice. The results are similar to those

6
2
obtained for the nitrile oxide cycloaddition reaction with cyclopentenyl amides. As previously noted, while synthetically useful, the
size of the solvent effect is somewhat smaller than expected and the data in Figure 1 seem to indicate a persistence of the HB
directivity even in good HBA solvents, since the data relative to polar protic solvents and DMF lie well above the clustered data
corresponding to apolar solvents. The most immediate impression is that only some HB directivity is lost due to solvation of the
directing groups.
R
R'
R' = H, R
O
Ph
O
N
H
O
O
Figure 2. Bifurcated hydrogen bonding.
The persistence of the HB even in good HBA solvents can be attributed to the residual interaction between the OH and the nitrile
oxide oxygen atom. The directing groups give rise to a sort of bifurcated hydrogen bond with two interactions of different
magnitude and presumably influence each other (Fig. 2). Bifurcated hydrogen bonds have been frequently noted in theoretical
13
1
2
calculations and the main evidence for their role comes from structural studies, which show that they are very common.
1
4
Spectroscopic evidence has also been provided.
Contrary to expectations, the metal-mediated cycloaddition reactions did not improve the syn-selectivity and can be easily
ascribed to the competitive complexation by the 4-hydroxy-2-cyclopentenone (6) through the carbonyl group (TS_A) that diverts
the metal ions from efficient coordination (TS_B) between the addends (Fig. 3). Competitive binding of the nitrile oxide to the
Lewis acids is also possible as an explanation for the poor performance of the metal salts.
Figure 3. Competitive TSs metal ion coordination during syn approach to the dienophile.
Finally, a further contributing factor must be accounted for. A recent review by Wang and Houk surveyed theoretical
1
5
calculations, leading to an understanding of the influence of the torsional effects on several stereoselective reactions. We cannot
exclude the different conformational arrangements required by the enone dipolarophile during addition of the dipole; these torsional
effect may modify the TS structures to incorporate H-bonding, justifying in the case of metal chelation the selectivity outcome.
4
. Conclusion
In conclusion, HB directing effects can be considered for the synthetic applications of 4-hydroxy-2-cyclopentenone (6); when
bulky substituents are located in position 4 of the cyclopentenone ring, the syn-selectivity is diverted and functionalization of the
double bond proceeds on the opposite face. This is of significant interest in view of the potential applications in nucleoside analogue
synthesis (Scheme 4), aiming to locate the nitrile oxide R group anti with respect to the heterobase moiety.
+
_
N
R = Aromatic
Polyaromatic
Heterocyclic
N
R
N O
O
R
O
O
N
4
14
O
N
Spacer
R
Scheme 4. Applications in nucleoside synthesis: strategy and
stereochemical outcome.
The cycloaddition of nitrile oxides to heterobase functionalized cyclopentenones of type 4 can be used to afford derivative 14
where a variety of substituents can be inserted via the 1,3-dipole moiety. In particular, we are currently interested in the introduction
of aromatic and polyaromatic residues to take advantage of their DNA intercalating properties, since recent results have reported
1
6
valuable activities against HPV and other viruses. Recent results have also accounted for the high level of antiviral activity found

7
in compounds bearing an anti relationship between the heterobase and substituents inserted via the nitrile oxide cycloaddition
1
7
reaction (Scheme 4). Aromatic heterocyclic 1,3-dipoles and the corresponding nitrosocarbonyl intermediates also offer promising
1
8
methodologies for the synthesis of antiviral compounds.
Acknowledgments
Financial support of University of Pavia and MIUR (PRIN 2011, CUP: F11J12000210001) is gratefully acknowledged. Many
tranks are due to CINMPIS for a research grant to AMC.
References and notes
1
2
3
.
.
.
Mantione, D.; Olaizola Aizpuru, O.; Memeo M. G.; Bovio, B.; Quadrelli, P. Eur. J. Org. Chem. 2016, 983-991.
Cardarelli, A.; Fassardi, V.; Memeo, M. G.; Quadrelli, P. Tetrahedron 2017, 73, 2602-2613.
(a) Kanemasa, S.; Okuda, K.; Yamamoto, H.; Kaga, S. Tetrahedron Lett. 1997, 38, 4095-4098. (b) Yamamoto, H.; Watanabe, S.; Kadotami, K.;
Hasegama, M.; Noguchi, M.; Kanemasa, S. Tetrahedron Lett. 2000, 41, 3131-3136.
4
5
.
.
Holland, H. L.; Brown, F. M.; Chenchaiah, P. C.; Rao, J. A. Can. J. Chem. 1990, 68, 282-286.
(a) Giorgi, G.; Lampariello, L. R.; Minetto, G.; Paoli, M. L.; Riello, V.; Rodriquez, M.; Sega, A. Eur. J. Org. Chem. 2003, 4777-4785. (b)
Adembri, G.; Paoli, M. L.; Sega, A. J. Chem. Res. (S) 2003, 126-127. (c) Quadrelli, P.; Mella, M.; Paganoni, P.; Caramella, P. Eur. J. Org. Chem.
2
000, 2613-2620.
(a) Caramella, P.; Cellerino, G. Tetrahedron Lett. 1974, 229-232. (b) Quadrelli, P.; Fassardi, V.; Paganoni, P.; Caramella, P. Eur. J. Org. Chem.
002, 2058-2065.
(a) Reichardt, C. in Solvents and Solvent Effects in Organic Chemistry, ed. VCH, Weinheim, 1988, p. 392. (b) Reichardt, C. Chem. Rev. 1994, 94,
319-2358 and references therein. (c) Kamlet, M. J.; Taft, R. W. J. Am. Chem. Soc. 1976, 98, 377-383. (d) Kamlet, M. J.; Taft, R. W. J. Am.
6
7
.
.
2
2
Chem. Soc. 1976, 98, 2886-2894. (e) Kamlet, M. J.; Abbaud, J. L. M.; Abraham, M. H.; Taft, R. W. J. Org. Chem. 1983, 48, 2877-2887.
8
9
.
.
Schwartz, J.; Loots, M. J.; Kosugi, H. J. Am. Chem. Soc. 1980, 102, 1333-1340.
12a: m.p. 101-103 °C from petroleum ether. IR (, cm-1): 1749 (C=O). H NMR (, CDCl
1
3
): 1.28 (s, 9H, t-Bu), 2.19 and 2.78 (AB syst., 2H,
CH
2
), 4.16 (d, 1H, J = 9 Hz, H3a), 4.38 (dd, 1H, J = 11, 8 Hz, CH-Ot-Bu), 5.45 (dd, 1H, J = 9, 5 Hz, H6a), 7.43 (m, 3H, arom.), 7.91 (m, 2H,
13
arom.). C NMR (, CDCl
3
): 27.9, 35.8, 57.1, 72.3, 75.4, 81.9, 127.1, 128.6, 128.7, 130.4, 153.1, 208.4. Elemental Analysis: C 71.25%, H
.10%, N 15.58%; calcd. for C16 C 71.34%, H 7.11%, N 15.60%.
2b: m.p. 144-147 °C from petrol ether. IR (, cm-1): 1752 (C=O). H NMR (, CDCl
H+1H, H3a and CH-Ot-Bu), 4.89 (d, 1H, J = 10 Hz, H6a), 7.43 (m, 3H, arom.), 7.68 (m, 2H, arom.). C NMR (, CDCl
8.1, 81.3, 126.6, 127.4, 128.1, 129.1, 129.6, 130.7, 134.2, 159.8, 206.4. Elemental Analysis: C 71.30%, H 7.09%, N 15.61%; calcd. for
C 71.34%, H 7.11%, N 15.60%.
The spectra of compounds 12a,b are given in the ESI.
7
1
1
6
H19NO
3
1
3
): 0.92 (s, 9H, t-Bu), 2.61 (AB syst., 2H, CH
2
), 4.56 (m,
13
3
): 27.7, 55.3, 55.6,
16 3
C H19NO
1
0. (a) Kanemasa, S.; Nishiuchi, M.; Kamimura, A.; Hori, K. J. Am. Chem. Soc. 1994, 116, 2324-2339. (b) Kamimura, A.; Kaneko, Y.; Ohta, A.;
Kakehi, A.; Matsuda, H.; Kanemasa, S. Tetrahedron Lett. 1999, 40, 4349-4352.
1
1
1
1
1
1
1. Kim, H. R.; Song, J. H.; Rhie, S. Y.; Ryu, E. K. Synth. Commun. 1995, 25, 1801-1807.
2. Newton, M. D.; Jeffrey, G. A.; Takagi, S. J. Am. Chem. Soc. 1979, 101, 1997-2001.
3. Jeffrey, G. A. in An Introduction to Hydrogen Bonding, Oxford Press Eds., New York, 1997.
4. Goutev, N.; Matsuura, H. J. Phys. Chem. A 2001, 105, 4741-4748.
5. Wang, H.; Houk, K. N. Chem. Sci. 2014, 5, 462-470.
6. (a) Moggio, Y.; Legnani, L.; Bovio, B. Memeo, M. G.; Quadrelli, P. Tetrahedron 2012, 68, 1384-1392. (b) Memeo, M. G.; Lapolla, F.; Maga, G.;
Quadrelli, P. Tetrahedron Lett. 2015, 56, 1986-1990.
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7. Memeo, M. G.; Quadrelli, P. Chem. Rev. 2017, 117, 2108-2200.
8. Quadrelli, P.; Mella, M.; Legnani, L.; Al-Saad, D. Eur. J. Org. Chem. 2013, 4655-4665.

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HIGHLIGHTS
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Facial selectivity in the nitrile oxide cycloadditions of 4-hydroxy-2-cyclopentenone is reported.
Quantitative evaluation of the solvent effect on the H-bonding directing ability was
investigated.
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The results are discussed in light of potential applications in nucleoside synthesis.

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Graphical Abstract
Nitrile oxide cycloaddition to 4-hydroxy-2-
cyclopentenone: solvent effect and selectivity
Leave this area blank for abstract info.
Vera Fassardi, Teresa Basile, Misal Giuseppe Memeo, Paolo Quadrelli*