First total synthesis of (+)-broussonetine W: Glycosidase inhibition of natural product & analogs

Article abstract of DOI:10.1039/c6ob00720a

The first total synthesis of (+)-broussonetine W (4), a naturally-occurring pyrrolidine iminosugar isolated from the traditional Chinese medical plant Broussonetia kazinoki SIEB (Moraceae), has been completed through a concise synthetic route starting from the readily available d-arabinose derived cyclic nitrone 10 in 11 steps and 31% overall yield, with regioselective installation of the α,β-unsaturated ketone functional group by the elimination of HBr from α-bromoketone as the key step. A number of analogs of (+)-broussonetine W (4) with variable side chain length, different polyhydroxylated pyrrolidine core configurations or saturated cyclohexanones have also been prepared to explore the glycosidase inhibition and the preliminary structure-activity relationship of this intriguing class of compounds. Glycosidase inhibition studies identified the natural product (+)-broussonetine W (4) as a selective and potent inhibitor of β-galactosidase (IC₅₀ = 0.03 μM), while its enantiomer was a selective and potent inhibitor of α-glucosidase (IC₅₀ = 0.047 μM). It was found that the configuration of the polyhydroxylated pyrrolidine ring played a key role on their glycosidase inhibitory activities. The length of side chain and α,β-unsaturated ketone functional group also exhibited some effect on their glycosidase inhibition.

Full text of DOI:10.1039/c6ob00720a

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First Total Synthesis of (+)-Broussonetine W: Glycosidase
Inhibition of Natural Product & Analogs
Ying-Ying Song,a,e Kyoko Kinami,b Atsushi Kato,*,b Yue-Mei Jia,a Yi-Xian Li,a George W. J. Fleetc,d and
Chu-Yi Yu*,a,d
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The first total synthesis of (+)-broussonetine W (4), a naturally-occurring pyrrolidine iminosugar isolated from the
traditional Chinese medical plant Broussonetia kazinoki SIEB (Moraceae), has been completed through a concise synthetic
www.rsc.org/
route starting from the readily available D-arabinose derived cyclic nitrone 10 in 11 steps and 31% overall yield, with
regioselective installation of the α,β-unsaturated ketone functional group by the elimination of HBr from α-bromoketone
as the key step. A number of analogs of (+)-broussonetine W (4) with variable side chain length, different polyhydroxylated
pyrrolidine core configurations or saturated cyclohexanones have also been prepared to explore the glycosidase inhibition
and the preliminary structure-activity relationship of this intriguing class of compounds. Glycosidase inhibition studies
identified the natural product (+)-broussonetine W (4) as a selective and potent inhibitor of β-galactosidase (IC50 = 0.03 μM
), while its enantiomer was a selective and potent inhibitor of α-glucosidase (IC50 = 0.047μM). It was found that the
configuration of the polyhydroxylated pyrrolidine ring played a key role on their glycosidase inhibitory activities. The
length of side chain and α,β-unsaturated ketone functional group also exhibited some effect on their glycosidase
inhibition.
5R pyrrolidine rings. Therefore, these compounds could be
viewed as homologues of 1,4-dideoxy-1,4-imino-D-arabinitol
4d,5
Introduction
(DAB,
5
)4 or 2,5-dideoxy-2,5-imino-
D
-mannitol (DMDP,
6
)
.
Broussonetines, a family of naturally-occurring iminosugar
alkaloids with a polyhydroxylated pyrrolidine ring as its core
structural segment, have been isolated from the branches of
Broussonetia kazinoki SIEB (Moraceae),1 which is a raw
material for handmade Japanese paper and traditional Chinese
medicines. Thus far, more than 30 of this class of alkaloids
have been isolated and characterized, namely broussonetines
A-X, J1, J2, M1, U1, and broussonetinines A and B, etc. (Figure
1).2
OH
H
N
H
O
∗
∗
N
O
HO
HO
H
HO
OH
HO
OH
DAB (5)
broussonetine H (1)
OH
OH
H
N
H
N
With broussonetines N (pyrrolizidine ring), U, and U1
(pyrroline ring) as exceptions, broussonetines and
OH
HO
HO
H
O
broussonetinines share
a
common polyhydroxylated
HO
OH
HO
OH
pyrrolidine core3 and a 13-carbon-atom side chain that
contains various functional groups at the C-5 position of the
pyrrolidine ring. Although a subset has been assigned as 2R, 3S,
4R, 5R configuration, most of these alkaloids have 2R, 3R, 4R,
broussonetine R (2)
DMDP (6)
O
O
H
N
H
N
1'
1''
HO
HO
2
5
5
5
3
4
HO
OH
HO
OGlc
a.Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China. Email: yucy@iccas.ac.cn
broussonetine W (4)
broussonetine X (3)
b.Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama
930-0194, Japan. E-mail: kato@med.u-toyama.ac.jp
Figure 1. Representative examples of broussonetines.
c. Chemistry Research Laboratory, Department of Chemistry, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, UK.
d.National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal
University, Nanchang 330022, PR China
Broussonetines have been attracted intense interest due to
their glycosidase inhibition activities and potential therapeutic
applications in diseases including cancer, HIV1e,1f,2,6 and
lysosomal storage disorders7. In particular, many
e. University of Chinese Academy of Sciences, Beijing 100049, China.
Electronic Supplementary Information (ESI) available: Copies of 1H, 13C and 2D
NMR spectra and results of the bioassay. See DOI: 10.1039/x0xx00000x
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broussonetines showed potent and selective inhibition against could be synthesized first and the protecting groups on the
β-glycosidases (β-glucosidases, β-galactosidases, or β- hydroxyl and amino groups can be converted to acetyl groups
mannosidases); for example, broussonetine H (1) is a potent for easy deprotection in the final step (Scheme 2).
inhibitor of β-galactosidases (IC50 = 0.002 μM, from bovine
liver) and β-glucosidase (IC50 = 0.036 μM, from sweet almond).
Moreover, synthetic L-enantiomers of some DMDP-related
iminosugars have been attractive targets in recent years due
to their potent and selective a-glucosidase inhibition.5b,9 Our
previous study on the synthesis and glycosidase inhibition of
broussonetines8, showed that the
L-enantiomers of
broussonetine I and J2 showed potent and selective inhibition
of α-glucosidases, and as such may have chemotherapeutic
potential in the treatment of type-II diabetes9g,10, cancer11, and
viral infections3f,12. In view of the interesting structures and
biological activities of the broussonetines family, efficient
synthetic methods for these alkaloids and their analogs,
including their enantiomers, need to be developed. However,
to date, relatively few syntheses have been reported.8,13
Broussonetine W (4) was isolated from Broussonetia in 2001
Scheme 1. Initial synthetic strategy for the synthesis of
broussonetine W ( ).
by Kusano and co-workers.1h The relative configuration of
broussonetine W was established on the basis of NOE
experiments and the absolute configuration was assigned as
(2R,3R,4R,5R) by analogy with the [α]D value (+16.0) of
broussonetine W with those of broussonetines C (+25.0) and D
(+22.9).1a However, the proposed structure can only be
determined unless unequivocally confirmed by total synthesis.
No biological evaluation has been reported for broussonetine
4
W (4). Because of the potent glycosidase inhibition of the
8
closely related broussonetine I and J2 , we became interested
in the synthesis of broussonetine W to establish both the
relative and absolute configurations of broussonetine W and
to study its biological activity.
Results and discussion
Our initial synthetic strategy for the total synthesis of
broussonetine W (4) is presented in Scheme 1. Construction of
the long side chain between the pyrrolidine and
cyclohexenone moieties could be accomplished by CM
reactions14, which proved to be a flexible strategy in the
synthesis of broussonetine I and J2.8 Therefore, the precursor
Scheme 2. Retrosynthesis of broussonetine W (4).
The α,β-unsaturated keto function18 in the target product
could be introduced by regioselective α-halogenation of
compound
pyrrolidine fragment
pyrrolidine can be obtained from
nitrone 10, which was easily prepared on a large scale by our
7
can be synthesized through CM reaction of
and cyclohexenone Clearly,
-arabinose derived cyclic
8
9.
ketone 13 18b-d,19
followed by elimination of HX from α-
,
8
D
haloketone 12. The key intermediate 13 could be synthesized
by the α-alkylation of the imine 14 with bromide 15, and
subsequent conversion of the protecting groups to acetyl
groups. Pyrrolidine fragment 15 could be obtained from cyclic
improved approach,15 while cyclohexenone
9 can be prepared
from 3, 4-2H-dihydropyran (11).16 Unfortunately, all attempts
at the regioselective hydrogenation17 of the C4’–C5’ double
15,20
nitrone 10 by successive Grignard reaction,
bond in compound 7, proved to be unsuccessful. It was not
hydroboration/oxidation and Appel halogenations of the
resulting alcohol.21
possible to reduce the carbon-carbon double bond of the side
chain whilst retaining the α,β-unsaturated ketone group.
Accordingly, the polyhydroxylated pyrrolidine moiety 17 was
Hydrogenation of
7 always resulted in the formation of a
first synthesized from D-arabinose derived cyclic nitrone 10
mixture of products with poor regioselectivity.
(Scheme 3). The addition of hept-6-en-1-ylmagnesium bromide
o
to the cyclic nitrone 10 at 0 C afforded hydroxylamine 16 as
Thus, the synthetic strategy was modified so that the α,β-
unsaturated ketone group could be introduced at the last step,
thereby avoiding the troublesome regioselective reduction of
the C4’–C5’ double bond. The cyclohexanone derivative 13
the only product,8,20f,22 which was used in the next step
without further purification. The newly formed chiral centre
2 | J. Name., 2012, 00, 1-3
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was determined as R-configuration by NOE experiments. Figure 2. Broussonetine W (
Reduction of hydroxylamine 16 by Zn-Cu(OAc)2-AcOH system Therefore, pyrrolidines fragments with a terminal bromide,
gave the corresponding amine, which was treated with CbzCl i.e. ent-15 3-epi-15 ent-3-epi-15 ent-15a and ent-15b, have
4) and its analogs.
,
,
,
to form the N-Cbz derivative 17 in 87% yield (3 steps). also been prepared by the same methodology as that for the
Hydroboration of 17 with BH3-THF and subsequent oxidation synthesis of 15, starting from the various corresponding cyclic
by H2O2 (30%) gave the primary alcohol 18 in 73% yield, which nitrones and Grignard reagents (Table 1).
on treatment with CBr4 and PPh3 afforded the corresponding
bromide 15 in 97% yield.
Table 1. Pyrrolidine fragments derived from different cyclic
nitrones or different Grignard reagents.
Entry
Cyclic Nitrone
Product
Yielda (%)
1
62
2
3
77
58
Cbz
N
Br
BnO
5
BnO
OBn
3-epi-15
4
5
6
53
70
79
Scheme 3. Synthesis of pyrrolidine 15
.
In order to determine unambiguously the relative and
absolute configurations of the natural product broussonetine
W, both broussonetine W (4) and ent-broussonetine W (ent-4)
were synthesized. Furthermore, in order to verify the
generality of this synthetic method for the synthesis of
broussonetine W-related compounds and explore the
preliminary structure-activity relationship of broussonetine W,
several analogs of broussonetine W (
length ent-4a ent-4b and different polyhydroxylated
pyrrolidine core configurations (3-epi-4
4) with varied side chain
aTotal yield in 5 steps starting from cyclic nitrones to the
corresponding bromide
(
,
)
,
ent-3-epi-4) were
prepared (Figure 2).
Scheme 4. Synthesis of ketone 19.
With the pyrrolidine fragments in hand, the next task was
the installation of cyclohexanone into the molecules. As an
example, α-alkylation of imine 14, which had been prepared
from the reaction of cyclohexanone and cyclohexylamine,23
with pyrrolidine bromide 15, followed by aqueous work-up
gave ketone 19 in 73% yield (Scheme 4).24 By the same
sequence, analogs of ketone 19, i.e. ent-19, 3-epi-19, ent-3-
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epi-19
Journal Name
,
ent-19a and ent-19b, were synthesized from the Scheme 5. Transformation of the protecting-groups.
corresponding bromides (Table 2).
Table 2. Ketones derived from the corresponding bromides.
Yield (%)a
Entry
Substrate
product
1
73
2
3
4
71
60
71
Figure 3. Cyclohexanone analogs of broussonetine W.
The final problem in the total synthesis of broussonetine W
was the introduction of α,β-unsaturated ketone group at the
end of the side chain,18 by an elimination reaction on a
corresponding α-haloketone. A number of reagents and
reaction conditions were screened to optimize the
regioselective α-halogenation of ketone 21 (Table 3).18b,18d
Treatment of ketone 21 with (TMS)2NH/NaI/TMSCl system
followed by NBS was the best method which produced the
desired α-bromoketone 12b (X=Br, Y=H) in excellent isolated
yield. Thus, α-bromination of ketone 21 and β-elimination of
the resulted α-bromoketone 12b yielded the acetyl-protected
broussonetine W (22) in 83% yield in two steps (Scheme 6).
Analogs of acetyl-protected broussonetine W, i.e. compounds
5
68
71
6
aIsolated yield.
The last challenge in the synthesis of broussonetine W
analogs was the formation of α,β-unsaturated ketone group
via α-halogenation-elimination of the cyclohexanone. In
order to avoid the potential side reactions that may be
caused by N-Cbz group in the α-halogenations of ketone 19
and also to prevent the reduction of the α,β-unsaturated
ketone group during the debenzylation process, the
protecting groups were first converted to acetyl groups,
which allowed final deprotection easily without any of the
above side reactions. Thus, Pd-catalyzed hydrogenolysis of
ketone 19 gave the broussonetine W analog 20 containing a
saturated cyclohexanone group at the end of the side chain,
22, ent-22, 3-epi-22, ent-3-epi-22, ent-22a and ent-22b, were
also synthesized by the same method (Table 4).
in 96% yield.
A
series of analogs with saturated
ent-20 3-epi-20 ent-3-epi-20 ent-
cyclohexanone group (20
,
,
,
,
20a and ent-20b) were obtained easily by this process (Figure
3). Treatment of compound 20 with conventional acetylation
methods provided fully protected compound 21 in 95% yield
(Scheme 5).
Scheme 6. Synthesis of 22
.
Table 3. Screening the α-halogenation conditions.
Solvent/ oC
CCl4/rt
Entry
Reagent
NBS
result
yield a
1
2
3
4
5
No reaction
No reaction
No reaction
12a:X=Y=Cl
12a:X=Y=Cl
-
NBS
CCl4/80
CCl4/120
CCl4/rt
-
NBS
-
SO2Cl2
SO2Cl2
100%
100%
CCl4/0
(TMS)2NH, NaI,
CH3CN/
0, then -20
12b:X=Br
6
95%
TMSCl, then NBS
Y=H
aConversion of 21
.
4 | J. Name., 2012, 00, 1-3
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Table 4. α,β-Unsaturated ketones derived from the reported NMR data, and therefore were carried out in CD3OD
corresponding ketones.
Entry
to obtain relatively better peak splits.
Substrate
Product
Yield
(%)a
A similar synthetic approach to ent-4, 3-epi-4 and ent-3-epi-
4
(Figure 2 and Figure 3) allowed a preliminary study of the
structure-activity relationship of broussonetine W and its
analogs. In addition, analogs with different side chain length
1
80
59
78
69
67
(
ent-4a, ent-4b) were prepared.
Glycosidase Inhibition.
2
3
4
5
Broussonetine W and its analogs were assayed26 as potential
glycosidase inhibitors of a range of enzymes (Table 5 and 6).
The synthetic D-broussonetine W (4) showed very powerful
inhibition of β-glucosidase from bovine liver (IC50 = 0.12 μM),
β-galactosidase from bovine liver (IC50 = 0.03 μM), and it also
showed potent inhibition toward β-glucuronidase from E.coli
(IC50 = 3.3 μM). In contrast, its enantiomer
ent-4) showed remarkable enhancements in α-glucosidases
from rice, rat intestinal maltase, rat intestinal sucrose (IC50
L-broussonetine W
(
=
0.73 μM, 0.047 μM, 0.20 μM, respectively), whereas ent-4
clearly decreased the inhibition of these β-glycosidases. The
enhanced α-glucosidase inhibition parallels that of
the core pyrrolidine structure. 3-Epi-4 was a much weaker
inhibitor than natural product (+)-broussonetine W ( ). This
L-DMDP in
aIsolated yield.
4
result indicated that the C3 configuration of polyhydroxylated
pyrrolidine ring played a key role on their glycosidase
inhibitory activity. However, it is noteworthy that dramatic
changes in the spectrum and potency of inhibition were found
for its enantiomer ent-3-epi-4. This compound still showed
potent inhibition of bovine liver β-glucosidase, bovine liver β-
galactosidase, with IC50 values 0.99 and 0.18 μM, respectively.
Furthermore, its inhibition toward α-glucosidases from rat
intestinal maltase and sucrose were clearly increased relative
Scheme 7. Completion of the total synthesis of broussonetine
W ( ).
4
to the natural product (+)-broussonetine W (
values 3.5 and 3.4 μM, respectively.
4), with IC50
Completion of the total synthesis was then achieved
smoothly by removal of the acetyl protecting groups from the
hydroxyl and amino groups. Thus, treatment of 22 with
MeONa/MeOH followed by concentrated hydrochloric acid
Variations in the length of the side chain did not have a
significant effect on their glycosidase inhibition through
comparison of ent-broussonetine W related (ent-4, ent-4a,
provided broussonetine W (
4
) in 92% yield (Scheme 7).25 The
ent-4b). The glycosidase inhibition activity was slightly
weakened, when the side chain length was shortened.
synthetic broussonetine W (
4) displayed identical spectral
properties (1H NMR, 13C NMR) to those reported in the
literature for the natural product (see the Supplementary
Information for the details); the specific rotation of the
The terminal substituents fixed at the end of the side chain
did not show significant effect on the patterns of glycosidase
inhibitory activities. However, some changes have a small
effect on the potency of inhibition against the same enzyme.
synthetic broussonetine W (4
) {[α]D20 +15.0 (c 0.4, MeOH)} was
consistent with that of the natural broussonetine W {[α]D +16.0
(c 0.07, MeOH)}.1h These measurements confirmed that both
the reported relative and absolute configurations of natural
broussonetine W were correct.
Compounds containing the saturated cylohexanone group (20
ent-20 3-epi-20 ent-3-epi-20 ent-20a ent-20b) were slightly
weaker inhibitors against the same enzyme than natural
product (+)-broussonetine W ( ) and its analogs containing the
same α,β-unsaturated cylohexenone group (ent-4 3-epi-4
ent-3-epi-4 ent-4a ent-4b). However, 3-epi-20 was notably
,
,
,
,
,
4
The NMR spectra of the natural product were performed in
pyridine in order to compare with the literature data reported
in pyridine. Other analogues were all new compounds without
,
,
,
,
found to be a much stronger inhibitor of α-glucosidases than
3-epi-4 which has the unsaturated cylohexenone group.
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Table 5. The glycosidase inhibition of Broussonetine W and Its Analogs (
Journal Name
4,
ent-4
, 3-epi-4, ent-3-epi-4, ent-4a, ent-4b)
IC50 (μM)
enzyme
4
ent-4
3-epi-4
ent-3-epi-4
ent-4a
ent-4b
α-glucosidase
yeast
22
119
407
0.73
0.047
1.5
NIa (23.7%)b
63
310
24
758
1.1
622
1.3
0.2
5.1
0.28
21
rice
rat intestinal maltase
intestinal isomaltase
rat intestinal sucrase
ER α-glucosidase II
β-glucosidase
almond
67
NI (43.9%)
NI (0%)
111
3.5
114
3.4
200
0.19
3.0
NI (29.3%)
216
0.20
7.5
0.25
15
NI (43.5%)
NI (13.2%)
9.8
NI (39.5%)
180
NI (31.8%)
44
92
NI (27.2%)
59
NI (13.4%)
263
bovine liver
0.12
0.99
α-galactosidase
coffee bean
NI (19.6%)
0.03
NI (4.2%)
127
NI (46.9%)
11
NI (15.8%)
0.18
NI (1.1%)
11
NI (19.1%)
105
β-galactosidase
bovine liver
α-mannosidase
jack bean
NI (15.1%)
282
NI (0%)
NI (0%)
NI (0%)
NI (8.3%)
NI (0%)
174
385
NI (5.4%)
NI (0%)
20.4
NI (0%)
NI (0%)
NI (0%)
NI (16.4%)
NI (16.2%)
591
NI (6.5%)
NI (1.2%)
NI (43.3%)
NI (10.0%)
NI (0%)
β-mannosidase
snail
NI (7.7%)
NI (12.3%)
NI (2.2%)
NI (2.8%)
NI (47.3%)
α-L-fucosidase
bovine kidney
α, α-trehalase
porcine kidney
amyloglucosidase
Aspergilusniger
α-L-rhamnosidase
Penicillium decumbens
β-glucuronidase
E.coli
NI (16.8%)
NI (0.8%)
30
NI (3.3%)
448
NI (35.1%)
166
1000
3.3
38
14
27
83.3
25
60
bovine liver
NI (46.1%)
379
NI (40.2%)
NI (46.7%)
186
a NI: No inhibition (less than 50% inhibition at 1000 μM).
b ( ): inhibition % at 1000 μM.
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Table 6. The glycosidase inhibition of Broussonetine W’s Analogs (20, ent-20, 3-epi-20, ent-3-epi-20, ent-20a, ent-20b).
IC50 (μM)
enzyme
20
ent-20
3-epi-20
ent-3-epi-20
ent-20a
ent-20b
α-glucosidase
yeast
80
70
NIa (32.7%)b
NI (44.0%)
7.9
NI (16.7%)
NI (46.8%)
1.4
NI (39.1%)
3.7
rice
1.7
0.15
3.7
33
13
rat intestinal maltase
intestinal isomaltase
rat intestinal sucrase
ER α-glucosidase II
β-glucosidase
almond
32
1.6
0.11
2.1
0.14
3.8
663
40.3
3.1
366
18
80
0.36
14
0.14
12
0.17
25
NI (46.9%)
157
458
43
NI (37.2%)
14
NI (25.4%)
27
NI (35.5%)
40
NI (35.8%)
237
NI (39.0%)
372
bovine liver
0.10
α-galactosidase
coffee bean
NI (13.8%)
0.046
NI (14.6%)
8.5
NI (29.4%)
35
NI (13.5%)
14
NI (0%)
42
NI (0.7%)
129
β-galactosidase
bovine liver
α-mannosidase
jack bean
NI (33.7%)
224
NI (0%)
NI (15.2%)
NI (0.7%)
NI (3.3%)
NI (28.3%)
152
245
NI (2.4%)
NI (0%)
28
NI (1.2%)
NI (0.9%)
NI (35.7%)
NI (10.0%)
NI (4.6%)
330
NI (0%)
NI (0%)
NI (7.6%)
NI (13.2%)
NI (1.5%)
410
β-mannosidase
snail
NI (0%)
NI (18.9%)
NI (0%)
NI (7.7%)
895
α-L-fucosidase
bovine kidney
α, α-trehalase
porcine kidney
amyloglucosidase
Aspergilusniger
α-L-rhamnosidase
Penicillium decumbens
β-glucuronidase
E.coli
NI (25.2%)
NI (0.8%)
41
NI (0%)
NI (8.6%)
443
NI (31.4%)
9.5
79
21
45
428
435
597
bovine liver
NI (39.7%)
NI (45.2%)
NI (39.0%)
NI (12.3%)
NI (31.9%)
a NI: No inhibition (less than 50% inhibition at 1000 μM).
b ( ): inhibition % at 1000 μM.
comparison of the specific rotations of the synthetic
broussonetine with that of the natural product.
W
Conclusion:
Furthermore, in order to explore the structure-activity
relationship of broussonetine W and related compounds, a
number of analogs of broussonetine W have also been
synthesized via the same synthetic procedure starting from
different cyclic nitrones. Glycosidase inhibition study revealed
In summary, the first total synthesis of broussonetine W has
been achieved in 11 steps and 31% total yield, starting from D-
arabinose derived cyclic nitrone 10; the key step of this
synthetic method is the regioselective installation of the α,β-
unsaturated ketone group by elimination of α-bromoketone.
The relative and absolute configurations of natural product
that natural product (+)-broussonetine
W (4) and its
enantiomer ent-4 showed clearly different inhibition
specificities. Ent-4 showed enhancements in α-glucosidases,
whereas it decreased the inhibition of these β-glycosidases.
The side chain length and α,β-unsaturated ketone group do
broussonetine
W have been confirmed unambiguously
through the synthesis of both enantiomers of broussonetine
1
W, by the clear study of their H and 13C NMR spectra and a
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not have significant effect on their glycosidase inhibition. This syrup. Data for 16: [α]D20 -8.0 (c 0.5, CH2Cl2); IR (KBr, cm-1):
concise and efficient synthetic strategy shows the value of 3238, 3064, 3030, 2926, 2856, 1497, 1454, 1363, 1100, 736,
1
sugar nitrones in a general approach to this class of alkaloids 697; H NMR (500 MHz, CDCl3) δ 7.28–7.16 (m, 15H), 6.02–
which will allow the detailed study of their structure-activity 5.55 (m, 2H), 4.95–4.82 (m, 2H), 4.50–4.35 (m, 6H), 3.88–3.85
relationship.
(m, 1H), 3.74–3.68 (m, 2H), 3.54–3.48 (m, 1H), 3.45 (dd, J =
10.5, 5.3 Hz, 1H), 3.10 (dt, J = 7.9, 5.5 Hz, 1H), 1.95 (q, J = 6.8
Hz, 2H), 1.78 (s, 1H), 1.45–1.36 (m, 1H), 1.35–1.17 (m, 6H). 13C
NMR (126 MHz, CDCl3) δ 139.2, 138.3, 138.2, 128.50, 128.48,
128.47, 128.1, 128.0, 127.84, 127.81, 127.75, 114.4, 86.9, 84.8,
73.5, 71.81, 71.77, 70.2, 70.1, 68.5, 33.9, 29.4, 29.0, 26.5.
HRMS ESI: calcd for C33H41NO4H+ [M + H]+ 516.31084, found
516.31133.]
Experimental section
Material and methods
All reagents were used as received from commercial sources
without further purification or prepared as described in the
literature. Acetonitrile and pyridine were dried with activated
4-Å molecular sieves before use. Tetrahydrofuran was distilled
from sodium and benzophenone immediately before use. TLC
plates were visualized by ultraviolet light or by treatment with
a 0.5% solution of KMnO4 in acetone or a spray of Pancaldi
reagent ((NH4)6MoO4, Ce(SO4)2, H2SO4, H2O). Chromatographic
purification of products was carried out by flash column
chromatography on silica gel (200–300 mesh). Acidic ion
exchange chromatography was performed on Dowex 50WX8-
400, H+ form. 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),
Methanol-d4 or Pyridine-d5 on a Bruker AV300 (1H at 300 MHz,
13C at 75 MHz), a Bruker AV400 (1H at 400MHz, 13C at 101
MHz) or a Bruker AV500 (1H at 500 MHz, 13C at 126 MHz)
magnetic resonance spectrometer. 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 a
Thermo Scientific LTQ/FT mass spectrometer or a GCT mass
spectrometer. Polarimetry was carried out using an Optical
Activity AA-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.
Zinc powder (3.07 g, 47.90 mmol) and Cu(OAc)2 (88 mg, 0.48
mmol) was added to acetic acid (20 mL), and the mixture was
stirred at room temperature for 15 min after which the color
turned to brown. Crude product hydroxylamine 16 was added,
and the reaction mixture was stirred at room temperature for
8 h. After the starting material disappeared, acetic acid was
removed under reduced pressure, then EtOAc was added and
the reaction mixture filtered to remove the solid. The filtrate
was washed with saturated aqueous solution of NaHCO3 until
the mixture became neutral. The combined organic layers
were dried with MgSO4 and concentrated in vacuo.
To a solution of the crude product in THF (about 20 mL,
o
including 1~2 mL secondary H2O) at 0 C was added NaHCO3
(0.80 g, 9.58 mmol) and CbzCl (0.8 mL, 5.75 mmol) slowly, and
the reaction mixture was stirred for 1 h at room temperature.
The reaction was quenched with water and extracted with
EtOAc (3 × 10 mL). The combined organic layers were dried
with MgSO4 and concentrated in vacuo. The residuewas
purified by flash column chromatography (silica gel, petroleum
ether/EtOAc = 15/1) to afford 17 (2.64 g, 4.16 mmol, 87% in 3
steps) as a light yellow syrup.
20
Data for 17: [α]D -27.6 (c 1.5, CH2Cl2); IR (KBr, cm-1): 3064,
3031, 2926, 2857, 1699, 1496, 1455, 1409, 1347, 1205, 1097,
1
735, 697; H NMR (500 MHz, CDCl3) δ 7.39–7.14 (m, 20H),
5.84–5.70 (m, 1H), 5.23–5.14 (m, 1H), 5.03 (d, J = 12.3 Hz, 1H),
5.01–4.89 (m, 2H), 4.67–4.56 (m, 1.5H), 4.49–4.41 (m, 2H),
4.41–4.31 (m, 2.5H), 4.25 (d, J = 10.0 Hz, 0.5H), 4.18–4.12 (m,
1.5H), 4.08–4.03 (m, 0.5H), 3.87–3.70 (m, 2.5H), 3.51–3.44 (m,
1H), 2.09–1.91 (m, 2.5H), 1.77–1.51 (m, 1.5H), 1.42–1.09 (m,
6H). 13C NMR (126 MHz, CDCl3) δ 154.8, 154.3, 139.2, 139.1,
138.6, 138.4, 138.1, 138.0, 137.79, 137.75, 136.74, 136.69,
128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 127.87, 127.85,
127.80, 127.76, 127.72, 127.67, 127.6, 114.4, 114.3, 84.5, 83.4,
83.2, 82.1, 73.13, 73.06, 71.3, 71.1, 70.9, 68.9, 67.9, 67.0, 66.9,
65.1, 64.8, 63.0, 62.7, 33.8, 33.7, 31.5, 30.2, 29.0, 28.9, 28.8,
26.51, 26.47. HRMS ESI: calcd for C41H47NO5H+ [M + H]+
634.35270, found 634.35182.
General procedures for synthesis of compound 17, ent-17
epi-17 ent-3-epi-17 ent-17a and ent-17b, with compound 17
as an example.
, 3-
,
,
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-1-
benzyloxycarbonyl-5-(hept-6-en-1-yl)pyrrolidine (17)
To a stirred solution of cyclic nitrone 10 (2.00 g, 4.79 mmol) in
anhydrous THF (10 mL) was added a solution of Grignard
reagent hept-6-en-1-ylmagnesium bromide in THF [prepared
by stirring Mg turnings (240 mg, 10.06 mmol) and 7-
bromohept-1-ene (1.46 mL, 9.58 mmol) in THF (5 mL)] at 0 oC,
under argon atmosphere. The reaction mixture was stirred for
30 min, quenched with a saturated aqueous solution of NH4Cl.
The aqueous layer was extracted with EtOAc (3 × 10 mL). The
combined extracts were dried and the solvents were removed
in vacuo to give the crude product hydroxylamine 16, which
was used directly in the next step of reaction without further
purification. [The sample for structure characterization was
obtained via purification by flash column chromatography
(silica gel, petroleum ether/EtOAc = 5/1) as a light yellow
Ent-17: light yellow syrup, 2.98 g, 4.69 mmol, 98% yield in 3
steps, starting from the corresponding cyclic nitrone ent-10
(2.00 g, 4.79 mmol).
20
Data for ent-16: colorless syrup, [α]D +10.9 (c 0.55, CH2Cl2);
IR (KBr, cm-1): 3244, 2927, 2857, 1639, 1497, 1454, 1363, 1100,
735, 697; 1H NMR (500 MHz, CDCl3) δ 7.36–7.24 (m, 15H), 6.13
(s, br, 1H), 5.84–5.74 (m, 1H), 5.01–4.95 (m, 1H), 4.94–4.90 (m,
1H), 4.57–4.42 (m, 6H), 3.94 (dd, J = 3.8, 2.7 Hz, 1H), 3.82–3.75
8 | J. Name., 2012, 00, 1-3
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(m, 2H), 3.58 (dd, J = 9.4, 6.9 Hz, 1H), 3.54–3.50 (m, 1H), 3.19– Ent-3-epi-17: light yellow syrup, 3.46 g, 5.46 mmol, 76% yield
3.14 (m, 1H), 2.05–1.99 (m, 2H), 1.78 (s, 1H), 1.45–1.36 (m, in 3 steps, starting from the corresponding cyclic nitrone ent-3-
1H), 1.35–1.17 (m, 6H). 13C NMR (126 MHz, CDCl3) δ 139.2, epi-10 (3.00 g, 7.19 mmol).
20
138.3, 138.21, 138.20, 128.49, 128.47, 128.46, 128.1, 128.0, Data for ent-3-epi-16: colorless syrup, [α]D
+7.3 (c 1.1,
127.83, 127.80, 127.7, 114.4, 86.9, 84.7, 73.5, 71.8, 71.7, 70.2, CH2Cl2); IR (KBr, cm-1): 3269, 2926, 2857, 1640, 1497, 1454,
1
70.1, 68.4, 33.9, 29.4, 29.0, 26.5. HRMS ESI: calcd for 1363, 1100, 734, 697; H NMR (500 MHz, CDCl3) δ 7.35–7.24
C33H41NO4H+ [M + H]+ 516.31084, found 516.31077.
(m, 15H), 5.85 (s, br, 1H), 5.83–5.75 (m, 1H), 5.01–4.95 (m, 1H),
20
Data for ent-17: [α]D +41.4 (c 1.4, CH2Cl2); IR (KBr, cm-1): 4.95–4.90 (m, 1H), 4.70 (d, J = 11.7 Hz, 1H), 4.63 (d, J = 11.9 Hz,
3064, 3031, 2927, 2857, 1699, 1497, 1454, 1409, 1348, 1205, 1H), 4.57 (d, J = 11.7 Hz, 1H), 4.55 (d, J = 11.9 Hz, 1H), 4.50 (d, J
1
1112, 736, 697; H NMR (300 MHz, CDCl3) δ 7.40–7.13 (m, = 11.9 Hz, 1H), 4.46 (d, J = 11.8 Hz, 1H), 4.20 (t, J = 5.0 Hz, 1H),
20H), 5.87–5.65 (m, 1H), 5.18 (t, J = 12.6 Hz, 1H), 5.06–4.88 (m, 3.85 (dd, J = 9.7, 7.0 Hz, 1H), 3.80 (dd, J = 9.7, 6.4 Hz, 1H), 3.67
3H), 4.66–4.53 (m, 1.5H), 4.48–4.39 (m, 2H), 4.39–4.22 (m, (dd, J = 7.0, 5.0 Hz, 1H), 3.51–3.47 (m, 1H), 3.32–3.26 (m, 1H),
3H), 4.20–4.11 (m, 1.5H), 4.07 (dd, J = 8.5, 3.9 Hz, 0.5H), 3.90– 2.06–1.98 (m, 2H), 1.72–1.62 (m, 1H), 1.50–1.41 (m, 2H), 1.41–
3.69 (m, 2.5H), 3.48 (t, J = 9.6 Hz, 1H), 2.13–1.89 (m, 2.5H), 1.25 (m, 5H). 13C NMR (126 MHz, CDCl3) δ 139.3, 138.4, 138.3,
1.79–1.47 (m, 1.5H), 1.41–1.07 (m, 6H). 13C NMR (75 MHz, 138.2, 128.50, 128.49, 127.99, 127.97, 127.94, 127.86, 127.79,
CDCl3) δ 154.7, 154.3, 139.1, 139.0, 138.6, 138.3, 138.0, 137.9, 127.77, 114.3, 83.3, 77.3, 73.7, 73.6, 72.8, 70.9, 68.9, 67.4,
137.72, 137.69, 136.7, 136.6, 128.54, 128.48, 128.41, 128.37, 33.9, 30.5, 29.4, 29.0, 26.9. HRMS ESI: calcd for C33H41NO4H+
128.2, 128.1, 128.0, 127.80, 127.75, 127.70, 127.66, 127.62, [M + H]+ 516.31084, found 516.3112.
20
127.56, 114.34, 114.30, 84.4, 83.3, 83.2, 82.0, 73.1, 73.0, 71.2, Data for ent-3-epi-17: [α]D +10.0 (c 0.8, CH2Cl2); IR (KBr, cm-
71.0, 70.9, 68.8, 67.8, 66.9, 66.8, 65.0, 64.7, 62.9, 62.6, 33.74, 1): 3064, 3031, 2927, 2857, 1699, 1499, 1454, 1407, 1351,
1
33.69, 31.4, 30.1, 28.94, 28.88, 28.7, 26.5, 26.4. HRMS ESI: 1215, 1095, 735, 697; H NMR (500 MHz, CDCl3) δ 7.41–7.14
calcd for C41H47NO5H+ [M + H]+ 634.35270, found 634.35204.
(m, 20H), 5.83–5.69 (m, 1H), 5.26–5.01 (m, 2H), 5.01–4.90 (m,
3-Epi-17: light yellow syrup, 5.01 g, 7.90 mmol, 66% yield in 3 2H), 4.85–4.74 (m, 1H), 4.73–4.51 (m, 4H), 4.42–4.34 (m, 1H),
steps, starting from the corresponding cyclic nitrone 3-epi-10 4.34–4.22 (m, 2H), 4.17–4.11 (m, 1H), 3.84–3.74 (m, 2H), 3.70
(5.00 g, 11.98 mmol).
(d, J = 6.9 Hz, 0.5H), 3.58 (d, J = 8.4 Hz, 0.5H), 2.04–1.87 (m,
20
Data for 3-epi-16: colorless syrup, [α]D -8.0 (c 1.0, CH2Cl2); IR 2.5H), 1.70–1.59 (m, 0.5H), 1.39–1.18 (m, 4H), 1.18–0.97 (m,
(KBr, cm-1): 3270, 2926, 2857,1639, 1497, 1454, 1362, 1097, 3H). 13C NMR (126 MHz, CDCl3) δ 154.7, 154.5, 139.0, 138.9,
1
734, 697; H NMR (500 MHz, CDCl3) δ 7.35–7.26 (m, 15H), 138.7, 138.4, 138.3, 136.7, 136.6, 128.5, 128.4, 128.2, 128.1,
5.84–5.75 (m, 1H), 5.49 (s, br, 1H), 5.01–4.95 (m, 1H), 4.95– 128.00, 127.96, 127.74, 127.66, 127.5, 127.40, 127.35, 127.2,
4.90 (m, 1H), 4.71 (d, J = 11.7 Hz, 1H), 4.63 (d, J = 11.9 Hz, 1H), 114.5, 114.4, 81.0, 79.8, 78.0, 77.6, 73.0, 72.9, 72.7, 72.5, 72.2,
4.58 (d, J = 8.9 Hz, 1H), 4.56 (d, J = 9.0 Hz, 1H), 4.51 (d, J = 11.9 71.9, 70.5, 69.1, 66.93, 66.85, 62.6, 62.3, 57.9, 57.8, 33.7, 33.6,
Hz, 1H), 4.47 (d, J = 11.9 Hz, 1H), 4.20 (t, J = 4.9 Hz, 1H), 3.86 33.2, 31.8, 28.9, 28.8, 28.7, 26.5, 26.3. HRMS ESI: calcd for
(dd, J = 9.7, 7.1 Hz, 1H), 3.81 (dd, J = 9.7, 6.3 Hz, 1H), 3.66 (dd, J C41H47NO5H+ [M + H]+ 634.35270, found 634.35187.
= 7.0, 4.9 Hz, 1H), 3.50–3.45 (m, 1H), 3.33–3.27 (m, 1H), 2.06– Ent-17a: light yellow syrup, 2.49 g, 4.02 mmol, 84% yield in 3
1.99 (m, 2H), 1.69–1.62 (m, 1H), 1.50–1.41 (m, 2H), 1.41–1.26 steps, starting from the corresponding cyclic nitrone ent-10
(m, 5H). 13C NMR (126 MHz, CDCl3) δ 139.3, 138.4, 138.3, 138.2, (2.00 g, 4.79 mmol), and Grignard reagent was hex-5-en-1-
128.53, 128.52, 128.48, 128.02, 127.98, 127.97, 127.89, 127.82, ylmagnesium bromide [prepared by heating Mg turnings (0.24
127.80, 114.3, 83.5, 73.8, 73.6, 72.9, 71.3, 68.8, 67.4, 33.9, g, 10.07 mmol) and 6-bromohex-1-ene (1.29 mL, 9.60 mmol)].
20
30.7, 29.4, 29.0, 26.9. HRMS ESI: calcd for C33H41NO4H+ [M + Data for ent-16a: [α]D +10.7 (c 0.75, CH2Cl2); IR (KBr, cm-1):
1
3240, 2926, 2860, 1640, 1497, 1454, 1362, 1099, 735, 697; H
H]+ 516.31084, found 516.31103.
20
Data for 3-epi-17: [α]D -2.2 (c 0.9, CH2Cl2); IR (KBr, cm-1): NMR (400 MHz, CDCl3) δ 7.42–7.16 (m, 15H), 6.24–5.86 (m,
3064, 3031, 2927, 2858, 1703, 1454, 1407, 1351, 1094, 735, 1H), 5.85–5.71 (m, 1H), 5.03–4.87 (m, 2H), 4.59–4.38 (m, 6H),
1
697; H NMR (300 MHz, CDCl3) δ 7.43–7.14 (m, 20H), 5.86– 3.93 (s, 1H), 3.83–3.73 (m, 2H), 3.61–3.54 (m, 1H), 3.52 (dd, J =
5.66 (m, 1H), 5.26–5.03 (m, 2H), 5.03–4.88 (m, 2H), 4.86–4.71 10.2, 5.3 Hz, 1H), 3.20–3.12 (m, 1H), 2.08–1.99 (m, 2H), 1.93–
(m, 1H), 4.71–4.49 (m, 4H), 4.44–4.34 (m, 1H), 4.33–4.20 (m, 1.80 (m, 1H), 1.55–1.44 (m, 1H), 1.44–1.31 (m, 4H). 13C NMR
2H), 4.19–4.07 (m, 1H), 3.85–3.73 (m, 2H), 3.70 (d, J = 8.6 Hz, (101 MHz, CDCl3) δ 139.1, 138.3, 138.2, 128.50, 128.47, 128.1,
0.5H), 3.58 (d, J = 7.2 Hz, 0.5H), 2.07–1.83 (m, 2.5H), 1.79–1.56 128.0, 127.84, 127.80, 127.7, 114.5, 86.8, 84.7, 73.5, 71.82,
(m, 0.5H), 1.41–1.17 (m, 4H), 1.17–0.95 (m, 3H). 13C NMR (75 71.76, 70.2, 70.1, 68.5, 33.8, 29.2, 28.6, 26.2. HRMS ESI: calcd
MHz, CDCl3) δ 154.7, 154.6, 139.0, 138.9, 138.8, 138.4, 138.3, for C32H39NO4H+ [M + H]+ 502.29519, found 502.29523.
20
136.8, 136.6, 128.5, 128.4, 128.3, 128.03, 127.99, 127.8, 127.7, Data for ent-
17a: [α]D +37.4 (c 1.6, CH2Cl2); IR (KBr, cm-1):
127.5, 127.44, 127.38, 127.3, 114.47, 114.44, 81.1, 79.9, 78.0, 3064, 3031, 2926, 2858, 1699, 1497, 1454, 1409, 1348, 1206,
1
77.4, 73.0, 72.7, 72.5, 72.3, 71.9, 70.6, 69.1, 67.0, 66.9, 62.7, 1093, 736, 697; H NMR (300 MHz, CDCl3) δ 7.31–7.01 (m,
62.3, 57.9, 57.8, 33.7, 33.2, 31.9, 28.92, 28.86, 28.7, 26.5, 26.4. 20H), 5.75–5.52 (m, 1H), 5.16–5.01 (m, 1H), 4.93 (d, J = 12.3
HRMS ESI: calcd for C41H47NO5H+ [M + H]+ 634.35270, found Hz, 1H), 4.88–4.76 (m, 2H), 4.58–4.43 (m, 1.5H), 4.36 (d, J = 5.8
634.35168.
Hz, 1H), 4.32 (d, J = 5.5 Hz, 1H), 4.30–4.20 (m, 2.5H), 4.17 (dd, J
= 10.5, 4.0 Hz, 0.5H), 4.10–4.02 (m, 1.5H), 3.97 (dd, J = 8.7, 4.2
Hz, 0.5H), 3.80–3.59 (m, 2.5H), 3.38 (td, J = 9.7, 1.7 Hz, 1H),
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2.03–1.87 (m, 1H), 1.81 (q, J = 6.9 Hz, 1H), 1.72–1.39 (m, 2H), 10 mL). The organic layers were combined, dried over MgSO4
1.37–0.98 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 154.6, 154.2, and concentrated under reduced pressure. The crude material
138.8, 138.7, 138.5, 138.3, 137.94, 137.89, 137.7, 137.6, was purified by flash column chromatography (silica gel,
136.63, 136.58, 128.5, 128.45, 128.38, 128.3, 128.2, 128.1, petroleum ether/EtOAc = 6/1) to afford alcohol 18 (1.80 g,
128.0, 127.8, 127.72, 127.69, 127.64, 127.59, 127.5, 114.5, 2.76 mmol, 73%) as a colorless syrup.
20
84.4, 83.3, 83.1, 81.9, 73.03, 72.96, 71.2, 71.0, 70.8, 68.7, 67.8, Data for 18: [α]D -35.4 (c 1.3, CH2Cl2); IR (KBr, cm-1): 3445,
66.9, 66.8, 65.0, 64.6, 62.9, 62.6, 33.7, 33.5, 31.3, 29.9, 28.6, 3064, 3031, 2929, 2857, 1699, 1497, 1455, 1417, 1349, 1115,
28.4, 25.9. HRMS ESI: calcd for C40H45NO5H+ [M + H]+ 738, 697; 1H NMR (300 MHz, CDCl3) δ 7.38–7.15 (m, 20H), 5.18
620.33705, found 620.33613.
(t, J = 12.4 Hz, 1H), 5.03 (d, J = 12.3 Hz, 1H), 4.68–4.55 (m,
Ent-17b: light yellow syrup, 2.70 g, 4.46 mmol, 93% yield, 1.5H), 4.50–4.41 (m, 2H), 4.40–4.29 (m, 2.5H), 4.25 (dd, J =
starting from the corresponding cyclic nitrone ent-10 (2.00 g, 10.6, 4.0 Hz, 0.5H), 4.19–4.11 (m, 1.5H), 4.05 (dd, J = 8.7, 4.2
4.79 mmol), Grignard reagent was pent-4-en-1-ylmagnesium Hz, 0.5H), 3.89–3.69 (m, 2.5H), 3.60 (q, 6.5 Hz, 2H), 3.52–3.43
bromide [prepared by heating Mg turnings (0.24 g, 10.07 (m, 1H), 2.10–1.96 (m, 0.5H), 1.79–1.60 (m, 1.5H), 1.59–1.46
mmol) and 5-bromopent-1-ene (1.14 mL, 9.60 mmol)].
20
(m, 2H), 1.38–1.09 (m, 8H). 13C NMR (75 MHz, CDCl3) δ 154.8,
Data for ent-16b: colorless syrup, [α]D +8.9 (c 0.9, CH2Cl2); IR 154.4, 138.6, 138.3, 138.02, 137.96, 137.74, 137.72, 136.6,
(KBr, cm-1): 3239, 2924, 2862, 1640, 1496, 1454, 1363, 1098, 128.6, 128.52, 128.45, 128.4, 128.2, 128.1, 127.83, 127.80,
1
735, 697; H NMR (500 MHz, CDCl3) δ 7.36–7.26 (m, 15H), 127.75, 127.70, 127.67, 127.6, 127.2, 84.5, 83.4, 83.2, 82.0,
5.84–5.74 (m, 1H), 5.09 (s, br, 1H), 5.03–5.97 (m, 1H), 4.96– 73.12, 73.05, 71.2, 71.1, 70.9, 68.8, 67.8, 67.0, 65.1, 64.8,
4.92 (m, 1H), 4.58–4.42 (m, 6H), 3.93 (dd, J = 4.0, 2.7 Hz, 1H), 63.05, 63.02, 62.99, 62.7, 32.8, 31.5, 30.0, 29.3, 29.2, 26.5,
3.81–3.74 (m, 2H), 3.59 (dd, J = 9.5, 6.6 Hz, 1H), 3.53 (dd, J = 26.4, 25.7, 25.6. HRMS ESI: calcd for C41H49NO6H+ [M + H]+
10.4, 5.8 Hz, 1H), 3.22–3.16 (m, 1H), 2.11–2.03 (m, 2H), 1.91– 652.36326, found 652.36241.
1.80 (m, 1H), 1.54–1.41 (m, 3H). 13C NMR (126 MHz, CDCl3) δ Data for ent-18: colorless syrup, 2.87 g, 4.40 mmol, 93% yield,
138.8, 138.3, 138.21, 138.17, 128.47, 128.45, 128.43, 128.1, derived from the corresponding olefin ent-17 (3.00 g, 4.73
128.0, 127.80, 127.77, 127.7, 114.7, 86.8, 84.6, 73.4, 71.8, mmol).
20
71.7, 70.2, 69.9, 68.3, 34.0, 28.5, 25.9. HRMS ESI: calcd for [α]D +34.0 (c 1.0, CH2Cl2); IR (KBr, cm-1): 3451, 3063, 3030,
1
C31H37NO4H+ [M + H]+ 488.27954, found 488.27954.Data for 2927, 2856, 1698, 1497, 1454, 1410, 1348, 1093, 736, 697; H
ent-17b: [α]D20 +36.0 (c 1.0, CH2Cl2); IR (KBr, cm-1): 3064, 3031, NMR (500 MHz, CDCl3) δ 7.37–7.14 (m, 20H), 5.22–5.13 (m,
1
2925, 2861, 1699, 1497, 1455, 1410, 1348, 1097, 736, 697; H 1H), 5.03 (dd, J = 12.3, 1.5 Hz, 1H), 4.66–4.55 (m, 1.5H), 4.49–
NMR (300 MHz, CDCl3) δ 7.41–7.13 (m, 20H), 5.86–5.59 (m, 4.40 (m, 2H), 4.40–4.30 (m, 2.5H), 4.29–4.23 (m, 0.5H), 4.18–
1H), 5.19 (t, J = 11.9 Hz, 1H), 5.03 (d, J = 12.4 Hz, 1H), 4.97– 4.12 (m, 1.5H), 4.08–4.03 (m, 0.5H), 3.88–3.70 (m, 2.5H), 3.56
4.84 (m, 2H), 4.67–4.54 (m, 1.5H), 4.47 (d, J = 6.2 Hz, 1H), 4.42 (q, J = 6.8 Hz, 2H), 3.47 (t, J = 9.6 Hz, 1H), 2.09–1.99 (m, 0.5H),
(d, J = 5.8 Hz, 1H), 4.40–4.30 (m, 2.5H), 4.26 (dd, J = 10.1, 2.9 1.86 (s, br, 1H), 1.76–1.61 (m, 1H), 1.61–1.43 (m, 2.5H), 1.37–
Hz, 0.5H), 4.20–4.12 (m, 1.5H), 4.06 (dd, J = 7.8, 3.4 Hz, 0.5H), 1.09 (m, 8H). 13C NMR (126 MHz, CDCl3) δ 154.7, 154.3, 138.5,
3.92–3.69 (m, 2.5H), 3.48 (t, J = 9.8 Hz, 1H), 2.17–1.98 (m, 138.3, 137.94, 137.88, 137.7, 137.6, 136.6, 128.5, 128.43,
1.5H), 1.98–1.85 (m, 1H), 1.83–1.53 (m, 1.5H), 1.49–1.16 (m, 128.36, 128.3, 128.1, 128.03, 127.98, 127.75, 127.71, 127.66,
2H). 13C NMR (75 MHz, CDCl3) δ 154.7, 154.3, 138.6, 138.43, 127.62, 127.58, 127.5, 84.4, 83.3, 83.1, 81.9, 73.03, 72.96,
138.37, 138.02, 137.98, 137.7, 136.7, 128.51, 128.47, 128.4, 71.1, 71.0, 70.8, 68.7, 67.8, 66.9, 66.8, 65.0, 64.7, 62.9, 62.8,
128.22, 128.18, 128.1, 127.83, 127.76, 127.72, 127.69, 127.63, 62.6, 32.71, 32.69, 31.4, 30.0, 29.3, 29.2, 26.45, 26.38, 25.63,
127.57, 114.71, 114.66, 84.5, 83.5, 83.2, 82.0, 73.1, 73.0, 71.3, 25.60. HRMS ESI: calcd for C41H49NO6H+ [M + H]+ 652.36326,
71.1, 70.9, 68.8, 67.9, 67.0, 66.9, 65.0, 64.7, 63.0, 62.7, 33.6, found 652.36254.
33.4, 31.1, 29.9, 26.01, 25.96. HRMS ESI: calcd for C39H43NO5H+ Data for 3-epi
-
18: colorless syrup, 0.93 g, 1.42 mmol, 100%
[M + H]+ 606.32140, found 606.32083.
yield, derived from the corresponding olefin 3-epi-17 (0.90 g,
General procedures for synthesis of compound 18, ent-18, 3- 1.42 mmol).
20
epi-18
as an example.
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-1-
benzyloxycarbonyl-5-(7-hydroxyheptyl)pyrrolidine (18)
,
ent-3-epi-18
,
ent
-
18a and ent
-
18b, with compound 18 [α]D -2.9 (c 0.7, CH2Cl2); IR (KBr, cm-1): 3447, 3063, 3031,
1
2929, 2857, 1698, 1497, 1454, 1409, 1352, 1097, 735, 698; H
NMR (500 MHz, CDCl3) δ 7.40–7.11 (m, 20H), 5.25–4.99 (m,
.
2H), 4.84–4.73 (m, 1H), 4.72–4.58 (m, 2.5H), 4.57–4.50 (m,
To a stirred solution of olefin 17 (2.40 g, 3.79 mmol) in 20 mL 1.5H), 4.42–4.34 (m, 1H), 4.33–4.21 (m, 2H), 4.13 (s, 1H), 3.83–
dry THF was slowly added a 1 M solution of BH3-THF in THF 3.74 (m, 2H), 3.70 (d, J = 6.9 Hz, 0.5H), 3.61–3.54 (m, 2.5H),
o
(7.6 mL, 7.57 mmol) at 0 C, under argon; the solution was 1.96–1.89 (m, 0.5H), 1.82 (s, br, 1H), 1.67–1.58 (m, 0.5H),
stirred at room temperature for 3 h. Then, the reaction was 1.56–1.43 (m, 2H), 1.35–1.19 (m, 5H), 1.18–0.95 (m, 4H). 13C
o
cooled to 0 C and an aqueous solution of NaOH (10 M, 2 mL) NMR (126 MHz, CDCl3) δ 154.6, 154.5, 138.9, 138.6, 138.3,
was added to get an alkaline reaction environment, followed 138.2, 136.6, 136.5, 128.5, 128.3, 128.2, 128.0, 127.9, 127.7,
by the addition of an aqueous solution of H2O2 (30%, 9 mL). 127.6, 127.5, 127.4, 127.3, 127.2, 81.0, 79.8, 77.9, 77.5, 73.0,
The reaction mixture was stirred for 1 h at room temperature. 72.9, 72.6, 72.4, 72.2, 71.8, 70.5, 69.0, 66.8, 62.8, 62.6, 62.3,
After the reaction was completed, it was quenched with a 57.8, 57.7, 33.2, 32.7, 31.7, 29.22, 29.18, 26.4, 25.6. HRMS ESI:
solution of HCl (10% in water) and extracted with EtOAc (3 × calcd for C41H49NO6H+ [M + H]+ 652.36326, found 652.36229.
10 | J. Name., 2012, 00, 1-3
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Data for ent-3-epi-18: colorless syrup, 1.43 g, 2.19 mmol, 73% General procedures for synthesis of compound 15
yield, derived from the corresponding olefin ent-3-epi-17 (1.90 epi-15 ent-3-epi-15 ent-15a and ent 15b, with compound 15
g, 3.00 mmol). as an example.
[α]D +5.9 (c 1.4, CH2Cl2); IR (KBr, cm-1): 3459, 3063, 3031, (2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-1-
2929, 2857, 1694, 1497, 1455, 1410, 1352, 1215, 1111, 735, benzyloxycarbonyl-5-(7-bromoheptyl)pyrrolidine (15)
, ent-15, 3-
,
,
-
20
.
1
697; H NMR (500 MHz, CDCl3) δ 7.40–7.14 (m, 20H), 5.24– Alcohol 18 (1.70 g, 2.61 mmol ) and CBr4 (2.16 g, 6.52 mmol)
4.99 (m, 2H), 4.84–4.74 (m, 1H), 4.72–4.58 (m, 2.5H), 4.57– were dissolved in dry CH2Cl2 (20 mL) and PPh3 (1.37 g, 5.22
o
4.51 (m, 1.5H), 4.42–4.34 (m, 1H), 4.34–4.21 (m, 2H), 4.16– mmol) was added to the solution in portions at 0 C. After
o
4.12 (m, 1H), 3.83–3.75 (m, 2H), 3.70 (d, J = 9.2 Hz, 0.5H), complete addition, the solution was stirred for 5 min at 0 C,
3.61–3.55 (m, 2.5H), 1.96–1.87 (m, 0.5H), 1.74 (s, br, 1H), then warmed to room temperature slowly and stirred for 2 h
1.67–1.54 (m, 0.5H), 1.57–1.44 (m, 2H), 1.36–1.19 (m, 5H), at the same temperature. When the starting material had
1.19–0.96 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 154.7, 154.5, disappeared, the reaction was quenched with saturated
138.9, 138.7, 138.3, 138.2, 136.7, 136.6, 128.5, 128.4, 128.21, aqueous solution of NaHCO3 and extracted with CH2Cl2 (3 × 10
128.16, 128.05, 127.97, 127.95, 127.7, 127.64, 127.62, 127.5, mL). The organic layers were combined, dried over MgSO4 and
127.4, 127.3, 127.2, 81.0, 79.8, 78.0, 77.5, 77.4, 73.0, 72.9, concentrated to 20 mL under reduced pressure, then 10 mL of
72.7, 72.4, 72.2, 71.8, 70.5, 69.0, 66.9, 62.8, 62.6, 62.3, 57.8, petroleum ether was added, a white precipitate was formed
57.7, 33.2, 32.7, 31.7, 29.24, 29.20, 26.4, 25.63, 25.59. HRMS and removed by filtration through celite. After concentration,
ESI: calcd for C41H49NO6H+ [M + H]+ 652.36326, found this crude material was purified by flash column
652.36266.
chromatography (silica gel, petroleum ether/EtOAc = 15/1) to
Data for ent-18a: colorless syrup, 1.40 g, 2.20 mmol, 91% yield, afford the corresponding bromide 15 (1.81 g, 2.53 mmol, 97%)
derived from the corresponding olefin ent-17a (1.50 g, 2.42 as a light yellow syrup.
20
mmol).
20
Data for 15: [α]D -29.6 (c 1.2, CH2Cl2); IR (KBr, cm-1): 3063,
[α]D +44.0 (c 1.0, CH2Cl2); IR (KBr, cm-1): 3462, 3063, 3031, 3031, 2929, 2856, 1699, 1496, 1454, 1409, 1348, 1096, 736,
1
2930, 2858, 1699, 1497, 1454, 1410, 1349, 1206, 1096, 737, 697; H NMR (300 MHz, CDCl3) δ 7.39–7.15 (m, 20H), 5.25–
1
698; H NMR (300 MHz, CDCl3) δ 7.40–7.13 (m, 20H), 5.18 (t, J 5.13 (m, 1H), 5.03 (d, J = 12.4 Hz, 1H), 4.68–4.55 (m, 1.5H),
= 12.6 Hz, 1H), 5.03 (d, J = 12.3 Hz, 1H), 4.68–4.55 (m, 1.5H), 4.50–4.41 (m, 2H), 4.41–4.30 (m, 2.5H), 4.25 (dd, J = 10.3, 3.8
4.47 (d, J = 5.9 Hz, 1H), 4.43 (d, J = 5.8 Hz, 1H),4.40–4.29 (m, Hz, 0.5H), 4.19–4.11 (m, 1.5H), 4.06 (dd, J = 8.5, 4.0 Hz, 0.5H),
2.5H), 4.25 (dd, J = 10.4, 3.9 Hz, 0.5H), 4.19–4.10 (m, 1.5H), 3.88–3.69 (m, 2.5H), 3.48 (t, J = 9.8 Hz, 1H), 3.36 (q, J = 6.8 Hz,
4.06 (dd, J = 8.7, 4.1 Hz, 0.5H), 3.89–3.69 (m, 2.5H), 3.59 (d, J = 2H), 2.10–1.97 (m, 0.5H), 1.87–1.61 (m, 3H), 1.60–1.49 (m,
6.5 Hz, 1H), 3.54 (d, J = 6.7 Hz, 1H), 3.47 (d, J = 9.8 Hz, 1H), 0.5H), 1.43–1.08 (m, 8H). 13C NMR (75 MHz, CDCl3) δ 154.7,
2.11–1.97 (m, 0.5H), 1.80–1.39 (m, 4.5H), 1.39–1.08 (m, 6H). 154.3, 138.6, 138.4, 138.0, 137.7, 136.7, 128.6, 128.52, 128.45,
13C NMR (75 MHz, CDCl3) δ 154.8, 154.3, 138.6, 138.4, 138.0, 128.4, 128.23, 128.15, 128.09, 127.84, 127.78, 127.73, 127.69,
137.8, 136.7, 128.6, 128.5, 128.4, 128.2, 128.1, 127.84, 127.79, 127.66, 127.6, 84.5, 83.5, 83.2, 82.1, 73.1, 71.3, 71.1, 70.9,
127.76, 127.71, 127.67, 127.6, 84.5, 83.5, 83.2, 82.1, 73.13, 68.8, 67.9, 66.94, 66.89, 65.1, 64.8, 63.0, 62.7, 34.1, 34.0, 32.9,
73.07, 71.3, 71.1, 71.0, 68.8, 67.9, 66.9, 65.0, 64.8, 63.0, 62.9, 32.8, 31.4, 30.1, 29.2, 29.0, 28.7, 28.6, 28.12, 28.09, 26.5.
62.7, 32.7, 31.4, 30.0, 29.1, 29.0, 26.5, 26.4, 25.6, 25.5. HRMS HRMS ESI: calcd for C41H4879BrNO5H+ [M + H]+ 714.27886,
ESI: calcd for C40H47NO6H+ [M + H]+ 638.34761, found found 714.27750.
638.34723.
Data for ent-15: light yellow syrup, 2.42 g, 3.39 mmol, 85%
Data for ent
-
18b: colorless syrup, 2.72 g, 4.36 mmol, 91% yield, derived from the corresponding alcohol ent-18 (2.60 g,
yield, derived from the corresponding olefin ent-17b (2.90 g, 3.99 mmol).
20
4.79 mmol).
20
[α]D +28.8 (c 1.6, CH2Cl2); IR (KBr, cm-1): 3063, 3031, 2929,
1
[α]D +32.6 (c 1.4, CH2Cl2); IR (KBr, cm-1): 3462, 3064, 3031, 2856, 1699, 1497, 1454, 1409, 1348, 1096, 737, 697; H NMR
2932, 2860, 1698, 1497, 1455, 1410, 1349, 1206, 1093, 737, (500 MHz, CDCl3) δ 7.36–7.15 (m, 20H), 5.23–5.14 (m, 1H),
1
698; H NMR (500 MHz, CDCl3) δ 7.47–7.10 (m, 20H), 5.23– 5.03 (dd, J = 12.3, 2.7 Hz, 1H), 4.66–4.55 (m, 1.5H), 4.48–4.40
5.13 (m, 1H), 5.03 (dd, J = 12.4, 2.7 Hz, 1H), 4.66–4.56 (m, (m, 2H), 4.40–4.30 (m, 2.5H), 4.26 (dd, J = 10.5, 4.0 Hz, 0.5H),
1.5H), 4.50–4.40 (m, 2H), 4.40–4.29 (m, 2.5H), 4.25 (d, J = 10.0 4.18–4.13 (m, 1.5H), 4.07 (dd, J = 8.7, 4.2 Hz, 0.5H), 3.87–3.70
Hz, 0.5H), 4.18–4.11 (m, 1.5H), 4.06 (dd, J = 8.0, 3.2 Hz, 0.5H), (m, 2.5H), 3.51–3.45 (m, 1H), 3.36–3.30 (m, 2H), 2.09–1.99 (m,
3.85 (d, J = 10.9 Hz, 0.5H), 3.81–3.70 (m, 2H), 3.57 (t, J = 6.4 Hz, 0.5H), 1.83–1.62 (m, 3H), 1.61–1.52 (m, 0.5H), 1.40–1.08 (m,
1H), 3.51–3.43 (m, 2H), 2.09–1.99 (m, 0.5H), 1.86–1.63 (m, 8H). 13C NMR (126 MHz, CDCl3) δ 154.6, 154.2, 138.5, 138.3,
1H), 1.62–1.46 (m, 2H), 1.44–1.28 (m, 3H), 1.24–1.11 (m, 137.94, 137.89, 137.7, 137.6, 136.62, 136.58, 128.5, 128.44,
2.5H). 13C NMR (126 MHz, CDCl3) δ 154.7, 154.3, 138.6, 138.3, 128.41, 128.36, 128.3, 128.14, 128.05, 128.0, 127.76, 127.75,
138.0, 137.9, 137.72, 137.69, 136.65, 128.6, 128.52, 128.45, 127.70, 127.65, 127.60, 127.57, 127.5, 84.4, 83.3, 83.1, 81.9,
128.4, 128.2, 128.1, 127.86, 127.85, 127.78, 127.72, 127.67, 73.02, 72.95, 71.1, 71.0, 70.8, 68.7, 67.8, 66.84, 66.79, 65.0,
127.65, 127.6, 84.5, 83.5, 83.1, 82.0, 73.12, 73.05, 71.2, 71.1, 64.6, 62.9, 62.6, 34.00, 33.95, 32.74, 32.69, 31.3, 30.0, 29.1,
70.9, 68.8, 67.8, 67.0, 66.9, 64.9, 64.7, 63.0, 62.9, 62.8, 62.7, 28.9, 28.6, 28.4, 28.01, 27.97, 26.4, 26.3. HRMS ESI: calcd for
32.7, 32.5, 31.4, 30.1, 26.31, 26.28, 25.44, 25.35. HRMS ESI: C41H4879BrNO5H+ [M + H]+ 714.27886, found 714.27784.
calcd for C39H45NO6H+ [M + H]+ 624.33196, found 624.33119.
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Data for 3-epi-15: light yellow syrup, 0.79 g, 1.11 mmol, 88% Data for ent-15b: light yellow syrup, 3.07 g, 4.47 mmol, 93%
yield, derived from the corresponding alcohol 3-epi-18 (0.82 g, yield, derived from the corresponding alcohol ent-18b (3.00 g,
1.26 mmol).
20
4.81 mmol).
20
[α]D -2.2 (c 0.9, CH2Cl2); IR (KBr, cm-1): 3063, 3031, 2929, [α]D +40.0 (c 1.1, CH2Cl2); IR (KBr, cm-1): 3063, 3031, 2934,
1
1
2856, 1698, 1497, 1454, 1408, 1352, 1096, 736, 697; H NMR 2860, 1698, 1496, 1454, 1409, 1348, 1093, 737, 698; H NMR
(500 MHz, CDCl3) δ 7.39–7.14 (m, 20H), 5.25–5.98 (m, 2H), (500 MHz, CDCl3) δ 7.38–7.14 (m, 20H), 5.25–5.12 (m, 1H),
4.84–4.74 (m, 1H), 4.72–4.57 (m, 2.5H), 4.57–4.49 (m, 1.5H), 5.06–4.98 (m, 1H), 4.67–4.55 (m, 1.5H), 4.48–4.39 (m, 2H),
4.41–4.35 (m, 1H), 4.34–4.22 (m, 2H), 4.16–4.10 (m, 1H), 3.84– 4.39–4.29 (m, 2.5H), 4.28–4.21 (m, 0.5H), 4.18–4.11 (m, 1.5H),
3.74 (m, 2H), 3.70 (d, J = 8.1 Hz, 0.5H), 3.59 (d, J = 8.0 Hz, 4.09–4.03 (m, 0.5H), 3.86–3.70 (m, 2.5H), 3.51–3.43 (m, 1H),
0.5H), 3.37–3.28 (m, 2H), 1.96–1.87 (m, 0.5H), 1.82–1.69 (m, 3.33 (t, J = 6.8 Hz, 1H), 3.24 (t, J = 6.6 Hz, 1H), 2.09–1.99 (m,
2H), 1.68–1.56 (m, 0.5H), 1.39–1.31 (m, 1H), 1.31–1.18 (m, 0.5H), 1.86–1.75 (m, 1H), 1.74–1.60 (m, 2H), 1.61–1.52 (m,
4H), 1.17–0.97 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 154.5, 0.5H), 1.51–1.34 (m, 1H), 1.34–1.08 (m, 3H). 13C NMR (126
154.3, 138.8, 138.6, 138.2, 138.1, 136.6, 136.4, 128.3, 128.2, MHz, CDCl3) δ 154.7, 154.3, 138.6, 138.3, 138.0, 137.9, 137.7,
128.1, 128.0, 127.83, 127.80, 127.6, 127.50, 127.48, 127.3, 137.6, 136.7, 136.6, 128.6, 128.52, 128.46, 128.4, 128.3,
127.23, 127.19, 127.1, 80.8, 79.7, 77.9, 77.4, 72.8, 72.7, 72.5, 128.22, 128.15, 128.1, 127.9, 127.82, 127.77, 127.7, 127.6,
72.3, 72.1, 71.7, 70.4, 68.9, 66.8, 66.75, 66.69, 62.5, 62.1, 57.7, 84.4, 83.4, 83.1, 81.9, 73.1, 73.0, 71.3, 71.1, 70.9, 68.8, 67.8,
57.6, 33.9, 33.8, 33.0, 32.6, 32.5, 31.6, 29.6, 29.0, 28.8, 28.4, 67.0, 66.9, 64.9, 64.5, 63.0, 62.7, 33.9, 33.8, 32.7, 32.4, 31.2,
28.3, 27.8, 26.3, 26.2. HRMS ESI: calcd for C41H4879BrNO5H+ [M 29.9, 27.9, 27.6, 25.7, 25.6. HRMS ESI: calcd for
+ H]+ 714.27886, found 714.27789.
Data for ent-3-epi-15: light yellow syrup, 1.0 g, 1.40 mmol, General procedures for synthesis of compound 19
96% yield, derived from the corresponding alcohol ent-3-epi- epi 19 ent-3-epi-19 ent-19a and ent-19b, with compound 19
as an example.
C39H4479BrNO5H+ [M + H]+ 686.24756, found 686.24651.
,
ent-19, 3-
-
,
,
18 (0.95 g, 1.46 mmol)
.
20
[α]D +7.1 (c 0.9, CH2Cl2); IR (KBr, cm-1): 3063, 3030, 2929, (2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-((benzyloxy)methyl)-1-
1
2856, 1699, 1497, 1454, 1407, 1351, 1096, 735, 697; H NMR benzyloxycarbonyl-5-(7-(2-cyclohexanone)heptyl)pyrrolidine
(500 MHz, CDCl3) δ 7.41–7.14 (m, 20H), 5.25–4.99 (m, 2H), (19)
4.84–4.74 (m, 1H), 4.73–4.58 (m, 2.5H), 4.58–4.51 (m, 1.5H),
A solution of cyclohexanone (20 g, 204 mmol) and
4.42–4.34 (m, 1H), 4.34–4.22 (m, 2H), 4.14 (dd, J = 6.4, 4.0Hz, cyclohexylamine (20 g, 204 mmol) in 150 mL of ether was
1H), 3.82–3.75 (m, 2H), 3.70 (d, J = 8.1 Hz, 0.5H), 3.58 (d, J = allowed to stand over 4-Å molecular sieves for 12 h. Filtration
8.3 Hz, 0.5H), 3.39–3.32 (m, 2H), 1.95–1.86 (m, 0.5H), 1.85– and removal of solvent followed by distillation afforded N-
1.71 (m, 2H), 1.69–1.59 (m, 0.5H), 1.40–1.33 (m, 1H), 1.33– cyclohexylidenecyclohexanamine (14, 35.4 g, 89%) as a white
1.18 (m, 4H), 1.17–0.97 (m, 4H). 13C NMR (126 MHz, CDCl3) δ solid: 1H NMR (400 MHz, CDCl3) δ 3.34–3.25 (m, 1H), 2.36–2.23
154.6, 154.4, 138.9, 138.7, 138.3, 138.2, 136.7, 136.5, 128.5, (m, 4H), 1.81–1.69 (m, 4H), 1.68–1.56 (m, 7H), 1.48–1.13 (m,
128.3, 128.2, 128.1, 128.0, 127.9, 127.7, 127.6, 127.5, 127.4, 5H). 13C NMR (101 MHz, CDCl3) δ 170.8, 57.9, 40.3, 34.2, 34.2,
127.35, 127.30, 127.2, 81.0, 79.8, 78.0, 77.5, 73.0, 72.95, 29.1, 27.9, 27.6, 26.2, 25.7, 25.1, 25.1.
72.87, 72.6, 72.4, 72.2, 71.8, 70.5, 69.0, 66.9, 66.8, 62.6, 62.2, To a solution of DIPA (0.12 mL, 0.84 mmol) in THF (10 mL) at
57.8, 57.7, 34.0, 33.9, 33.1, 32.70, 32.65, 31.7, 29.7, 29.1, 28.9, 0°C was added n-BuLi (2.4 M in THF; 0.29 mL, 0.70 mmol). To
28.5, 28.4, 28.0, 26.4, 26.3. HRMS ESI: calcd for this reaction mixture was added
C41H4879BrNO5H+ [M + H]+ 714.27886, found 714.27774.
cyclohexylidenecyclohexanamine (14; 0.10 g, 0.56 mmol) in
Data for ent-15a: light yellow syrup, 1.32 g, 1.88 mmol, 92% THF (1 mL) dropwise, and the solution was stirred for 1 h at 0
a solution of N-
yield, derived from the corresponding alcohol ent
-
18a (1.30 g, °C. To the resulting mixture were added HMPA (0.12mL, 0.70
mmol) and followed by a solution of bromide 15 (0.20 g, 0.28
2.04 mmol).
20
[α]D +36.5 (c 1.2, CH2Cl2); IR (KBr, cm-1): 3063, 3031, 2929, mmol) in THF (2 mL) at 0 °C; the resulting solution was stirred
1
2857, 1701, 1496, 1454, 1408, 1348, 1094, 736, 697; H NMR for 2 h at room temperature. After the starting material
(300 MHz, CDCl3) δ 7.39–7.13 (m, 20H), 5.26–5.12 (m, 1H), disappeared, the reaction was quenched with saturated
5.03 (dd, J = 12.4, 1.9 Hz, 1H), 4.68–4.55 (m, 1.5H), 4.47 (d, J = aqueous solution of NH4Cl and extracted with EtOAc (3 × 5
5.3 Hz, 1H ), 4.43 (d, J = 4.8 Hz, 1H), 4.40–4.29 (m, 2.5H), 4.26 mL). The organic layers were combined, dried over MgSO4 and
(dd, J = 10.4, 3.8 Hz, 0.5H), 4.20–4.11 (m, 1.5H), 4.06 (dd, J = concentrated under reduced pressure. The crude material was
8.6, 4.0 Hz, 0.5H), 3.88–3.69 (m, 2.5H), 3.48 (t, J = 9.7 Hz, 1H), purified by flash column chromatography (silica gel, petroleum
3.35 (t, J = 6.8 Hz, 1H), 3.29 (t, J = 6.8 Hz, 1H), 2.11–1.96 (m, ether/EtOAc = 15/1) to afford ketone 19 (0.15 g, 73%) as a light
0.5H), 1.86–1.57 (m, 3.5H), 1.46–1.20 (m, 4H), 1.20–1.07 (m, yellow syrup.
20
2H). 13C NMR (75 MHz, CDCl3) δ 154.7, 154.3, 138.6, 138.4, Data for 19: [α]D -30.0 (c 1.0, CH2Cl2); IR (KBr, cm-1): 3031,
138.0, 137.7, 136.6, 128.5, 128.43, 128.39, 128.20, 128.17, 2929, 2856, 1704, 1497, 1454, 1409, 1348, 1313, 1206, 1094,
1
128.1, 127.9, 127.7, 127.6, 84.5, 83.4, 83.1, 82.0, 73.1, 73.0, 1028, 737, 698; H NMR (300 MHz, CDCl3) δ 7.32–7.06 (m,
71.3, 71.1, 70.9, 68.8, 67.9, 67.0, 66.9, 65.0, 64.7, 63.0, 62.7, 20H), 5.17–5.05 (m, 1H), 4.96 (d, J = 12.2 Hz, 1H), 4.60–4.47
34.0, 33.9, 32.8, 32.7, 31.4, 30.1, 28.6, 28.3, 28.1, 27.9, 26.4, (m, 1.5H), 4.43–4.31 (m, 2.5H), 4.30–4.22 (m, 2H), 4.17 (dd, J =
26.3. HRMS ESI: calcd for C40H4679BrNO5H+ [M + H]+ 700.26321, 10.5, 4.1 Hz, 0.5H), 4.10–4.02 (m, 1.5H), 3.97 (dd, J = 8.7, 4.1
found 700.26222.
Hz, 0.5H), 3.80–3.61 (m, 2.5H), 3.44–3.34 (m, 1H), 2.35–2.26
12 | J. Name., 2012, 00, 1-3
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(m, 1H), 2.25–2.10 (m, 2H), 2.07–1.86 (m, 2H), 1.82–1.43 (m, 31.8, 29.6, 29.4, 28.0, 27.1, 26.5, 24.8. HRMS ESI: calcd for
6H), 1.29–0.99 (m, 12H). 13C NMR (75 MHz, CDCl3) δ 213.7, C47H57NO6H+ [M + H]+ 732.42587, found 732.42444.
213.6, 154.8, 154.3, 138.6, 138.4, 138.1, 138.0, 137.79, 137.75, Data for ent-19a, light yellow syrup, 140 mg, 0.20 mmol, 68%
136.73, 136.71, 128.6, 128.5, 128.44, 128.41, 128.2, 128.1, yield, derived from the corresponding bromide ent-15a (200
128.0, 127.82, 127.77, 127.72, 127.69, 127.64, 127.58, 84.5, mg, 0.21 mmol).
20
83.4, 83.2, 82.1, 73.1, 73.0, 71.2, 71.1, 70.9, 68.8, 67.9, 66.91, [α]D +31.7 (c 1.2, CH2Cl2); IR (KBr, cm-1): 2928, 2857, 1704,
66.87, 65.1, 64.8, 63.0, 62.7, 50.9, 42.1, 33.95, 33.92, 31.5, 1454, 1409, 1348, 1096, 737, 698; 1H NMR (300 MHz, CDCl3) δ
30.2, 29.8, 29.6, 29.52, 29.48, 29.3, 28.1, 27.3, 26.7, 24.9. 7.38–7.14 (m, 20H), 5.24–5.13 (m, 1H), 5.03 (d, J = 12.3 Hz,1H),
HRMS ESI: calcd for C47H57NO6H+ [M + H]+ 732.42587, found 4.67–4.55 (m, 1.5H), 4.50–4.29 (m, 4.5H), 4.25 (dd, J = 10.5, 4.0
732.42474.
Hz, 0.5H), 4.18–4.10 (m, 1.5H), 4.05 (dd, J = 8.7, 4.2 Hz, 0.5H),
Data for ent-19: light yellow syrup, 100 mg, 0.14 mmol, 71% 3.88–3.69 (m, 2.5H), 3.52–3.42 (m, 1H), 2.46–2.15 (m, 3H),
yield, derived from the corresponding bromide ent-15 (137 2.13–1.95 (m, 2H), 1.90–1.46 (m, 6H), 1.45–1.02 (m, 10H). 13C
mg, 0.19 mmol). NMR (75 MHz, CDCl3) δ 213.7, 213.6, 154.8, 154.3, 138.6,
[α]D +34.0 (c 1.0, CH2Cl2); IR (KBr, cm-1): 3031, 2928, 2856, 138.4, 138.0, 137.79, 137.75, 136.7, 128.6, 128.51, 128.45,
20
1704, 1496, 1454, 1408, 1348, 1313,1206, 1094, 1028, 737, 128.4, 128.2, 128.1, 127.8, 127.70, 127.65, 127.6, 84.5, 83.4,
1
698; H NMR (400 MHz, CDCl3) δ 7.30–7.07 (m, 20H), 5.16– 83.2, 82.1, 73.1, 73.0, 71.2, 71.1, 70.9, 68.8, 67.9, 66.9, 65.1,
5.05 (m, 1H), 4.96 (d, J = 12.1 Hz, 1H), 4.59–4.47 (m, 1.5H), 64.8, 63.0, 62.7, 50.8, 42.1, 34.0, 31.5, 30.2, 29.8, 29.7, 29.5,
4.42–4.30 (m, 2.5H), 4.30–4.22 (m, 2H), 4.17 (dd, J = 10.5, 3.9 29.3, 28.2, 27.2, 26.6, 24.9. HRMS ESI: calcd for C46H55NO6H+
Hz, 0.5H), 4.10–4.03 (m, 1.5H), 3.97 (dd, J = 8.6, 4.1 Hz, 0.5H), [M + H]+ 718.41021, found 718.40914.
3.79–3.62 (m, 2.5H), 3.44–3.35 (m, 1H), 2.34–2.26 (m, 1H), Data for ent-19b, light yellow syrup, 73 mg, 0.10 mmol, 71%
2.24–2.10 (m, 2H), 2.05–1.88 (m, 2H), 1.82–1.41 (m, 6H), 1.24– yield, derived from the corresponding bromide ent-15b (100
0.99 (m, 12H). 13C NMR (101 MHz, CDCl3) δ 213.7, 213.6, 154.7, mg, 0.15 mmol).
20
154.3, 138.6, 138.4, 138.1, 138.0, 137.78, 137.74, 136.72, [α]D +36.0 (c 1.0, CH2Cl2); IR (KBr, cm-1): 2932, 2858, 1704,
1
136.70, 128.6, 128.5, 128.43, 128.40, 128.2, 128.1, 128.0, 1497, 1454, 1409, 1348, 1095, 737, 698; H NMR (300 MHz,
127.82, 127.77, 127.72, 127.69, 127.64, 127.58, 84.5, 83.4, CDCl3) δ 7.42–7.12 (m, 20H), 5.25–5.15 (m, 1H), 5.03 (d, J =
83.2, 82.1, 73.1, 73.0, 71.2, 71.1, 70.9, 68.8, 67.9, 66.90, 66.86, 12.2 Hz, 1H), 4.69–4.54 (m, 1.5H), 4.52–4.29 (m, 4.5H), 4.25
65.1, 64.8, 63.0, 62.7, 50.9, 42.1, 33.95, 33.92, 31.5, 30.2, 29.8, (dd, J = 10.5, 3.9 Hz, 0.5H), 4.19–4.09 (m, 1.5H), 4.05 (dd, J =
29.6, 29.51, 29.47, 29.3, 28.1, 27.3, 26.7, 24.9. HRMS ESI: calcd 8.5, 4.0 Hz, 0.5H), 3.88–3.68 (m, 2.5H), 3.47 (t, J = 9.8 Hz, 1H),
for C47H57NO6H+ [M + H]+ 732.42587, found 732.42468.
Data for 3-epi-19: light yellow syrup, 270 mg, 0.37 mmol, 60% 1.76 (m, 1H), 1.77–1.51 (m, 4H), 1.44–1.05 (m, 8H). 13C NMR
2.43–2.33 (m, 1H), 2.32–2.12 (m, 2H), 2.12–1.94 (m, 3H), 1.91–
yield, derived from the corresponding bromide 3-epi
-
15 (440 (75 MHz, CDCl3) δ 213.4, 154.7, 154.3, 138.6, 138.4, 138.0,
mg, 0.62 mmol).
137.7, 136.7, 128.52, 128.47, 128.4, 128.2, 128.0, 127.8, 127.7,
[α]D –11.4 (c 0.7, CH2Cl2); IR (KBr, cm-1): 2928, 2856, 1705, 127.60, 127.56, 84.5, 83.4, 83.2, 82.1, 73.1, 73.0, 71.2, 71.1,
1454, 1407, 1352, 1096, 736, 698; 1H NMR (300 MHz, CDCl3) δ 70.9, 68.8, 66.8, 65.1, 64.8, 63.0, 62.7, 50.7, 42.0, 33.9, 30.1,
7.43–7.11 (m, 20H), 5.27–4.99 (m, 2H), 4.85–4.71 (m, 1H), 29.6, 29.3, 28.1, 27.1, 26.5, 24.9. HRMS ESI: calcd for
4.70–4.49 (m, 4H), 4.43–4.34 (m, 1H), 4.34–4.20 (m, 2H), 4.19– C45H53NO6H+ [M + H]+ 704.39456, found 704.39369.
20
4.10 (m, 1H), 3.85–3.74 (m, 2H), 3.70 (d, J = 7.9 Hz, 0.5H), 3.58 General procedures for synthesis of compound 20
(d, J = 7.3 Hz, 0.5H), 2.43–2.16 (m, 3H), 2.15–1.54 (m, 7H), epi-20 ent-3-epi-10 ent-10a and ent 10b, with compound 20
1.46–0.96 (m, 13H). 13C NMR (75 MHz, CDCl3) δ 213.5, 154.6, as an example.
, ent-20, 3-
,
,
-
138.8, 138.4, 136.8, 128.5, 128.4, 128.2, 128.0, 127.64, 127.59, (2R,3R,4R,5R)-3,4-Dihydroxy-2-hydroxymethyl-5-[7-(2-
127.4, 127.3, 81.1, 79.9, 78.1, 77.4, 73.0, 72.7, 72.5, 72.2, 71.9, cyclohexanone)heptyl]pyrrolidine (20)
70.6, 69.1, 66.8, 62.7, 62.4, 57.9, 50.8, 42.0, 33.9, 33.3, 31.9, 10% Pd/C (30 mg) and 6 N HCl (0.5 mL) were added to a
29.7, 29.5, 28.1, 27.2, 26.6, 24.9. HRMS ESI: calcd for solution of 19 (100 mg, 0.14 mmol) in MeOH (10 mL, replaced
C47H57NO6H+ [M + H]+ 732.42587, found 732.42491.
with argon 3 times). After the resulting suspension was stirred
Data for ent-3-epi-19: light yellow syrup, 580 mg, 0.79 mmol, under an atmosphere of H2 at room temperature for 8 h, TLC
71% yield, derived from the corresponding bromide ent-3-epi- (EtOAc/MeOH: 3/1) revealed the formation of a polar
15 (800 mg, 1.12 mmol).
compound. The Pd/C was filtered off, and the solution was
[α]D +8.6 (c 0.7, CH2Cl2); IR (KBr, cm-1): 2928, 2856, 1705, concentrated in vacuo, the residue was dissolved in MeOH and
1454, 1408, 1352, 1098, 736, 698; 1H NMR (300 MHz, CDCl3) δ neutralized with aqueous ammonium solution, concentrated in
7.44–7.12 (m, 20H), 5.28–4.98 (m, 2H), 4.85–4.70 (m, 1H), vacuo. The above procedure was repeated for three times to
4.69–4.50 (m, 4H), 4.43–4.35 (m, 1H), 4.34–4.20 (m, 2H), 4.19– ensure complete neutralization. The residue was purified by an
4.10 (m, 1H), 3.84–3.74 (m, 2H), 3.71 (d, J = 7.3 Hz, 0.5H), 3.58 acid resin column (DOWEX 50W × 8, 100-200 mesh), eluting
(d, J = 7.3 Hz, 0.5H), 2.43–2.15 (m, 3H), 2.14–1.54 (m, 7H), with distilled water (100 mL) and then 6N NH4OH (50 mL),
1.46–0.96 (m, 13H). 13C NMR (75 MHz, CDCl3) δ 213.3, 154.6, affording 20 (43 mg, 0.13 mmol, 96%) as a light yellow syrup.
20
138.7, 138.3, 136.7, 128.4, 128.3, 128.1, 127.9, 127.6, 127.5, Data for 20: [α]D +17.8 (c 0.7, MeOH); IR (KBr, cm-1): 3357,
127.4, 127.3, 81.0, 79.9, 78.0, 77.4, 72.9, 72.6, 72.4, 72.2, 2927, 2855, 1701, 1131, 1076, 1042; 1H NMR (300 MHz,
20
71.9, 70.5, 69.0, 66.8, 62.6, 62.3, 57.9, 50.8, 42.0, 33.9, 33.2, MeOD) δ 3.87 (t, J = 6.4 Hz, 1H), 3.82–3.65 (m, 3H), 3.17–3.09
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(m, 1H), 3.06–2.95 (m, 1H), 2.54–2.32 (m, 2H), 2.27–2.05 (m, 1H), 3.75–3.59 (m, 3H), 3.18–3.09 (m, 1H), 3.04–2.94(m, 1H),
2H), 2.01–1.89 (m, 1H), 1.89–1.65 (m, 4H), 1.63–1.21 (m, 14H). 2.45–2.25 (m, 1H), 2.11–1.88 (m, 2H), 1.81–1.55 (m, 5H), 1.55–
13C NMR (75 MHz, MeOD) δ 216.1, 83.1, 79.2, 64.6, 62.9, 62.7, 1.11 (m, 11H). 13C NMR (126 MHz, MeOD) δ 216.2, 82.1, 78.3,
51.8, 42.8, 35.3, 34.8, 30.8, 30.7, 30.6, 30.5, 29.3, 28.2, 27.6, 64.9, 63.3, 61.6, 51.7, 42.8, 35.3, 33.7, 30.8, 30.5, 29.3, 28.1,
25.8. HRMS ESI: calcd for C18H33NO4H+ [M + H]+ 328.24824, 27.3, 25.8. HRMS ESI: calcd for C16H29NO4H+ [M
found 328.24796.
H]+300.21693, found 300.21679.
Data for ent-20: light yellow syrup, 75 mg, 0.23 mmol, 84% General procedures for synthesis of compound 21
yield, derived from the corresponding ketone ent-19 (200 mg, epi-21 ent-3-epi-21 ent 21a and ent
0.27 mmol). as an example.
[α]D -13.3 (c 1.5, MeOH); IR (KBr, cm-1): 3357, 2927, 2855, (2R,3R,4R,5R)-3,4-Diyldiacetate-2-(acetoxymethyl)-1-acetyl-5-
1701, 1132, 1076, 1042; 1H NMR (400 MHz, MeOD) δ 3.81 (t, J (7-(2-cyclohexanone)heptyl)pyrrolidine (21)
+
,
ent-21
,
3-
,
,
-
-21b, with compound 21
20
.
= 6.3 Hz, 1H), 3.75–3.61 (m, 3H), 3.14–3.07 (m, 1H), 3.02–2.94 To a solution of 20 (130 mg, 0.40 mmol) in pyrdine (10 mL)
(m, 1H), 2.42–2.26 (m, 2H), 2.19–1.98 (m, 2H), 1.90–1.81 (m, were added DMAP (cat. 10 mg) and Ac2O (0.2 mL, 2.40 mmol);
1H), 1.79–1.58 (m, 4H), 1.57–1.12 (m, 14H). 13C NMR (101 the solution was stirred for 5h at room temperature. After the
MHz, MeOD) δ 217.0, 83.6, 79.7, 65.5, 63.9, 63.1, 52.6, 43.7, starting material had disappeared, the reaction was quenched
36.2, 35.2, 31.7, 31.52, 31.46, 31.3, 30.2, 29.1, 28.4, 26.7. with H2O and extracted with EtOAc (3 × 5 mL). The organic
HRMS ESI: calcd for C18H33NO4H+ [M + H]+ 328.24824, found layers were combined, dried over MgSO4 and concentrated
328.24786.
under reduced pressure. The crude material was purified by
Data for 3-epi-20: light yellow syrup, 60 mg, 0.18 mmol, 75% flash column chromatography (silica gel, petroleum
yield, derived from the corresponding ketone 3-epi
-19 (180 ether/EtOAc = 3/1) to afford ketone 21 (191 mg, 0.39 mmol,
mg, 0.25 mmol).
20
95%) as a yellow syrup.
20
[α]D +25.7 (c 0.7, MeOH); IR (KBr, cm-1): 3394, 2927, 2855, Data for 21: [α]D -31.6 (c 0.6, CH2Cl2); IR (KBr, cm-1): 2930,
1
1
1701, 1112, 618; H NMR (300 MHz, MeOD) δ 4.20 (s, 1H), 2857, 1747, 1708, 1652, 1371, 1221, 1040, 882, 604; H NMR
4.07–3.90 (m, 3H), 3.75 (s, 1H), 3.54–3.40 (m, 1H), 2.54–2.28 (400 MHz, CDCl3) δ 5.15 (s, 1H), 5.08 (d, J = 5.6 Hz, 1H), 4.51
(m, 2H), 2.25–2.02 (m, 2H), 2.00–1.61 (m, 6H), 1.60–1.17 (m, (dd, J = 10.1, 2.8 Hz, 0.5H), 4.40 (dd, J = 10.1, 2.6 Hz, 0.5H),
14H). 13C NMR (75 MHz, MeOD) δ 216.3, 77.5, 71.8, 63.4, 62.0, 4.32–4.16 (m, 1H), 4.12–3.94 (m, 1.5H), 3.74 (d, J = 10.1 Hz,
59.4, 51.8, 42.8, 35.3, 32.0, 30.8, 30.6, 30.33, 30.33, 29.3, 28.2, 0.5H), 2.41–2.16 (m, 4H), 2.15–1.89 (m, 13H), 1.88–1.57 (m,
27.5, 25.8. HRMS ESI: calcd for C18H33NO4H+ [M + H]+ 5H), 1.49–1.11 (m, 13H). 13C NMR (101 MHz, CDCl3) δ 213.7,
328.24824, found 328.24799.
213.6, 171.0, 170.9, 169.9, 169.7, 169.6, 169.5, 169.2, 169.1,
Data for ent-3-epi-20: light yellow syrup, 180 mg, 0.55 mmol, 78.6, 77.8, 77.5, 76.3, 65.8, 65.4, 63.0, 62.8, 62.3, 60.5, 50.8,
79% yield, derived from the corresponding ketone ent-3-epi- 42.04, 42.01, 34.0, 33.91, 33.88, 33.3, 30.1, 29.72, 29.68, 29.5,
19 (520 mg, 0.71 mmol).
20
29.4, 29.3, 28.1, 27.2, 26.3, 26.2, 24.90, 24.86, 22.9, 21.09,
[α]D -20.0 (c 0.4, MeOH); IR (KBr, cm-1): 3370, 2929, 2855, 21.05, 21.0, 20.9, 20.8. HRMS ESI: calcd for C26H41NO8H+ [M +
1
1706, 1124, 618; H NMR (300 MHz, MeOD) δ 4.15 (s, 1H), H]+496.29049, found 496.28962.
3.94–3.71 (m, 3H), 3.52 (s, 1H), 3.29–3.18 (m, 1H), 2.45–2.27 Data for ent-21: light yellow syrup, 325 mg, 0.66 mmol, 94%
(m, 2H), 2.20–2.00 (m, 2H), 1.99–1.56 (m, 6H), 1.56–1.09 (m, yield, derived from the corresponding compound ent-20 (230
14H). 13C NMR (75 MHz, MeOD) δ 216.2, 78.2, 72.6, 62.5, 62.0, mg, 0.70 mmol).
20
60.7, 51.8, 42.8, 35.3, 33.6, 30.8, 30.59, 30.59, 30.4, 29.3, 28.2, [α]D +38.6 (c 1.5, CH2Cl2); IR (KBr, cm-1): 2931, 2857, 1747,
1
27.7, 25.8. HRMS ESI: calcd for C18H33NO4H+ [M + H]+ 1709, 1652, 1373, 1220, 1042, 882, 604; H NMR (300 MHz,
328.24824, found 328.24800.
CDCl3) δ 5.16 (s, 1H), 5.09 (s, 1H), 4.52 (d, J = 9.7 Hz, 0.5H),
Data for ent-20a: light yellow oil, 36 mg, 0.11 mmol, 82% yield, 4.41 (d, J = 9.5 Hz, 0.5H), 4.34–4.15 (m, 1H), 4.14–3.95 (m,
derived from the corresponding ketone ent-19a (100 mg, 0.14 1.5H), 3.75 (d, J = 11.5 Hz, 0.5H), 2.43–2.17 (m, 4H), 2.17–1.95
mmol).
(m, 13H), 1.93–1.56 (m, 5H), 1.54–1.10 (m, 13H). 13C NMR (75
[α]D -13.3 (c 0.2, MeOH); IR (KBr, cm-1): 3374, 2927, 2855, MHz, CDCl3) δ 213.6, 213.5, 171.0, 170.9, 169.8, 169.6, 169.4,
1701, 1076, 1042;1H NMR (300 MHz, MeOD) δ 3.66 (t, J = 6.5 169.2, 169.0, 78.6, 77.8, 77.5, 76.3, 65.7, 65.4, 62.9, 62.8, 62.3,
Hz, 1H), 3.58 (dd, J = 11.3, 4.2 Hz, 1H), 3.54–3.46 (m, 2H), 2.91 60.5, 50.8, 42.01, 41.98, 34.0, 33.89, 33.85, 33.3, 30.0, 29.70,
(q, J = 6.2 Hz, 1H), 2.79 (q, 7.1 Hz, 1H), 2.33–2.15 (m, 3H), 29.65, 29.45, 29.37, 29.3, 28.1, 27.2, 26.3, 26.2, 24.9, 24.8,
2.08–1.88 (m, 2H), 1.82–1.48 (m, 5H), 1.43–1.02 (m, 11H). 13C 22.8, 21.1, 21.03, 20.96, 20.9, 20.8. HRMS ESI: calcd for
NMR (75 MHz, MeOD) δ 216.1, 83.4, 79.4, 64.5, 63.0, 62.8, C26H41NO8H+ [M + H]+ 496.29049, found 496.28975.
20
51.7, 42.8, 35.3, 35.0, 30.8, 30.7, 30.6, 29.3, 28.2, 27.6, 25.8. Data for 3-epi
HRMS ESI: calcd for C17H31NO4H+ [M + H]+ 314.23258, found yield, derived from the corresponding compound 3-epi-20 (150
314.23196. mg, 0.46 mmol).
-21: light yellow syrup, 173 mg, 0.35 mmol, 76%
20
Data for ent-20b: light yellow oil, 390 mg, 1.30 mmol, 83% [α]D +3.5 (c 1.2, CH2Cl2); IR (KBr, cm-1): 2929, 2857, 1745,
yield, derived from the corresponding ketone ent
-
19b (1.10 g, 1708, 1654, 1393, 1368, 1225, 1107, 1043; 1H NMR (500 MHz,
CDCl3) δ 5.45 (dd, J = 7.7, 4.0 Hz, 0.5H), 5.38–5.30 (m, 1.5H),
1.56 mmol).
20
[α]D -16.0 (c 0.5, MeOH); IR (KBr, cm-1): 3370, 2931, 2858, 4.55 (t, J = 8.2 Hz, 0.5H), 4.51–4.43 (m, 1H), 4.37–4.28 (m,
1699, 1124, 1076; 1H NMR (300 MHz, D2O) δ 3.83 (t, J = 7.0 Hz, 1.5H), 3.97 (d, J = 10.2 Hz, 0.5H), 3.73 (d, J = 10.6 Hz, 0.5H),
14 | J. Name., 2012, 00, 1-3
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2.42–2.19 (m, 5H), 2.19–1.93 (m, 12H), 1.90–1.59 (m, 5H), (TMS)2NH (0.1 mL, 0.47 mmol) was added to a solution of 21
1.54–1.11 (m, 13H). 13C NMR (126 MHz, CDCl3) δ 213.73, (130 mg, 0.26 mmol) in CH3CN (10 mL) at 0oC. After 10 min,
213.65, 170.4, 170.3, 170.1, 170.0, 169.8, 169.7, 169.6, 75.2, NaI (50 mg, 0.34 mmol) and TMSCl (40 μL, 0.34 mmol) were
74.1, 70.1, 68.9, 63.6, 63.5, 62.7, 60.9, 56.7, 55.1, 50.8, 42.1, successively added and the resulting mixture was stirred for 3
o
42.0, 34.7, 34.0, 33.9, 31.3, 29.8, 29.70, 29.66, 29.5, 29.40, h. The mixture was cooled to -20 C, and NBS (49 mg, 0.28
29.35, 29.3, 28.1, 27.2, 26.4, 26.3, 24.92, 24.89, 23.1, 22.2, mmol) was added. After 30 min, the reaction was allowed to
21.1, 21.0, 20.8, 20.7, 20.5. HRMS ESI: calcd for C26H41NO8H+ reach room temperature, and the mixture was stirred for 3 h.
[M + H]+ 496.29049, found 496.28902.
The reaction was quenched with saturated aqueous NaHCO3,
Data for ent-3-epi-21: light yellow syrup, 142 mg, 0.29 mmol, and the mixture was extracted with EtOAc (3 × 5 mL). The
94% yield, derived from the corresponding compound ent-3- combined organic extracts were dried and concentrated to
epi-20 (100 mg, 0.31 mmol).
20
afford the corresponding bromo compound, which was used in
[α]D -3.6 (c 0.6, CH2Cl2); IR (KBr, cm-1): 2931, 2857, 1747, the next step of reaction without further purification.
1
1708, 1652, 1395, 1368, 1225, 1107, 1043; H NMR (300 MHz, LiBr (27 mg, 0.31 mmol) and Li2CO3 (23 mg, 0.31 mmol) were
CDCl3) δ 5.46 (dd, J = 7.7, 4.4 Hz, 0.5H), 5.42–5.25 (m, 1.5H), successively added to a solution of bromo compound (0.26
4.59–4.40 (m, 1.5H), 4.40–4.25 (m, 1.5H), 3.97 (d, J = 9.9 Hz, mmol) in DMF (10 mL). The reaction mixture was heated at
o
0.5H), 3.75 (d, J = 10.4 Hz, 0.5H), 2.45–2.19 (m, 5H), 2.18–1.92 120 CoCfor 4 h and then quenched by addition of water; the
(m, 12H), 1.90–1.57 (m, 5H), 1.51–1.12 (m, 13H). 13C NMR (75 solvent was removed under reduced pressure. The residue was
MHz, CDCl3) δ 213.3, 213.2, 170.1, 170.0, 169.75, 169.72, dissolved in EtOAc and washed with brine. The organic layers
169.6, 169.41, 169.35, 75.0, 73.9, 69.9, 68.7, 63.4, 63.2, 62.5, were combined, dried over MgSO4 and concentrated under
60.6, 56.5, 54.9, 50.5, 41.8, 34.4, 33.8, 33.7, 31.0, 29.44, 29.39, reduced pressure. The crude material was purified by flash
29.22, 29.18, 29.12, 29.08, 29.0, 27.9, 26.9, 26.1, 26.0, 24.7, column chromatography (silica gel, petroleum ether/EtOAc =
24.6, 22.8, 21.9, 20.8, 20.7, 20.5, 20.4, 20.3. HRMS ESI: calcd 3/1) to afford the corresponding α,β-unsaturated ketone 22
for C26H41NO8H+ [M + H]+ 496.29049, found 496.28986.
(107 mg, 0.22 mmol, 83%) as a yellow syrup.
20
Data for ent-21a: light yellow syrup, 628 mg, 1.30 mmol, 93% Data for 22: [α]D -26.7 (c 1.4, CH2Cl2); IR (KBr, cm-1): 2928,
yield, derived from the corresponding compound ent
-
20a (440 2856, 1746, 1652, 1373, 1221, 1096, 1039; 1H NMR (300 MHz,
CDCl3) δ 6.73–6.67 (m, 1H), 5.16 (s, 1H), 5.10 (d, J = 3.5 Hz, 1H),
mg, 1.40 mmol).
20
[α]D +25.0 (c 0.8, CH2Cl2); IR (KBr, cm-1): 2932, 2858, 1745, 4.53 (dd, J = 9.7, 3.4 Hz, 0.5H), 4.41 (dd, J = 9.4, 2.9 Hz, 0.5H),
1
1708, 1652, 1371, 1222, 1040; H NMR (300 MHz, CDCl3) δ 4.34–3.95 (m, 2.5H), 3.76 (dd, J = 11.5, 2.3 Hz, 0.5H), 2.46–2.29
5.16 (s, 1H), 5.09 (d, J = 3.9 Hz, 1H), 4.52 (dd, J = 9.7, 3.4 Hz, (m, 4H), 2.24–2.03 (m, 13H), 2.03–1.91 (m, 2H), 1.91–1.56 (m,
0.5H), 4.41 (dd, J = 9.4, 2.9 Hz, 0.5H), 4.33–4.17 (m, 1H), 4.14– 2H), 1.54–1.19 (m, 11H). 13C NMR (75 MHz, CDCl3) δ 199.59,
3.96 (m, 1.5H), 3.75 (dd, J = 11.6, 2.6 Hz, 0.5H), 2.44–2.18 (m, 199.57, 170.94, 170.87, 169.9, 169.60, 169.56, 169.4, 169.2,
4H), 2.14–1.97 (m, 13H), 1.95–1.56 (m, 5H), 1.55–1.10 (m, 169.0, 145.0, 144.9, 139.91, 139.88, 78.6, 77.8, 77.5, 76.3,
11H). 13C NMR (75 MHz, CDCl3) δ 213.6, 213.5, 171.0, 170.9, 65.7, 65.4, 62.9, 62.7, 62.3, 60.5, 38.6, 33.2, 30.0, 29.6, 29.5,
169.9, 169.6, 169.5, 169.2, 169.1, 78.6, 77.8, 76.4, 65.8, 65.4, 29.33, 29.28, 29.2, 28.64, 28.55, 26.3, 26.2, 26.1, 23.2, 22.8,
63.0, 62.8, 62.3, 60.5, 50.8, 42.1, 42.0, 34.0, 33.9, 33.3, 30.1, 21.1, 21.0, 20.95, 20.9, 20.7. HRMS ESI: calcd for C26H39NO8H+
29.6, 29.4, 29.3, 28.1, 27.1, 26.3, 26.2, 25.0, 24.9, 22.9, 21.09, [M + H]+ 494.27484, found 494.27398.
21.06, 21.0, 20.9, 20.8. HRMS ESI: calcd for C25H39NO8H+ [M + Data for ent-22: yellow syrup, 338 mg, 0.68 mmol, 85% yield,
H]+ 482.27484, found 482.27417.
derived from the corresponding compound ent-21 (400 mg,
Data for ent-21b: light yellow syrup, 610 mg, 1.30 mmol, 90% 0.81mmol).
20
yield, derived from the corresponding compound ent
-
20b (430 [α]D +27.2 (c 1.3, CH2Cl2); IR (KBr, cm-1): 2930, 2856, 1747,
1
1655, 1370, 1220, 1123, 1042; H NMR (300 MHz, CDCl3) δ
mg, 1.44 mmol).
20
[α]D +20.0 (c 1.1, CH2Cl2); IR (KBr, cm-1): 2934, 2859, 1744, 6.70 (s, 1H), 5.16 (s, 1H), 5.09 (s, 1H), 4.52 (d, J = 6.9 Hz, 0.5H),
1
1708, 1652, 1371, 1221, 1039; H NMR (300 MHz, CDCl3) δ 4.41 (d, J = 7.9 Hz, 0.5H), 4.35–3.95 (m, 2.5H), 3.76 (d, J = 10.7
4.93 (s, 1H), 4.86 (s, 1H), 4.29 (d, J = 7.5 Hz, 0.5H), 4.19 (d, J = Hz, 0.5H), 2.51–2.29 (m, 4H), 2.26–2.05 (m, 13H), 2.05–1.91
7.7 Hz, 0.5H), 4.09–3.95 (m, 1H), 3.94–3.80 (m, 1H), 3.76 (d, J = (m, 2H), 1.90–1.55 (m, 2H), 1.54–1.18 (m, 11H). 13C NMR (101
8.9 Hz, 0.5H), 3.57 (d, J = 10.4 Hz, 0.5H), 2.23–1.73 (m, 17H), MHz, CDCl3) δ 199.74, 199.71, 171.1, 171.0, 170.0, 169.74,
1.72–1.34 (m, 5H), 1.34–0.84 (m, 9H). 13C NMR (75 MHz, CDCl3) 169.69, 169.5, 169.3, 169.1, 145.1, 145.0, 140.1, 140.0, 78.7,
δ 212.6, 212.4, 170.3, 170.2, 169.3, 169.0, 168.9, 168.8, 168.6, 77.9, 77.6, 77.4, 76.4, 65.9, 65.5, 63.0, 62.9, 62.4, 60.6, 38.7,
168.5, 78.1, 77.4, 77.2, 77.0, 75.8, 65.1, 64.8, 62.5, 62.3, 61.8, 33.4, 30.1, 29.7, 29.6, 29.5, 29.41, 29.36, 28.8, 28.7, 26.4, 26.3,
59.9, 50.1, 41.5, 33.6, 33.5, 33.4, 32.6, 29.4, 28.9, 28.8, 27.6, 26.2, 23.3, 22.9, 21.2, 21.12, 21.05, 21.0, 20.9. HRMS ESI: calcd
26.4, 25.5, 24.4, 24.3, 22.3, 20.43, 20.37, 20.3, 20.2.HRMS ESI: for C26H39NO8H+ [M + H]+ 494.27484, found 494.27416.
calcd for C24H37NO8H+ [M + H]+ 468.25919, found 468.25892.
General procedures for synthesis of compound 22 ent-22
epi-22 ent-3-epi-22 ent-22a and ent
as an example.
(2R,3R,4R,5R)-3,4-Diyldiacetate-2-(acetoxymethyl)-1-acetyl-5- 1655, 1369, 1226, 1107, 1043; H NMR (400 MHz, CDCl3) δ
Data for 3-epi-22: yellow syrup, 140 mg, 0.28 mmol, 78% yield,
, 3- derived from the corresponding compound 3-epi-21 (180 mg,
,
,
,
-22b, with compound 22 0.36 mmol).
20
[α]D +8.9 (c 0.5, CH2Cl2); IR (KBr, cm-1): 2927, 2856, 1747,
1
[7-(cyclohexy-2-on-1(6)-enyl)heptyl]pyrrolidine (22)
.
6.73–6.68 (m, 1H), 5.46 (dd, J = 8.0, 4.4 Hz, 0.5H), 5.40–5.27
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(m, 1.5H), 4.58–4.51 (m, 0.5H), 4.51–4.42 (m, 1H), 4.38–4.26 21.01, 20.94, 20.88, 20.7. HRMS ESI: calcd for C24H35NO8H+ [M
(m, 1.5H), 4.00–3.93 (m, 0.5H), 3.77–3.69 (m, 0.5H), 2.42 (t, J = + H]+ 466.24354, found 466.24285.
6.5 Hz, 1.5H), 2.39–2.31 (m, 1.5H), 2.22 (s, 2H), 2.19–2.09 (m, General procedures for synthesis of broussonetine W (4) and
6H), 2.09–2.02 (m, 5H), 2.02–1.92 (m, 2.5H), 1.86–1.58 (m, its analogs ent-4
1.5H), 1.49–1.13 (m, 12H). 13C NMR (101 MHz, CDCl3) δ 199.7, broussonetine W (4) as an example.
170.5, 170.3, 170.09, 170.05, 169.9, 169.71, 169.66, 145.1, Broussonetine W
, 3-epi-4, ent-3-epi-4, ent-4a and ent-4b, with
(4)
145.0, 140.01, 139.97, 75.2, 74.1, 70.1, 69.0, 63.7, 63.5, 62.7, To a solution of 22 (200 mg, 0.41 mmol) in MeOH (10 mL) was
60.9, 56.7, 55.1, 38.7, 34.7, 31.3, 29.6, 29.5, 29.4, 29.3, 28.7, added a 1 M solution of MeONa in MeOH (1 mL); the solution
28.6, 26.5, 26.3, 26.2, 23.3, 23.1, 22.2, 21.1, 21.0, 20.8, 20.7, was stirred for 5 h at room temperature. Then concentrated
20.5. HRMS ESI: calcd for C26H39NO8H+ [M + H]+ 494.27484, HCl (about 1 mL) was slowly added dropwise to acidify
found 494.27396.
reaction mixture; the solution was stirred for 8 h at room
Data for ent-3-epi-22: yellow syrup, 149 mg, 0.30 mmol, 83% temperature. After the reaction was complete, the solution
yield, derived from the corresponding compound ent-3-epi-21 was concentrated in vacuo, and the residue was dissolved in
(180 mg, 0.36 mmol).
20
MeOH and neutralized with aqueous ammonium solution, and
[α]D -6.0 (c 1.0, CH2Cl2); IR (KBr, cm-1): 2928, 2856, 1747, the solution was concentrated in vacuo. The above procedure
1
1655, 1369, 1226, 1107, 1042; H NMR (400 MHz, CDCl3) δ was repeated for three times to insure completeneutralization.
6.70 (d, J = 4.0 Hz, 1H), 5.45 (dd, J = 7.9, 4.5 Hz, 0.5H), 5.41– The residue was purified by an acid resin column (DOWEX 50W
5.25 (m, 1.5H), 4.57–4.51 (m, 0.5H), 4.50–4.41 (m, 1H), 4.39– × 8, 100-200 mesh), eluting with distilled water (100 mL) and
4.24 (m, 1.5H), 3.97 (d, J = 8.5 Hz, 0.5H), 3.78–3.69 (m, 0.5H), then 6N NH4OH (50 mL), affording compound
4 (121 mg, 0.37
2.41 (t, J = 6.6 Hz, 1.5H), 2.38–2.30 (m, 1.5H), 2.22 (s, 2H), mmol, 92%) as a light yellow oil.
20
2.19–2.09 (m, 6H), 2.09–2.01 (m, 5H), 2.01–1.91 (m, 2.5H), Data for 4
: [α]D +15.0 (c 0.4, MeOH); IR (KBr, cm-1): 3358,
1.89–1.57 (m, 1.5H), 1.50–1.11 (m, 12H). 13C NMR (101 MHz, 2926, 2855, 1655, 1455, 1381, 1047; 1H NMR (500 MHz, Pyr) δ
CDCl3) δ 199.7, 170.4, 170.3, 170.1, 170.0, 169.9, 169.7, 169.6, 6.91 (s, br, 3H), 6.57 (s, 1H), 4.70 (t, J = 6.2 Hz, 1H), 4.43 (t, J =
145.1, 145.0, 140.00, 139.96, 75.2, 74.1, 70.1, 68.9, 63.7, 63.5, 6.5 Hz, 1H), 4.35–4.17 (m, 2H), 3.94–3.82 (m, 1H), 3.69–3.55
62.7, 60.9, 56.7, 55.1, 38.7, 34.7, 31.3, 29.6, 29.5, 29.4, 29.3, (m, 1H), 2.38 (t, J = 6.6 Hz, 2H), 2.24 (t, J = 7.2 Hz, 2H), 2.19–
28.7, 28.65, 28.56, 26.4, 26.3, 26.2, 23.3, 23.1, 22.2, 21.1, 21.0, 2.10 (m, 2H), 2.10–2.00 (m, 1H), 1.90–1.72 (m, 3H), 1.72–1.59
20.8, 20.7, 20.5. HRMS ESI: calcd for C26H39NO8H+ [M + H]+ (m, 1H), 1.59–1.48 (m, 1H), 1.46–1.35 (m, 2H), 1.35–1.13 (m,
494.27484, found 494.27396.
6H). 13C NMR (126 MHz, Pyr) δ 198.8, 145.2, 139.9, 83.5, 79.6,
Data for ent-22a: yellow syrup, 147 mg, 0.31 mmol, 74% yield, 65.2, 63.0, 62.8, 38.9, 34.8, 30.14, 30.09, 29.8 (2C), 29.1, 27.2,
21a (200 mg, 26.2, 23.6. HRMS ESI: calcd for C18H31NO4H+ [M + H]+
derived from the corresponding compound ent
-
0.42 mmol).
20
326.23258, found 326.23227.
[α]D +24.0 (c 1.0, CH2Cl2); IR (KBr, cm-1): 2929, 2857, 1744, Data for ent-4: light yellow oil, 36 mg, 0.11 mmol, 78% yield,
1
1670, 1373, 1222, 1040; H NMR (400 MHz, CDCl3) δ 6.70 (s, derived from the corresponding compound ent-22 (70 mg,
1H), 5.15 (s, 1H), 5.09 (s, 1H), 4.56–4.47 (m, 0.5H), 4.44–4.37 0.14 mmol).
20
(m, 0.5H), 4.32–4.25 (m, 0.5H), 4.24–4.16 (m, 0.5H), 4.14–3.94 [α]D -18.0 (c 0.5, MeOH); IR (KBr, cm-1): 3324, 2927, 2856,
(m, 1.5H), 3.75 (d, J = 11.6 Hz, 0.5H), 2.40 (s, 2H), 2.34 (s, 2H), 1670, 1561, 1410, 1124; 1H NMR (300 MHz, Pyr) δ 6.54 (s, 1H),
2.18–2.02 (m, 14H), 1.97 (s, 2H), 1.89–1.76 (m, 0.5H), 1.69– 6.04 (s, br, 4H), 4.69 (t, J = 6.4 Hz, 1H), 4.42 (t, J = 6.6 Hz, 1H),
1.56 (m, 0.5H), 1.51–1.19 (m, 9H). 13C NMR (101 MHz, CDCl3) δ 4.33–4.16 (m, 2H), 3.92–3.83 (m, 1H), 3.65–3.53 (m, 1H), 2.35
199.7, 171.0, 170.9, 170.0, 169.7, 169.6, 169.5, 169.2, 169.1, (t, J = 6.7 Hz, 2H), 2.26–2.15 (m, 2H), 2.15–2.07 (m, 2H), 2.07–
145.1, 145.0, 139.9, 139.8, 78.6, 77.8, 76.3, 65.8, 65.4, 62.9, 1.96 (m, 1H), 1.89–1.67 (m, 3H), 1.67–1.43 (m, 2H), 1.42–1.09
62.8, 62.3, 60.5, 38.6, 33.3, 30.1, 29.7, 29.6, 29.5, 29.2, 28.5, (m, 8H). 13C NMR (75 MHz, Pyr) δ 198.8, 145.2, 139.8, 83.2,
26.3, 26.2, 26.1, 23.2, 22.8, 21.04, 20.97, 20.9, 20.8. HRMS ESI: 79.3, 65.0, 62.8, 62.6, 38.8, 34.5, 30.1, 30.0, 29.7, 28.99, 28.99,
calcd for C25H37NO8H+ [M + H]+ 480.25919, found 480.25848.
27.1, 26.1, 23.5. HRMS ESI: calcd for C18H31NO4H+ [M + H]+
Data for ent-22b: yellow syrup, 368 mg, 0.79 mmol, 74% yield, 326.23258, found 326.23287.
derived from the corresponding compound ent
-21b (500 mg, Data for 3-epi-4: light yellow oil, 59 mg, 0.18 mmol, 89% yield,
1.07 mmol).
derived from the corresponding compound 3-epi-22 (100 mg,
20
[α]D +25.9 (c 0.9, CH2Cl2); IR (KBr, cm-1): 2934, 2859, 1744, 0.20 mmol).
1716, 1652, 1371, 1223, 1040; H NMR (300 MHz, CDCl3) δ [α]D +24.0 (c 0.3, MeOH); IR (KBr, cm-1): 3359, 2926, 2854,
1
6.74–6.66 (m, 1H), 5.16 (s, 1H), 5.09 (d, J = 3.3 Hz, 1H), 4.53 1655, 1119; H NMR (300 MHz, MeOD) δ 6.86 (t, J = 3.9 Hz,
1
20
(dd, J = 9.7, 3.3 Hz, 0.5H), 4.41 (d, J = 8.0 Hz, 0.5H), 4.23–4.19 1H), 4.18–4.12 (m, 1H), 3.94–3.72 (m, 3H), 3.56–3.44 (m, 1H),
(m, 1H), 4.19–4.03 (m, 1H), 3.99 (d, J = 9.6 Hz, 0.5H), 3.75 (d, J 3.29–3.18 (m, 1H), 2.46–2.35 (m, 2H), 2.21–2.09 (m, 2H), 2.04–
= 9.9 Hz, 0.5H), 2.46–2.29 (m, 4H), 2.25–2.04 (m, 14H), 2.03– 1.90 (m, 2H), 1.83–1.22 (m, 14H). 13C NMR (75 MHz, MeOD) δ
1.56 (m, 4H), 1.55–1.23 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 202.2, 148.2, 140.8, 78.5, 72.8, 62.6, 62.1, 60.9, 39.6, 33.8,
199.54, 199.47, 170.94, 170.87, 169.9, 169.7, 169.6, 169.4, 30.7, 30.7, 30.52, 30.48, 30.0, 27.9, 27.2, 24.4. HRMS ESI: calcd
169.2, 169.0, 145.2, 145.0, 139.9, 139.8, 78.7, 77.8, 77.6, 76.4, for C18H31NO4H+ [M + H]+ 326.23258, found 326.23227.
65.8, 65.4, 63.0, 62.8, 62.3, 60.5, 38.6, 33.2, 30.0, 29.7, 29.51,
29.48, 29.1, 28.6, 28.5, 26.11, 26.05, 26.0, 23.2, 22.8, 21.04,
16 | J. Name., 2012, 00, 1-3
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Data for ent-3-epi-4: light yellow oil, 48 mg, 0.15 mmol, 77%
yield, derived from the corresponding compound ent-3-epi-
22(95 mg, 0.19 mmol).
Nakamura, N. Akazawa and G. Kusano, Chem. Pharm. Bull.,
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1048–1050; (d) M. Shibano, S. Nakamura, M. Kubori, K.
Minoura and G. Kusano, Chem. Pharm. Bull., 1998, 46
,
[α]20 -20.0 (c 0.1, MeOH); IR (KBr, cm-1): 3358, 2925, 2854,
D
1
1659, 1123; H NMR (300 MHz, MeOD) δ 6.86 (t, J = 4.1 Hz,
,
1H), 4.13 (t, J = 3.6 Hz, 1H), 3.93–3.72 (m, 3H), 3.49–3.39 (m,
1H), 3.24–3.13 (m, 1H), 2.47–2.35 (m, 2H), 2.22–2.13 (m, 2H),
2.04–1.93 (m, 2H), 1.81–1.23 (m, 14H). 13C NMR (75 MHz,
MeOD) δ 202.0, 148.0, 140.7, 78.5, 72.8, 62.3, 62.0, 61.0, 39.4,
34.0, 30.60, 30.58, 30.39, 30.36, 29.9, 27.8, 27.0, 24.3. HRMS
ESI: calcd for C18H31NO4H+ [M + H]+ 326.23258, found
326.23232.
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Data for ent-4a: light yellow oil, 56 mg, 0.18 mmol, 86% yield,
derived from the corresponding compound ent-22a (100 mg,
0.21 mmol).
20
2. M. Shibano, D. Tsukamoto and G. Kusano, Heterocycles,
2002, 57, 1539-1553.
[α]D -17.1 (c 0.4, MeOH); IR (KBr, cm-1): 3375, 2928, 2857,
1
1652, 1384, 1076; H NMR (300 MHz, MeOD) δ 6.87 (t, J = 4.0 3. (a) B. Ganem, Accounts Chem. Res., 1996, 29, 340–347; (b)
Hz, 1H), 3.94 (t, J = 5.9 Hz, 1H), 3.88–3.72 (m, 3H), 3.44–3.56
(m, 1H), 3.29–3.19 (m, 1H), 2.66–2.55 (m, 1H), 2.46–2.36 (m,
2H), 2.23–2.13(m, 1H), 2.05–1.94 (m, 1H), 1.94–1.78 (m, 2H),
1.77–1.57 (m, 2H), 1.56–1.24 (m, 9H). 13C NMR (75 MHz,
MeOD) δ 202.0, 148.2, 140.6, 81.0, 77.2, 65.2, 63.8, 60.3, 39.4,
32.6, 30.5, 30.2, 30.1, 29.7, 27.1, 27.0, 24.2.HRMS ESI: calcd for
C17H29NO4H+ [M + H]+ 312.21693, found 312.21665.
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Data for ent-4b: light yellow oil, 47 mg, 0.16 mmol, 74% yield,
derived from the corresponding compound ent-22b (100 mg,
0.21 mmol).
20
[α]D -8.0 (c 0.3, MeOH); IR (KBr, cm-1): 3363, 2927, 2857,
1662, 1383, 1131, 1076; 1H NMR (300 MHz, MeOD) δ 6.87 (t, J
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Acknowledgements
Financial support from National Basic Research Program of
China (No. 2012CB822101), the National Natural Science
Foundation of China (No. 21202173 and 21272240), National
Science and Technology Major Projects for "Major New Drugs
Q. Wang, J. Kang and R. Y. Chen, Carbohydr. Res., 2014, 384
,
Innovation
and
Development"
(2013ZX09508104),
9–12.
Development Fund for Collaborative Innovation Center of
Glycoscience of Shandong University and National Engineering
Research Center for Carbohydrate Synthesis of Jiangxi Normal
University is gratefully acknowledged. This work was also
supported in part by a Leverhulme Emeritus Research
Fellowship (GWJF) and a Grant-in-Aid for Scientific Research
(C) (No: 26460143) (AK) from the Japanese Society for the
Promotion of Science (JSPS).
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