Total synthesis of ent-calystegine B4 via nitro-Michael/aldol reaction

Article abstract of DOI:10.1039/c2ob25386k

Optically active ent-calystegine B4 was prepared in 13 steps from commercially available chiral l-dimethyl tartrate. The synthesis was achieved by the Michael addition and the aldol reaction of nitromethane to form cycloheptanone in a stereoselective manner. Reduction of the nitro group in the presence of Boc₂O accomplished an efficient conversion to amino cycloheptanone, which readily afforded the desired ent-calystegine B4.

Full text of DOI:10.1039/c2ob25386k

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Total synthesis of ent-calystegine B4 via nitro-Michael/aldol reaction†
Akio Kamimura,*a Koichiro Miyazaki,a Shuzo Suzuki,a Shingo Ishikawaa and Hidemitsu Unob
Received 22nd February 2012, Accepted 10th April 2012
DOI: 10.1039/c2ob25386k
Optically active ent-calystegine B4 was prepared in 13 steps from commercially available chiral
L-dimethyl tartrate. The synthesis was achieved by the Michael addition and the aldol reaction of
nitromethane to form cycloheptanone in a stereoselective manner. Reduction of the nitro group in the
presence of Boc2O accomplished an efficient conversion to amino cycloheptanone, which readily
afforded the desired ent-calystegine B4.
Introduction
Results and discussion
Calystegines are a family of polyhydroxylated nortropane alka-
loids, which were first isolated in 1988 from Calystegia sepium.1
So far, more than 10 calystegines have been isolated.2 The calys-
tegine family can be categorized according to the number of
hydroxyl groups present as follows: calystegine A containing
three hydroxyl groups, calystegine B containing four hydroxyl
groups, and calystegine C containing five hydroxyl groups.
Calystegine shows bioactivity similar to castanospermine and
swainsonine, which are known to be glycosidase inhibitors.3 The
structure of calystegine contains a bicyclic ring unit that is simul-
taneously formed by aminocycloheptanone.4 Thus, the total syn-
thesis of calystegine will be achieved by developing a new
method for the construction of the cycloheptane ring. Several
synthetic efforts have been reported to date.5
Aliphatic nitro compounds are useful synthetic building
blocks because activation by the nitro group facilitates the for-
mation of carbon–carbon bonds under mild conditions.6 The
nitroaldol and nitro-Michael reactions are representative methods
for this purpose.7 We are interested in an intramolecular nitro-
aldol reaction to for medium sized ring structure.7b,8 If the acti-
vation of nitromethane for the carbon–carbon bond formation
effectively works twice, it will provide a short-step synthesis of
cycloheptanes. In this paper, we report a new method to prepare
ent-calystegine B4 using nitromethane as the key unit for the for-
mation of the cycloheptane structure.
The outline of our synthesis is depicted in Scheme 1. It is known
that the bridged structure will be spontaneously formed when
aminocycloheptane A is generated. Our aim was to form amino-
cycloheptanone A more efficiently. The nitro group was expected
to be a good precursor of the amino unit and a good activating
group for the formation of cycloheptanone. Thus, we planned to
form the ring from intermediate C and nitromethane via Michael
addition followed by intramolecular aldol reaction of B. The for-
mation of calystegine B2 or B4 depends on the stereoselectivity
of the nitroaldol reaction; if the OH occupies the pseudo-axial
position, calystegine B4 will be prepared, whereas the OH group
comes to pseudo-equatorial position, calystegine B2 will be gen-
erated. The precursor C will be converted from optically active
tartaric acid, which is readily available in both enantiomers. In
this study, we have started with more readily available L-tartrate,
which will afford antipode of naturally occurring calystegine B.
The first stage of the synthesis was the conversion of natural
dimethyl L-tartrate 1 to compound 6 (Scheme 2). Treatment of 1
with 2,2-dimethoxypropane gave dimethylacetal 2, which was
reduced by LiAlH4 to afford diol 3 in 75% yield.9 Monoprotec-
tion of 3 was achieved by a reported method using cyclopentyl
methyl ether (CPME) and mono-TBS ether 4 was obtained in
aDepartment of Applied Molecular Bioscience, Graduate School of
Medicine, Yamaguchi University, Ube 755-8611, Japan. E-mail:
ak10@yamaguchi-u.ac.jp; Fax: +81 836 85 9231; Tel: +81 836 85
9231
bDepartment of Chemistry, Graduate School of Science and
Engineering, Ehime University, Matsuyama 790-8577, Japan
†Electronic supplementary information (ESI) available: 1H and 13C
NMR data for compounds 2–4 and 6–13 and CIF data and ORTEP
charts for 11 and 12. CCDC 857315 (11) and 868308 (12). For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2ob25386k
Scheme 1 Retrosynthetic analysis for ent-calystegine B.
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Scheme 2 Reagents and conditions; i, (CH3)2C(OMe)2, p-TsOH,
CHCl3, reflux, 5 h, 88%; ii, LiAlH4, THF, reflux, 3 h, 75%; iii, TBSCl,
NaH, CPME, 82%; iv, (COCl)2/DMSO/CH2Cl2; v, Et3N; vi,
CH2vCHMgBr/THF, 55% (2 steps).
Scheme 4 Reagents and conditions; i, AcOH–THF–MeOH, 62%; ii,
Dess–Martin periodinane/CH2Cl2; iii, TMG/DMF/rt, 40% (2 steps).
Scheme 3 Reagents and conditions; i, Dess–Martin periodinane/
CH2Cl2; ii, CH3NO2/base/rt, see Table 1.
Table 1 Conjugate addition of nitromethane to 7
Fig. 1 Plausible origin of the stereoselectivity of the nitroaldol
reaction.
Entry
Base
Solvent
Time (h)
Yielda (%)
1
2
3
Et3N
DBU
TMG
CH3CN
DMF
DMF
2
24
36
18
35
63
We examined several conditions for the removal of the TBS
group from 8 and found that the treatment with acetic acid
afforded nitroalcohol 9 in 62% yield, although HF-pyridine
afforded 9 in 57% yields (Scheme 4). Oxidation of the primary
alcohol was achieved by Dess–Martin periodinate oxidation.11
We performed the subsequent intramolecular nitroaldol reaction
without further purification because aldehyde 10 was unstable.
The intramolecular nitroaldol reaction proceeded smoothly in the
presence of TMG as the catalyst, affording the desired cyclohep-
tane 11 in 40% yield as a single isomer. Stereochemistry deter-
mined by X-ray crystallographic analysis showed the
configuration unambiguously.12 This stereoselectivity allowed us
to prepare ent-calystegine B4.
The reaction appears to favour the Felkin–Anh type nucleo-
philic attack that affords an S-configuration at the C8 hydroxyl
position. Subsequent protonation at the C7 nitronate occurred in
a thermodynamically controlled manner to afford 9, because the
nitro group occupies the pseudo-equatorial position that avoids
steric congestion (Fig. 1).13,14
The final stage of our synthesis continued with the reduction
of 11 to amino cycloheptane (Scheme 5).15 Although simple
hydrogenation occurred smoothly, it was very difficult to isolate
the reduced compounds. This was probably due to the instability
of aminoketone that was expected to be generated under the reac-
tion conditions. Thus, we investigated the entrapment of the
amino group by conversion to tert-butyl carbamate (Boc) amide
that prevented the undesirable side reaction by the amino group.
Treatment of 11 under hydrogenation conditions in the presence
a Isolated yield.
82% yield.10 The Swern oxidation led to quantitative conversion
of 4 into aldehyde 5; however, we proceeded to next step
without purification owing to lability of 5. A vinyl group was
introduced by treatment with vinyl magnesium bromide to form
allyic alcohol 6, which was isolated in 55% yield. Compound 6
contained the two diastereomers in about 1 : 1 ratio.
Oxidation of 6 was carried out using Dess–Martin periodi-
nane,11 forming the corresponding vinyl ketone 7 quantitatively
(Scheme 3). This vinyl ketone was very unstable and readily
polymerized when concentrated and maintained at room temp-
erature for several hours. Thus, the next stage, the nitro-Michael
reaction with nitromethane, was performed without purification
of 7. Exposure of 7 to nitromethane in the presence of catalytic
amounts of a base resulted in the formation of 8. The yield of 8
depended on the reaction conditions. The results are summarized
in Table 1.
The reaction catalysed by Et3N afforded 8 in 18% yield (entry
1). The use of tetramethylguanidine (TMG) and DBU, which are
known as effective bases for the nitro-Michael reaction,6c
improved the yield of 8 to 35% and 63% (entries 2 and 3),
respectively, although the reaction time required was more than
24 h. Compound 8 was a stable compound and easily handled in
further stages.
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nitrogen atmosphere unless otherwise mentioned. Dess–Martin
periodinane was prepared by a reported procedure.11 Other com-
pounds were purchased from Aldrich Co. Ltd. and were used
without further purification. Anhydrous THF was purchased
from Kanto Kagaku Co. Ltd. CPME was donated from Zeon Co.
Ltd.
Scheme 5 Reagents and conditions; i, (Boc)2O/Pd-C/H2/THF/rt, 84%;
ii, 12 M HCl/THF; iii, Dowex-SBR/MeOH, 50% (2 steps).
Preparation of (4R,5R)-dimethyl 2,2-dimethyl-1,3-dioxolane-4,5-
dicarboxylate (2)
of Boc2O formed Boc-protected cycloheptanone 12 in 84%
yield. The structure of 12 was unambiguously determined by
X-ray crystallographic analysis.16 This was isolated as a single
isomer, indicating that no undesirable epimerization occurred.
The final stage was global deprotection under acidic conditions.
Exposure of 12 to a catalytic amount of conc. HCl readily
formed the calystegine B4 HCl salt. The crude salt was isolated
by the simple removal of the solvent under reduced pressure.
Conversion of the HCl salt to ent-calystegine B4 was carried out
by treatment with Dowex acidic resin in MeOH. This procedure
offered a significant advantage because removal of water, which
is a usually troublesome procedure requiring freeze dry appar-
atus, was not necessary. ent-Calystegine B4 13 was readily iso-
lated by passing a MeOH solution of the crude product through
a Dowex short column and then removing MeOH by using a
conventional rotary evaporator. 13C NMR data for compound 13
were identical to the data for previously reported calystegine
B4.3d The observation that H4 signal appeared at 3.74 ppm as
triplet (J = 3.1 Hz) also supports the structure. The optical
rotation was positive, and our compound was an antipode of the
natural product.
A solution of 1 (114.5 g, 0.643 mol), 2,2-dimethoxypropane
(81.471 g, 0.785 mol) and p-toluenesulfonic acid hydrate
(1.2272 g, 6.45 mmol) in CHCl3 (350 mL) was heated at
refluxing temperature for 5 h. The reaction mixture was neutral-
ized by adding K2CO3 (1.271 g) and filtered. The filtrate was
concentrated in vacuo to give compound 2 in 88% yield
(118.75 g), which was used for the next step without further
purification. Oil; [α]D −37.46° (c 1.34, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 4.81 (2H, s), 3.82 (6H, s), 1.49 (6H, s);
13C NMR (126 MHz, CDCl3) δ 170.0, 113.8, 52.7, 26.3; IR
(neat) ν 2995, 1743, 1207, 1109 cm−1; HRMS (ESI M + Na)
m/z 241.0691. Calcd for C9H14O6Na 241.0688.
Preparation of ((4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)-
dimethanol (3)
A solution of 2 (10.91 g, 50 mmol) in THF (20 mL) was slowly
added to a suspension of LiAlH4 (5.6925 g, 150 mmol) in THF
(40 mL). The reaction mixture was heated at refluxing tempera-
ture for 3 h. After cooling, EtOAc (10 mL) was added slowly,
and the resulting mixture was filtered. The filtrated was concen-
trated in vacuo and the residue was purified by flash chromato-
graphy (silica gel/hexane–EtOAc) to give compound 3 in 75%
yield (6.1295 g). Pale yellow oil; [α]D +1.86° (c 2.58, CHCl3);
1H NMR (500 MHz, CDCl3) δ 4.16–3.93 (2H, m), 3.84–3.79
(2H, m), 3.73–3.67 (2H, m), 2.03–1.98 (2H, m), 1.57 (6H, s);
13C NMR (126 MHz, CDCl3) δ 109.3, 78.4, 62.2, 26.9; IR
Conclusion
In conclusion we have successfully achieved the total synthesis
of ent-calystegine B4 in 13 steps starting from commercially
available L-tartrate. The key reaction was the intramolecular
nitroaldol reaction that yielded polyhydroxylated cyclohepta-
none. The reaction occurred in a stereoselective manner to form
nitrocycloheptanone as a single isomer. Conversion of the nitro
group to amine was readily achieved under pressurized hydro-
genation conditions in the presence of Boc2O. We believe that
the intermediate Boc-amide cycloheptanone would be useful for
conversion to other calystegine compounds such as A3.
Although we prepared antipodes of naturally occurring calyste-
gine, natural forms would be synthesized if the starting material
was D-tartrate. We think this procedure will provide a convenient
synthesis of calystegine alkaloids.
(neat) ν 3200–3600, 2987, 1045 cm−1
.
Preparation of ((4S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)methanol (4)
Under a nitrogen atmosphere, a solution of 3 (18.99 g,
50.5 mmol) in CPME (20 mL) was added to a suspension of
NaH (2.351 g, 60%, 59.13 mmol) in CPME (180 mL) over
15 min at 0 °C. TBSCl (8.018 g, 53.2 mmol) in CPME (20 mL)
was added to the reaction mixture at 0 °C and the resulting sol-
ution was stirred at the same temperature for additional 15 min
and at room temperature for 3 h. Saturated NH4Cl aq (30 mL)
was added and the organic phase was separated. The aqueous
solution was extracted with EtOAc (100 mL × 3). Organic
phases were combined, washed with brine (20 mL) and dried
over Na2SO4. After filtration, the organic solution was concen-
trated. The residue was purified by flash chromatography (silica
gel/hexane–EtOAc 50 : 1, 30 : 1 then 10 : 1) to give 4 in 82%
yield (11.399 g). Colorless oil; [α]D +16.90° (c 1.28, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 4.06–3.74 (3H, m), 3.76–3.51
(3H, m), 2.79–2.58 (1H, m), 1.37 (3H, s), 1.36 (3H, s), 0.86
Experimental section
General
1
All H and 13C NMR spectra were recorded on JEOL Delta-500
1
or Lambda-500 (500 MHz for H and 125 MHz for 13C) spec-
trometer. High resolution mass spectra (HRMS) were measured
at Tokiwa Instrumentation Centre, Yamaguchi University and
Integrated Centre for Sciences, Ehime University, Matsuyama,
Japan. All reactions in this paper were performed under a
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(9H, s), 0.04 (3H, s), 0.03 (3H, s); 13C NMR (126 MHz, CDCl3)
δ 109.1, 80.1, 78.0, 63.7, 62.7, 27.0, 26.9, 25.8, 18.3, −5.5,
−5.6; IR (neat) ν 3200–3600, 1371, 1251, 1080 cm−1; HRMS
(ESI M + H) m/z 277.1838. Calcd for C13H29O4Si 277.1835.
with NaHCO3 and brine, and then dried over Na2SO4. After fil-
tration, the filtrate was concentrated in vacuo. The residue was
purified by flash chromatography (silica gel/hexane–EtOAc) to
1
give 7 in 92% yield (1.3782 g). H NMR (500 MHz, CDCl3) δ
6.83 (1H, dd, J = 17.5, 10.6 Hz), 6.45 (1H, dd, J = 17.5, 1.7
Hz), 5.83 (1H, dd, J = 10.6, 1.6 Hz), 4.54 (1H, d, J = 7.2 Hz),
4.14 (1H, dt, J = 11.1, 3.9 Hz), 3.87 (1H, dd, J = 11.2, 3.8 Hz),
3.77 (1H, dd, J = 11.2, 3.9 Hz), 1.46 (3H, s), 1.40 (3H, s), 0.90
(9H, s), 0.08 (3H, s), −0.01 (3H, s).
Preparation of 1-((4S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol (6)
DMSO (10.0 mL, 140.8 mmol) was added to a solution of
oxalyl chloride (12.5 mL, 145.95 mmol) in CH2Cl2 (300 mL) at
−78 °C over 20 min. A solution of compound 5 (29.784 g,
107.7 mmol) in CH2Cl2 (50 mL) was added to the solution at
the same temperature over 30 min. Et3N (34.0 mL, 243.9 mmol)
was added to the reaction mixture over 30 min. The resulting sol-
ution was stirred for an additional 30 min at the same tempera-
ture and then at room temperature for 4 h. Water (100 mL) was
added and the organic phase was separated. The water phase was
extracted with CH2Cl2 (30 mL × 3). The organic phases were
combined and dried over Na2SO4. After filtration, the filtrate was
TMG (0.1 g) was added to a solution of 7 (1.3782 g,
4.59 mmol) and CH3NO2 (1.58 mL, 22.9 mmol) in DMF
(3 mL), and the resulting solution was allowed to stand at room
temperature for 14 h. aq. NH4Cl (10 mL) was added and the
mixture was extracted with ether (3 × 50 mL). The organic phase
was washed with brine, and then dried over Na2SO4. After fil-
tration, the filtrate was concentrated in vacuo. The residue was
purified by flash chromatography (silica gel/hexane–EtOAc) to
give 8 in 69% yield (1.1409 g). Pale yellow oil; [α]D +31.83° (c
1
0.98, CHCl3); H NMR (500 MHz, CDCl3) δ 4.44 (2H, t, J =
6.6 Hz), 4.34 (1H, d, J = 7.6 Hz), 4.02 (1H, dt, J = 7.4, 3.6 Hz),
3.88 (1H, dd, J = 11.3, 3.5 Hz), 3.75 (1H, dd, J = 11.3, 3.8 Hz),
2.90–2.76 (2H, m), 2.32–2.24 (2H, m), 1.44 (3H, s), 1.41 (3H,
s), 0.89 (9H, s), 0.07 (6H, s); 13C NMR (126 MHz, CDCl3) δ
208.8, 111.0, 81.1, 78.9, 74.5, 62.8, 34.9, 26.8, 26.4, 25.9, 25.6,
concentrated in vacuo. The resulting crude aldehyde
5
(33.842 g) was used to the next step without further purification.
Crude aldehyde 5 (33.756 g,) was dissolved in THF (350 mL)
and cooled to 0 °C. A THF solution of vinyl magnesium
bromide (1.0 M, 140 mL, 140 mmol) was added to the solution
over 1 h, and the reaction mixture was stirred at room tempera-
ture for 60 h. Saturated NH4Cl aq (120 mL) was added to the
reaction mixture and THF was removed by using a rotary evap-
orator. The aqueous residue was extracted with EtOAc (50 mL ×
3) and the organic phase was dried over Na2SO4. After filtration,
the filtrate was concentrated in vacuo. The residue was purified
by flash chromatography (silica gel/hexane–EtOAc) to give 6 in
55% yield (18.047 g). Isolated as a mixture of the two diastereo-
isomers. Pale yellow viscous oil; [α]D +24.2° (c 0.99, CHCl3);
1H NMR (500 MHz, CDCl3) δ 5.93 (1H, ddd, J = 16.5, 10.4,
5.7 Hz), 5.41 (1H for major isomer, dt, J = 17.2, 1.6 Hz), 5.39
(1H for minor isomer, dt, J = 17.2, 1.6 Hz), 5.26 (1H, dt, J =
10.6, 1.5 Hz), 4.25–4.18 (1H, m), 4.01–3.94 (1H, m), 3.82 (2H,
ddd, J = 17.1, 9.7, 3.7 Hz), 3.74–3.66 (1H, m), 3.12 (1H for
major isomer, d, J = 2.2 Hz), 2.68 (1H for minor isomer, d, J =
7.8 Hz), 1.42 (3H for minor isomer, s), 1.41 (3H for major
isomer, s), 1.40 (3H for minor isomer, s), 1.39 (3H for major
isomer, s), 0.91 (9H for major isomer, s), 0.90 (9H for minor
isomer, s), 0.10 (6H for major isomer, s), 0.08 (6H for minor
isomer, s); 13C NMR (68 MHz, CDCl3) δ 137.3, 136.6, 116.9,
116.7, 111.7, 109.5, 81.9, 81.6, 78.8, 77.3, 72.8, 71.9, 64.1,
63.8, 27.1, 27.0, 26.9, 26.8, 25.9, 18.4, 18.3, −5.5, −5.6.; IR
(neat) ν 3600–3200, 1707, 1371, 1217, 1051 cm−1; HRMS (ESI
M + H) m/z 303.1990. Calcd for C15H31O4Si 303.1992.
20.6, −3.6, −5.5; IR (KBr) ν 2929, 1722, 1554, 1373 cm−1
;
Anal. Calcd for C16H31NO6Si: C, 53.16; H, 8.64; N, 3.87.
Found: C, 53.32; H, 8.71; N, 3.89.
Preparation of 1-((4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)-4-nitrobutan-1-one (9)
A solution of 8 (688.8 mg, 1.907 mmol) in AcOH–THF–H2O
(1.8 mL : 0.6 mL : 0.6 mL) was allowed to stand at 40 °C for
14 h. Saturated NaHCO3 aq (20 mL) was added and THF was
removed in vacuo. The resulting aqueous mixture was extracted
with CH2Cl2 (3 × 50 mL) and organic phase was dried over
Na2SO4. After filtration, the filtrate was concentrated in vacuo.
The residue was purified by flash chromatography (silica gel/
hexane–EtOAc) to give 9 in 62% yield (292.0 mg). Colorless
1
oil; [α]D +21.24° (c 1.07, CHCl3); H NMR (500 MHz, CDCl3)
δ 4.45 (2H, t, J = 6.6 Hz), 4.30 (1H, d, J = 8.0 Hz), 4.08 (1H,
dt, J = 8.0, 3.6 Hz), 3.93 (1H, ddd, J = 12.0, 4.4, 3.4 Hz), 3.74
(1H, ddd, J = 13.4, 8.6, 3.8 Hz), 3.00–2.73 (2H, m), 2.38–2.18
(2H, m), 1.95 (1H, dd, J = 8.6, 4.5 Hz), 1.47 (3H, s), 1.42 (3H,
s); 13C NMR (126 MHz, CDCl3) δ 209.1, 110.8, 81.0, 78.2,
74.3, 61.9, 34.9, 26.5, 25.9, 20.3; IR (neat) ν 3600–3200, 2924,
1717, 1552, 1373, 1091 cm−1; Anal. Calcd for C10H17NO6: C,
48.48; H, 6.93; N, 5.67. Found: C, 48.30; H, 6.95; N, 5.41.
Preparation of 1-((4R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutan-1-one (8)
Preparation of (3aR,7S,8S,8aS)-8-hydroxy-2,2-dimethyl-
7-nitrotetrahydro-3aH-cyclohepta[d][1,3]dioxol-4(5H)-one (11)
Dess–Martin periodinane (3.1798 g, 7.5 mmol) was added to a
solution of 6 (1.5084 g, 5.0 mmol) in CH2Cl2 (50 mL) at room
temperature and the resulting mixture was stirred for 30 min.
The Na2S2O3 (12 g) solution in saturated NaHCO3 aq (55 mL)
was added to the reaction mixture and the resulting mixture was
extracted with ether (3 × 50 mL). The organic phase was washed
Dess–Marin periodinane (556.8 mg, 1.31 mmol) was added to a
solution of 9 (211.6 mg, 0.876 mmol) in CH2Cl2 (16 mL) at
room temperature and the resulting mixture was stirred for
60 min. The Na2S2O3 (2.2 g) solution in saturated NaHCO3 aq
(11 mL) was added to the reaction mixture and the resulting
mixture was extracted with ether (3 × 50 mL). The organic phase
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was washed with NaHCO3 and brine and then dried over
Na2SO4. After filtration, the filtrate was concentrated in vacuo to
give crude 10 in 221.5 mg, which was used in the next step
without further purification. Crude 10 (221.5 mg) was dissolved
in DMF (400 mL) and TMG (1 drop) was added. The reaction
mixture was allowed to stand for 48 h. DMF was removed under
reduced pressure. The residue was subjected to flash chromato-
graphy (silica gel/hexane–EtOAc) to give 11 in 40% yield
(86.2 mg). The product was further purified by recrystallization
from CH2Cl2. White solid; mp 152–153 °C; [α]D +53.8° (c 1.18,
Acknowledgements
We are grateful for the financial support from Yamaguchi Uni-
versity based on The YU Strategic Program for Fostering
Research Activities (2010–2011).
Notes and references
1 D. Tepfer, A. Goldman, N. Panmboukdjian, M. Maille, A. Lepingle,
D. Chevalier, J. Dénarié and C. Rosenberg, J. Bacteriol., 1988, 170,
1153.
1
CHCl3); H NMR (500 MHz, CDCl3) δ 5.14 (1H, d, J = 10.0
2 (a) B. Dräger, Nat. Prod. Rep., 2004, 21, 211; (b) N. Asano,
K. Yokoyama, M. Sakurai, K. Ikeda, H. Kizu, A. Kato, M. Arisawa,
D. Höke, B. Dräger, A. A. Watoson and R. J. Nash, Phytochemistry,
2001, 57, 721; (c) A. A. Watson, D. R. Davis, N. Asano, B. Winchester,
A. Kato, R. J. Molyneux, B. L. Stegelmeier and R. J. Nash, in ACS Sym-
posium Series 745: Natural and Selected Synthetic Toxins-Biological
Implications; (d) N. Asano, A. Kato, Y. Yokoyama, M. Miyauchi,
M. Yamamoto, H. Kizu and K. Matsui, Carbohydr. Res., 1996, 284, 169.
3 (a) Y. School, N. Asano and B. Dräger, J. Chromatogr., A., 2001, 928,
217; (b) N. Asano, R. J. Nash, R. J. Molyneux and G. W. J. Fleet, Tetra-
hedron: Asymmetry, 2000, 11, 1645; (c) Iminosugarsas Glycosidase Inhi-
biors-Nojirimycin and Beyond, ed. A. E. Stutz, Wiley-VCH, Weinheim,
Germany, 1999; (d) N. Asano, A. Kato, Y. Yokoyama, M. Miyauchi,
M. Yamamoto, H. Kizu and K. Matsui, Carbohydr. Res., 1996, 284, 195.
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Synlett, 1992, 357; (b) F.-D. Boyer and J. Y. Lallemand, Synlett, 1992,
969; (c) F.-D. Boyer and J. Y. Lallemand, Tetrahedron, 1994, 50, 10443.
5 (a) P. Moosophon, M. C. Baird, S. Kanokmedhakul and S. G. Pyne,
Eur. J. Org. Chem., 2010, 3337; (b) R. N. Monard, C. B. Pipper and
R. Madsen, Eur. J. Org. Chem., 2009, 3387; (c) M. I. García-Moreno,
C. Ortiz Mellet and J. M. García Fernández, Eur. J. Org. Chem., 2004,
1803; (d) P. R. Skaaderup and R. Madsen, J. Org. Chem., 2003, 68,
2115; (e) M. I. García-Moreno, J. M. Benito, C. Ortiz Mellet and J.
M. García Fernández, J. Org. Chem., 2001, 66, 7604; (f) F.-D. Boyer and
I. Hanna, Tetrahedron Lett., 2001, 42, 1275.
Hz), 5.08–5.05 (1H, m), 4.42 (1H, d, J = 11.6 Hz), 3.94 (1H, dd,
J = 10.0, 1.8 Hz), 2.84 (1H, ddd, J = 19.5, 5.9, 2.5 Hz), 2.77
(1H, ddd, J = 14.3, 4.3, 2.4 Hz), 2.76–2.72 (1H, m), 2.49–2.45
(1H, m), 2.42 (1H, ddd, J = 16.3, 10.4, 2.7 Hz), 1.56 (3H, s),
1.48 (3H, s); 13C NMR (126 MHz, CDCl3) δ 202.4, 111.8, 86.3,
78.1, 68.2, 37.7, 26.7, 26.6, 18.9, 0.1; IR (KBr) ν 3500–3200,
1985, 1722, 1556, 1375, 1165, 1084 cm−1; Anal. Calcd for
C10H15NO6: C, 48.98; H, 6.17; N, 5.71. Found: C, 49.01; H,
6.22 N, 5.68.
Preparation of tert-butyl ((3aS,4S,5S,8aR)-4-hydroxy-2,2-dimethyl-
8-oxohexahydro-3aH-cyclohepta[d][1,3]dioxol-5-yl)carbamate (12)
A mixture of 11 (96.4 mg, 0.39 mmol), Boc2O (440.8 mg,
2.02 mmol) and 10% Pd/C (98.6 mg) in THF (17 mL) was
shaken at room temperature in an autoclave under a hydrogen
atmosphere at 5 MPa for 16 h. Pd/C was removed by filtration
on Celite, and the filtrate was concentrated under reduced
pressure. The residue was purified by flash chromatography
(silica gel/hexane–EtOAc) to give compound 12 in 84% yield
(103.7 mg). White solid; mp 186–187 °C; [α]D −38.8° (c 0.78,
6 (a) A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold and S.
V. L e y, Org. Biomol. Chem., 2005, 3, 84; (b) N. Ono, The Nitro Group in
Organic Synthesis, VCH, New York, 2001; (c) D. Simoni, F. P. Invidiata,
S. Manfredini, R. Ferroni, I. Lampronti, M. Roberti and G. P. Pollini,
Tetrahedron Lett., 1997, 38, 2749.
1
CHCl3); H NMR (500 MHz, CDCl3) δ 5.35 (1H, d, J = 8.7
Hz), 5.06 (1H, d, J = 10.0 Hz), 4.29 (1H, s), 3.90 (1H, dd, J =
10.0, 1.5 Hz), 3.68 (1H, t, J = 10.1 Hz), 2.72 (1H, s), 2.65 (1H,
ddd, J = 20.0, 5.9, 2.1 Hz), 2.44 (1H, ddd, J = 19.7, 13.2, 2.5
Hz), 2.25 (1H, dd, J = 25.5, 12.4 Hz), 1.79–1.69 (2H, m), 1.45
(3H, s), 1.43 (12H, s); 13C NMR (126 MHz, CDCl3) δ 204.6,
155.1, 110.9, 80.0, 78.4, 77.8, 69.0, 52.6, 38.9, 28.5, 26.9, 26.5,
23.3; IR (KBr) ν 3500–3400, 2980, 1714, 1697, 1494,
1163 cm−1; Anal. Calcd for C15H25NO6: C, 57.13; H, 7.99; N,
4.44. Found: C, 57.15; H, 7.93 N, 4.26.
7 (a) G. Giorgi, S. Miranda, M. Ruiz, J. Rodriguez, P. López-Alvarado and
J. C. Menéndez, Eur. J. Org. Chem., 2011, 2101; (b) E. Román, M.
V. Berrocal, M. V. Gil, J. A. Serrano, M. B. Hursthouse and M. E. Light,
Tetrahedron Lett., 2005, 46, 3673; (c) R. Ballini, G. Bosica, D. Fiorini,
A. Palmieri and M. Petrini, Chem. Rev., 2005, 105, 933; (d) O.
M. Berner, L. Tedeschi and D. Enders, Eur. J. Org. Chem., 2002, 1877;
(e) G. Rosini and R. Ballini, Synthesis, 1988, 833.
8 (a) V. B. Kurteva and C. A. M. Afonso, Chem. Rev., 2009, 109, 6809;
(b) S. Anwar, H.-J. Chang and K. Chen, Org. Lett., 2011, 13, 2200;
(c) X. Shi, Y. Chen, C. Zhong, X. Sun, N. G. Akhmedov and J.
L. Peterson, Chem. Commun., 2009, 5150; (d) F. Dinon, E. Richards, P.
J. Murphy, D. E. Hibbs, M. B. Hursthouse and K. M. A. Malik, Tetra-
hedron Lett., 1999, 40, 3279.
9 (a) E. A. Mash, K. A. Nelson, S. V. Deusen and S. B. Hemperly, Org.
Synth., 1990, 68, 92; (b) B. M. Kim, S. J. Bae, S. M. So, H. T. Yoo, S.
K. Chang, J. H. Lee and J. Kang, Org. Lett., 2001, 3, 2349.
10 (a) D. Uemura, K. Araki, K. Suenaga and T. Sengoku, Tetrahedron,
2002, 58, 1983; (b) E. A. Mash, S. B. Hemperly, K. A. Nelson, P.
C. Heidt and S. V. Deusen, J. Org. Chem., 1990, 55, 2045.
11 R. K. Boeckman, Jr., P. Shao and J. J. Mullins, Org. Synth., 2000, 77,
141.
12 Crystallographic data (excluding structure factors) for the structures of 11
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 857315.
13 Y. Misumi and K. Matsumoto, Angew. Chem., Int. Ed., 2002, 41, 1031.
14 X-ray crystallography of 11 indicated that is there no hydrogen bonding
between the nitro group and the hydroxyl group.
15 G. Bégis, T. D. Sheppard, D. E. Cladingboel, W. B. Motherwell and
D. A. Tocher, Synthesis, 2005, 3186.
16 Crystallographic data (excluding structure factors) for the structures of 12
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 868308.
Preparation of (+)-calystegine B4 (13)
HCl aq (12 M, 0.1 mL) was added to a solution of 12 (44.1 mg,
0.14 mmol) in THF (1.5 mL) at room temperature and the reac-
tion mixture was stirred for 4 h. The resulting mixture was con-
centrated to a solid under reduced pressure. The residue was
dissolved in MeOH (3 mL) and passed through a Dowex SBR
column. The eluent was concentrated in vacuo to give (+)-
calystegine B4 in 50% yield (11.6 mg). Colorless oil; [α]D
+81.21° (c 0.39, H2O) (lit.3d −63.0° (c 0.65, H2O); H NMR
1
(500 MHz, D2O) δ 3.74 (1H, t, J = 3.1 Hz), 3.56 (1H, s), 3.56
(1H, s), 3.36 (1H, dd, J = 7.8, 3.0 Hz), 2.15–2.00 (1H, m),
2.00–1.91 (1H, m), 1.54–1.39 (2H, m); 13C NMR (126 MHz,
D2O) δ 92.4, 79.4, 74.7, 73.6, 59.0, 29.6, 24.9; HRMS (FAB
M + H) m/z 176.0926. Calcd for C7H14O4N 176.0923.
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Org. Biomol. Chem.