Total synthesis and glycosidase inhibition of broussonetine i and J 2

Article abstract of DOI:10.1021/jo4010553

The first total synthesis of both broussonetine I and J₂ together with their enantiomers have been accomplished via the same synthetic route through 18 and 16 steps in excellent overall yields (18% and 19%, respectively), starting from R-glyceraldehyde. Broussonetine I was found to be a potent inhibitor of β-glucosidase (IC₅₀ = 2.9 μM), while ent-broussonetine I and ent-broussonetine J₂ were found to be potent inhibitors of α-glucosidase (IC₅₀ = 0.33 and 0.53 μM, respectively).

Full text of DOI:10.1021/jo4010553

Article
pubs.acs.org/joc
Total Synthesis and Glycosidase Inhibition of Broussonetine I and J2
Hui Zhao,†,§ Atsushi Kato,‡ Kasumi Sato,‡ Yue-Mei Jia,† and Chu-Yi Yu*,†
†Beijing National Laboratory of Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute
of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
‡Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
§University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: The first total synthesis of both broussonetine I
and J2 together with their enantiomers have been accom-
plished via the same synthetic route through 18 and 16 steps in
excellent overall yields (18% and 19%, respectively), starting
from R-glyceraldehyde. Broussonetine I was found to be a
potent inhibitor of β-glucosidase (IC50 = 2.9 μM), while ent-
broussonetine I and ent-broussonetine J2 were found to be
potent inhibitors of α-glucosidase (IC50 = 0.33 and 0.53 μM,
respectively).
INTRODUCTION
■
Broussonetines are a family of naturally occurring iminosugars,
or polyhydroxylated pyrrolidine alkaloids, isolated from the
branches of the deciduous tree Broussonetia kazinoki SIEB
(Moraceae),1 which is widely growing in several Far East
countries, especially in Japan and China. Broussonetia kazinoki
has been used as a folk medicine in China since ancient times
and was found to possess some important functions, such as
diuretic, detoxicating, hemostatic, tonic, and antiedema
functions.2 To date, 29 congeners of this family of alkaloids,
broussonetines A−J, J2, K−M, M2, O, P, and R−Z, have been
isolated by Kusano and co-workers.1h Most of these
compounds show potent glycosidase inhibitory activities and
as such have enormous therapeutic potential as antitumor and
anti-HIV agents.1h,3 Therefore, the synthesis and biological
evaluation of these alkaloids have attracted much attention.4
Figure 1. Representative broussonetines.
Studies have shown that polyhydroxypyrrolidine core and/or
piperidine core play an important role in natural alkaloids with
important biological activities.5 Broussonetines I (6), J (7), J1
suitable pyrrolidine and piperidine substrates. The disconnec-
tion between C4′′−C5′′ was based on the previously modeled
(8), and J2 (9) possess unique structures in the broussonetine
family (Figure 1), i.e., a polyhydroxylated pyrrolidine connected
reactions, which showed that disconnection at this position may
with a chiral piperidine through a long hydrocarbon chain. This
give the best results of the CM reaction. Thus, the target
intriguing structure may have unexpected effects on bio-
compound 6 can be synthesized through CM reaction of
activities. Herein, we report the total synthesis and glycosidase
pyrrolidine 10 and piperidine 11. Pyrrolidine 10 can be
prepared from the sugar-derived cyclic nitrone 12.7 Piperidine
inhibition of broussonetine I (6) and J2 (9).
11, containing a terminal olefinic bond, can be prepared by
RESULTS AND DISCUSSION
addition of vinylmagnesium bromide to the terminal epoxide
derived from 13. The piperidine 13 can be synthesized starting
from 14, which can be prepared from the aldol reaction
between R-glyceraldehyde (15)8 and cyclopentanone (16),
through four critical steps: (1) Baeyer−Villiger oxidation; (2)
■
Retrosynthetic Analysis. Our retrosynthetic analysis is
presented in Scheme 1. The first challenge is how to construct
the long side chain which connects the pyrrolidine and
piperidine moieties. Cross-metathesis or CM reaction6 seems
to be the best method to connect the pyrrolidine ring and the
piperidine ring because broussonetine I (6) and J2 (9) could be
efficiently synthesized through the same method starting from
Received: May 18, 2013
Published: July 6, 2013
© 2013 American Chemical Society
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Scheme 1. Retrosynthesis of Broussonetine I (6)
reduction by lithium aluminum hydride; (3) dimesylation; and
(4) nucleophilic substitution by allylamine.9
Synthesis of Pyrrolidine 10. To execute the synthesis of
indicated that the aldol reaction proceeded in nonclassical way
to give the desired syn product, which could be explained with
the model proposed by Heathcock et al. in 1991.11 Then,
ketone 14 underwent m-CPBA promoted Baeyer−Villiger
oxidation smoothly to afford lactone 20. Protection of the
free hydroxyl group turned out to be a tricky task. Many
attempts of trying to protect the free hydroxyl group of lactone
20 failed to give decent results, such as protecting with TBS,
MOM, etc. Finally, it was found that diphenylmethyl12 works
well as protecting group for lactone 20. The protected lactone
21 was then treated with lithium aluminum hydride and
methanesulfonyl chloride successively, followed by nucleophilic
substitution of allylamine, to give N-allyl piperidine 13 in
excellent overall yields. A number of reagents and conditions
had been attempted to remove the allylic group, including α-
chloroethyl carbonochloridate13 or Pd(PPh3)4,14 but were not
successful. Fortunately, deprotection of 13 employing ethyl
chloroformate with sodium bicarbonate as additives worked
well to give N-carbamate 22. Then, removal of the acetonide in
acidic methanol and conversion of dihydroxyl to epoxide by
conventional procedure afforded the epoxide 23 in excellent
overall yields.15 Treatment of 23 with vinylmagnesium
bromide, followed by sodium hydride, provided the desired
bicyclic compound 11.16
pyrrolidine 10, as depicted in Scheme 2, D-arabinose derived
Scheme 2. Construction of the Polyhydroxylated Pyrrolidine
Moiety 10
cyclic nitrone 12 was treated with Grignard reagent pent-4-en-
1-ylmagnesium bromide to furnish hydroxylamine 17 in 92%
yield as the only product of the reaction.10 Reduction of
hydroxylamine 17 with Zn/Cu(OAc)2/AcOH and acylation of
the resulting secondary amine afforded the desired product 10
in 94% yield over two steps.
Synthesis of Piperidine 11. To execute the synthesis of
piperidine 11, as depicted in Scheme 3, cyclopentanone
derivative 14 was prepared from R-glyceraldehyde (15) and
commercially available cyclopentanone (16) in 84% yield with
excellent diastereoselectivity (Scheme 3). NOESY study
(interaction between H-5 and OMe, H-7 and OMe) of the
ketal 19, prepared by treating 14 with PPTS in methanol,
Completion of the Total Synthesis. With both key
intermediates in hand, we started attempts on the coupling
reaction of 10 and 11. After screening a number of conditions,
Scheme 3. Synthesis of Fragment 11
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it was found that CM reaction of 10 and 11 proceeded well in
the presence of the Grubbs’ reagent 25 in refluxing dichloro-
methane to give product 26 (inseparable mixture of E/Z
isomers) in 80.5% yield (Table 1). The spectacular increase in
ent-broussonetine I (ent-6) and J2 (ent-9), had also been
synthesized starting from ent-12 and ent-15 via the same
synthetic procedure (Figure 2). Broussonetine I (6) and J2 (9)
Table 1. CM Coupling of 10 and 11
Figure 2. Enantiomers of broussonetine I and J2.
together with ent-broussonetine I (ent-6) and J2 (ent-9) were
assayed as potential glycosidase inhibitors of a range of enzymes
(Table 2).18 It was found that the natural products and their
Table 2. Concentration of Iminosugars Giving 50%
a,b
Inhibition of Various Glycosidases
a
entry
10/11
Grubbs’ reagent
solvent
CH2Cl2
yield (%)
IC50 (μM)
ent-6
1
2
3
4
1:1
2:1
2:1
2:1
25
25
24
25
12
enzyme
6
9
ent-9
CH2Cl2
80.5
<5
α-glucosidase
yeast
CH2Cl2
NI (33.7%) NI (12.0%) NI (15.8%) NI (18.8%)
ClCH2CH2Cl
trace
rice
NI (43.7%) NI (18.6%) 2.2
5
a
Isolated yield.
rat intestinal maltase NI (28.4%) NI (15.9%) 0.33
0.53
β-glucosidase
yield from entry 1 to entry 2 (Table 1) might be attributed to
that the homodimers of compound 10 (Type I olefin) could
participate in CM reaction again, which precluded the
dimerization of compound 11 (Type II olefin).6a Then,
conversion of the N-carbamate to N-acyl derivative proceeded
efficiently in three conventional steps: (1) using 2 M KOH-
EtOH to destroy oxazine ring;17 (2) acylated the second amine
and hydroxyl; (3) selective removal of the acyl group from
oxygen. At last, broussonetine I (6) was obtained after
hydrogenation in the presence of 12 N HCl (Scheme 4).
almond
652
2.9
1000
10
NI (36.6%) NI (5.6%)
327 120
bovine liver
α-galactosidase
coffee beans
NI (8.2%) NI (12.3%) NI (15.3%) NI (16.6%)
β-galactosidase
bovine liver
2.7
10
250
72
α-mannosidase
jack beans
408
NI (17%)
NI (33%)
NI (0%)
NI (0%)
NI (22%)
NI (0%)
β-mannosidase
Helix pomatia
α-L-fucosidase
bovine kidney
amyloglucosidase
Aspergillus niger
α-L-rhamnosidase
NI (44%)
Scheme 4. Completion of the Total Synthesis of
NI (5.9%) NI (7.9%) NI (8.7%) NI (18.7%)
52 54 NI (16.7%) NI (24.9%)
193 214
a
Broussonetine I (6) and J2 (9)
Penicillium decumbens NI (5.8%) NI (0%)
a
NI: No inhibition (less than 50% inhibition at 1000 μM).
Parentheses: inhibition % at 1000 μM.
b
a
enantiomers showed different inhibition patterns of glyco-
sidases. Broussonetine I (6) showed potent inhibition of β-
glucosidase (IC50 = 2.9 μM, against bovine liver), while ent-
broussonetine I (ent-9) of α-glucosidase (IC50 = 0.33 μM,
against rat intestinal maltase). Although, broussonetine J2 (9)
gave moderate inhibition of β-glucosidase (IC50 = 10 μM,
against bovine liver), ent-broussonetine J2 (ent-9) was a little
better of α-glucosidase (IC50 = 0.53 μM, against rat intestinal
maltase). The natural products also showed inhibition of β-
galacosidase (IC50 = 2.7 μM and 10 μM, respectively for I and
J2, against bovine liver), but their enantiomers showed weak
inhibition or no inhibition at all. It seemed that the enantiomers
of the natural products inhibited α-glucosidase selectively.
Reagents and conditions: (a) 2 M KOH−EtOH, 90 °C; (b) Ac2O
(2.5 equiv), NEt3 (5 equiv), DMAP (cat.), CH2Cl2, rt; (c) MeONa (1
M in MeOH, 1 equiv), MeOH, rt; (d) 10% Pd/C (0.3 equiv), H2, 12
N HCl, MeOH, rt, 83% over four steps.
Broussonetine J2 (9) was also obtained after oxazine ring-
opening, followed by catalytic hydrogenation involving 12 N
HCl. The 1H and 13C NMR spectra of the synthetic
broussonetine I (6) and J2 (9) were identical to those reported
for the natural products (see the Supporting Information for
the details). The optical rotation of the synthetic broussonetine
I (6) [[α]20 +3.7 (c = 0.3, in MeOH)] and broussonetine J2
D
(9) [[α]20D +3.6 (c = 0.5, in MeOH)] were similar to those of
the natural broussonetine I [[α]25D +2.9 (c = 0.26, in MeOH)]
and broussonetine J2 [[α]25 +2.7 (c = 0.43, in MeOH)].1d,g
Evaluation of GlycosidDase Inhibition. In order to study
the basic structure−activity relationship of this class of natural
products, the enantiomers of these two natural products, i.e.,
CONCLUSIONS
■
In summary, the first total synthesis of broussonetine I and J2
have been accomplished via a same synthetic route through 18
and 16 steps in excellent overall yields (18% and 19%,
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was dried with MgSO4 and concentrated in vacuo. To a stirred
solution of the crude product in CH2Cl2 (40 mL) at 0 °C were slowly
added NaHCO3 (0.69 g, 8.2 mmol) and Ac2O (0.47 mL, 4.9 mmol),
and then the mixture was stirred at room temperature for 2 h.
Saturated NaHCO3 was added to quench the reaction, and then the
resulting mixture was extracted with CH2Cl2 (3 × 10 mL) and the
combined organic layer dried with MgSO4 and concentrated in vacuo.
The residue was purified by column chromatography (EtOAc/
petroleum ether = 1:5) to afford compound 10 (1.98 g, 94% yield)
respectively) starting from R-glyceraldehyde. In order to study
the basic structure−activity relationship of this class of natural
products, the enantiomers (ent-6 and ent-9) had also been
synthesized starting from ent-12 and ent-15 via the same
synthetic procedure. The synthetic strategy developed for this
class of natural products will be useful for the synthesis of a
variety of analogues of these alkaloids, and therefore, are
significant for the future work on the discovery of new lead
compounds of selective and potent glycosidase inhibitors.
Furthermore, the method for the construction of the
homochiral 2-substituted piperidine 11 provided an efficient
way for the synthesis of this kind of compounds. The results
obtained from the preliminary structure−activity relationship
study are valuable for future work on the design and synthesis
of iminosugar-based glycosidase inhibitors.
as a red oil. [α]25 = −26.2 (c 1.45, CH2Cl2). IR (KBr, cm−1): 2923,
D
1
1644. H NMR (300 MHz, CDCl3): δ = 7.41−7.13 (m, 15H), 5.85−
5.64 (m, 1H), 4.98 (d, J = 9.9 Hz, 1H), 4.92 (d, J = 9.9 Hz, 1H), 4.64
(dd, J = 12.1, 5.3 Hz, 1H), 4.55 (d, J = 10.8 Hz, 1H), 4.51−4.37 (m,
4H), 4.32 (dd, J = 12.1, 5.3 Hz, 1H), 4.17 (d, J = 13.6 Hz, 1H), 4.11−
3.98 (m, 1H), 3.84 (d, J = 12.5 Hz, 1H), 3.75−3.51 (m, 1.5H), 3.40−
3.30 (m, 0.5H), 2.17−1.83 (m, 6H), 1.61−1.18 (m, 3H). 13C NMR
(75 MHz, CDCl3): δ 170.0, 138.7, 138.6, 138.0, 137.9, 137.8, 137.7,
137.6, 137.5, 128.6, 128.5, 128.5, 128.4, 128.3, 127.94, 127.87, 127.79,
127.75, 127.7, 127.6, 127.53, 127.49, 115.2, 114.6, 84.5, 83.6, 83.1,
81.5, 73.0, 71.4, 71.0, 70.9, 69.6, 67.3, 66.0, 64.6, 64.2, 62.7, 33.6, 33.2,
32.3, 29.5, 26.0, 25.9, 23.0, 22.9. HRMS ESI: calcd for C33H40NO4 [M
+ H]+ 514.2952, found 514.2948.
EXPERIMENTAL SECTION
■
General Methods. All reagents were used as received from
commercial sources or prepared as described in the literature. 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. Acidic ion exchange chromatog-
raphy was performed on Amberlite IR-120 (H+) or Dowex 50WX8-
400, H+ form. Melting points were determined using an electrothermal
melting point apparatus. NMR spectra were measured in CDCl3 (with
TMS as internal standard) or D2O on a magnetic resonance
spectrometer (1H at 300 MHz, 13C at 75 MHz). Chemical shifts (δ)
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 an LTQ/FT linear
ion trap mass spectrometer. Concentrations (c) are given in gram per
ent-10. Red oil, 1.98 g, 94% yield. [α]25D = +17.0 (c 1.65, CH2Cl2).
IR (KBr, cm−1): 2923, 1644. 1H NMR (300 MHz, CDCl3): δ = 7.39−
7.15 (m, 15H), 5.84−5.64 (m, 1H), 4.98 (d, J = 9.7 Hz, 1H), 4.92 (d, J
= 9.7 Hz, 1H), 4.64 (dd, J = 12.1, 5.2 Hz, 1H), 4.55 (d, J = 10.8 Hz,
1H), 4.51−4.37 (m, 4H), 4.32 (dd, J = 12.1, 5.3 Hz, 1H), 4.17 (d, J =
13.7 Hz, 1H), 4.13−3.99 (m, 1H), 3.84 (d, J = 12.4 Hz, 1H), 3.75−
3.50 (m, 1.5H), 3.40−3.30 (m, 0.5H), 2.17−1.82 (m, 6H), 1.62−1.16
(m, 3H). 13C NMR (75 MHz, CDCl3): δ 170.0, 169.7, 138.7, 138.6,
138.0, 137.8, 137.7, 137.6, 137.5, 128.6, 128.52, 128.49, 128.4, 128.3,
127.94, 127.87, 127.8, 127.8, 127.7, 127.6, 127.54, 127.49, 115.2,
114.6, 84.5, 83.6, 83.1, 81.5, 73.2, 73.0, 71.4, 71.0, 70.9, 69.6, 67.3,
66.0, 64.6, 64.3, 62.7, 33.6, 33.2, 32.3, 29.5, 26.0, 25.9, 23.0, 22.9.
HRMS ESI: calcd for C33H40NO4 [M + H]+ 514.2952, found
514.2948.
1
100 mL. The presence of impurities in the sample, indicated by H
NMR, are the “best” quality spectra available.
(S)-2-((S)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl)-
cyclopentanone (14). To a stirred solution of LDA (151 mL, 2 M in
THF, 0.302 mol) in THF (150 mL) was slowly added cyclopentanone
(16) (25.4 mL, 0.279 mol) at −78 °C under N2, and then the mixture
was stirred at this temperature for 2.5 h and TMEDA (62.8 mL, 0.419
mol) was added in one portion. After 0.5 h, (R)-glyceraldehyde (15)
(30 g, 0.233 mol) in THF (50 mL) was added to the mixture in 5 min.
After the addition was complete, the mixture was stirred for 2 h at −78
°C. Saturated NH4Cl was added to quench the reaction, and then the
resulting mixture was extracted with EtOAc (3 × 50 mL). The
combined organic layer was dried with MgSO4 and concentrated in
vacuo. The residue was purified by column chromatography (EtOAc/
petroleum ether =1:5) to afford compound 14 (42.0 g, 84.1% yield) as
a colorless oil. [α]25D = −29.5 (c 1.1, CH2Cl2). IR (KBr, cm−1): 3454,
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-5-(pent-
4-en-1-yl)pyrrolidin-1-ol (17). To a stirred solution of Mg (150 mg,
6.25 mmol) and I2 (cat.) in THF (10 mL) under N2 atmosphere was
quickly added 0.05 mL of 5-bromopent-1-ene (0.681 mL, 6 mmol, in 5
mL THF), and then the resulting mixture was heated by hairdryer
until the color of the mixture disappeared and the remaining 5-
bromopent-1-ene added slowly. After addition was complete, the
mixture was heated to reflux for 1 h, and then the resulting mixture
was cooled to room temperature. To a stirred solution of 12 (2 g, 5
mmol) in THF, the prepared Grignard reagent was added slowly by
syringe at 0 °C under N2 atmosphere. Saturated NH4Cl was added to
quench the reaction, and the resulting mixture was extracted with ethyl
acetate (3 × 10 mL). The combined organic layer was dried with
MgSO4 and concentrated in vacuo. The residue was purified by
column chromatography (EtOAc/petroleum ether = 1:5) to afford
compound 17 (2.149 g, 92% yield) as a colorless oil. [α]25D = −7.36 (c
1.9, CH2Cl2). IR (KBr, cm−1): 3232, 2934, 1454. 1H NMR (300 MHz,
CDCl3): δ 7.30−7.09 (m, 15H), 6.65 (s, 1H), 5.70 (ddt, J = 16.8, 10.1,
6.6 Hz, 1H), 4.94−4.84 (m, 2H), 4.50−4.34 (m, 6H), 3.92−3.83 (m,
1H), 3.77−3.63 (m, 2H), 3.57−3.37 (m, 2H), 3.08 (dd, J = 12.0, 5.8
Hz, 1H), 1.97 (dd, J = 12.9, 6.3 Hz, 2H), 1.1.82−1.79 (m, 1H), 1.50−
1.30 (m, 3H). 13C NMR (75 MHz, CDCl3): δ 138.7, 138.2, 138.14,
138.11, 128.39, 128.37, 128.36, 128.0, 127.9, 127.72, 127.69, 127.6,
114.6, 86.8, 84.6, 73.4, 71.7, 71.6, 70.1, 69.8, 68.2, 33.9, 25.9. HRMS
ESI: calcd for C31H38NO4 [M + H]+ 488.27954, found 488.27951.
1-((2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-5-
(pent-4-en-1-yl)pyrrolidin-1-yl)ethanone (10). To a stirred solution
of Cu(OAc)2 (82 mg, 0.4 mmol) in AcOH (40 mL) was added Zn
(1.335 g, 20.5 mmol) in one portion. After 0.5 h, 17 (2 g, 4.1 mmol) in
CH2Cl2 (10 mL) was added to the mixture slowly. After the addition
was complete, the mixture was stirred for 6 h, then the solid was
filtered out, and the resulting mixture was concentrated in vacuo. The
residue was dissolved in CH2Cl2 and was washed with aq NaHCO3
and brine water until the pH turned to neutral. Then the organic layer
1
2985, 2982, 1735. H NMR (300 MHz, CDCl3): δ 4.10−4.04 (m,
2H), 4.03−3.94 (m, 2H), 2.88 (s, 1H), 2.49−2.37 (m, 1H), 2.37−2.25
(m, 1H), 2.19−1.92 (m, 4H), 1.71−1.89 (m, 1H), 1.40 (s, 3H), 1.35
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 221.1, 109.3, 76.7, 69.8, 66.9,
52.0, 38.8, 26.8, 25.3, 22.8, 20.6. HRMS ESI: calcd for C11H17O3 [M −
H2O + H]+ 197.11722, found 197.11719 (only fragment peaks in MS-
ESI).
ent-14. Colorless oil, 41.7 g, 84% yield. [α]25 = +35.4 (c 1.3,
D
1
CH2Cl2). IR (KBr, cm−1): 3446, 2985, 1733. H NMR (300 MHz,
CDCl3) δ 4.13−4.06 (m, 2H), 4.05−3.90 (m, 2H), 2.81 (s, 1H),
2.49−2.37 (m, 1H), 2.37−2.25 (m, 1H), 2.19−1.92 (m, 4H), 1.89−
1.74 (m, 1H), 1.40 (s, 3H), 1.35 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 109.3, 109.3, 76.7, 69.8, 66.8, 52.0, 38.8, 26.8, 25.3, 22.8, 20.6.
HRMS ESI: calcd for C11H17O3 [M − H2O + H]+ 197.11722, found
197.11719 (only fragment peaks in MS-ESI).
(2R,3S,3aS,6aS)-2-(Hydroxymethyl)-6a-methoxyhexahydro-2H-
cyclopenta[b]furan-3-ol (19). To a stirred solution of 14 (0.163 g,
0.758 mmol) in MeOH (15 mL) was added PPTS (19 mg, 0.19
mmol) at room temperature, and then the mixture was heated to reflux
for 6 h. NaHCO3 was added to neutralize the PPTS, and MeOH was
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removed under reduced pressure. The residue was dissolved with
water (5 mL), and the resulting mixture was extracted with CH2Cl2 (3
× 5 mL). The combined organic layer was dried with MgSO4 and
concentrated in vacuo. The residue was purified by column
chromatography (EtOAc) to afford compound 19 (0.139 g, 98%
yield) as a colorless oil. [α]25D = +5.0 (c 0.8, CH2Cl2). IR (KBr, cm−1):
at 0 °C. After the addition was complete, the mixture was stirred for
0.5 h. NaOH (10%) was added to quench the reaction, and the solid
was filtered out. The solvent was removed under reduced pressure. To
a stirred mixture of the crude product in CH2Cl2 (20 mL) were added
TEA (0.175 mL, 1.3 mmol) and DMAP (5 mg) at 0 °C, then MsCl
(59 μL, 0.8 mmol) was added slowly. After the addition was complete,
the mixture was stirred at room temperature for 2 h. Saturated
NaHCO3 was added to quench the reaction, and the resulting mixture
was extracted with CH2Cl2 (3 × 5 mL). The combined organic layer
was dried with MgSO4 and concentrated in vacuo. To a stirred
solution of the crude product in MeOH (20 mL) was added allylamine
(94 μL, 1.3 mmol), and the mixture was heated to reflux for 12 h. The
mixture was concentrated in vacuo, and the residue was purified by
column chromatography (EtOAc/petroleum ether = 1:10) to afford
1
3389, 2950, 2871. H NMR (600 MHz, CDCl3): δ 3.90 (dt, J = 7.5,
3.8 Hz, 1H), 3.85 (d, J = 11.9 Hz, 1H), 3.79 (s, 1H), 3.73 (d, J = 11.0
Hz, 1H), 3.31 (s, 3H), 2.80 (s, 1H), 2.40−2.30 (m, 2H), 1.96−1.93
(m, 1H), 1.93−1.84 (m, 1H), 1.72−1.78 (m, 1H), 1.65−1.55 (m, 3H).
13C NMR (75 MHz, CDCl3): δ 119.3, 83.9, 78.8, 62.0, 56.8, 50.7, 34.7,
29.7, 24.6. HRMS ESI: calcd for C8H13O3 [M − CH4O + H]+
157.08592, found 157.08591 (only fragment peaks in MS-ESI).
(S)-6-((S)-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl)-
tetrahydro-2H-pyran-2-one (20). To a stirred solution of 14 (0.1 g,
0.5 mmol) and NaHCO3 (84 mg, 1 mmol) in CH2Cl2 (50 mL) was
added m-CPBA (0.173 g, 1 mmol) over 5 min at room temperature.
After the addition was complete, the mixture was stirred for 2 h, and
then the solid in the mixture was filtered out. The solution was
concentrated to 10 mL under reduced pressure, and the precipitated
solid was filtered out again. The resulting mixture was washed with
saturated NaHCO3 (3 × 10 mL), and the combined organic layer was
dried with MgSO4 and concentrated in vacuo. The residue was purified
by column chromatography (EtOAc/petroleum ether = 1:3) to afford
compound 13 (67 mg, 63% yield) as a white solid. [α]25 = +4.2 (c
D
1
1.1, CH2Cl2). Mp: 54−56 °C. IR (KBr, cm−1): 2933, 1454, 1093. H
NMR (300 MHz, CDCl3): δ 7.36−7.07 (m, 10H), 5.76 (s, 1H), 5.44
(ddt, J = 17.1, 10.4, 6.7 Hz, 1H), 4.92−4.80 (m, 2H), 4.43 (t, J = 7.2
Hz, 1H), 4.21 (d, J = 4.1 Hz, 1H), 4.13 (t, J = 7.4 Hz, 1H), 3.96 (t, J =
7.3 Hz, 1H), 3.04 (dd, J = 14.5, 6.1 Hz, 1H), 2.87 (dd, J = 14.5, 7.3 Hz,
1H), 2.74 (d, J = 11.4 Hz, 1H), 2.17 (d, J = 11.4 Hz, 1H), 2.05 (dt, J =
11.8, 2.6 Hz, 1H), 1.91 (d, J = 12.5 Hz, 1H), 1.67 (d, J = 12.8 Hz, 1H),
1.50 (d, J = 12.4 Hz, 1H), 1.43−1.32 (m, 4H), 1.28 (s, 3H), 1.95−0.95
(m, 1H), 0.82−0.68 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 142.8,
142.5, 132.9, 128.4, 128.1, 127.9, 127.6, 127.1, 126.8, 118.2, 107.2,
100.0, 83.0, 75.7, 74.2, 64.6, 61.7, 56.5, 53.6, 26.6, 26.4, 25.8, 24.5.
HRMS ESI: calcd for C27H36NO3 [M + H]+ 422.2690, found
422.2686.
compound 20 (91.4 mg, 87% yield) as a colorless oil. [α]25 = +21.6
D
1
(c 1.0, CH2Cl2). IR (KBr, cm−1): 3427, 2986, 1732. H NMR (300
MHz, CDCl3) δ 4.47−4.42 (m, 1H), 4.08−3.92 (m, 3H), 3.80 (s, 1H),
3.18 (s, 1H), 2.54 (d, J = 17.1 Hz, 1H), 2.38 (d, J = 17.1 Hz, 1H),
1.80−1.89 (m, 4H), 1.34 (s, 3H), 1.27 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 172.1, 109.6, 81.3, 74.6, 72.9, 67.1, 29.8, 26.8, 25.1, 21.1,
18.2. HRMS ESI: calcd for C11H19O5 [M + H]+ 231.12270, found
231.12267.
ent-13. White solid, 68 mg, 63% yield. [α]25 = −2.9 (c 0.7,
D
CH2Cl2). Mp: 53−54 °C. IR (KBr, cm−1): 2933. 1H NMR (300 MHz,
CDCl3): δ 7.36−7.07 (m, 10H), 5.81 (s, 1H), 5.61−5.39 (m, 1H),
4.92 (dd, J = 13.5, 7.2 Hz, 2H), 4.48 (t, J = 7.1 Hz, 1H), 4.26 (d, J =
4.0 Hz, 1H), 4.17 (t, J = 7.4 Hz, 1H), 4.01 (t, J = 7.3 Hz, 1H), 3.09
(dd, J = 14.5, 6.1 Hz, 1H), 2.92 (dd, J = 15.0, 7.9 Hz, 1H), 2.79 (d, J =
11.4 Hz, 1H), 2.22 (d, J = 11.2 Hz, 1H), 2.10 (dt, J = 11.8, 2.5 Hz,
1H), 1.96 (d, J = 12.5 Hz, 1H), 1.72 (d, J = 12.7 Hz, 2H), 1.53 (t, J =
15.0 Hz, 1H), 1.43 (s, 4H), 1.33 (s, 4H), 1.16−1.03 (m, 1H), 0.86−
0.70 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 142.8, 142.5, 133.0,
128.3, 128.1, 127.9, 127.6, 127.1, 126.8, 118.1, 107.2, 83.0, 75.7, 74.2,
64.6, 61.7, 56.5, 53.6, 26.6, 26.4, 25.8, 24.5, 24.5. HRMS ESI: calcd for
C27H36NO3 [M + H]+ 422.2690, found 422.2686.
ent-20. Colorless oil, 92.7 mg, 88% yield. [α]25 = −24.6 (c 1.3,
D
1
CH2Cl2). IR (KBr, cm−1): 3434, 2985, 1732. H NMR (300 MHz,
CDCl3) δ 4.55−4.51 (m, 1H), 4.12−4.09 (m, 1H), 4.08−3.96 (m,
2H), 3.85 (dd, J = 7.7, 2.8 Hz, 1H), 2.65−2.56 (m, 1H), 2.49−2.37
(m, 1H), 2.04−1.77 (m, 5H), 1.41 (s, 3H), 1.34 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 172.3, 109.6, 81.4, 74.7, 72.8, 67.2, 29.8, 26.7,
25.1, 20.8, 18.2. HRMS ESI: calcd for C11H19O5 [M + H]+ 231.12270,
found 231.12268.
(S)-6-((S)-(Benzhydryloxy)((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-
methyl)tetrahydro-2H-pyran-2-one (21). To a stirred solution of 20
(0.1 g 0.4 mmol) in toluene (15 mL) was added freshly prepared
diphenyldiazomethane (151 mg, 0.8 mmol) at room temperature, and
then the mixture was heated to reflux for 6 h and the color of the
mixture was changed from purple to yellow. Toluene was removed in
vacuo, and the residue was chromatographed (EtOAc/petroleum ether
= 1:10) to afford compound 21 (1.457 g, 85% yield) as a white solid.
(R)-Ethyl 2-((S)-(Benzhydryloxy)((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)methyl)piperidine-1-carboxylate (22). To a stirred solution of 8
(63 mg, 0.15 mmol) and NaHCO3 (25 mg, 0.3 mmol) in
ClCH2CH2Cl (10 mL) was added ethyl chloroformate (28 μL, 0.3
mmol) at room temperature, and the mixture was heated to reflux for
12 h. The mixture was concentrated in vacuo, and the residue was
purified by column chromatography (EtOAc/petroleum ether = 1:10)
[α]25 = +58.4 (c 1.2, CH2Cl2). Mp: 110−112 °C. IR (KBr, cm−1):
to afford compound 22 (68 mg, quant) as a colorless oil. [α]25
=
D
D
1
1
2985, 1739. H NMR (300 MHz, CDCl3): δ 7.45−7.15 (m, 10H),
−69.4 (c 1.7, CH2Cl2). IR (KBr, cm−1): 2934,1694. H NMR (300
MHz, CDCl3): δ 7.41−7.14 (m, 10H), 6.02 (s, 1H), 4.29 (t, J = 7.2
Hz, 1H), 4.19−4.13 (m, 4H), 4.09 (t, J = 8.0 Hz, 1H), 4.01−3.93 (m,
1H), 3.75−3.60 (m, 1H), 2.05 (s, 1H), 1.58−1.38 (m, 4H), 1.36 (s,
3H), 1.31 (t, J = 7.1 Hz, 4H), 1.26 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 155.9, 143.1, 141.9, 129.0, 128.3, 128.0, 127.7, 126.7, 126.2,
108.5, 82.9, 78.0, 72.6, 64.3, 61.2, 52.4, 39.6, 26.5, 26.3, 25.3, 25.0,
20.0, 14.8. HRMS ESI: calcd for C27H36NO5 [M + H]+ 454.25880,
found 454.25876.
5.78 (s, 1H), 4.56 (dd, J = 7.2, 2.7 Hz, 1H), 4.09 (dd, J = 13.7, 6.2 Hz,
1H), 3.96 (dd, J = 8.3, 6.3 Hz, 1H), 3.84 (dd, J = 7.6, 2.6 Hz, 1H), 3.47
(dd, J = 8.3, 6.1 Hz, 1H), 2.53−2.43 (m, 1H), 2.23−2.10 (m, 1H),
1.96−1.70 (m, 4H), 1.29 (s, 3H), 1.27 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 171.2, 142.3, 141.8, 128.5, 128.3, 127.9, 127.7, 127.3, 126.9,
109.4, 83.8, 81.8, 78.8, 74.5, 67.5, 29.8, 26.5, 25.3, 21.8, 18.3. HRMS
ESI: calcd for C24H28O5Na [M + Na]+:419.1829, found 419.1827.
ent-21. White solid, 1.47 g, 85% yield. [α]25 = −55.4 (c 1.1,
D
1
CH2Cl2). Mp: 109−111 °C. IR (KBr, cm−1): 2985, 1739. H NMR
(R)-Ethyl 2-((S)-(Benzhydryloxy)((S)-oxiran-2-yl)methyl)-
piperidine-1-carboxylate (23). To a stirred solution of 22 (0.1 g,
0.2 Mmol) in MeOH (10 mL) was added DOWEX 50 H+ (cat.), and
then the resulting mixture was heated to reflux for 12 h. Acidic resin
was filtered out, and MeOH was removed in vacuo. To a stirred
solution of the crude product in CH2Cl2 (10 mL) were added TEA
(92 μL, 0.7 mmol), DMAP (5 mg), and TBSCl (50 mg, 0.3 mmol) at
0 °C, and then the mixture was stirred at room temperature for 12 h.
Saturated NaHCO3 was added to quench the reaction, and the
resulting mixture was extracted with CH2Cl2 (3 × 5 mL). The
combined organic layer was dried with MgSO4 and concentrated in
vacuo. To a stirred solution of the crude product in pyridine (10 mL)
(300 MHz, CDCl3) δ 7.42−7.19 (m, 10H), 5.78 (s, 1H), 4.64−4.49
(m, 1H), 4.09 (dd, J = 13.4, 6.3 Hz, 1H), 4.04−3.90 (m, 1H), 3.84
(dd, J = 7.6, 2.2 Hz, 1H), 3.47 (dd, J = 8.1, 6.2 Hz, 1H), 2.53−2.43 (m,
1H), 2.26−2.09 (m, 1H), 2.23−2.10 (m, 1H), 1.99−1.70 (m, 4H),
1.29 (s, 3H), 1.27 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 171.2,
142.3, 141.8, 128.5, 128.2, 127.9, 127.7, 127.3, 126.9, 109.5, 83.8, 81.8,
78.8, 74.5, 67.5, 29.8, 26.5, 25.3, 21.8, 18.3. HRMS ESI: calcd for
C24H28O5Na [M + Na]+ 419.1829, found 419.1827.
(R)-1-Allyl-2-((S)-(benzhydryloxy)((R)-2,2-dimethyl-1,3-dioxolan-
4-yl)methyl)piperidine (13). To a stirred solution of 21 (0.1 g, 0.25
mmol) in THF (20 mL) was slowly added LiAlH4 (62 mg, 1.5 mmol)
7900
dx.doi.org/10.1021/jo4010553 | J. Org. Chem. 2013, 78, 7896−7902

The Journal of Organic Chemistry
Article
were added DMAP (5 mg) and MsCl (26 μL, 0.3 mmol) at 0 °C, and
then the resulting mixture was stirred at room temperature for 2 h.
Saturated NaHCO3 was added to quench the reaction, and the
resulting mixture was extracted with CH2Cl2 (3 × 5 mL). The
combined organic layer was dried with MgSO4 and concentrated in
vacuo. To a stirred solution of the crude product THF (10 mL) was
added TBAF (173 mg, 0.7 mmol), and the mixture was stirred at room
temperature for 1 h. NaOH (10%) was added to the mixture, and after
0.5 h, the mixture was extracted with ethyl acetate (3 × 5 mL). The
combined organic layer was dried with MgSO4 and concentrated in
vacuo. The residue was purified by column chromatography (EtOAc/
petroleum ether = 1:15) to afford compound 23 (81 mg, 93% yield) as
a colorless oil. [α]25D = −73.4 (c 1.2, CH2Cl2). IR (KBr, cm−1): 2934,
4.02 (t, J = 8.7 Hz, 2H), 3.93−3.77 (m, 2H), 3.75−3.62 (m, 1H),
3.62−3.55 (m, 0.5H), 3.42−3.22 (m, 2H), 2.66 (t, J = 11.9 Hz, 1H),
2.46−2.30 (m, 1H), 2.20−2.01 (m, 5H), 2.01−1.83 (m, 3H), 1.83−
1.71 (m, 1H), 1.71−1.10 (m, 9H). 13C NMR (75 MHz, CDCl3): δ
169.9, 160.5, 153.6, 147.0, 141.9, 141.7, 141.6, 141.5, 141.1, 138.6,
138.2, 137.9, 137.8, 137.7, 137.6, 137.5, 136.0, 133.8, 133.3, 133.0,
131.3, 128.6, 128.5, 128.4, 128.3, 127.9, 127.8, 127.8, 127.8, 127.7,
127.7, 127.6, 127.6, 127.5, 125.4, 125.2, 124.8, 124.5, 123.9, 123.8,
84.5, 83.4, 81.5, 73.2, 73.0, 71.4, 71.0, 69.6, 67.2, 64.7, 64.2, 62.7, 59.7,
45.0, 32.4, 27.7, 26.2, 24.7, 23.6, 23.0, 22.9. HRMS ESI: calcd for
C55H63N2O7 [M + H]+ 863.4635, found 863.4631.
Broussonetine I (6). Compound 26 (0.1 g, 0.1 mmol) was dissolved
in 2 M KOH−EtOH (8 mL), and the mixture was stirred at 90 °C for
2 h. The solvent was removed under reduced pressure, and the residue
was dissolved with CH2Cl2 and water. The resulting mixture was
extracted with CH2Cl2 (3 × 3 mL), and the combined organic layer
was dried with MgSO4. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography
(EtOAc/MeOH = 1:5). To a stirred solution of the crude product in
CH2Cl2 (8 mL) were added TEA (49 μL, 0.3 mmol), DMAP (2 mg),
and Ac2O (26 μL, 0.3 mmol) at 0 °C, and then the mixture was stirred
at room temperature for 2 h. Saturated NaHCO3 was added to quench
the reaction, and the mixture was extracted with CH2Cl2 (3 × 3 mL).
The combined organic layer was dried with MgSO4 and concentrated
in vacuo. The residue was dissolved in MeOH (5 mL), and MeONa (1
mL, 1 M in MeOH) was added to the stirred mixture at room
temperature. After 2 h, MeOH was removed under reduced pressure,
and the residue was dissolved with CH2Cl2 and water.The resulting
mixture was extracted with CH2Cl2 (3 × 3 mL), and the combined
organic layer was dried with MgSO4. The mixture was concentrated
under reduced pressure, and the residue was purified by column
chromatography (EtOAc/petroleum ether = 3:1). To a stirred solution
of the crude product in MeOH (8 mL) and 12 N HCl (1 mL) was
added 10% Pd/C (10 mg), and the resulting mixture was stirred under
H2 atmosphere at room temperature for 48 h.The solid was filtered,
and MeOH was removed under reduced pressure. The residue was
dissolved in MeOH (1 mL) and NH3·H2O (4 mL, 17 N), and the
mixture was concentrated again under reduced pressure. The residue
was purified by column chromatography (acidic ion-exchange resin) to
afford compound 6 (39 mg, 83% yield) as a colorless oil. [α]25D = +3.7
1
1693. H NMR (300 MHz, CDCl3): δ 7.41−7.14 (m, 10H), 5.91 (s,
1H), 4.52 (s, 1H), 4.28−4.12 (m, 2H), 3.93 (s, 1H), 3.34 (t, J = 7.8
Hz, 1H), 3.13−3.06 (m, 1H), 2.81 (t, J = 4.5 Hz, 1H), 2.52 (dd, J =
4.8, 2.7 Hz, 1H), 2.35 (s, 1H), 1.75−1.61 (m, 2H), 1.61−1.48 (m,
3H), 1.48−1.30 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 156.2, 143.1, 141.7, 128.4, 128.4, 128.1, 127.7, 126.9,
126.2, 81.0, 61.3, 53.9, 52.3, 43.5, 39.9, 26.3, 25.1, 20.2, 14.8. HRMS
ESI: calcd for C24H30NO4 [M + H]+ 396.21693, found 396.21704.
(3S,4S,4aR)-3-Allyl-4-(benzhydryloxy)hexahydropyrido[1,2-c]-
[1,3]oxazin-1(3H)-one (11). To a stirred solution of 23 (230 mg, 0.6
mmol) and CuI (12 mg, 0.06 mmol) in THF (10 mL) was slowly
added vinylmagnesium bromide (0.64 mL, 0.64 mmol) at 0 °C under
N2 atmosphere, and then the resulting mixture was stirred at room
temperature for 2 h. Saturated NH4Cl was added to quench the
reaction, and the resulting mixture was extracted with ethyl acetate (3
× 5 mL). The organic layer was dried with MgSO4 and concentrated
in vacuo. The residue was dissolved again in THF (10 mL), and then
NaH (48 mg, 60% with oil, 1.2 mmol) was added slowly to the stirred
mixture at 0 °C and the resulting mixture was stirred at room
temperature for 2 h. Cold water was added to quench the reaction, and
the mixture was extracted with ethyl acetate (3 × 5 mL). The
combined organic layers were dried with MgSO4 and concentrated in
vacuo. The residue was purified by column chromatography (EtOAc/
petroleum ether =1:3) to afford compound 11 (192 mg, 85% yield) as
a white solid. [α]25 = −11.2 (c 1.1, CH2Cl2). Mp: 135−137 °C. IR
D
1
(KBr, cm−1): 2933, 1683. H NMR (300 MHz, CDCl3) δ 7.41−7.14
(m, 10H), 5.61−5.42 (m, 2H), 5.06−4.85 (m, 2H), 4.48 (dd, J = 13.2,
1.9 Hz, 1H), 4.11 (t, J = 7.1 Hz, 1H), 3.81 (d, J = 3.9 Hz, 1H), 3.38−
3.22 (m, 1H), 2.64 (td, J = 12.9, 3.0 Hz, 1H), 2.44 (ddd, J = 14.5, 7.1,
6.0 Hz, 1H), 2.12 (dt, J = 14.7, 7.4 Hz, 1H), 1.73 (d, J = 7.2 Hz, 1H),
1.61 (d, J = 14.5 Hz, 1H), 1.52−1.34 (m, 2H), 1.32−1.22 (m, 2H).
13C NMR (75 MHz, CDCl3) δ 153.4, 141.6, 141.5, 133.0, 128.4, 128.3,
127.9, 127.8, 127.6, 118.2, 84.7, 77.9, 71.3, 59.6, 45.0, 34.9, 27.8, 24.6,
23.6. HRMS ESI: calcd for C24H28NO3 [M + H]+ 378.2070, found
378.2062.
1
(c 0.3, MeOH). IR (KBr, cm−1): 3348, 2929, 1607. H NMR (300
MHz, pyr): δ 4.96 (d, J = 13.2 Hz, 1H), 4.75 (t, J = 6.3 Hz, 1H), 4.58
(s, 1H), 4.47 (t, J = 6.5 Hz, 1H), 4.30−4.20 (m, 3H), 3.94 (s, 2H),
3.67 (s, 1H), 2.85 (t, J = 11.9 Hz, 1H), 2.42 (s, 3H), 2.09 (s, 4H), 1.90
(s, 4H), 1.80−1.46 (m, 10H), 1.38 (s, 6H). 13C NMR (75 MHz, pyr):
δ 172.5, 84.8, 80.8, 73.0, 72.8, 70.8, 66.7, 64.4, 64.1, 57.8, 52.4, 38.7,
37.1, 31.8, 31.7, 28.7, 28.3, 28.1, 27.5, 24.3, 21.8.. HRMS ESI: calcd for
C20H39N2O6 [M + H]+ 403.2803, found 403.2801.
ent-Broussonetine I (ent-6). Colorless oil, 37 mg, 83% yield. [α]25
ent-11. White solid, 194 mg, 85% yield. [α]25 = +9.5 (c 1.0,
D
D
1
= −4.2 (c 0.4, MeOH). IR (KBr, cm−1): 3348, 2929, 1607. H NMR
1
CH2Cl2). Mp: 134−135 °C. IR (KBr, cm−1): 2933, 1683. H NMR
(300 MHz, MeOD): δ 4.49 (d, J = 12.8 Hz, 1H), 4.14 (dd, J = 9.9, 3.0
Hz, 1H), 3.88 (d, J = 10.0 Hz, 1H), 3.80 (t, J = 6.4 Hz, 2H), 3.71 (dd, J
= 11.4, 4.2 Hz, 1H), 3.65 (dd, J = 9.4, 3.9 Hz, 2H), 3.62−3.55 (m,
2H), 3.34−3.31 (m, 1H), 3.09−3.02 (m, 1H), 2.98−2.90 (m, 1H),
2.75−2.65 (m, 1H), 2.16 (s, 2H), 2.14 (s, 1H), 1.92−1.83 (m, 1H),
1.81−1.33 (m, 20H). 13C NMR (75 MHz, MeOD): δ 173.7, 83.3,
79.3, 71.6, 69.8, 64.6, 62.9, 62.8, 57.1, 38.3, 35.4, 34.9, 30.7, 27.6, 27.1,
27.0, 26.5, 22.2, 20.6. HRMS ESI: calcd for C20H39N2O6 [M + H]+
403.2803, found 403.2801.
(300 MHz, CDCl3): δ 7.43−7.16 (m, 10H), 5.63−5.44 (m, 2H),
5.00−4.88 (m, 2H), 4.50 (d, J = 13.2 Hz, 1H), 4.12 (t, J = 7.1 Hz, 1H),
3.83 (d, J = 3.9 Hz, 1H), 3.42−3.24 (m, 1H), 2.66 (td, J = 12.9, 2.8 Hz,
1H), 2.50−2.41 (m, 1H), 2.19−2.05 (m, 1H), 1.76 (d, J = 13.3 Hz,
1H), 1.63 (d, J = 13.6 Hz, 1H), 1.58−1.36 (m, 2H), 1.36−1.21 (m,
2H). 13C NMR (75 MHz, CDCl3): δ 153.4, 141.61, 141.55, 133.1,
128.4, 128.3, 127.9, 127.8, 127.6, 118.1, 84.7, 77.9, 71.3, 70.6, 59.6,
45.0, 34.9, 27.8, 24.7, 23.6. HRMS ESI: calcd for C24H28NO3 [M +
H]+ 378.2070, found 378.2062.
Broussonetine J2 (9). Compound 26 (0.1 g, 0.1 mmol) was
dissolved in 2 M KOH−EtOH (8 mL), and the mixture was stirred at
90 °C for 2 h. The solvent was removed under reduced pressure, and
then the residue was dissolved with CH2Cl2 and water. The resulting
mixture was extracted with CH2Cl2 (3 × 3 mL), and the combined
organic layer was dried with MgSO4. The mixture was concentrated
under reduced pressure, and the residue was purified by column
chromatography (EtOAc/MeOH = 1:5). To a stirred solution of the
crude product in MeOH (8 mL) and 12 N HCl (1 mL), 10% Pd/C
(10 mg) was added, and the resulting mixture was stirred under H2
atmosphere at room temperature for 12 h. The catalyst was filtered
(3S,4S,4aR)-3-(6-((2R,3R,4R,5R)-1-Acetyl-3,4-bis(benzyloxy)-5-
((benzyloxy)methyl)pyrrolidin-2-yl)hex-2-en-1-yl)-4-
(benzhydryloxy)hexahydropyrido[1,2-c][1,3]oxazin-1(3H)-one (26).
To a stirred solution of 10 (0.272 g, 0.5 mmol) and 11 (0.1 g, 0.3
mmol) in CH2Cl2 (10 mL) was added Grubbs’ reagent (11 mg, 0.01
mmol) in CH2Cl2 (3 mL) at room temperature, and then the resulting
mixture was heated to reflux for 24 h. The mixture was purified by
column chromatography (EtOAc/petroleum ether = 1:3) to afford 26
(211 mg, 80.5% yield) as a gray oil. [α]32 = −14.3 (c 0.7, CH2Cl2).
D
1H NMR (300 MHz, CDCl3): δ 7.46−7.14 (m, 25H), 5.56−5.47 (m,
1H), 5.25−4.94 (m, 2H), 4.72−4.29 (m, 8H), 4.24−4.07 (m, 2H),
7901
dx.doi.org/10.1021/jo4010553 | J. Org. Chem. 2013, 78, 7896−7902

The Journal of Organic Chemistry
Article
out, and MeOH was removed under reduced pressure. The residue
was dissolved in MeOH (1 mL) and NH3·H2O (4 mL, 17 N), and the
mixture was concentrated again under reduced pressure. The residue
was purified by column chromatography (acidic ion-exchange resin) to
afford compound 9 (40 mg, 95% yield) as a colorless oil. [α]25D = +3.6
J. Carbohydr. Chem. 2003, 22, 719. (d) Trost, B. M.; Horne, D. B.;
Woltering, M. J. Angew. Chem., Int. Ed. 2003, 42, 5987. (e) Trost, B.
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see: (a) Stutz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin
and Beyond; Wiley-VCH: Weinheim, 1999. (b) Molyneux, R. J.; Pan,
Y. T.; Tropea, J. E.; Elbein, A. D.; Lawyer, C. H.; Hughes, D. J.; Fleet,
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11360. For some recent applications of CM reaction in the synthesis
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A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem.Eur. J.
2009, 15, 7808. (b) Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.;
Goti, A. Tetrahedron Lett. 2003, 44, 2315. (c) Desvergnes, S.; Py, S.;
1
(c 0.5, MeOH). IR (KBr, cm−1): 3309, 2929. H NMR (300 MHz,
pyr) δ 4.70 (t, J = 6.5 Hz, 1H), 4.45−4.37 (m, 1H), 4.32−4.16 (m,
2H), 4.06−3.94 (m, 1H), 3.91−3.81 (m, 1H), 3.63−3.53 (m, 1H),
3.32−3.27 (m, 1H), 2.75 (t, J = 12.1 Hz, 1H), 2.13−1.20 (m, 16H).
13C NMR (75 MHz, pyr) δ 83.8, 79.8, 75.1, 72.7, 65.3, 63.2, 62.9, 60.5,
46.1, 35.1, 34.9, 31.1, 30.1, 29.2, 28.5, 28.3, 27.9, 27.2, 26.8, 26.4, 25.9,
25.5, 24.7, 24.3. HRMS ESI: calcd for C18H37N2O5 [M + H]+
361.2697, found 361.2695.
ent-Broussonetine J2 (ent-9). Colorless oil, 39 mg, 95% yield.
1
[α]25D = −4.5 (c 0.7, MeOH). IR (KBr, cm−1): 3309, 2929. H NMR
(400 MHz, MeOD) δ 3.79−3.73 (m, 1H), 3.69−3.56 (m, 4H), 3.32−
3.32 (m, 1H), 3.25 (dd, J = 7.2, 1.3 Hz, 1H), 3.19−3.11 (m, 1H),
3.00−2.95 (m, 1H), 2.89−2.79 (m, 2H), 2.76−2.66 (m, 1H), 1.84 (d, J
= 11.9 Hz, 1H), 1.78 (d, J = 13.1 Hz, 1H), 1.68 (d, J = 8.2 Hz, 2H),
1.64−1.24 (m, 15H). 13C NMR (101 MHz, MeOD) δ 82.4, 78.4, 74.7,
70.9, 63.1, 62.0, 61.3, 58.9, 45.5, 33.9, 33.5, 29.4, 29.3, 27.2, 26.3, 25.5,
24.4, 23.3. HRMS ESI: calcd for C18H37N2O5 [M + H]+ 361.2697,
found 361.2696.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
́
Vallee, Y. J. Org. Chem. 2005, 70, 1459. (d) Carmona, A. T.;
AUTHOR INFORMATION
Corresponding Author
*E-mail: yucy@iccas.ac.cn.
Notes
Whigtman, R. H.; Robina, I.; Vogel, P. Helv. Chim. Acta 2003, 86,
3066. (e) Wang, W.-B.; Huang, M.-H.; Li, Y.-X.; Rui, P.-X.; Hu, X.-G.;
Zhang, W.; Su, J.-K.; Zhang, Z.-L.; Zhu, J.-S.; Xu, W.-H.; Xie, X.-Q.; Jia,
Y.-M.; Yu, C.-Y. Synlett 2010, 488.
■
(8) Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Phillips, J. L.;
Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J. Org. Chem.
1991, 56, 4056.
The authors declare no competing financial interest.
(9) (a) Ruttens, B.; Van der Eycken, J. Tetrahedron Lett. 2002, 43,
2215. (b) Wennekes, T.; Meijer, A. J.; Groen, A. K.; Boot, R. G.;
Groener, J. E.; van Eijk, M.; Ottenhoff, R.; Bijl, N.; Ghauharali, K.;
Song, H.; O’Shea, T. J.; Liu, H.; Yew, N.; Copeland, D.; van den Berg,
R. J.; van der Marel, G. A.; Overkleeft, H. S.; Aerts, J. M. J. Med. Chem.
2009, 53, 689.
ACKNOWLEDGMENTS
■
Financial support from National Basic Research Program of
China (No. 2012CB822101 and 2011CB808603) and The
Natural Science Foundation of China (No. 21272240) is
gratefully acknowledged. We thank Dr. Jun-Feng Xiang for the
help on the NMR analysis.
(10) Delso, I.; Tejero, T.; Goti, A.; Merino, P. Tetrahedron 2010, 66,
1220.
(11) Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.;
Heathcock, C. H. J. Org. Chem. 1991, 56, 2499.
(12) Best, D.; Jenkinson, S. F.; Rule, S. D.; Higham, R.; Mercer, T. B.;
Newell, R. J.; Weymouth-Wilson, A. C.; Fleet, G. W. J.; Petursson, S.
Tetrahedron Lett. 2008, 49, 2196.
(13) (a) Magnus, P.; Thurston, L. S. J. Org. Chem. 1991, 56, 1166.
(b) Cooley, J. H.; Evain, E. J. Synthesis 1989, 1.
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A.; Piniella, J. F. J. Org. Chem. 2003, 68, 2437.
(16) The structure of 11 was confirmed by crystal structure. The
crystal structure of compound 11 has been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition number
CCDC 900101. See the Supporting Information for the details.
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