A concise stereoselective synthesis of (-)-erycibelline

Article abstract of DOI:10.1039/c1ob06244a

(-)-Erycibelline, the dihydroxynortropane alkaloid isolated from Erycibe elliptilimba Merr. et Chun., was synthesized using a cyclic nitrone as advanced intermediate, wherein the key step was the SmI₂-induced intramolecular reductive coupling o

Full text of DOI:10.1039/c1ob06244a

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PAPER
A concise stereoselective synthesis of (-)-erycibelline†
Zhao-Lan Zhang,a,c Shinpei Nakagawa,b Atsushi Kato,b Yue-Mei Jia,a Xiang-Guo Hua and Chu-Yi Yu*a
Received 25th July 2011, Accepted 11th August 2011
DOI: 10.1039/c1ob06244a
(-)-Erycibelline, the dihydroxynortropane alkaloid isolated from Erycibe elliptilimba Merr. et Chun.,
was synthesized using a cyclic nitrone as advanced intermediate, wherein the key step was the
SmI2-induced intramolecular reductive coupling of cyclic nitrone with aldehyde which resulted in good
yield and stereoselectivity.
to (-)-erycibelline 4, for example, bao gong teng C 2 and bao gong
teng A 3, isolated from the same species of Chinese herb Erycibe
obtusifolia benth,5 the latter of which has hypotensive and miotic
activity and has been used for the treatment of glaucoma.6 Other
related compounds include mono-hydroxylated nortropanes, such
as nor-y-tropine 1,7 and tri-hydroxylated nortropanes, such as 5,
Introduction
Tropane alkaloids,1 which possess the 8-azabicyclo[3.2.1]octane
framework, are a large family of alkaloids with more than
200 members. Due to their unique structures and promising
pharmaceutical applications,2 tropane alkaloids continue to draw
the attention of both synthetic and medicinal chemists since their
first discovery in the mid 19th century.3 (-)-Erycibelline 4 (Fig.
1) is the first naturally occurring dihydroxynortropane alkaloid
isolated from the Chinese herb medicine Erycibe elliptilimba
Merr. et Chun., which has been used for the treatment of
rheumatic disease and as a pain-killer.4 There are a number of
hydroxylated nortropane alkaloids which are structurally related
6
7,8 and calystegines 7 to 9,9 which are potent glycosidase inhibitors
and have great potential in the treatment of viral infection,10
cancer,11 diabetes,12 and lysosomal storage disorders.13
In view of their intriguing structures and biological activities,
it is significant to develop efficient methods for the syntheses
of this class of nortropanes. There are only a few reports on
the syntheses of compounds possessing the 2,6-dihydroxylated
nortropane framework. Bao gong teng A 3, has been synthesized
via 1,3-dipolar cycloaddition of acrylonitrile or acrylate of methyl
(S)-lactate to 3-hydroxypyridinium salt,14 molybdenum-mediated
[5 + 2] cycloaddition,15 and intramolecular reductive coupling of
N-acyl N,O-acetal with aldehyde.16
In the context of our continuing interest in iminosugars17 and
their derivatives,18 we wish to develop an efficient and general
strategy for the synthesis of the hydroxylated nortropane skeleton.
(-)-Erycibelline 4 was chosen as the target compound because it
might be a valuable compound in the structure–activity study of
the hydroxylated nortropanes and the synthesis will help to fully
determine the structure of this compound.19
Our retrosynthetic analysis of (-)-erycibelline 4 is outlined in
Scheme 1. The cis vicinal amino alcohol in the piperidine ring
Fig. 1 Natural hydroxylated nortropane alkaloids.
aBeijing National Laboratory for Molecular Science (BNLMS), CAS
Key Laboratory of Molecular Recognition and Function, Institute
of Chemistry, Chinese Academy of Sciences, Beijing 100191, China.
E-mail: yucy@iccas.ac.cn
bDepartment of Hospital Pharmacy, University of Toyama, 2630 Sugitani,
Toyama 930-0194, Japan
cGraduate University of The Chinese Academy of Sciences, Beijing 100049,
China
† Electronic supplementary information (ESI) available: Characterization
data (1H, 13C and 2D NMR spectra) of the intermediates and final
products. See DOI: 10.1039/c1ob06244a
Scheme 1 Retrosynthetic analysis of (-)-erycibelline (4).
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Table 1 Grignard addition to cyclic nitrone (12)
Entry
T/◦C
Lewis acid
14 : 15a
Yieldb (%)
1
2
3
4
5
6
-78
0
0
0
30
60
None
None
ZnI2
MgBr2
None
None
67 : 33
56 : 44
62 : 38
66 : 34
65 : 35
62 : 38
96
97
93
89
79
81
Scheme 2 Initial attempt at the cross-coupling reaction.
of the observation of the signal of the HC N proton displayed in
the 1H NMR spectra (d 6.74 ppm, triplet, J = 1.5 Hz).
a Determined by 1H NMR. b Isolated yield.
With nitrone 16 in hand, we commenced our attempt on the for-
mation of the nortropane framework by intramolecular reductive
pinacol-type coupling of aldehyde and nitrone. Nitrone umpolung
mediated by samarium diiodide has attracted much attention
in recent years, reactions of nitrones with aldehydes/ketones,25
imines,26 and a,b-unsaturated acid derivatives27 have been well
documented in the literature. However, to the best of our
knowledge, the construction of the nortropane skeleton by in-
tramolecular coupling of cyclic nitrone with aldehyde has not been
reported yet. To liberate the aldehyde group, 16 was subjected to
acidic hydrolysis. However, it turned out that the O-TBS group was
very sensitive toward acidic hydrolysis conditions and liberation
of the aldehyde always resulted in O-TBS deprotected products.
Thus, the approach of constructing the nortropane 19 via the
intramolecular nitrone-aldehyde coupling of 18 was abandoned
(Scheme 2).
An alternative strategy was therefore devised in which TBS
was first converted to the non-acid-sensitive benzyl group before
hydrolyzing the acetal. TBAF mediated deprotection of the silyl
group and subsequent protection of the hydroxyl group with
benzyl in a “one-pot” two-step process gave nitrone 20 in 95%
yield. In the course of converting the acetal to aldehyde 21, an
unknown byproduct was generated; efforts to purify the aldehyde
led to lower yield due to its instability (Scheme 3).
can be constructed by an intramolecular pinacol-type coupling
of cyclic nitrone 10 which possesses both nitrone and aldehyde
functional groups. Nitrone 10 can be derived from the oxidation
of hydroxylamine 11 which can be readily obtained by nucleophilic
addition to cyclic nitrone 12.
Results and discussion
Synthesis of (-)-erycibelline
The requisite nitrone 1220 was prepared through a reported method
starting from trans-4-hydroxy-L-proline in three steps with a total
yield of 40%.
The organometallic addition of (3,3-dimethoxypropyl)-
magnesium bromide 13 to nitrone 12 was then attempted (Table
1). Organometallic addition to cyclic nitrones bearing a vicinal
alkoxy substituent, such as a benzyloxy group, preferentially gave
trans adducts,21 but little attention has been paid to organometallic
addition to cyclic nitrones without an a-substituen◦t. It turned
out that Grignard addition of 13 to nitrone 12 at 0 C afforded
hydroxylamine 14 and 15 in good yields but with poor diastereoiso-
meric excess. Optimization of the diastereoselectivity via addition
of Lewis acid (Table 1, Entry 3 and 4) or lowering the reaction
temperature (Table 1, Entry 1) only slightly improved the ratio of
the trans adduct (dr = 67 : 33 ~ 62 : 38). Fortunately, the two adducts
could be easily separated by flash column chromatography. The
stereochemistry of the two isomers were determined by NOE
experiments.
To transform the hydroxylamine 14 into the desired aldo nitrone
22
16, compound 14 was treated with activated MnO2 to give a
separable mixture ofaldo nitrone16 and keto nitrone17 inexcellent
overall yield with regio-selectivity favouring the formation of aldo
nitrone 16 (16 : 17 = 2 : 1, Scheme 2). Previous reports have shown
that the regio-selectivity of the oxidation of cyclic hydroxylamine
is largely dependent on the structures of the substrates, i.e., 2-
substituted 1-hydroxypyrrolidines tending to form keto nitrones,23
whereas a b-alkoxy group has a strong influence on regioselectivity
and favors the abstraction of the vicinal anti proton.24 The
preferential formation of aldo nitrone 16 confirmed that the vicinal
alkoxy group was crucial for directing regio-selectivity of the
oxidation. Assignment of the aldo nitrone 16 was on the basis
Scheme 3 Synthesis of (-)-erycibelline (4).
The subsequent intramolecular reductive coupling reaction
of 21 was then attempted without further purification of the
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Table 2 Concentration of iminosugar giving 50% inhibition of various
crude aldehyde. It was found that the coupling reaction did not
commence in the absence of additives such as proton sources
(MeOH, H2O or t-BuOH)28 or HMPA.29 The reaction resulted
in the formation of only the single diastereoisomer 22, the desired
nortropane derivative, in 55% yield within two steps, by addition
of t-BuOH as promoter. The excellent diastereoselectivity can be
deduced as arising from coordination of a samarium(III) ketyl
radical to the oxygen atom of nitrone with the C O group which
preferentially gives cis amino alcohol (Fig. 2).
glycosidases
IC50 (mM)
Enzyme
4
29
a-glucosidase
yeast
rice
rat intestinal maltase
b-glucosidase
almond
NIa (0%)b
NI (18.2%)
NI (20.2%)
NI (0%)
NI (13.5%)
NI (8.6%)
NI (0%)
NI (0%)
bovine liver
NI (11.2%)
NI (9.7%)
a-galactosidase
coffee beans
b-galactosidase
bovine liver
a-mannosidase
jack beans
NI (21.2%)
NI (17.3%)
NI (0%)
NI (9.0%)
NI (15.6%)
NI (0%)
NI (0%)
NI (0%)
NI (0%)
NI (0%)
NI (0%)
Fig. 2 Proposed coordinated transition state for reductive coupling.
b-mannosidase
snail
NI (0%)
Deprotection of 22 via Pd-catalysed hydrogenolysis in acidic
methanol solution resulted in the formation of fully deprotected
hydroxylamine 23, which was treated with Fe–Cu(OAc)2/HOAc
to afford the amine 4 in 87% yield within two steps. The
hydroxylamine 23 was isolated and fully characterized by ESI-
MS analysis and NMR experiment. The NOESY spectrum (D2O)
of 23 further supported the cis stereochemistry based on the strong
NOE effect between H-2 and H-7. The 13C NMR experiment of
the synthetic (-)-erycibelline 4 was carried out in various solvents
such as D2O, MeOD, DMSO-d6, pyridine-d5 and CDCl3 (see
supporting information). To our delight, the chemical shift of
synthetic (-)-erycibelline 4 in MeOD was identical to those of the
natural product reported by Lu4 et al. Furthermore, the optical
rotation of compound 4 {[a]2D0 -11.6 (c 0.5 in EtOH)} matched well
with that of the natural product {[a]1D0 -12.5 (c 0.57 in EtOH)}.
a-L-fucosidase
bovine kidney
a,a-trehalase
porcine kidney
amyloglucosidase
Aspergillus niger
a-L-rhammosidase
Penicillium decumbens
NI (0%)
NI (9.3%)
NI (0%)
NI (0%)
a NI: No inhibition (less than 50% inhibition at 1000 mM. b (): inhibition%
at 1000 mM.
Synthesis of 7-epi-(+)-erycibelline
The synthetic sequence for the synthesis of 4 was then applied to
the synthesis of 7-epi-(+)-erycibelline 29. Oxidation of 15 afforded
aldo nitrone 24 as the main regio-isomer, which was subjected to a
three step sequence transformation to provide the benzyl protected
aldehyde 26. The aldehyde 26 underwent intramolecular coupling
reaction promoted by SmI2 in the presence of H2O to afford 27 as
a single diastereoisomer. The cis configuration of the new stereo-
center in 27 was unambiguously established through 2D NOESY
experiment which exhibited strong correlation between H-2 and
CH2Ph. Subsequent hydrogenation and reduction furnished 7-epi-
(+)-erycibelline 29 in excellent yield (Scheme 4).
Evaluation of glycosidase inhibition towards various enzymes
Scheme 4 Synthesis of 7-epi-(+)-erycibelline (29).
(-)-Erycibelline 4 and 7-epi-(+)-erycibelline 29 can be seen as the
dehydroxylated derivatives of the calystegines which are potent
inhibitors of glycosidases. Therefore, these two compounds were
assayed as potential glycosidase inhibitors of a range of enzymes,
but neither showed any inhibition toward the tested enzymes
(Table 2).
accomplished using a cyclic nitrone as advanced intermediate,
wherein the key step was the SmI2-induced intramolecular reduc-
tive coupling of cyclic nitrone with aldehyde which resulted in good
yield and stereoselectivity. This synthetic approach is versatile and
gives general access to hydroxylated nortropane alkaloids and their
analogues. The glycosidase-inhibiting results observed herein may
be valuable for further structure–activity studies on hydroxylated
nortropane alkaloids.
Conclusion
In summary, the first stereoselective synthesis of (-)-erycibelline 4
together with its diastereomer, 7-epi-(+)-erycibelline 29, has been
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-4.86; dC(Dept-135; 75 MHz; CDCl3) positive, 104.42, 67.15,
66.74, 52.62, 25.78, -4.86; negative, 38.87, 29.67; HRMS (ESI)
calcd for C15H33NO4SiH+ [M + H]+ 320.2252, found 320.2252.
15: [a]2D0 +31.7 (c 0.63 in CH2Cl2); nmax/cm-1 3231m, 2953vs,
2931vs, 2857s, 1471m, 1462m, 1384m, 1363m, 1255s, 1195m,
1129s, 1050s, 912m, 837s, 776s; dH(300 MHz; CDCl3) 4.36–4.31
(2 H, m, 8-H, 4-H), 3.28 (6 H, s, 2¥OCH3), 3.14 (1 H, dd, J 1.8
and 11.1, 5-H), 2.94 (1 H, dd, J 6.6 and 11.1, 5-H), 2.77–2.67
(1H, m, 2-H), 2.36–2.26 (1 H, m, 3-H), 1.89–1.78 (1 H, m, 6-H),
1.64–1.57 (2 H, m, 7-H), 1.49–1.30 (2 H, m, 6-H and 3-H), 0.83 (9
H, s), 0.00 (6 H, s); dC(75 MHz; CDCl3) 104.49 (C8), 68.65 (C4),
67.82 (C2), 66.68 (C5), 52.66, 52.53 (OCH3), 39.32 (C3), 29.59
(C7), 28.41 (C6), 25.79, 17.99, -4.79, -4.87; dC(Dept-135; 75 MHz;
CDCl3) positive, 104.49, 68.64, 67.82, 52.66, 52.53, 25.79, -4.79,
-4.87; negative, 66.68, 39.33, 29.60, 28.41; HRMS (ESI) calcd for
C15H33NO4SiH+ [M + H]+ 320.2252, found 320.2252.
Experimental
Material and methods
All reagents were used as received from commercial sources with-
out further purification or prepared as described in the literature.
Tetrahydrofuran was distilled from sodium and benzophenone
immediately before use. Reactions were stirred using Teflon-
coated magnetic stirring bars. Analytical TLC was performed
with 0.20 mm silica gel 60 F plates with 254 nm fluorescent
indicator. TLC plates were visualized by ultraviolet light or
by treatment with a spray of Pancaldi reagent {(NH4)6MoO4,
Ce(SO4)2, H2SO4, H2O} or a solution 0.5% ninhydrin in acetone.
Chromatographic purification of products was carried out by
flash column chromatography on silica gel (230–400 mesh). Acidic
ion exchange chromatography was performed on Amberlite IR-
120 (H+) or Dowex 50WX8-400, H+ form. Melting points were
determined using an electrothermal melting point apparatus.
Both melting points and boiling points are uncorrected. Infrared
spectra were recorded on a JASCO FT/IR-480 plus Fourier
transform spectrometer. NMR spectra were measured in CDCl3
(with TMS as internal standard) or D2O on a Bruker AV300 (1H
at 300 MHz, 13C at 75 MHz) or a Bruker AV400 (1H at 400
MHz, 13C at 100 MHz) or a Bruker AV600 (1H at 600 MHz,
13C at 150 MHz) magnetic resonance spectrometer. Chemical
shifts (d) are reported in ppm, and coupling constants (J) are
in Hz. The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet. High-resolution mass spectra (HRMS) were recorded
on a Thermo Scientific LTQ/FT mass spectrometer or a GCT
mass spectrometer. Polarimetry was carried out using an Optical
ActivityAA-10R polarimeter and the measurements were made at
the sodium D-line with a 0.5 dm path length cell. Concentrations
(c) are given in gram per 100 mL.
(3R,5R)-3-(tert-Butyldimethylsilyloxy)-5-(3,3-
dimethoxypropyl)pyrroline N-oxide (16) and
(4R)-2-(3,3-dimethoxypropyl)-4-(tert-
butyldimethylsilyloxy)pyrroline N-oxide (17)
Activated manganese dioxide (0.65 g, 7.52 mmol) was added
portionwise to a cooled (0 ◦C) solution of N-hydroxypyrrolidine
14 (1.2 g, 3.76 mmol) in CH2Cl2 (30 mL). The suspension was
stirred at room temperature overnight. The resultant mixture was
filtrated with celite, and concentrated in vacuo. The crude product
was purified by flash chromatography (silica gel, petroleum
ether/AcOEt = 2/1) to afford aldo nitrone 16 and keto nitrone
17 as a yellow oil (1.09 g, 92%). 16 : 17 = 2 : 1.
16: [a]2D0 +27.7 (c 0.65 in CH2Cl2); nmax/cm-1 2952s, 2932s,
2895m, 2857m, 1573m, 1467m, 1365m, 1256m, 1127s, 1064s,
1007w; dH(300 MHz; CDCl3) 6.74 (1 H, t, J 1.5), 4.82–4.79 (m,
1H), 4.30 (1 H, t, J 5.4), 4.18–4.04 (1 H, m), 3.25 (6 H, s), 2.17–
2.13 (2 H, m), 2.07–2.00 (1 H, m), 1.62–1.49 (3 H, m), 0.80 (9 H,
s), 0.00 (6 H, s); dC(75 MHz; CDCl3) 134.50 (C2), 104.31, 71.13,
69.98, 53.23, 53.18, 36.82, 28.04, 27.27, 25.66, 18.01, -4.68, -4.81;
HRMS (ESI) calcd for C15H31NO4SiH+ [M + H]+ 318.2095, found
318.2098.
(2R,4R)-1-Hydroxy-2-(3,3-dimethoxypropyl)-4-(tert-
butyldimethylsilyloxy)pyrrolidine (14) and
(2S,4R)-1-hydroxy-2-(3,3-dimethoxypropyl)-4-(tert-
butyldimethylsilyloxy)pyrrolidine (15)
To a well stirred solution of cyclic nitrone 12 (10 g, 0.046 mol) in
anhydrous THF (50 mL) was added a solution of Grignard reagent
in THF (1 M, 115 mL) [prepared by stirring Mg turnings (2.88 g,
0.12 mol) and bromide (15.7 mL, 0.115 mol) in THF (115 mL)]
at -78 ◦C. The reaction mixture was stirred for 30 min, quenched
with a saturated aqueous solution of NH4Cl. The aqueous layer
was extracted with ethyl acetate (3 ¥ 20 mL). The combined
extracts were dried and the solvents were removed in vacuo. The
residue was purified by flash chromatography (silica gel, petroleum
ether/AcOEt = 5/1–1/1) to afford 14 and 15 (14.12 g, 96%) as a
colorless oil.
14: [a]2D0 -17.9 (c 0.67 in CH2Cl2); nmax/cm-1 3229m, 2953vs,
2931vs, 2857s, 1469m, 1383m, 1255m, 1195m, 1129s, 1075s,
1007m, 905m, 837s, 778s; dH(300 MHz; CDCl3) 4.37–4.33 (2 H,
m, 8-H, 4-H), 3.52 (1 H, dd, J 6.0 and 11.1, 5-H), 3.27 (6 H, s,
2¥OCH3), 3.04–3.01 (1 H, m, 2-H), 2.78 (1 H, dd, J 5.7 and 11.1,
5-H), 1.84–1.70 (2 H, m, 3-H and 6-H), 1.64–1.54 (3 H, m, 3-H
and 7-H), 1.38–1.36 (1 H, m, 6-H), 0.83 (9 H, s), 0.00 (6 H, s);
dC(75 MHz; CDCl3) 104.42 (C8), 67.16 (C4), 66.74 (C2 and C5),
52.62 (OCH3), 38.87 (C3), 29.67 (C7), 27.35 (C6), 25.78, 17.99,
17: [a]2D0 -7.5 (c 0.80 in CH2Cl2); nmax/cm-1 2952s, 2932s, 2896m,
2857m, 2831m, 1600m, 1469m, 1441m, 1375m, 1253m, 1205m,
1162m, 1125s, 1082s, 997m, 919m; dH(300 MHz; CDCl3) 4.43 (1
H, td, J 4.2 and 6.3), 4.30 (1 H, t, J 5.4), 4.11 (1 H, dd, J 6.0 and
14.1), 3.81–3.73 (1 H, m), 3.27 (6 H, s), 2.99 (1 H, dd, J 6.6 and
18.1), 2.58–2.45 (3 H, m), 1.82–1.75 (2 H, m), 0.80 (9 H, s), 0.00
(6 H, s); dC(75 MHz; CDCl3) 146.18, 104.19, 70.74, 64.07, 53.55,
53.38, 42.53, 27.99, 25.63, 21.87, 17.89, -4.88; HRMS (ESI) calcd
for C15H31NO4SiH+ [M + H]+ 318.2095, found 318.2093.
(3R,5R)-3-(Benzyloxy)-5-(3,3-dimethoxypropyl)pyrroline N-oxide
(20)
To a solution of nitrone 16 (1.27 g, 4.0 mmol) dissolved in
anhydrous THF (20 mL) was added TBAF (1.05 g, 4.0 mmol),
after stirring for 5 min, NaH (60%, 0.19 g, 4.8 mmol) and BnBr
(0.57 mL, 4.8 mmol) were added to the above mixture successively,
the reaction was continued for another 30 min, then quenched
by adding saturated aqueous NH4Cl (5 mL), concentrated, then
dissolved in ethyl acetate (10 mL), the organic layer was separated
7716 | Org. Biomol. Chem., 2011, 9, 7713–7719
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and aqueous layer was extracted by ethyl acetate (3 ¥ 5 mL),
the organic phases combined, dried, concentrated. The aqueous
layer which contained TBS deprotected nitrone was concentrated
and extracted with THF, the crude nitrone was subjected to NaH
and BnBr again, repeating the procedure twice. The crude oil
20 was purified by flash chromatography (silica gel, petroleum
ether/AcOEt = 1/1) to afford nitrone 20 as light yellow oil (1.11 g,
95%); [a]2D0 +34.1 (c 1.35 in CH2Cl2); nmax/cm-1 2936m, 2832m,
1571m, 1454m, 1360m, 1280m, 1261m, 1195m, 1127s, 1065s;
dH(300 MHz; CDCl3) 7.31–7.21 (5 H, m, PhCH2O), 6.87 (1 H, s,
2-H), 4.58–4.55 (1 H, m, 3-H), 4.51–4.42 (2 H, m, PhCH2O), 4.31–
4.28 (1 H, m, 8-H), 4.13–4.10 (1 H, m, 5-H), 3.25 (6 H, s, 2¥OCH3),
2.36–2.28 (1 H, m, 4-H), 2.17–2.02 (2 H, m, 4-H and 6-H), 1.62–
1.49 (3 H, m, 6-H and 2 ¥ 7-H); dC(75 MHz; CDCl3) 136.33, 131.47
(C2), 127.62, 127.38, 127.13, 126.83, 103.27 (C8), 74.99 (C3), 70.38
(PhCH2O), 70.12 (C5), 52.21, 52.18 (OCH3), 32.56 (C4), 26.95
(C7), 26.27 (C6); dC(Dept-135; 75 MHz; CDCl3) positive, 131.48,
127.62, 127.13, 126.83, 103.26, 74.99, 70.12, 52.21, 52.18; negative,
70.38, 32.56, 26.95, 26.28; HRMS (ESI) calcd for C16H23NO4H+
[M + H]+ 294.1700, found 294.1702.
at room temperature for 2 h, the hydroxylamine 22 was judged
to diminish by TLC, The flask was bubbled with Ar, and the
Pd/C was filtered off. After the solution was concentrated in
vacuo, the residue dissolved in acetic acid (2 mL) was subjected
to pre-activated Fe/Cu(OAc)2 suspended in acetic acid for further
reduction of hydroxylamine 23, the reaction mixture was stirred at
r.t. overnight, acetic acid was removed under reduced pressure,
the residue was dissolved in MeOH, the Fe powder removed
by filtration with Celite, Neutralized with aqueous ammonium
solution, concentrated in vacuo. The above procedure was repeated
three times to ensure complete neutralization. The residue was
purified by an acid resin column (DOWEX 50WX8-400, H+ form)
affording 4 (26 mg, 87%) as a brown syrup.
23: [a]2D0 +2.5 (c 0.8 in EtOH), nmax/cm-1 3340s, 2974s, 1563s,
1422s, 1136m, 1091s, 1048s; dH(300 MHz; D2O) 4.18 (1 H, dd, J
3.3 and 7.8, 7-H), 4.04–3.94 (1 H, m, 2-H), 3.90–3.81 (1 H, m,
5-H), 3.59–3.51 (1 H, m, 1-H), 2.24 (1 H, dd, J 7.8 and 14.1, 6-H),
2.12–2.05 (1 H, m, 6-H), 1.90–1.80 (1 H, m, 4-H), 1.46–1.41 (1
H, m, 4-H), 1.32–1.29 (2 H, m, 3-H); dC(75 MHz; D2O) 78.05
(C1), 71.52 (C7), 68.08 (C2), 67.25 (C5), 34.95 (C6), 25.50 (C4),
21.79 (C3); dC(Dept-135; 75 MHz; D2O) positive, 78.05, 71.52,
68.07, 67.25; negative, 34.95, 25.49, 21.79; HRMS (ESI): calcd for
C7H13NO3H+ [M + H]+ 160.0968, found 160.0969.
(1S,2S,5R,7R)-7-(Benzyloxy)-8-azabicyclo[3.2.1]octane-2,8-diol
(22)
4: [a]2D0 -11.6 (c 0.5 in EtOH), [Lit. [a]1D0 -12.5 (c 0.57 in EtOH)];
To a well stirred solution of nitrone 20 (0.18 g, 0.61 mmol) in
acetone : H2O (30 mL, 4 : 1) was added catalytic p-TsOH (12 mg,
0.061 mmol). The reaction mixture was stirred for 1 h at reflux. The
acetone was removed in vacuo. The aqueous layer was extracted
with THF (8 ¥ 2 mL). The combined organic layers were dried,
filtered and the solvents were removed under reduced pressure.
The crude aldehyde 21 was used directly for the cross-coupling
reaction.
n
max/cm-1 3310vs, 2938vs, 1560s, 1401s, 1113s, 1070s, 1044s, 1004s;
dH(300 MHz; CDCl3) 4.33–4.19 (3 H, m, NH, 2 ¥ OH), 3.82–3.76
(1 H, m), 3.73 (1 H, d, J 6.6), 3.62–3.59 (1 H, m), 3.46–3.39 (1 H,
m), 2.24 (1 H, q, J 7.2), 1.96–1.92 (1 H, m), 1.84–1.78 (1 H, m),
1.64–1.57 (1 H, m), 1.50–1.38 (1 H, m), 1.29–1.25 (1 H, m); dC(75
MHz; MeOD) 71.29, 69.89, 65.78, 56.91, 38.49, 26.34, 25.05, [Lit.4
dC 67.7, 67.5, 62.2, 54.3, 35.5, 22.8, 22.3]; HRMS (ESI) calcd for
C7H13NO2H+ [M + H]+ 144.1019, found 144.1019.
To a stirring and carefully deoxygenated solution of aldehyde 21
(directly obtained from the last step, 0.61 mmol) in THF (18 mL)
was added t-BuOH (0.46 mL, 4.88 mmol) under an Ar atmosphere.
The mixture was cooled to -78 ◦C to which was added freshly
prepared SmI2 in THF (15 mL, 1.22 mmol). The reaction was
completed within 10 min, then quenched by successively adding
aqueous solutions of Na2S2SO3 (5 mL) and NaHCO3 (5 mL), the
aqueous layer was extracted with ethyl acetate (3 ¥ 10 mL), and
the combined organic layers were washed with a saturated aqueous
solution of NaCl, dried over MgSO4. Filtration, concentration in
vacuo and purification by chromatography (silica gel, petroleum
ether/AcOEt = 2/1) afforded the N-hydroxylamino alcohol 22 (83
mg, 55%) as a colorless oil. [a]2D0 +3.7 (c 0.53 in CH2Cl2); nmax/cm-1
3370s, 2947s, 2866s, 1496m, 1453s, 1400m, 1364m, 1244m, 1195s,
1092s, 1074s, 1007s; dH(300 MHz; CDCl3) 7.25–7.19 (5 H, m),
4.50–4.39 (2 H, m), 3.87 (1 H, dd, J 2.1 and 6.3), 3.75–3.66 (1 H,
m), 3.60–3.56 (1 H, m), 3.42–3.38 (1 H, m), 2.07–1.94 (1 H, m),
1.92–1.70 (2 H, m), 1.53–1.48 (1 H, m), 1.32–1.27 (1 H, m), 1.22–
1.13 (1 H, m); dC(75 MHz; CDCl3) 137.75, 128.47, 127.84, 127.76,
80.57, 76.08, 71.53, 69.44, 67.11, 33.75, 27.15, 23.77; HRMS (ESI)
calcd for C14H19NO3H+ [M + H]+ 250.1438, found 250.1440.
(3R,5S)-3-(tert-Butyldimethylsilyloxy)-5-(3,3-
dimethoxypropyl)pyrroline N-oxide (24) and
(4R)-2-(3,3-dimethoxypropyl)-4-(tert-
butyldimethylsilyloxy)pyrroline N-oxide (17)
Activated manganese dioxide (0.70 g, 8.02 mmol) was added
portionwise to a cooled (0 ◦C) solution of N-hydroxypyrrolidine
15 (1.28 g, 4.01 mmol) in CH2Cl2 (30 mL). The suspension was
stirred at room temperature overnight. The resultant mixture was
filtrated with celite, and concentrated in vacuo. The crude product
was purified by flash chromatography (silica gel, AcOEt) to afford
aldo nitrone 24 and keto nitrone 17 as a light yellow oil (1.19 g,
94%). 24 : 17 = 2 : 1; 24: [a]2D0 +44.9 (c 1.78 in CH2Cl2); nmax/cm-1
2952s, 2932s, 1577m, 1469m, 1365m, 1255m, 1192w, 1129s, 1069s,
1008w; dH(300 MHz; CDCl3) 6.74 (1 H, s), 4.84 (1 H, d, J 5.1),
4.30 (1 H, t, J 5.4), 3.84 (1 H, t, J 3.9), 3.24 (6 H, s), 2.64–2.54
(1 H, m), 2.14–2.03 (1 H, m), 1.82–1.67 (2 H, m), 1.65–1.53 (2 H,
m), 0.8 (9 H, s), 0.00 (6 H, s); dC(75 MHz; CDCl3) 135.24, 104.30,
71.92, 70.01, 53.14, 52.88, 36.02, 28.06, 27.76, 25.62, 17.90, -4.75,
-4.86; HRMS (ESI) calcd for C15H31NO4SiH+ [M + H]+ 318.2095,
found 318.2096.
(-)-Erycibelline (4)
(3R,5S)-3-(Benzyloxy)-5-(3,3-dimethoxypropyl)pyrroline N-oxide
(25)
10% Pd/C (10 mg) and 6 N HCl (2 mL) was added to a solution
of hydroxylamine 22 (53 mg, 0.21 mmol) in MeOH (10 mL).
The resulting suspension was stirred under an atmosphere of H2
To a solution of nitrone 24 (0.47 g, 1.48 mmol) dissolved in anhy-
drous THF (10 mL) was added TBAF (0.39 g, 1.48 mmol), after
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stirring for 5 min, NaH (60%, 71 mg, 1.78 mmol) and BnBr (0.21
mL, 1.78 mmol) were added to the above mixture successively,
the reaction was continued for another 30 min, then quenched
by adding saturated aqueous NH4Cl (5 mL), concentrated, then
dissolved in ethyl acetate (10 mL), the organic layer was separated
and aqueous layer was extracted by ethyl acetate (3 ¥ 5 mL),
and the combined organic phase, dried, and concentrated. The
aqueous layer which contained TBS deprotected nitrone was
concentrated and extracted with THF, the crude nitrone was
subjected to NaH and BnBr again, repeating the procedure twice.
The crude oil 25 was purified by flash chromatography (silica gel,
AcOEt) to afford nitrone 25 as a yellow oil (0.4 g, 93%). [a]2D0 +66.7
(c 1.5 in CH2Cl2); nmax/cm-1 2941m, 2831m, 1574s, 1521w, 1495w,
1454m, 1360m, 1248m, 1194w, 1128s, 1068s; dH(300 MHz; CDCl3)
7.31–7.21 (5 H, m, PhCH2O), 6.83 (1 H, s), 4.61–4.58 (1 H, m, 3-H),
4.53–4.43 (2 H, m, PhCH2O), 4.33–4.30 (1 H, m, 8-H), 3.87–3.84 (1
H, m, 5-H), 3.25 (6 H, s, 2 ¥ OCH3), 2.65–2.55 (1 H, m, 4-H), 2.14–
2.08 (1 H, m, 6-H), 1.89–1.71 (2 H, m, 4-H and 6-H), 1.70–1.58
(2 H, m, 7-H); dC(75 MHz; CDCl3) 137.36, 132.84 (C2), 128.60,
128.11, 127.83, 104.28 (C8), 76.20(C3), 71.94(PhCH2), 71.62 (C5),
53.17, 52.94 (OCH3), 32.85 (C4), 28.13 (C7), 27.92 (C6); dC(Dept-
135; 75 MHz; CDCl3) positive, 132.84, 128.61, 128.11, 127.83,
104.28, 76.20, 71.94, 53.17, 52.94; negative, 71.62, 32.84, 28.12,
27.92; HRMS (ESI) calcd for C16H23NO4H+ [M + H]+ 294.1700,
found 294.1705.
23.79; HRMS (ESI) calcd for C14H19NO3H+ [M + H]+ 250.1438,
found 250.1441.
7-epi-(+)-Erycibelline (29)
10% Pd/C (5 mg) and 6 N HCl (1 mL) were added to a solution
of hydroxylamine 27 (24 mg, 0.096 mmol) in MeOH (10 mL).
The resulting suspension was stirred under an atmosphere of H2
at room temperature for 2 h, the hydroxylamine 27 was judged
to diminish by TLC, The flask was bubbled with Ar, and the
Pd/C was filtered off. After the solution was concentrated in
vacuo, the residue dissolved in acetic acid (2 mL) was subjected
to pre-activated Fe/Cu(OAc)2 suspended in acetic acid for further
reduction of hydroxylamine 28, the reaction mixture was stirred at
r.t. overnight, acetic acid was removed under reduced pressure, the
residue was dissolved in MeOH, filtered through Celite to remove
the Fe powder, neutralized with aqueous ammonium solution
and concentrated in vacuo. The above procedure was repeated
three times to ensure complete neutralization. The residue was
purified by an acid resin column (DOWEX 50WX8-400, H+ form)
affording 29 as a brown syrup (12 mg, 88%); [a]2D0 + 47.0 (c 0.38
in EtOH); nmax/cm-1 3337s, 2971s, 2925s, 1563m, 1412m, 1118s,
1051s; dH(300 MHz; D2O) 4.62–4.55 (1 H, m, 7-H), 4.12–4.05 (1
H, m, 2-H), 3.76–3.74 (1 H, m, 5-H), 3.63–3.54 (1 H, m, 1-H), 2.52–
2.41 (1 H, m, 6-H), 2.14–1.90 (2 H, m, 3-H and 4-H), 1.67–1.55
(3 H, m, 3-H, 4-H and 6-H); dC(75 MHz; D2O) 68.38 (C7), 63.84
(C2), 60.74 (C1), 54.34 (C5), 32.94 (C6), 25.23, 22.63 (C3 and C4);
dC(Dept-135; 75 MHz; D2O) positive, 68.36, 63.83, 60.73, 54.34;
negative, 32.93, 25.22, 22.62; HRMS (ESI) calcd for C7H13NO2H+
[M + H]+ 144.1019, found 144.1018.
(1R,2R,5S,7R)-7-(Benzyloxy)-8-azabicyclo[3.2.1]octane-2,8-diol
(27)
To a well stirred solution of nitrone 25 (50 mg, 0.17 mmol) in
acetone : H2O (10 mL, 4 : 1) was added catalytic p-TsOH (3 mg,
0.017 mmol). The reaction mixture was stirred for 1 h at reflux.
Acetone was removed in vacuo. The residue was extracted with
THF (8 ¥ 2 mL). The organic layers were combined, dried, filtered
and the solvents were removed under reduced pressure. The crude
aldehyde was used directly for the cross-coupling reaction.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 20672117), the National Basic Research
Program of China (No. 2009CB526511, 2011CB808603), the
Ministry of Science and Technology and the Ministry of Health
of the P.R. China (No. 2009ZX09501-006).
To a stirring and carefully deoxygenated solution of aldehyde
26 (directly obtained from the last step, 0.17 mmol) in THF
(5 mL) was added H2O (0.24 mL, 13.6 mmol) under an Ar
atmosphere. The mixture was cooled to -78 ◦C to which was
added freshly prepared SmI2 in THF (4.3 mL, 0.34 mmol).
The reaction was completed within 10 min, then quenched by
successively adding aqueous solutions of Na2S2SO3 (2 mL) and
NaHCO3 (2 mL), the aqueous layer was extracted with ethyl
acetate (3 ¥ 5 mL), and the combined organic layers were
washed with a saturated aqueous solution of NaCl, dried over
MgSO4. Filtration, concentration in vacuo and purification by
chromatography (petroleum ether/AcOEt = 1/1) afforded the N-
hydroxylamino alcohol 27 as colorless oil (24 mg, 57%); [a]2D0 -14.0
(c 1.6 in CH2Cl2); nmax/cm-1 3331s, 2950s, 2861s, 1454s, 1359m,
1074s, 1005s; dH(300 MHz; CDCl3) 7.35–7.28 (5 H, m, PhCH2O),
4.91 (2 H, br, OH), 4.65–4.59 (1 H, m, 7-H), 4.55–4.49 (2 H, m,
PhCH2O), 4.20–4.09 (1 H, m, 2-H), 3.79–3.67 (1 H, m, 1-H), 3.56–
3.54 (1 H, m, 5-H), 2.61–2.51 (1 H, m, 6-H), 2.11–1.94 (2 H, m,
3-H and 4-H), 1.65–1.47 (3 H, m, 3-H, 4-H and 6-H); dC(75 MHz;
CDCl3) 138.26, 128.42, 127.66, 127.39, 78.75 (C7), 72.94 (PhCH2),
71.87 (C1), 68.72 (C2), 65.24 (C5), 31.56 (C6), 28.11, 23.79 (C4
and C3); dC(Dept-135; 75 MHz; CDCl3) positive, 128.43, 127.66,
127.39, 78.75, 71.87, 68.72, 65.24; negative, 72.94, 31.57, 28.10,
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