Efficient and structurally controlled synthesis of novel polyhydroxylated indolizidine derivatives with an amino group

Article abstract of DOI:10.1016/j.tet.2009.01.026

Novel polyhydroxylated indolizidine derivatives containing an amino group have been efficiently and divergently synthesized from azasugar aldehyde. The key steps of the strategy involved an effectively microwave assisted 1,3-dipolar cycloaddition of azasu

Full text of DOI:10.1016/j.tet.2009.01.026

Tetrahedron 65 (2009) 2322–2328
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Tetrahedron
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Efficient and structurally controlled synthesis of novel polyhydroxylated
indolizidine derivatives with an amino group
,
b
,
a
a
a
a
c
a
Xiaoliu Li a , Zhengang Zhu , Kefang Duan , Hua Chen , Zhiwei Li , Zhe Li , Pingzhu Zhang
*
a Laboratory of Chemical Biology, College of Chemistry and Environmental Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education,
Hebei University, Baoding, Hebei 071002, China
b The State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
c Institute of Polymer Chemistry and Physics, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel polyhydroxylated indolizidine derivatives containing an amino group have been efficiently and
divergently synthesized from azasugar aldehyde. The key steps of the strategy involved an effectively
microwave assisted 1,3-dipolar cycloaddition of azasugar nitrone and methacrylate for installing a potential
amino group and an ester group with a extended chain, and a structurally controlled intramolecular
cyclo-amidation for constructing the indolizidine ring system via a key tricyclic indolizinone-containing
intermediate.
Received 11 November 2008
Received in revised form 2 January 2009
Accepted 6 January 2009
Available online 14 January 2009
Keywords:
Polyhydroxylated indolizidine
Azasugar
Ó 2009 Elsevier Ltd. All rights reserved.
1,3-Dipolar cycloaddition
Nitrones
1. Introduction
intramolecular annulations of g- or d g- or d-
-amino acids,4 or
amino alcohol derivatives.5 However, to the best of our knowledge,
most of the synthesized polyhydroxylated indolizidines were the
alternative epimers and/or other structural analogues of the natural
compounds, and those with the functional group other than hy-
droxyl, such as amino group, were scarce.8 To meet the ever-
growing requirements for diverse polyhydroxylated indolizidine
derivatives in the structure–activity relationship study and the
drug discovery, the design and stereoselective synthesis of novel
structural variants of polyhydroxylated indolizidine with different
functional groups and substituents are of high importance.
Polyhydroxylated indolizidine alkaloids, such as the well known
(ꢀ)-swainsonine (A) and (þ)-castanospermine (B) (Fig. 1), are
naturally occurring and typical bicyclic azasugar analoges,1 and
exhibited effective glycosidase inhibition and potential therapeutic
applications as antidiabetic, antiviral, anticancer, and anti-
metastatic immunoregulating agents.2 Such promising applications
and the interesting bicyclic structure of polyhydroxylated indoli-
zidines have attracted great interests to approach the convenient
and efficient synthetic methods and to build up the diversity of the
compounds for studying the structure–activity relationship, im-
proving their biological activity and selectivity, and diminishing
toxicity.3 In literature, considerable synthetic routes for synthesiz-
ing polyhydroxylated indolizidine derivatives have been well
documented.3–7 Of the most convenient methods are the
Retrosynthetically, the target amino polyhydroxylated indolizi-
dines (T) could be obtained from the reduction of the key in-
termediates (C) or (G), which would be generated from the 1,3-DC
adducts (D)9 via the process (a) or (b), respectively, as shown in
Scheme 1. In the process (a), the reductive cleavage of N–O bond10
would result in the g- or d-amino ester-like intermediate (E), which
followed by competitively intermolecular cyclo-amidation in
routes (i) or/and (ii), would produce the intermediates (C) or/and
(F), respectively. However, the process (b) involving the tricyclic
intermediate (G) produced by a trifluoroacetamide hydrolysis of (D)
and then intermolecular cyclo-amidation would be in favor of ex-
clusively resulting the indolizidine skeleton. The potential amino
group in target molecule and the carboxyl group for constructing
indolizidine ring could be simultaneously installed by the divergent
and stereoselective 1,3-DC of an azasugar nitrone (2) and an
acrylate.
OH
OH
H
OH
OH
OH
H
HO
HO
N
N
B
A
Figure 1. Swainsonine (A) and castanospermine (B).
* Corresponding author. Tel./fax: þ86 312 5971116.
E-mail address: lixl@hbu.cn (X. Li).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.026

X. Li et al. / Tetrahedron 65 (2009) 2322–2328
2323
R
R
HO
R
compound 3c also matched to the structures of 3a and 3c, sup-
porting the structural elucidation of compound 3b.
O
HO
O
O
H
H
N
N
H
N
N
N
N
Firstly we explored the synthesis of the amino indolizinone
derivative (C) via the intermediate (E) via the route of the reductive
cleavage of the O–N bond (Scheme 1 step a) and cyclo-amidation
(Scheme 1 step i) by treating 3 with Zn-AcOH-H2O at room tem-
perature following our previous report10 as shown in Scheme 3. As
expected in Scheme 1, the reaction should form a bipyrrolidinyl
intermediate (F) (Scheme 1 step ii) or/and the amino indolizinone
derivative (C) (Scheme 1 step i) via g- or/and d-cyclo-amidation of
the intermediate (E), respectively. However, under the reductive
treatment the cycloadduct 3b gave the bipyrrolidinyl derivative 4b,
H
H
BnO
H
HO
OH
OH
BnO
OH
G
T
C
i
b
i
ii
HN
a
O
N
b
H
TFA
N
CF3
H
O
R'O2C
HO
R
N
a
R'O2C
H
BnO
E
R
BnO
D
OH
OH
which might involve the generation of a
g,
d-diamino acid in-
termediate (E) (Scheme 1, step a) and then the favorite
g-cyclo-
ii
amidation (Scheme 1, attack ii) to form the product exclusively. In
the cases of 3a and 3c, the tricyclic intermediates 5a and 5c were
mainly obtained, respectively, via the acidic trifluoroacetamide
O
CF3
OH
CF3
O
CF3
O
O
HO
N
H
H
O
N
N
N
O
N
hydrolysis and
d-cyclo-amidation by the step b as shown in
R
BnO
Scheme 1, without the generation of O–N bond cleavage/cyclo-
amidation products. These results implied that the reaction of 3 to
form the tricyclic intermediates 5 may be depended upon the
structure of 3, namely being stereo-structurally controlled.
To explore the conversion of 3 to the tricyclic intermediates 5,
the cycloadduct 3c was treated with NaOH/MeOH/H2O solution
(pH¼12) to hydrolysize trifluoroacetamide and propyl ester, and
then acidifying (pH¼2) with hydrochloric acid to furnish the cyclo-
amidation (Scheme 4, (i)). As a result, white solid of 5c was afforded
in 89.6% yield. With intermediate 5c, the debenzylation and O–N
bond cleavage were next investigated by catalytic hydrogenation
with Pd(OH)2/C in MeOH, which in the presence of an equivalent of
hydrochloric acid afforded the amino polyhydroxylated indolizi-
none 6c in 92.8% yield (Scheme 4, (ii)).
Following the same procedures, the tricyclic intermediate (5a)
was obtained from 3a in yields of 91.1%, which, followed by catalytic
hydrogenation, gave the indolizinone derivative (6a) in 90.0%
(Scheme 4). However, in the case of 3b, following the same treat-
ments the bipyrrolidinyl derivative (6b) was finally formed, and the
corresponding intermediate (5b) was not generated in the first step
(Scheme 4, (i)) according to the TLC monitoring. The results further
indicated that the cyclo-amidation of 3 to form the intermediate 5
would be structurally controlled.
The structure of 5c was confirmed by its single-crystal X-ray
analysis (Fig. 3),13 and the structure of 4b was determined based on
the structure of 3b and the spectral analyses. The HMBC correlation
between C(C]O) and H(CH3–N) of 4b indicated the existence of an
amido N-methyl group, strongly supporting the pyrrolidinone
structure of 4b. Similar correlations were also observed in the
HMBC spectra of 6b (Scheme 4).
Moreover, in the supposed structure of 5b (Fig. 5a) the N and O
atoms in the isoxazolidine ring were antarafacial to the piperidone
ring. According to its optimized conformation (Fig. 5b) by Chem3D
Pro 10.0 (ChemOfficeÒ 2006, CambridgeSoftÒ Corporation) calcu-
lation, the N-linked bridge sp3carbon (inside the green circle)
shared by the isoxazolindine ring and piperidinone ring could not
build up a normal tetrahedron connection, that is, such structure
was unfavorable and would be impossible, strongly indicating that
the intramolecular cyclo-amidation was stereocontrolled by the
structure of its product 5.
BnO
OH
BnO
F
OH
1
2
Scheme 1. Retrosynthetic analysis of amino polyhydroxylated indolizidines.
2. Results and discussion
The requisite azasugar nitrone (2) was prepared from the aza-
sugar aldehyde (1)11 following the Dondoni’s procedure.12 The 1,3-
DC of nitrone (2) with propyl methacrylate was carried out at room
temperature to afford the corresponding cycloadducts of the iso-
xazolidines 3a, 3b, and 3c in total yield of 66.7% with the ratio of
1.47:0.81:1. Theoretically, the cycloaddition should produce four
diastereomers of 3a, 3b, 3c, and 3d, but under both reaction con-
ditions the reaction stereoselectively provided three isomers of 3a,
3b, and 3c (Scheme 2).
The structure of 3a was confirmed by its single-crystal X-ray
analysis (Fig. 2), showing the newly generated chiral carbons of C-30
and C-50 to be in (R) and (S) configurations, respectively.13 Similarly,
the C-30 and C-50 in 3c could be deduced to have (S) and (R) con-
figurations, respectively, according to the single-crystal X-ray
analysis of its derivative 5c (Fig. 3)13 generated from 3c as shown in
Scheme 3. The cycloadduct 3b was determined to be of 30-(R) and
50-(R) based on the structures of 3a and 3c and by comparing the
NOESY analyses of 3b with those of 3a and 3c (Fig. 4).
As shown in Figure 4 of 2D-NOESY correlation analyses of 3a, 3b,
and 3c, the correlations between H-4/Ha-40, H-5/H-30, H-30/Hb-40,
and Ha-40/H-50CH3 in compound 3b were observed, and no corre-
lation between H-4/H-30 and H-30/Ha-40 existed, indicating its
structure to be identical to the proposed. Similarly, the correlations
between H-4/Ha-40, H-5/H-30, H-30/Hb-40 and Hb-40/H-50CH3 in
compound 3a, and H-4/H-30, H-30/Ha-40, and Ha-40/H-50CH3 in
O
CF3
OH
2'
1'
H
O
5
CF3
2
N
C3H7OOC
O
O
N
H
N
O
N
5'
3'
1
COOC3H7-n
4'
4 3
C3H7OOC
BnO
3b
CH3
+
BnO
OH
i
3a
It should be mentioned that in the absence of hydrochloric acid
the hydrogenation of 5c also generated the by-products of the
debenzylated intermediate 7 and the methylated derivative 8, be-
sides the desired product 6c, as shown in Scheme 5, probably be-
cause the new generated amine group in 6c lowered the activity of
the palladium catalyst by poisoning.
O
CF3
OH
CF3
O
CF3
H
H
N
N
O
N
N
O
C3H7OOC
N
N
O
C3H7OOC
BnO
BnO
3d (not obtained)
OH
BnO
3c
OH
2
Toward the final amino polyhydroxylated indolizidine de-
rivatives, the reduction of the carbonyl into methylene was
Scheme 2. Conditions and reagents: (i) rt, 95 h, 66.7% (3a:3b:3c¼1.47:0.81:1).

2324
X. Li et al. / Tetrahedron 65 (2009) 2322–2328
Figure 2. ORTEP drawings of compound 3a.
Figure 3. ORTEP drawings of compound 5c.
approached with lithium aluminum hydride (LiAlH4)4h,6d,14 using
the tricyclic indolizinone intermediates 5a, instead of 6a due to its
poor solubility in THF. As shown in Scheme 6, under the condition A
(LiAlH4/THF, rt) the amido carbonyl of 5a was reduced to afford the
corresponding indolizidine derivative 9a possessing a hemiacetal-
like structure in 91.8% yield. Next, the exhaustively catalytic hydro-
genation of 9a involving the reductions of hemiacetal and O–N
bond, and debenzylation provided the novel amino indolizidine
derivatives 11a in 90.2% yield (Scheme 6). Following the same
procedure, 5c was converted into the corresponding 11c in 90%
yield in two steps. However, in the presence of Lewis acid AlCl3
(Scheme 6, condition B), the reduction of 5c could proceed
smoothly and directly gave the indolizidine derivative 10c in 91.6%
yield, but in the case of 5a, the reaction produced the corre-
sponding 10a (41.0%), as well as the debenzylated derivative (10a1)
(54.7%). Subsequently, the exhaustive hydrogenation of 10 provided
the final product 11 in excellent yields (Scheme 6). The spectral data
(1H NMR, 13C NMR, 2D NOESY, HRMS) of all the new compounds
were matched to their proposed structures.
Glycosidase inhibition and antitumor activities were pre-
liminarily evaluated with compounds 6a, 6c and 11a, 11c. The cy-
totoxicity of the compounds against Hela cell lines (human cervical
cancer cells) was examined by the modified Mosmann’s protocol,15
and the glycosidase inhibitory activities were measured on hy-
drolytic reactions of a-amylase, a-glucosidase, and b-glucosidase by
colorimetric analysis and by comparison with acarbose, re-
spectively. However, the compounds did not show obvious
activities.
O
O
CF3
O
O
O
HO
O
O
CF3
N
H
H
H
N
N
H
N
H
O
N
N
N
N
i
In conclusion, we have provided a new strategy of highly effi-
cient synthesis of novel amino polyhydroxylated indolizidine and
indolizinone derivatives from azasugar aldehyde by stereoselective
1,3-DC and structurally controlled cyclo-amidation. The divergent
1,3-DC of azasugar nitrone (2) and propyl methacrylate simulta-
neously introduced a carboxyl group for constructing the indolizi-
dine ring and the potential amino group. The followed structurally
dependent cyclo-amidation, which formed the key tricyclic indo-
lizinone intermediates (5) determined the skeleton of poly-
hydroxylated indolizidine bearing an amino group. The preliminary
biological evaluation of the synthesized compounds 6 and 11
showed weak glycosidase inhibitory activity, but no antitumor ac-
tivities. The further application of the strategy to synthesize novel
variants of such amino bicyclic azasugar and their biological testing
are underway.
H
H
BnO
H
C3H7OOC
BnO
OH
BnO
OH
3a, 3b, 3c
BnO
5c
OH
OH
5a
4b
Scheme 3. Conditions and reagents: (i) AcOH/H2O/Zn, 70 ꢁC; 5a: 66.2%, 5c: 58.2%, 4b:
27.8%.
1'
2'
CF
O
O
3
O
H3C
C3H7OOC
H3C
O
5'
CF
3
CF
1
N
O
O
3
Ha N
Ha N
H
H3C
Ha
N
3'
3'
5
C H OOC
5'
N
3
7
N
5
5
5'
H
4
3'
C3H7OOC
4'
4'
4'
2
H
H
Hb
H
Hb
H
H
Hb
3
H
H
BnO
3a
4
4
OH
BnO
3c
OH
BnO
OH
3b
Figure 4. NOE correlations of compounds 3a–3c.

X. Li et al. / Tetrahedron 65 (2009) 2322–2328
2325
HO
H
HO
H
O
O
O
O
O
O
O
CF3
H
H
O
O
O
O
N
O
N
H
N
N
H
N
H
N
i
N
N
N
N
+
N
N
H
BnO
5c
+
N
H
N
For 3a, 3c
H
C3H7OOC
H
H
H
HO
BnO
3a,3b,3c
OH
BnO
BnO
5a
HO
HO
OH
OH
OH
OH
OH
OH
5c
6c
7
8
i
For 3b
i, ii
ii
Scheme 5. Conditions and reagents: (i) Pd(OH)2/C, H2, MeOH, 6c: 52.7%, 7: 24.4%; 8:
9.3%.
O
HO
H
HO
O
O
O
O
N
N
H
H
N
H
H
N
N
N
HO
N
N
H
BnO
5b
(colorless syrup, 0.30 g, 16.5%), 3c (colorless syrup, 0.37 g 20.3%)
(a:b:c¼1.47:0.81:1) in total yield of 66.7%. A single crystal of 3a for
X-ray analysis was obtained from hexane solution.
H
H
H
OH
HO
HO
OH
HO
OH
OH
6b
6a
6c
Scheme 4. Conditions and reagents: (i) NaOH/MeOH/H2O, rt, then HCl (0.2 mol/L)
(pH¼2); 5a: 91.1%, 5c: 89.6%; (ii) Pd(OH)2/C, H2, MeOH/HCl; 6a: 90.0%, 6c: 92.8%, 6b:
75.4% (two steps from 3b).
20
3.2.1.1. Compound 3a. White solid, mp: 69–71 ꢁC, [
CHCl3); 1H NMR (400 MHz, CDCl3),
a
]
þ3.91 (c 2.7,
D
d
: 0.91 (t, J¼7.4 Hz, 3H, CH2CH3),
1.49 (s, 3H, CH3), 1.65 (m, 2H, CH2CH3), 2.42 (t, J¼11.1 Hz, 1H, H-7a),
2.64 (s, 3H, N-CH3), 2.71 (dd, J¼13.2, 6.8 Hz, 1H, H-7b), 3.70–3.73
(m, 2H, H-2b, H-6), 3.94 (dd, J¼12.4, 4.1 Hz, 1H, H-2a), 4.05 (m, 2H,
CH2O), 4.10 (s, 1H, H-4), 4.20 (m, 1H, H-3), 4.38 (d, J¼2.3 Hz, 1H, H-
5), 4.57 (s, 2H, PhCH2), 6.32 (d, J¼7.0 Hz, 1H, OH), 7.21–7.34 (m, 5H,
3. Experimental
3.1. General methods
ArH); 13C NMR (100 MHz, CDCl3),
d: 10.5, 22.1, 23.9, 42.9, 46.7, 56.5,
Melting points were measured on an SGWÒ X-4 micro melting
point apparatus and were uncorrected. Optical rotations were
determined on an SGWÒ-1 automatic polarimeter. NMR experi-
65.0, 67.8, 68.2, 72.1, 72.5, 82.4, 82.6, 116.4, 127.2–128.9, 137.6, 157.1,
174.3; HRMS (ESI): calcd for C22H29F3N2O6 (Mþ): 474.1978, found:
474.1983.
ments were recorded on
a FT-NMR Bruker AVANCE 400
20
3.2.1.2. Compound 3b. Colorless syrup, [
a
]
ꢀ3.50 (c 3.8, CHCl3);
(400 MHz) and Bruker AVANCE 600 (600 MHz) spectrometers,
chemical shifts are given in parts per million using tetrame-
thylsilane (Me4Si) as an internal standard. X-ray crystallographic
measurements were made on a Bruker SMART CCD diffractometer.
Mass Spectra (MS) and High Resolution Mass Spectra (HRMS)
were carried out on a FTICR-MS (Ionspec 7.0T) mass spectrometer
with electrospray ionization (ESI). TLC was performed on silica gel
plates (Qingdao GF254) with detection by UV (254 nm) light or
with phosphomolybdic reagent. Flash chromatography was
performed using 200–300 mesh silica gel. Solvents were distilled
and dried immediately prior to use.
D
1H NMR (400 MHz, CDCl3),
d
: 0.87 (t, J¼7.1 Hz, 3H, CH2CH3), 1.15 (s,
3H, CH3), 1.51–1.63 (m, 3H, H-7a, CH2CH3), 2.54 (s, 3H, N-CH3), 3.19
(dd, J¼11.1, 7.9 Hz, 1H, H-7b), 3.75 (d, J¼11.1 Hz, 1H, H-2b), 3.86–
3.90 (m, 2H, H-2a, H-6), 3.95 (s,1H, H-4), 4.00 (m, 2H, OCH2), 4.11 (s,
1H, H-3), 4.22 (d, 1H, J¼3.8 Hz, H-5), 4.47 (d, J¼11.8 Hz, 1H, PhCH2),
4.61 (d, J¼12.2 Hz, 1H, PhCH2), 6.86 (s, 1H, OH), 7.22–7.28 (m, 5H,
ArH); 13C NMR (100 MHz, CDCl3),
d: 10.6, 22.1, 23.4, 43.1, 48.2, 56.5,
65.6, 67.6, 69.4, 71.5, 72.3, 81.2, 84.2, 116.4, 128.4–129.0, 137.5, 157.2,
174.2; HRMS (ESI): calcd for C22H29F3N2O6 (Mþ): 474.1978, found:
474.1986.
20
3.2.1.3. Compound 3c. Colorless syrup, [
1H NMR (400 MHz, CDCl3),
a]
ꢀ8.53 (c 3.3, CHCl3);
D
3.2. Experimental procedures
d
: 0.93 (t, J¼7.1 Hz, 3H, CH2CH3), 1.49 (s,
3H, CH3), 1.69 (m, 2H, CH2CH3), 2.09 (dd, J¼13.1, 8.7 Hz, 1H, H-7b),
2.75 (s, 3H, N-CH3), 3.00 (dd, J¼13.1, 7.2 Hz,1H, H-7a), 3.49–3.56 (m,
2H, H-6, H-2a), 4.05–4.10 (m, 4H, H-2b, OCH2, H-4), 4.26 (s, 1H, H-
3), 4.37 (m, 1H, H-5), 4.58 (s, 2H, PHCH2), 7.29–7.34 (m, 5H, ArH);
3.2.1. General procedure of 1,3-dipolar cycloaddition of nitrone (2)
with propyl methacrylate (Scheme 2)
A solution of nitrone 2 (1.34 g, 3.88 mmol) and methyl meth-
acrylate (10 mL) was stirred under nitrogen atmosphere at room
temperature for 95 h till the reaction completed. The reaction so-
lution was concentrated in vacuo and the residue was subjected to
silica gel column chromatography (petroleum ether/ethyl acetate v/
v¼8:1–6:1) to afford the adducts 3a (white solid, 0.55 g, 29.9%), 3b
13C NMR (100 MHz, CDCl3),
d: 10.6, 22.3, 24.4, 40.8, 44.7, 53.7, 64.8,
67.1, 67.5, 72.1, 74.8, 82.2, 84.3, 116.5, 128.1–129.0, 138.1, 156.9,
175.2; HRMS (ESI): calcd for C22H30F3N2O6 (MþHþ): 475.2050,
found: 475.2056.
3.2.2. Treatment of 3 with Zn/AcOH/H2O (Scheme 3)
A
mixture of 3c (538 mg, 1.14 mmol) and Zn (1.654 g,
(a)
(b)
25.3 mmol) in AcOH aqueous solution (30 mL, vAcOH=vH O¼1:2)
2
was stirred at 70 ꢁC till the reactant disappeared on TLC. The
H3C
O
O
H3C
N
H
N
O
HO
X
O
H
O
N
H
N
H
N
i or ii
iii
BnO
N
N
OH
N
H
PO
H
H
H
OH
HO
BnO
5a
5c
OH
OH
9a (X= OH, P= Bn)
10a (X=OH, P=Bn)
10a1 (X=OH, P=H)
10c (X = H, P= Bn)
11a
11c
Scheme 6. Conditions and reagents: (i) LiAlH4/THF, rt, 9a: 91.8% (from 5a); (ii) LiAlH4/
AlCl3/THF, rt, 10a: 41.5%, 10a1: 54.7% (from 5a), 10c: 91.6% (from 5c); (iii) Pd(OH)2/C, H2,
MeOH/HCl, 11: 90.2%–92.6% (from 9 or 10).
Figure 5. The supposed structure of 5b (a) and its optimized conformation with
minimum energy (b) by Chem3D Pro 10.0 calculation.

2326
X. Li et al. / Tetrahedron 65 (2009) 2322–2328
solution was neutralized with NaHCO3, filtered, and co-evaporated
with toluene several times. The residue was extracted with CH2Cl2,
concentrated, and then purified by chromatography (petroleum
ether/ethyl acetate v/v¼1:5) to afford 5c (211 mg, 58.2%) as a white
solid. The single crystal for X-ray analysis was obtained from ethyl
acetate/hexane solution.
Following the same procedure, the cycloadduct 3a (355 mg,
0.75 mmol) and 3b (150 mg, 0.32 mmol) were treated, and 5a
(white solid, 158 mg, 66.2%) and 4b (colorless syrup, 37 mg, 27.8%)
were obtained, respectively.
chromatography (ethyl acetate/methanol v/v¼5:1 then 3:1) to give
6c (143 mg, 92.8%) as a white solid.
Following the same procedure, the hydrogenation of 5a
(134 mg, 0.42 mmol) afforded 6a (87 mg, 90.0%) as a white solid.
For cycloadduct 3b, the above treatments were combined as
follows: A solution of 3b (392 mg, 0.83 mmol) in MeOH (4.0 ml)
and 0.2 mol/L aqueous NaOH solution (4 ml) was stirred for 1 h and
acidified with diluted HCl solution (0.2 mol/L) to pHz2. The solu-
tion was again stirred for 10 min, neutralized with aqueous NaHCO3
to pHz7, concentrated in vacuo, and co-evaporated with toluene
several times. The residue was extracted with MeOH (5 mL) two
times. The resulting solution was hydrogenated in the presence of
25
3.2.2.1. Compound 5a. White solid, mp: 142–144 ꢁC, [
2.0, CHCl3); 1H NMR (400 MHz, CDCl3),
a]
þ94.40 (c
D
d
: 1.51 (s, 3H, CH3), 2.12 (d,
Pd(OH)2/C (92 mg) and concentrated hydrochloric acid (50 mL,
J¼12.4 Hz, 1H, 7-Ha), 2.31 (dd, J¼12.4, 4.3 Hz, 1H, 7-Hb), 2.73 (s, 3H,
N-CH3), 3.35 (dd, J¼12.9, 6.1 Hz, 1H, 2-Hb), 3.42 (s, 1H, 6-H), 3.57 (d,
J¼6.6 Hz, 1H, 5-H), 3.75 (d, J¼7.8 Hz, 1H, 4-H), 3.95 (d, J¼12.7 Hz,
1H, 7-Ha), 4.33 (s, 1H, 3-H), 4.59 (d, J¼11.8 Hz, 1H, PhCH2), 4.81 (d,
J¼11.8 Hz, 1H, PhCH2), 7.28–7.40(m, 5H, ArH); 13C NMR (100 MHz,
0.58 mmol). After usual work-up and chromatographic purification
(ethyl acetate/methanol v/v¼3:1), 6b (144 mg, 75.4%) was obtained
as a white solid.
25
3.2.4.1. Compound 6a. White solid, mp: 75–77 ꢁC, [
a
]
ꢀ17.51 (c
D
CDCl3),
d
: 19.0, 34.5, 47.3, 51.5, 63.4, 66.7, 69.1, 72.8, 75.0, 81.9, 85.5,
2.0, MeOH); 1H NMR (400 MHz, CD3OD),
d: 1.43 (s, 3H, CH3), 2.04
125.6–129.0, 138.1, 171.3; HRMS (ESI): calcd for C17H22N2O4Na
(dd, J¼13.8, 8.1 Hz, 1H, 7-Ha), 2.23 (dd, J¼13.8, 4.9 Hz, 1H, 7-Hb),
2.67 (s, 3H, N-CH3), 3.36 (m, 1H, 2-Hb), 3.41 (dd, J¼12.5, 5.5 Hz, 1H,
6-H), 3.58 (t, J¼7.7 Hz, 1H, 5-H), 3.64 (dd, J¼12.5, 2.2 Hz, 1H, 2-Ha),
3.97 (t, J¼7.2 Hz, 1H, 4-H), 4.13 (dd, J¼12.7, 5.7 Hz, 1H, 3-H); 13C
(MþNaþ): 341.1472, found: 341.1480.
30
3.2.2.2. Compound 4b. Colorless syrup, [
a
]
þ13.61 (c, 2.8, CHCl3);
D
1H NMR (400 MHz, CDCl3),
d
: 1.43 (s, 3H, CH3), 2.03 (dd, J¼14.7,
NMR (CD3OD), d: 25.5, 31.7, 39.1, 50.0, 56.5, 64.2, 70.5, 74.0, 80.6,
3.1 Hz, 1H, 7-H), 2.37 (dd, J¼14.7, 9.5 Hz, 1H, 7-H), 2.88 (s, 3H, N-
CH3), 3.82 (d, J¼11.9 Hz, 1H, 2-H), 4.03 (dd, J¼12.0, 5.2 Hz, 1H, 2-H),
4.25 (s,1H, 5-H), 4.42 (s,1H, 3-H), 4.56 (m, 2H, 6-H, 4-H), 4.70 (s, 2H,
172.5; HRMS (ESI): calcd for C10H19N2O4 (MþHþ): 231.1339, found:
231.1347.
25
PhCH2), 7.25–7.39 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3),
d: 23.4,
3.2.4.2. Compound 6b. White solid, mp: 204–206 ꢁC, [
a
]
D
þ16.10 (c
37.2, 31.3, 54.2, 57.7, 70.3, 71.6, 73.6, 73.8, 83.0, 116.4, 128.3–129.0,
137.9, 157.5, 177.5; HRMS (ESI): calcd for C19H23F3N2O5 (Mþ):
416.1559, found: 416.1566.
2.4, MeOH); 1H NMR (400 MHz, D2O),
d: 1.30 (s, 3H, CH3), 2.18 (dd,
J¼14.7, 2.6 Hz, 1H, 7-Hb), 2.32 (dd, J¼14.5, 8.7 Hz, 1H, 7-Ha), 2.82 (s,
3H, N-CH3), 3.57 (d, J¼12.9 Hz, 1H, 2-Ha), 3.42 (dd, J¼12.4, 4.2 Hz,
1H, 2-Hb), 3.78 (t, J¼3.8 Hz, 1H, 5-H), 4.06–4.08 (m, 2H, 6-H, 4-H),
26
3.2.2.3. Compound 5c. White solid, mp: 155–156 ꢁC, [
2.0, CHCl3); 1H NMR (400 MHz, CDCl3),
a
]
ꢀ24.03 (c
4.23 (t, J¼1.4 Hz, 1H, 3-H); 13C NMR (100 MHz, CD3OD),
d: 21.8, 27.8,
D
d
: 1.53 (s, 3H, CH3), 2.33 (d,
35.2, 51.5, 57.3, 66.0, 72.8, 75.4, 77.3, 176.1; HRMS (ESI): calcd for
J¼12.0 Hz, 1H, 7-Ha), 2.40 (dd, J¼12.0, 6.0 Hz, 1H, 7-Hb), 2.68 (s, 3H,
N-CH3), 3.29 (dd, J¼12.3, 3.5 Hz, 1H, 2-Ha), 3.39 (d, J¼5.7 Hz, 1H, 6-
H), 3.62 (s, 1H, 5-H), 3.83 (s, 1H, 4-H), 4.04 (d, J¼12.3 Hz, 1H, 2-Hb),
4.15 (s, 1H, 5-H), 4.56 (d, J¼11.8 Hz, 1H, PhCH2), 4.71 (d, J¼11.8 Hz,
C10H19N2O4 (MþHþ): 231.1339, found: 231.1342.
24
3.2.4.3. Compound 6c. White solid, mp: 163–165 ꢁC, [
1.0, MeOH); 1H NMR (400 MHz, CD3OD),
a
]
ꢀ18.11 (c
D
d
: 1.37 (s, 3H, CH3), 1.96 (d,
1H, PhCH2), 7.27–7.39 (5H, m, ArH); 13C NMR (100 MHz, CDCl3),
d:
J¼15.1 Hz, 1H, 7-Ha), 2.38 (dd, J¼15.0, 3.6 Hz, 1H, 7-Hb), 2.53 (s, 3H,
N-CH3), 3.16 (d, J¼3.03 Hz, 1H, 2-Ha), 3.48 (dd, J¼11.6, 4.0 Hz, 1H, 6-
H), 3.62 (m, 2H, 5-H, 2-H), 4.06 (m, 2H, 4-H, 3-H); 13C NMR
17.3, 38.6, 52.4, 63.7, 69.1, 72.6, 72.9, 81.0, 85.8, 128.2–129.0, 138.0,
169.7; HRMS (ESI): calcd for C17H23N2O4 (MþHþ): 319.1652, found:
319.1657.
(100 MHz, CD3OD), d: 26.0, 33.9, 37.9, 50.3, 53.2, 67.4, 70.2, 73.7,
76.3, 172.5; HRMS (ESI): calcd for C10H19N2O4 (MþHþ): 231.1339,
3.2.3. Treatment of 3 with NaOH/MeOH/H2O (Scheme 4)
The cycloadduct 3c (317 mg, 0.67 mmol) was dissolved in MeOH
(3.0 mL), to the solution was added NaOH aqueous solution
(0.2 mol/L, 3 mL) with stirring. After the reaction completed within
1 h, the solution was acidified with diluted HCl solution (0.2 mol/L)
to pHz2, and then was stirred for 10 min at room temperature. The
solution was neutralized with aqueous NaHCO3 to pHz7, concen-
trated in vacuo, and extracted with CH2Cl2. The organic solution
was dried and concentrated. The residue was purified by column
chromatography (petroleum ether/ethyl acetate v/v¼1:5) to give 5c
(191 mg, 89.6%) as a white solid.
found: 231.1344.
3.2.5. Catalytic hydrogenation of 5c in the absence of hydrochloric
acid (Scheme 5)
A mixture of compound 5c (151 mg, 0.47 mmol), Pd(OH)2/C
(98 mg) in methanol (10 mL) was stirred under the atmospheric
pressure of hydrogen for 8 h. The catalyst was removed by filtration
through Celite and the filtrate was evaporated to give white solid,
which was purified by silica gel column chromatography (ethyl
acetate/methanol v/v¼5:1 then 3:1) to provide 6c (57 mg, 52.7%),
the N–O bond remaining intermediate 7 (28 mg, 26.0%), and the
methylated derivative 8 (10 mg, 8.7%) as white solids, probably
because the newly generated amine group in 6c lowered the ac-
tivity of the palladium catalyst by poisoning.
Similarly, 423 mg (91.1%) of 5a was obtained as a white solid
from 694 mg (1.46 mmol) of 3a.
3.2.4. Catalytic hydrogenation of 5 in the presence of hydrochloric
acid (Scheme 4)
24
3.2.5.1. Compound 7. White solid, mp: 171–172 ꢁC, [
a]
ꢀ41.71 (c
D
A mixture of compound 5c (213 mg, 0.67 mmol), Pd(OH)2/C
1.0, MeOH); 1H NMR (400 MHz, CD3OD),
d: 1.45 (s, 3H, CH3), 2.36 (d,
(105 mg), and concentrated hydrochloric acid (60
m
L, 0.7 mmol) in
J¼12.1 Hz, 1H, 7-Ha), 2.51 (dd, J¼12.1, 6.0 Hz, 1H, 7-Hb), 2.74 (s, 3H,
N-CH3), 3.30 (m, 2H, 2-Ha, 6-H), 3.42 (dd, J¼8.7, 2.1 Hz, 1H, 5-H),
3.57 (m, 1H, 2-H), 4.08 (m, 2H, 4-H, 3-H); 13C NMR (100 MHz,
methanol (10 mL) was stirred under the atmospheric pressure of
hydrogen for 2 h. After the reaction was complete, 0.5 g of solid
NaHCO3 was added to neutralize the acid, and the solid was re-
moved by filtration through Celite. The filtrate was evaporated to
give white solid, which was purified by silica gel column
CD3OD), d: 16.2, 29.7, 37.8, 46.6, 49.5, 61.8, 67.2, 74.6, 75.5, 80.4,
170.1; HRMS (ESI): calcd for C10H16N2O4Na (MþNaþ): 251.1002,
found: 251.1008.

X. Li et al. / Tetrahedron 65 (2009) 2322–2328
2327
24
3.2.5.2. Compound 8. White solid, mp: 177–178 ꢁC, [
1.0, MeOH); 1H NMR (400 MHz, D2O),
a
]
ꢀ13.97 (c
4.23 (d, J¼7.6 Hz, 1H, 4-H), 4.28 (d, J¼5.8 Hz, 1H, 3-H); 13C NMR
D
d
: 1.31 (s, 3H, CH3), 2.20 (dd,
(100 MHz, CD3OD), d: 20.6, 33.2, 46.2, 59.3, 61.1, 63.3, 72.8, 77.6,
J¼15.9, 6.4 Hz, 1H, 7-Ha), 2.28 (dd, J¼15.9, 4.2 Hz, 1H, 7-Hb), 2.5 (s,
6H, N-CH3), 3.23 (dd, J¼12.5, 6.7 Hz, 1H, 2-Ha), 3.65 (m, 2H, 5-H, 6-
H), 3.81 (dd, J¼8.1, 4.4 Hz, 1H, 2-H), 4.11 (m, 2H, 4-H, 3-H); 13C NMR
78.5, 79.3; HRMS (ESI): calcd for C10H19N2O3 (MþHþ): 215.1390,
found: 215.1396.
27
(100 MHz, CD3OD),
d
: 28.3, 34.5, 42.8, 49.9, 56.7, 65.2, 69.5, 73.9,
3.2.7.3. Compound 10c. Colorless syrup, [
1H NMR (400 MHz, CDCl3),
a
]
D
þ11.89 (c 1.0, MeOH);
76.3, 174.5; HRMS (ESI): calcd for C11H21N2O4 (MþHþ): 245.1496,
d
: 1.33 (s, 3H, CH3), 1.88 (d, J¼11.6 Hz,
found: 245.1502.
1H, 7-H), 2.25 (ddd, J¼11.6, 5.6, 1.9 Hz, 1H, 7-H), 2.63 (s, 3H, N-CH3),
2.68 (d, J¼12.7 Hz, 1H, 2-H), 2.78 (d, J¼12.8 Hz, 1H, 2-H), 2.92 (d,
J¼2.2 Hz, 1H, 6-H), 3.13 (d, J¼10.4 Hz, 1H, 9-H), 3.18 (d, J¼5.5 Hz, 1H,
5-H), 3.46 (dd, J¼10.4, 6.0 Hz, 1H, 9-H), 3.81 (s, 1H, 4-H), 4.14 (d,
J¼5.8 Hz, 1H, 3-H), 4.56 (d, J¼12.0 Hz, 1H, PhCH2), 4.70 (d,
J¼12.0 Hz, 1H, PhCH2), 7.27–7.34 (m, 5H, ArH); 13C NMR (100 MHz,
3.2.6. Reduction of 5 with LiAlH4 in THF solution (Scheme 6,
conditions A)
To a solution of compound 5a (150 mg, 0.47 mmol) in THF
(2 mL) was added LiAlH4 (30 mg, 0.79 mmol) with stirring under N2
at room temperature. After 2 h ethyl acetate (0.5 mL) was added
dropwise and the resulting mixture was evaporated in vacuo. The
residue was applied to silica gel column chromatography (petro-
leum ether/ethyl acetate v/v¼1:5) to give 9a (138 mg, 91.8%) as
a colorless syrup.
Similarly, the reduction of 5c (172 mg, 0.54 mmol) with LiAlH4
provided the corresponding 9c, which, after work-up, was directly
used in the next step of catalytic hydrogenation to afford the target
compound 11c (105 mg) in 90.0% yield (two steps) as a white solid.
CDCl3), d: 21.5, 40.3, 47.3, 60.0, 63.2, 65.0, 68.8, 72.0, 74.8, 81.4, 89.3,
128.1–128.8, 138.6; HRMS (ESI): calcd for C17H24N2O3 (Mþ):
304.1787, found: 304.1795.
3.2.8. Catalytic hydrogenation of 9 and 10 in the presence of
hydrochloric acid (Scheme 6)
A mixture of compound 9a (125 mg, 0.39 mmol), Pd(OH)2/C
(48 mg), and concentrated hydrochloric acid (20 mL, 0.23 mmol)
in methanol (3 mL) was stirred under the atmospheric pressure
of hydrogen for 2 h. After the reaction complete, 0.2 g of solid
NaHCO3 was added for neutralization, and the solid was re-
moved by filtration through Celite. The filtrate was evaporated in
vacuo and the residue was purified by silica gel column chro-
matography (ethyl acetate/methanol v/v¼1:1) to afford the
amino polyhydroxylated indolizidine 11c (76 mg, 90.2%) as
a white solid.
Following the same procedure, compounds 10a, 10a1, and 10c
were hydrogenated to afford the corresponding amino poly-
hydroxylated indolizidine 11a, 11a, and 11c as white solids in yields
of 91.2%, 92.3%, and 92.6%, respectively.
29
3.2.6.1. Compound 9a. White solid, mp: 115–116 ꢁC, [
1.0, CHCl3); 1H NMR (400 MHz, CDCl3),
a
]
þ42.42 (c
D
d
: 1.34 (s, 3H, CH3), 1.68 (dd,
J¼11.8, 4.3 Hz, 1H, 7-Ha), 2.22 (dd, J¼16.6, 4.3 Hz, 1H, 7-Hb), 2.73 (s,
3H, N-CH3), 2.71–2.77 (br m, 1H, 2-Ha), 3.00 (d, J¼10.4 Hz, 1H, 2-H),
3.18 (d, J¼4.0 Hz, 1H, 6-H), 3.28 (d, J¼4.3 Hz, 1H, 5-H), 3.46 (s, 1H, 4-
H), 4.21 (s, 1H, 3-H), 4.38 (s, 1H, 9-H), 4.50 (dd, J¼14.5, 11.9 Hz, 2H,
PhCH2), 7.29–7.38 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3),
d: 21.0,
30.3, 47.6, 58.4, 64.0, 68.8, 72.2, 76.1, 80.9, 81.3, 97.0, 128.1–129.0,
138.1; HRMS (ESI): calcd for C17H24N2O4 (Mþ): 320.1736, found:
320.1741.
29
3.2.7. Reduction of 5 with LiAlH4 in THF solution in the presence of
AlCl3 (Scheme 6, conditions B)
3.2.8.1. Compound 11a. White solid, mp: 119–120 ꢁC, [
2.6, MeOH); 1H NMR (400 MHz, D2O),
a
]
D
ꢀ8.71 (c
d
: 1.19 (s, 3H, CH3), 1.38 (t,
To a solution of compound 5c (178 mg, 0.56 mmol) in THF
(5 mL) were added LiAlH4 (212 mg, 5.59 mmol) and anhydrate AlCl3
(224 mg, 1.68 mmol) with stirring under N2 at room temperature.
After 2 h, ethyl acetate (2 mL) was added dropwise, the solution
was neutralized to pHz7 with 1 mol/L aqueous NaOH solution, and
evaporated in vacuo. The residue was applied to silica gel column
chromatography (petroleum ether/ethyl acetate v/v¼1:5) to give
10c (156 mg, 91.6%) as a colorless syrup.
Following the same procedure, the 5a (170 mg, 0.53 mmol) was
reduced with LiAlH4 (84 mg, 2.2 mmol) in the presence of AlCl3
(88 mg, 0.66 mmol) to afford a white solid of 10a (66 mg, 41.0%) and
the debenzylated 10a1 (62 mg, 54.7%) as a colorless syrup.
J¼12.1 Hz, 1H, 9-H), 1.93 (d, J¼14.7 Hz, 1H, 6-H), 1.98 (d, J¼10.0 Hz,
1H, 9-H), 2.11 (dd, J¼12.1, 3.8 Hz,1H, 9-H), 2.60 (s, 3H, N-CH3), 2.57–
2.61 (m, 1H, 2-H), 2.70 (d, J¼10.6 Hz, 1H, 7-H), 2.76 (dd, J¼11.1,
4.2 Hz, 1H, 2-H), 3.17 (m, 1H, 5-H), 3.86 (dd, J¼7.9, 2.7 Hz, 1H, 4-H),
3.96 (m, 1H, 3-H); 13C NMR (100 MHz, D2O),
d: 25.9, 30.6, 39.2, 57.4,
60.7, 62.6, 69.7, 69.8, 77.2, 81.9; HRMS (ESI): calcd for C10H21N2O3
(MþHþ): 217.1547, found: 217.1552.
28
3.2.8.2. Compound 11c. White solid, mp: 63–65 ꢁC, [
1.0, MeOH); 1H NMR (400 MHz, D2O),
a
]
D
þ4.39 (c
d
: 1.18 (s, 3H, CH3), 1.62 (d,
J¼15.5 Hz, 1H, 9-H), 2.17 (d, J¼12.1 Hz, 1H, 7-H), 2.24 (d, J¼16.2 Hz,
1H, 9-H), 2.31 (d, J¼7.8 Hz, 1H, 2-H), 2.66 (t, J¼10.3 Hz, 1H, 7-H),
2.74 (s, 3H, N-CH3), 2.89 (s, 1H, 6-H), 2.92 (s, 1H, 2-H), 3.49 (s, 1H, 5-
H), 4.02 (d, J¼8.3 Hz, 1H, 4-H), 4.09 (d, J¼6.3 Hz, 1H, 3-H); 13C NMR
30
3.2.7.1. Compound 10a. White solid, mp: 115–117 ꢁC, [
(c 2.0, MeOH); 1H NMR (400 MHz, CD3OD),
a
]
þ59.27
D
d
: 1.32 (s, 3H, CH3),
(100 MHz, D2O) d: 27.1, 32.4, 34.5, 54.6, 60.0, 63.3, 69.8, 70.1, 76.1,
2.11 (s, 2H, 9-H), 2.63 (s, 3H, N-CH3), 2.88 (d, J¼11.4 Hz, 1H, 7-H),
2.94 (d, J¼12.2 Hz, 1H, 2-H), 3.04 (d, J¼11.4 Hz, 1H, 7-H), 3.25 (d,
J¼5.4 Hz, 1H, 2-H), 3.30 (m, 1H, 6-H), 3.43 (s, 1H, 5-H), 3.87
(d, J¼7.0 Hz, 1H, 4-H), 4.35 (dd, J¼3.4, 2.1 Hz, 1H, 3-H), 4.57 (d,
J¼11.7 Hz, 1H, PhCH2), 4.75 (d, J¼11.7 Hz, 1H, PhCH2), 7.27–7.36
77.7; HRMS (ESI): calcd for C10H21N2O3 (MþHþ): 217.1547, found:
217.1551.
Acknowledgements
(m, 5H, ArH); 13C NMR (100 MHz, CD3OD),
d: 21.3, 33.6, 46.3,
The financial supports from the National Natural Science
Foundation of China (NSFC) (20472015, 20672027), the Natural
Science Foundation of Hebei (2005000106, B2008000588), and
Open research fund of the State Key Laboratory of Natural and
Biomimetic Drugs, Peking University are gratefully acknowledged.
60.1, 61.4, 64.7, 70.7, 72.3, 77.5, 80.7, 87.8, 127.9–128.5, 138.5;
HRMS (ESI): calcd for C17H24N2O3 (Mþ): 304.1787, found:
304.1790.
31
3.2.7.2. Compound 10a1. Colorless syrup,
MeOH); 1H NMR (400 MHz, CD3OD),
[a
]
þ5.74 (c 2.0,
D
d
: 1.40 (s, 3H, CH3), 2.34 (s, 2H,
References and notes
9-H), 2.73 (s, 3H, N-CH3), 3.21 (d, J¼6.5 Hz, 1H, 7-H), 3.25 (d,
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2.5 Hz, 1H, 6-H), 3.63 (dd, J¼12.9, 5.8 Hz, 1H, 2-H), 3.79 (s, 1H, 5-H),
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compounds 3a and 5c, respectively, for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223 336033.
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