Antifungal activity of 1′-homo-N-1,2,3-triazol-bicyclic carbonucleosides: A novel type of compound afforded by azide-enolate (3+2) cycloaddition

Article abstract of DOI:10.1016/j.bioorg.2016.09.003

The first report of 1′-homo-N-1,2,3-triazol-bicyclic carbonucleosides (7a and 7b) is described herein. Azide-enolate (3+2) cycloaddition afforded the synthesis of this novel type of compound. Antifungal activity was evaluated in vitro against four filamentous fungi (Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae and Mucor hiemalis) as well as nine species of Candida spp. as yeast specimens. These pre-clinical studies suggest that compounds 7a and 7b are promising candidates for complementary biological studies due to their good activity against Candida spp.

Full text of DOI:10.1016/j.bioorg.2016.09.003

Accepted Manuscript
Preliminary Communications$Communications
Antifungal activity of 1’-homo-N-1,2,3-triazol-bicyclic carbonucleosides: a
novel type of compound afforded by azide-enolate (3+2) cycloaddition
Davir González-Calderón, María G. Mejía-Dionicio, Marco A. Morales-Reza,
José G. Aguirre-de Paz, Alejandra Ramírez-Villalva, Macario Morales-
Rodríguez, Aydeé Fuentes-Benítes, Carlos González-Romero
PII:
S0045-2068(16)30069-4
DOI:
http://dx.doi.org/10.1016/j.bioorg.2016.09.003
YBIOO 1949
Reference:
Bioorganic Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 June 2016
1 September 2016
14 September 2016
Please cite this article as: D. González-Calderón, M.G. Mejía-Dionicio, M.A. Morales-Reza, J.G. Aguirre-de Paz,
A. Ramírez-Villalva, M. Morales-Rodríguez, A. Fuentes-Benítes, C. González-Romero, Antifungal activity of 1’-
homo-N-1,2,3-triazol-bicyclic carbonucleosides: a novel type of compound afforded by azide-enolate (3+2)
cycloaddition, Bioorganic Chemistry (2016), doi: http://dx.doi.org/10.1016/j.bioorg.2016.09.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Short Communication
Antifungal activity of 1'-homo-N-1,2,3-triazol-bicyclic carbonucleosides: a
novel type of compound afforded by azide-enolate (3+2) cycloaddition
Davir González-Calderón,a,* María G. Mejía-Dionicio,a Marco A. Morales-Reza,a José G. Aguirre-de
Paz,a Alejandra Ramírez-Villalva,a Macario Morales-Rodríguez,b Aydeé Fuentes-Benítes,a and Carlos
González-Romero,a,*
a Departamento de Química Orgánica, Facultad de Química, Universidad Autónoma del Estado de México, Paseo
Colón/Paseo Tollocan s/n, Toluca, Estado de México, 50120, Mexico.
b
Departamento de Microbiología, Facultad de Química, Universidad Autónoma del Estado de México, Paseo
Colón/Paseo Tollocan s/n, Toluca, Estado de México, 50120, Mexico.
 Corresponding author: Tel: +52 722 217 5109x113; Fax: +52 722 217 3890; e-mail: cgonzalezr@uaemex.mx (C.
González-Romero) and qfb_dgonzalez@yahoo.com.mx (D. González-Calderón).
Abstract
The first report of 1'-homo-N-1,2,3-triazol-bicyclic carbonucleosides (7a and 7b) is
described herein. Azide-enolate (3+2) cycloaddition afforded the synthesis of this novel
type of compound. Antifungal activity was evaluated in vitro against four filamentous
fungi (Aspergillus fumigatus, Trichosporon cutaneum, Rhizopus oryzae and Mucor
hiemalis) as well as nine species of Candida spp. as yeast specimens. These pre-clinical
studies suggest that compounds 7a and 7b are promising candidates for complementary
biological studies due to their good activity against Candida spp.
Keywords: 1’-Homonucleosides; 1,2,3-Triazole; Antifungal activity; Azide-enolate
cycloaddition
1. Introduction
The chemistry and biology of nucleoside analogues has consolidated a very particular
and proper field of study in organic and medicinal chemistry.[1] A certain classification
of such compounds, convenient for the purpose of the present study, is described in Fig.
1. One of the most important modifications of nucleosides Aa[2] has been the
replacement of the oxygen atom of the furanose ring with a methylene group, resulting
in carbocyclic nucleosides Ab[3] (also called ‘carbonucleosides’ in short form). The
recognition of 1,2,3-triazole scaffolds as potent pharmacophores[4] has revolutionized
nucleoside analogs allowing for their conversion to the corresponding triazole
derivatives Ba[5] and Bb.[6]

Het
Het
Het
X
1'
iii
X
X
ii
i
Aa
: X= O, Nucleosides
Ab: X= CH2, Carbocyclic Nucleosides
Ca: X= O, 1'-Homonucleosides
Ea
: X= O, Bicyclic nucleosides
Cb
: X= CH2, 1'-Homocarbocyclic
Nucleosides
Eb: X= CH2, Bicyclic carbonucleosides
(Carbonucleosides)
N
N
N
N
N
N
Het
O
1'
O
X
1'
ii
i
F
: 1'-Homo-bicyclic nucleosides
D
: 1'-Homo-N-triazol-nucleosides
Ba: X= O, Triazole Nucleosides
Bb
: X= CH2, Triazole Carbocyclic
Nucleosides
N
N
G
: 1'-Homo-N-triazol-
bicyclic carbonucleosides.
Novel type of compunds
(this work)
N
iii
1'
ii
i
Fig. 1. General classification of nucleoside analogues reported in literature. Possible positions (i, ii, and
iii) for bicyclic derivatives E and F are known. A novel type of compound G is herein proposed.
1’-Homonucleosides (Ca[7] and Cb[8]) are a special class of modified nucleosides,
in which the nucleobase (Het) and the sugar moiety (at its 1’-position) are separated by
a carbon bridge. In addition to greater conformational flexibility and rotational freedom,
this gives them more resistance to hydrolytic or enzymatic cleavage compared to the
relatively reactive aminal linkage of common nucleosides.[9] Modified triazolic
nucleosides D[10] can be found in literature, and the discovery of certain natural
bicyclic nucleosides Ea[11] (e.g. Ezomycin[12] and Octosyl[13]) along with their
potent antifungal activity[14] has sparked new research into the design and synthesis of
novel carbonucleoside derivatives Eb[15] as well as their 1’-homo mimetics F.[16]
Sesquiterpene lactones (carbobicyclic lactones) are amongst the most abundant
natural products. More than 8000 structures have been reported, [17] and they have
broad structural and functional diversity including their antifungal activity [e.g.
Sclareolide[18] (Fig. 2)]. The introduction of these scaffolds to nucleosides analogs (H
and I) has been performed by Castillón.[19] The chemical structure of certain antifungal
nucleoside analogs (J[20] and K[21] among others[22]) has inspired the design and
synthesis of 1'-homo-N-1,2,3-triazol-bicyclic carbonucleosides 7a and 7b. To the best of
our knowledge, this type of compound (G) has not yet been reported.

Antifungal compounds
O
O
N
Bicyclic nucleosides
O
NH
NH
O
H
O
H
O
O
O
H
N
O
O
H
O
Sclareolide
(lactone scaffold)
O
H
SePh
H
I
This work
N
HO
R2
R1
N
N
O
N
N
H
R2
OH OH
J: Carbocyclic nucleoside
N
1'
N
1'
O
R
N
R1
=
O
N
N
H
OH
O
Haworth projection
OH
1'
O
7a: R1= Me, R2= COMe
1
2
7b
: R = Ph, R = COPh
OBn
HO
K:1'-Homo-N-triazol-nucleosides
FIGURE 2. The current antifungal compounds Sclareolide, J and K as well as H and I inspired the
design of novel nucleoside analogs 7a and 7b.
2. Results and discussion
2.1 Chemistry
The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) has largely been the
conventional approach for synthesizing triazole nucleosides.[5] In recent years, azide-
enolate (3+2) cycloaddition (AEC) has emerged as a novel and potent tool for the
synthesis of 1,2,3-triazole moieties.[23] As a pioneering strategy we describe the
synthesis of 7a and 7b afforded by a versatile AEC (Scheme 1).
Our initial study began by obtaining silylated ‘Corey lactone’ 2, according to our
previous report,[24] as the key precursor for the present synthesis. This compound is an
excellent supplier of the pseudosugar ring (cyclopentane) required for the highly
stereospecific configuration of all suitable functional groups. A convenient protection–
deprotection strategy for alcohols was planned for the present study involving the
esterification of 2 with p-phenylbenzoyl chloride (PBCl) in dichloromethane and
pyridine to form the ester lactone 3.

O
O
O
O
O
three steps
[Ref. 24]
O
O
O
(i)
(ii)
OH
OTBS
OTBS
PBPCO2
PBPCO2
HO
O
1
4
3
2
PBP= p-Ph C6H4
O
O
O
(v)
(iii)
(iv)
7a 7b
or
N
N
N
I
R2
PBPCO2
PBPCO2
5
1
2
R1
6a
: R = Me, R = COMe
1
2
6b
: R = Ph, R = COPh
SCHEME 1. Reagents and conditions: (i) PBCl (1.1 eq), Py anh., DCM, r.t., N2, 1 h, 90%. (ii)
AlCl36H2O cat, MeOH, 60 ºC, 12 h, 93%. (iii) PPh3 (2.5 eq), I2 (2.0 eq.), Im (2.5 eq.), MeCN anh., 80 ºC,
N2, 3 h, 85% (iv) For 6a: NaN3 (1.1 eq), DMF anh., 60 ºC, N2, 6 h, then acetylacetone (1.1 eq), DBU (1.1
eq), 12 h, 60 ºC, 72%. For 6b: NaN3 (1.1 eq), DMF anh, 60 ºC, N2, 6 h, then 2-benzoylacetophenone (1.1
eq), DBU (1.1 eq), 12 h, 60 ºC, 67%. (v) Both 7a and 7b: DBN cat, MeOH, r.t. 12 h, 87% and 81%
respectively.
Previously,[25] we investigated the AlCl36H2O cleavage of silyl ethers in methanol.
Thus, desilylation of 3 was accomplished by such a protocol to afford alcohol 4, which
was functionalized to the corresponding iodide derivative 5 according to the Garegg-
Samuelsson procedure (PPh3/I2/Im/ROH system).[26] On the other hand, we
recently[27] published a straightforward approach to the synthesis of 1,4,5-trisubstituted
1,2,3-triazoles by the coupling of three-components (alkyl halides, sodium azide, and
ketones) through an AEC. This method proved to be a very rapid and elegant way to
access triazole building blocks 6a and 6b by the coupling of acetylacetone and 2-
benzoylacetophenone, respectively. Finally, transesterification of 6a and 6b by
treatment with DBN in MeOH gave the corresponding carbonucleosides 7a and 7b.
Compounds 7a and 7b were evaluated for their in vitro antifungal activity against
four filamentous fungi (Aspergillus fumigatus ATCC-16907, Trichosporon cutaneum
ATCC-28592, Rhizopus oryzae ATCC-10329 and Mucor hiemalis ATCC-8690), as
well as Candida utilis ATCC-9226, Candida albicans ATCC-10231 and Candida
tropicalis ATCC-13803 as yeast specimens. In addition, other strains for Candida spp.
(C. lipolytica, C. pseudotropicalis, C. krusei, C. parapsilosis, C. glabrata, and Candida
famata) were collected from inpatients and evaluated under the aforementioned

protocol. CLSI standardized methods were employed to carry out the microbiological
tests. We used the M38-A2[28] microdilution method to determine the sensitivity of
filamentous fungi, and the M27-A3[29] method for Candida yeasts. The antifungal
activity of compounds 7a and 7b was compared with itraconazole, a standard antifungal
drug. The minimum inhibitory concentration (MIC) values of compounds and standard
drugs, expressed in micrograms per milliliter, were determined in 96-well plates by
using RPMI 1640 medium buffered with MOPS (3-[N-morpholino]propane sulfonic
acid; Sigma-Aldrich).
2.2 Antifungal activity
The antifungal activity of the evaluated compounds is summarized in Table 1.
Compounds 7a and 7b showed good activity in some of the yeast strains, including C.
utilis, C. lipolytica, C. glabrata and C. famata, demonstrating ‘sensitivity’* according to
the parameters of document M27-A3 (Table 2). Only slight antifungal activity against
C. albicans, C. tropicalis, C. pseudotropicalis, C. krusei, and C. parapsilosis was
observed. Whereas there was evident resistance by M. hiemalis, slight activity was
found against the rest of the filamentous fungi tested (A. fumigatus, T. cutaneum, and R.
oryzae).
Table 1. In vitro antifungal activities of synthetized compounds (MIC, µg/mL).
Yeast fungi
Filamentous fungi
Comp.
C. alb. C. trop.
C. uti.
0.12
0.12
0.25
C. lipo. C. pseu. C. kru. C. para. C. gla.
C. fam.
0.06
0.5
M. hie.
>16
>16
4
A. fum.
T. cut.
R. ory.
0.25
2
0.5
2
0.12
0.12
0.03
0.5
1
4
4
2
4
0.5
0.5
4
8
8
>16
2
4
8
1
1
2
Standardᵅ
0.03
0.25
0.12
0.25
0.12
0.06
0.06
0.5
Abbreviations: C. alb., Candida albicans; C. trop., Candida tropicalis; C. uti., Candida utilis; C. lipo., Candida lipolytica;
C. pseu., Candida pseudotropicalis; C. kru., Candida krusei; C. para., Candida parapsilosis; C.gla., Candida glabrata;
C.fam., Candida famata; M. hie., Mucor hiemalis; A. fum., Aspergillus fumigatus; T. cut., Trichosporon cutaneum; R. ory.,
Rhizopus oryzae;
a Itraconazole
*
‘S’, ‘SDD’ and ‘R’ are represented by standardized values (breakpoints) used to appreciate the clinical value of the in vitro
antifungal testing result and predicting the response of patients infected. Sensitivity is dependent on achieving the maximum
dosages in plasma (breakpoints) to obtain optimal response. For itraconazole, an MIC within the susceptible-dose dependent (SDD)
range indicates the need for plasma concentrations 0.25-0.5 µg/mL for an optimal response. Actual breakpoints are described in
Table 4 (See ref. 29b).

Table 2. Sensitivity of yeast strains according to the document M27-A3: Susceptible (S),
dose dependent sensitive (SDD) and resistant (R).
Compound
C. alb.
SDD
R
C. trop.
SDD
R
C. uti.
C. lipo. C. pseu. C. kru. C. para. C. gla.
C. fam.
S
S
S
S
SDD
R
R
R
R
R
S
SDD
SDD
S
S
SDD
S
1
2
S
Standardᵅ
S
SDD
SDD
S
SDD
a Itraconazole. Interpretive criteria: Breakpoints (MIC, µg/mL) =
3. Conclusion
In conclusion, we report the first synthesis of a novel type of compound, represented
by 1'-homo-N-1,2,3-triazol-bicyclic carbonucleosides 7a and 7b, which showed good
activity against some of the yeast strains tested. Moreover, AEC was employed as a
synthetic strategy. These advances make the present study a breakthrough in the field of
nucleoside chemistry. The pre-clinical study of these compounds show a good
antifungal scope for Candida spp., representing new leads for further development of
pharmacomodulator in this series.
4. Experimental
4.1 General
The reagents were purchased from Aldrich Chemical Co. and were used without
further purification. Dichloromethane, pyridine, acetonitrile, and dimethylformamide
were dried according to literature.[30] Flash column chromatography: SiO2 60 (230–
400 mesh). TLC: Silica-gel plates (SiO2; 0.20-mm thickness); visualization with UV
light at 254 nm or by staining with base soln. of CoCl2/H2SO4 ac. (2g/100 mL H2SO4
10%) followed by heating 140 ºC. m.p.: Fischer-Johns Scientific melting point
1
apparatus; uncorrected. H- and 13C-NMR spectra: Bruker Avance 300 MHz and a
Varian 500 MHz; δ in ppm rel. to Me4Si as internal standard, J in Hz. MS: Shimadzu
GCMS-QP2010 Plus; in m/z (rel. %).
4.1.1. (3aR,4S,5R,6aS)-4-((tert-butyldimethylsilyloxy)methyl)-2-oxo hexahydro-2H-
cyclopenta[b]furan-5-yl biphenyl-4-carboxylate (3). To a solution of Corey lactone-
alcohol 2 (2.0 g, 6.98 mmol) in anhydrous dichloromethane (DCM, 15.0 mL) and
anhydrous pyridine (Py, 5.0 mL) at room temperature under inert atmosphere was added
p-phenylbenzoyl chloride (1.66 g, 7.68 mmol). The reaction mixture was stirred for 1 h,

and then water (70 mL) was added to the reaction mixture and washed with DCM
(3×10 mL). In order to remove the excess Py, the organic layer was washed with CuSO4
5% sol. (5–8×20 mL until strong blue color of watery layer gradually turned to slightly
blue color). The organic layer was dried with anhydrous Na2SO4 and the solvent was
concentrated in vacuo. The crude product was purified by flash column chromatography
1
to give the white solid 3 (2.94 g, 90%). m.p. 91–95 ºC. Rf: 0.35 (Hex/EtOAc 8:2). H
NMR: (300 MHz, CDCl3) δ = 8.06 (d, J= 8.4 Hz, 2 Ar-H), 7.64 (dd, J= 15.7, 7.7 Hz, 4
Ar-H), 7.49–7.33 (m, 3 Ar-H), 5.37 (dt, J= 5.8, 2.9 Hz, 1 H), 5.09 (t, J= 5.9 Hz, 1 H),
3.72 (qd, J= 10.2, 4.7 Hz, 2 H), 3.00–2.86 (m, 2 H), 2.65–2.42 (m, 2 H), 2.34 (d, J=
13
17.2 Hz, 2 H), 0.90 (s, 9 H), 0.07 (s, 6 H) ppm. C NMR: (75 MHz, CDCl3) δ = 176.86
(C=O), 165.86 (C=O), 145.84 (C), 139.92 (C), 130.14 (2 CH), 128.89 (2 CH), 128.52
(C), 128.12 (CH), 127.24 (2 CH), 127.12 (2 CH), 85.42 (CH), 78.78 (CH), 63.43 (CH2),
55.16 (CH), 40.53 (CH), 39.07 (CH2), 36.24 (CH2), 25.84 (3 CH3), 18.17 (C), -5.53 (2
CH3) ppm. MS-EI+ m/z (%): 409 [C23H25O5Si•] (20), 256 (100), 211 (69), 182 (76), 152
•
(90), 127 (23), 91 (20), 75 (43), 57 [C4H9 ] (20).
4.1.2.(3aR,4S,5R,6aS)-4-(hydroxymethyl)-2-oxohexahydro-2H-cyclopenta [b]furan-
5-yl biphenyl-4-carboxylate (4). To a solution of silyl ether 3 (2.0 g, 4.29 mmol) in
methanol (18.0 mL) was added a catalytic amount of AlCl36H2O (0.05 g, 0.2 mmol).
The reaction mixture was stirred at 60 ºC for 12 h. The solvent was removed under
reduced pressure. The crude product was purified by flash column chromatography
1
affording a white solid 4 (1.4 g, 93%). m.p. 147–150 ºC. Rf: 0.3 (Hex/EtOAc 2:8). H
NMR: (300 MHz, CDCl3+(CD3)2SO) δ = 8.04 (d, J= 8.4 Hz, 2 Ar-H), 7.63 (dd, J= 14.3,
7.6 Hz, 4 Ar-H), 7.50–7.33 (m, 3 Ar-H), 5.43 (dt, J= 5.5, 2.7 Hz, 1 H), 5.10 (t, J= 5.7
Hz, 1 H), 4.55 (t, J= 5.1 Hz, 1 H), 3.60 (td, J= 5.4, 3.2 Hz, 2 H), 3.01–2.86 (m, 2 H),
2.65–2.38 (m, 2 H), 2.38–2.26 (m, 2 H) ppm. 13C NMR: (75 MHz, CDCl3+(CD3)2SO) δ
= 177.00 (C=O), 165.53 (C=O), 145.43 (C), 139.52 (C), 129.99 (2 CH), 128.86 (2 CH),
128.56 (C), 128.11 (CH), 127.02 (2 CH), 126.85 (2 CH), 85.10 (CH), 78.47 (CH), 61.99
(CH2), 55.26 (CH), 40.14 (CH), 38.44 (CH2), 36.21 (CH2), ppm. MS-EI+ m/z (%): 353
[M++1] (73), 200 (100), 183 (82), 180 (31), 151 (64), 125 (53), 79 (25), 41 (35).
4.1.3. (3aR,4R,5R,6aS)-4-(iodomethyl)-2-oxohexahydro-2H-cyclopenta [b]furan-5-
yl biphenyl-4-carboxylate (5). To a solution of alcohol 4 (2.0 g, 5.68 mmol),
triphenylphosphine (3.72 g, 14.19 mmol), and imidazole (0.96 g, 14.19 mmol) in

anhydrous acetonitrile (35.0 mL) was added I2 (2.88 g, 11.35 mmol). The solution was
stirred for 3 h at 80 ºC under nitrogen atmosphere. After this time, the reaction mixture
was added to brine (150 mL) and washed with EtOAc (3×30 mL). The organic layer
was dried (Na2SO4) and the solvent was evaporated under reduced pressure. The crude
was purified by flash column chromatography to afford the white solid 5 (2.2 g, 85%).
m.p. 142–145 ºC. Rf: 0.4 (Hex/EtOAc 6:4). 1H NMR: (300 MHz, CDCl3) δ = 8.06 (d, J
= 8.4 Hz, 2 Ar-H), 7.76–7.33 (m, 7 Ar-H), 5.33–5.23 (m, 1 H), 5.07 (td, J = 6.4, 1.8 Hz,
1 H), 3.36 (dd, J = 10.3, 5.2 Hz, 1 H), 3.22 (dd, J = 10.3, 7.7 Hz, 1 H), 2.95 (dd, J =
17.8, 10.1 Hz, 1 H), 2.87–2.76 (m, 1 H), 2.66–2.49 (m, 2 H), 2.46–2.27 (m, 2 H) ppm.
13C NMR: (75 MHz, CDCl3) δ = 176.11 (C=O), 165.65 (C=O), 146.02 (C), 139.72 (C),
130.19 (2 CH), 128.90 (2 CH), 128.20 (CH), 127.99 (C), 127.21 (2 CH), 127.12 (2 CH),
83.71 (CH), 79.45 (CH), 54.05 (CH), 44.28 (CH), 37.86 (CH2), 35.72 (CH2), 7.03 (CH2-
I) ppm. MS-EI+ m/z (%): 463 [M+1]+ (78), 335 (21), 277 (74), 200 (76), 180 (100), 154
(77), 127 (41), 109 (40), 91 (89), 77 (87), 54 (73), 39 (56).
4.1.4.
(3aR,4S,5R,6aS)-4-((4-acetyl-5-methyl-1H-1,2,3-triazol-1-yl)methyl)-2-
oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate (6a). The alkyl
halide 5 (1.0 g, 2.16 mmol) and sodium azide (0.16 g, 2.38 mmol) were added to
anhydrous dimethylformamide (17.0 mL). The reaction mixture was stirred at 60 °C for
6 h under nitrogen atmosphere. After this time, TLC indicated the disappearance of the
starting material. Then, acetylacetone (0.24 mL, 2.38 mmol) and DBU (0.36 mL, 2.38
mmol) were added to the reaction mixture which was stirred for 12 h at 60 °C. Brine
(100.0 mL) was added to the reaction mixture and washed with EtOAc (3×30 mL).
The organic layer was dried (Na2SO4) and the solvent evaporated under reduced
pressure. Flash column chromatography afforded the yellow solid 6a (0.71 g, 72%).
1
m.p. 56–60ºC. Rf: 0.4 (Hex/EtOAc 3:7). H NMR: (300 MHz, CDCl3) δ = 8.05–7.95
(m, 2 Ar-H), 7.72–7.56 (m, 4 Ar-H), 7.54–7.35 (m, 3 Ar-H), 5.32–5.20 (m, 1 H), 5.18–
5.07 (m, 1 H), 4.55–4.30 (m, 2 H), 3.07–2.95 (m, 1 H), 2.93–2.78 (m, 1 H), 2.77–2.52
13
(m, 8 H), 2.45–2.21 (m, 2 H), 1.45–1.11 (m, 1 H), 0.97–0.82 (m, 1 H) ppm. C NMR:
(75 MHz, CDCl3) δ = 194.03 (C=O), 175.66 (C=O), 165.69 (C=O), 146.27 (C), 143.67
(C), 139.61 (C), 136.81 (C), 130.11 (2 CH), 128.91 (2 CH), 128.26 (CH), 127.48 (C),
127.19 (2 CH), 127.15 (2 CH), 83.26 (CH), 77.13 (CH), 51.66 (CH2), 48.57 (CH), 41.21
(CH), 37.68 (CH2), 35.33 (CH2), 27.58 (CH3), 9.09 (Ar-CH3) ppm. MS-EI+ m/z (%):
459 [M+], 181 (15), 149 (14), 91 (12), 71 (22), 57 (42), 48 (100), 41 (50).

4.1.5. (3aR,4S,5R,6aS)-4-((4-benzoyl-5-phenyl-1H-1,2,3-triazol-1-yl) methyl)-2-
oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate (6b). The alkyl
halide 5 (1.0 g, 2.16 mmol) and sodium azide (0.16 g, 2.38 mmol) were added to
anhydrous dimethylformamide (17.0 mL). The reaction mixture was stirred at 60 °C for
6 h under nitrogen atmosphere. After this time, TLC indicated the disappearance of the
starting material. Then, 2-benzoylacetophenone (0.54 g, 2.38 mmol) and DBU (0.36
mL, 2.38 mmol) were added to the reaction mixture which was stirred for 12 h at 60 °C.
Brine (100.0 mL) was added to the reaction mixture and washed with EtOAc (3×30
mL). The organic layer was dried (Na2SO4) and the solvent evaporated under reduced
pressure. Flash column chromatography afforded the slightly yellow solid 6b (0.84 g,
1
67%). m.p. 71–76 ºC. Rf: 0.55 (Hex/EtOAc 3:7). H NMR: (500 MHz, CDCl3) δ =
8.24–8.22 (m, 1 Ar-H), 8.22–8.21 (m, 1 Ar-H), 7.93 (d, J= 2.0 Hz, 1 Ar-H), 7.91 (d, J=
2.0 Hz, 1 Ar-H), 7.65–7.64 (m, 1 Ar-H), 7.63–7.62 (m, 1 Ar-H), 7.61–7.59 (m, 1 Ar-H),
7.61–7.56 (m, 1 Ar-H), 7.58–7.55 (m, 1 Ar-H), 7.53–7.49 (m, 3 Ar-H), 7.50–7.45 (m, 2
Ar-H), 7.48–7.43 (m, 2 Ar-H), 7.46–7.39 (m, 3 Ar-H), 5.16–5.12 (m, 1 H), 5.01 (td, J=
6.5, 2.2 Hz, 1 H), 4.53 (dd, J= 14.1, 6.9 Hz, 1 H), 4.44 (dd, J= 14.2, 7.7 Hz, 1 H), 2.84–
13
2.79 (m, 2 H), 2.63–2.52 (m, 2 H), 2.28–2.21 (m, 1 H), 2.19–2.13 (m, 1 H) ppm. C
NMR: (125 MHz, CDCl3) δ = 186.10 (C=O), 175.55 (C=O), 165.50 (C=O), 146.22 (C),
143.82 (C), 141.93 (C), 139.71 (C), 136.83 (C), 133.14 (C), 130.61 (2 CH2), 130.37
(CH), 130.15 (2 CH2), 129.54 (2 CH2), 129.16 (2 CH2), 128.93 (2 CH2), 128.28 (C),
128.25 (2 CH2), 127.58 (CH), 127.27 (2 CH2), 127.14 (2 CH2), 125.90 (CH), 82.91
(CH), 77.21 (CH), 51.59 (CH2), 49.21 (CH), 41.11 (CH), 37.61 (CH2), 35.12 (CH2)
ppm.
4.1.6.
(3aR,4S,5R,6aS)-4-((4-acetyl-5-methyl-1H-1,2,3-triazol-1-yl)methyl)-5-
hydroxyhexahydro-2H-cyclopenta[b]furan-2-one (7a). To a solution of ester 6a (0.6
g, 1.31mmol) in MeOH (5.0 mL) was added a catalytic amount of DBN (0.008 mL,
0.065 mmol). The reaction mixture was stirred at room temperature for 12 h. Then
solvent was removed under reduced pressure. The crude was purified by flash column
chromatography to give the thick yellow oil 7a (0.32 g, 87%). Rf: 0.3 (Hex/EtOAc
5:95). 1H NMR: (500 MHz, CDCl3) δ = 4.94 (td, J= 6.8, 3.1 Hz, 1 H), 4.42–4.29 (m, 2
H), 4.03 (q, J= 6.8 Hz, 1 H), 2.79–2.72 (m, 2 H), 2.69 (s, 3 H), 2.61 (s, 3 H), 2.51 (dt,
J= 14.9, 6.8 Hz, 1 H), 2.30 (p, J= 7.0 Hz, 1 H), 2.26–2.17 (m, 2 H), 2.05 (ddd, J= 14.9,

6.8, 3.2 Hz, 1 H) ppm. 13C NMR: (125 MHz, CDCl3) δ = 194.17 (C=O), 176.19
(C=O), 143.68 (C), 137.03 (C), 82.13 (CH), 74.36 (CH), 52.68 (CH2), 48.08 (CH),
40.51 (CH2), 40.34 (CH), 34.66 (CH2), 27.72 (CH3), 9.13 (CH3) ppm. MS-EI+ m/z
(%): 279 [M+] (20), 167 (77), 148 (35), 127 (84), 112 (32), 85 (85), 70 (87), 55 (81),
41 (83).
4.1.7. (3aR,4S,5R,6aS)-4-((4-benzoyl-5-phenyl-1H-1,2,3-triazol-1-yl) methyl)-5-
hydroxyhexahydro-2H-cyclopenta[b]furan-2-one (7b). This compound was prepared
from 6b (0.7 g, 1.2 mmol) according to the synthetic procedure for 7a. The crude was
purified by flash column chromatography to afford the thick yellow oil 7b (0.392 g,
1
81%). Rf: 0.35 (Hex/EtOAc 1:9). H NMR: (500 MHz, CDCl3) δ = 7.96–7.93 (m, 3 Ar-
H), 7.69–7.66 (m, 1 Ar-H), 7.64–7.61 (m, 1 Ar-H), 7.50–7.42 (m, 5 Ar-H), 3.57–3.51
(m, 2 H), 3.48–3.41 (m, 3 H), 3.40–3.35 (m, 3 H), 2.63–2.57 (m, 2 H), 2.18 (s, 1 OH),
1.80–1.75 (m, 1 H) ppm. 13C NMR: (125 MHz, CDCl3) δ = 177.34 (C=O), 166.93
(C=O), 143.88 (C), 140.33 (C), 134.53 (C), 131.16 (2 CH), 128.84 (2 CH), 128.47 (2
CH), 127.60 (C), 127.20 (CH), 127.16 (CH), 127.07 (2 CH), 77.42 (CH), 77.22 (CH),
49.62 (CH2), 45.00 (CH), 37.15 (CH), 35.31 (2 CH), 29.96 (CH2) ppm. MS-EI+ m/z
••
••
••
(%): 351 [C19H17N3O4 ] (38), 52 [C4H4 ] (14), 183 [C8H4N2O3 ] (72), 276 (80), 246
(22), 199 (90), 152 (88), 127 (100), 99 (60), 69 (80), 55 (97).
Acknowledgments
Financial support from SIEA-UAEMex (project No. 3804/2014/CID) and
CONACYT-Mexico (postgraduate scholarship No. 227581 and No. 273644) is
gratefully acknowledged. The authors would like to thank the referee for valuable
comments and suggestions, Signa S.A. de C.V. for some graciously donated solvents
and reagents, M.N. Zavala-Segovia and L. Triana-Cruz (CCIQS UAEMex‒UNAM) for
technical support.
References
(1)
(a) P. Merino, (Ed.) Chemical Synthesis of Nucleoside Analogues, John
Wiley Sons, Inc., Hoboken, NJ, USA. 2013. DOI:
&
10.1002/9781118498088. (b) L. H. Zhang, Z. Xi, J. Chattopadhyaya (Eds.)
Medicinal Chemistry of Nucleic Acids, John Wiley & Sons, Inc., Hoboken,
NJ, USA. 2011. DOI: 10.1002/9781118092804. (c) C. Simons, Nucleoside
Mimetics: Their Chemistry and Biological Properties, Taylor & Francis Ltd,
2000, ISBN-13: 9789056993245. (d) C. K. Chu, (Ed.), Recent Advances in

Nucleosides: Chemistry and Chemotherapy. Elsevier Science B.V., 2002,
ISBN: 978-0-444-50951-2.
(2)
(a) U. Pradere, E. C. Garnier-Amblard, S. J. Coats, F. Amblard, R. F.
Schinazi, Chem. Rev.114 (2014), 9154–9218. (b) P. Clivio, S. Coantic-
Castex, D. Guillaume, Chem. Rev. 113 (2013), 7354−7401. (c) T. Pathak,
Chem. Rev. 102, (2002), 1623-1667. (d) A. Mieczkowski, V. Roy, L. A
Agrofoglio, Chem. Rev. 110 (2010), 1828–1856. (e) J. Štambaský, M. Hocek,
P. Kočovský, Chem. Rev. 109, (2009), 6729–6764. (f) L. A. Agrofoglio, I.
Gillaizeau, Y. Saito, Chem. Rev. 103, (2003), 1875-1916. (g) J. S.
Cooperwood, G. Gumina, F. D. Boudinot, C. K. Chu, Nucleoside and
Nucleotide Prodrugs, in: Recent Advances in Nucleosides: Chemistry and
Chemotherapy. C. K. Chu (Ed.), Elsevier Science B.V., 2002,
doi:10.1016/B978-044450951-2/50005-9.
(3)
(a) E. S. Matyugina, A. L. Khandazhinskaya, Russ. Chem. Bull. Int. Ed. 63,
(2014), 1069–1080. (b) O. Boutureira, M. I. Matheu, Y. Díaz, S. Castillón,
Chem. Soc. Rev. 42, (2013), 5056-5072. (c) E. Leclerc, Chemical Synthesis
of Carbocyclic Analogues of Nucleosides, in: Chemical Synthesis of
Nucleoside Analogues, P. Merino (Ed), John Wiley & Sons, Inc., Hoboken,
NJ, USA. 2013. doi: 10.1002/9781118498088.ch12. (d) J. Wang, R. K.
Rawal, C. K. Chu, Recent Advances in Carbocyclic Nucleosides: Synthesis
and Biological Activity, in: Medicinal Chemistry of Nucleic Acids. L. H.
Zhang, Z. Xi, J. Chattopadhyaya (Eds.), John Wiley & Sons, Inc., Hoboken,
NJ, USA. 2011. doi: 10.1002/9781118092804.ch1. (e) S. W. Schneller, K. L.
Seley, V. R. Hegde, V. P. Rajappan, 5’-Norcarbanucleosides in L-Like
Configurations, in: Recent Advances in Nucleosides: Chemistry and
Chemotherapy. C. K. Chu, (Ed.), Elsevier Science B.V., 2002,
doi:10.1016/B978-044450951-2/50009-6. (f) M. Ferrero, V. Gotor, Chem.
Rev. 100, (2000), 4319-4347.
(4)
(a) F. de Carvalho da Silva, M. F. do Carmo Cardoso, P. Garcia-Ferreira, V.
F. Ferreira, Biological Properties of 1H -1,2,3- and 2H -1,2,3-Triazoles, in:
Chemistry of 1,2,3-triazoles. W. Dehaen, V. A. Bakulev, (Eds.), Springer
International Publishing, Switzerland, 2015. DOI: 10.1007/7081_2014_124.
(b) A. Massarotti, S. Aprile, V. Mercalli, E. Del Grosso, G. Grosa, G. Sorba,
G. C. Tron, ChemMedChem 9 (2014), 2497–2508. (c) S. G. Agalave, S. R.
Maujan, V. S. Pore, Chem. Asian J. 6 (2011), 2696–2718. (d) A. Lauria, R.
Delisi, F. Mingoia, A. Terenzi, A. Martorana, G. Barone, A. M. Almerico,
Eur. J. Org. Chem. (2014), 3289–3306. (e) P. Thirumurugan, D. Matosiuk, K.
Jozwiak, Chem. Rev. 113, (2013), 4905−4979. (f) J. F. Lutz, Z. Zarafshani,
Adv. Drug Deliv. Rev. 60 (2008), 958–970.
(5)
(6)
(a) F. Amblard, J. H. Cho, R. F. Schinazi, Chem. Rev. 109, (2009), 4207–
4220. (b) W. Zou, M. Bhasin, K. Vembaiyan, D. T. Williams, Carbohydrate
Res. 344 (2009), 1024–1027. (c) V. Aragao-Leoneti, V. L. Campo, A. S.
Gomes, R. A. Field, I. Carvalho, Tetrahedron 66 (2010), 9475–9492.
(a) L. Kiss, E. Forró, R. Sillanpää, F. Fülöp, Tetrahedron 66, (2010), 3599–
3607. (b) N. Joubert, R. F. Schinazi, L. A. Agrofoglio, Tetrahedron 61
(2005), 11744–11750. (c) J. H. Cho, D. L. Bernard, R. W. Sidwell, E. R.
Kern, C. K. Chu, J. Med. Chem. 49 (2006), 1140–1148. (d) I. Pérez-Castro,
O. Caamaño, F. Fernández, M. D. García, C. López, E. De Clercq, Org.
Biomol. Chem. 5 (2007), 3805–3813. (e) Y. Saito, V. Escuret, D. Durantel, F.

Zoulim, R. F. Schinazi, L. A Agrofoglio, Bioorg. Med. Chem. 11 (2003),
3633–3639.
(7)
(8)
(9)
(a) U. Chiacchio, M. G. Saita, L. Crispino, G. Gumina, S. Mangiafico, V.
Pistarà, G. Romeo, A. Piperno, E. De Clercq, Tetrahedron 62, (2006), 1171–
1181. (b) C. L. Scremin, J. H. Boal, A. Wilk, L. R. Phillips, S. L. Beaucage,
Bioorg. Med. Chem. Lett. 6 (1996), 207-212. (c) J. H. Boal, A. Wilk, C. L.
Scremin, G. N. Gray, L. R. Phillips, S. L. Beaucage, J. Org. Chem. 61,
(1996), 8617-8626. (d) N. Hossain, N. Blaton, O. Peeters, J. Rozenski, P. A.
Herdewijn, Tetrahedron 52 (1996), 5563-5578. (e) M. W. Winkley,
Carbohydrate Res. 31 (1973), 245-254.
(a) V. P. Rajappan, X. Yin, S. W. Schneller, Tetrahedron, 58 (2002), 9889-
9895. (b) F. Abad, F. Álvarez, F. Fernández, X. García-Mera, J. E.
Rodríguez-Borges, Nucleos. Nucleot. Nucleic acids 20 (2001) 1127–1128. (c)
U. Dhuppad, V. Aravat, S. Navhat, A. Thomas, S. Kadam, (Glenmark
Pharmaceuticals S.A., Switzerland). Pharmaceutical Containing Melogliptin
Dipeptidyl Peptidase-IV Inhibitor. U.S. Pat. Appl. Publ. 2010, US 2010-
683696; US 20100173964 A1, July 8, 2010; SciFinder Scholar: AN
2010:85194.
C. Lamberth, Org. Prep. Proc. Int. 34 (2002), 149-167.
(10) (a) A. Kayet, D. Datta, G. Kumar, A. Sundar, A. S. Ghosh, T. Pathak, RSC
Adv. 4 (2014), 63036–63038. (b) A. Kayet, T. Pathak, J. Org. Chem. 78
(2013), 9865–9875. (c) B. Bhatt, R. J. Thompson, M. von Itsztein,
Tetrahedron Lett. 52 (2011), 2741–2743. (d) R. P. Tripathi, A. K. Yadav, A.
Ajay, S. S. Bisht, V. Chaturvedi, S. K. Sinha, Eur. J. Med. Chem. 45 (2010),
142–148. (e) R. V. Somu, H. Boshoff, C. Qiao, E. M. Bennett, C. E. Barry
III, C. C. Aldrich, J. Med. Chem. 49 (2006), 31-34. (f) A. Goeminne, M.
McNaughton, G. Bal, G. Surpateanu, P. Van der Veken, S. De Prol, W.
Versées, J. Steyaert, S. Apers, A. Haemers, K. Augustyns, Bioorg. Med.
Chem. Lett. 17 (2007), 2523–2526. (g) P. Norris, D. Horton, B. R. Levine,
Heterocycles 43 (1996), 2643–2655. (h) N. Singh, S. K. Pandey, R. P.
Tripathi, Carbohydrate Res. (2010), 1641–1648. (i) D. R. da Rocha, W. C.
Santos, E. S. Lima, V. F. Ferreira, Carbohydrate Res. 350 (2012), 14–19. (j)
T. M. Potewar, K. T. Petrova, M. T. Barros, Carbohydrate Res. 379 (2013),
60–67.
(11) (a) S. Hanessian, S. Marcotte, R. Machaalani, G. Huang, Org. Lett. 5, (2003),
4277–4280. (b) For a complete Review about synthetic bicyclic nucleosides
see: J. Lebreton, J. M Escudier, L. Arzel, C. Len, Chem. Rev. 110 (2010),
3371–3418.
(12) (a) K. Sakata, A. Bakurai, S. Tamura, Agric. Biol. Chem. 37 (1973), 697–
699. (b) K. Sakata, A. Sakurai, S. Tamura, Agric. Biol. Chem. 39 (1975),
885–892.
(13) (c) K. Isono, P. F. Crain, J. A. McCloskey, J. Am. Chem. Soc. 97 (1975),
943–945.
(14) (a) S. Hanessian, G. Huang, C. Chenel, R. Machaalani, O. Loiseleur, J. Org.
Chem. 70 (2005), 6721–6734. (b) A. Datta, Synthetic Studies on Antifungal
Peptidyl Nucleoside Antibiotics, in Chemical Synthesis of Nucleoside
Analogues, P. Merino (Ed.), John Wiley & Sons, Inc., Hoboken, NJ, USA.
2013. doi: 10.1002/9781118498088.ch18.
(15) (a) D. C. Pryde, D. S. Middleton, P. T. Stephenson, P. Wainwright, A.
Maddaford, X. Zhang, D. Leese, R. Glen, J. Hart, N. Forrest, T. Guyot,

Tetrahedron Lett. 52 (2011), 6415–6419. (b) M. J. Comin, D. A. Parrish, J. R.
Deschamps, V. E. Marquez, Org. Lett. 8 (2006), 705-708. (c) B. Richichi, S.
Cicchi, U. Chiacchio, G. Romeo, A. Brandi, Tetrahedron 59 (2003), 5231–
5240.
(16) N. R. Swamy, N. Suryakiran, P. P. Naidu, Y. Venkateswarlu, Carbohydrate
Res. 352 (2012), 191–196.
(17) (a) A. Santana, J. M. G. Molinillo, F. A. Macías, Eur. J. Org. Chem. (2015),
2093–2110. (b) B. M. Fraga, Nat. Prod. Rep. 29 (2012), 1334–1366.
(18) M. I. Choudhary, S. G. Musharraf, A. Sami, Atta-ur-Rahman, Helv. Chim.
Acta, 87 (2004), 2685–2694.
(19) M. Kassou, S. Castillón, J. Org. Chem. 62 (1997), 3696–3701.
(20) M. Ikbal, C. Cerceau, F. Le Goffic, S. Sicsic, Eur. J. Med. Chem. 24 (1989),
415-420.
(21) L. V. R. Reddy, P. V. Reddy, N. N. Mishra, P. K. Shukla, G. Yadav, R.
Srivastava, A. K. Shaw, Carbohydr. Res. 345 (2010), 1515–1521.
(22) (a) C. S. Stauffer, A. W. Fothergill, M. G. Rinaldi, A. Dutta, Future Med.
Chem. 1 (2009), 379-389. (b) X. Yin, G. Zhao, S. W. Schneller, Tetrahedron
Lett. 48 (2007), 4809–4811. (c) C. S. Stauffer, P. Bhaket, A. W. Fothergill,
M. G. Rinaldi, A. Datta, J. Org. Chem. 72 (2007), 9991-9997. (d) M. Winn,
R. J. M. Goss, K. Kimura, T. D. H. Bugg, Nat. Prod. Rep. 27 (2010), 279–
304. (e) R. Srivastava, A. Bhargava, R. K. Singh, Bioorg. Med. Chem. Lett.
17 (2007), 6239–6244. (f) C. S. Stauffer, A. Datta, J. Org. Chem. 73 (2008),
4166–4174.
(23) (a) C. G. S. Lima, A. Ali, S. S. van Berkel, B. Westermann, M. W. Paixão,
Chem. Commun. 51, (2015), 10784-10796. (b) J. John, J. Thomas, W.
Dehaen, Chem. Commun. 51 (2015), 10797-10806. (c) S. S. V. Ramasastry,
Angew. Chem. Int. Ed. 53 (2014), 14310–14312.
(24) C. A. González-González, A. Fuentes-Benítes, E. Cuevas-Yañez, D. Corona-
Becerril, C. González-Romero, D. González-Calderón, Tetrahedron Lett. 54
(2013), 2726-2728.
(25) D. González-Calderón, L. J. Benitez-Puebla, C. A. González-González, M. E.
García-Eleno, A. Fuentes-Benítes, E. Cuevas-Yañez, D. Corona-Becerril, C.
González-Romero, Synth. Commun. 44, (2014), 1258–1265.
(26) P. J. Garegg, B. J. C. S. Samuelsson, J. Chem. Soc., Chem. Commun. (1979),
978–980.
(27) D. González-Calderón, J. G. Aguirre-De Paz, C. A. González-González, A.
Fuentes-Benítes, C. González-Romero, Tetrahedron Lett. 56 (2015), 1713–
1715.
(28) (a) National Committee for Clinical Laboratory Standards Institute (CLSI),
Document M38-A2: Reference Method for Broth Dilution Antifungal
Susceptibility Testing of Filamentous Fungi, Approved StandardeSecond
Edition, Clinical and Laboratory Standards Institute, Wayne, PA, 2002; (b)
A.L. Barry, An overview of the Clinical and Laboratory Standards Institute
(CLSI) and its impact on antimicrobial susceptibility tests, in: R. Schwalbe,
L. Steele-Moore, A.C. Goodwin (Eds.), Antimicrobial Susceptibility Testing
Protocols, CRC Press Taylor & Francis Group, Florida, 2007, pp. 1-6. ISBN:
9780824741006. (c) A. Espinel-Ingroff, E. Canton, Antifungal susceptibility
testing of filamentous fungi, in: R. Schwalbe, L. Steele-Moore, A.C.
Goodwin (Eds.), Antimicrobial Susceptibility Testing Protocols, CRC Press
Taylor & Francis Group, Florida, 2007, pp. 209-241. ISBN: 9780824741006.

(29) (a) National Committee for Clinical and Laboratory Standards Institute
(CLSI), M27-A3: Reference Method for Broth Dilution Antifungal
Susceptibility Testing of Yeasts, Approved StandardeThird Edition, Clinical
and Laboratory Standards Institute, Wayne, PA, 2008. ISBN: 1-56238-666-2.
(b) A. Espinel-Ingroff, E. Canton, Antifungal susceptibility testing of yeasts,
in: R. Schwalbe, L. Steele-Moore, A.C. Goodwin (Eds.), Antimicrobial
Susceptibility Testing Protocols, CRC Press Taylor & Francis Group, Florida,
2007, pp.173-208. ISBN: 9780824741006; (c) A.W. Fothergill, Antifungal
Susceptibility Testing: Clinical Laboratory and Standards Institute (CLSI)
methods, in: G.S. Hall (Ed.), Interactions of Yeasts, Moulds, and Antifungal
Agents. How to Detect Resistance, Springer Science-Business Media, 2012,
pp. 65-74, http://dx.doi.org/10.1007/978-1-59745-134-5_2.
(30) W.L.F. Armarego, C. Chai, Purification of Laboratory Chemicals, 7th Ed.,
Elsevier, Oxford, UK, 2013. ISBN-13: 978-0123821614

Graphical Abstract

Highlights

The first report of 1'-homo-N-1,2,3-triazol-bicyclic carbonucleosides as novel type of
compounds is described.


The azide-enolate (3+2) cycloaddition afforded the synthesis of such compounds.
Good activities against Candida spp. for synthetized compounds