Facile and efficient synthesis of carbohybrids as stereodivergent druglike small molecules

Article abstract of DOI:10.1021/jo800190v

(Chemical Equation Presented) A facile and efficient one-pot synthesis of acyclic polyols fused with pyrazolo[1,5-a]pyrimidines and 1,2,4-triazolo[1,5-a] pyrimidines as novel carbohybrids with regioselectivity was achieved through the condensation of 2-C-

Full text of DOI:10.1021/jo800190v

Facile and Efficient Synthesis of Carbohybrids as
Stereodivergent Druglike Small Molecules
Ram Sagar and Seung Bum Park*
Department of Chemistry, Seoul National UniVersity,
Seoul 151-747 Korea
sbpark@snu.ac.kr
ReceiVed January 24, 2008
FIGURE 1. Bioactive small molecule with pyrazolo- and triazolo-
[1,5-a]pyrimidines (I-IV) and carbohybrids fused with acyclic polyols
(V-VIII). (I) Zaleplon, a drug for the treatment of insomnia; (II-
III) selective binders to subtype BZ1 benzodiazepine receptor; (IV)
an anticancer agent; (V) a novel open-chain glycosidic linkage in the
lipopolysacharide (LPS); (VI) Bengazoles, an antifungal marine natural
product; (VII) riboflavin (vitamin B2); (VIII) Relenza, an anti-influenza
drug; (IX) our novel carbohybrids, hydrophilic acyclic polyols fused
with privileged heterocycles.
A facile and efficient one-pot synthesis of acyclic polyols
fused with pyrazolo[1,5-a]pyrimidines and 1,2,4-triazolo[1,5-
a]pyrimidines as novel carbohybrids with regioselectivity was
achieved through the condensation of 2-C-formyl glycals
with 3-aminopyrazoles and 3-amino-1,2,4-triazoles in excel-
lent yields under the microwave irradiation.
Acyclic polyols are widely dispersed in the nature, and
antibacterial and anticancer macrolides contain polyols as a
structural motif.7 Interestingly, a new type of open-chain
glycosidic linkage (V) was identified in Proteus bacteria as a
unique skeleton with an acyclic polyol moiety.8 Various natural
and synthetic acyclo-C-nucleosides with acyclic polyols have
demonstrated antiviral activities against herpes virus, vaccinia,
and simian immunodeficiency virus (SIV).9 For example,
bengazoles (VI) are antifungal marine natural products with a
unique bisoxazole moiety containing carbohydrate-like acyclic
polyols.10 In terms of molecular skeletons, sialic acid, and
relenza (VIII) are molecules containing acyclic polyols fused
with druglike privileged heterocycles through a carbon linkage.11
A collection of “natural-product-like” small molecules that
specifically perturb the individual functions of gene products
are facilitating the exploration of biological pathways.1 There-
fore, the development of an efficient route for the synthesis of
druglike small molecules has been the focus of research for
medicinal chemists and chemical biologists.2 Diversity-oriented
synthesis (DOS) that aims to populate the chemical space with
skeletally and stereochemically diverse small molecules with
high appending potentials has been proven to be an essential
tool for the discovery of bioactive small molecules.3 The
incorporation of privileged substructural motifs has become an
essential element in DOS pathways.4 Pyrazolo- and 1,2,4-
triazolo[1,5-a]pyrimidines have been proven as privileged core
structures and confirmed in bioactive natural products and in
various pharmaceutical agents, as shown in Figure 1 (I-IV).
An exhaustive literature survey reveals that the pyrazolo[1,5-
a]pyrimidine skeleton has been applied in various therapeutic
areas such as antitumor, antidiabetic, benzodiazepine receptor
activities, etc.5 The biological importance of 1,2,4-triazolo[1,5-
a]pyrimidines, a subtype of purine bioisosteric analogs, is also
well documented in diverse biological fields with antihyper-
tensive and antitumor activities, etc.6
(5) (a) Gregg, B. T.; Tymoshenko, D. O.; Razzano, D. A.; Johnson, M.
R. J. Comb. Chem. 2007, 9, 507. (b) Kiessling, A.; Wiesinger, R.; Sperl,
B.; Berg, T. ChemMedChem 2007, 2, 627. (c) Selleri, S.; Bruni, F.; Costagli,
C.; Costanzo, A.; Guerrini, G.; Ciciani, G.; Gratteri, P.; Besnard, F.; Costa,
B.; Montali, M.; Martini, C.; Fohlin, J.; De Siena, G.; Aiello, P. A. J. Med.
Chem. 2005, 48, 6756. (d) Mason, J. S.; Morize, I.; Menard, P. R.; Cheney,
D. L.; Hulme, C.; Labaudiniere, R. F. J. Med. Chem. 1995, 42, 3251.
(6) (a) Cavallaro, C. L.; Harikrishnan, L. S.; Chi, F.; Dodd, D.; Purandare,
A. J. Comb. Chem. 2008, 10, 28 and reference cited therein. (b) Zhang, N.;
Ayral-Kaloustian, S.; Nguyen, T.; Afragola, J.; Hernandez, R.; Lucas, J.;
Gibbons, J.; Beyer, C. J. Med. Chem. 2007, 50, 319. (c) Zhao, X-L.; Zhao,
Y-F.; Guo, S-C.; Song, H-S.; Wang, D.; Gong, P. Molecules 2007, 12, 1136.
(7) Williams, D. E.; Roberge, M.; Soest, R. V.; Andersen, R. J. J. Am.
Chem. Soc. 2003, 125, 5296.
(8) (a) Vinogradov, E.; Bock, K. Angew. Chem. Int. Ed. 1999, 38, 671.
(b) Hindsgaul, O. Nature 1999, 399, 644.
(9) (a) Schaeffer, H. J.; Beauchamp, L.; Miranda, P. de; Elion, G. B.;
Bauer, D. J.; Collins, P. Nature 1978, 272, 583. (b) Clercq, E. D.; Descamps,
J.; Somer, P. D.; Holy´, A. Science 1978, 200, 563.
(10) Philip, A.; Searle, P. A.; Rowena, K.; Richter, R. K.; Tadeusz, F.;
Molinski, T. F. J. Org. Chem. 1996, 61, 4073.
(11) (a) Hong, Z.; Liu, I.; Hsu, C-C.; Wong, C.-H. Angew. Chem. Int.
Ed. 2006, 45, 7417. (b) Angata, T.; Varki, A. Chem. ReV. 2002, 102, 439.
(c) Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason, J. C.; Jin,
B.; Van, P. T.; Smythe, M. L.; White, H. F.; Oliver, S. W. Nature 1993,
363, 418.
(1) Schreiber, S. L. Bioorg. Med. Chem. 1998, 6, 1127.
(2) Schreiber, S. L. Science 2000, 287, 1964.
(3) (a) Koehler, A. N.; Shamji, A. F. and Schreiber, S. L. J. Am. Chem
Soc. 2003, 125, 8420. (b) Bruke, M. D. and Schreiber, S. L. Angew. Chem.
Int. Ed. 2004, 43, 46.
(4) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger,
R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang,
R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K.
A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235.
10.1021/jo800190v CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/20/2008
3270
J. Org. Chem. 2008, 73, 3270-3273

TABLE 1. Synthesis of Pyrazolo- and Triazolo[1,5-a]pyrimidines
entry
substrate (enals)
nucleophile
reaction condition
EtOH, 77 °C, 6 h
EtOH:THF (1:1), K2CO3, 80 °C, 8 h
AcOH, rt, 1 h
µW, 250W, 110 °C, toluene, 20 min
µW, 200W, 110 °C, toluene:AcOH (10:1) 10 min
µW, 200W, 110 °C, AcOH, 5 min
EtOH, 77 °C, 6 h
EtOH:THF (1:1), K2CO3, 80 °C, 12 h
AcOH, rt, 24 h
product
yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
1
3a
3a
3a
3a
3a
3a
4a
4a
4a
4a
4a
5
5
5
5
5
5
-
6
6
-
62
62
72
85
87
93
no rxn
65
23
10
11
µW, 250W, 110 °C, toluene, 30 min
µW, 200W, 110 °C, AcOH, 20 min
no rxn
76
6
A number of iminoalditols with acyclic polyols chains have been
identified as the inhibitors of glycosyltransferases and glycosi-
dase for therapeutic application against cancer, AIDS, and
diabetes.12
On the basis of their abundancy in literature, we were
confident that the carbohybrids13shydrophilic acyclic-polyols
fused with privileged heterocyclesswould provide the important
structural motifs for the discovery of novel bioprobes or
therapeutic agents. In continuation of our research on DOS of
druglike small molecules,14 we designed and synthesized acyclic
polyols fused with pyrazolo- and 1,2,4-triazolo[1,5-a]pyrim-
idines as novel carbohybrids (IX).
For the development of efficient and facile methods for the
synthesis of novel carbohybrids, we identified 2-C-formyl
glycals 1 and 2,15a chiral synthons incorporating an s-cis enal
system, as the key intermediates15b that can be transferred to
our designed carbohybrids. The syntheses of molecules contain-
ing pyrazole,16a-c pyrimidine,16d and pyridine/pyridone16e-f
systems using 2-C-formyl glycals were reported in poor to fair
yields.
We initiated our synthetic protocol with 2-C-formyl glycal
(1-2) obtained from 3,4,6-tri-O-benzyl glycal via the Vils-
meier-Haack reaction.15a The core of the strategy followed in
the present study is depicted in Scheme 1. The condensation
reaction of 2-C-formyl glucal 1 with 3-aminopyrazole 3a was
performed under several different conditions. Pyrazolo[1,5-
a]pyrimidine derivative 5 as a carbohybrid was obtained in 62%
yield by the treatment of 1 with 3a in refluxing ethanol for 6 h
(Table 1, entry 1). The mechanism of this transformation can
be postulated as follows: an amino group of 3-aminopyrazoles
3 attacks an aldehyde moiety of 1 to generate an imine
intermediate, followed by the subsequent attack of the nucleo-
philic nitrogen of 3 on C-1 position to provide 5 through an
intramolecular pyran ring opening (see Scheme 1).
To optimize the synthetic reaction conditions for 5, we tested
a mild inorganic base (K2CO3) and various organic bases (n-
BuLi, NaH, NaOMe, and t-BuOK) with no improvement
observed in the yields and reaction time. Conversely, strong
organic bases led to a deterioration in the yields (10∼20%) of
the desired 5, due to the instability of 2-C-formyl glucal 1
against strong bases in a polar solvent. As shown in entry 3
(Table 1), acetic acid as a solvent can successfully complete
this transformation within 1 h with an improved yield (72%)
through the activation of enals on 2-C-formyl glycal (1-2).
Next, we focused on the application of microwave for this
transformation.17 Without much difficulty, the desired 5 from
2-C-formyl glucal 1 with 3-aminopyrazole 3a was successfully
obtained in fairly good yields (85%) by the microwave
irradiation in toluene (entry 4, Table 1). Considerable attempts
were made in order to optimize the reaction condition under
the microwave irradiation by changing solvents, temperatures,
and microwave energy.
As shown in Table 1, the optimized microwave reaction
condition (200 W, 110 °C, 5 min) in glacial acetic acid provides
the desired 5 in excellent yields (93%). In the case of the
condensation of 2-C-formyl glucal 1 with 3-amino-1,2,4-triazole
4a, a slightly different reaction pattern was observed. In our
initial attempts, the condensation of 1 with 3-aminotriazole 4a
in refluxing ethanol over 12 h (entry 7, Table 1) did not yield
the desired product 6. Comparing entries 1 and 7 in Table 1, it
was concluded that 3-aminopyrazole 3a is a better nucleophile
than 3-amino-1,2,4-triazole 4a. After an extensive survey of the
reaction condition, the regioselective synthesis of the desired
1,2,4-triazolo[1,5-a]pyrimidine derivatives 6 was achieved in
good yields (entry 11, Table 1). Due to the equilibrium of
(12) (a) Doddi, V. R.; Vankar, Y. D.; Eur. J. Org. Chem. 2007, 5583.
(b) Carmona, A. T.; Fuentes, J.; Robina, I.; Garc´ıa, E. R.; Demange, R.;
Vogel, P.; Winters, A. L. J. Org. Chem. 2003, 68, 3874.
(13) (a) Service, R. F. Science 2001, 291, 2342. (b) Nilsson, U. J.;
Fournier, E. J. L.; Fryz, E. J.; Hindsgaul, O. Comb. Chem. High Throughput
Screening 1999, 2, 335.
(14) (a) An, H.; Eum, S-J.; Koh, M.; Lee, S. K.; Park, S. B. J. Org.
Chem. 2008, ASAP Article; DOI: 10.1021/jo702196f. (b) Lee, S.-C.; Park,
S. B. J. Comb. Chem. 2007, 9, 828. (c) Ko, S. K.; Jang, H. J.; Kim, E.;
Park, S. B. Chem. Commun. 2006, 28, 2962.
(15) (a) Ramesh, N. G.; Balasubramanian, K. K. Tetrahedron Lett. 1991,
32, 3875. (b) Ramesh, N. G.; Balasubramanian, K. K. Eur. J. Org. Chem.
2003, 4477.
(16) (a) Rudloff, I.; Peseke, K. Reinke, H.; J. Prakt. Chem. 1998, 340,
334. (b) Montero, A.; Michalik, M.; Feist, H.; Reinke, H.; Rudloff, I.;
Peseke, K. J. Carbohydr. Chem. 2004, 23, 313. (c) Yadav, J. S.; Reddy, B.
V. S.; Satheesh, G.; Lakshmi, P. N.; Kumar, S. K.; Kunwar, A. C.
Tetrahedron Lett. 2004, 45, 8587. (d) Montero, A.; Feist, H.; Michalik,
M.; Quincoces, J.; Peseke, K. J. Carbohydr. Chem. 2002, 21, 305. (e)
Rudloff, I.; Michalik, M.; Montero, A.; Peseke, K. Synthesis 2001, 1686.
(f) Montero, A.; Feist, H.; Michalik, M.; Quincoces, J.; Peseke, K. Synthesis
2002, 664.
(17) Chebanov, V. A.; Muravyova, E. A.; Desenko, S. M.; Musatov, V.
I.; Knyazeva, I. V.; Shishkina, S. V.; Shishkin, O. V.; Kappe, C. O. J.
Comb. Chem. 2006, 8, 427.
J. Org. Chem, Vol. 73, No. 8, 2008 3271

TABLE 2. Synthesis of Carbohybrids Fused with
Pyrazolo[1,5-a]pyrimidines Skeleton
SCHEME 1. Retrosynthetic Analysis and Plausible
Mechanism
amino-
yield
(%)
entry enals pyrazole product R1
R2 R3
OBn
OBn Ph
R4
1
2
1
1
1
1
1
2
2
2
2
2
3a
3b
3c
3d
3e
3a
3b
3c
3d
3e
5
7
H
H
H
H
H
Ph
93
94
84
89
3
8
H
OBn
OBn
OBn
H
H
H
H
H
Ph
H
H
H
4
9
H
2-pyridinyl
5
6
7
8
9
10
10
11
12
13
14
15
H
2-thiophenyl 90
SCHEME 2. Further Modification of Carbohybrids
through Glycosidation and Debenzylation
OBn
OBn
OBn
OBn
OBn
H
H
Ph
88
98
97
98
H
H
H
H
2-pyridinyl
2-thiophenyl 96
TABLE 3. Synthesis of Carbohydrids with
1,2,4-Triazolo[1,5-a]pyrimidine Skeleton
amino-
time yield
(min) (%)
entry enals triazole producta R1
R2
R3
the isolated yields of 3-aminotriazole 4a and substituted
3-aminotriazoles 4b and 4c having an electron donating and an
electron withdrawing group, respectively, at the R3 position.
Therefore, we accomplished the practical and efficient synthetic
protocol for the transformation of 2-C-formyl glucal 1 and 2-C-
formyl galactal 2 into novel carbohybrids with orthogonally
substituted pyrazolo[1,5-a]pyrimidines (5, 7-15) and 1,2,4-
triazolo[1,5-a]-pyrimidines (6, 16-20) in excellent yields and
regioselectivity.
1
2
3
4
5
6
1
1
1
2
2
2
4a
4b
4c
4a
4b
4c
6
16
17
18
19
20
H
H
H
OBn
OBn
OBn
OBn
OBn SMe
OBn COOMe
H
H
H
H
20
15
20
15
15
20
76
85
80
82
90
86
H
SMe
COOMe
a The regioselectivity was >99%. See the Supporting Information for
crude H NMR and crude LC/MS data to support regioselectivity
1
For a further diversification, these carbohybrids were pursued
through a glycosidation reaction on a free hydroxyl group at
C-3′ on carbohybrid 7 with 2,3,4,6-tetra-O-acetyl-R-D-glucopy-
ranosyl bromide (Scheme 2). After a survey of the glycosidation
reactions using different halophiles, it was observed that the
use of AgOTf in CH2Cl2 at 0 °C for 4 h provides the desired
glycosidic product 21 in good yields. The resulting 21 was
identified as a single â-glycosidated carbohybrid stereoisomer
due to the neighboring group participation, which was confirmed
tautomers in 3-amino-1,2,4-triazole 4a, the formation of two
regioisomers is possible, but the single regioisomer 6 was
isolated under the optimized reaction condition.18 The molecular
structure of regioisomer 6 was confirmed by various spectro-
scopic tools (see Supporting Information). In particular, 1-D
1H NOE spectra provided a definitive clue on the structural
determination: the absence of an NOE cross-peak between H-2/
H-5 and H-2/H-7 confirms the molecular skeleton of the
obtained regioisomer 6.19
Having obtained the optimized condition, we probed the scope
of this transformation with respect to both 2-C-formyl glycals
(1-2) and 3-aminopyrazoles (3a-e). As shown in Table 2, both
2-C-formyl glucal 1 and 2-C-formyl galactal 2 were successfully
coupled with 3-amiopyrazoles (3a-e) to produce the respective
pyrazolo[1,5-a]pyrimidines 5, 7-15 under the optimized condi-
tion in excellent yields. The substituents at the R3 and R4 posi-
tions do not significantly influence the yields and reaction rates.
Subsequently, the generality in the transformation of 2-C-
formylglycals (1-2) with substituted 3-amino-1,2,4-triazoles
(4a-c) for the synthesis of 1,2,4-triazolo[1,5-a]pyrimidines 6,
16-20 was successfully demonstrated with good to excellent
yields (Table 3). There was no significant difference between
1
by H and 13C NMR spectra. 2-C-formylgalactal-derived car-
bohybrid 12 was also glycosidated under the identical reaction
protocol to provide â-glycosidated product 22 in good yields.
The debenzylation of these carbohybrids was then pursued.
Surprisingly, a catalytic hydrogenation with Pd-C/H2 or Pd-
(OH)2/H2 was not successful because of the incomplete depro-
tection even under an extended reaction time, elevated pressure,
and temperature. In contrast, a catalytic hydrogen transfer using
Pd(OH)2/1,4-cyclohexadiene21 at 70 °C in ethanol was found
superior to the catalytic hydrogenation. The debenzylation of
compounds 21 and 22 was performed under the optimized
catalytic transfer hydrogenation to provide fully debenzylated
acyclic-polyols 23 and 24 in acceptable yields (Scheme 2).
(20) Mitchell, S. A.; Pratt, M. R.; Hruby, V. J.; Robin, Polt, R. J. Org.
Chem. 2001, 66, 2327.
(21) Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki, C.;
Meienhofer, J. J. Org. Chem. 1978, 43, 4194.
(18) Kunstlinger, M.; Breitamaier, E.; Synthesis 1983, 44.
(19) Kawase, M.; Hirabayashi, M.; Saito, S.; Yamamoto, K. Tetrahedron
Lett. 1999, 40, 2541.
3272 J. Org. Chem., Vol. 73, No. 8, 2008

Hz, 1H), 4.09 (d, J ) 11.5 Hz, 1H), 4.06 (m, 1H), 3.74-3.72 (m,
2H), 3.63 (dd, J ) 8.5, 2.5 Hz, 1H), 2.64 (brd, J ) 7.0 Hz, 1H,
OH). 13C NMR (125 MHz, CDCl3): δ 156.3, 155.0, 137.6, 136.7,
136.5, 134.9, 128.9, 128.8, 128.6, 128.5, 128.37, 128.3, 128.1,
122.9, 104.9, 80.6, 75.8, 74.4, 73.8, 72.5, 70.6, 70.0. FAB HRMS
m/z: calcd for C30H30N4O4 [M + H]+, 511.2345; found, 511.2350.
Similarly, compounds 7 and 11 were debenzylated as per our
optimized reaction condition to give compound 25 and 26
respectively in 60% yield. The left-half of the carbohybrid with
glycosylated polyols 24 was found to be superimposable with
the left-half of the novel open-chain glycosidic linkage (V)
presented in the core part of lipopolysacharide (LPS) in the cell
wall of Gram-negative Proteus bacteria (see Figure 1).8
In summary, we have developed a efficient synthetic protocol
for the synthesis of novel carbohybridssacyclic polyols fused
with pyrazolo- and 1,2,4-triazolo[1,5-a]pyrimidinessfrom 2-C-
formyl glycals under microwave irradiation in one step. These
carbohybrids were designed through the recombination of
acyclic chiral polyols found in abundance in bioactive natural
products with druglike privileged heterocycles through a carbon
linkage that is stable under a chemical and enzymatic hydrolysis.
Subsequently, we successfully demonstrated a further diversi-
fication of C-3′-OH on the carbohybrids via glycosylation,
followed by global debenzylation; this opens new avenue for a
further diversification on these novel carbohybrids. The complete
library realization of these novel carbohybrids using DOS and
associated biological evaluations will be reported in due course.
Glycosidation. Synthesis of 21 and 22. 2,3,4,6-Tetra-O-acetyl-
glucopyranosyl bromide (158 mg, 0.384 mmol) and glycosyl
acceptor 7 (150 mg, 0.256 mmol) were placed in a aluminum foil
covered RB flask in CH2Cl2 (3 mL) along with 100 mg of 4 Å
molecular sieves under nitrogen atmosphere and cooled to 0 °C.
AgOTf (98.6 mg, 0.384 mmol) in dry toluene (1.5 mL) was added
dropwise within 10 min. After 4 h of stirring at 0 °C, the reaction
was quenched by the addition of iPr2NEt (1 mL) and stirred for
additional 10 min. The reaction mixture was filtered through Celite,
and the filtrate was concentrated under reduced pressure. The crude
mixture was chromatographed to obtain â-glycosidated product 21
(173 mg) in 74% yield. Similarly, â-glycosidated product 22 was
obtained from 12 in 73% yield.
Compound 21. Amorphous solid (173 mg, 74%). [R]D28 -28.60
1
(c 0.363, CHCl3). TLC: Rf ) 0.54 (1:1, EtOAc:hexane, v/v). H
NMR (500 MHz, CDCl3): δ 8.51 (d, J ) 2.0 Hz, 1H), 8.41 (d, J
) 2.0 Hz, 1H), 8.00 (dd, J ) 7.7, 1.5 Hz, 2H), 7.48 (t, J ) 8.5 Hz,
2H), 7.41 (t, J ) 7.5 Hz, 1H), 7.35-7.25 (m, 10H), 7.10-7.05
(m, 5H), 6.96 (s, 1H), 5.19 (t, J ) 9.5 Hz, 1H), 5.07 (t, J ) 10.0
Hz, 1H), 4.99 (dd, J ) 9.5, 8.0 Hz, 1H), 4.76 (d, J ) 8.5 Hz, 1H),
4.71 (d, J ) 4.0 Hz, 1H), 4.57 (d, J ) 11.5 Hz, 1H), 4.52 (d, J )
11.5 Hz, 1H), 4.50-4.47 (m, 2H), 4.45 (d, J ) 11.5 Hz, 1H), 4.32
(d, J ) 11.5 Hz, 1H), 4.22 (m, 1H), 4.16 (dd, J ) 12.5, 4.5 Hz,
1H), 3.99 (dd, J ) 12.5, 2.0 Hz, 1H), 3.88 (m, 1H), 3.86 (dd, J )
11.5, 3.0 Hz, 1H), 3.63 (dd, J ) 11.0, 5.5 Hz, 1H), 3.55 (ddd, J )
10.0, 4.5, 2.5 Hz, 1H), 2.01, 2.00, 1.97, 1.96 (4s, 12H). 13C NMR
(125 MHz, CDCl3): δ 170.7, 170.4, 169.4, 169.5, 156.6, 149.8,
149.6, 137.9, 137.4, 133.9, 133.0, 129.2, 129.0, 128.7, 128.6, 128.3,
128.2, 128.1, 128.0, 127.9, 127.6, 119.8, 99.6, 93.7, 81.9, 77.8,
77.1, 75.0, 73.7, 72.9, 72.1, 71.8, 71.7, 69.3, 68.4, 61.7, 20.9, 20.81,
20.80. FAB HRMS m/z: calcd for C51H53N3O13 [M + H]+,
916.3657; found, 916.3657.
Experimental Section
General Procedure for the Synthesis of 5 and 6 under
Microwave Irradiation in Glacial AcOH. A mixture of 2-C-
formyl glucal 1 (110 mg, 0.250 mmol) and 3-aminopyrazole 3a
(31.1 mg, 0.375 mmol, 1.5 equiv) dissolved in glacial AcOH (1.5
mL) was heated in capped microwave vessel under microwave
irradiation (200 W, 110 °C) for 5 min. Controlled air cooling was
applied to maintain the temperature. Resulting product mixture was
diluted with EtOAc (15 mL) and neutralized by saturated aqueous
NaHCO3. The organic layer was separated and the aqueous layer
extracted with EtOAc (3 × 5 mL). The combined organic layer
was washed with brine and dried over anhydrous Na2SO4. The crude
product was concentrated in vacuo and purified by flash column
chromatography to yield desired compound 5 (118 mg) in 93%
yield. All other compounds 7-15 were synthesized by the
condensation of 2-C-formyl glycals 1-2 with respective 3-ami-
nopyrazole 3b-e under same reaction procedure.
Debenzylation. Compounds 7 and 11 were debenzylated as per
optimized reaction condition to yield compound 25 and 26
respectively in 60% yield. Compound 25: Amorphous solid,
1
TLC: Rf ) 0.52 (1:4, MeOH:CH2Cl2,v/v). H NMR (500 MHz,
DMSO-d6): δ 8.09 (brs, 1H), 7.75 (d, J ) 2.0 Hz, 1H), 7.24 (brd,
J ) 7.0 Hz, 2H), 6.70 (t, J ) 7.7 Hz, 2H), 6.63 (t, J ) 8.0 Hz,
1H), 6.39 (s, 1H), 4.62 (d, J ) 6.5 Hz, 1H), 4.23 (d, J ) 5.0 Hz,
1H), 3.97 (d, J ) 8.5 Hz, 1H), 3.91 (d, J ) 5.5 Hz, 1H), 3.62 (t,
J ) 5.5 Hz, 1H), 2.86-2.80 (m, 2H), 2.69-2.65 (m, 2H). 13C NMR
(125 MHz, DMSO-d6): δ 155.3, 150.9, 149.2, 133.3, 129.5, 126.7,
125.8, 93.2, 74.7, 72.1, 68.5, 64.1. FAB HRMS m/z: calcd for
C16H17N3O4 [M + H]+, 316.1297; found, 316.1293.
A similar reaction protocol was applied when 2-C-formyl glycals
1-2 were reacted with 3-amino-1,2,4-triazoles 4a-c. The desired
products 6, 16-20 were obtained in good isolable yield (76-90%)
after 15-20 min of microwave irradiation (200 W, 110 °C). We
observed greater than 99% regioselectivity in all the cases for the
1
synthesis of triazolo[1,5-a]pyrimidines from their crude H NMR
spectra and LC/MS of crude product.
Compound 5. Amorphous solid (118 mg, 93%). [R]D28 -37.73
1
(c 0.343, CHCl3). TLC: Rf ) 0.27 (1:1, EtOAc:hexane, v/v). H
NMR (500 MHz, CDCl3): δ 8.54 (d, J ) 2.0 Hz, 1H), 8.42 (d, J
) 2.5 Hz, 1H), 8.11 (d, J ) 2.5 Hz, 1H), 7.34-7.25 (m, 10H),
7.06-7.05 (m, 3H), 6.95 (dd, J ) 7.5, 2.0 Hz, 2H), 6.69 (d, J )
2.0 Hz, 1H), 4.77 (d, J ) 2.5 Hz, 1H), 4.58 (d, J ) 11.5 Hz, 1H),
4.53 (brs, 2H), 4.42 (d, J ) 11.0 Hz, 1H), 4.32 (d, J ) 11.5 Hz,
1H), 4.14 (d, J ) 11.0 Hz, 1H), 4.06 (m, 1H), 3.68-3.67 (m, 2H),
3.62 (dd, J ) 8.0, 2.5 Hz, 1H), 2.62 (brd, J ) 6.0 Hz, 1H). 13C
NMR (125 MHz, CDCl3): δ 149.8, 148.3, 145.2, 137.6, 137.0,
136.8, 134.0, 128.8, 128.7, 128.5, 128.3, 128.2, 119.5, 97.0, 80.9,
76.0, 74.5, 73.7, 72.0, 70.7, 70.0. FAB HRMS m/z: calcd for
C31H31N3O4 [M + H]+, 510.2393; found, 510.2393.
Acknowledgment. This work was supported by (1) the
Korea Science and Engineering Foundation (KOSEF), (2)
MarineBio21, Ministry of Maritime Affairs and Fisheries, Korea
(MOMAF), and (3) the Molecular and Cellular BioDiscovery
Research Program, the Ministry of Science & Technology
(MOST). R.S. is grateful for the postdoctoral fellowship from
the Brain Korea 21 Program.
Supporting Information Available: Text giving experimental
procedures, structures of the compounds, and figures showing
complete spectroscopic data and NOE experiments along with the
Compound 6. Amorphous solid (96.5 mg, 76%). [R]D28 -50.56
1
copies of H and 13C NMR spectra of all compounds 5-26. This
1
(c 0.396, CHCl3). TLC: Rf ) 0.33 (4:1, EtOAc:hexane, v/v). H
material is available free of charge via the Internet at http://pubs.
acs.org.
NMR (500 MHz, CDCl3): δ 8.66 (d, J ) 2.0 Hz, 1H), 8.61 (d, J
) 2.0 Hz, 1H), 8.46 (s, 1H), 7.35-7.24 (m, 10H), 7.01-6.98 (m,
3H), 6.88 (dd, J ) 7.5, 1.0 Hz, 2H), 4.88 (d, J ) 2.5 Hz, 1H),
4.57-4.54 (m, 3H), 4.47 (d, J ) 11.5 Hz, 1H), 4.38 (d, J ) 12.0
JO800190V
J. Org. Chem, Vol. 73, No. 8, 2008 3273