Click chemistry: An efficient synthesis of heterocycles substituted with steroids, saponins, and digitalis analogues

Article abstract of DOI:10.1055/s-0031-1289606

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) has been used for the construction of 1,2,3-triazole containing steroids in good to excellent yields. Combination of propargylic glycosides and steroidal azides as reaction partner allowed the synthesis of a privileged class of natural product analogues. The versatility of this protocol makes this chemistry a useful attractive approach for the synthesis of target molecules. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289606

PAPER
4003
Click Chemistry: An Efficient Synthesis of Heterocycles Substituted with
Steroids, Saponins, and Digitalis Analogues
Natural Product
A
n
nalogues Con
n
taining 1, 2,3
a
-Triazole SystemM. Deobald,a Leandro R. S. Camargo,a,b Diego Alves,c Julio Zukerman-Schpector,b Arlene G. Corrêa,a
Márcio W. Paixão*a
a
Laboratório de Síntese de Produtos Naturais, Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP,
13565-905, Brazil
Fax 55(16)33518350; E-mail: mwpaixao@ufscar.br
Laboratório de Cristalografia, Estereodinâmica e Modelagem Molecular, Departamento de Química, Universidade Federal de São Carlos,
São Carlos, SP, 13565-905, Brazil
b
c
Laboratório de Síntese Orgânica Limpa, Universidade Federal de Pelotas, Pelotas, RS, 96001-970, Brazil
Received 21 August 2011; revised 10 October 2011
tion partners, for example, peptides, proteins, nucleosides,
steroids, and carbohydrates.9 Recently, Li’s group report-
ed the synthesis of 1,2,3-triazolic heterocycles containing
lithocholic acid and their application as inhibitors of a-
Abstract: The copper-catalyzed azide-alkyne cycloaddition
(CuAAC) has been used for the construction of 1,2,3-triazole con-
taining steroids in good to excellent yields. Combination of propar-
gylic glycosides and steroidal azides as reaction partner allowed the
synthesis of a privileged class of natural product analogues. The 2,3-sialyltransferase.10 Additionally, there are only two
versatility of this protocol makes this chemistry a useful attractive
approach for the synthesis of target molecules.
specific examples, which described the application of
click chemistry for binding a steroid with a carbohydrate
by an 1,2,3-triazole scaffold.11 For example, Chang and
Key words: click chemistry, 1,2,3-triazole, sugars, steroids, sa-
ponins, digitalis
co-workers have synthesized cyclopamine derivatives and
applied them as lead compounds in anticancer drug dis-
covery.11b Therefore, it remains the necessity for a deep
Steroidal glycosides constitute a structurally and biologi- study on the combinations between the reaction partners
cally diverse class of molecules, which has been isolated for the synthesis of saponins and digitalic analogues.
from a wide variety of both plant and animal species.1
Herein, we describe our contribution to the application of
Members of this class of biomolecules have demonstrated
the copper-catalyzed azide–alkyne cycloaddition
cardiotonic activity and therapeutic potential as antiviral
(CuAAC) reaction for the synthesis of 1,2,3-triazoles con-
and antitumoral agents.2 The Chinese folk medicine con-
taining a steroidal moiety. In order to get the best reaction
tains steroidal glycosides as major components, which are
conditions for the 1,3-dipolar cycloaddition of phenyl-
gylcoconjugate templates in drug design and develop-
acetylene with the azidocholesterol 1a12 the reaction was
ment.3 Thus, taking inspiration from bioactive compounds
carried out in a mixture of THF–H2O (1:1) in the presence
isolated from nature, many glycoconjugate derivatives
of 10 mol% Cu(OAc)2·H2O and sodium ascorbate (20
mol%). To our delight the desired product 3a was ob-
tained in quantitative yield (Table 1, entry 1). The experi-
have been prepared and evaluated as drug candidates.4
The replacement of the glycosidic bond with different
linkers provides steroidal glycoside mimics with im-
mental procedure involves the in situ generation of Cu(I)
proved stability and enlarges molecular length.5
species by reducing Cu(OAc)2·H2O with sodium ascor-
In this context, 1,2,3-triazole scaffolds are attractive link- bate in aqueous solution.13 When the reaction time was
er units, because they are stable regarding metabolic deg- decreased from 12 to 6 hours the chemical yield was dra-
radation. Furthermore these heterocyclic compounds are matically dropped to 56% (Table 1, entry 1 vs 2). The use
able to form hydrogen bonds, which are important in bind- of different amounts of copper salt and sodium ascorbate
ing bimolecular targets and to increase their solubility. were also studied. Decreasing the copper catalyst loading
The unique chemistry behavior of this moiety aroused the to 5 mol% along with 10 mol% of sodium ascorbate the
chemist’s interest, ranging from a synthetic point of view 1,2,3-triazole 3a was obtained in 65% yield (entry 3). Us-
to the context of biological and pharmacological applica- ing 5 mol% of Cu(OAc)2·H2O with 20 mol% of sodium
tions.6 The 1,3-dipolar cycloaddition reaction is a power- ascorbate the triazole 3a was obtained in a reasonable
ful synthetic protocol for the synthesis of 1,2,3-triazoles.7 chemical yield of 82% (entry 4). By changing the copper
In 2002, Sharpless and Meldal independently discovered acetate to CuBr2 (10 mol%) the cholesterol containing the
the copper-catalyzed azide–alkyne cycloaddition triazole ring was obtained in 45% yield (entry 5).
(CuAAC) for the synthesis of five-membered heterocy-
The additional parameters were also analyzed including
cles.8 These click chemistry protocols have shown to be
change of the solvent and temperature. A mixture of etha-
regioselective and compatible with a wide range of reac-
nol–water (1:1) gave the desired product in 25% yield (en-
try 6). When the reaction was run in PEG 400–H2O or
[BMIM]BF4–H2O at room temperature for 12 hours the
triazole 3a was obtained with 28% and 35% yield, respec-
SYNTHESIS 2011, No. 24, pp 4003–4010
Advanced online publication: 16.11.2011
DOI: 10.1055/s-0031-1289606; Art ID: M81211SS
x
x.
x
x
.
2
0
1
1
tively (entries 7 and 8).
© Georg Thieme Verlag Stuttgart · New York

4004
A. M. Deobald et al.
PAPER
Moreover, investigation of the temperature effects on the
reaction revealed that raising the temperature had no sig-
nificant influence on the yield although the reaction time
could be decreased to six hours (see entries 1, 9, and 10).
On the other hand moderate yields were obtained under
microwave irradiation using 100 W as maximum potency
at different temperatures (entries 11–14).
Table 1 Optimization Studies of the Copper-Catalyzed 1,3-Dipolar
Cycloaddition of 3-b-azidocholesterol (1a) with Phenylacetylene
Ph
H
CuX2, sodium ascorbate
cholesterol
solvent–H2O
temperature, time
N3
H
Once the optimal conditions were obtained, we examined
the possibilities and limitation of this cycloaddition reac-
tion by varying the nature of the terminal alkyne
1
H
H
N
N
N
Table 2 Substrate Scope of CuAAC: Variation of the Alkyne Part-
ner
Ph
3a
Entry Copper salt
Solvent–H2O
(1:1)
Temp
°C)
Yield
(%)a
R
H
Cu(OAc)2•H2O (10 mol%)
1
2b
3c
4
Cu(OAc)2·H2O
10 mol%
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
80
100
56
65
82
45
25
28
35
90
70
66
40
75
75
cholesterol
sodium ascorbate (20 mol%)
THF–H2O (1:1)
N3
H
1a
Cu(OAc)2·H2O
10 mol%
THF
r.t., 12 h
H
H
N
N
N
Cu(OAc)2·H2O
5 mol%
THF
R
3a–e
Cu(OAc)2·H2O
5 mol%
THF
Entry
1
Product
Yield (%)a
5
CuBr2
10 mol%
THF
cholesterol
N
N
N
6
Cu(OAc)2·H2O
10 mol%
EtOH
PEG 400
[BMIM]BF4
THF
100
7
Cu(OAc)2·H2O
10 mol%
3a
8
Cu(OAc)2·H2O
10 mol%
cholesterol
N
N
N
9b
10b
Cu(OAc)2·H2O
10 mol%
2
3
96
92
Cu(OAc)2·H2O
10 mol%
THF
100
60
3b
cholesterol
N
N
11d,e Cu(OAc)2·H2O
10 mol%
THF
N
12d,e Cu(OAc)2·H2O
10 mol%
THF
80
HO
3c
13d,f
Cu(OAc)2·H2O
10 mol%
THF
100
100
cholesterol
N
N
N
14d,g Cu(OAc)2·H2O
10 mol%
THF
4
5
87
88
NH2
a Unless otherwise noted, all reactions were carried out on a 0.3 mmol
scale using 1 mL of solvent for 12 h, 20 mol% of sodium ascorbate.
All yields are given for isolated products after column chromatogra-
phy.
3d
cholesterol
N
N
N
b Reaction time of 6 h.
c 10 mol% of sodium ascorbate was used.
d Reaction was carried out under microwave irradiation using 100 W
as maximum potency.
O
OEt
3e
e Reaction time of 30 min.
a Unless otherwise noted, all reactions were carried out on a 0.3 mmol
scale using 1 mL of solvent for 12 h. All yields are given for isolated
products after column chromatography.
f Reaction time of 20 min.
g Reaction time of 40 min.
Synthesis 2011, No. 24, 4003–4010 © Thieme Stuttgart · New York

PAPER
Natural Product Analogues Containing 1,2,3-Triazole System
4005
(Table 2). The results showed that several substituted ter- ed smoothly with 3-b-prop-2-ynyloxycholesterol to give
minal alkynes coupled efficiently with the 3-b-azidocho- the product 3j in 75% yield. With regard to stereochemis-
lesterol (1a) to provide the corresponding 1,2,3-triazoles try on the anomeric carbon of the galactopyranosyl azide,
3a–e in excellent isolated yields (>87%). When the reac- we observed that the stereoconfiguration does not play an
tion was carried out using hex-1-yne as a reaction partner important role in determining the degree of chemical
the click product was obtained in 96% yield (Table 2, en- yield. For instance, 2,3,4,6-tetra-O-acetyl-a-D-glucopyra-
try 2). Alkylalkynes bearing hydroxy and amino groups nosyl azide underwent click coupling with similar level of
were also successfully employed in the 1,3-dipolar cy- yield as the b-analogue (3j vs 3k).
cloaddition reaction (entries 3 and 4). Likewise, when a
To fully explore this transformation, the CuAAC was then
strong electron-withdrawing group was present in the ter-
successfully applied to the reaction between propargylic
minal alkyne, the product was obtained in very good
glycosides and azido-functionalized steroids. We were
able to synthesize a library of saponins and digitalis deriv-
chemical yield (entry 5).
Next, the reactivity of terminal alkynes derived from cho- atives containing the triazole moiety.15 The natural ver-
lesterol towards different azides was evaluated. Benzylic sions of these two classes of compounds are widely
azides with electron-neutral and electron-deficient sub- recognized for their antifungal, cardiovascular, and anti-
stituent react with 3-b-prop-2-ynyloxycholesterol (2f) to tumor activity.2
give the expected 1,2,3-triazoles in good to excellent
Effectively, the click chemistry involving 2-propynyl-
yields (Scheme 1, products 3f, 3g, and 3h). The hindered
2,3,4,6-tetra-O-acetyl-a-D-glucopyranoside and azido-
ortho-biphenyl azide was also used forming 3i in 84%
steroids were performed to give the steroidal glycosides.
yield. The use of this methodology has proven that differ-
Different azidosteroids were evaluated and in all the cases
ent groups attached to the aryl ring are compatible with
the corresponding products were obtained in rather good
this reaction,14 thus, providing an opportunity for further
levels of chemical yield (Table 3, entries 1–4). When the
propargylic partner was changed from b-D-glucose pen-
taacetate to a disaccharide or trisaccharide, the analogues
functionalization of the product. In addition, the 2,3,4,6-
tetra-O-acetyl-b-D-galactopyranosyl azide (1j) also react-
R
N3
1f–j
H
Cu(OAc)2•H2O
(10 mol%)
H
H
H
cholesterol
sodium ascorbate
(20 mol%)
THF–H2O (1:1)
r.t., 12 h
O
R
N
2
N
N
3f–k
N
N
N
cholesterol
cholesterol
cholesterol
cholesterol
N
O
O
N
N
Br
3f (95% yield)
3g (88% yield)
N
N
N
N
O
cholesterol
N
O
Br
N
3h (85% yield)
3i (84% yield)
OAc
OAc
cholesterol
AcO
α
O
O
O
AcO
N
O
OAc
N
N
N
AcO
N
β
N
AcO
AcO
3j (75% yield)
3k (65% yield)
Scheme 1 Scope of the click reaction using alkynylcholesterol building block
Synthesis 2011, No. 24, 4003–4010 © Thieme Stuttgart · New York

4006
A. M. Deobald et al.
PAPER
of this special class of natural product were also obtained In summary, we have employed the click chemistry con-
in satisfactory yields (entries 5 and 6).
cept for the synthesis of 1,2,3-triazole containing steroids.
As an application of this approach, combinations of dif-
Table 3 Synthesis of Saponins and Digitalis Derivatives
H
Cu(OAc)2•H2O (10 mol%)
sodium ascorbate (20 mol%)
N
N
N
steroid
N3
sugar
+
THF–H2O (1:1)
r.t., 12 h
sugar
3k–o
Entry Steroidal azide
Product
Yield
(%)a
OAc
O
AcO
AcO
N
N
1
85
75
N
N
N
H
H
cholesterol
N3
O
H
O
Ac
3l
OAc
O
O
H
AcO
O
2
N
N
diosgenin
N3
H
AcO
O
H
O
Ac
3m
O
OAc
O
OMe
H
N
N
3
70
80
lithocholic acid
N3
AcO
H
H
N
O
H
AcO
O
Ac
3n
OMe
OH
OAc
O
O
H
N
N
4
5
N3
N
cholic acid
AcO
O
H
AcO
O
Ac
OH
3o
OAc
O
OAc
AcO
H
H
80
O
cholesterol
N3
O
N
N
AcO
O
H
Ac
O
AcO
O
Ac
3p
O
OAc
O
H
OAc
O
OBn
Bn
O
N
H
6
68
O
N
diosgenin
N3
H
N
AcO
O
O
AcO
O
O
O
AcO
O
Ac
BnO
Ac
3q
a Unless otherwise noted, all reactions were carried out on a 0.3 mmol scale using 1 mL of solvent for 12 h. All yields are given for isolated
products after column chromatography.
Synthesis 2011, No. 24, 4003–4010 © Thieme Stuttgart · New York

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Natural Product Analogues Containing 1,2,3-Triazole System
4007
1H NMR (400 MHz, CDCl3): d = 7.32 (s, 1 H), 5.45–5.43 (m, 1 H),
4.37–4.29 (m, 1 H), 3.76–3.73 (m, 1 H), 2.71 (t, J = 8.0 Hz, 3 H),
2.54–2.50 (m, 1 H), 2.09–1.99 (m, 5 H), 1.87–1.83 (m, 2 H), 1.68–
1.58 (m, 3 H), 1.55–1.47 (m, 4 H), 1.43–1.32 (m, 4 H), 1.29–1.22
(m, 3 H), 1.19–1.12 (m, 4 H), 1.09 (s, 3 H), 1.06–0.99 (m, 4 H),
0.95–0.91 (m, 6 H), 0.88–0.85 (m, 6 H), 0.69 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 147.91, 139.36, 123.02, 118.18,
60.60, 56.65, 56.11, 50.03, 42.27, 39.67, 39.56, 39.47, 37.82, 36.70,
36.15, 35.74, 31,82, 31.77, 31.61, 29.29, 28.18, 27.97, 25.44, 24.24,
23.79, 22.77, 22.52, 22.34, 20.96, 19.36, 18.69, 13.80, 11.83.
ferent saccharides and steroids building blocks have been
used and a small library of saponins and digitalis ana-
logues bearing an 1,2,3-triazole moieties as surrogate of
the glycosidic linkage, was obtained. The high yields and
the feasibility of the method highlights the efficiency of
this methodology and prompt us for further extension of
this approach, which will be reported in due course.
1H and 13C NMR spectra were recorded on a Bruker ARX-400 (400
and 100 MHz, respectively). Optical rotations were measured with
a Perkin-Elmer Polarimeter, Model 241, at 589 nm, 25 °C. High-
resolution mass spectra were recorded on a Bruker BioApex 70eV
spectrometer. Gas chromatography (GC) was performed using a
Varian 3800 gas chromatograph with a Hydrodex b-3P columm.
Column chromatography was performed using Merck Silica Gel
(230–400 mesh). Thin-layer chromatography (TLC) was performed
using Merck Silica Gel GF254, 0.25 mm thickness. For visualization,
TLC plates were either placed under ultraviolet light, or stained
with iodine vapor, or acidic vanillin. Most reactions were monitored
by TLC for disappearance of starting material. The following sol-
vents were dried and purified by distillation from the reagents indi-
cated: tetrahydrofuran from sodium with a benzophenone ketyl
indicator; dichloromethane from calcium hydride; acetonitrile from
phosphorus pentoxide. All other solvents were ACS or HPLC grade
unless otherwise noted. Air- and moisture-sensitive reactions were
conducted in flame-dried or oven-dried glassware equipped with
tightly fitted rubber septa and under a positive atmosphere of dry ar-
gon. Reagents and solvents were handled using standard syringe
techniques. Temperatures above room temperature were main-
tained by use of a mineral oil bath with an electrically heated coil
connected to a Variac controller.
HRMS (ESI): m/z calcd for C33H55N3 [M + H]+: 494.4396; found:
494.4468.
3c
Yield: 0.135 g (92%); white solid; mp 110 °C; [a]D +12.5 (c = 0.004
g/mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.42 (s, 1 H), 5.46–5.44 (m, 1 H),
4.38–4.30 (m, 1 H), 4.12 (q, J = 7.2 Hz, 1 H), 3.96–3.93 (m, 1 H),
2.94 (t, J = 6.0 Hz, 2 H), 2.87 (s, 1 H), 2.78–2.71 (m, 1 H), 2.55–
2.50 (m, 1 H), 2.11–1.98 (m, 6 H), 1.87–1.80 (m, 2 H), 1.63–1.47
(m, 4 H), 1.39–1.32 (m, 3 H), 1.29–1.21 (m, 4 H), 1.19–1.12 (m, 3
H), 1.09 (s, 3 H), 1.06–0.97 (m, 4 H), 0.92 (d, J = 6.4 Hz, 3 H),
0.88–0.85 (m, 6 H), 0.69 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 145.00, 139.19, 123.17, 119.28,
61.64, 60.77, 56.63, 56.09, 50.01, 42.26, 39.64, 39.52, 39.46, 37.78,
36.69, 36.13, 35.74, 31.80, 31.74, 29.23, 28.67, 28.16, 27.97, 24.23,
23.78, 22.77, 22.52, 20.95, 19.33, 18.67, 11.81.
HRMS (ESI): m/z calcd for C31H51N3O [M + H]+: 482.4032; found:
482.4104.
3d
Yield: 0.129 g (87%); yellow solid; mp 120 °C; [a]D +12.5
(c = 0.005 g/mL, CH2Cl2).
Triazoles 3a–o; General Click Procedure
To a solution of the desired azido derivative (0.3 mmol) in THF (1.0
mL) were added the respective alkyne (0.33 mmol) and distilled
H2O (0.5 mL). Then a fresh solution of sodium ascorbate (20 mol%,
0.012 g) and Cu(OAc)2·H2O (10 mol%, 0.006 g) in distilled H2O
(0.5 mL) was added and the mixture stirred under air for 12 h. Brine
(3 mL) was added and the mixture extracted with CH2Cl2 (3 × 5
mL). The organic layers were combined, washed with brine (3 mL),
and dried (MgSO4). The solvent was removed under vacuum and
the product was isolated by column chromatography using hexane–
EtOAc as eluent.
1H NMR (400 MHz, CDCl3): d = 7.65 (s, 1 H), 5.45–5.44 (m, 1 H),
4.41–4.33 (m, 1 H), 4.12 (q, J = 7.2 Hz, 2 H), 3.73 (s, 2 H), 3.43 (q,
J = 7.2 Hz, 1 H), 2.78–2.71 (m, 1 H), 2.56–2.51 (m, 1 H), 2.36 (s, 6
H), 2.11–2.00 (m, 5 H), 1.87–1.81 (m, 2 H), 1.61–1.47 (m, 4 H),
1.39–1.32 (m, 3 H), 1.27–1.24 (m, 3 H), 1.19–1.12 (m, 3 H), 1.09
(s, 3 H), 1.06–0.99 (m, 3 H), 0.92 (d, J = 6.4 Hz, 3 H), 0.87–0.85
(m, 6 H), 0.69 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 143.17, 139.20, 123.25, 120.93,
60.89, 60.40, 56.67, 56.14, 53.85, 50.05, 44.45, 42.30, 39.68, 39.53,
39.50, 37.80, 36.72, 36.18, 35.78, 31.85, 31.79, 29.26, 28.21, 28.00,
24.27, 23.82, 22.82, 22.57, 20.99, 19.36, 18.72, 11.86.
3a
Yield: 0.154 g (~100%); white solid; mp 200 °C; [a]D +12.5
HRMS (ESI): m/z calcd for C32H54N4 [M + H]+: 495.4348; found:
495.4421.
(c = 0.009 g/mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.83 (d, J = 7.6 Hz, 2 H), 7.78 (s,
1 H), 7.41 (t, J = 7.6 Hz, 2 H), 7.31 (t, J = 7.6 Hz, 1 H), 5.48–5.46
(m, 1 H), 4.46–4.39 (m, 1 H), 2.84–2.77 (m, 1 H), 2.61–2.56 (m, 1
H), 2.16–2.13 (m, 2 H), 2.06–1.99 (m, 4 H), 1.88–1.82 (m, 3 H),
1.63–1.48 (m, 5 H), 1.37–1.23 (m, 8 H), 1.12 (s, 3 H), 1.07–0.99 (m,
4 H), 0.93 (d, J = 6.4 Hz, 3 H), 0.87–0.85 (m, 6 H), 0.70 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 147.29, 139.21, 130.85, 128.77,
127.96, 125.65, 123.29, 117.36, 60.93, 56.68, 56.15, 50.07, 42.31,
39.69, 39.59, 39.50, 37.84, 36.74, 36.17, 35.77, 31.85, 31.80, 29.35,
28.21, 28.00, 24.25, 23.82, 22.79, 22.53, 21.00, 19.39, 18.71, 11.85.
3e
Yield: 0.132 g (88%); white solid; mp 136 °C; [a]D +12.9 (c = 0.005
g/mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 8.11 (s, 1 H), 5.49–5.46 (m, 1 H),
4.42 (q, J = 7.2 Hz, 3 H), 2.78–2.71 (m, 1 H), 2.59–2.55 (m, 1 H),
2.17–2.00 (m, 6 H), 1.88–1.79 (m, 2 H), 1.63–1.48 (m, 7 H), 1.43–
1.26 (m, 8 H), 1.19–1.01 (m, 9 H), 0.93–0.86 (m, 9 H), 0.69 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 160.97, 144.77, 138.70, 125.25,
123.74, 61.25, 56.67, 56.16, 50.03, 42.32, 39.74, 39.67, 39.52,
39.46, 37.71, 36.70, 36.19, 35.79, 31.85, 31.79, 29.29, 28.23, 28.03,
24.27, 23.84, 22.84, 22.58, 21.01, 19.36, 18.73, 14.36, 11.87.
HRMS (ESI): m/z calcd for C35H51N3 [M + H]+: 514.4083; found:
514.4155.
HRMS (ESI): m/z calcd for C32H51N3O2 [M + H]+: 510.3981; found:
510.4054.
3b
Yield: 0.143 g (96%); white solid; mp 158 °C; [a]D –24.2 (c = 3.3
g/mL, CH2Cl2).
Synthesis 2011, No. 24, 4003–4010 © Thieme Stuttgart · New York

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3f
A. M. Deobald et al.
PAPER
36.85, 36.24, 35.83, 35.11, 32.00, 31.92, 28.28, 28.22, 28.06, 24.33,
23.87, 22.86, 22.61, 21.11, 19.40, 18.76, 17.70, 11.92.
HRMS (ESI): m/z calcd for C43H59N3O [M + H]+: 634.4658; found:
Yield: 0.156 g (95%); white solid; mp 121 °C; [a]D –12.9 (c = 0.006
g/mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.45 (s, 1 H), 7.38–7.36 (m, 3 H),
7.28–7.27 (m, 2 H), 5.50 (s, 2 H), 5.35–5.33 (m, 1 H), 4.65 (s, 2 H),
3.33–3.26 (m, 1 H), 2.40–2.36 (m, 1 H), 2.25–2.22 (m, 1 H), 2.17
(s, 1 H), 2.02–1.80 (m, 6 H), 1.58–1.42 (m, 7 H), 1.38–1.25 (m, 4
H), 1.19–1.07 (m, 8 H), 0.98 (s, 3 H), 0.92–0.86 (m, 9 H), 0.67 (s, 3
H).
13C NMR (100 MHz, CDCl3): d = 146.41, 140.67, 134.61, 129.12,
128.76, 128.19, 122.22, 121.83, 79.00, 61.72, 56.78, 56.17, 54.18,
50.17, 42.34, 39.80, 39.54, 39.03, 37.18, 36.86, 36.22, 35.82, 31.95,
31.91, 30.97, 28.30, 28.26, 28.03, 24.32, 23.84, 22.86, 22.60, 21.09,
19.38, 18.76, 11.89.
634.4598.
3j
Yield: 0.175 g (75%); white solid; mp 93 °C; [a]D +99.7 (c = 0.006
g/mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.57 (s, 1 H), 5.45–5.43 (m, 1 H),
5.25–5.18 (m, 2 H), 5.13–5.07 (m, 2 H), 5.02–4.97 (m, 2 H), 4.93–
4.91 (m, 1 H), 4.85–4.78 (m, 2 H), 4.70 (d, J = 8.0 Hz, 1 H), 4.40–
4.38 (m, 1 H), 4.31–4.28 (m, 2 H), 4.16–4.13 (m, 2 H), 3.75–3.71
(m, 2 H), 2.79–2.72 (m, 1 H), 2.54–2.50 (m, 2 H), 2.12–1.98 (m, 15
H), 1.87–1.82 (m, 1 H), 1.64–1.48 (m, 4 H), 1.37–1.26 (m, 5 H),
1.13–1.01 (m, 8 H), 0.93 (d, J = 6.4 Hz, 3 H), 0.89 (d, J = 6.4 Hz,
6 H), 0.74 (s, 3 H).
HRMS (ESI): m/z calcd for C37H55N3O [M + H]+: 558.4345; found:
558.4417.
13C NMR (100 MHz, CDCl3): d = 170.65, 170.20, 169.42, 169.37,
143.59, 139.21, 123.30, 120.74, 99.85, 72.79, 71.90, 71.20, 68.29,
63.34, 61.13, 60.97, 56.65, 56.35, 55.86, 50.03, 42.24, 39.65, 39.59,
39.48, 37.95, 36.70, 36.21, 35.43, 31.74, 31.02, 29.28, 28.33, 27.15,
24.07, 23.11, 22.91, 22.64, 20.98, 20.76, 20.60, 20.15, 19.39, 18.72,
11.92.
3g
Yield: 0.166 g (88%); white solid; mp 173 °C; [a]D –10.6 (c = 0.005
g/mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.50 (d, J = 8.0 Hz, 2 H), 7.46 (s,
1 H), 7.15 (d, J = 8.0 Hz, 2 H), 5.46 (s, 2 H), 5.35–5.33 (m, 1 H),
4.66 (s, 1 H), 3.34–3.26 (m, 1 H), 2.40–2.35 (m, 1 H), 2.25–2.18 (m,
1 H), 2.04–1.91 (m, 3 H), 1.88–1.80 (m, 2 H), 1.58–1.42 (m, 8 H),
1.38–1.24 (m, 6 H), 1.18–1.04 (m, 8 H), 0.99 (s, 3 H), 0.91 (d,
J = 8.0 Hz, 3 H), 0.87–0.85 (m, 6 H), 0.67 (s, 3 H).
HRMS (ESI): m/z calcd for C44H67N3O10 [M + H]+: 798.4826;
found: 798.4899.
3k
Yield: 0.134 g (65%); white solid; mp 155–157 °C; [a]D +51.0
13C NMR (100 MHz, CDCl3): d = 146.60, 140.58, 133.59, 132.23,
129.71, 122.87, 122.09, 121.81, 79.01, 61.65, 56.71, 56.11, 53.40,
50.10, 42.27, 39.73, 39.49, 38.98, 37.12, 36.79, 36.15, 35.74, 31.90,
31.84, 28.24, 28.20, 27.97, 24.26, 23.78, 22.79, 22.54, 21.02, 19.32,
18.69, 11.83.
HRMS (ESI): m/z calcd for C37H54BrN3O [M + H]+: 636.3450;
found: 636.3523.
(c = 0.005 g/mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.63 (s, 1 H), 6.33 (d, J = 4.0 Hz,
2 H), 6.25 (t, J = 8.0 Hz, 1 H), 5.33–5.21 (m, 1 H), 4.69 (s, 2 H),
4.34–4.30 (m, 2 H), 4.25–4.21 (m, 2 H), 4.13–4.06 (m, 2 H), 4.00–
3.96 (m, 2 H), 3.34–3.27 (m, 2 H), 2.39–2.34 (m, 2 H), 2.25–2.19
(m, 2 H), 2.04–2.03 (m, 8 H), 2.00 (s, 3 H), 1.97–1.92 (m, 2 H), 1.84
(s, 3 H), 1.57–1.41 (m, 5 H), 1.38–1.29 (m, 3 H), 1.25–1.21 (m, 2
H), 1.14–1.03 (m, 5 H), 0.98 (s, 3 H), 0.89 (d, J = 8.0 Hz, 3 H),
0.84–0.83 (m, 6 H), 0.65 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.37, 170.12, 169.64, 169.54,
145.77, 140.49, 124.52, 121.89, 81.30, 79.16, 71.02, 70.45, 69.79,
68.01, 61.44, 61.25, 56.73, 56.13, 50.14, 42.29, 39.74, 39.50, 39.05,
37.15, 36.83, 36.17, 35.76, 31.92, 31.88, 28.30, 28.21, 27.97, 24.28,
23.80, 22.80, 22.56, 21.06, 20.63, 20.58, 20.31, 19.34, 18.71, 14.19,
11.86.
3h
Yield: 0.159 g (85%); white solid; mp 141 °C; [a]D –14.2 (c = 0.005
g/mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.63–7.59 (m, 1 H), 7.57 (s, 1 H),
7.34–7.13 (m, 3 H), 5.65 (s, 2 H), 5.35–5.29 (m, 1 H), 4.67 (s, 2 H),
3.39–3.23 (m, 1 H), 2.45–2.34 (m, 2 H), 2.29–2.14 (m, 1 H), 2.04–
1.80 (m, 5 H), 1.59–1.32 (m, 9 H), 1.16–0.85 (m, 23 H), 0.67 (s, 3
H).
13C NMR (100 MHz, CDCl3): d = 146.39, 140.69, 134.25, 133.21,
130.44, 130.38, 128.23, 123.51, 122.58, 121.83, 79.02, 61.74,
56.80, 56.20, 53.79, 50.19, 42.36, 39.82, 39.56, 39.07, 37.21, 36.88,
36.24, 35.82, 31.98, 31.92, 28.34, 28.27, 28.05, 24.33, 23.87, 22.86,
22.61, 21.11, 19.40, 18.76, 11.90.
HRMS (ESI): m/z calcd for C44H67N3O10 [M + H]+: 798.4905;
found: 798.4895.
3l
Yield: 0.199 g (85%); white solid; mp 135 °C; [a]D –2.9 (c = 0.007
g/mL, CH2Cl2).
HRMS (ESI): m/z calcd for C37H54BrN3O [M + H]+: 636.3450;
found: 636.3523.
1H NMR (400 MHz, CDCl3): d = 7.57 (s, 1 H), 5.46–5.44 (m, 1 H),
5.25–5.18 (m, 2 H), 5.13–5.07 (m, 2 H), 5.04–4.99 (m, 2 H), 4.94–
4.91 (m, 1 H), 4.84–4.78 (m, 2 H), 4.70 (d, J = 8.0 Hz, 1 H), 4.38–
4.37 (m, 1 H), 4.30–4.26 (m, 2 H), 4.16–4.13 (m, 2 H), 3.77–3.72
(m, 2 H), 2.79–2.72 (m, 1 H), 2.56–2.50 (m, 2 H), 2.09–1.98 (m, 15
H), 1.87–1.82 (m, 1 H), 1.62–1.47 (m, 4 H), 1.37–1.26 (m, 5 H),
1.14–1.01 (m, 8 H), 0.93 (d, J = 6.4 Hz, 3 H), 0.87 (d, J = 6.4 Hz,
6 H), 0.70 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.62, 170.17, 169.42, 169.34,
143.58, 139.08, 123.32, 120.64, 99.84, 72.78, 71.85, 71.24, 68.29,
63.06, 61.83, 60.93, 56.65, 56.11, 55.92, 50.03, 42.29, 39.65,
39.52, 39.47, 37.77, 36.70, 36.15, 35.75, 31.84, 31.76, 29.28, 28.20,
27.97, 24.24, 23.79, 22.81, 22.54, 20.98, 20.72, 20.65, 20.56, 19.33,
18.70, 11.84.
3i
Yield: 0.158 g (84%): pale yellow solid; mp 154 °C; [a]D –20.6
(c = 0.005 g/mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.64–7.61 (m, 1 H), 7.59–7.50 (m,
3 H), 7.28–7.26 (m, 3 H), 7.19 (s, 1 H), 7.11–7.08 (m, 2 H), 5.34–
5.32 (m, 1 H), 4.60 (s, 2 H), 3.20–3.12 (m, 1 H), 2.31–2.27 (m, 1 H),
2.18–2.11 (m, 2 H), 2.05–1.94 (m, 2 H), 1.85–1.80 (m, 4 H), 1.68–
1.25 (m, 15 H), 1.19–1.08 (m, 6 H), 0.98 (m, 3 H), 0.92–0.91 (m, 3
H), 0.87–0.85 (m, 6 H), 0.68 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 145.70, 140.67, 137.11, 131.13,
129.88, 128.71, 128.57, 128.51, 127.99, 126.72, 124.63, 121.82,
78.18, 61.14, 56.83, 56.20, 50.24, 42.36, 39.83, 39.56, 38.96, 37.13,
Synthesis 2011, No. 24, 4003–4010 © Thieme Stuttgart · New York

PAPER
Natural Product Analogues Containing 1,2,3-Triazole System
4009
HRMS (ESI): m/z calcd for C44H67N3O10 [M + H]+: 798.4826;
4.99 (t, J = 8.0 Hz, 2 H), 4.91–4.74 (m, 4 H), 4.65 (d, J = 8.0 Hz, 1
found: 798.4899.
H), 4.49–4.28 (m, 3 H), 4.21–4.13 (m, 3 H), 4.05 (q, J = 8.0 Hz, 1
H), 4.00–3.87 (m, 3 H), 3.68–3.64 (m, 1 H), 2.74–2.67 (m, 1 H),
2.50–2.46 (m, 1 H), 2.16 (s, 1 H), 2.07 (s, 3 H), 2.03 (s, 6 H), 1.97
(s, 6 H), 1.96 (s, 6 H), 1.94 (s, 3 H), 1.93 (s, 3 H), 1.91 (s, 3 H), 1.55–
1.41 (m, 4 H), 1.29–1.17 (m, 4 H), 1.08–0.97 (m, 6 H), 0.86 (d,
J = 6.4 Hz, 3 H), 0.81–0.79 (m, 6 H), 0.63 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.49, 170.46, 170.34, 170.05,
169.63, 169.36, 138.86, 123.44, 121.17, 99.56, 95.44, 88.75, 75.20,
72.49, 72.26, 72.17, 71.92, 71.69, 69.93, 69.63, 69.23, 68.39, 67.92,
67.82, 62.70, 62.50, 61.41, 61.35, 61.21, 56.58, 56.06, 49.95, 42.23,
39.59, 39.42, 39.32, 37.66, 36.64, 36.09, 35.69, 31.77, 31.71, 29.12,
28.13, 27.93, 24.19, 23.74, 22.74, 22.49, 20.92, 20.82, 20.60, 20.51,
19.26, 18.65, 11.78.
3m
Yield: 0.182 g (75%); white solid; mp 118 °C; [a]D –56.6 (c = 0.006
g/mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.27 (s, 1 H), 5.34–5.31 (m, 1 H),
5.26–5.21 (m, 2 H), 5.12–5.07 (m, 2 H), 5.03–4.98 (m, 2 H), 4.78
(d, J = 8.0 Hz, 2 H), 4.43–4.39 (m, 1 H), 4.37–4.36 (m, 3 H), 4.30–
4.25 (m, 2 H), 4.16–4.12 (m, 2 H), 3.75–3.71 (m, 2 H), 3.53–3.44
(m, 2 H), 3.39–3.33 (m, 1 H), 2.50–2.49 (m, 2 H), 2.31–2.22 (m, 2
H), 2.09 (s, 3 H), 2.05 (s, 3 H), 2.02 (s, 3 H), 2.01 (s, 3 H), 1.88–1.81
(m, 2 H), 1.78–1.71 (m, 1 H), 1.67–1.56 (m, 3 H), 1.52–1.43 (m, 2
H), 1.32–1.24 (m, 2 H), 1.20–1.06 (m, 2 H), 1.02 (s, 3 H), 0.96 (d,
J = 8.0 Hz, 3 H), 0.79–0.77 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 170.55, 170.14, 169.33, 169.30,
140.76, 121.26, 109.17, 98.02, 80.71, 78.00, 75.46, 72.65, 71.81,
71.53, 70.85, 69.71, 68.19, 66.72, 61.99, 61.66, 56.42, 55.84, 49.95,
42.15, 41.50, 40.16, 39.68, 37.13, 36.54, 31.94, 31.74, 31.49, 31.33,
31.27, 30.18, 28.70, 20.77, 20.63, 20.58, 20.50, 19.32, 17.05, 16.19,
14.43.
HRMS (ESI): m/z calcd for C56H83N3O18 [M + H]+: 1086.5672;
found: 1086.5594.
3q
Yield: 0.309 g (68%); white solid; mp 95 °C; [a]D –80.0 (c = 0.004
g/mL, CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.53–7.34 (m, 3 H), 7.31 (s, 1 H),
7.26–7.15 (m, 2 H), 6.78–6.63 (m, 5 H), 6.51–6.37 (m, 5 H), 5.45–
5.42 (m, 2 H), 4.58–4.50 (m, 2 H), 4.45–4.40 (m, 3 H), 3.51–3.48
(m, 2 H), 3.42–3.36 (m, 3 H), 3.30–3.28 (m, 1 H), 3.04 (s, 5 H),
2.56–2.51 (m, 3 H), 2.08–1.97 (m, 6 H), 1.94–1.85 (m, 5 H), 1.83–
1.73 (m, 8 H), 1.70–1.60 (m, 10 H), 1.57–1.44 (m, 8 H), 1.35–1.27
(m, 3 H), 1.21–1.12 (m, 5 H), 1.09 (s, 3H ), 1.06 (s, 6 H), 1.00–0.98
(m, 6 H), 0.85 (s, 1 H), 0.82–0.80 (m, 9 H).
13C NMR (100 MHz, CDCl3): d = 138.72, 128.96, 128.58, 127.92,
127.49, 126.94, 123.59, 109.35, 82.02, 80.90, 80.80, 77.27, 73.68,
73.15. 72.60, 71.77, 67.62, 66.88, 62.20, 62.08, 56.54, 56.40, 56.34,
50.07, 49.87, 47.76, 43.02, 42.27, 41.63, 40.69, 40.28, 39.82, 39.67,
39.37, 39.16, 38.81, 37.29, 37.24, 37.10, 36.88, 36.67, 36.54, 33.17,
32.63, 32.05, 31.83, 31.77, 3.63, 31.47, 31.40, 31.35, 30.30, 29.49,
28.98, 28.82, 25.00, 24.25, 22.93, 22.51, 20.84, 20.30, 20.02, 19.75,
19.45, 19.25, 17.17, 16.66, 16.31, 14.55, 11.64.
HRMS (ESI): m/z calcd for C44H63N3O12 [M + H]+: 826.4412;
found: 826.4509.
3n
Yield: 0.165 g (70%); yellow oil; [a]D +27.5 (c = 0.012 g/mL,
CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.32 (s, 1 H), 3.69 (s, 3 H), 3.68–
3.61 (m, 2 H), 2.42–2.35 (m, 2 H), 2.29–2.21 (m, 2 H), 2.01–1.96
(m, 2 H), 1.91–1.77 (m, 6 H), 1.68 (s, 6 H), 1.62–1.51 (m, 4 H),
1.47–1.23 (m, 15 H), 1.20–1.04 (m, 7 H), 1.01–0.98 (m, 1 H), 0.96–
0.92 (m, 7 H), 0.67 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 174.84, 71.93, 77.25, 75.28,
73.23, 56.53, 55.98, 51.52, 42.77, 42.13, 41.91, 40.47, 40.19, 36.49,
35.89, 35.83, 35.41, 35.38, 34.61, 31.10, 31.05, 30.58, 29.74, 28.22,
27.22, 26.45, 24.24, 23.41, 20.87, 18.31, 12.07.
HRMS (ESI): m/z calcd for C83H107N3O25 [M + H]+: 1546.7194;
found: 1546.7209.
HRMS (ESI): m/z calcd for C41H61N3O12 [M + H]+: 788.4255;
found: 788.4305.
3o
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Yield: 0.165 g (80%); colorless oil; [a]D +5.2 (c = 0.006 g/mL,
CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 7.58 (s, 1 H), 5.22–5.17 (m, 1 H),
5.12–5.07 (m, 1 H), 5.03–4.98 (m, 1 H), 4.91–4.78 (m, 2 H), 4.72
(d, J = 8.0 Hz, 1 H), 4.35–4.30 (m, 1 H), 4.28–4.24 (m, 1 H), 4.16–
4.09 (m, 2 H), 4.00 (s, 1 H), 4.88 (s, 1 H), 3.79–3.74 (m, 1 H), 3.66
(s, 3 H), 2.88 (s, 1 H), 2.77–2.67 (m, 1 H), 2.41–2.34 (m, 2 H), 2.30–
2.22 (m, 2 H), 2.08 (s, 3 H), 2.04 (s, 3 H), 2.02 (s, 3 H), 1.99 (s, 3
H), 1.97 (s, 3 H), 1.97–1.71 (m, 6 H), 1.63–1.58 (m, 4 H), 1.44–1.30
(m, 2 H), 1.27–1.24 (m, 2 H), 1.20–1.11 (m, 2 H), 0.99–0.97 (m, 6
H), 0.71 (s, 3 H).
Acknowledgment
The authors are indebted to FAPESP (09/07281-0 to M.W.P.),
CNPq (306532/2009-3; 305545/2010-5, to J.Z.-S and M.W.P, re-
spectively), INCT Catálise, and CAPES-PROEX for financial sup-
port. A.M.D. and L.R.S.C. thank FAPESP for Ph.D. fellowships.
We also thank Dr. Senthil Narayanaperumal for helpful suggestions
about English grammar and style.
13C NMR (100 MHz, CDCl3): d = 174.68, 170.78, 170.13, 169.39,
143.20, 120.85, 99.88, 72.87, 71.70, 71.22, 68.38, 67.96, 63.07,
62.02, 61.00, 60.31, 53.49, 51.42, 47.14, 46.55, 41.98, 41.88, 39.45,
36.55, 35.59, 35.29, 34.80, 34.30, 31.07, 30.82, 28.24, 28.05, 27.46,
26.67, 23.13, 22.50, 20.70, 20.61, 20.52, 17.24, 14.15, 12.50.
HRMS (ESI): m/z calcd for C42H63N3O14 [M + H]+: 834.4388;
found: 834.4412.
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Synthesis 2011, No. 24, 4003–4010 © Thieme Stuttgart · New York

4010
A. M. Deobald et al.
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(15) During the reviewing process of this manuscript, Rivera and
co-workers reported a similar work on ‘click’ synthesis of
triazole linkage as surrogate of the glycosidic bond.
However, the authors only described the application of
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Synthesis 2011, No. 24, 4003–4010 © Thieme Stuttgart · New York