Desymmetrization of 1,4-pentadien-3-ol by the asymmetric 1,3-dipolar cycloaddition of azomethine imines

Article abstract of DOI:10.1002/chem.201302889

Desymmetrization of the divinyl carbinol 1,4-pentadien-3-ol was accomplished by the asymmetric 1,3-dipolar cycloaddition of azomethine imines based on a magnesium-mediated, multinucleating chiral reaction system utilizing diisopropyl (R,R)-tartrate as the chiral auxiliary. The corresponding optically active trans-pyrazolidines, each with three contiguous stereogenic centers, were obtained with excellent regio-, diastereo-, and enantioselectivity, with results as high as 99 %ee. This reaction was shown to be applicable to both aryl- and alkyl-substituted azomethine imines. The use of a catalytic amount of diisopropyl (R,R)-tartrate was also effective when accompanied by the addition of MgBr₂.

Full text of DOI:10.1002/chem.201302889

DOI: 10.1002/chem.201302889
Full Paper
&
Stereoselective Reactions
Desymmetrization of 1,4-Pentadien-3-ol by the Asymmetric 1,3-
Dipolar Cycloaddition of Azomethine Imines
Mari Yoshida, Naotaro Sassa, Tomomitsu Kato, Shuhei Fujinami, Takahiro Soeta,
Katsuhiko Inomata, and Yutaka Ukaji*[a]
Dedicated to Professor Teruaki Mukaiyama on the 40th anniversary of the Mukaiyama aldol reaction
Abstract: Desymmetrization of the divinyl carbinol 1,4-pen-
tadien-3-ol was accomplished by the asymmetric 1,3-dipolar
cycloaddition of azomethine imines based on a magnesium-
mediated, multinucleating chiral reaction system utilizing di-
isopropyl (R,R)-tartrate as the chiral auxiliary. The corre-
sponding optically active trans-pyrazolidines, each with
three contiguous stereogenic centers, were obtained with
excellent regio-, diastereo-, and enantioselectivity, with re-
sults as high as 99% ee. This reaction was shown to be appli-
cable to both aryl- and alkyl-substituted azomethine imines.
The use of a catalytic amount of diisopropyl (R,R)-tartrate
was also effective when accompanied by the addition of
MgBr2.
reported.[5] Recently, we developed the asymmetric 1,3-dipolar
cycloaddition reaction of azomethine imines to allylic and ho-
moallylic alcohols, utilizing either stoichiometric or catalytic
amounts of diisopropyl (R,R)-tartrate [(R,R)-DIPT] to furnish
trans-pyrazolidines with high regio-, diastereo-, and enantiose-
lectivity.[6] To construct multiple chiral centers through our 1,3-
dipolar cycloaddition of azomethine imines, enantiotopic dif-
ferentiation of the two vinyl groups of the prochiral divinyl car-
binols is required, which is a challenging process. Herein, we
describe the desymmetrization of a divinyl carbinol 1,4-penta-
dien-3-ol by the asymmetric 1,3-dipolar cycloaddition of azo-
methine imines, utilizing (R,R)-DIPT as the chiral auxiliary.
Introduction
The desymmetrization of achiral or meso compounds has
proved to be a powerful technique in asymmetric synthesis be-
cause it allows the formation of multiple stereogenic centers in
one symmetry-breaking operation. This strategy has therefore
attracted considerable attention with regard to the synthesis
of optically active natural products or biologically active sub-
stances.[1] Group-selective desymmetrization of divinyl carbi-
nols and their derivatives is one of the most promising strat-
egies for the production of new optically active alcohol deriva-
tives containing an unreacted olefinic moiety, which could be
a useful functional group for further transformations. The Kat-
suki–Sharpless epoxidation of 1,4-pentadien-3-ols results in de-
symmetrization to yield epoxy alcohols, which are versatile
synthetic intermediates for the preparation of oxygen-function-
alized biologically active compounds.[2,3] However, techniques
that allow the desymmetrization of divinyl carbinols as
a means of forming multiple stereocenters along with the for-
mation of new CÀC bonds are quite limited.
Results and Discussion
We initially investigated the 1,3-dipolar cycloaddition reaction
of 1-benzylidene-3-oxopyrazolidin-1-ium-2-ide (2a) with 1,4-
pentadien-3-ol (1), based on a mag-
nesium-mediated, multinucleating
chiral reaction system of our own
design, as depicted in Figure 1.[6–8]
Pyrazolidines are biologically active[4] and are versatile syn-
thetic intermediates for the synthesis of nitrogen-containing
chemicals; various enatioselective syntheses of pyrazolidines
by asymmetric 1,3-dipolar cycloaddition reactions have been
In this process,
a mixture of
1
(1.0 equiv) and (R,R)-DIPT
(1.0 equiv) is treated with MeMgBr
(3.0 equiv) in MeCN, followed by
the addition of azomethine imine
2a (1.0 equiv), after which the re-
action mixture is held at 808C for
Figure 1. Intended asymmet-
ric 1,3-dipolar cycloaddition of
an azomethine imine to 1,4-
pentadien-3-ol.
[a] M. Yoshida, N. Sassa, T. Kato, Dr. S. Fujinami, Dr. T. Soeta,
Prof. Dr. K. Inomata, Prof. Dr. Y. Ukaji
Division of Material Sciences
Graduate School of Natural Science and Technology
Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192 (Japan)
Fax: (+81)76-264-5742
two days. It was gratifying to observe that the desymmetriza-
tion proceeded under these conditions to give only one diaste-
reomer of the corresponding pyrazolidine 3a with excellent
enantioselectivity (Table 1, entry 1).[9] The use of the alternate
solvent EtCN further enhanced the reaction yield (Table 1,
E-mail: ukaji@staff.kanazawa-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201302889.
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Table 1. Desymmetrization of 1,4-pentadien-3-ol (1) by the stoichiometric
asymmetric 1,3-dipolar cycloaddition of azomethine imines 2.
Table 2. Desymmetrization of 1,4-pentadien-3-ol (1) by the catalytic
asymmetric 1,3-dipolar cycloaddition of azomethine imines 2.
Entry
R’MgX
n
R
t
[d]
Yield
[%]
ee
[%][a]
Entry
R’MgX
R
t
[d]
Yield
[%]
ee
[%][a]
1[b]
2
3
4
5
6
7
8
MeMgBr
MeMgBr
nBuMgCl
nBuMgCl
nBuMgCl
nBuMgCl
nBuMgCl
nBuMgCl
nBuMgCl
1.0
1.0
1.0
1.0
1.0
1.0
3.0
1.0
1.0
Ph
a
2
2
2
2
2
2
2
3
3
50
57
93
98
98
99
99
99
99
63
97
99
98
1
2
3[b]
4
5
6
7[d]
8
nBuMgCl
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
Ph
a
5
2
2
5.5
5.5
2
2
2
30
68
64
40
84
95
91
93
96
79
85
95
98
p-MeOC6H4
p-ClC6H4
nC5H11
b
c
d
p-MeOC6H4
p-ClC6H4
nC5H11
b
c
d
97
60
14[c]
33[c]
80
13[c]
10[c]
69
cC6H11
tBu
e
f
cC6H11
tBu
e
f
9
56
9
5.5
75
[a] Enantioselectivities were determined by HPLC analysis (Daicel CHIRAL-
CEL OD-H). [b] The solvent was MeCN instead of EtCN. [c] Byproduct 4,
produced through rearrangement of 2d to form an enamine intermedi-
ate, was obtained in 33 (entry 6) and 27% (entry 7) yields.
[a] Enantioselectivities were determined by HPLC analysis (Daicel CHIRAL-
CEL OD-H). [b] MgBr2 was not added in step 1. [c] Byproduct 4 was ob-
tained in 24 (entry 6) and 27% (entry 7) yields. [d] Compound
1 (2.2 equiv) and MeMgBr (2.6 equiv) were employed.
entry 2). The halogen in the Grignard reagent also had an
effect on the reaction;[10] when nBuMgCl was used, the yield of
the cycloadduct 3a was significantly improved (Table 1,
entry 3).
paring the enantioselectivity shown in Table 2, entry 2 with the
result obtained in the absence of MgBr2 (Table 2, entry 3).
The catalytic asymmetric cycloaddition reactions of
a number of other azomethine imines 2b–2 f to the divinyl
carbinol 1 were attempted in EtCN at 808C. The aryl-substitut-
ed azomethine imines 2b and 2c once again resulted in excel-
lent enantioselectivity, even when applied in this modified cat-
alytic process (Table 2, entries 4 and 5). The cycloaddition of
pentyl-substituted azomethine imine 2d proceeded quite
slowly to give the desired cycloadduct 3d in low yield in addi-
tion to the dimerized byproduct 4 (Table 2, entries 6 and 7).
The cycloaddition of cyclohexyl- and tert-butyl-substituted azo-
methine imines 2e and 2 f still afforded the corresponding pyr-
azolidines in good chemical yields with excellent enantioselec-
tivity (Table 2, entries 8 and 9).
The desymmetrization of 1,4-pentadien-3-ol (1) by the asym-
metric cycloaddition of several azomethine imines, 2b–2 f, was
subsequently investigated in EtCN at 808C. The aryl-substitut-
ed azomethine imines 2b and 2c afforded the corresponding
cycloadducts 3b and 3c with excellent enantioselectivity and
complete regio- and diastereoselectivity in each case (Table 1,
entries 4 and 5). The cycloaddition of the pentyl-substituted
azomethine imine 2d proceeded in an enantioselective
manner, although
a
significant
quantity of the byproduct
4
(Figure 2) was obtained (Table 1,
entry 6). The use of an excess of
carbinol 1 slightly improved the re-
action yield (Table 1, entry 7). The
cycloaddition of the cyclohexyl-
and tert-butyl-substituted azome-
The absolute configuration of the enantiomerically enriched
3a (98% ee) was determined by treating this product with
(1S)-camphanic chloride and Et3N in the presence of a catalytic
amount of 4-(N,N-dimethylamino)pyridine (DMAP) in CH2Cl2 to
generate the corresponding ester 5 [99%; Eq. (1)]. Recrystalliza-
tion gave diastereomerically pure compound 5 and the abso-
lute stereochemistry at each of its three chiral centers was de-
termined to be R,R,R by X-ray crystallographic analysis of
a single crystal (Figure 3). From this result, the absolute config-
uration of 3a was confirmed to be 5R,7R,1’R. The absolute con-
figurations tentatively assigned to the other products were
5R,7R,1’R for 3b, 3c, 3e, and 3 f and 5S,7R,1’R for 3d, which
has the same configurational arrangement of substituents at
the 5- and 7-positions as the other products.
Figure 2. Byproduct 4.
thine imines 2e and 2 f also afforded cycloadducts 3e and 3 f
with enantioselectivities of 99 and 98% ee, respectively
(Table 1, entries 8 and 9).
To increase the efficiency of the procedure, we subsequently
employed only a catalytic amount of (R,R)-DIPT as the chiral
auxiliary.[6c] In this revised procedure, 1.5 equivalents of
nBuMgCl and azomethine imine 2a were added successively
to a mixture of 1 (1.1 equiv), (R,R)-DIPT (0.2 equiv), and MgBr2
(1.0 equiv) in EtCN and the reaction mixture was held at 808C
for five days. Although the corresponding pyrazolidine 3a was
obtained with 84% ee, the reaction proceeded quite slowly
and yield was insufficient (Table 2, entry 1). When MeMgBr was
used in place of nBuMgCl, both the enantioselectivity and
chemical yield were increased (Table 2, entry 2). The addition
of the magnesium salt was confirmed to be effective by com-
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the steric hindrance. The diastereoselection between the T3
and T4 states is therefore less effective than that between the
T1 and T2 states, although the exact stereochemistry of the
major product of this reaction has not yet been determined.
The pyrazolidines could be transformed into the 1,3-diamine
derivatives.[11] We have simply demonstrated the reduction of
3a by use of Raney nickel. Although only the double bond
was reduced under an ordinary atmosphere, the NÀN bond
was successfully cleaved to give 8 under a high-pressure hy-
drogen atmosphere. Furthermore, the attractive reductive or
oxidative transformation of 3a was realized. The reduction of
the amide moiety with LiAlH4 afforded a one-of-a-kind tricyclic
Figure 3. X-ray crystal structure of compound 5. Thermal ellipsoids are
drawn at the 50% probability level.
hexahydro-1-oxa-2a1,4a-diazacyclopentapentalene skeleton
9
We have previously reported that the 1,3-dipolar cycloaddi-
tion of 2a to homoallylic alcohols proceeded with excellent
enantioselectivity.[6c] In this study, we also examined the de-
symmetrization of the homoallylic-type dialkenyl carbinol 1,6-
heptadien-4-ol (6). The corresponding cycloadduct 7 was ob-
tained with moderate enantioselectivity and the diastereose-
lectivity was low [Eq. (2)].
in good yield. The use of a large excess of LiAlH4 induced re-
ductive ring opening of the oxazolidine moiety to give a bicy-
clic hydrazine derivative 10. In addition, the hydrazide moiety
in 3a was chemoselectively oxidized by treatment with meta-
chloroperoxybenzoic acid (mCPBA) to furnish a unique N-oxide
11, in which the olefinic moiety had remained intact
(Scheme 1). The novel structures of 9, 10, and 11 might have
potential as, for example, new types of organocatalyst.
Although the precise mechanism by which this reaction pro-
ceeds is not yet clear, we propose the following transition-
state model. In this model, the carbonyl oxygen in 2, rather
than the imine nitrogen, coordinates with the magnesium salt
of DIPT (Figure 4). In the case of the T2 transition state, steric
repulsion between the pro-R vinyl group and the azomethine
imine skeleton disturbs the cycloaddition to the pro-S vinyl
group. As a result, it is more likely that the T1 transition state
actually occurs because in this configuration it is primarily the
pro-R olefin that approaches the azomethine imine group,
giving the R,R,R product. During the reaction of the homoallyl-
ic-type alcohol 6, the extension of the side chains by one
carbon atom compared with the divinyl carbinol 1 makes
these chains more flexible, especially around C4, and reduces
Scheme 1. Transformation of 3a.
Conclusion
An attractive and unique reaction scheme allowing the desym-
metrization of 1,4-pentadien-3-ol by the asymmetric 1,3-dipolar
cycloaddition of azomethine imines has been developed. This
process generates highly enantiomerically pure pyrazolidines
possessing three contiguous stereogenic centers as single dia-
stereomers. The obtained pyrazolidines contain a double bond
and a hydroxyl group on the side chain, both of which might
allow further functionalization. This method would be useful
for the preparation of optically active nitrogen- and oxygen-
containing chemicals.[12]
Experimental Section
General remarks
1H NMR spectroscopy was performed in CDCl3 by using a JEOL ECS
400 NMR (400 MHz) spectrometer. Chemical shifts (d) were deter-
Figure 4. Proposed transition states during the 1,3-dipolar cycloaddition of
an azomethine imine to 1 (T1) and 6 (T3).
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mined relative to TMS (d=0 ppm) as an internal standard. 13C NMR
spectroscopy was performed in CDCl3 on a JEOL ECS 400 NMR
(100 MHz) spectrometer and chemical shifts (d) were determined
relative to CDCl3 (d=77.0 ppm) as an internal standard. IR spectra
were acquired on a JASCO FT/IR-230 spectrometer. Melting points
were determined on a micromelting apparatus (Yanagimoto–Seisa-
kusho) and are uncorrected. The specific optical rotations were re-
corded on a JASCO DIP-370 spectrometer. HPLC was performed by
using a chiral column with a JASCO PU980 plus JASCO UV970
chromatograph. X-ray crystallography was performed on a Rigaku/
MSC Mercury diffractometer with graphite-monochromated MoKa
radiation. Elemental analysis was performed on a Yanaco CHN
Corder MT-5 elemental analyzer. Mass spectra were obtained by
using JMS-700 and JMS-T100TD mass spectrometers. All solvents
were distilled prior to use and stored over drying agents. Merck
silica gel 60 PF254 (Art. 7749), Cica silica gel 60N spherical neutral
(37563–84), and JAIGL-SIL (s-043–15) were used for thin-layer chro-
matography (TLC), flash column chromatography, and recycle
HPLC, respectively. The retention factors (Rf) of various compounds
were determined by TLC.
(5R,7R)-7-[(R)-1-Hydroxyallyl]-5-(4-methoxyphenyl)tetra-
hydropyrazolo[1,2-a]pyrazol-1(5H)-one (3b)
Compound 3b (141 mg, 98%) was obtained as an oil; Rf =0.60
(AcOEt); [a]2D5 = +53 (c=1.4 in EtOH); the ee was determined to be
99% by HPLC (Daicel CHIRALCEL OD-H, hexane/EtOH=10:1,
0.5 mLminÀ1, 254 nm, t=36 (major), 29 min (minor)); 1H NMR
(CDCl3, 400 MHz): d=2.37 (dt, 1H, J=13.3, 9.2 Hz), 2.45 (ddd, 1H,
J=13.3, 7.8, 5.0 Hz), 2.73–2.84 (m, 2H), 2.86–2.99 (m, 1H), 3.33–
3.37 (m, 1H), 3.48–3.53 (m, 1H), 3.81 (s, 3H), 3.88 (ddd, 1H, J=9.2,
8.7, 5.0 Hz), 4.32 (dd, 1H, J=8.7, 7.4 Hz), 5.28 (d, 1H, J=10.5 Hz),
5.45 (d, 1H, J=17.0 Hz), 5.82 (ddd, 1H, J=17.0, 10.5, 7.4 Hz), 6.50
(brs, 1H), 6.89 (d, 2H, J=8.7 Hz), 7.25 ppm (d, 2H, J=8.7 Hz);
13C NMR (CDCl3, 100 MHz): d=36.5, 41.2, 50.2, 55.3, 60.0, 68.2, 75.3,
114.1, 118.8, 128.4, 129.0, 136.2, 159.6, 166.1 ppm; IR (neat): n˜ =
3271, 2838, 1651, 1612, 1514, 1444, 1420, 1359, 1302, 1248, 1176,
1151, 1033, 997, 833, 767 cmÀ1; HRMS (FAB+): m/z calcd for
C16H21N2O3: 289.1552 [M+H]+; found: 289.1555.
(5R,7R)-5-(4-Chlorophenyl)-7-[(R)-1-hydroxyallyl]tetrahydro-
pyrazolo[1,2-a]pyrazol-1(5H)-one (3c)
Compound 3c (144 mg, 97%) was obtained as a solid. Rf =0.65
(AcOEt); [a]2D5 = +58 (c=1.4 in EtOH); the ee was determined to be
99% by HPLC (Daicel CHIRALCEL OD-H, hexane/EtOH=10:1,
0.5 mLminÀ1, 254 nm, t=35 (major), 27 min (minor)); m.p. 123–
1298C (recrystallized from EtOH); 1H NMR (CDCl3, 400 MHz): d=
2.34 (dt, 1H, J=13.3, 9.2 Hz), 2.48 (ddd, 1H, J=13.3, 7.3, 4.6 Hz),
2.75–2.84 (m, 2H), 2.91–3.02 (m, 1H), 3.35–3.40 (m, 1H), 3.52 (dd,
1H, J=9.2, 7.8 Hz), 3.87 (ddd, 1H, J=9.2, 8.7, 4.6 Hz), 4.33 (dd, 1H,
J=8.7, 7.3 Hz), 5.29 (d, 1H, J=10.6 Hz), 5.45 (d, 1H, J=17.4 Hz),
5.81 (ddd, 1H, J=17.4, 10.6, 7.3 Hz), 6.49 (brs, 1H), 7.28 (d, 2H, J=
8.2 Hz), 7.34 ppm (d, 2H, J=8.2 Hz); 13C NMR (CDCl3, 100 MHz): d=
36.4, 41.3, 50.3, 59.8, 67.8, 74.7, 118.7, 128.4, 128.8, 133.9, 135.96,
136.03, 165.7 ppm; IR (KBr): n˜ =3404, 3049, 2977, 2920, 2834, 1657,
1496, 1446, 1421, 1305, 1264, 1234, 1135, 1091, 1028, 937, 849,
731, 711 cmÀ1; elemental analysis calcd (%) for C15H17N2O2Cl: C
61.54, H 5.85, N 9.57; found: C 61.28, H 6.01, N 9.38.
Representative procedure for the stoichiometric asymmetric
1,3-dipolar cycloaddition of azomethine imine 2e (Table 1,
entry 8)
Butylmagnesium chloride (1.50 mmol, 1.70 mL of a 0.91m solution
in THF) was added to a solution of 1,4-pentadien-3-ol (1; 42 mg,
0.50 mmol) and (R,R)-DIPT (117 mg, 0.50 mmol) in EtCN (3 mL) at
08C under an argon atmosphere and the mixture was stirred for
1 h. Azomethine imine 2e (90 mg, 0.50 mmol) was added to the
resulting solution and the mixture was stirred for 0.5 h at RT and
then for three days at 808C. The reaction was quenched by the ad-
dition of a saturated aqueous solution of NH4Cl and the mixture
was subsequently extracted with CHCl3. The combined extracts
were dried over Na2SO4 and condensed under reduced pressure.
The residue was purified by column chromatography (SiO2,
hexane/AcOEt=1:1 to 0:1) to give the corresponding pyrazolidine
3e (106 mg, 80%) with a selectivity of 99% ee. In a similar manner,
the pyrazolidines 3a–3d, 3 f, and 7 were prepared from azome-
thine imines 2a–2d and 2 f.
(5S,7R)-7-[(R)-1-Hydroxyallyl]-5-pentyltetrahydropyrazolo-
[1,2-a]pyrazol-1(5H)-one (3d)
Compound 3d (33 mg, 33%) was obtained as an oil. Rf =0.60
(AcOEt); [a]2D5 = +36 (c=0.3 in EtOH); the ee was determined to be
97% by HPLC (Daicel CHIRALCEL OD-H, hexane/EtOH=20:1,
0.5 mLminÀ1, 254 nm, t=34 (major), 24 min (minor)); 1H NMR
(CDCl3, 400 MHz): d=0.89 (t, 3H, J=6.4 Hz), 1.28–1.36 (m, 7H),
1.50–1.60 (m, 1H), 2.03 (ddd, 1H, J=12.8, 9.6, 9.2 Hz), 2.19 (ddd,
1H, J=12.8, 7.3, 5.0 Hz), 2.44–2.51 (m, 1H), 2.72–2.82 (m, 2H),
2.92–3.04 (m, 1H), 3.53–3.59 (m, 1H), 3.65 (ddd, 1H, J=9.2, 8.7,
5.0 Hz), 4.22 (dd, 1H, J=8.7, 7.3 Hz), 5.28 (d, 1H, J=10.6 Hz), 5.42
(d, 1H, J=17.4 Hz), 5.80 (ddd, 1H, J=17.4, 10.6, 7.3 Hz), 6.67 ppm
(brs, 1H); 13C NMR (CDCl3, 100 MHz): d=13.9, 22.4, 25.7, 31.8, 32.0,
36.6, 38.0, 51.5, 59.7, 65.0, 75.0, 118.5, 136.3, 165.1 ppm; IR (neat):
n˜ =3431, 2980, 2931, 1741, 1660, 1453, 1376, 1263, 1131, 1105,
1031, 701 cmÀ1; HRMS (FAB+): m/z calcd for C14H25N2O2: 253.1916
[M+H]+; found: 253.1920.
(5R,7R)-7-[(R)-1-Hydroxyallyl]-5-phenyltetrahydropyrazolo-
[1,2-a]pyrazol-1(5H)-one (3a)
Compound 3a (120 mg, 93%) was obtained as a solid. Rf =0.65
(AcOEt); [a]2D5 = +55 (c=1.2 in EtOH); the ee was determined to be
99% by HPLC (Daicel CHIRALCEL OD-H, hexane/EtOH=10:1,
0.5 mLminÀ1, 254 nm, t=33 (major), 25 min (minor)); m.p. 76–778C
(recrystallized from EtOH); 1H NMR (CDCl3, 400 MHz): d=2.40 (dt,
1H, J=13.3, 9.6 Hz), 2.49 (ddd, 1H, J=13.3, 7.8, 5.0 Hz), 2.74–2.86
(m, 2H), 2.91–3.01 (m, 1H), 3.38 (dd, 1H, J=9.2, 7.8 Hz), 3.55 (dd,
1H, J=9.2, 6.4 Hz), 3.89 (ddd, 1H, J=9.6, 8.7, 5.0 Hz), 4.31–4.36 (m,
1H), 5.29 (d, 1H, J=10.5 Hz), 5.46 (d, 1H, J=17.0 Hz), 5.82 (ddd,
1H, J=17.0, 10.5, 7.3 Hz), 6.54 (brs, 1H), 7.31–7.39 ppm (m, 5H);
13C NMR (CDCl3, 100 MHz): d=36.4, 41.2, 50.3, 59.8, 68.5, 75.0,
118.7, 127.1, 128.2, 128.7, 136.1, 137.3, 165.9 ppm; IR (KBr): n˜ =
3189, 3063, 3033, 2978, 2931, 2865, 1649, 1455, 1421, 1366, 1339,
1315, 1146, 1067, 1001, 929, 760, 700 cmÀ1; elemental analysis
calcd (%) for C15H18N2O2: C 69.74, H 7.02, N 10.85; found: C 69.75,
H 7.11, N 10.79.
(5R*,6R*,7R*)-6-Butyl-7-(3-oxopyrazolidine-1-yl)-5-
pentyltetrahydropyrazolo[1,2-a]pyrazol-1(5H)-one (4)
Rf =0.30 (AcOEt); m.p. 153–1548C (recrystallized from AcOEt);
1H NMR (CDCl3, 400 MHz): d=0.88–0.92 (m, 6H), 1.24–1.43 (m,
11H), 1.51–1.69 (m, 3H), 2.05–2.11 (m, 1H), 2.36–2.52 (m, 3H),
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2.63–2.73 (m, 2H), 3.05–3.14 (m, 1H), 3.56 (dt, 1H, J=11.0, 7.8 Hz),
3.64–3.76 (m, 2H), 4.48 (d, 1H, J=5.0 Hz), 7.80 ppm (brs, 1H);
13C NMR (CDCl3, 100 MHz): d=13.9, 14.0, 22.4, 22.8, 25.7, 29.4, 30.2,
31.0, 31.1, 31.8, 32.2, 47.9, 49.7, 50.8, 72.5, 81.0, 174.1, 175.6 ppm;
IR (KBr): n˜ =3154, 3070, 2954, 2930, 2898, 2858, 1682, 1471, 1420,
1344, 1313, 1289, 1273, 1179, 1095, 1081, 966, 767, 663 cmÀ1; ele-
mental analysis calcd (%) for C18H32N4O2: C 64.24, H 9.60, N 16.65;
found: C 63.94, H 9.66, N 16.49; crystal data: C18H32N4O2; FW =
336.48; monoclinic; P21/n; a=10.0073(8), b=8.1555(6), c=
(m, 3H), 2.87 (td, 1H, J=10.1, 9.6 Hz), 3.68–3.75 (m, 1H), 3.75–3.83
(m, 1H), 3.98 (brs, 1H), 4.16–4.23 (m, 1H), 5.00–5.04 (m, 1H), 5.12
(d, 1H, J=10.1 Hz), 5.13 (d, 1H, J=17.0 Hz), 5.87 (ddt, 1H, J=17.0,
10.1, 7.3 Hz), 7.13–7.39 ppm (m, 5H); 13C NMR (CDCl3, 100 MHz):
d=36.1, 40.9, 42.6, 44.4, 48.9, 51.0, 67.3, 68.9, 117.7, 127.5, 128.3,
128.8, 134.7, 137.3, 166.1 ppm; IR (KBr): n˜ =3387, 3069, 2978, 2924,
2845, 1662, 1495, 1370, 1342, 1305, 1146, 1072, 1034, 996, 915,
755, 703 cmÀ1; HRMS (FAB+): m/z calcd for C17H23N2O2: 287.1760
[M+H]+; found: 287.1756.
23.033(2) ꢁ; V=1845.6(3) ꢁ3; b=100.960(2)8; Z=4; 1calcd
=
Minor diastereomer: Rf =0.60 (AcOEt); [a]2D5 = +13 (c=0.13 in
1.211 gcmÀ3; R=0.037 (Rw =0.046) for 2936 reflections with I>
3.00s(I) and 217 variable parameters. CCDC-951615 (4) contains
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
EtOH); the ee was determined to be 68% by HPLC (Daicel CHIRAL-
CEL OD-H, hexane/EtOH=10:1, 0.5 mLminÀ1
, 254 nm, t= 27
(major enantiomer of the minor diastereomer), 20 min (minor
1
enantiomer); H NMR (CDCl3, 400 MHz): d=1.74 (ddd, 1H, J=13.7,
10.1, 4.6 Hz), 1.90 (ddd, 1H, J=13.7, 10.1, 3.2 Hz), 2.22–2.37 (m,
3H), 2.39–2.50 (m, 2H), 2.66 (ddd, 1H, J=12.8, 8.7, 6.0 Hz), 3.05 (q,
1H, J=10.1 Hz), 3.16 (td, 1H, J=10.1, 3.2 Hz), 3.85–3.94 (m, 2H),
4.31–4.40 (m, 1H), 4.46 (brs, 1H), 5.09 (d, 1H, J=10.1, Hz), 5.11 (d,
1H, J=17.0 Hz), 5.89 (ddt, 1H, J=17.0, 10.1, 7.4 Hz), 7.21–7.28 (m,
2H), 7.32–7.40 ppm (m, 3H); 13C NMR (CDCl3, 100 MHz): d=34.8,
41.6, 42.9, 43.0, 46.2, 50.4, 66.1, 67.7, 117.1, 127.8, 128.3, 128.9,
135.1, 137.1, 169.6 ppm; IR (neat): n˜ =3385, 3068, 2962, 2921, 2849,
1663, 1604, 1495, 1418, 1368, 1302, 1261, 1141, 1087, 1031, 915,
802, 756, 703 cmÀ1; HRMS (FAB+): m/z calcd for C17H23N2O2:
287.1760 [M+H]+; found: 287.1757.
(5R,7R)-5-Cyclohexyl-7-[(R)-1-hydroxyallyl]tetrahydro-
pyrazolo[1,2-a]pyrazol-1(5H)-one (3e)
Compound 3e (106 mg, 80%) was obtained as an oil. Rf =0.65
(AcOEt); [a]2D5 = +16 (c=1.1 in EtOH); the ee was determined to be
99% by HPLC (Daicel CHIRALCEL OD-H, hexane/EtOH=20:1,
0.5 mLminÀ1, 254 nm, t=37 (major), 28 min (minor)); 1H NMR
(CDCl3, 400 MHz): d=0.88–1.02 (m, 2H), 1.08–1.25 (m, 3H), 1.36–
1.43 (m, 1H), 1.66–1.77 (m, 5H), 2.06–2.11 (m, 2H), 2.35 (dd, 1H,
J=8.2, 6.9 Hz), 2.70–2.82 (m, 2H), 2.92–2.99 (m, 1H), 3.53–3.62 (m,
2H), 4.23 (dd, 1H, J=8.7, 6.9 Hz), 5.26 (d, 1H, J=10.1 Hz), 5.42 (d,
1H, J=17.0 Hz), 5.80 (ddd, 1H, J=17.0, 10.1, 6.9 Hz), 6.82 ppm
(brs, 1H); 13C NMR (CDCl3, 100 MHz): d=25.7, 25.8, 26.1, 28.6, 30.0,
35.3, 36.5, 40.5, 53.3, 59.5, 69.8, 74.2, 118.2, 136.1, 164.3 ppm; IR
(neat): n˜ =3258, 2925, 2852, 1658, 1449, 1421, 1353, 1297, 1285,
1158, 1049, 997, 929, 894, 714 cmÀ1; HRMS (FAB+): m/z calcd for
C15H25N2O2: 265.1916 [M+H]+; found: 265.1911.
Representative procedure for the catalytic asymmetric 1,3-
dipolar cycloaddition of azomethine imine 2e (Table 2,
entry 8)
1,2-Dibromoethane (144 mg, 0.50 mmol) was added to a suspen-
sion of Mg turnings (12 mg, 0.50 mmol) in THF (3 mL) at RT under
an argon atmosphere and the mixture was stirred for 3 h until all
of the Mg turnings were converted into MgBr2. A solution of 1,4-
pentadien-3-ol (1; 47 mg, 0.55 mmol) and (R,R)-DIPT (24 mg,
0.10 mmol) in EtCN (3 mL) was added to the solution. After the ad-
dition of methylmagnesium bromide (0.75 mmol, 0.76 mL of
a 0.99m solution in THF) at 08C, the mixture was stirred for 1 h.
Azomethine imine 2e (90 mg, 0.50 mmol) was added to the result-
ing solution and the mixture was stirred for 0.5 h at RT and then
for two days at 808C. The reaction was quenched by the addition
of a saturated aqueous solution of NH4Cl and the mixture was sub-
sequently extracted with CHCl3. The combined extracts were dried
over Na2SO4 and condensed under reduced pressure. The residue
was purified by column chromatography (SiO2, hexane/AcOEt=1:1
to 0:1) to give the corresponding pyrazolidine 3e (91 mg, 69%)
with a selectivity of 95% ee.
(5R,7R)-5-tert-Butyl-7-[(R)-1-hydroxyallyl]tetrahydropyrazolo-
[1,2-a]pyrazol-1(5H)-one (3 f)
Compound 3 f (67 mg, 56%) was obtained as an oil. Rf =0.75
(AcOEt); [a]2D5 =À13 (c=0.9 in EtOH); the ee was determined to be
99% by HPLC (Daicel CHIRALCEL OD-H, hexane/EtOH=20:1,
0.5 mLminÀ1, 254 nm, t=34 (major), 27 min (minor)); 1H NMR
(CDCl3, 400 MHz): d=0.90 (s, 9H), 1.94–2.06 (m, 2H), 2.36 (dd, 1H,
J=8.7, 6.9 Hz), 2.72 (dd, 1H, J=15.1, 7.8 Hz), 2.83 (dt, 1H, J=13.3,
8.2 Hz), 2.93–3.02 (m, 1H), 3.45 (td, 1H, J=8.7, 8.2 Hz), 3.60 (t, 1H,
J=8.7 Hz), 4.23 (dd, 1H, J=8.7, 6.9 Hz), 5.27 (d, 1H, J=10.5 Hz),
5.44 (d, 1H, J=16.9 Hz), 5.82 (ddd, 1H, J=16.9, 10.1, 6.9 Hz),
6.96 ppm (brs, 1H); 13C NMR (CDCl3, 100 MHz): d=26.3, 26.9, 33.2,
33.9, 36.7, 55.0, 60.1, 73.7, 118.1, 135.9, 163.9 ppm; IR (neat): n˜ =
3237, 2958, 2870, 1657, 1452, 1422, 1299, 1252, 1152, 1132, 1052,
994, 929 cmÀ1; HRMS (FAB+): m/z calcd for C13H23N2O2: 239.1760
[M+H]+; found: 239.1754.
(R)-1-{(1R,3R)-7-Oxo-3-phenylhexahydropyrazolo[1,2-a]pyra-
zol-1-yl}allyl (1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo-
[2.2.1]heptane-1-carboxylate (5)
7-(2-Hydroxy-4-penten-1-yl)-5-phenyltetrahydropyrazolo-
A solution of the pyrazolidine 3a (85 mg, 0.33 mmol, 98% ee) in
CH2Cl2 (1 mL) was added to a mixture of (S)-camphanic chloride
(217 mg, 1.00 mmol), triethylamine (0.14 mL, 1.00 mmol), and 4-(di-
methylamino)pyridine (16 mg) in CH2Cl2 (1 mL) at RT under a nitro-
gen atmosphere and the mixture was stirred for three days at RT.
The solvent was evaporated and the residue was partitioned be-
tween AcOEt and water, followed by extraction with AcOEt. The
combined extracts were dried over Na2SO4. After evaporation of
the solvent, the residue was purified by TLC on SiO2 (hexane/
AcOEt=1:1) to afford 5 (143 mg, 99%) as a solid. Diastereomerical-
ly pure 5 was obtained by recrystallization (Et2O/hexane). Rf =0.40
[1,2-a]pyrazol-1(5H)-one (7)
A 16:9 mixture of diastereomers 7 (40 mg, 28%) was obtained as
an oil. The mixture was further separated by recycle HPLC (AcOEt/
EtOH=15:1) to give the major and minor products.
Major diastereomer: Rf =0.50 (AcOEt); [a]2D5 = +41 (c=0.22 in
EtOH); the ee was determined to be 78% by HPLC (Daicel CHIRAL-
PAK IA, hexane/EtOH=10:1, 0.5 mLminÀ1, 254 nm, t=35 (major
enantiomer of the major diastereomer), 27 min (minor enantio-
1
mer)); H NMR (CDCl3, 400 MHz): d=1.77 (dd, 1H, J=14.6, 6.9 Hz),
2.25–2.35 (m, 3H), 2.42 (ddd, 1H, J=12.8, 6.4, 3.7 Hz), 2.52–2.68
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(hexane/AcOEt=1:1); [a]D25 = +49 (c=1.43 in CHCl3); m.p. 164–
1658C (recrystallized from Et2O/hexane); H NMR (CDCl3, 400 MHz):
(2R,2aR,4R)-4-Phenyl-2-vinylhexahydro-2H-1-oxa-2a1,4a-di-
azacyclopenta[cd]pentalene (9)
1
d=0.95 (s, 3H), 1.08 (s, 3H), 1.11 (s, 3H), 1.67 (ddd, 1H, J=13.7,
9.6, 4.6 Hz), 1.90–2.02 (m, 1H), 1.92 (ddd, 1H, J=13.3, 10.5, 4.6 Hz),
2.02 (ddd, 1H, J=13.7, 9.2, 4.6 Hz), 2.38–2.53 (m, 3H), 2.60–2.67
(m, 1H), 2.95–3.05 (m, 1H), 3.21–3.27 (m, 1H), 3.77–3.84 (m, 1H),
4.25–4.32 (m, 1H), 5.48 (d, 1H, J=10.5 Hz), 5.57 (d, 1H, J=16.0 Hz),
5.90–5.99 (m, 2H), 7.22–7.25 (m, 2H), 7.32–7.38 ppm (m, 3H);
13C NMR (CDCl3, 100 MHz): d=9.4, 16.4, 16.6, 28.7, 30.4, 34.7, 38.3,
47.2, 54.0, 54.6, 67.1, 73.7, 77.2, 90.8, 121.1, 127.5, 128.2, 128.6,
131.0, 136.9, 165.8, 168.4, 177.8 ppm; IR (KBr): n˜ =2968, 2841, 1779,
1755, 1666, 1431, 1415, 1320, 1258, 1168, 1110, 1062 cmÀ1; elemen-
tal analysis calcd (%) for C25H30N2O5: C 68.47, H 6.90, N 6.39; found:
C 68.14, H 6.88, N 6.39; crystal data: C25H30N2O5; FW 438.52; mono-
clinic; C2; a=28.417(2), b=8.1392(7), c=9.7820(7) ꢁ; V=
2262.3(3) ꢁ3; b=90.608(1)8; Z=4; 1calcd =1.287 gcmÀ3; R=0.035
(Rw =0.046) for 4763 reflections with I>3.00s(I) and 290 variable
parameters. CCDC-948017 (5) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
A solution of 3a (99% ee, 39 mg, 0.15 mmol) in THF (0.5 mL) was
added to a suspension of LiAlH4 (12 mg, 0.30 mmol) in THF
(1.0 mL) at 08C and the resultant suspension was stirred for 2 h at
reflux. After the reaction was cooled to 08C, H2O (0.01 mL), aque-
ous NaOH (30%, 0.01 mL), and H2O (0.03 mL) were consecutively
added, followed by stirring for 30 min at RT. The mixture was fil-
tered through a bed of Celite and the filtrate was condensed
under reduced pressure. The residue was purified by TLC on SiO2
(hexane/AcOEt=1:1) to afford 9 (32 mg, 88%) as an oil. Rf =0.40
(hexane/AcOEt=2:1); [a]2D5 = +117 (c=0.39 in EtOH); 1H NMR
(CDCl3, 400 MHz): d=2.29–2.33 (m, 3H), 2.39–2.46 (m, 1H), 2.88–
2.94 (m, 1H), 3.10–3.16 (m, 1H), 3.64–3.66 (m, 1H), 3.92 (dd, 1H,
J=11.0, 5.9 Hz), 4.32–4.33 (m, 1H), 5.11–5.15 (m, 2H), 5.25 (d, 1H,
J=15.5 Hz), 5.84 (ddd, 1H, J=15.5, 11.0, 5.9 Hz), 7.17–7.21 (m, 1H),
7.27 (t, 2H, J=7.1 Hz), 7.36 ppm (d, 2H, J=7.1 Hz); 13C NMR (CDCl3,
100 MHz): d=32.9, 44.5, 50.5, 67.8, 68.1, 86.3, 97.6, 116.1, 127.2,
127.4, 128.4, 136.3, 140.9 ppm; IR (KBr): n˜ =2940, 1640, 1490, 1450,
1300, 1090 cmÀ1; HRMS (FAB+): m/z calcd for C15H19N2O: 243.1497
[M+H]+; found: 243.1501.
(5R,7R)-7-[(R)-1-Hydroxypropyl]-5-phenyltetrahydropyrazolo-
[1,2-a]pyrazol-1(5H)-one
(R)-1-(1R,3R)-3-Phenylhexahydropyrazolo[1,2-a]pyrazol-1-
yl)prop-2-en-1-ol (10)
Potassium hydroxide (27 mg, 0.50 mmol) in H2O and nickel/alumi-
num alloy (421 mg) were consecutively added to a solution of 3a
(99% ee, 52 mg, 0.20 mmol) in MeOH (1.4 mL) at RT.[13] The mixture
was stirred at RT for three days and filtered through a bed of
Celite. The filtrate was condensed under reduced pressure. The res-
idue was purified by column chromatography (SiO2, AcOEt only) to
A solution of 3a (99% ee, 103 mg, 0.40 mmol) in THF (2.0 mL) was
added to a suspension of LiAlH4 (151 mg, 4.0 mmol) in THF
(8.0 mL) at 08C and the resultant suspension was stirred for 1 h at
reflux. After the reaction was cooled to 08C, H2O (0.15 mL), aque-
ous NaOH (30%, 0.15 mL), and H2O (0.45 mL) were consecutively
added, followed by stirring for 30 min at RT. The mixture was fil-
tered through a bed of Celite and the filtrate was condensed
under reduced pressure. The residue was purified by column chro-
matography (SiO2, AcOEt only–AcOEt/MeOH=10:1–5:1) to afford
10 (60 mg, 61%) as a solid. Rf =0.35 (AcOEt/MeOH=5:1); [a]2D5 = +
give
(5R,7R)-7-[(R)-1-hydroxypropyl]-5-phenyltetrahydropyrazolo-
[1,2-a]pyrazol-1(5H)-one (18 mg, 35%) as an oil. Rf =0.70 (AcOEt
only); [a]2D5 = +117 (c=0.18 in EtOH); 1H NMR (CDCl3, 400 MHz):
d=1.05 (t, 3H, J=7.3 Hz), 1.41–1.52 (m, 1H), 1.57–1.64 (m, 1H),
2.39–2.51 (m, 2H), 2.76–2.91 (m, 3H), 3.35–3.39 (m, 1H), 3.61–3.65
(m, 1H), 3.76 (td, 1H, J=8.7, 2.8 Hz), 3.83–3.89 (m, 1H), 6.29 (brs,
1H), 7.26–7.29 ppm (m, 5H); 13C NMR (CDCl3, 100 MHz): d=9.4,
26.6, 36.3, 41.1, 49.9, 61.0, 68.7, 73.3, 127.2, 128.3, 128.8, 138.0,
166.3 ppm; IR (neat): n˜ =3270, 2930, 1650, 1460, 1420, 1160,
3
(c=0.61 in EtOH); m.p. 122.0–125.08C (recrystallized from
1
AcOEt); H NMR (CDCl3, 400 MHz): d=2.02–2.14 (m, 2H), 2.24–2.31
(m, 1H), 2.43–2.54 (m, 3H), 2.94–3.01 (m, 1H), 3.12 (brs, 1H), 3.17–
3.24 (m, 1H), 3.60 (brs, 1H), 4.08–4.12 (m, 1H), 4.36 (brs, 1H), 5.19
(dd, 1H, J=10.5, 1.4 Hz), 5.37 (dd, 1H, J=17.0, 1.4 Hz), 5.90 (ddd,
1H, J=17.0, 10.5, 5.5 Hz), 7.24–7.28 (m, 1H), 7.30 (t, 2H, J=7.1 Hz),
7.39 ppm (d, 2H, J=7.1 Hz); 13C NMR (CDCl3, 100 MHz): d=25.9,
35.3, 46.7, 51.0, 65.1, 67.1, 74.6, 115.5, 127.2, 127.7, 128.3, 139.0,
139.6 ppm; IR (KBr): n˜ =3086, 2974, 1641, 1603, 1494, 1449, 1361,
1286, 1140, 1061, 932, 766 cmÀ1; HRMS (DART): m/z calcd for
C15H21N2O: 245.1654 [M+H]+; found: 245.1650.
980 cmÀ1
; HRMS (DART): m/z calcd for C15H21N2O2: 261.1603
[M+H]+; found: 261.1593.
(6S,8S)-8-[(R)-1-Hydroxypropyl]-6-phenyl-1,5-diazocan-2-one (8)
A solution of 3a (99% ee, 52 mg, 0.20 mmol) in EtOH (2 mL) was
combined with Raney nickel (W-2; 100 mg, wet weight). The mix-
ture was stirred at RT under an atmosphere of hydrogen (50 atm)
for three days.[11b] The mixture was filtered through a bed of Celite
and condensed under reduced pressure. The residue was purified
by column chromatography (SiO2, AcOEt only–AcOEt/MeOH=10:1)
to give 8 as a solid. Rf =0.30 (AcOEt/MeOH=5:1); [a]2D5 =À19 (c=
0.27 in CHCl3); m.p. 97.5–99.08C (recrystallized from AcOEt);
1H NMR (CDCl3, 400 MHz): d=0.97 (t, 3H, J=7.4 Hz), 1.41–1.48 (m,
2H), 1.92–1.99 (m, 1H), 2.22–2.34 (m, 2H), 2.36–2.43 (m, 1H), 2.54–
2.62 (m, 1H), 2.76–2.83 (m, 1H), 3.08–3.15 (m, 1H), 3.21–3.27 (m,
1H), 3.52–3.56 (m, 1H), 3.55 (brs, 1H), 4.08 (td, 1H, J=4.1,
10.5 Hz), 7.17–7.32 ppm (m, 5H); the signal of one OH or NH
proton was not clearly observed; 13C NMR (CDCl3, 100 MHz): d=
10.2, 28.3, 30.3, 32.8 (2C), 43.6, 56.6, 75.8, 126.0, 128.2, 128.5, 141.6,
172.7 ppm; IR (KBr): n˜ =3310, 2960, 1640, 1440, 1300, 1100,
1000 cmÀ1; HRMS (DART): m/z calcd for C15H23N2O2: 263.1760
[M+H]+; found: 263.1771.
(1R,3R)-1-[(R)-1-Hydroxyallyl]-7-oxo-3-phenylhexahydro-1H-
pyrazolo[1,2-a]pyrazole 4-oxide (11)
mCPBA (70%, 48 mg, 0.19 mmol) was added to a solution of 3a
(99% ee, 52 mg, 0.20 mmol) in CH2Cl2 (2 mL) at 08C and the result-
ing solution was stirred at RT for 1 h. A saturated aqueous solution
of NaHCO3 was added and the mixture was subsequently extracted
with CHCl3. The aqueous layer was separated and extracted with
CHCl3. The combined organic layers were dried over Na2SO4 and
condensed under reduced pressure. The mixture was filtered
through a bed of Celite and condensed under reduced pressure.
The residue was purified by column chromatography (SiO2,
hexane/AcOEt=1:1–AcOEt only–AcOEt/MeOH=5:1–1:1) to give 11
as an oil. Rf =0.30 (AcOEt/MeOH=5:1); [a]2D5 = +30 (c=0.45 in
1
EtOH); H NMR (CDCl3, 400 MHz): d=1.44–1.53 (m, 1H), 2.10 (brs,
1H), 2.77–2.87 (m, 2H), 3.65–3.71 (m, 1H), 3.96–4.03 (m, 1H), 4.14–
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Chem. Asian J. 2011, 6, 2009–2014; m) D. M. Rubush, M. A. Morges, B. J.
Rose, D. H. Thamm, T. Rovis, J. Am. Chem. Soc. 2012, 134, 13554–13557.
[4] For examples of biologically active compounds containing a pyrazoli-
dine skeleton, see: a) H. Berenson, US Pat., 1976, 3931406; b) B. Cross,
C. P. Grasso, B. L. Walworth, US Pat., 1976, 3948936; c) P. D. Boatman,
C. O. Ogbu, M. Eguchi, H.-O. Kim, H. Nakanishi, B. Cao, J. P. Shea, M.
Kahn, J. Med. Chem. 1999, 42, 1367–1375; d) R. St. Charles, J. H. Mat-
thews, E. Zhang, A. Tulinsky, J. Med. Chem. 1999, 42, 1376–1383; e) N.
Fuchi, T. Doi, T. Harada, J. Urban, B. Cao, M. Kahn, T. Takahashi, Tetrahe-
dron Lett. 2001, 42, 1305–1308; f) Y. Wang, A. Benn, N. Flinn, T. Monk,
M. Ramjee, J. Watts, M. Quibell, Bioorg. Med. Chem. Lett. 2005, 15,
1327–1331; recently, compounds with the tetrahydropyrazolo[1,2-
a]pyrazol-1(5H)-one skeleton were reported to exhibit bioactivities:
4.21 (m, 1H), 4.24–4.26 (m, 1H), 4.90 (tt, 1H, J=7.4, 1.4 Hz), 5.04 (d,
1H, J=8.2 Hz), 5.24 (dt, 1H, J=10.5, 1.4 Hz), 5.49 (dt, 1H, J=16.9,
1.4 Hz), 5.97 (ddd, 1H, J=16.9, 10.5, 5.0 Hz), 7.28–7.29 (m, 2H),
7.45–7.42 ppm (m, 3H); 13C NMR (CDCl3, 100 MHz): d=32.1, 33.2,
61.4, 63.0, 71.4, 88.4, 116.0, 129.4, 129.9, 131.0, 132.9, 138.9,
169.3 ppm; IR (KBr): n˜ =3400, 2930, 1730, 1645, 1450, 1350, 1280,
1200, 980 cmÀ1; HRMS (DART): m/z calcd for C15H19N2O3: 275.1396
[M+H]+; found: 275.1395.
Acknowledgements
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[10] The reaction was designed on the assumption that the Grignard re-
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groups in both 1 and DIPT to initially form the corresponding halomag-
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the reaction.
This work was financially supported in part by a Grant-in-Aid
for Scientific Research from the Japan Society for the Promo-
tion of Science (JSPS).
Keywords: azomethine
imines
·
cycloaddition
·
desymmetrization · diisopropyl tartrate · pyrazolidines
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Received: July 23, 2013
Published online on January 8, 2014
Chem. Eur. J. 2014, 20, 2058 – 2064
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