Resolution, absolute configuration, and synthetic transformations of 7-amino-tetrahydroindazolones

Article abstract of DOI:10.1016/j.tetasy.2011.03.010

The chiral resolution of 7-amino-1-aryl-4,5,6,7-tetrahydro-indazol-4-ones was achieved via salt formation with O,O′-dibenzoyl tartaric acid. The transformation of enantiomerically enriched 7-amino-THIs into their corresponding azides proceeds with no decr

Full text of DOI:10.1016/j.tetasy.2011.03.010

Tetrahedron: Asymmetry 22 (2011) 728–739
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Resolution, absolute configuration, and synthetic transformations
of 7-amino-tetrahydroindazolones
Inta Strakova a, Ilze Kumpinßa a,b, Vitalijs Rjabovs a, Jevgenßija Luginßina a, Sergey Belyakov b, Maris Turks a,
⇑
¯
¯
a Faculty of Material Science and Applied Chemistry, Riga Technical University, 14/24 Azenes Str., Riga LV-1007, Latvia
b Latvian Institute of Organic Synthesis, 21 Aizkraukles Str., Riga LV-1006, Latvia
a r t i c l e i n f o
a b s t r a c t
Article history:
The chiral resolution of 7-amino-1-aryl-4,5,6,7-tetrahydro-indazol-4-ones was achieved via salt forma-
tion with O,O0-dibenzoyl tartaric acid. The transformation of enantiomerically enriched 7-amino-THIs
into their corresponding azides proceeds with no decrease in their ee’s. A comparison of the X-ray struc-
tures of the racemic and enantiopure forms of the title compounds explains the rather large melting point
differences between both the series. The enantiopure azides obtained from the corresponding 7-amino-
THIs were employed in copper-catalyzed Huisgen 1,3-dipolar cycloaddition reactions with various
alkynes. The use of enantiomerically enriched THI scaffolds is demonstrated by the preparation of diaste-
reomerically pure products when the former are conjugated with alkynes arising from natural sources.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 8 March 2011
Accepted 25 March 2011
Available online 4 May 2011
1. Introduction
are potent inhibitors of Heat-Shock Protein 90.9 Additionally, 5-ami-
no-4,5,6,7-tetrahydroindazoles possess dopaminergic activity10 and
Since the first report on their synthesis in 1903, tetrahydroin-
dazoles 2 (THIs)1 as a subclass of pyrazoles 1 have caught the inter-
est of organic and medicinal chemists (Fig. 1). Indeed, the
molecular scaffold of THIs consists of both, a planar pyrazole unit
and a C4-tether, which is built from tetrahedral carbons. Such a
skeleton helps to diversify the vectors of pharmacophore orienta-
tion in 3D space. As a consequence, the tetrahydroindazole core
can be found in many biologically active compounds. By modifying
the substituents, the applications of THIs can range from herbi-
cides2 to novel antituberculosis agents.3
As a result, even a short survey of the literature data shows a vivid
renaissance in the field of THIs. Thus, compounds containing the latter
scaffold were very recently reported to be useful corticotropin releas-
ing factor (CRF) receptor antagonists.4 Down-regulation of increased
endogenous levels of CRF is applicable in the treatment of several gas-
trointestinal disorders, major depressive disorders, and dementia of
Alzheimer’s type. Cognitive abilities can also be improved by tetra-
hydroindazolones of general structure 2a.5 The same type of com-
pounds also possesses antitumor activity while being less toxic than
other available antitumor drugs. On the other hand, compounds 2b
THI-substituted 3,5-dihydroxy-6-heptenoic acids have shown HMG-
CoA reductase inhibiting activity with IC50 = 3.0 nM.11 Very recently,
THIs have also been documented as farnesoid-X-receptor modulators
that found use in prevention or treatment of high LDL cholesterol lev-
els.12 Other potential uses of THIs include inhibition of bacterial type
II topoisomerases13 and mimicking of the heterobicyclic P1-arginine
side-chain. The latter observation led to the discovery of thrombin
inhibitors.14 In addition, cannabinoid modulators15 and compounds
en route to the selective and drug-like ligands for the opioid r1 recep-
tor16 have been documented within the tetrahydroindazole series.
The aforementioned list of possible applications of tetrahydroin-
dazoles/tetrahydroindazolones is not a comprehensive one. Never-
theless, it is rather clear why structural17 and synthetic interest in
the field of differently substituted 4,5,6,7-THIs has continued.18 Re-
cently, the orthogonal and regioselective synthesis of N-alkyl-3-
substituted tetrahydroindazolones has been reported.19 Fluorine
containing THIs have also been described.20 Several processes to-
ward tetrahydroindazole derivatives under microwave irradiation
have been documented. These include Diels–Alder reactions,21 as
well as syntheses starting from enaminoketones.22 Claramunt,
Lopez et al.23 have studied the synthesis and particularly the
tautomeric equilibrium of tetrahydroindazolones. Various tetra-
hydroindazol-3-yl alanine derivatives24 as well as novel THI-based
chiral auxiliaries25 have been obtained over the last decade.
Enantiomerically enriched tetrahydroindazole derivatives have
been obtained from (5R)-dihydrocarvone,26 and also from
(ꢀ)-menthone27 and have been used in the formation of transition
metal complexes. The analogues of the latter have been applied,
for example, in asymmetric allylic alkylations.28
are known for their selectivity toward GABA-A
a 5 receptors and
are useful for enhancing cognition.6 More recently, other THI-3-car-
boxamides have been found to regulate the mitotic motor protein
Eg5.7 The specific inhibition of the latter prevents uncontrollable divi-
sion of malignant cells. Furthermore, THIs 2c were shown to be active
against various carcinomas.8 Compounds with the general formula 2d
⇑
Corresponding author. Tel.: +371 67089251; fax: +371 67615765.
E-mail address: maris_turks@ktf.rtu.lv (M. Turks).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.03.010

I. Strakova et al. / Tetrahedron: Asymmetry 22 (2011) 728–739
729
Recently, we have reported a straightforward synthesis of racemic
7-(4-alkyl/aryl-[1,2,3]triazol-1-yl)-1-aryl-4,5,6,7-tetrahydro-1H-
indazol-4-ones.29 These molecular scaffolds are interesting in terms
of medicinal chemistry. In order to use this approach for conjugation
with compounds from natural sources (carbohydrates, peptides, etc.)
and/or oligomerization, enantiopure forms of 1-aryl-7-azido-4,5,6,7-
tetrahydro-1H-indazol-4-ones are required. Hence, we herein report
a full account on the synthesis of enantiomerically enriched amines 3
(Fig. 1), their transformation into their corresponding azides and X-
ray studies of both series of compounds. The use of such enantiome-
rically pure building blocks is demonstrated by their reactions with
various monosaccharide derivatives: diastereomerically pure THI–
sugar conjugates were obtained.
With racemic amines ( )-3a,b in hand, we turned our attention
to their resolution into single enantiomers. Several commercially
available chiral acids including mandelic acid, a-methoxy-a-phen-
ylacetic acid, camphorsulfonic acid, tartaric acid, and O,O0-diben-
zoyl tartaric acid were attempted. Thus, camphorsulfonic acid
provided well-formed crystals of diastereomerically pure salt
albeit in a low isolated yield. Tartaric acid showed certain positive
results but mandelic acid and its 2-O-methylderivative did not pro-
duce solid salts. From the aforementioned group of chiral acids
O,O0-dibenzoyl tartaric acid proved to be the best. Enantiomeric ex-
cesses of (+)-3a (97% ee) and (ꢀ)-3a (98% ee) were determined by
direct measurement using HPLC with Pirkle type stationary phase.
The enantiomeric purity of 3a can be increased up to 99.5% by sim-
ple crystallization. On the other hand, the ee’s of (+)-3b and (ꢀ)-3b
after resolution were 92% and 93%, respectively. The experimental
procedure of the chiral resolution consists of mixing the racemic 7-
amino-tetrahydroindazolone 3a or 3b with 1 equiv of the appropri-
ate enantiomer of O,O0-dibenzoyl tartaric acid in methanol in order
to form the acidic salt of type 3ꢁ5 (Scheme 2). It was empirically ob-
served that when (+)-(2S,3S)-di-O,O0-dibenzoyl tartaric acid (+)-5
R1
NH2
R7 R8 R1
R1
R6
R5
R4
R3
A4
A1
N
N
N
A3
A2
7
4
6
5
1
N
N
N
3
R2
R2
R2
O
O
1
2
3 (7-amino-
tetrahydroindazolone)
(D
-form) was used, salt (+)-3aꢁ(+)-5 crystallized preferably in the
2a:5 R2 = H, Alk, c-Alkyl, Ar
2b:6,7 R2 = -C(O)NHAr
2c:8 R1 = -(CH2)n-Ar(Het)
2d:9 R1 = Ar, Het
presence of its diastereoisomer (ꢀ)-3aꢁ(+)-5. Thus, enantiomeri-
cally enriched amine (+)-3a was obtained by treating the former
with potassium carbonate solution. Similarly, the filtrate contain-
ing mainly diastereoisomer (ꢀ)-3aꢁ(+)-5 was also treated with
potassium carbonate solution in order to obtain the enantiomeri-
cally enriched form of amine (ꢀ)-3a. The latter was then treated
resolution
and
transformations
Figure 1. Generalized scaffolds of tetrahydroindazolones.
with (ꢀ)-(2R,3R)-di-O,O0-dibenzoyl tartaric acid (ꢀ)-5 (
L-form)
and after salt formation, crystallization, and basic work-up pro-
duced the complementary form of enantiopure amine (ꢀ)-3a.
The absolute configuration of chirally homogeneous amine (+)-
3a was established by single crystal X-ray studies of its derivative
(ꢀ)-6 obtained in the reaction with commercially available (1S)-
(ꢀ)-camphanic chloride (Scheme 5). An identical route was used
to prove independently the absolute configuration of (ꢀ)-3a. In
the case of (+)-3b and (ꢀ)-3b (Scheme 3) we did not succeed in
obtaining a crystalline material which would combine the newly
formed amine moiety and a chiral auxiliary. However, X-ray stud-
ies of imine (ꢀ)-7 obtained from (+)-3b with 78% yield demon-
strated anomalous-dispersion effects of the relatively heavy
bromine atom and thus allowed us to determine the absolute con-
figuration within the 3b series (Scheme 6). As expected, it kept the
same empirical rule: the salt of general formula (+)-3ꢁ(+)-5 prefer-
ably crystallizes in the presence of (ꢀ)-3ꢁ(+)-5 while the salt of
general formula (ꢀ)-3ꢁ(ꢀ)-5 preferably crystallizes in the presence
of (+)-3ꢁ(ꢀ)-5.
2. Results and discussions
2.1. Synthesis and absolute configuration of chiral 7-amino-
tetrahydroindazolones
The target amines ( )-3a,b were obtained from the correspond-
ing azides ( )-4a,b30 via catalytic reduction over Pd/C (Scheme 1).
It is interesting to note that earlier attempts used SnCl2 as a reduc-
ing agent which lead to partial formation of 7-chloroderivatives.
N3
NH2
Ph
Ph
N
N
H2 (1 atm), Pd/C
N
N
R1
R1
O
O
( )-4a: R1=H
( )-3a: R1=H, 89%
( )-3b: R1=Me, 82%
( )-4b: R1=Me
Scheme 1. Catalytic hydrogenation of racemic 7-azidotetrahydroindazolones.
NH3
Ph
NH2
NH2
Ph
Ph
OBz
O
N
N
N
O
K2CO3
(7S)
(7S)
(7R)
N
OH
OH
N
N
O
OBz
OBz
O
O
O
O
HO
NH2
O
(+)-3a·(+)-5, 41%
Ph
OH
(+)-3a, 95%, 97%ee
(-)-3a, 96%, 98%ee
precipitate
N
O
OBz
(+)-5
N
K2CO3
OBz
NH3
Ph
NH3
OBz
O
Ph
O
N
1) K2CO3
O
N
(7R)
( )-3a
O
(7R)
N
N
OH
OBz
O
O
OBz
O
OBz
HO
2)
O
OH
O
(-)-3a·(+)-5
(-)-3a·(-)-5, 42%
O
OBz
(-)-5
filtrate; contains also (+)-3a·(+)-5
Scheme 2. Resolution of 7-amino-6,6-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-one 3a.

730
I. Strakova et al. / Tetrahedron: Asymmetry 22 (2011) 728–739
2.2. Synthetic transformations of enantiomerically pure 7-
amino-tetrahydroindazolones
ble 1). Moreover, within the triazole series one can easily improve
the enantiomeric purity by recrystallization. Next, we turned our
attention to a dimerization experiment (Scheme 7) and obtained
(+)-8d in 40% yield as a single diastereoisomer.
Newly obtained enantiomerically enriched amines 3 were
transformed into the corresponding azides by a diazo transfer sys-
tem consisting of trifluoromethanesulfonyl azide and a catalytic
amount of CuSO4ꢁ5H2O (Scheme 4).31 The isolated yields of enanti-
omerically pure azides range from 83% to 91%. With azides 4 in the
hand, we proceeded to further functionalize the tetrahydroindazo-
lone scaffold via CuAAC reactions.32 Thus, we prepared triazoles
8a–c reported earlier,29 albeit in enantiomerically enriched form
(Scheme 4, Table 1). This was achieved by mixing the correspond-
ing azides with either phenylacetylene or propargylic alcohol in
the presence of Cu+ generating Cu0/Cu2+ redox system at +40 °C.
The expected 7-triazolyl-tetrahydroindazolones were obtained in
moderate to good yields. One can acknowledge that the overall
yields in the sequence chiral amine ? chiral azide ? chiral triazole
are satisfactory; additionally, no decrease in ee’s was observed (Ta-
Sugar–heterocycle conjugates have attracted scientific interest
for many decades. The most prominent examples are known from
nucleoside analogues as antiviral and anticancer drugs. As a result,
since the discovery of an efficient and regioselective 1,4-disubsti-
tuted 1,2,3-triazole synthesis, the field of carbohydrate–triazole
conjugates has become particularly attractive.33 Hence, the logical
development of the field of sugar–heterocycle conjugates involves
a conjugation of a heterocycle of choice with a carbohydrate
scaffold via a triazole linker.34 It has been shown that such an
arrangement can improve biological targeting abilities.35
In this context we proceeded to conjugate our scaffolds to three
different carbohydrate skeletons via a triazole linker. Thus, the use
of propynyl 2,3,4,6-tetra-O-acetyl-b-
azides (+)-4a and (ꢀ)-4a resulted in the (7R)-conjugate (ꢀ)-8e
D
-glucopyranoside 936 and
NH3
Ph
NH2
NH2
Ph
Ph
OBz
O
N
N
N
O
K2CO3
(7R
(7S)
(7R)
N
OH
OH
N
N
O
OBz
OBz
O
O
O
O
HO
NH2
O
(-)-3b·(-)-5, 38%
Ph
OH
(-)-3b, 93% (93% ee)
(+)-3b, 91% (92% ee)
precipitate
N
O
OBz
(-)-5
N
K2CO3
OBz
NH3
Ph
NH3
OBz
O
Ph
O
N
1) K2CO3
O
(7S)
N
( )-3b
O
(7S)
N
N
OH
OBz
O
O
OBz
O
OBz
HO
2)
O
OH
O
(+)-3b·(-)-5
(+)-3b·(+)-5, 48%
O
OBz
(+)-5
filtrate; contains also (-)-3b·(-)-5
Scheme 3. Resolution of 7-amino-3,6,6-trimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-one 3b.
R2
R2
N
N
N
N
NH2
N3
N
O
N
O
NH2
O
N3
O
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
N
N
N
R2
Cu(I)
R2
Cu(I)
TfN3
TfN3
N
N
N
N
N
N
CuSO4
CuSO4
R1
R1
R1
R1
(+)-8
R1
(-)-3
R1
(+)-4
O
O
(+)-3
(-)-4
(-)-8
Scheme 4. Synthesis of enantiomerically pure 7-triazolyl-tetrahydroindazolones.
O
H
O
O
NH2
NH2
Ph
Ph
N
N
O
Cl
Br
EtOH
N
N
Py
O
O
(-)-7, 78%
(+)-3b
(-)-6, 73%
(+)-3a
Scheme 5. Synthesis and X-ray analysis of camphanic amide (ꢀ)-6.
Scheme 6. Synthesis and X-ray analysis of imine (ꢀ)-7.

I. Strakova et al. / Tetrahedron: Asymmetry 22 (2011) 728–739
731
Table 1
Synthesis of enantiomerically pure 7-triazolyl-tetrahydroindazolones
N
Ph
N
N
N
N
N3
O
Entry Amine 3 R1 Azide 4, yield% Alkyne, R2 Triazole 8, yield (ee)
Ph
O
O
O
N
AcO
AcO
1
2
3
4
5
6
(+)-3a
(ꢀ)-3a
H
H
(ꢀ)-4a, 91%
(+)-4a, 91%
Ph
CH2OH
Ph
CH2OH
Ph
Ph
(ꢀ)-8a, 76% (98%)
(ꢀ)-8b, 60% (>99%)
(+)-8a, 80% (98%)
(+)-8b, 58% (>99%)
(ꢀ)-8c, 48% (>99%)
(+)-8c, 50% (>99%)
Cu(I)
N
OAc
(-)-8e, 67%
(+)-4a
OAc
(+)-3b
(ꢀ)-3b
Me (ꢀ)-4b, 89%
Me (+)-4b, 83%
O
O
O
O
O
AcO
O
O
O
N
N
N
N
AcO
OAc
O
O
O
(CH2)6
Ph
OAc
OMs
N3
O
N
N
Ph
Ph
11
10
9
N
N
N
N
N
N
Cu(I)
Cu(I)
O
O
N3
Ph
N
(+)-4a
(+)-8d, 40%
N
Scheme 7. Synthesis of THI dimer (+)-8d with an extended bis-triazole-linker.
(-)-4a
O
O
and (7S)-conjugate (ꢀ)-8f in 67% and 64% yield, respectively
(Scheme 8). In another experiment, (ꢀ)-4a was treated with pro-
tected 3-O-propynyl glucose 1037 to produce (ꢀ)-8g in 93% yield.
O
Finally, an interesting L-nucleoside-like structure (+)-8h was ob-
O
tained by coupling azide (ꢀ)-4a with alkynyl sugar 11.38
All sugar–tetrahydroindazole conjugates 8e–h were obtained as
pure diasteroisomers in good to excellent isolated yields.
O
O
O
O
N
N
O
N
Ph
N
N
N
2.3. X-ray crystallographic analysis
Ph
N N
N
N
N
N
O
Ph
N
N
AcO
AcO
N
The structures of the racemic and enantiopure forms of 3a were
established by X-ray structure analysis. Figure 2 illustrates the
packing diagram of chirally homogeneous molecule (ꢀ)-3a crys-
tals. The molecular packing in the axial orthorhombic crystal lat-
tice (space group is P212121) is characterized by the weak
intermolecular hydrogen bonds of NHꢁꢁꢁO and NHꢁꢁꢁN types (see
Fig. 1). The lengths of these bonds are equal 3.140(2)Å (N–
HꢁꢁꢁO = 169°, HꢁꢁꢁO = 2.22 Å) and 3.191(2)Å (N–HꢁꢁꢁN = 149°,
HꢁꢁꢁN = 2.35 Å). The racemic compound ( )-3a is crystallized in
the planaxial monoclinic lattice (space group is P21/n). The molec-
ular packing of this compound is shown in Figure 3. In the crystal
structure there are moderate intermolecular hydrogen bonds of
NHꢁꢁꢁO type with NꢁꢁꢁO length 3.075(2)Å (N–HꢁꢁꢁO = 148°,
HꢁꢁꢁO = 2.18 Å). The molecular chains along crystallographic direc-
tion [1 0 1] form in the crystals by means of these bonds. The race-
mic compound is significantly more dense (Dcalcd = 1.303 g/cm3)
than the enantiopure crystals (Dcalcd = 1.263 g/cm3) notwithstand-
ing the higher temperature of X-ray analysis for the racemic form.
Usually the crystal lattice energy is higher for a more dense form;
therefore, it should be concluded that the crystal structure for the
racemic compound is energetically more stable than the one for
the homochiral form. It explains the relatively high melting point
(166–167 °C) of the racemic compound in comparison with the
pure enantiomer (128–129 °C).
O
O
O
O
O
OMs
AcO
OAc
(-)-8f, 64%
(+)-8h, 78%
(-)-8g, 93%
Scheme 8. Synthesis of THI–carbohydrate conjugates.
single crystal X-ray analysis of the racemic compound ( )-4a were
not obtained, the debyegram is similar to the powder pattern of the
pure enantiomer (ꢀ)-4a, which is theoretically simulated from the
obtained crystal structure. Figure 6 gives these powder patterns.
Thus, the racemate ( )-4a most probably crystallizes in the mono-
clinic lattice (space group P21/c) giving molecular packing near to
that represented in Figure 5. Normally compounds with such crys-
tal structures form solid solutions on the whole area of composi-
tion variation. This fact can explain the relatively near melting
point of the pure enantiomer (ꢀ)-4a (79–80 °C) and the corre-
sponding racemate ( )-4a (100–101 °C). For unambiguous confir-
mation of the structure and absolute configuration the single
crystals of (ꢀ)-6 and (ꢀ)-7 were examined by X-ray analysis.
The presence of the bromine atom in structure (ꢀ)-7 provided
significant anomalous-dispersion; the crystal structure full
matrix least squares refinement using all independent diffraction
reflection with Friedel pairs gave the value of Flack’s x parameter
0.03(2). This allowed us to determine the absolute configuration
of the crystal as the expected values are 0 (within 3 esd’s) for the
correct structure and +1 for the inverted absolute structure.39
All of investigated structures are characterized by almost iso-
lated double bonds in tetrahydroindazolone systems. Table 2 lists
the principal bond lengths in the studied molecules. These values
show the weak conjugation in the molecular structures.
The chiral compound (ꢀ)-4a gives axial monoclinic crystals
(space group is P21). The peculiarity of these crystals is the follow-
ing: in the asymmetric unit of the crystal structure there are two
independent molecules, which are connected by a center of
pseudoinversion (Figure 4). The coordinates of the pseudoinversion
centers are (0.5, 0.187, 0.25). The projection of the crystal structure
is given on Figure 5. It can be assumed that this structure and cen-
trosymmetric crystal structure of racemic compound ( )-4a are
pseudoisomorphous to each other. Although suitable samples for

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I. Strakova et al. / Tetrahedron: Asymmetry 22 (2011) 728–739
Figure 2. Projection of the crystal structure of (ꢀ)-3a down the crystallographic a axis.
Figure 3. Projection of the crystal structure of ( )-3a down the monoclinic axis.

I. Strakova et al. / Tetrahedron: Asymmetry 22 (2011) 728–739
733
Figure 4. Asymmetric unit of the enantiopure azide (ꢀ)-4a.
3. Conclusion
Figure 6. Calculated diffraction pattern (a) from single crystal data of the
enantiomerically pure azide (ꢀ)-4a and diffraction pattern (b) of the racemate
( )-4a obtained on the powder diffractometer.
A practical method for the resolution of 7-amino-1-aryl-4,5,6,7-
tetrahydro-indazol-4-ones has been achieved via salt formation
with either enantiomer of O,O0-dibenzoyl tartaric acid. Further
chemical transformations of enantiomerically pure 7-amino-THIs
are possible without erosion of their ee’s. The aforementioned
enantiomerically pure heterocycles can be successfully conjugated
to different sugar-derived scaffolds in order to produce carbohy-
drate–tetrahydroindazole conjugates. This might open up possibil-
ities to study the biological targeting of the aforementioned
structures, and thus might qualitatively elevate the level of biolog-
ical activity research of tetrahydroindazoles as pharmacophores in
the future.
used as an internal references for 1H and 13C NMR spectra, respec-
tively. Coupling constants are reported in Hertz. Analytical thin
layer chromatography (TLC) was performed on Kieselgel 60 F254
glass plates precoated with a 0.25 mm thickness of silica gel. Yields
refer to chromatographically and spectroscopically homogeneous
materials. GC–MS (EI: 70 eV) analyses where appropriate were
done on HP-5; 5% phenylmethylsiloxane column (30 m, 250
lm,
0,25 m); He carrier gas; flow rate 1 mL/min; temperature regime:
l
100 °C hold 3 min; increase rate 50 °C/min until 250 °C, hold
1 min; increase rate 100 °C/min until 310 °C, hold 15 min. Injection
volume: 1 lL (c 1 mg/mL; CHCl3).
4. Experimental
4.1. ( )-7-Amino-6,6-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-
indazol-4-one ( )-3a
1H and 13C NMR spectra were recorded at 200, 300 or 400 MHz
and at 100 or 75 MHz, respectively. The proton signals for residual
non-deuterated solvents (d 7.26 for CDCl3 and d 2.50 for DMSO-d6)
and carbon signals (d 77.1 for CDCl3 and d 39.5 for DMSO-d6) were
To a solution of ( )-4a (10.0 g, 35.5 mmol) in EtOH (150 mL) and
THF (50 mL) was added 10% Pd/C (0.8 g, 8 wt %) and gaseous H2
Figure 5. Projection of the crystal structure of (ꢀ)-4a down the monoclinic axis, showing the centers of pseudoinversion.

734
I. Strakova et al. / Tetrahedron: Asymmetry 22 (2011) 728–739
Table 2
The principal bond lengths (Å) in tetrahydroindazolones 3–6
Bond
Compound (ꢀ)-3a
Compound ( )-3a
Compound (ꢀ)-4a
Compound (ꢀ)-6
Compound (ꢀ)-7
N(1)–N(2)
N(1)–C(8)
N(2)–C(3)
C(3)–C(9)
C(4)–C(9)
C(4)–O
1.384(2)
1.362(3)
1.326(3)
1.408(3)
1.457(3)
1.225(2)
1.385(3)
1.383(2)
1.359(3)
1.319(3)
1.407(3)
1.456(3)
1.228(3)
1.380(3)
1.385(5)
1.349(5)
1.335(6)
1.400(6)
1.455(6)
1.224(5)
1.365(5)
1.372(3)
1.368(3)
1.327(3)
1.400(3)
1.461(3)
1.213(3)
1.387(3)
1.390(7)
1.337(8)
1.329(8)
1.419(9)
1.467(9)
1.235(7)
1.371(8)
C(8)–C(9)
was passed through the resulting reaction mixture for 2 h (TLC
control). The catalyst was filtered through Celite and the filtrate
was evaporated under reduced pressure. The residue was crystal-
lized from hexane/CHCl3 yielding ( )-3b (8.07 g, 89%) as beige crys-
tals. Mp 166–167 °C. 1H NMR (CDCl3, 200 MHz) d, ppm: 8.04 (s, 1H,
H–C(3)), 7.85–7.80 (m, 2H, H–C(Ph)), 7.57–7.45 (m, 3H, H–C(Ph)),
3.76 (s, 1H, H–C(7)), 2.72, 2.22 (2d, AB syst., 2H, 2J = 16.6 Hz, H–
C(5)), 1.42 (br s, 2H, H2N–C(7)), 1.14, 1.00 (2s, 6H, H3C–C(6)). 13C
NMR (CDCl3, 75 MHz) d, ppm: 192.4, 150.9, 138.8, 137.9, 129.4,
H–C(Ph)), 7.48 (t, 1H, 3J = 7.4 Hz, H–C(Phr)), 5.80 (s, 2H, H–C(20,30)),
3.97 (s, 1H, H–C(7)), 2.94, 2.07 (2d, AB syst., 2H, 2J = 17.6 Hz, H–
C(5)), 1.10, 0.89 (2s, 6H, H3C–C(6)). 13C NMR (DMSO-d6,
100.6 MHz) d, ppm: 191.6, 167.4, 164.7, 149.0, 138.4, 137.4,
133.8, 129.3, 129.2, 128.8, 128.7, 128.3, 124.0, 118.8, 71.8, 51.2,
46.2, 38.8, 25.9, 25.1. IR (KBr)
2965, 2640, 1725, 1700, 1685, 1600, 1545, 1505, 1270, 1120,
1070, 1025, 970.
The filtrate from above was evaporated to dryness yielding a
mixture of salts (+)-3aꢁ(+)-5 and (ꢀ)-3aꢁ(+)-5. The latter was
poured into a vigorously stirred mixture consisting of 10% aqueous
solution of K2CO3 (100 mL) and CHCl3 (50 mL). The resulting mix-
ture was stirred for 30 min and the layers were separated. The
aqueous phase was extracted with CHCl3 (2 ꢂ 30 mL). The com-
bined organic layer was sequentially washed with 10% aqueous
solution of K2CO3 (30 mL) and saturated aqueous solution of NaCl
(30 mL), dried over Na2SO4, and evaporated under reduced pres-
sure. The residue after drying in vacuo yielded partially enantiome-
rically enriched amine (ꢀ)-3a (2.11 g, 91% HPLC purity). The latter
was dissolved in abs EtOH (10 mL) and treated with a solution of
(ꢀ)-5 (2.69 g, 7.5 mmol, 1 equiv to pure amine 3a) in abs EtOH
(8 mL). The resulting mixture was stirred at ambient temperature
for 6 h, filtered, and washed on the filter with abs EtOH (2 mL).
The residue was crystallized from abs EtOH yielding (ꢀ)-3bꢁ(ꢀ)-5
(3.41 g, 42%). Mp 204–205 °C. 1H and 13C NMR data identical to
(+)-3bꢁ(+)-5.
m
max, cmꢀ1: 3425, 3150, 3070,
128.5, 124.2, 118.5, 53.0, 46.9, 39.4, 26.3, 25.4. IR (KBr) mmax
,
cmꢀ1: 3360, 3330, 3060, 2970, 2890, 2875, 1675, 1600, 1540,
1495, 1480, 1400, 1230, 1080, 1060, 1045, 970, 910. GH-MS(EI):
tR = 8.09 min; mass calcd for C15H17N3O 255.1; found 255.1. Anal.
Calcd for C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C, 70.62;
H, 6.74; N, 16.48.
4.2. ( )-7-Amino-3,6,6-trimethyl-1-phenyl-4,5,6,7-tetrahydro-
1H-indazol-4-one ( )-3b
To a solution of ( )-4b (8.00 g, 27.1 mmol) in EtOH (100 mL)
and THF (20 mL) was added 10% Pd/C (0.8 g, 10 wt %) and gaseous
H2 was passed through the resulting reaction mixture for 2 h (TLC
control). The catalyst was filtered through Celite and the filtrate
was evaporated under reduced pressure. The residue was dried
in vacuo for 24 h yielding ( )-3b (5.97 g, 82%) of as an amorphous
powder. 1H NMR (CDCl3, 400 MHz) d, ppm: 7.77 (d, 2H, 3J = 8.0 Hz,
H–C(Ph)), 7.49 (t, 2H, 3J = 8.0 Hz, H–C(Ph)), 7.42 (t, 1H, 3J = 8.0 Hz,
H–C(Ph)), 3.71 (s, 1H, H–C(7)), 2.69 (d, AB syst., 1H, 2J = 17.0 Hz,
Ha-C(5)), 2.53 (s, 3H, H3C–C(3)), 2.19 (d, AB syst., 1H, 2J = 17.0 Hz,
Hb-C(5)), 1.41 (bs, 2H, H2N–C(7)), 1.12, 1.00 (2s, 6H, H3C–C(6)).
13C NMR (CDCl3, 100.6 MHz) d, ppm: 193.1, 151.8, 149.5, 138.9,
129.4, 128.3, 124.3, 115.7, 53.2, 47.4, 39.4, 26.4, 25.5, 13.3. IR (film)
4.4. (+)-(7S)-7-Amino-6,6-dimethyl-1-phenyl-4,5,6,7-
tetrahydro-1H-indazol-4-one (+)-3a
Salt (+)-3aꢁ(+)-5 (3.34 g, 5.44 mmol) was poured into a vigor-
ously stirred mixture consisting of 10% aqueous solution of K2CO3
(70 mL) and CHCl3 (40 mL). The resulting mixture was stirred for
30 min and the layers were separated. The aqueous phase was ex-
tracted with CHCl3 (2 ꢂ 30 mL). The combined organic layer was
sequentially washed with 10% aqueous solution of K2CO3 (30 mL)
and saturated aqueous solution of NaCl (30 mL), dried over Na2SO4
and evaporated under reduced pressure. The residue after drying
in vacuo yielded enantiomerically enriched amine (+)-3a (1.32 g,
95%, 97% ee). Crystallization of an analytical sample of (+)-3a from
m
max, cmꢀ1: 3385, 3315, 3055, 2960, 2870, 1670, 1650, 1600, 1540,
1505, 1585, 1440, 1405, 1370, 1290, 1130, 1100, 1070, 1045, 950,
925, 905. GH-MS(EI): tR = 8.13 min; mass calcd for C16H19N3O
269.2; found 269.1. Anal. Calcd for C16H19N3O: C, 71.35; H, 7.11;
N, 15.60. Found: C, 70.53; H, 7.39; N, 15.38.
4.3. (7S)-6,6-Dimethyl-4-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-
indazol-7-yl-ammonium (2S,3S)-2,3-bis-benzoyloxy-3-carb-
oxy-propionate (+)-3aꢁ(+)-5 and (7R)-6,6-dimethyl-4-oxo-1-
phenyl-4,5,6,7-tetrahydro-1H-indazol-7-yl-ammonium (2R,3R)-
2,3-bis-benzoyloxy-3-carboxy-propionate (ꢀ)-3aꢁ(ꢀ)-5
hexane/CHCl3 increased the ee up to 99.5%. ½a D22
¼ 26 (c 2.3, CHCl3).
ꢃ
Anal. Calcd for C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C,
70.41; H, 6.71; N, 16.52. Other analytical data of (+)-3a are identical
to those of ( )-3a. Enantiomeric excess was determined by HPLC
[Pirkle covalent (R,R)-Whelk-O1]: tR[(ꢀ)-3a] = 8.44 min; tR[(+)-
3a] = 9.34 min. Eluent system: hexanes/dioxane = 2:1 in isocratic
mode; flow rate 0.8 mL/min; UV detector at 254 nm.
A solution of (+)-5 (4.77 g, 13.3 mmol) in abs EtOH (10 mL) was
added to a solution of ( )-3a (3.40 g, 13.3 mmol) in abs EtOH
(15 mL) at ambient temperature. The resulting reaction mixture
was stirred at ambient temperature for 5 days. The crude salt
was filtered, washed on the filter with abs EtOH (2 mL), and crys-
tallized from abs EtOH yielding (+)-3bꢁ(+)-5 (3.34 g, 41%). Mp
204–205 °C. 1H NMR (DMSO-d6, 400 MHz) d, ppm: 8.08 (s, 1H,
H–C(3)), 8.00 (d, 4H, 3J = 7.0 Hz, H–C(Ph)), 7.85 (d, 2H, 3J = 7.4 Hz,
H–C(Ph)), 7.70 (t, 2H, 3J = 7.4 Hz, H–C(Ph)), 7.59–7.55 (m, 6H,
4.5. (ꢀ)-(7R)-7-Amino-6,6-dimethyl-1-phenyl-4,5,6,7-
tetrahydro-1H-indazol-4-one (ꢀ)-3a
Salt (ꢀ)-3aꢁ(ꢀ)-5 (3.41 g, 5.56 mmol) was poured into a vigor-
ously stirred mixture consisting of 10% aqueous solution of

I. Strakova et al. / Tetrahedron: Asymmetry 22 (2011) 728–739
735
K2CO3 (70 mL) and CHCl3 (40 mL). The resulting mixture was stir-
red for 30 min and the layers were separated. The aqueous phase
was extracted with CHCl3 (2 ꢂ 30 mL). The combined organic layer
was sequentially washed with 10% aqueous solution of K2CO3
(30 mL) and saturated aqueous solution of NaCl (30 mL), dried over
Na2SO4, and evaporated under reduced pressure. The residue after
drying in vacuo yielded enantiomerically enriched amine (ꢀ)-3a
(1.36 g, 96%, 98% ee). Crystallization of an analytical sample of
salt (+)-3bꢁ(+)-5 (0.35 g, 4%). Thus, the total yield of salts (ꢀ)-
3bꢁ(ꢀ)-5 and (+)-3bꢁ(+)-5 were 38% and 48%, respectively.
4.7. (ꢀ)-(7R)-7-Amino-3,6,6-trimethyl-1-phenyl-4,5,6,7-
tetrahydro-1H-indazol-4-one (ꢀ)-3b
Salt (ꢀ)-3bꢁ(ꢀ)-5 (2.65 g, 4.2 mmol) was poured into a vigor-
ously stirred mixture consisting of 10% aqueous solution of
K2CO3 (50 mL) and CHCl3 (30 mL). The resulting mixture was
stirred for 30 min after which the layers were separated. The aque-
ous phase was extracted with CHCl3 (2 ꢂ 20 mL). The combined or-
ganic layer was sequentially washed with 10% aqueous solution of
K2CO3 (30 mL) and saturated aqueous solution of NaCl (30 mL),
dried over Na2SO4, and evaporated under reduced pressure. The
residue after drying in vacuo yielded enantiomerically enriched
(ꢀ)-3a from hexanes/CHCl3 increased ee up to 99.5%. (½a D22
¼ ꢀ26
ꢃ
(c 1.1, CHCl3). Anal. Calcd for C15H17N3O: C, 70.56; H, 6.71; N,
16.46. Found: C, 70.50; H, 6.89; N, 16.28. Other analytical data of
(ꢀ)-3a are identical to those of ( )-3a. Enantiomeric excess was
determined by HPLC [Pirkle covalent (R,R)-Whelk-O1]: tR[(ꢀ)-
3a] = 8.44 min; tR[(+)-3a] = 9.34 min. Eluent system: hexanes/diox-
ane = 2:1 in isocratic mode; flow rate 0.8 mL/min; UV detector at
254 nm.
amine (ꢀ)-3b (1.05 g, 93%, 93% ee). ½a D20
¼ ꢀ19:6 (c 6.6, CHCl3).
ꢃ
HRMS (TOF-ESI) calcd for [C16H19N3O+H]+ 270.1606; found
270.1581. Other analytical data of (ꢀ)-3b are identical to those of
( )-3b. Enantiomeric excess was determined by HPLC [Pirkle cova-
lent (R,R)-Whelk-O1]: tR[(ꢀ)-3b] = 16.90 min; tR[(+)-3b] = 18.35
min. Eluent system: hexanes/THF/MeCN = 85.2:14.2:0.5 in iso-
cratic mode; flow rate 1 mL/min; UV detector at 254 nm.
4.6. (7R)-3,6,6-Trimethyl-4-oxo-1-phenyl-4,5,6,7-tetrahydro-
1H-indazol-7-yl-ammonium (2R,3R)-2,3-bis-benzoyloxy-3-
carboxy-propionate (ꢀ)-3bꢁ(ꢀ)-5 and (7S)-3,6,6-trimethyl-4-
oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indazol-7-yl-ammonium
(2S,3S)-2,3-bis-benzoyloxy-3-carboxy-propionate (+)-3bꢁ(+)-5
A solution of (ꢀ)-5 (4.87 g, 13.6 mmol) in abs EtOH (10 mL)
was added to a solution of ( )-3b (3.66 g, 13.6 mmol) in abs EtOH
(15 mL) at ambient temperature. The resulting reaction mixture
was stirred at ambient temperature for 5 days. The crude salt
was filtered, washed on the filter with abs EtOH (2 mL), and crys-
tallized from abs EtOH yielding (ꢀ)-3bꢁ(ꢀ)-5 (2.65 g, 31%). Mp
175–177 °C. 1H NMR (DMSO-d6, 300 MHz) d, ppm: 8.00 (d, 4H,
3J = 7.5 Hz, H–C(Ph)), 7.87 (d, 2H, 3J = 7.9 Hz, H–C(Ph)), 7.71 (t,
2H, 3J = 7.9 Hz, H–C(Ph)), 7.60–7.53 (m, 6H, H–C(Ph)), 7.46 (t,
4.8. (+)-(7S)-7-Amino-3,6,6-trimethyl-1-phenyl-4,5,6,7-
tetrahydro-1H-indazol-4-one (+)-3b
Salt (+)-3bꢁ(+)-5 (3.73 g, 5.94 mmol) was poured into a vigor-
ously stirred mixture consisting of 10% aqueous solution of
K2CO3 (70 mL) and CHCl3 (40 mL). The resulting mixture was stir-
red for 30 min after which the layers were separated. The aqueous
phase was extracted with CHCl3 (2 ꢂ 30 mL). The combined organ-
ic layer was sequentially washed with a 10% aqueous solution of
K2CO3 (30 mL) and a saturated aqueous solution of NaCl (30 mL),
dried over Na2SO4, and evaporated under reduced pressure. The
residue after drying in vacuo yielded enantiomerically enriched
3
1H, J = 7.3 Hz, H–C(Ph)), 5.81 (s, 2H, H–C(20,30)), 3.80 (s, 1H, H–
C(7)), 2.88 (d, AB syst., 1H, 2J = 17.0 Hz, Ha-C(5)), 2.41 (s, 3H,
H3C–C(3)), 2.01 (d, AB syst., 1H, 2J = 17.0 Hz, Hb-C(5)), 1.08, 0.88
(2s, 6H, H3C–C(6)). 13C NMR (DMSOd3, 75 MHz) d, ppm: 192.6,
167.5, 164.8, 149.8, 148.0, 138.5, 133.9, 129.4, 129.3, 129.0,
128.9, 128.1, 124.0, 115.8, 71.7, 51.6, 46.6, 38.9, 26.0, 25.3, 13.1.
amine (+)-3b (1.46 g, 91%, 92% ee). ½a D20
¼ þ19:8 (c 6.8, CHCl3).
ꢃ
HRMS (TOF-ESI) calcd for [C16H19N3O+H]+ 270.1606; found
270.1617. Other analytical data of (+)-3b are identical to those of
( )-3b. Enantiomeric excess was determined by HPLC [Pirkle cova-
lent (R,R)-Whelk-O1]: tR[(ꢀ)-3b] = 16.90 min; tR[(+)-3b] = 18.35
min. Eluent system: hexanes/THF/MeCN = 85.2:14.2:0.5 in
isocratic mode; flow rate 1 mL/min; UV detector at 254 nm.
IR (KBr) m
max, cmꢀ1: 3430, 3140, 3070, 2970, 2655, 2600, 1725,
1670, 1600, 1490, 1265, 1180, 1120, 1070, 1030, 955, 905. Anal.
Calcd for C34H33N3O9: C, 65.06; H, 5.30; N, 6.69. Found: C,
65.33; H, 5.14; N, 6.51.
The filtrate from the above was evaporated to dryness yielding a
mixture of salts (ꢀ)-3bꢁ(ꢀ)-5 and (+)-3bꢁ(ꢀ)-5. The latter was
poured into a vigorously stirred mixture consisting of 10% aqueous
solution of K2CO3 (100 mL) and CHCl3 (50 mL). The resulting mix-
ture was stirred for 30 min and the layers were separated. The
aqueous phase was extracted with CHCl3 (2 ꢂ 30 mL). The com-
bined organic layer was sequentially washed with a 10% aqueous
solution of K2CO3 (30 mL) and a saturated aqueous solution of NaCl
(30 mL), dried over Na2SO4, and evaporated under reduced pres-
sure. The residue after drying in vacuo yielded partially enantiome-
rically enriched amine (+)-3b (2.82 g, 87% HPLC purity). The latter
was dissolved in abs EtOH (15 mL) and treated with solution of (+)-
5 (3.26 g, 9.1 mmol, 1 equiv to pure amine 3b) in abs EtOH (10 mL).
The resulting mixture was stirred at ambient temperature for 4 h,
filtered, and washed on the filter with abs EtOH (2 mL). The residue
was crystallized from abs EtOH yielding (+)-3bꢁ(+)-5 (3.73 g, 44%).
Mp 177–178 °C. 1H and 13C NMR data identical to (ꢀ)-3bꢁ(ꢀ)-5.
Anal. Calcd for C34H33N3O9: C, 65.06; H, 5.30; N, 6.69. Found: C,
64.75; H, 5.20; N, 6.56.
4.9. Camphanic amide (ꢀ)-6
(1S)-(ꢀ)-Camphanic chloride (0.216 g, 1.00 mmol) was added to
a solution of (+)-3a (0.12 g, 0.47 mmol) and a catalytic amount of
DMAP (6 mg, 10 mol %) in abs pyridine (5 mL) at ꢀ15 °C. The
resulting reaction mixture was allowed to reach ambient temper-
ature and stirred for 22 h. Then it was diluted with Et2O (50 mL)
and successively washed with saturated aqueous solution of CuSO4
(4 ꢂ 15 mL), saturated aqueous solution of NaHCO3 (3 ꢂ 20 mL),
and brine (15 mL). The resulting organic layer was dried over
Na2SO4 and evaporated under reduced pressure. The residue was
crystallized from ethanol to provide amide (ꢀ)-6 (0.15 g, 73%).
Mp 198–199 °C,
½
a 2D0
ꢃ
¼ ꢀ27 (c 1.0, CHCl3). 1H NMR (CDCl3,
200 MHz) d, ppm: 8.06 (s, 1H, H–C(3)), 7.53–7.37 (m, 5H, H–
C(Ph)), 6.42 (d, 1H, 3J = 9.5 Hz, HN–C(7)), 5.45 (d, 1H, 3J = 9.5 Hz,
H–C(7)), 2.53, 2.44 (2d, AB syst., 2H, 2J = 16.9 Hz, H–C(5)), 2.09,
2.18, 1.54, 1.19 (4ddd, 1H, 2J = 13.2 Hz, 3J = 10.8 Hz, 3J = 4.4 Hz,
H–C(camph)), 1.18, 1.06, 1.05, 1.04, 0.89 (5s, 15H, H3C–C(6),
H3C–C(camph)). 13C NMR (CDCl3, 75 MHz) d, ppm: 191.6, 177.7,
166.6, 146.3, 138.5, 137.9, 129.4, 129.0, 124.6, 120.2, 92.1, 55.1,
53.8, 49.7, 49.6, 39.9, 30.2, 28.8, 27.0, 24.3. 16.8, 16.7, 9.5. IR
The filtrate from (+)-3bꢁ(+)-5 was basified and extracted with
CHCl3 as described above. This resulted in a recovery of virtually
racemic amine ( )-3b (0.98 g, 91% HPLC purity). The latter was
treated sequentially with (ꢀ)-5 and (+)-5 as described above. This
produced an additional portion of salt (ꢀ)-3bꢁ(ꢀ)-5 (0.60 g, 7%) and
(KBr)
m
max, cmꢀ1: 3415, 2970, 2930, 2895, 1800, 1690, 1675,

736
I. Strakova et al. / Tetrahedron: Asymmetry 22 (2011) 728–739
1540, 1515, 1480. Anal. Calcd for C25H29N3O4: C, 68.95; H, 6.71; N,
9.65. Found: C, 68.73; H, 6.73; N, 9.53.
4.12. (+)-(7R)-7-Azido-6,6-dimethyl-1-phenyl-4,5,6,7-
tetrahydro-1H-indazol-4-one (+)-4a
4.10. (ꢀ)-(7S)-7-[(4-Bromo-benzylidene)-amino]-3,6,6-tri-
methyl-1-phenyl-1,5,6,7-tetrahydro-1H-indazol-4-one (ꢀ)-7
Product (+)-4a was prepared according to general procedure of
the diazo transfer. Thus, (ꢀ)-3a (1.41 g, 5.52 mmol) provided (+)-
4a (1.41 g, 91%). Mp 79–80 °C, ½a D20
¼ 94 (c 1.7, CHCl3). Other ana-
ꢃ
4-Bromo-benzaldehyde (0.09 g, 0.5 mmol) was added to a solu-
tion of (+)-3b (0.13 g, 0.5 mmol) in EtOH (3 mL). The resulting reac-
tion mixture was refluxed for 4 h, and then it was cooled to +5 °C,
and triturated with brine. The resulting precipitate was filtered and
washed on the filter with water. The filter cake was dried until a
constant mass and recrystallized from hexane/EtOAc mixture.
lytical data of (+)-4a are identical to those of (ꢀ)-4a described
above.
4.13. (ꢀ)-(7S)-7-Azido-3,6,6-trimethyl-1-phenyl-4,5,6,7-
tetrahydro-1H-indazol-4-one (ꢀ)-4b
Yield of (ꢀ)-7: 0.17 g (78%). Mp 107–108 °C, ½a D20
ꢃ
¼ ꢀ54 (c 4.0,
Product (ꢀ)-4b was prepared according to the general proce-
dure of diazo transfer. Thus, (+)-3b (1.14 g, 4.23 mmol) provided
(ꢀ)-4b as a yellowish oil, which was dissolved in toluene/EtOAc
(1:2) mixture (20 mL) and passed through a pad of silica gel. Evap-
CHCl3). 1H NMR (CDCl3, 300 MHz) d, ppm: 7.57 (s, 1H, HC = NC(3)),
7.47 (d, 2H, 3J = 8.5 Hz, H–C(p-Br–C6H4)), 7.42–7.39 (m, 3H, H–
C(Ph)), 7.37 (d, 2H, 3J = 8.5 Hz, H–C(p-Br–C6H4)), 7.30–7.26 (m,
2H, H–C(Ph)), 4.18 (s, 1H, H–C(7)), 2.95 (d, AB syst., 2J = 16.4 Hz,
Ha-C(5)), 2.56 (s, 3H, H3C–C(3)), 2.25 (d, AB syst., 2J = 16.9 Hz,
Hb-C(5)), 1.12, 0.96 (2s, 6H, H3C–C(6)). 13C NMR (CDCl3, 75 MHz)
d, ppm: 193.7, 161.3, 149.4, 148.9, 138.4, 134.1, 131.9, 129.7,
129.3, 129.1, 126.0, 125.9, 116.3, 70.5, 49.1, 39.9, 26.5, 26.3, 13.4.
oration of filtrate gave (ꢀ)-4b (1.11 g, 89%). ½a D20
¼ ꢀ86 (c 2.2,
ꢃ
CHCl3). 1H NMR (CDCl3, 400 MHz) d, ppm: 7.58–7.48 (m, 5H, H–
C(Ph)), 4.22 (s, 1H, H–C(7)), 2.72 (d, AB syst., 1H, 2J = 17.2 Hz, Ha-
C(5)), 2.56 (s, 3H, H3C–C(3)), 2.24 (d, AB syst., 1H, 2J = 17.2 Hz,
Hb-C(5)), 1.24, 1.06 (2s, 6H, H3C–C(6)). 13C NMR (CDCl3, 75 MHz)
d, ppm: 192.2, 149.7, 145.8, 138.1, 129.7, 129.2, 124.9, 116.5,
IR (KBr)
1375, 1070, 1010. GH-MS(EI): tR = 9.67 min; mass calcd for
23H2279BrN3O 435.1; found 435.0. Anal. Calcd for C23H22BrN3O:
m
max, cmꢀ1: 2970, 2940, 1675, 1640, 1590, 1490, 1445,
61.7, 48.1, 40.8, 26.3, 26.2, 13.3. IR (film) m
max, cmꢀ1: 2980, 2965,
C
2945, 2870, 2100, 1665, 1595, 1555, 1500, 1440, 1335, 1234,
1045, 905. HRMS (TOF-ESI) calcd for [C16H17N5O+H]+ 296.1511;
found 296.1497. Enantiomeric excess of (ꢀ)-4b/(+)-4b was not
determined by HPLC as no separation between the enantiomers
was observed on the available columns. Further transformation
of (ꢀ)-4b to the corresponding triazoles showed the conservation
of enantiomeric purity.
C, 63.31; H, 5.08; N, 9.63. Found: C, 63.33; H, 5.02; N, 9.60. Analo-
gously, (ꢀ)-3b provided (+)-6 (75%). ½a D20
¼ 53 (c 2.6, CHCl3). GH-
ꢃ
MS(EI): tR = 9.70 min; mass calcd for C23H2279BrN3O 435.1; found
435.0.?>
4.11. (ꢀ)-(7S)-7-Azido-6,6-dimethyl-1-phenyl-4,5,6,7-
tetrahydro-1H-indazol-4-one (ꢀ)-4a
4.14. (+)-(7R)-7-Azido-3,6,6-trimethyl-1-phenyl-4,5,6,7-
tetrahydro-1H-indazol-4-one (+)-4b
General procedure for diazo transfer: First, a fresh solution of
TfN3 was prepared by intensive 2 h stirring of a biphasic system
consisting of NaN3 (1.99 g, 30.54 mmol, 6 equiv) and Tf2O
(2.57 mL, 15.27 mmol, 3 equiv) in water (7 mL) and CH2Cl2
(7 mL) at 0 °C. The organic layer was then separated and the
aqueous phase was extracted once with CH2Cl2 (6 mL). The com-
bined organic layer (ꢄ13 mL) was washed with saturated aque-
ous solution of NaHCO3 (3 mL) and thus was ready for the
diazo transfer reaction. The above mentioned solution of TfN3
was added at ambient temperature to a suspension of amine
(+)-3a (1.30 g, 5.09 mmol, 1 equiv), CuSO4ꢁ5H2O (25 mg,
0.10 mmol, 2 mol %), and NaHCO3 (0.37 g, 4.40 mmol, 0.87 equiv)
in water (13 mL). The resulting reaction mixture was diluted
with methanol (ꢄ45 mL) until it became homogeneous. Next, it
was stirred for 24 h at ambient temperature. Organic solvents
were evaporated at reduced pressure and after the addition of
brine (20 mL), the aqueous phase was extracted with EtOAc
(3 ꢂ 10 mL). The combined organic layer was dried over Na2SO4,
filtered, and evaporated in vacuo. The residue was crystallized
from hexanes/CHCl3 providing (ꢀ)-4a (1.31 g, 91%). Mp 79–
Product (+)-4b was prepared according to the general procedure
of diazo transfer. Thus, (ꢀ)-3b (1.00 g, 3.71 mmol) provided (+)-4b
as a yellowish oil, which was dissolved in toluene/EtOAc (1:2) mix-
ture (20 mL) and passed through a pad of silica gel. Evaporation of
the filtrate gave (+)-4b (0.91 g, 83%). ½a D20
¼ 84 (c 2.4, CHCl3). Other
ꢃ
analytical data of (+)-4b are identical to those of (ꢀ)-4b.
4.15. (ꢀ)-(7S)-6,6-Dimethyl-1-phenyl-7-(4-phenyl-[1,2,3]-
triazol-1-yl)-4,5,6,7-tetrahydro-1H-indazol-4-one (ꢀ)-8a
General procedure I of triazole formation: To a solution of azide
(ꢀ)-4a (0.14 g, 0.50 mmol, 1.0 equiv) and phenylacetylene (60
lL,
0.55 mmol, 1.1 equiv) in 2-butanol (4.0 mL) and water (2.0 mL)
were added CuSO4ꢁ5H2O (19 mg, 0.075 mmol, 0.15 equiv) and Cu
powder (100 mg) at ambient temperature. The resulting mixture
was stirred at 40 °C for 8 h, cooled to ambient temperature, and
ethyl acetate (30 mL) was added. The resulting suspension was fil-
tered and the filtrate was evaporated under reduced pressure. The
residue consisted of chromatographically homogeneous (GC–MS)
triazole (ꢀ)-8a, which after crystallization from hexane/EtOAc
mixture provided analytically pure (ꢀ)-8a (0.13 g, 76%). Mp 181–
80 °C, ½a 2D0
ꢃ
¼ ꢀ95 (c 1.8, CHCl3). 1H NMR (CDCl3, 300 MHz) d,
ppm: 8.10 (s, 1H, H–C(3)), 7.58–7.51 (m, 5H, H–C(Ph)), 4.26 (s,
1H, H–C(7)), 2.74, 2.28 (2d, AB syst., 2H, 2J = 17.0 Hz, H–C(5)),
1.26, 1.06 (2s, 6H, H3C–C(6)). 13C NMR (CDCl3, 75 MHz) d, ppm:
191.4, 145.3 (2C), 138.1, 129.8, 129.4, 124.9, 119.4, 61.5, 47.8,
182 °C, ½a 2D0
ꢃ
¼ ꢀ39 (c 1.0, CHCl3). 1H NMR (CDCl3, 200 MHz) d,
ppm: 8.22 (s, 1H, H–C(3)), 7.76 (dd, 2H, 3J = 7.8 Hz, 4J = 2.3 Hz,
Ar), 7.48 (s, 1H, H–C(50)), 7.45–7.35 (m, 6H, Ar), 7.02 (dd, 2H,
3J = 7.8 Hz, 4J = 2.3 Hz, Ar), 5.64 (s, 1H, H–C(7)), 2.85, 2.43 (2d, 2H,
AB syst., 2J = 17.2 Hz, H–C(5)), 1.25, 0.94 (2s, 6H, H3C–C(6)). 13C
NMR (CDCl3, 100.6 MHz) d, ppm: 190.9, 148.1, 143.2, 138.3,
137.4, 129.6, 129.6, 129.5, 128.9, 128.6, 125.7, 124.4, 120.6,
40.9, 26.3, 26.1. IR (KBr)
m
max, cmꢀ1: 2980, 2870, 2100, 1680,
1650, 1600, 1540, 1505, 1460, 1320, 1250, 1125, 1060, 1020.
HRMS (TOF-ESI) calcd for [C15H15N5O+H]+ 282.1355; found
282.1348. Enantiomeric excess of (ꢀ)-4a/(+)-4a was not deter-
mined by HPLC as no separation between enantiomers was
observed on the available columns. Further transformation of
(ꢀ)-4a to the corresponding triazoles showed the conservation
of the enantiomeric purity.
118.7, 60.8, 48.0, 40.1, 27.1, 25.9. IR (KBr)
2970, 1685, 1500, 1475, 1230, 970, 765, 695. Anal. Calcd for
23H21N5O: C, 72.04; H, 5.52; N, 18.26. Found: C, 71.82; H, 5.40;
N, 18.30. Enantiomeric excess was determined by HPLC [Pirkle
m
max, cmꢀ1: 3125,
C

I. Strakova et al. / Tetrahedron: Asymmetry 22 (2011) 728–739
737
covalent
(R,R)-Whelk-O1]:
tR[(+)-8a] = 19.59 min;
tR[(ꢀ)-
dioxane = 3:1 in isocratic mode; flow rate 0.7 mL/min; UV detector
at 254 nm.
8a] = 23.02 min. Eluent system: hexanes/dioxane = 3:1 in isocratic
mode; flow rate 0.7 mL/min; UV detector at 254 nm.
4.20. (+)-(7R)-3,6,6-Trimethyl-1-phenyl-7-(4-phenyl-[1,2,3]-
triazol-1-yl)-4,5,6,7-tetrahydro-1H-indazol-4-one (+)-8c
4.16. (+)-(7R)-6,6-Dimethyl-1-phenyl-7-(4-phenyl-[1,2,3]triazol-
1-yl)-4,5,6,7-tetrahydro-1H-indazol-4-one (+)-8a
Product (+)-8c was prepared analogously to product (ꢀ)-8c.
Yield 50%. Mp 128–129 °C (EtOAc/hexanes), ½a D20
¼ þ52 (c 1.0,
ꢃ
Product (+)-7a was prepared according to the general procedure
I of triazole formation. Yield 80%. Mp 179–180 °C, ½a D20
¼ þ40 (c
ꢃ
CHCl3). Other analytical data of (+)-7c are identical to those of
(ꢀ)-8c. Enantiomeric excess was determined by HPLC [Pirkle cova-
1.0, CHCl3). Other analytical data of (+)-8a are identical to those
of (ꢀ)-8a. Enantiomeric excess was determined by HPLC [Pirkle
lent
(R,R)-Whelk-O1]:
tR[(+)-8c] = 16.63 min;
tR[(ꢀ)-
covalent
(R,R)-Whelk-O1]:
tR[(+)-8a] = 19.59 min;
tR[(ꢀ)-
7c] = 19.26 min. Eluent system: hexanes/dioxane = 3:1 in isocratic
8a] = 23.02 min. Eluent system: hexanes/dioxane = 3:1 in isocratic
mode; flow rate 0.7 mL/min; UV detector at 254 nm.
mode; flow rate 0.7 mL/min; UV detector at 254 nm.
4.21. (+)-(7R,70R)-7,70-(4,40-(Hexane-1,6-diyl)bis(1H-1,2,3-tria-
zole-4,1-diyl))bis(6,6-dimethyl-1-phenyl-4,5,6,7-tetrahydro-
1H-indazol-4-one (+)-8d
4.17. (ꢀ)-(7S)-7-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)-6,6-di-
methyl-1-phenyl-4,5,6,7-tetra-hydro-1H-indazol-4-one (ꢀ)-8b
Product (ꢀ)-8b was prepared according to the general proce-
The title compound was prepared by the same procedure as
that described for the preparation of (+)-8a, using 2 equiv of (+)-
4a and 1,9-decadiyne instead of phenylacetylene. Reaction temper-
ature 40 °C, reaction time 55 h. Yield 40%. Mp 174–175 °C (EtOAc/
dure I of triazole formation by using propargyl alcohol instead of
phenylacetylene. Yield 60%. Mp 219–221 °C, ½a D20
¼ ꢀ54 (c 1.0,
ꢃ
CHCl3). 1H NMR (CDCl3, 200 MHz) d, ppm: 8.18 (s, 1H, H–C(3)),
7.42–7.37 (m, 3H, Ar), 7.30 (s, 1H, H–C(50)), 7.00–6.95 (m, 2H,
hexanes), ½a 2D0
ꢃ
¼ þ56 (c 1.0, CHCl3). 1H NMR (CDCl3, 200 MHz) d,
3
Ar), 5.60 (s, 1H, H–C(7)), 4.75 (d, 2H, J = 5.5 Hz, HOCH2–C(40)),
ppm: 8.17 (s, 2H, H–C(3)), 7.42–7.35 (m, 6H, H–C(Ar)), 7.02 (s,
2H, H–C(50)), 6.99–6.92 (m, 4H, H–C(Ar)), 5.55 (s, 2H, H–C(7)),
2.78 (d, 2H, AB syst., 2J = 17.1 Hz, Ha-C(5)), 2.63 (t, 4H, 3J = 7.7 Hz,
H–C(100), H–C(600)), 2.38 (d, 2H, AB syst., 2J = 17.1 Hz, Hb-C(5)),
1.66–1.52 (m, 4H, H–C(200), H–C(500)), 1.36–1.28 (m, 4H, H–C(300),
H–C(400)), 1.20, 0.85 (2s, 12H, H3C–C(6)). 13C NMR (CDCl3,
100.6 MHz) d, ppm: 190.9, 148.6, 143.3, 138.2, 137.5, 129.5,
129.4, 124.2, 120.5, 120.0, 60.5, 48.0, 40.0, 29.0, 28.6, 27.0, 25.8,
2.78, 2.40 (2d, 2H, AB syst., 2J = 17.2 Hz, H–C(5)), 2.33 (t, 1H,
3J = 5.5 Hz, HOCH2–C(40)), 1.21, 0.87 (2s, 6H, H3C–C(6)). 13C NMR
(CDCl3, 100.6 MHz) d, ppm: 191.3, 148.4, 143.3, 138.2 (2C), 137.2,
129.5, 124.3, 121.5, 120.4, 60.6, 55.7, 47.8, 40.0, 26.9, 25.6. IR
(KBr)
m
max, cmꢀ1: 3420, 3130, 2965, 2875, 1660, 1505, 1395,
1225, 1030. Anal. Calcd for C18H19N5O2: C, 64.08; H, 5.68; N,
20.76. Found: C, 64.39; H, 5.51; N, 20.53. Enantiomeric excess
was determined by HPLC [Pirkle covalent (R,R)-Whelk-O1]:
tR[(+)-8b] = 32.31 min; tR[(ꢀ)-8b] = 35.38 min. Eluent system: hex-
anes/dioxane = 3:1 in isocratic mode; flow rate 0.7 mL/min; UV
detector at 254 nm.
25.3. IR (KBr)
m
max, cmꢀ1: 3130, 2935, 2855, 1690, 1550, 1505,
1225, 970, 765, 695. Anal. Calcd for C40H44N10O2: C, 68.94; H,
6.36; N, 20.10. Found: C, 68.98; H, 6.37; N, 20.11. Enantiomeric ex-
cess was determined by HPLC [Pirkle covalent (R,R)-Whelk-O1]:
tR[(+)-8d] = 18.18 min; tR[(ꢀ)-8d] = 20.66 min; tR[8dmeso] = 19.36 -
min. Eluent system: hexanes/dioxane = 3:1 in isocratic mode; flow
rate 0.8 mL/min; UV detector at 254 nm.
4.18. (+)-(7R)-7-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)-6,6-di-
methyl-1-phenyl-4,5,6,7-tetra-hydro-1H-indazol-4-one (+)-8b
Product (+)-8b was prepared analogously to product (ꢀ)-8b.
4.22. b-Glucopyranose-(7R)-THI conjugate (ꢀ)-8e
Yield 58%. Mp 218–219 °C, ½a D20
¼ þ57 (c 1.0, CHCl3). Other analyt-
ꢃ
ical data of (+)-8b are identical to those of (ꢀ)-8b. Enantiomeric ex-
cess was determined by HPLC [Pirkle covalent (R,R)-Whelk-O1]:
tR[(+)-8b] = 32.31 min; tR[(ꢀ)-8b] = 35.38 min. Eluent system: hex-
anes/dioxane = 3:1 in isocratic mode; flow rate 0.7 mL/min; UV
detector at 254 nm.
General procedure II of triazole formation: To a vigorously stirred
solution of glucose derivative 9 (0.19 g, 0.5 mmol) and (+)-4a
(0.14 g, 0.5 mmol) in acetone (5 mL) was added CuSO4ꢁ5H2O
(10 mg, 0.04 mmol) solution in water (0.5 mL) followed by sodium
ascorbate (10 mg, 0,05 mmol) solution in water (0.5 mL) at ambi-
ent temperature. The resulting reaction mixture was stirred for
22 h at ambient temperature, then it was diluted with brine
(15 mL) and extracted with EtOAc (20 mL ꢂ 3). The combined or-
ganic layers were dried over anhyd Na2SO4, filtered, and evapo-
rated under reduced pressure. The residue was purified by silica
gel column chromatography (EtOAc/toluene = 3:2). Yield 0.22 g
4.19. (ꢀ)-(7S)-3,6,6-Trimethyl-1-phenyl-7-(4-phenyl-[1,2,3]-
triazol-1-yl)-4,5,6,7-tetrahydro-1H-indazol-4-one (ꢀ)-8c
Product (ꢀ)-8c was prepared according to the general proce-
dure I of triazole formation by using (ꢀ)-4b instead of (ꢀ)-4a. Yield
48%. Mp 128–129 °C (EtOAc/hexanes), ½a D20
ꢃ
¼ ꢀ52 (c 1.0, CHCl3). 1H
(67%). ½a 2D0
ꢃ
¼ ꢀ1 (c 5.0, CHCl3). 1H NMR (CDCl3, 300 MHz) d,
NMR (CDCl3, 200 MHz) d, ppm: 7.80–7.75 (m, 2H, Ar), 7.50 (s, 1H,
H–C(50)), 7.46–7.34 (m, 6H, Ar), 7.02–6.97 (m, 2H, Ar), 5.60 (s, 1H,
H–C(7)), 2.82 (d, 1H, AB syst., 2J = 17.2 Hz, Ha-C(5)), 2.64 (s, 3H,
H3C–C(3)), 2.40 (d, 1H, AB syst., 2J = 17.2 Hz, Hb-C(5)), 1.24, 0.92
(2s, 6H, H3C–C(6)). 13C NMR (CDCl3, 100.6 MHz) d, ppm: 191.7,
150.0, 148.0, 143.7, 137.4, 129.7, 129.5, 129.3, 128.8, 128.5,
125.7, 124.3, 118.7, 117.7, 61.1, 48.3, 40.0, 27.1, 25.9, 13.4. IR
ppm: 8.18 (s, 1H, H–C(3)), 7.44–7.37 (m, 3H, Ar), 7.31 (s, 1H, H–
C(50)), 6.97–6.92 (m, 2H, Ar), 5.54 (s, 1H, H–C(7)), 5.19 (dd, 1H,
3J = 9.4, 9.2 Hz, H–C(3gluc)), 5.09 (dd, 1H, 3J = 9.8, 9.4 Hz, H–
C(4gluc)), 4.99 (dd, 1H, 3J = 7.9, 9.2 Hz, H–C(2gluc)), 4.87, 4.76 (2d,
AB syst., 2H, 2J = 12.6 Hz, H2C–O–C(1gluc)), 4.63 (d, 1H, 3J = 7.9, H–
C(1gluc)), 4.25 (dd, AB syst., 1H, 2J = 12.4, 3J = 4.5 Hz, Ha-C(6gluc)),
4.12 (dd, AB syst., 1H, 2J = 12.4, 3J = 2.3 Hz, Hb-C(6gluc)), 3.71
(ddd, 1H, 3J = 9.8, 4.5, 2.3 Hz, H–C(5gluc)), 2.79, 2.37 (2d, AB syst.,
2H, 2J = 17.1 Hz, H–C(5)), 2.06, 2.02, 1.99, 1.96 (4s, 12H, AcO-
C(2,3,4,6gluc)), 1.21, 0.85 (2s, 6H, H3C–C(6)). 13C NMR (CDCl3,
75 MHz) d, ppm: 190.8, 170.6, 170.2, 169.4, 169.3, 144.7, 143.0,
138.3, 137.4, 129.7, 129.6, 124.4, 122.4, 120.6, 100.0, 72.6, 72.0,
(KBr) m
max, cmꢀ1: 2970, 1680, 1600, 1555, 1510, 1490, 1040, 765,
695. Anal. Calcd for C24H23N5O: C, 72.52.08; H, 5.83; N, 17.62.
Found: C, 72.15; H, 5.76; N, 17.65. Enantiomeric excess was deter-
mined by HPLC [Pirkle covalent (R,R)-Whelk-O1]: tR[(+)-
8c] = 16.63 min; tR[(ꢀ)-8c] = 19.26 min. Eluent system: hexanes/

738
I. Strakova et al. / Tetrahedron: Asymmetry 22 (2011) 728–739
71.1, 68.2, 62.6, 61.7, 60.8, 47.9, 40.1, 27.1, 25.9, 20.7, 20.6,
20.5 (2C). IR (film)
max, cmꢀ1: 3140, 3075, 2970, 2880, 1755,
1685, 1600, 1555, 1505, 1475, 1435, 1375, 1230, 1045, 970, 905.
HRMS (TOF-ESI) calcd for [C32H37N5O11+H]+ 668.2568; found
668.2581.
75 MHz) d, ppm: 198.8, 146.1, 143.0, 138.3, 137.4, 129.7 (2C),
m
124.4, 121.6, 120.6, 112.5, 105.0, 79.8, 72.9, 65.5, 60.9, 50.0, 47.9,
40.1, 37.1, 27.1, 26.6, 26.2, 25.9. IR (film) m
max, cmꢀ1: 3125, 2985,
1675, 1505, 1355, 1170, 1095, 1035, 990, 960. HRMS (TOF-ESI)
calcd for [C26H31N5O7S+H]+ 558.2022; found 558.2047.
X-ray powder analysis of a polycrystalline sample of the race-
mic compound 4 was carried out on an X-ray powder diffractome-
ter Rigaku Ultima IV. All measurements of single crystal X-ray
analysis were made on a Bruker-Nonius KappaCCD imaging plate
area detector with graphite monochromated MoK radiation
(k = 0.71073 Å). The structures were solved by direct methods
with SIR-94 and SIR-97 and refined by full matrix least squares
with SHELXL-97 and MAXUS software package. Crystal data are
follows:
4.23. b-Glucopyranose-(7S)-THI conjugate (ꢀ)-8f
Product (ꢀ)-8f was prepared according to the general procedure
II of triazole formation by using (ꢀ)-4a instead of (+)-4a. Yield 64%.
½
a 2D0
ꢃ
¼ ꢀ42 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz) d, ppm: 8.17
(s, 1H, H–C(3)), 7.54–7.38 (m, 3H, Ar), 7.30 (s, 1H, H–C(50)), 6.97–
6.94 (m, 2H, Ar), 5.55 (s, 1H, H–C(7)), 5.18 (t, 1H, 3J = 9.4 Hz, H–
C(3gluc)), 5.07 (dd, 1H, 3J = 9.8, 9.4 Hz, H–C(4gluc)), 4.98 (dd, 1H,
3J = 7.9, 9.4 Hz, H–C(2gluc)), 4.87, 4.77 (2d, AB syst., 2H,
2J = 12.8 Hz, H2C–O–C(1gluc)), 4.60 (d, 1H, 3J = 7.9, H–C(1gluc)), 4.29
(dd, AB syst., 1H, 2J = 12.4, 3J = 4.5 Hz, Ha-C(6gluc)), 4.10 (dd, AB
syst., 1H, 2J = 12.4, 3J = 2.3 Hz, Hb-C(6gluc)), 3.71 (ddd, 1H, 3J = 9.8,
4.5, 2.3 Hz, H–C(5gluc)), 2.80, 2.34 (2d, AB syst., 2H, 2J = 17.3 Hz,
H–C(5)), 2.06, 2.02, 1.98, 1.89 (4s, 12H, AcO-C(2,3,4,6gluc)), 1.22,
0.85 (2s, 6H, H3C–C(6)). 13C NMR (CDCl3, 75 MHz, +55 °C) d, ppm:
190.4, 170.4, 170.0, 169.2, 169.0, 144.9, 143.3, 138.3, 137.8,
129.7, 129.6, 124.6, 122.3, 120.8, 100.2, 72.9, 72.3, 71.5, 68.7,
62.7, 62.0, 61.1, 48.2, 40.1, 27.2, 25.9, 20.6, 20.5, 20.4 (2C). IR (film)
4.26. Homochiral compound (ꢀ)-3a
(CCDC-766065): C15H17N3O, FW = 255.32, orthorhombic,
P212121 (No. 19), colorless prism, a = 8.4365(2)Å, b = 12.0165(4)Å,
c = 13.2480(4)Å, V = 1343.05(7)Å3, T = 173 K, Z = 4, Dcalcd = 1.263
g/cm3,
l
= 0.082 mmꢀ1, R = 0.0468.
4.27. Racemic compound ( )-3
m
max, cmꢀ1: 3135, 2970, 2880, 1760, 1685, 1600, 1555, 1505, 1475,
(CCDC-766066): C15H17N3O, FW = 255.32, monoclinic, P21/n
(No. 14), colorless prism, a = 12.3477(9)Å, b = 8.4775(7)Å,
c = 12.9711(9)Å, b = 106.580(4)°, V = 1301.3(2)Å3, T = 223 K, Z = 4,
1435, 1375, 1225, 1040, 970, 905. HRMS (TOF-ESI) calcd for
[C32H37N5O11+H]+ 668.2568; found 668.2595.
Dcalcd = 1.303 g/cm3,
l
= 0.084 mmꢀ1, R = 0.0643.
4.24.
a-Glucofuranose-(7S)-THI conjugate (ꢀ)-8g
4.28. Homochiral compound (ꢀ)-4a
Product (ꢀ)-8g was prepared according to the general proce-
dure II of triazole formation by using glucose derivative 10 instead
(CCDC-766067): C15H17N3O, FW = 281.32, monoclinic, P21 (No.
of 9 and (ꢀ)-4a instead of (+)-4a. Yield 93%. ½a D20
¼ ꢀ41 (c 2.5,
ꢃ
4),
c = 19.3520(9)Å, b = 99.365(2)°, V = 1449.6(1)Å3, T = 173 K, Z = 4,
Dcalcd = 1.289 g/cm3, = 0.090 mmꢀ1, R = 0.0555.
colorless
prism,
a = 6.5261(2)Å,
b = 11.6327(5)Å,
CHCl3). 1H NMR (CDCl3, 300 MHz) d, ppm: 8.19 (s, 1H, H–C(3)),
7.41–7.37 (m, 4H, H–C(50), Ar), 7.01–6.96 (m, 2H, Ar), 5.86 (d, 1H,
3J = 3.7 Hz, H–C(1gluc)), 5.60 (s, 1H, H–C(7)), 4.78, 4.69 (2d, 2H, AB
syst., 2H, 2J = 12.8 Hz, H2C–O–C(3gluc)), 4.56 (d, 1H, 3J = 3.7 Hz, H–
C(2gluc)), 4.23 (dt, 1H, 3J = 8.1 Hz, 3J = 5.5 Hz, H–C(5gluc)), 4.08–
4.03 (m, 2H, H–C(4gluc), H–C(6agluc)), 3.98 (dd, 1H, AB syst.,
2J = 8.7 Hz, 3J = 5.5 Hz, H–C(6bgluc)), 3.94 (d, 1H, 3J = 3.2 Hz, H–
C(3gluc)), 2.80, 2.44 (2d, AB syst., 2H, 2J = 17.2 Hz, H–C(5)), 1.49,
1.36, 1.31, 1.26 (4s, 12H, H3C–C–O–C(1gluc and 5gluc)), 1.22, 0.87
(2s, 6H, H3C–C(6)), 13C NMR (CDCl3, 75 MHz) d, ppm: 190.9,
145.2, 143.0, 138.3, 137.4, 129.5, 128.8, 128.4, 128.4, 124.3,
121.9, 120.5, 111.8, 109.1, 105.1, 82.4, 81.7, 80.9, 78.9, 72.1, 67.3,
l
4.29. Compound (ꢀ)-6
(CCDC-764782): C25H29N3O4, FW = 435.52, orthorhombic,
P212121 (No. 19), colorless prism, a = 6.3197(1)Å, b = 11.9939(2)Å,
c = 29.4468(6)Å, V = 2232.00(7)Å3, T = 173 K, Z = 4, Dcalcd = 1.296 g/
cm3,
l
= 0.080 mmꢀ1, R = 0.0440.
4.30. Compound (ꢀ)-7
63.7, 60.9, 48.1, 40.1, 27.1, 26.8, 26.1, 25.6, 25.3. IR (film) mmax
,
cmꢀ1: 3130, 3095, 2980, 2940, 2905, 2880, 1680, 1595, 1555,
1504, 1375, 1220, 1075, 1040, 1025. HRMS (TOF-ESI) calcd for
[C30H37N5O7+H]+ 580.2771; found 580.2751.
(CCDC-764781): C23H22BrN3O, FW = 436.35, orthorhombic,
P212121 (No. 19), colorless plate, a = 6.0806(2)Å, b = 16.4672(5)Å,
c = 20.2648(7)Å, V = 2029.1(1)Å3, T = 173 K, Z = 4, Dcalcd = 1.428 g/
cm3,
l
= 2.044 mmꢀ1, R = 0.0671.
For further details, see crystallographic data for these com-
pounds deposited with the Cambridge Crystallographic Data Cen-
tre as Supplementary publications of corresponding CCDC
numbers. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.
4.25. C-Nucleoside-like conjugate (+)-8h
Product (+)-8h was prepared according to the general proce-
dure II of triazole formation by using monosaccharide 11 instead
of 9 and (ꢀ)-4a instead of (+)-4a. Yield 78%. ½a D20
¼ þ27 (c 1.0,
ꢃ
CHCl3). 1H NMR (CDCl3, 300 MHz) d, ppm: 8.17 (s, 1H, H–C(3)),
7.44–7.39 (m, 3H, Ar), 7.33 (s, 1H, H–C(50)), 6.98–6.94 (m, 2H,
Ar), 5.94 (d, 1H, 3J = 3.6 Hz, H–C(1sug)), 5.58 (s, 1H, H–C(7)), 4.96
(d, 1H, 3J = 10.5 Hz, H–C(4sug)), 4.85 (dd, 1H, 3J = 4.1, 3.6 Hz, H–
C(2sug)), 4.51 (dd, AB syst., 1H, 2J = 10.2, 3J = 9.9 Hz, CH2–C(3sug)),
4.40 dd, AB syst., 1H, 2J = 10.2, 3J = 5.5 Hz, CH2–C(3sug)), 2.98 (s,
3H, H3CSO2-CH2–C(3sug)), 2.77 (d, AB syst., 1H, 2J = 17.3 Hz, Ha-
C(5)), 2.66 (dddd, 1H, 3J = 10.5, 9.9, 5.5, 4.1 Hz, H–C(3sug)), 2.39
(d, AB syst., 1H, 2J = 17.3 Hz, Hb-C(5)), 1.55, 1.36 (2s, 6H, H3C–C–
O–C(1sug)), 1.21, 0.86 (2s, 6H, H3C–C(6)). 13C NMR (CDCl3,
Acknowledgments
This work has been supported by the European Social Fund
within the project «Support for the implementation of doctoral stud-
ies at Riga Technical University», by the Latvian Council of Science
Grant 09.1557, and by Latvian-Belarus joint Grant L7630. Authors
thank JSC ‘Olainfarm’ for kind donation of diacetone-D-glucose
and for scholarship to J.L. Analytical support by Syntagon Baltic
Ltd and Bapeks Ltd is kindly acknowledged.

I. Strakova et al. / Tetrahedron: Asymmetry 22 (2011) 728–739
19. Kim, J.; Song, H.; Park, S. B. Eur. J. Org. Chem. 2010, 3815–3822.
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