Synthesis of regio-and stereoisomers of highly functionalized 1,2,3-triazole-substituted cyclopentanes

Article abstract of DOI:10.2174/157017811795038359

Highly functionalized regio-and stereoisomers of 1,2,3-triazole-substituted cyclopentanes were prepared in six steps from either bicyclic β-lactam 7 or γ-lactam 23 by 1,3-dipolar cycloaddition of the azido cyclopentanol intermediates with acetylenes. The reactions of azido aminocyclopentanols with non-symmetric acetylenes resulted regioselectively in the corresponding 1,4-disubstitued triazole derivatives under both thermal and Cu(I)-catalysed conditions. These compounds can be regarded as highly functionalized 1,2,3-triazole-modified carbocyclic nucleoside analogues.

Full text of DOI:10.2174/157017811795038359

220
Letters in Organic Chemistry, 2011, 8, 220-228
Synthesis of Regio- and Stereoisomers of Highly Functionalized 1,2,3-
Triazole-substituted Cyclopentanes
Loránd Kissa, Enikꢀ Forróa and Ferenc Fülöp*,a,b
aInstitute of Pharmaceutical Chemistry; bResearch Group of Stereochemistry of the Hungarian Academy of
Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
Received August 09, 2010: Revised January 11, 2011: Accepted January 11, 2011
Abstract: Highly functionalized regio- and stereoisomers of 1,2,3-triazole-substituted cyclopentanes were prepared in six
steps from either bicyclic ꢁ-lactam 7 or ꢂ-lactam 23 by 1,3-dipolar cycloaddition of the azido cyclopentanol intermediates
with acetylenes. The reactions of azido aminocyclopentanols with non-symmetric acetylenes resulted regioselectively in
the corresponding 1,4-disubstitued triazole derivatives under both thermal and Cu(I)-catalysed conditions. These
compounds can be regarded as highly functionalized 1,2,3-triazole-modified carbocyclic nucleoside analogues.
Keywords: Amino alcohols, azides, carbocyclic nucleosides, click chemistry, 1,3-dipolar cycloaddition, enzymes, 1,2,3-
triazoles.
INTRODUCTION
of the antiviral agent ribavirin (1) [4a-c] and its
carbanucleoside equivalent (3), [4d]. which are considered
strong antiviral agents. The 1,2,3-triazole analogue of the
well-known carbanucleoside Neplanocin A (5) exhibits
antiviral activity [3]. In recent years, a number of carbocyclic
1,2,3-triazolo ribavirin analogues and other 1,2,3-triazole-
modified derivatives have been described as important
bioactive compounds [1d, 5].
Triazole-modified nucleosides constitute a rather novel
area of nucleoside chemistry that has recently generated
great interest among synthetic and medicinal chemists
recently [1, 2]. The 1,2,4- or 1,2,3-triazole skeleton as nucl-
eobase is a component of many nucleosides or carbanucl-
eosides with antiviral or antitumour activity (Fig. 1) [1, 2].
For example, the 1,2,4-triazole ring is a component
HN
CONH2
N
CONH2
NH2
N
N
N
N
N
N
N
N
HO
HO
HO
O
O
OH
OH
OH
OH
OH
OH
N
1
2
3
CH2R
CONH2
CONH2
N
N
N
N
N
N
N
N
AcO
HO
HO
O
OAc OAc
OH
OH
OH
6
4
5
Fig. (1). Several bioactive triazole-modified nucleoside analogues.
RESULTS AND DISCUSSION
The cycloaddition of azides to alkynes is probably the
most useful and powerful method for the preparation of
1,2,3-triazoles [6] Our goal in the present work was the
preparation of multifunctionalized cyclopentanes via an
*Address correspondence to this author at the Research Group of
Stereochemistry of the Hungarian Academy of Sciences, University of
Szeged, H-6720 Szeged, Eötvös u. 6, Hungary; Tel: 3662545564; Fax:
3662545705: E-mail: fulop@pharm.u-szeged.hu
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Synthesis of Regio- and Stereoisomers of Highly Functionalized
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
221
R
N3
O
N
N
OH
NHBoc
N
OH
NHBoc
NH
HO
HO
Scheme 1. Retrosynthetic analysis for the preparation of highly functionalized 1,2,3-triazole-substituted cyclopentanes from the bicyclic ꢀ-
lactam.
R
OH
OH
N3
N
N
N
OH
OH
O
BocHN
BocHN
HN
N
R
N
N3
N
HO
HO
OH
OH
BocHN
BocHN
Scheme 2. Retrosynthetic analysis for the preparation of highly functionalized 1,2,3-triazole- substituted cyclopentanes from the bicyclic ꢁ-
lactam.
azide-alkyne click-chemistry strategy, starting from bicyclic
ꢀ- or ꢁ-lactams (7 or 23) via the corresponding azido amino
cyclopentanol or azido-substituted cyclopentanecarboxylates
by reaction with different acetylenes (Schemes 1, 2).
h, yielding the corresponding azido-substituted aminocyclo-
pentanols 10 and 11 (Scheme 3). The 1,2,3-triazole ring was
constructed on the carbocycle by 1,3-dipolar cycloaddition
of the azide function with diethyl acetylenedicarboxylate
(DEAD), analogously to the functionalized cispentacins [8].
The transformation was performed in EtOH at 70 °C, giving
the corresponding target triazolo derivatives 12 and 13 in
moderate yields (49% and 62%, Scheme 3). The reactions
were accompanied by formation ꢂ during the prolonged
heating ꢂ of polymeric substances, which is probably a
reason of the rather moderate yields observed for compounds
12 or 13.
The earlier synthetized azido-functionalized amino ester
diastereomers 8, 9, 14 and 15 [7] (Schemes 3 and 4) derived
from the bicyclic ꢀ-lactam 7 were considered to be suitable
compounds for the preparation of highly functionalized
triazole-substituted cyclopentanes, as 1,2,3-triazole-modified
carbanucleoside analogues.
In order to prepare the target 1,2,3-triazolocyclopentanes,
the carboxylate group of the azido-substituted ꢀ-amino esters
The NaBH4 reduction of the ester function of azido
aminocyclopentanecarboxylate diastereomer 15, in which the
ester and the protected amino group are in a trans relative
8
and
9
was first reduced to the corresponding
hydroxymethyl function. The ester reduction of 8 and its C-1
epimer 9 was performed with NaBH4 in EtOH at 70 °C for 6
CO2Et
EtO2C
N3
CO2Et
N3
NaBH4, EtOH
DEADC
EtOH, 70 °C
8 h, 49%
OH
NHBoc
N
N
OH
NHBoc
N
ref. 7
70 °C, 6 h, 57%
HO
NHBoc
HO
HO
12
O
8
10
NH
7
CO2Et
EtO2C
ref. 7
N3
CO2Et
N3
NaBH4, EtOH
DEADC
OH
NHBoc
N
N
OH
NHBoc
N
70 °C, 6 h, 64%
EtOH, 70 °C
8 h, 62%
HO
NHBoc
HO
9
HO
13
11
Scheme 3. Synthesis of multifunctionalized 1,2,3-triazole-substituted cyclopentanes 12 and 13.

222 Letters in Organic Chemistry, 2011, Vol. 8, No. 3
Kiss et al.
CO2Et
N3
O
ref. 7
NH
NHBoc
HO
15
7
ref. 7
NaBH4, EtOH
70 °C, 6 h, 67%
EtO2C
CO2Et
CO2Et
N3
N3
NaBH4, EtOH
DEADC
N
N
OH
N
OH
NHBoc
70 °C, 6 h, 58%
EtOH, 70 °C
8 h, 65%
NHBoc
HO
HO
NHBoc
HO
17
14
16
Scheme 4. Synthesis of multifunctionalized 1,2,3-triazole-substituted cyclopentane 17.
steric arrangement, afforded the corresponding amino
alcohol 16 (67%, Scheme 4). Under similar conditions the
reduction of amino ester diastereomer 14, in which the ester
and amino moieties are in a cis relative relationship,
furnished the same azido alcohol 16 (58%). During the
reduction process, epimerization occurred at C-1 (Scheme 4).
To avoid this base-mediated isomerization, the ester reduc-
tion was attempted at lower temperatures in the presence of
NaBH4 in different solvents (THF or EtOH) or with other
reducing agents, such as NaCNBH3/AcOH, but the desired
amino alcohol with the amino and hydroxymethyl groups in
a cis relative position was not formed: only the epimerized
amino alcohol 16 could be isolated.
with azido aminocyclopentanol 10 derived from azido amino
ester 8 (Scheme 5). Azido amino alcohol 10 was subjected to
1,3-dipolar cycloaddition with terminal acetylenes such as
ethyl propiolate, phenylacetylene or 1-pentyne (Scheme 5,
path A). The reactions were carried out under thermal
conditions in refluxing CH3CN; only ethyl propiolate
furnished the 1,4-disubstitued triazole cycloadduct 20. No
transformations were detected under these conditions in the
reactions with phenylacetylene or 1-pentyne. When the
reactions were performed under room temperature instead of
under thermal conditions under catalytic conditions in the
presence of CuSO4 and ascorbic acid in EtOH/H2O, all three
acetylenes selectively gave the corresponding 1,4-
disubstituted (anti) triazoles 20-22 in moderate yields (48-
51%, Scheme 5).
Azido alcohol 16 was then subjected through its azide
function to 1,3-dipolar cycloaddition with DEAD in EtOH at
70 °C, which resulted in the corresponding functionalized
1,2,3-triazole-modified carbocyclic stereoisomer 17 (65%,
Scheme 4).
When the same catalytic reactions were performed by the
addition of CuI in refluxing CH3CN, the same 1,4-
disubstituted triazoles 20-22 were obtained in good yields
(58-89%, Scheme 5, path A). No 1,5-disubstituted (syn)
triazoles were detected in any of the reactions. Triazolo
amino alcohols 21 and 22 could also be synthetized in
Next, 1,2,3-triazole ring construction for the synthesis of
other new multisubstituted cyclopentane derivatives was
investigated by reacting several non-symmetric acetylenes
CO2Et
N3
N3
OH
NHBoc
HO
NHBoc
HO
8
10
R
ref. 10
path A
MeCN, 70 °C, 8 h
R
CuI or CuSO4, ascorbic acid if R = Ph,
Pr
R
CO2Et
N
N
N
NaBH4, THF, 65 °C
N
N
N
6 h
OH
NHBoc
HO
path B
NHBoc
HO
18: R = Ph; 69% (ref. 10)
19: R = Pr; 39% (ref. 10)
20: R = CO2Et; 64% from 10
21: R = Ph; 89% from 10 (62% from 18)
22: R = Pr; 58% from 10 (46% from 19)
Scheme 5. Synthesis of triazole-substituted amino alcohols 20-22.

Synthesis of Regio- and Stereoisomers of Highly Functionalized
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
223
N3
O
HN
HO
ref. 9
OH
BocHN
23
24
R
R'
path A
ref. 10
MeCN, 70 °C, 8 h
CuI if R = Ph, Pr and R' = H
R
R
N
N
N
N
N
R'
NaBH4, THF, 65 °C
N
CO2Et
6 h
HO
HO
path B
OH
BocHN
BocHN
25: R = Ph, 70% (ref. 10)
26: R = Pr, 67% (ref. 10)
27: R, R' = CO2Et; 61% from 24
28: R = CO2Et, R' =H; 68% from 24
29: R = Ph, R' = H; 65% from 24 (56% from 25)
30: R = Pr, R' = H; 62% from 24 (52% from 26)
Scheme 6. Synthesis of 1,2,3-triazole-substituted aminocyclopentanols 27-30.
moderate yields in an alternative way by ester reduction of
the triazole-substituted cispentacins 18 and 1910 (Scheme 5,
path B).
good yields. The reactions of 24 with phenylacetylene and 1-
pentyne could be accomplished in the presence of Cu(I) as
catalyst, resulting in the corresponding 1,4-disubstituted
(anti) triazoles 29 and 30 (Scheme 6, path A). The latter two
triazolo-aminocyclopentanols (29 and 30) were synthetized
by an alternative route from triazole-substituted ꢀ-
aminocyclopentanecarboxylates 25 and 26 [10] through
reduction of their ester group (Scheme 6, path B).
The ꢀ-lactam 23 (Vince lactam), which is the regioisomer
of bicyclic ꢁ-lactam 7, offered an opportunity for the
preparation of new regio- and stereoisomers of other highly
functionalized 1,2,3-triazole-substituted cyclopentanes.
ꢀ-Lactam 23 was earlier transformed into azido amino
alcohol regioisomers 24 and 31 (Schemes 6, 7) [9]. The
reaction of azido aminocyclopentanol 24 with diethyl
acetylenedicarboxylate or ethyl propiolate in refluxing
CH3CN led to triazole-substituted derivatives 27 and 28 in
Azido amino alcohol 31, regioisomer of 24, on reaction
with acetylenes led to other novel triazole-substituted
cyclopentanols 33-35, regioisomers of 27-30 (Scheme 7,
path A).
OH
O
HN
N3
ref. 9
OH
BocHN
23
31
R
R'
ref. 10
path A
MeCN, 70 °C, 8 h
CuI if R = Ph, Pr; R' = H
Ph
R
N
R'
OH
OH
NaBH4, THF, 65 °C
CO2Et
N
N
N
N
6 h
N
OH
path B
BocHN
32: 73% (ref. 10)
BocHN
33: R, R' = CO2Et; 60% from 31
34: R = CO2Et, R' = H; 59% from 31
35: R = Ph, R' = H; 51% from 31
(42% from 32)
Scheme 7. Synthesis of triazole-modified carbonucleoside analogues 33-35.

224 Letters in Organic Chemistry, 2011, Vol. 8, No. 3
Kiss et al.
The synthetic route to these 1,2,3-triazole-substituted
aminocyclopentanol stereoisomers is applicable for the
preparation of their enantiomers via enzymatic resolution of
racemic lactams 7 or 23 followed by the above steps. One
eloquent example is presented in Scheme 8. Racemic ꢀ-
lactam 23 was first subjected to enzymatic ring opening in
the presence of CAL-B (lipase B from Candida antarctica,
produced by the submerged fermentation of a genetically
modified Aspergillus oryzae microorganism and adsorbed on
a macroporous resin) in t-butyl methylether [9] (Scheme 8).
The unreacted enantiopure lactam (+)-23 (ee > 99%)
furnished azido amino ester regioisomers (-)-36 ([ꢁ]D = -
13.1, c 0.9, EtOH) and (-)-37 ([ꢁ]D = -28.4, c 0.65, EtOH)
(for the opposite enantiomers, see ref. 9). These were then
transformed by 1,3-dipolar cycloaddition with phenyl-
acetylene via the corresponding triazole-functionalized
amino ester enantiomers (+)-25 and (-)-32 [10] to the desired
highly functionalized triazole-substituted cyclopentanes (+)-
29 and (+)-35.
added and the mixture was stirred under reflux for 6 h. The
reaction mixture was then concentrated under reduced
pressure and the residue was taken up in CH2Cl2 (35 mL)
and washed with water (30 mL). The organic layer was dried
(Na2SO4) and concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica gel (n-hexane/EtOAc 1:2).
tert-Butyl (1R*,2R*,3R*,5R*)-3-azido-2-hydroxy-5-(hydro-
xymethyl)cyclopentylcarbamate (10)
A white solid; mp 108-110 °C; yield: 57%. Rf = 0.60 (n-
1
hexane/EtOAc 1:2); H NMR (DMSO, 400 MHz): ꢀ = 1.41.
(s, 9H, tBu), 1.49-1.60 (m, 1H, CH2), 1.79-1.88 (m, 1H,
CH2), 2.20-2.27 (m, 2H, H-5), 3.19-3.42 (m, 2H, OCH2),
3.82-3.99 (m, 3H, H-1, H-2 and H-3), 4.42 (brs, 1H, O-H),
5.36 (brs, 1H, O-H), 6.23 (brs, 1H, N-H). 13C NMR (DMSO,
400 MHz): ꢀ = 29.1, 30.7, 40.4, 54.8, 62.1, 65.8, 77.1, 79.8,
195.0. Anal. Calcd. for C11H20N4O4: C, 48.52; H, 7.40; N,
20.58. Found: C, 48.11; H, 7.12; N, 20.18.
tert-Butyl (1R*,2R*,3R*,5S*)-3-azido-2-hydroxy-5-(hydro-
xymethyl)cyclopentylcarbamate (11)
EXPERIMENTAL
A yellow-brownish oil; yield: 64%. Rf = 0.55 (n-
hexane/EtOAc 1:2); H NMR (CDCl3, 400 MHz): ꢀ = 1.17-
The chemicals were purchased from Aldrich or Fluka.
Melting points were determined with a Kofler apparatus.
NMR spectra were recorded on a Bruker DRX 400
spectrometer. Chemical shifts are given in ppm relative to
TMS as internal standard in CDCl3 or DMSO as solvent. The
solvents were used as received from the supplier. Optical
1
1.35 (m, 1H, CH2), 1.38 (s, 9H, tBu), 1.96-2.06 (m, 1H,
CH2), 2.15-2.21 (m, 1H, H-5), 3.49-3.55 (m, 1H, H-1), 3.57-
3.63 (m, 1H, H-3), 3.68-3.76 (m, 2H, OCH2), 3.73-4.02 (m,
1H, H-2), 5.22 (brs, 1H, N-H). 13C NMR (DMSO, 400
MHz): ꢀ = 28.2, 29.3, 43.2, 53.5, 62.6, 64.9, 76.2, 79.3,
155.4. Anal. Calcd. for C11H20N4O4: C, 48.52; H, 7.40; N,
20.58. Found: C, 48.18; H, 7.08; N, 20.14.
rotations were measured with
a
Perkin-Elmer 341
polarimeter. Mass spectra were recorded on a Finnigan MAT
95S spectrometer. Elemental analyses were performed with a
Perkin-Elmer CHNS-2400 Ser II Elemental Analyzer.
tert-Butyl (1R*,2S*,3S*,5R*)-3-azido-2-hydroxy-5-(hydro-
xymethyl)cyclopentylcarbamate (16)
General Procedure for the Reduction of Azido Esters 8,
9, 14 and 15
A white solid; mp 133-134 °C; yield: 67%. Rf = 0.60 (n-
hexane/EtOAc 1:2); H NMR (400 MHz, DMSO): ꢀ = 1.38
1
(s, 9H, tBu), 1.50-1.57 (m, 1H, CH2), 1.76-1.86 (m, 1H,
CH2), 3.18-3.32 (m, 1H, H-5), 3.37-3.42 (m, 1H, H-1), 3.55-
3.68 (m, 2H, OCH2), 4.47-4.51 (m, 1H, H-3), 5.29-5.34 (m ,
To a solution of 500 mg (1.6 mmol) azido ester 8, 9, 14
or 15 in EtOH (15 mL), 120 mg (3.2 mmol) NaBH4 was
O
HN
Ph
Ph
N
N
N3
N
N
see
ref. 9
2S
N
23
N
HO
3S
CO2Et
H2O
3S
4R
2S
1R
HO
1R
HO
CO2Et
CAL-B
t-BuOMe
OH
2S
3S
Scheme 6
4S
BocHN
(-)-36
1S
BocHN
4S
BocHN
O
HN
1S
(+)-29
(+)-25
4R
Ph
(+)-23
Ph
OH
OH
2R
OH
3R
2R
N3
CO2Et
N
N
CO2Et
see
ref. 9
N
N
N
3R
N
1R
OH
3R
1R
2R
4S
4S
BocHN
Scheme 7
4S
BocHN
1S
BocHN
(-)-37
(-)-32
(+)-35
Scheme 8. Synthesis of triazole-modified carbonucleoside enantiomers (+)-29 and (+)-35.

Synthesis of Regio- and Stereoisomers of Highly Functionalized
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
225
1H, H-2), 6.85 (brs, 1H, N-H). 13C NMR (400 MHz,
DMSO): ꢀ = 28.3, 28.8, 40.2, 55.7, 57.4, 60.9, 77.7, 79.4,
155.7. Anal. Calcd. for C11H20N4O4: C, 48.52; H, 7.40; N,
20.58. Found: C, 48.13; H, 7.13; N, 20.20.
159.3, 160.5. Anal. Calcd. for C19H30N4O8: C, 51.58; H,
6.83; N, 12.66. Found: C, 51.18; H, 6.46; N, 12.21.
Diethyl 1-[(1S*,2S*,3R*,4S*)-3-(tert-butoxycarbonyl-
amino)-2-hydroxy-4-(hydroxymethyl)cyclopentyl]-1H-
1,2,3-triazole-4,5-dicarboxylate (17)
General procedures for Azide-Alkyne Dipolar Cyclo-
addition
A white solid; mp 96-98 °C; yield: 65%. Rf = 0.35 (n-
hexane/EtOAc 1:2); H NMR (400 MHz, CDCl3): ꢀ = 1.26
1
(t, 3H, CH3, J = 7.20 Hz), 1.37 (t, 3H, CH3, J = 7.20 Hz),
1.43 (s, 9H, tBu), 2.29-2.36 (m, 2H, CH2), 3.62-3.70 (m, 1H,
H-4), 3.71-3.87 (m, 2H, OCH2), 4.07-4.17 (m, 3H, OCH2
and H-3), 4.37-4.55 (m, 4H, OCH2, H-2 and O-H), 4.58 (brs,
1H, O-H), 5.05-5.09 (m, 1H, H-1), 5.60 (brs, 1H, N-H). 13C
NMR (400 MHz, DMSO): ꢀ = 14.5, 14.8, 29.1, 30.1, 40.6,
57.3, 62.2, 62.9, 63.4, 64.8, 78.8, 80.2, 132.6, 139.2, 156.5,
159.3, 160.5. MS: (ESI, pos) m/z = 443 (M+1). Anal. Calcd.
for C19H30N4O8: C, 51.58; H, 6.83; N, 12.66. Found: C,
51.20; H, 6.52; N, 12.31.
Procedure A (thermal 1,3-dipolar cycloaddition)
To a solution of azido alcohol 10, 11, 16, 24 or 31 (500
mg, 1.83 mmol) in EtOH or CH3CN (15 mL), alkyne (1.1
equiv) was added and the solution was stirred at 70 °C for 8
h. The mixture was then concentrated and the residue was
crystallized from n-hexane:EtOAc or purified by column
chromatography on silica gel (eluent: n-hexane/EtOAc 1:2).
Procedure B (Cu-catalysed 1,3-dipolar cycloaddition)
To a solution of azido alcohol 10, 24 or 31 (500 mg, 1.83
mmol) in CH3CN, CuI (1 equiv) and alkyne (1.1 equiv) were
added and the mixture was stirred at 70 °C for 6 h. The
solvent was then evaporated off and the residue was purified
by column chromatography on silica gel (eluent: n-
hexane/EtOAc 1:2).
Ethyl 1-((1R*,2R*,3R*,4R*)-3-(tert-butoxycarbonyl)-2-
hydroxy-4-(hydroxymethyl)cyclopentyl)-1H-1,2,3-triazole-
4-carboxylate (20)
A white solid; mp 128-130 °C; yield: 64% (from 10). Rf
1
= 0.33 (n-hexane/EtOAc 1:2); H NMR (400 MHz, CDCl3):
Procedure C (Cu-catalysed 1,3-dipolar cycloaddition)
ꢀ = 1.40 (t, 3H, CH3), 1.46 (s, 9H, tBu), 2.36-2.40 (m, 2H,
CH2), 2.78-2.82 (m, 1H, H-4), 3.64-3.79 (m, 2H, OCH2),
4.29-4.36 (m, 1H, H-3), 4.38-4.47 (m, 3H, OCH2 and H-2),
4.79-4.86 (m, 1H, H-1), 5.34 (brs, 1H, N-H). 13C NMR (400
MHz, CDCl3): ꢀ = 14.7, 28.7, 29.2, 41.3, 55.4, 61.5, 61.8,
66.9, 78.3, 80.0, 122.4, 140.6, 161.1, 170.3. MS: (ESI, pos)
m/z = 763 (2M+Na). Anal. Calcd. for C16H26N4O6: C, 51.88;
H, 7.08; N, 15.13. Found: C, 51.60; H, 6.82; N, 15.36.
To a solution of azido alcohol 10, 24 or 31 (500 mg, 1.83
mmol) in EtOH (6 ml) and H2O (0.5 mL), CuSO4 (1 equiv),
ascorbic acid (1 equiv) and alkyne (1.1 equiv) were added
and the mixture was stirred at 20 °C for 14 h. The solvent
was then evaporated off and the residue was purified by
column chromatography on silica gel (eluent: n-
hexane/EtOAc 1:2).
tert-Butyl (1R*,2R*,3R*,5R*)-2-hydroxy-5-(hydroxymethyl)-
3-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclopentylcarbamate
(21)
Diethyl 1-[(1R*,2R*,3R*,4R*)-3-(tert-butoxycarbonyl-
amino)-2-hydroxy-4-(hydroxymethyl)cyclopentyl]-1H-
1,2,3-triazole-4,5-dicarboxylate (12)
A white solid; mp 139-141 °C; yield: 89% (from 10). Rf
= 0.45 (n-hexane/EtOAc 1:2); 1H NMR (400 MHz, DMSO):
ꢀ = 1.42 (s, 9H, tBu), 2.00-2.07 (m, 1H, CH2), 2.11-2.17 (m,
1H, CH2), 2.50-2.55 (m, 1H, H-5), 3.47-3.53 (m, 1H, OCH2),
4.07-4.12 (m, 1H, OCH2), 4.32 )4.36 )m, 1H, H-1), 4.48-4.51
(m, 1H, H-2), 4.91-4.94 (m, 1H, H-3), 5.41 (brs, 1H, O-H),
6.54 (brs, 1H, N-H), 7.30-7.36 (m, 1H, Ar-H), 7.42-7.48 (m,
2H, Ar-H), 7.83-7.87 (m, 2H, Ar-H), 8.65 (s, 1H, Ar-H). 13C
NMR (400 MHz, CDCl3): ꢀ = 28.7, 30.5, 41.8, 55.4, 61.5,
66.7, 78.0, 80.5, 121.0, 126.1, 128.8, 129.3, 130.6, 150.5,
172.2. Anal. Calcd. for C19H26N4O4: C, 60.95; H, 7.00; N,
14.96. Found: C, 60.67; H, 6.78; N, 14.69.
A yellow oil; yield: 49%. Rf = 0.40 (n-hexane/EtOAc
1:2); 1H NMR (400 MHz, CDCl3): ꢀ = 1.30 (t, 3H, CH3, J =
7.20 Hz), 1.42 (t, 3H, CH3, J = 7.20 Hz), 1.46 (s, 9H, tBu),
2.29-2.42 (m, 2H, CH2), 2.83-2.86 (m, 1H, H-4), 3.37 (brs,
1H, O-H), 3.62-3.78 (m, 2H, OCH2), 3.89 (brs, 1H, O-H),
4.33-4.50 (m, 5H, 2 x OCH2 and H-3), 4.54-4.57 (m, 1H, H-
2), 5.07-5.14 (m, 1H, H-1), 5.21 (brs, 1H, N-H). 13C NMR
(400 MHz, DMSO): ꢀ = 14.5, 14.8, 29.1, 32.1, 41.8, 55.2,
61.9, 62.2, 63.8, 66.0, 77.7, 89.1, 133.0, 141.5, 155.8, 160.0,
161.6. MS: (ESI, pos) m/z = 465 (M + 23). Anal. Calcd. for
C19H30N4O8: C, 51.58; H, 6.83; N, 12.66. Found: C, 51.14;
H, 6.98; N, 12.29.
tert-Butyl (1R*,2R*,3R*,5R*)-2-hydroxy-5-(hydroxymethyl)-
3-(4-propyl-1H-1,2,3-triazol-1-yl)cyclopentylcarbamate
(22)
Diethyl 1-[(1R*,2R*,3R*,4S*)-3-(tert-butoxycarbonyl-
amino)-2-hydroxy-4-(hydroxymethyl)cyclopentyl]-1H-
1,2,3-triazole-4,5-dicarboxylate (13)
A white solid; mp 148-151 °C; yield: 58% (from 10). Rf
= 0.45 (n-hexane/EtOAc 1:2); H NMR (400 MHz, CDCl3):
A yellow oil; yield: 62%. Rf = 0.35 (n-hexane/EtOAc
1:2); 1H NMR (400 MHz, DMSO): ꢀ = 1.26 (t, 3H, CH3, J =
7.20 Hz), 1.30 (t, 3H, CH3, J = 7.20 Hz), 1.36 (s, 9H, tBu),
1.82-1.93 (m, 1H, CH2), 2.00-2.12 (m, 1H, CH2), 2.21-2.30
(m, 1H, H-4), 3.36-3.49 (m, 2H, OCH2), 3.72-3.81 (m, 1H,
H-3), 4.20-4.27 (m, 1H, H-2), 4.25-4.35 (m, 2H, OCH2),
4.33-4.43 (m, 2H, OCH2), 4.58-4.64 (m, 1H, H-1), 4.89 (brs,
1H, O-H), 5.33 (brs, 1H, O-H), 6.50 (brs, 1H, N-H). 13C
NMR (400 MHz, DMSO): ꢀ = 14.5, 14.8, 29.1, 31.5, 44.8,
53.8, 62.3, 62.9, 63.8, 66.6, 75.8, 78.6, 132.4, 139.2, 156.3,
1
ꢀ = 1.01 (t, 3H, CH3), 1.49 (s, 9H, tBu), 1.64-1.77 (m, 2H,
CH2), 2.32-2.35 (m, 2H, CH2), 2.67-2.73 (m, 2H, CH2), 2.77-
2.80 (m, 1H, H-5), 3.64-3.74 (m, 2H, OCH2), 4.32-4.36 (m,
1H, H-1), 4.45-4.49 (m, 1H, H-2), 4.75-4.83 (m, 1H, H-3),
5.38 (brs, 1H, N-H), 7.38 (s, 1H, Ar-H). 13C NMR (400
MHz, DMSO): ꢀ = 14.5, 23.0, 28.1,29.1, 32.0, 41.5, 55.3,
62.0, 65.3, 77.8, 78.8, 157.0, 160.5, 170.0. Anal. Calcd. for

226 Letters in Organic Chemistry, 2011, Vol. 8, No. 3
Kiss et al.
C16H28N4O4: C, 56.45; H, 8.29; N, 16.46. Found: C, 56.70;
H, 7.98; N, 16.09.
14.2, 22.9, 28.0, 28.8, 31.4, 43.4, 52.7, 62.7, 68.1, 77.6, 80.2,
157.0, 160.2, 168.3. Anal. Calcd. for C16H28N4O4: C, 56.45;
H, 8.29; N, 16.46. Found: C, 56.11; H, 7.93; N, 16.10.
Diethyl 1-[(1S*,2S*,3S*,5R*)-3-(tert-butoxycarbonylamino)-
2-hydroxy-5-(hydroxymethyl)cyclopentyl]-1H-1,2,3-
triazole-4,5-dicarboxylate (27)
Diethyl 1-[(1R*,2R*,3S*,5S*)-5-(tert-butoxycarbonyl-
amino)-2-hydroxy-3-(hydroxymethyl)cyclopentyl]-1H-
1,2,3-triazole-4,5-dicarboxylate (33)
A yellow oil; yield: 61%. Rf = 0.35 (n-hexane/EtOAc
1:2); 1H NMR (400 MHz, DMSO): ꢀ = 1.27 (t, 3H, CH3, J =
7.15 Hz), 1.31 (t, 3H, CH3, J = 7.15 Hz), 1.40 (s, 9H, tBu),
1.52-1.63 (m, 1H, CH2), 2.18-2.27 (m, 1H, CH2), 2.42-2.50
(m, 1H, H-5), 3.37-3.43 (m, 2H, OCH2), 4.01-4.10 (m, 1H,
H-3), 4.23-4.29 (m, 1H, H-2), 4.30-4.38 (m, 2H, OCH2),
4.39-4.43 (m, 2H, OCH2), 4.70 (brs, 1H, O-H), 4.78-4.83 (m,
1H, H-1), 5.44 (brs, 1H, O-H), 6.42 (brs, 1H, N-H). 13C
NMR (400 MHz, DMSO): ꢀ = 14.5, 14.8, 29.1, 32.3, 44.2,
52.2, 62.2, 63.2, 63.7, 69.2, 76.8, 78.7, 132.7, 139.1, 156.0,
159.3, 160.6. MS: (ESI, pos) m/z = 907 (2M + 23). Anal.
Calcd. for C19H30N4O8: C, 51.58; H, 6.83; N, 12.66. Found:
C, 51.19; H, 6.54; N, 12.28.
A yellow oil; yield: 60%. Rf = 0.40 (n-hexane/EtOAc
1:2); H NMR (400 MHz, DMSO): ꢀ = 1.29 (s, 9H, tBu),
1
1.31 (t, 3H, CH3, J = 7.15 Hz), 1.33 (t, 3H, CH3, J = 7.15
Hz), 1.65-1.75 (m, 1H, CH2), 2.17-2.26 (m, 1H, CH2), 2.32-
2.40 (m, 1H, H-3), 3.47-3.53 (m, 1H, OCH2), 3.57-3.64 (m,
1H, OCH2), 4.17-4.24 (m, 1H, H-5), 4.37-4.46 (5H, 2 x
OCH2 and O-H), 4.49-4.55 (m, 1H, H-2), 4.74-4.83 (m, 1H,
H-1), 5.44 (brs, 1H, O-H), 7.08 (brs, 1H, N-H). 13C NMR
(400 MHz, DMSO): ꢀ = 14.5, 14.8, 28.9, 32.1, 42.5, 55.6,
61.3, 62.2, 63.5, 74.0, 75.7, 78.8, 132.4, 139.5, 148.2, 155.8,
159.0. MS: (ESI, pos) m/z = 907 (2M + 23). Anal. Calcd. for
C19H30N4O8: C, 51.58; H, 6.83; N, 12.66. Found: C, 51.24;
H, 6.56; N, 12.99.
Ethyl 1-((1S*,2S*,3S*,5R*)-3-(tert-butoxycarbonyl)-2-
hydroxy-5-(hydroxymethyl)cyclopentyl)-1H-1,2,3-triazole-
4-carboxylate (28)
Ethyl 1-((1R*,2R*,3S*,5S*)-5-(tert-butoxycarbonyl)-2-
hydroxy-3-(hydroxymethyl)cyclopentyl)-1H-1,2,3-triazole-
4-carboxylate (34)
A white solid; mp 112-115 °C; yield: 68%. Rf = 0.40 (n-
1
hexane/EtOAc 1:2); H NMR (400 MHz, DMSO): ꢀ = 1.34
A white solid; mp 127-130 °C; yield: 59%. Rf = 0.35 (n-
1
(t, 3H, CH3), 1.39 (s, 9H, tBu), 1.47-1.52 (m, 1H, CH2),
2.14-2.18 (m, 1H, CH2), 2.22-2.36 (m, 1H, H-5), 3.36-3.40
(m, 2H, OCH2), 3.90-4.01 (m, 1H, H-3), 4.12-4.18 (m, 1H,
H-2), 4.24-4.29 (m, 2H, OCH2), 4.51-4.56 (m, 1H, H-1),
4.68 (brs, 1H, O-H), 5.32 (brs, 1H, O-H), 6.32 (brs, 1H, N-
H), 8.78 (s, 1H, Ar-H). 13C NMR (400 MHz, DMSO): ꢀ =
15.1, 29.1, 32.4, 43.7, 51.9, 61.3, 62.8, 69.3, 76.6, 78.6,
129.1, 139.7, 156.0, 161.2. Anal. Calcd. for C16H26N4O6: C,
51.88; H, 7.08; N, 15.13. Found: C, 51.57; H, 6.79; N, 15.31.
hexane/EtOAc 1:2); H NMR (400 MHz, CDCl3): ꢀ = 1.40
(t, 3H, CH3), 1.42 (s, 9H, tBu), 1.91-1.96 (m, 1H, CH2),
2.38-2.46 (m, 1H, CH2), 2.55-2.60 (m, 1H, H-3), 3.78-3.85
(m, 1H, OCH2), 3.99-4.05 (m, 1H, OCH2), 4.33-4.37 (m, 1H,
H-5), 4.384.46 (m, 2H, OCH2), 4.72-4.77 (m, 1H, H-2),
4.81- 4.86 (m, 1H, H-1), 5.14 (brs, 1H, N-H), 8.29 (s, 1H,
Ar-H). 13C NMR (400 MHz, CDCl3): ꢀ = 14.7, 28.6, 31.4,
40.2, 53.7, 61.7, 62.7, 73.3, 76.8, 80.2, 141.5, 155.7, 161.0,
174.2. Anal. Calcd. for C16H26N4O6: C, 51.88; H, 7.08; N,
15.13. Found: C, 51.56; H, 7.37; N, 14.87.
tert-Butyl (1S*,2S*,3S*,4R*)-2-hydroxy-4-(hydroxymethyl)-
3-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclopentylcarbamate
(29)
tert-Butyl (1S*,2R*,3R*,4S*)-3-hydroxy-4-(hydroxymethyl)-
2-(4-phenyl-1H-1,2,3-triazol-1-yl)cyclopentylcarbamate
(35)
A white solid; mp 131-136 °C; yield: 65% (from 24). Rf
= 0.40 (n-hexane/EtOAc 1:2); 1H NMR (400 MHz, DMSO):
ꢀ = 1.41 (s, 9H, tBu), 1.52-1.58 (m, 1H, CH2), 2.23-2.28 (m,
1H, CH2), 2.26-2.42 (m, 1H, H-4), 3.42-3.49 (m, 2H, OCH2),
3.98-4.10 (m, 1H, H-1), 4.22-4.28 (m, 1H, H-2), 4.53-4.58
(m, 1H, H-3), 4.78 (brs, 1H, O-H), 5.45 (brs, 1H, O-H), 6.42
(brs, 1H, N-H), 7.33-7.38 (m, 1H, Ar-H), 7.48-7.52 (m, 2H,
Ar-H), 7.80-7.86 (m, 2H, Ar-H), 8.60 (s, 1H, Ar-H). 13C
NMR (400 MHz, DMSO): ꢀ = 29.1, 32.5, 44.0, 52.2, 62.9,
69.0, 76.8, 78.6, 121.6, 126.0, 128.6, 129.7, 131.8, 147.1,
156.0. Anal. Calcd. for C19H26N4O4: C, 60.95; H, 7.00; N,
14.96. Found: C, 60.68; H, 6.69; N, 15.22.
A white solid; mp 151-152 °C; yield: 51% (from 31). Rf
= 0.40 (n-hexane/EtOAc 1:2); 1H NMR (400 MHz, DMSO):
ꢀ = 1.35 (s, 9H, tBu), 1.70-1.80 (m, 1H, CH2), 2.29-2.39 (m,
1H, CH2), 2.50-2.54 (m, 1H, H-4), 3.73-3.87 (m, 2H, CH2),
4.32-4.41 (m, 1H, H-1), 4.67-4.70 (m, 2H, H-2 and H-3),
7.33-7.48 (m, 3H, Ar-H), 7.82-7.86 (m, 2H, Ar-H), 8.37 (m,
1H, Ar-H). Anal. Calcd. for C19H26N4O4: C, 60.95; H, 7.00;
N, 14.96. Found: C, 60.60; H, 6.66; N, 14.67.
Separation of the Enantiomers
For (+)-29: 1 mg was dissolved in n-hexane/iPrOH
(90/10) (1 mL), the solution was filtered, and the
enantiomers were separated by HPLC. Retention times (min)
[Chiralcel OD-H column (manufactured by Daicel), eluent:
n-hexane (containing 0.1% diethylamine)/i-PrOH 90:10,
flow: 0.5 ml/min, room temperature, detection at 210 nm]:
66.4 (antipode: 46.5).
tert-Butyl (1S*,2S*,3S*,4R*)-2-hydroxy-4-(hydroxymethyl)-
3-(4-propyl-1H-1,2,3-triazol-1-yl)cyclopentylcarbamate
(30)
A white solid; mp 119-121 °C; yield: 62% (from 24). Rf
= 0.40 (n-hexane/EtOAc 1:2); 1H NMR (400 MHz, DMSO):
ꢀ = 0.91 (t, 3H, CH3), 1.39 (s, 9H, tBu), 1.49-1.64 (m, 3H,
CH2), 2.13-2.19 (m, 1H, CH2), 2.29-2.35 (m, 1H, H-4), 2.55-
2.62 (m, 2H, CH2), 3.31-3.36 (m, 2H, OCH2), 3.97-4.03 (m,
1H, H-1), 4.12-4.16 (m, 1H, H-2), 4.46-4.52 (m, 1H, H-3),
4.79 (brs, 1H, O-H), 5.32 (brs, 1H, O-H), 6.31 (brs, 1H, N-
H), 7.87 (s, 1H, Ar-H), 13C NMR (400 MHz, DMSO): ꢀ =
For (+)-35: 1 mg was dissolved in n-hexane/iPrOH (92/8)
(1 mL), the solution was filtered, and the enatiomers
separated by HPLC. Retention times (min) [Chiralcel OD-H
column (manufactured by Daicel), eluent: n-hexane/i-PrOH

Synthesis of Regio- and Stereoisomers of Highly Functionalized
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
227
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hydroxymethyl carbanucleosides via 'click' cycloaddition.
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Ethyl (1R,2S,3S,4S)-4-(tert-butoxycarbonyl)-3-hydroxy-2-
(4-phenyl-1H-1,2,3-triazol-1-yl)cyclopentanecarboxylate
[(+)-25]
A white solid; mp 186-189 °C; yield: 53% (from (-)-36);
the 1H NMR data were similar to those of the racemic
compound.10 [ꢀ]D20 = +5.5 (c 0.8, EtOH).
Ethyl (1R,2R,3R,4S)-4-(tert-butoxycarbonyl)-2-hydroxy-3-
(4-phenyl-1H-1,2,3-triazol-1-yl)cyclopentanecarboxylate [(-
)-32]
[2]
A white solid; mp 183-186 °C; yield: 55% (from (-)-37);
1
the H NMR data were similar to those of the racemic
compound.10 [ꢀ]D20 = -28 (c 0.7, EtOH).
tert-Butyl (1S,2S,3S,4R)-2-hydroxy-4-(hydroxymethyl)-3-
(4-phenyl-1H-1,2,3-triazol-1-yl)cyclopentylcarbamate [(+)-
29]
1
A white solid; mp 86-89 °C; yield: 65%; the H NMR
data were similar to those of the racemic compound. ee >
98%. [ꢀ]D20 = +15.5 (c 0.6, EtOH).
tert-Butyl (1S,2R,3R,4S)-3-hydroxy-4-(hydroxymethyl)-2-
(4-phenyl-1H-1,2,3-triazol-1-yl)cyclopentylcarbamate [(+)-
35]
1
A white solid; mp 179-180 °C; yield: 51%; the H NMR
data were similar to those of the racemic compound. ee >
98%. [ꢀ]D20 = +22 (c 0.2, EtOH).
CONCLUSION
Benhida,
R.
Tandem
azide-alkyne
1,3-dipolar
Regio- and stereosiomers of 1,2,3-triazole-substituted
cyclopentanols were efficiently synthtized from bicyclic ꢀ-
or ꢁ-lactam involving as key steps selective azidation and
azide-alkyne 1,3-dipolar cycloadditions.
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ACKNOWLEDGEMENTS
We are grateful to the Hungarian Research Foundation
(OTKA No. NK81371) for financial support and for the
granting of Bolyai János Fellowships to Loránd Kiss and
Enikꢂ Forró.
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