A new synthetic access to bicyclic polyhydroxylated alkaloid analogues from pyranosides

Article abstract of DOI:10.1039/b923180c

A facile, versatile and stereoselective synthesis of bicyclic polyhydroxylated alkaloids as castanospermine analogues is described. The synthetic route started from methyl pyranosides. The key steps involved a high-yielding expeditious one-pot tandem reaction from alkenes to N-substituted δ-lactams. The δ-lactams were stereoselectively vinylated to give the dienes, which were followed by the ring-closing metathesis to produce the cyclized products. The functional group transformations of the resulting bicyclic compounds furnished diverse polyhydroxylated alkaloids in good yields. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b923180c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A new synthetic access to bicyclic polyhydroxylated alkaloid analogues from
pyranosides†
Ning Wang, Li-He Zhang and Xin-Shan Ye*
Received 5th November 2009, Accepted 17th March 2010
First published as an Advance Article on the web 7th April 2010
DOI: 10.1039/b923180c
A facile, versatile and stereoselective synthesis of bicyclic polyhydroxylated alkaloids as
castanospermine analogues is described. The synthetic route started from methyl pyranosides. The key
steps involved a high-yielding expeditious one-pot tandem reaction from alkenes to N-substituted
d-lactams. The d-lactams were stereoselectively vinylated to give the dienes, which were followed by the
ring-closing metathesis to produce the cyclized products. The functional group transformations of the
resulting bicyclic compounds furnished diverse polyhydroxylated alkaloids in good yields.
advantage of the carbohydrates’ stereocenters.13 In recent years,
asymmetric synthesis from non-carbohydrate substrates has also
Introduction
become popular.14 However, most methods mentioned above
only provided one type of target with a certain ring size. To
meet the ever-growing needs for diverse bicyclic polyhydroxylated
iminosugars for drug discovery and structure–activity relation-
ship studies, more flexible, universal, and efficient methods that
could lead to more targets with shorter synthetic routes are
desired.
In this article, we describe a new access to bicyclic polyhy-
droxylated iminosugars that involves only 7–8 synthetic steps
from commercially available methyl D-pyranosides and the diverse
target iminosugars that are obtained by using this synthetic
access (Scheme 1). As shown in Scheme 1, starting from different
pyranosides, the different final polyhydroxylated alkaloids will be
constructed. The amine moiety will be introduced via a reductive
amination process. The use of alkenylamines with different side
chain lengths will allow the achievement of different ring sizes for
the final bicyclic frameworks. A ring-closing metathesis will be
applied to form a double bond in the bicyclic framework, which
will be subjected to hydroxylation and/or deprotection to result
in the polyhydroxylated alkaloids.
Naturally occurring polyhydroxylated alkaloids, also known as
iminosugars, have increasingly attracted great interest from syn-
thetic chemists because they are frequently found to be potent
inhibitors of many carbohydrate-processing enzymes involved
in important biological systems.1 These unique molecules have
tremendous potential as therapeutic agents in a wide range of
diseases such as diabetes,2 viral infections,3 tumor metastasis,4 and
lysosomal storage disorders.5 Bicyclic polyhydroxylated alkaloids,
for example, (+)-castanospermine (1) and (-)-swainsonine (2)
(Fig. 1), and their chemically modified derivatives are also effective
antiviral, antitumor, and immunomodulating agents.6 However,
less than 10 naturally occurring bicyclic polyhydroxylated imi-
nosugars have been isolated so far, covering only a small fraction
of the possible iminosugars that could hold therapeutic potential.7
Therefore, to test the entire chemical space occupied by these
iminosugars, diversity-oriented synthesis of these compounds is
in great demand.
Results and discussion
The starting material glucosyl alkene 3 was easily obtained from
methyl a-D-glucopyranoside via three steps15 or five steps in
high overall yield (77%).16 As shown in Scheme 2, the d-lactams
were hinged on various side chains on nitrogen, allowing the
introduction of the alkenyl chains. The N-substituted d-lactams
4a–c were produced from 3 in high yields through a one-pot tan-
dem procedure with lactone as intermediate following the recent
procedure reported by us.17 The d-lactams 4a–c were then treated
with vinylmagnesium bromide followed by hydride reduction to
yield the expected diene products 5a–c. It is noteworthy that
only one isomer of the two possible stereo-isomers was obtained
in acceptable yields (60–70%). It is assumed that the reduction
process involves the iminium ion (Scheme 3).18 If reaction path-
ways are restricted in chair-like transition states, an analysis of
the relative energy of two transition states, namely 8 and 9 can
be made. Quantum chemistry studies in conformational analysis
Fig. 1 Structures of castanospermine and swainsonine.
In the past decades, a number of different hydroxyl substi-
tuted and ring-expanded analogues of these iminosugars were
synthesized by many research groups.8–12 The majority of the
published synthetic pathways to these bicyclic polyhydroxylated
iminosugars used carbohydrates as the starting materials, taking
State Key Laboratory of Natural and Biomimetic Drugs, Peking University,
and School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd
No. 38, Beijing 100191, China. E-mail: xinshan@bjmu.edu.cn; Fax: +86 10
62014949; Tel: +86 10 82801570
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra for compounds. See DOI: 10.1039/b923180c
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Scheme 1 Design of the synthetic route.
Scheme 2 Synthesis of polyhydroxylated alkaloids 7a–c from glucosyl alkene 3.
using Gaussian 03 software (semi-empirical AM1 method) suggest
that the energy transition state 9 holds, and will be favored over
that of 8. The higher energy of 8 might be attributed to the
stronger intramolecular van der Waals repulsive force because
of the approach of 1,3-diaxial protons on both faces. Thus,
the conformational analysis would predict 9 to be more stable
because of its lower energy (around 10 kcal mol-1 lower than 8),
leading to the formation of products 5a–c in a stereoselective
manner, that is, the reductant attacks on the less hindered
face opposite to the 1,3-diaxial benzyloxy substituents to yield
products.
With the dialkenylamines 5a–c in hand, the next key step is
the construction of the desired bicyclic framework by way of
a ring-closing metathesis (RCM). However, in most cases, an
acyl or a benzyl protected amine is necessary when applying
RCM reaction to construct the N-heterocycles.19a–c It was once
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Scheme 3 Conformational analyses of 8 and 9.
reported that RCM by using Grubbs catalyst could be performed
with no decrease in yield when an amine protected by an alkyl
group was converted to its hydrochloride salt form.19d Inspired
by these results, dialkenylamines 5a–c were also converted to
the hydrochloride salts. Different metathesis catalysts (Grubbs
1st generation and Grubbs 2nd generation) were tried in both
toluene and CH2Cl2 at various temperatures, and the best results
were finally obtained by using Grubbs 1st generation catalyst
6a–c afforded the corresponding bicyclic trihydroxylated alkaloids
7a–c in nearly quantitative yield (Scheme 2).
To increase structural diversity, more alkaloid analogues were
prepared from precursors 6a–b (Scheme 4). The alkene 6a was
oxidized by N-methylmorpholine N-oxide in the presence of cat-
20–22
alytic amount of OsO4
resulting in the desired dihydroxylated
product 10a, which was subjected to catalytic hydrogenolysis
over Pd/C to provide the pentahydroxylated alkaloid 11a. In
the same way, alkaloid 11b was also obtained smoothly from
alkene 6b. In addition, to further test the flexible functional
group transformations of the double bond, the monohydroxylated
◦
(25% mol) in CH2Cl2 at 45 C. Though some aromatic products
were detected, the desired cyclized products 6a–c were produced
in 34–81% isolated yields. Catalytic hydrogenolysis of compounds
Scheme 4 Synthesis of polyhydroxylated alkaloids 11a, 11b, and 13.
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compound 12 was prepared from alkene 6b by hydroboration
with borane–methyl sulfide followed by oxidation with H2O2.23
Full deprotection of 12 led to the tetrahydroxylated alkaloid 13
in almost quantitative yield. Theoretically, the modification of
the double bond could possibly produce other stereo-isomers.
However, the reaction took place highly stereoselectively and only
a single isomer was isolated. This could be explained by the fact
that the oxidation occurred antiperiplanarly to the b-benzyloxy
groups of the alkenes in the ring systems due to steric hindrance. In
such systems, the antiperiplanar attacks were much more favored,
affording compounds 10a, 10b, and 12 as pure stereo-isomers.
Moreover, to widen the substrate scope of this synthetic strat-
egy, some polyhydroxylated alkaloid analogues 18a–c were also
prepared in high yields from mannose-type alkene 14 in the same
way mentioned above (Scheme 5). Similarly, the polyhydroxylated
alkaloid 20 was successfully derived from the alkene intermediate
17b (Scheme 6).
NOESY) of either themselves or their precursors. The config-
uration determination of 10b (the precursor of 11b) and 20 is
exemplified in Fig. 2 and Table 1. Firstly we identified most of the
proton signals such as H-1, H-2, and H-9a signals through their
COSY spectra (Fig. 2) since they are not superimposed in their
1H NMR spectra. The stereochemistry of three O-benzyl groups
in the starting materials 3 and 14 ensures the configuration of the
substituents at C-7, C-8, C-9 positions in compound 10b (H7–H8
trans, H8–H9 trans) and the substituents at C-1, C-2, C-3 positions
in 20 (H1–H2 trans, H2–H3 syn). Based on the coupling constants
(the coupling constants for axial–axial coupling are in the range of
9.5–12.0 Hz, whereas the coupling constants for axial–equatorial
or equatorial–equatorial couplings are in the range of 1.0–5.0 Hz),
the coupling constants of 10b (J1,9a = 9.5 Hz, J9,9a = 2.5 Hz, J1,2
=
3.5 Hz) indicated the trans-diaxial relationship between H-1 and
H-9a, the syn-relationship between H-9 and H-9a, and further
concluded the syn-relationship between H-1 and H-2; the key
All structures of target polyhydroxylated alkaloids 7a–c, 11a–
b, 13, 18a–c, and 20 were identified by careful analyses of the
1D- (1H, 13C) and 2D-NMR spectra (COSY, HSQC, gHMBC,
coupling constants of 20 (J1,9a = 1.0 Hz, J9,9a = 10.5 Hz, J8,9 =
3.0 Hz) indicated the syn-relationship between H-1 and H-9a,
the trans-diaxial relationship between H-9 and H-9a, and further
Scheme 5 Synthesis of polyhydroxylated alkaloids 18a–c from mannosyl alkene 14.
Scheme 6 Synthesis of polyhydroxylated alkaloid 20.
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Fig. 2 2D-NMR spectra of 10b and 20.
Table 1 Selective coupling constants J [Hz] for 10b and 20
of other target compounds was assigned. In addition, compounds
7a, 7b, 11a, 13, and 18a are known compounds and their struc-
tures were further confirmed by comparison with the published
data.22,24–26
compound
J1,2
J9,9a
J1,9a
J8,9
J6ax,7
J6eq,7
J7,8
10b
3.5
2.5
9.5
3.5
5.0
J8,9
J1,9a
J9,9a
J1,2
J3,4ax
J3,4eq
J2,3
Conclusion
20
3.0
1.0
10.5
4.0
12.0
3.5
A new efficient route to bicyclic polyhydroxylated alkaloid ana-
logues from pyranosides was developed. Through this access, 10
polyhydroxylated alkaloids were smoothly prepared by a seven-
or eight-step sequence in good overall yields (around 20%). The
synthetic pathway is rapid, flexible, and highly stereoselective. The
synthesis can be easily altered by changing either the starting
pyranosides or the amines used in the reductive amination to
produce various bicyclic iminosugar structures. Owing to the less
synthetic steps involved and the versatility of synthetic targets, the
disclosed strategy may find wide applications in the synthesis of
polyhydroxylated alkaloids.
concluded the syn-relationship between H-8 and H-9. So the
structures of 10b and 20 were unambiguously determined. With
the structures of compounds 10b and 20 determined, the steric
structures of their related compounds 11b, 7b, 5b, and 18b were
easily determined. Furthermore, in order to confirm the structure
determination of the target compounds, the NMR spectra of
some important intermediates such as 16a were also carefully
analyzed, proving the coincident configuration with 18a (see
supplementary information). In a similar way, the stereochemistry
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(ESI) Anal. Calcd for C31H35NO4Na [M + Na]+: 508.2458, found:
508.2470.
Experimental
(3S,4R,5S)-1-Allyl-3,4,5-tris(benzyloxy)piperidin-2-one (4a)
(2S,3R,4R,5S)-1-Allyl-3,4,5-tris(benzyloxy)-2-vinylpiperidine (5a)
A solution of 327 (200 mg, 0.45 mmol) in MeOH (10 mL) at -78 ◦C
was bubbled with O3 until the solution became pale blue. The
solution was stirred at -78 ◦C for 3 min and bubbled with N2
until the solution became colorless. To the mixture, allylamine
(0.07 mL, 0.9 mmol), NaCNBH3 (53.7 mg, 0.9 mmol) and ZnCl2
(12.0 mg, 0.09 mmol) were added, and the mixture was heated
under reflux for 2 h. The reaction was quenched with saturated
NaHCO3. After removal of the solvent, the mixture was dissolved
in ethyl acetate (80 mL) and washed with brine (2 ¥ 20 mL). The
organic phase was dried over anhydrous sodium sulfate. The dried
solution was filtered and the filtrate was concentrated. The residue
was purified by column chromatography on silica gel (petroleum
ether–ethyl acetate 6 : 1) to provide the product 4a (168 mg, 83%)
as a colorless oil. Rf 0.45 (petroleum ether–ethyl acetate, 2 : 1).
1H NMR (300 MHz, CDCl3) d 3.23-3.38 (m, 2H), 3.71-3.77 (m,
1H), 3.84 (t, J = 6.6 Hz, 1H), 3.94-4.02 (m, 3H), 4.55-4.78 (m,
5H), 5.11-5.21 (m, 3H), 5.66-5.79 (m, 1H), 7.26-7.45 (m, 15H);
13C NMR (75 MHz, CDCl3) d 46.95, 49.14, 72.13, 73.76, 74.26,
75.95, 79.28, 82.01, 118.15, 127.65, 127.70, 127.85, 127.93, 128.30,
128.35, 128.44, 132.36, 137.68, 137.93, 137.98, 168.61. Anal. Calcd
for C29H31NO4: C, 76.12; H, 6.83; N, 3.06; Found: C, 75.87; H, 6.61;
N, 3.03; ESI-MS: 458 [M + H+].
Vinylmagnesium bromide (1.0 M solution in THF, 2.63 mL,
2.63 mmol) was added dropwise to a solution of 4a (300 mg,
0.66 mmol) in dry ether at 0 ◦C under nitrogen. The ice bath
was removed and the mixture was stirred at r◦oom temperature
for 1 h. The reaction mixture was cooled to 0 C again. LiAlH4
(236 mg, 6.6 mmol) was added and the mixture was stirred
for 2 h. The reaction was quenched at 0 ◦C by the careful
addition of a 10% NaOH aqueous solution. The organic layer
was separated and the aqueous layer was extracted with ethyl
acetate (2 ¥ 80 mL). The organic layers were combined, dried
over Na2SO4, and concentrated. The residue was purified by
column chromatography on silica gel (petroleum ether–ethyl
acetate 20 : 1→15:1→12:1) to provide 5a (205 mg, 68%) as a syrup.
Rf 0.60 (petroleum ether–ethyl acetate, 3 : 1). 1H NMR (300 MHz,
CDCl3) d 2.45 (t, J = 10.2 Hz, 1H, H-6ax), 2.85 (dd, J = 4.8 Hz,
J = 11.4 Hz, 1H, H-6eq), 2.98 (dd, J = 6.3 Hz, J = 13.8 Hz, 1H,
NCH2), 3.13 (dd, J = 6.6 Hz, J = 13.8 Hz, 1H, NCH2), 3.54-3.70
(m, 4H, H-2, H-3, H-4, H-5), 4.57-4.90 (m, 6H, PhCH2), 5.09-
=
=
5.15 (m, 2H, CH2), 5.25 (d, J = 17.1 Hz, 1H, CH2), 5.42 (d,
=
=
J = 10.2 Hz, 1H, CH2), 5.67-5.80 (m, 1H, -CH ), 5.96-6.08 (m,
1H, -CH ), 7.28-7.33 (m, 15H, Ar); 13C NMR (75 MHz, CDCl3) d
=
49.64, 57.37, 63.40, 72.20, 73.06, 75.48, 78.94, 80.72, 82.58, 117.56,
121.53, 127.41, 127.56, 127.60, 127.78, 127.98, 128.26, 128.36,
130.12, 135.53, 138.42, 138.56, 139.09; HRMS (ESI) Anal. Calcd
for C31H36NO3 [M + H]+: 470.2690, found: 470.2694.
(3S,4R,5S)-3,4,5-Tris(benzyloxy)-1-(but-3-enyl)piperidin-2-one
(4b)
Compound 4b was prepared from 3 as described in the preparation
of 4a with 1-buteneamine, yielding 4b (83% yield) as a colorless
oil. Rf 0.50 (petroleum ether–ethyl acetate, 2 : 1). [a]2D6 = -13.9 (c =
(2S,3R,4R,5S)-3,4,5-Tris(benzyloxy)-1-(but-3-enyl)-2-
vinylpiperidine (5b)
1
0.0063, MeOH). H NMR (300 MHz, CDCl3) d 2.28 (dd, J =
=
6.6 Hz, J = 13.2 Hz, 2H, -CH2–C ), 3.27-3.45 (m, 4H, NCH2,
Compound 5b was prepared from 4b as described in the prepa-
ration of 5a, yielding 5b (64% yield) as a colorless oil. Rf 0.62
(petroleum ether–ethyl acetate, 3 : 1). [a]2D6 = -31.8 (c = 0.0426,
MeOH). 1H NMR (300 MHz, CDCl3) d 2.12-2.15 (m, 2H, CH2–
H-6), 3.73 (dt, J = 5.1 Hz, J = 7.2 Hz, 1H, H-5), 3.82 (t, J =
6.3 Hz, 1H, H-4), 3.97 (d, J = 6.9 Hz, 1H, H-3), 4.55-4.79 (m,
=
5H, PhCH2), 4.99-5.13 (m, 3H, PhCH2, CH2), 5.71-5.80 (m, 1H,
-CH ), 7.25-7.44 (m, 15H, Ar); 13C NMR (125 MHz, CDCl3)
=
=
C ), 2.37-2.57 (m, 3H, NCH2, H-6ax), 2.83 (dd, J = 5.1 Hz,
d 31.89, 46.51, 48.19, 72.15, 73.69, 74.11, 76.12, 79.38, 82.06,
116.99, 127.68, 127.72, 127.88, 127.92, 128.29, 128.35, 128.45,
135.00, 137.72, 137.97, 138.03,168.56; HRMS (ESI) Anal. Calcd
for C30H34NO4 [M + H]+: 472.2482, found: 472.2483.
J = 12.0 Hz, 1H, H-6eq), 3.50 (dd, J = 3.9 Hz, J = 10.5 Hz, 1H,
H-2), 3.57-3.71 (m, 3H, H-3, H-4, H-5), 4.59-4.91 (m, 6H, PhCH2),
=
4.95-5.03 (m, 2H, CH2), 5.26 (dd, J = 1.8 Hz, J = 16.8 Hz,
=
=
1H, CH2), 5.41 (dd, J = 1.8 Hz, J = 10.2 Hz, 1H, CH2), 5.67-
=
=
5.81 (m, 1H, -CH ), 5.96-6.09 (m,1H, -CH ), 7.26-7.37 (m, 15H,
Ar); 13C NMR (75 MHz, CDCl3) d 32.06, 49.97, 53.54, 63.41,
72.30, 73.09, 75.42, 78.94, 80.74, 82.65, 115.52, 121.11, 127.37,
127.55, 127.77, 127.94, 128.22, 128.34, 130.31, 136.42, 138.42,
138.56, 139.09; HRMS (ESI) Anal. Calcd for C32H38NO3 [M + H]+:
484.2846, found: 484.2852.
(3S,4R,5S)-3,4,5-Tris(benzyloxy)-1-(pent-4-enyl)piperidin-2-one
(4c)
Compound 4c was prepared from 3 as described in the preparation
of 4a with 1-penteneamine, yielding 4c (88% yield) as a colorless
oil. Rf 0.45 (petroleum ether–ethyl acetate, 3 : 1). [a]2D6 = -13.0
1
(c = 0.0196, MeOH). H NMR (300 MHz, CDCl3) d 1.57-1.66
(2S,3R,4R,5S)-3,4,5-Tris(benzyloxy)-1-(pent-4-enyl)-2-
vinylpiperidine (5c)
(m, 2H, C-CH2–C), 2.02-2.06 (dd, J = 6.6 Hz, J = 14.1 Hz, 2H,
=
-CH2–C ), 3.26-3.46 (m, 4H, NCH2, H-6), 3.71-3.76 (m, 1H, H-
5), 3.83 (t, J = 6.0 Hz, 1H, H-4), 3.98 (d, J = 7.2 Hz, 1H, H-3),
4.56 (d, J = 12.0 Hz, 1H, PhCH2), 4.64-4.79 (m, 4H, PhCH2),
Compound 5c was prepared from 4c as described in the prepa-
ration of 5a, yielding 5c (65% yield) as a colorless oil. Rf 0.60
(petroleum ether–ethyl acetate, 4 : 1). [a]2D6 = -2.56 (c = 0.0156,
MeOH). 1H NMR (300 MHz, CDCl3) d 1.41-1.55 (m, 2H,
=
4.95-5.03 (m, 2H, PhCH2, CH2), 5.12 (d, J = 11.7 Hz, 1H,
CH2), 5.73-5.79 (m, 1H, -CH C), 7.25-7.45 (m, 15H, Ar); 13C
=
=
=
NMR (75 MHz, CDCl3) d 26.42, 30.90, 46.62, 47.93, 72.06, 73.69,
74.16, 76.18, 79.36, 82.02, 115.07, 127.67, 127.74, 127.87, 127.94,
128.30, 128.35, 128.45, 137.68, 137.95, 137.99, 168.55; HRMS
-CH2-), 1.97-2.04 (m, 2H, -CH2–C ), 2.29-2.51 (m, 3H, NCH2,
H-6ax), 2.81 (dd, J = 5.4 Hz, J = 12.0 Hz, 1H, H-6eq), 3.45-3.57
(dd, J = 3.9 Hz, J = 9.6 Hz, 1H, H-2), 3.59-3.71 (m, 3H, H-3,
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H-4, H-5), 4.59-4.69 (m, 3H, PhCH2), 4.74 (d, J = 11.7 Hz, 1H,
PhCH2), 4.82 (d, J = 10.8 Hz, 1H, PhCH2), 4.87-5.01 (m, 3H,
H-10a), 4.63-4.92 (m, 6H, PhCH2), 5.86-5.90 (m, 1H, H-10), 6.03-
6.04 (m, 1H, H-9), 7.27-7.36 (m, 15H, Ar); 13C NMR (75 MHz,
CDCl3) d 22.15, 29.20, 48.95, 58.55, 59.36, 71.82, 72.88, 75.50,
79.86, 80.97, 82.79, 127.36, 127.42, 127.51, 127.60, 127.72, 128.02,
128.21, 128.25, 128.33, 129.63, 133.90, 138.70, 139.20; HRMS
(ESI) Anal. Calcd for C31H36NO3 [M + H]+: 470.2690, found:
470.2690.
=
=
PhCH2, CH2), 5.24 (dd, J = 1.8 Hz, J = 16.8 Hz, 1H, CH2),
=
5.40 (dd, J = 1.8 Hz, J = 10.2 Hz, 1H, CH2), 5.71-5.85 (m,
1H, -CH ), 5.96-6.08 (m, 1H, -CH ), 7.25-7.37 (m, 15H, Ar); 13C
NMR (125 MHz, CDCl3) d 26.66, 31.32, 50.02, 53.42, 63.44, 72.35,
73.13, 75.47, 79.10, 80.86, 82.78, 114.59, 121.04, 127.39, 127.57,
127.61, 127.80, 127.97, 127.99, 128.24, 128.28, 128.37, 130.41,
138.52, 138.63, 139.16; HRMS (ESI) Anal. Calcd for C33H40NO3
[M + H]+: 498.3003, found: 498.3014.
=
=
(6S,7R,8R,8aS)-Octahydroindolizine-6,7,8-triol (7a)
To the solution of 6a (20.1 mg, 0.046 mmol) in MeOH (4 mL)
were added hydrogen chloride (1.25 M in methanol, 0.2 mL)
and Pd/C (10% wt, 8.0 mg). The reaction mixture was stirred
under the atmosphere of hydrogen gas for 2 days. The mixture
was filtered through Celite pad and the filtrate was concentrated.
The residue was subjected to a C-18 reversed-phase column
chromatography (H2O as eluent) to give 7a (7.1 mg, 89%) as a
foam after lyophilization. [a]2D6 = +40.9 (c = 0.00042, MeOH).
1H NMR (500 MHz, CD3OD) d 1.70-1.86 (m, 3H), 1.88-1.94 (m,
1H), 2.33 (q, J = 9.0 Hz, J = 18.0 Hz, 1H), 2.60-2.63 (m, 2H), 3.01
(dd, J = 3.0 Hz, J = 12.0 Hz, 1H), 3.04-3.08 (m, 1H), 3.71-3.73
(m, 2H), 3.84 (t, J = 3.5 Hz, 1H); 13C NMR (125 MHz, CD3OD)
d 21.34, 24.74, 55.16, 55.32, 63.72, 70.98, 71.18, 71.29; HRMS
(ESI) Anal. Calcd for C8H16NO3 [M + H]+: 174.1125, found:
174.1129. The spectroscopic data coincide with those reported
previously.24
(6S,7R,8R,8aS)-6,7,8-Tris(benzyloxy)-3,5,6,7,8,8a-
hexahydroindolizine (6a)
To a solution of 5a (21.0 mg, 0.045 mmol) in dichloromethane
(4 mL), hydrogen chloride (1.25 M in methanol, 0.1 mL) was
added. The solvent was then removed. The residue was redissolved
in dry dichloromethane (3 mL) and Grubbs 1st generation catalyst
(10.0 mg, 0.011 mmol) was added. The reaction mixture was stirred
at 45 ◦C for 24 h under argon atmosphere. The flask was opened
to the air for 24 h before the addition of 0.1 N NaOH. The organic
layer was separated and the aqueous layer was extracted with
dichloromethane (2 ¥ 50 mL). The organic layers were combined
and dried over Na2SO4. After removal of the volatiles, the residue
was purified by column chromatography on silica gel (chloroform)
to yield 6a (11.0 mg, 57%) as a yellow syrup. Rf 0.60 (chloroform–
methanol 30 : 1). [a]2D6 = -21.2 (c = 0.00042, MeOH). H NMR
1
(300 MHz, CDCl3) d 2.79 (t, J = 9.9 Hz, 1H), 3.20 (dd, J = 3.3 Hz,
J = 9.9 Hz, 1H), 3.50-3.54 (m, 1H), 3.62 (br.s, 1H), 3.69-3.80 (m,
3H), 3.97 (br.s, 1H), 4.44-4.70 (m, 6H), 5.70-5.72 (m, 1H), 5.94-
5.96 (m, 1H), 7.26-7.34 (m, 15H); 13C NMR (75 MHz, CDCl3)
d 49.89, 61.56, 65.26, 71.73, 71.89, 78.59, 79.23, 80.50, 127.49,
127.57, 127.66, 127.75, 128.24, 128.37, 129.30, 138.22, 138.45.
HRMS (ESI) Anal. Calcd for C29H32NO3 [M + H]+: 442.2377,
found: 442.2386.
(1R,2R,3S,9aS)-Octahydro-1H-quinolizine-1,2,3-triol (7b)
Compound 7b was prepared from 6b as described in the prepa-
ration of 7a, yielding 7b (92% yield) as a foam. [a]2D6 = +14.9
(c = 0.0154, MeOH). 1H NMR (500 MHz, D2O) d 1.52-1.54 (m,
1H), 1.66-1.71 (m, 2H), 1.81-1.87 (m, 3H), 2.99 (dt, J = 3.0 Hz,
J = 13.0 Hz, 1H), 3.24 (td, J = 1.5 Hz, J = 13.0 Hz, 1H), 3.32-
3.37 (m, 3H), 3.74-3.75 (m, 1H), 3.95-3.97 (m, 2H); 13C NMR
(125 MHz, D2O) d 22.16, 23.40, 26.21, 56.26 (2C), 62.22, 66.98,
67.73, 70.74; HRMS (ESI) Anal. Calcd for C9H18NO3 [M + H]+:
188.1281, found: 188.1287. The spectroscopic data coincide with
those reported previously.25
(1R,2R,3S,9aS)-1,2,3-Tris(benzyloxy)-2,3,4,6,7,9a-hexahydro-
1H-quinolizine (6b)
Compound 6b was prepared from 5b as described in the prepa-
ration of 6a, yielding 6b (81% yield) as a yellow syrup. Rf 0.65
(chloroform–methanol 30 : 1). [a]2D6 = -8.73 (c = 0.00875, MeOH).
1H NMR (300 MHz, CDCl3) d 1.83-1.90 (m, 1H), 2.42 (br.s, 1H),
2.64-2.67 (m, 1H), 2.83-2.96 (m, 3H), 3.50-3.57 (m, 4H), 4.56-4.70
(m, 6H), 5.69 (d, J = 10.5 Hz, 1H), 5.81-5.85 (m, 1H), 7.26-7.32
(m, 15H); 13C NMR (75 MHz, CDCl3) d 22.03, 50.82, 51.12, 57.88,
72.31, 72.59, 74.04, 78.67, 124.86, 126.39, 127.55, 127.82, 127.90,
127.98, 128.25, 128.33, 138.60, 138.65, 138.73; HRMS (ESI) Anal.
Calcd for C30H34NO3 [M + H]+: 456.2533, found: 456.2533.
(1R,2R,3S,10aS)-Decahydropyrido[1,2-a]azepine-1,2,3-triol (7c)
Compound 7c was prepared from 6c as described in the prepara-
tion of 7a, yielding 7c (93% yield) as a colorless oil. [a]2D6 = +33.6
1
(c = 0.00235, MeOH). H NMR (500 MHz, D2O) d 1.43-1.52
(m, 2H), 1.66 (br.s, 2H), 1.80-1.91 (m, 4H), 2.84-2.93 (m, 3H),
3.06-3.11 (m, 1H), 3.19 (d, J = 6.0 Hz, 1H), 3.53 (br.s, 1H), 3.67
(br.s, 2H); 13C NMR (100 MHz, D2O) d 22.84, 25.61 (2C), 26.96,
55.50, 63.23 (2C), 69.89, 72.23 (2C); HRMS (ESI) Anal. Calcd for
C10H20NO3 [M + H]+: 202.1438, found: 202.1437.
(1R,2R,3S,10aS,Z)-1,2,3-Tris(benzyloxy)-1,2,3,4,6,7,8,10a-
octahydropyrido[1,2-a]azepine (6c)
(1R,2S,6S,7R,8R,8aS)-6,7,8-Tris(benzyloxy)octahydroindolizine-
1,2-diol (10a)
Compound 6c was prepared from 5c as described in the prepa-
ration of 6a, yielding 6c (34% yield) as a yellow syrup. Rf 0.75
(chloroform–methanol 30 : 1). 1H NMR (300 MHz, CDCl3) d
1.33-1.38 (m, 1H, H-7), 1.67-1.80 (m, 1H, H-7), 2.13-2.22 (m, 1H,
H-8), 2.29-2.34 (m, 1H, H-8), 2.62 (dd, J = 3.9 Hz, J = 11.1 Hz,
1H, H-4), 2.82-2.89 (m, 1H, H-4), 3.01-3.09 (m, 1H, H-6), 3.17-
3.22 (m, 1H, H-6), 3.57-3.69 (m, 3H, H-1, H-2, H-3), 3.94 (br.s, 1H,
To the solution of 6a (12.1 mg, 0.027 mmol) in acetone (0.8 mL)
and H2O (0.2 mL), were added 4-methylmorpholine-N-oxide (50%
w/w aqueous solution, 12 mL, 0.054 mmol) and OsO4 (1 M
solution in t-butanol, 18 mL, 0.018 mmol). After stirring at 0 ◦C for
1 h, NaHSO3 (excess) was added, and the mixture was stirred for
another 30 min. The reaction mixture was then filtered through a
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short column (NaHSO3) and the filtrate was concentrated. The
residue was purified by column chromatography on silica gel
(chloroform–methanol 50 : 1) to yield 10a (9.0 mg, 75%) as a
(ESI) Anal. Calcd for C9H18NO5 [M + H]+: 220.1180, found:
220.1179.
1
yellowish syrup. Rf 0.35 (chloroform–methanol 30 : 1). H NMR
(1S,7S,8R,9R,9aS)-7,8,9-Tris(benzyloxy)octahydro-1H-
(500 MHz, CDCl3) d 2.27 (dd, J = 4.0 Hz, J = 10.0 Hz, 1H,
H-3), 2.46-2.52 (m, 2H, H-5, H-8a), 2.99 (dd, J = 3.5 Hz, J =
12.0 Hz, 1H, H-5), 3.47-3.50 (m, 2H, H-3, H-6), 3.65 (t, J =
2.5 Hz, 1H, H-7), 3.72 (br.s, 1H, H-8), 4.22-4.28 (m, 2H, H-
1, H-2), 4.38-4.68 (m, 6H, PhCH2), 7.18-7.35 (m, 15H, Ar); 13C
NMR (75 MHz, CDCl3) d 52.58, 61.98, 65.31, 67.71, 69.86, 71.44,
71.85, 72.32, 72.56, 73.19, 73.89, 126.05, 127.62, 127.71, 127.83,
127.95, 128.32, 128.40, 128.49, 137.92, 138.32, 138.54; HRMS
(ESI) Anal. Calcd for C29H34NO5 [M + H]+: 476.2431, found:
476.2438.
quinolizin-1-ol (12)
To a solution of 6b (20.0 mg, 0.044 mmol) in dry THF (4 mL),
borane–methyl sulfide (1.0 M solution in THF, 88 mL, 0.09 mmol)
◦
was added at 0 C under nitrogen atmosphere. The ice bath was
removed and the mixture was stirred at room temperature for 2
h. The reaction was followed by hydrolyzing with a solution of
THF–glycerol–3 N HCl (1 : 1 : 1, 3 mL). After the completion of
the reaction, the reaction mixture was oxidized by using 6 N NaOH
(1 mL) and 30% hydrogen peroxide (1 mL). After 5 h, the aqueous
phase was saturated with anhydrous K2CO3 and was extracted
with ethyl acetate (3 ¥ 20 mL). The crude reaction mixture was
dried over Na2SO4. After removal of the volatiles, the residue was
purified by column chromatography on silica gel (chloroform–
methanol 50 : 1) to yield 12 (17.0 mg, 82%) as a syrup. Rf 0.40
(chloroform–methanol 30 : 1). [a]2D6 = +13.8 (c = 0.00315, MeOH).
1H NMR (300 MHz, CDCl3–D2O) d 1.25-1.31 (m, 1H), 1.50-1.55
(m, 1H), 1.75-1.84 (m, 1H), 2.01-2.18 (m, 3H), 2.44 (dd, J =
3.0 Hz, J = 12.0 Hz, 1H), 2.80 (d, J = 11.7 Hz, 1H), 2.89 (dd, J =
3.9 Hz, J = 12.0 Hz, 1H), 3.49-3.50 (m, 1H), 3.67-3.76 (m, 2H),
3.95 (dt, J = 4.2 Hz, J = 10.2 Hz, 1H), 4.43-4.64 (m, 5H), 4.70
(d, J = 11.7 Hz, 1H), 7.26-7.33 (m, 15H); 13C NMR (75 MHz,
CDCl3) d 21.63, 33.67, 53.97, 55.55, 65.34, 65.50, 71.55, 72.67,
73.31, 73.98, 74.27, 77.20, 127.57, 127.75, 127.82, 127.88, 128.07,
128.33, 128.40, 128.55, 128.66, 138.11, 138.21, 138.71; HRMS
(ESI) Anal. Calcd for C30H36NO4 [M + H]+: 474.2639, found:
474.2655.
(1R,2S,7S,8R,9R,9aS)-7,8,9-Tris(benzyloxy)octahydro-1H-
quinolizine-1,2-diol (10b)
Compound 10b was prepared from 6b as described in the
preparationof 10a, yielding 10b (85%yield)as ayellowish syrup. Rf
0.38 (chloroform–methanol 30 : 1). 1H NMR (500 MHz, CDCl3)
d 1.71-1.74 (m, 1H, H-3), 1.93-2.00 (m, 1H, H-3), 2.51 (dd, J =
3.5 Hz, J = 12.0 Hz, 1H, H-6ax), 2.53-2.56 (m, 1H, H-4eq), 2.61-
2.65 (m, 1H, H-4ax), 2.70 (dd, J = 2.5 Hz, J = 9.5 Hz, 1H,
H-9a), 2.90 (dd, J = 5.0 Hz, J = 12.5 Hz, 1H, H-6eq), 3.51
(dd, J = 4.0 Hz, J = 8.0 Hz, 1H, H-7), 3.67-3.71 (m, 2H, H-
8, H-9), 4.00 (dd, J = 3.5 Hz, J = 10.0 Hz, 1H, H-1), 4.01-4.03
(m, 1H, H-2), 4.46-4.62 (m, 5H, PhCH2), 4.71 (d, J = 12.0 Hz,
1H, PhCH2), 7.25-7.35 (m, 15H, Ar); 13C NMR (125 MHz,
CDCl3) d 27.61, 48.60, 53.23, 57.97, 66.86, 67.95, 71.74, 72.90,
73.13, 74.03, 74.60, 74.83, 127.63, 127.77, 127.81, 127.89, 128.10,
128.35, 128.41, 128.55, 128.62, 137.97, 138.17, 138.54; HRMS
(ESI) Anal. Calcd for C30H36NO5 [M + H]+: 490.2588, found:
490.2592.
(1R,2R,3S,9S,9aS)-Octahydro-1H-quinolizine-1,2,3,9-tetraol
(13)
Compound 13 was prepared from 12 as described in the prepara-
tion of 7a, yielding 13 (95% yield) as a solid after lyophilization.
[a]2D6 = +34.3 (c = 0.0106, MeOH). 1H NMR (400 MHz, D2O) d
1.52 (dt, J = 4.0 Hz, J = 12.4 Hz, 1H, H-7), 1.69-1.74 (m, 1H,
H-7), 1.86-1.90 (m, 1H, H-8), 2.08-2.12 (m, 1H, H-8), 2.97 (dt,
J = 3.2 Hz, J = 12.8 Hz, 1H, H-6), 3.07 (dd, J = 1.6 Hz, J =
10.4 Hz, 1H, H-4), 3.29-3.39 (m, 3H, H-4, H-6, H-9a), 3.83-3.89
(m, 1H, H-9), 3.95-3.96 (m, 1H, H-3), 4.00 (t, J = 2.8 Hz, 1H, H-
2), 4.17-4.18 (m, 1H, H-1). The spectroscopic data coincide with
those reported previously.25
(1R,2S,6S,7R,8R,8aS)-Octahydroindolizine-1,2,6,7,8-pentaol
(11a)
Compound 11a was prepared from 10a as described in the
preparation of 7a, yielding 11a (82% yield) as a solid after
lyophilization. [a]D26 = +19.4 (c = 0.0026, MeOH). 1H NMR
(300 MHz, D2O) d 2.11 (dd, J = 5.4 Hz, J = 10.5 Hz, 1H), 2.33-
2.45 (m, 2H), 2.77 (dd, J = 3.0 Hz, J = 12.6 Hz, 1H), 3.25 (dd, J =
6.6 Hz, J = 10.8 Hz, 1H), 3.66 (br.s, 1H), 3.77-3.78 (m, 2H), 3.89
(t, J = 7.8 Hz, 1H), 4.03 (dd, J = 6.9 Hz, J = 12.3 Hz, 1H); 13
C
NMR (75 MHz, D2O) d 53.98, 60.75, 65.12, 67.28, 68.54, 69.19,
69.65 (2C). The spectroscopic data coincide with those reported
previously.26
(3S,4R,5R)-1-Allyl-3,4,5-tris(benzyloxy)piperidin-2-one (15a)
Compound 15a was prepared from 1428 as described in the
preparation of 4a, yielding 15a (87% yield) as a solid. Rf 0.46
(petroleum ether–ethyl acetate, 2 : 1). 1H NMR (300 MHz, CDCl3)
d 3.22 (dd, J = 4.5 Hz, J = 12.3 Hz, 1H, H-6), 3.43 (dd, J = 6.3 Hz,
J = 12.3 Hz, 1H, H-6), 3.85 (dd, J = 2.1 Hz, J = 6.3 Hz, 1H, H-
4), 3.92-3.97 (m, 2H, NCH2), 4.03-4.08 (m, 1H, H-5), 4.19 (d, J =
6.6 Hz, 1H, H-3), 4.55-4.71 (m, 4H, PhCH2), 4.75 (d, J = 11.4 Hz,
(1R,2R,3S,8S,9R,9aS)-Octahydro-1H-quinolizine-1,2,3,8,9-
pentaol (11b)
Compound 11b was prepared from 10b as described in the
preparation of 7a, yielding 11b (85% yield) as a solid after
lyophilization. [a]D26 = +35.0 (c = 0.0099, MeOH). 1H NMR
(300 MHz, D2O) d 1.87-1.90 (m, 2H, H-7), 3.12-3.28 (m, 3H,
H-4, H-6), 3.32-3.39 (m, 2H, H-4, H-9a), 3.85 (dd, J = 2.7 Hz,
J = 10.8 Hz, 1H, H-9), 3.91-3.94 (m, 1H, H-3), 3.95-3.96 (m, 1H,
H-2), 4.05-4.06 (m, 2H, H-1, H-8); 13C NMR (125 MHz, D2O) d
27.62, 49.54, 56.49, 59.37, 66.00, 66.14, 66.36, 66.77, 67.56; HRMS
=
1H, PhCH2), 5.06-5.21 (m, 3H, PhCH2, CH2), 5.66-5.79 (m, 1H,
-CH ), 7.27-7.40 (m, 15H, Ar); 13C NMR (75 MHz, CDCl3) d
=
47.06, 48.96, 71.67, 72.41, 74.54, 117.55, 127.62, 127.79, 128.16,
128.32, 128.42, 131.96, 137.82, 138.07, 167.86; HRMS (ESI) Anal.
Calcd for C29H32NO4 [M + H]+: 458.2326, found: 458.2322.
2646 | Org. Biomol. Chem., 2010, 8, 2639–2649
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(3S,4R,5R)-3,4,5-Tris(benzyloxy)-1-(but-3-enyl)piperidin-2-one
(15b)
(br.s, 1H), 3.60 (br.s, 1H), 3.87-3.90 (m, 1H), 4.34-4.67 (m, 6H),
4.93-5.22 (m, 4H), 5.67-5.76 (m, 1H), 5.88-5.96 (m, 1H), 7.17-7.32
(m, 15H); 13C NMR (125 MHz, CDCl3) d 28.68, 49.56, 54.29,
63.49, 71.11, 72.64, 73.58, 73.99, 74.38, 79.90, 115.46, 117.49,
127.48, 127.52, 127.62, 127.68, 127.79, 128.24, 128.33, 128.42,
136.75, 137.89, 138.16, 138.67, 138.88; HRMS (ESI) Anal. Calcd
for C32H38NO3 [M + H]+: 484.2846, found: 484.2851.
Compound 15b was prepared from 14 as described in the
preparation of 4a with 1-buteneamine, yielding 15b (95% yield)
as a colorless oil. Rf 0.50 (petroleum ether–ethyl acetate, 2 : 1).
1
=
H NMR (300 MHz, CDCl3) d 2.26-2.33 (m, 2H, CH2–C ), 3.27
(dd, J = 4.5 Hz, J = 12.0 Hz, 1H, H-6), 3.35-3.40 (m, 2H, NCH2),
3.47 (dd, J = 6.6 Hz, J = 12.0 Hz, 1H, H-6), 3.83 (dd, J =
2.0 Hz, J = 6.1 Hz, 1H, H-4), 4.05 (br.s, 1H, H-5), 4.14 (d, J =
6.3 Hz, 1H, H-3), 4.54-4.76 (m, 5H, PhCH2), 4.99-5.08 (m, 3H,
(2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-1-(pent-4-enyl)-2-
vinylpiperidine (16c)
=
=
PhCH2, CH2), 5.72-5.81 (m, 1H, -CH ), 7.21-7.36 (m, 15H, Ar);
13C NMR (75 MHz, CDCl3) d 31.18, 46.34, 47.82, 71.55, 72.22,
74.26, 76.64, 76.73, 116.79, 127.47, 127.49, 127.52, 127.68, 128.02,
128.16, 128.19, 128.30, 134.85, 137.74, 137.95, 138.00, 167.70;
HRMS (ESI) Anal. Calcd for C30H33NO4Na [M + Na]+: 494.2302,
found: 494.2308.
Compound 16c was prepared from 15c as described in the
preparation of 5a, yielding 16c (71% yield) as a colorless oil. Rf
0.60 (petroleum ether–ethyl acetate, 4 : 1). H NMR (300 MHz,
1
CDCl3) d 1.51-1.56 (m, 2H), 1.94-1.97 (m, 2H), 2.29-2.39 (m, 1H),
2.56-2.63 (m, 2H), 2.86 (dd, J = 4.5 Hz, J = 10.5 Hz, 1H), 3.10-
3.13 (m, 1H), 3.46 (br.s, 1H), 3.60-3.62 (m, 1H), 3.84-3.91 (m, 1H),
4.34-4.67 (m, 6H), 4.90-5.23 (m, 4H), 5.73-5.99 (m, 2H), 7.17-7.39
(m, 15H); 13C NMR (75 MHz, CDCl3) d 23.58, 31.70, 49.59, 54.46,
63.83, 71.10, 72.62, 73.51, 74.40, 77.18, 79.91, 114.40, 127.50,
127.62, 127.69, 127.74, 127.92, 127.99, 128.24, 128.39, 128.53,
138.57, 138.70, 138.89; HRMS (ESI) Anal. Calcd for C33H40NO3
[M + H]+: 498.3003, found: 498.3015.
(3S,4R,5R)-3,4,5-Tris(benzyloxy)-1-(pent-4-enyl)piperidin-2-one
(15c)
Compound 15c was prepared from 14 as described in the
preparation of 4a with 1-penteneamine, yielding 15c (78% yield)
as a colorless oil. Rf 0.45 (petroleum ether–ethyl acetate, 3 : 1).
[a]2D6 = -66.2 (c = 0.019, MeOH). H NMR (300 MHz, CDCl3)
1
(6R,7R,8R,8aS)-6,7,8-Tris(benzyloxy)-3,5,6,7,8,8a-
hexahydroindolizine (17a)
d 1.56-1.68 (m, 2H), 2.05 (dd, J = 6.9 Hz, J = 14.1 Hz, 2H),
3.22-3.30 (m, 2H), 3.34-3.48 (m, 2H), 3.84 (dd, J = 1.5 Hz, J =
5.7 Hz, 1H), 4.05 (br.s, 1H), 4.14 (d, J = 6.0 Hz, 1H), 4.54-4.76 (m,
Compound 17a was prepared from 16a as described in the
preparation of 6a, yielding 17a as a yellow syrup. Rf 0.55
(chloroform–methanol 30 : 1). Compound 17a was unstable and
directly used for the next step.
5H), 4.94-5.08 (m, 3H), 5.75-5.84 (m, 1H), 7.29-7.36 (m, 15H); 13
C
NMR (75 MHz, CDCl3) d 25.77, 30.76, 46.42, 47.58, 71.64, 72.28,
74.40, 76.69, 76.83, 114.94, 127.53, 127.74, 128.08, 128.23, 128.36,
137.67, 137.78, 137.99, 138.02, 167.75; HRMS (ESI) Anal. Calcd
for C31H35NO4Na [M + Na]+: 508.2458, found: 508.2470.
(1R,2R,3R,9aS)-1,2,3-Tris(benzyloxy)-2,3,4,6,7,9a-hexahydro-
1H-quinolizine (17b)
(2S,3R,4R,5R)-1-Allyl-3,4,5-tris(benzyloxy)-2-vinylpiperidine
(16a)
Compound 17b was prepared from 16b as described in the
preparation of 6a, yielding 17b (76% yield) as a yellow syrup.
Rf 0.60 (chloroform–methanol 30 : 1). [a]2D6 = +0.21 (c = 0.0029,
Compound 16a was prepared from 15a as described in the
preparation of 5a, yielding 16a (67% yield) as a colorless oil. Rf 0.60
(petroleum ether–ethyl acetate, 3 : 1). [a]2D6 = +11.0 (c = 0.0138,
MeOH). 1H NMR (300 MHz, CDCl3) d 2.51 (t, J = 10.5 Hz, 1H,
H-6ax), 2.84-2.91 (m, 2H, H-6eq, NCH2), 3.09 (d, J = 8.7 Hz,
1H, H-2), 3.32 (dd, J = 5.7 Hz, J = 13.8 Hz, 1H, NCH2), 3.47
(br.s, 1H, H-3), 3.61 (t, J = 3.3 Hz, 1H, H-4), 3.86-3.90 (m, 1H,
1
MeOH). H NMR (500 MHz, CDCl3) d 1.93 (d, J = 14.0 Hz,
1H), 2.45-2.48 (m, 2H), 2.59 (t, J = 10.5 Hz, 1H), 2.83-2.88 (m,
2H), 3.02 (br.s, 1H), 3.39 (br.s, 1H), 3.77 (br.s, 1H), 3.98-4.00 (m,
1H), 4.36-4.72 (m, 6H), 5.25 (d, J = 9.5 Hz, 1H), 5.75-5.77 (m,
1H), 7.19-7.35 (m, 15H); 13C NMR (125 MHz, CDCl3) d 25.43,
52.07, 53.78, 58.95, 71.22, 72.69, 72.85, 73.44, 74.65, 77.13, 126.31,
127.07, 127.50, 127.53, 127.55, 127.75, 127.79, 127.95, 128.22,
128.29, 128.32, 128.41, 138.16, 138.71, 138.77; HRMS (ESI) Anal.
Calcd for C30H34NO3 [M + H]+: 456.2533, found: 456.2540.
=
H-5), 4.34-4.67 (m, 6H, PhCH2), 5.12-5.21 (m, 4H, CH2), 5.83-
6.00 (m, 2H, -CH ), 7.17-7.32 (m, 15H, Ar); 13C NMR (75 MHz,
=
CDCl3) d 49.56, 58.26, 64.04, 71.05, 72.62, 73.54, 74.27, 79.83,
117.92, 118.25, 127.49, 127.62, 127.69, 128.26, 128.44, 134.32,
138.11, 138.65, 138.86; HRMS (ESI) Anal. Calcd for C31H36NO3
[M + H]+: 470.2690, found: 470.2691.
(1R,2R,3R,10aS,Z)-1,2,3-Tris(benzyloxy)-1,2,3,4,6,7,8,10a-
octahydropyrido[1,2-a]azepine (17c)
Compound 17c was prepared from 16c as described in the
preparation of 6a, yielding 17c (37% yield) as a yellow syrup.
Rf 0.70 (chloroform–methanol 30 : 1). [a]2D6 = +13.4 (c = 0.0172,
MeOH). 1H NMR (300 MHz, CDCl3) d 1.70 (br.s, 1H), 2.12-2.32
(m, 3H), 2.52-2.63 (m, 1H), 2.78-2.82 (m, 2H), 3.24-3.34 (m, 2H),
3.68 (s, 1H), 3.90 (br.s, 1H), 4.30-4.72 (m, 6H), 5.69-5.71 (m, 2H),
7.21-7.35 (m, 15H); 13C NMR (100 MHz, CDCl3) d 24.69, 55.92,
59.35, 71.34, 72.65, 72.82, 74.59, 79.63, 126.97, 127.53, 127.65,
127.80, 128.29, 128.32, 128.49, 128.68, 130.25, 131.57, 138.06,
(2S,3R,4R,5R)-3,4,5-Tris(benzyloxy)-1-(but-3-enyl)-2-
vinylpiperidine (16b)
Compound 16b was prepared from 15b as described in the
preparation of 5a, yielding 16b (67% yield) as a colorless oil. Rf 0.62
(petroleum ether–ethyl acetate, 3 : 1). [a]2D6 = +1.88 (c = 0.0016,
MeOH). 1H NMR (300 MHz, CDCl3) d 2.16-2.24 (dd, J = 7.5 Hz,
J = 15.3 Hz, 2H), 2.43-2.52 (m, 1H), 2.63-2.72 (m, 2H), 2.86 (dd,
J = 3.9 Hz, J = 10.5 Hz, 1H), 3.15 (d, J = 9.0 Hz, 1H), 3.45
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138.66, 138.78; HRMS (ESI) Anal. Calcd for C31H36NO3 [M + H]+:
470.2690, found: 470.2691.
(c = 0.0126, MeOH). 1H NMR (500 MHz, D2O) d 1.93-2.08 (m,
2H, H-7), 3.18 (t, J = 12.0 Hz, 1H, H-4ax), 3.25-3.38 (m, 3H,
H-4eq, H-6), 3.47 (dd, J = 1.5 Hz, J = 10.5 Hz, 1H, H-9a), 3.93
(dd, J = 3.0 Hz, J = 10.5 Hz, 1H, H-9), 4.12 (t, J = 3.5 Hz, 1H,
H-2), 4.21 (dd, J = 2.5 Hz, J = 6.0 Hz, 1H, H-8), 4.24-4.28 (m,
1H, H-3), 4.29 (dd, J = 1.0 Hz, J = 4.0 Hz, 1H, H-1); 13C NMR
(125 MHz, D2O) d 27.93, 49.53, 52.64, 58.41, 62.82, 66.08, 66.13,
66.31, 68.83; HRMS (ESI) Anal. Calcd for C9H18NO5 [M + H]+:
220.1180, found: 220.1179.
(6R,7R,8R,8aS)-Octahydroindolizine-6,7,8-triol (18a)
Compound 18a was prepared from 17a as described in the
preparation of 7a, yielding 18a (82% yield) as a solid after
1
lyophilization. [a]2D6 = +8.97 (c = 0.00248, MeOH). H NMR
(300 MHz, D2O) d 1.55-1.77 (m, 4H), 2.40-2.44 (m, 2H), 2.74
(br.s, 1H), 2.93-3.02 (m, 2H), 3.80 (br.s, 2H), 3.86-3.91 (m, 1H); 13C
NMR (125 MHz, D2O) d 20.87, 22.89, 51.20, 53.60, 63.13, 65.28,
67.98, 70.07; HRMS (ESI) Anal. Calcd for C8H16NO3 [M + H]+:
174.1125, found: 174.1129. The spectroscopic data coincide with
those reported previously.22
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China, “973” and “863” grants from the
Ministry of Science and Technology of China.
(1R,2R,3R,9aS)-Octahydro-1H-quinolizine-1,2,3-triol (18b)
Compound 18b was prepared from 17b as described in the
preparation of 7a, yielding 18b (91% yield) as a colorless oil.
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