Concise and divergent total synthesis of swainsonine, 7-alkyl swainsonines, and 2,8a-diepilentiginosine via a chiral heterocyclic enaminoester intermediate

Article abstract of DOI:10.1016/j.tet.2008.03.080

The concise and divergent total syntheses of (-)-swainsonine, (-)-7-alkyl swainsonines, and (-)-2,8a-diepilentiginosine from a common chiral heterocyclic enaminoester intermediate in five-step sequences are presented. The highly efficient annulation reaction of the chiral heterocyclic enaminoester with various α,β-unsaturated carboxylates, and a straightforward carboxy inversion constituted the key features of the synthetic pathway. This work provides an example for divergent synthesis of different natural and unnatural polyhydroxylated indolizidines from a readily available platform.

Full text of DOI:10.1016/j.tet.2008.03.080

Tetrahedron 64 (2008) 5005–5012
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Concise and divergent total synthesis of swainsonine, 7-alkyl swainsonines,
and 2,8a-diepilentiginosine via a chiral heterocyclic enaminoester intermediate
*
Gao-Feng Shi, Jia-Qi Li, Xiao-Ping Jiang, Ying Cheng
Chemistry Department, Beijing Normal University, Beijing 100875, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The concise and divergent total syntheses of (ꢀ)-swainsonine, (ꢀ)-7-alkyl swainsonines, and (ꢀ)-2,8a-
diepilentiginosine from a common chiral heterocyclic enaminoester intermediate in five-step sequences
are presented. The highly efficient annulation reaction of the chiral heterocyclic enaminoester with
various a,b-unsaturated carboxylates, and a straightforward carboxy inversion constituted the key fea-
tures of the synthetic pathway. This work provides an example for divergent synthesis of different
natural and unnatural polyhydroxylated indolizidines from a readily available platform.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 16 January 2008
Received in revised form 19 March 2008
Accepted 25 March 2008
Available online 28 March 2008
Keywords:
Swainsonine
2,8a-Diepilentiginosine
Heterocyclic enaminoester
Polyhydroxylated indolizidine
Total synthesis
1. Introduction
Surprisingly, however, utilization of heterocyclic secondary en-
amines in the synthesis of polyhydroxylated indolizidine alkaloids
Polyhydroxylated indolizidine alkaloids1 such as (þ)-lentigino-
sine 1,2 (ꢀ)-2-epi-lentiginosine 2,3 (ꢀ)-swainsonine 3,4 and
(þ)-castanospermine 45 (Fig. 1) have been attracting enormous
attention since their isolation owing to their biological activities.
Lentiginosine, swainsonine, and castanospermine, for instance,
have been shown to inhibit various glycosidases.6 They show
significant anti-HIV,7 antimetastatic,8 immunoregulating,9 antitu-
mor-proliferative,10 and anticancer activities.11 Because of their
interesting and stereochemically rich structures, and also due to the
need of their analogues in the study of structure–activity re-
lationships, the interest in the synthesis of lentiginosine and
swainsonine remains undiminished. Numerous syntheses docu-
mented to date are based on carbohydrate starting materials or
asymmetric reactions using non-carbohydrate substrates.12 Al-
though some syntheses are efficient and useful, further de-
velopment of general and practical methods for the preparation of
natural and unnatural polyhydroxylated indolizidine products is of
great importance.
has remained largely unexplored. Very recently, we showed the
first example of the synthesis of polyhydroxylated indolizidine
derivatives from post-transformations of the fused N-heterocycles
derived from the annulation reaction of a dihydroxylated hetero-
cyclic secondary enamine.14 We envisioned that the fused N-het-
erocyclic intermediate would serve as the key platform for the
synthesis of naturally occurring indolizidines. Herein, we report the
concise and divergent synthesis of (ꢀ)-2,8a-diepilentiginosine,
(ꢀ)-swainsonine, and its 7-alkylated analogues starting from
a dihydroxylated chiral heterocyclic enaminoester.
2. Results and discussion
We startedour study with the total synthesis of (ꢀ)-swainsonine.
Retrosynthetically, the N-fused ring system of (ꢀ)-swainsonine
might be constructed by the annulation of either a five-membered
heterocyclic enaminoester 5 with an a,b-unsaturated component or
a six-membered heterocyclic enaminoester 6 with a two-carbon
Heterocyclic secondary enamines are versatile building blocks
in organic synthesis.13 As the bis-nucleophilic species, their annu-
lation reaction with bis-electrophiles have generated a variety of
N-fused heterocycles. Applications of heterocyclic secondary en-
amines in natural product synthesis have been reported.13
OH
OH
OH
OH
OH
OH
H
N
H
H
H
HO
HO
OH
OH
OH
N
4
N
1
N
3
2
(+)-Castanospermine
(+)-Lentiginosine
(-)-Swainsonine
(-)-2-Epilentiginosine
* Corresponding author. Tel.: þ86 1058805558; fax: þ86 1058802075.
E-mail address: ycheng2@bnu.edu.cn (Y. Cheng).
Figure 1. Some polyhydroxylated indolizidine alkaloids.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.080

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G.-F. Shi et al. / Tetrahedron 64 (2008) 5005–5012
OH
HO
OH
OH
+
OH
H
α,β−unsaturated
carboxylate
two-carbon
biselectrophile
+
OH
N
H
N
H
N
RO2C
CO2R
6
5
3
Figure 2. Retrosynthetical pathways using chiral heterocyclic enamine as the key intermediate.
bis-electrophilic reagent (Fig. 2). Having considered the stereo-
chemistry of (ꢀ)-swainsonine 3, and the availability of -erythronic
been scatteringly found in literature.17b,c,18 We applied the carboxy-
inversion reaction as the shortest route to introduce the 8-hydroxyl
group of swainsonine. Thus, acid 9, which was derived from the
hydrolysis of ester 8, was treated with m-chloroperbenzoic acid
(MCPBA) and dicyclohexylcarbodiimide (DCC) in dichloromethane
at 0 ꢁC. The resulting diacyl peroxide intermediate 10, without
isolation, was converted into 11A through the thermolytic rear-
rangement in toluene. Subsequent hydrolysis in the presence of
NaOH in methanol afforded 8-hydroxylated indolizinone 12A in
49% yield from acid 9. We accomplished the total synthesis of
(ꢀ)-swainsonine 3 after the reduction of 8-hydroxylindolizinone
12A with borane followed by hydrolysis under acidic conditions
(Scheme 1). The physical and spectral data of the synthetic com-
pound is in agreement with those reported for (ꢀ)-swainsonine.19
The stereochemistry of the carboxy-inversion merits comments.
The carboxy-inversion reaction has been proposed to proceed via
a caged radical or an ion-pair mechanism in the rearrangement of
diacyl peroxide to ester (see the conversion of 10 to 11A in Scheme
1).20 In many examples,17b,c,21 the carboxy-inversion reactions have
been shown to occur predominantly with retention of configura-
tion of the migrated group. That feature has been successfully ap-
plied in the total synthesis of some natural products such as
prostaglandins17b and widdrol.17c In sharp contrast to that docu-
mented in the literature, however, we found that the carboxy in-
version of acid 9 produced an alcohol 12A with the inversion of
configuration, since none of the epimer 12B was observed. Al-
though the detailed mechanism awaits further study, we proposed
that the rearrangement of diacyl peroxide 10 to ester 11 took place
from the less sterically hindered face of the fused heterocycle,
yielding 11A in a highly stereoselective manner.
D
acid g-lactone, in which the diol has the same absolute configura-
tions as that in (ꢀ)-swainsonine, we decided to choose the annu-
lation strategy using a five-membered heterocyclic enamine with
a a,b-unsaturated carboxylate. Another advantage of the choice is
that the enamine intermediate 5 might also act as the precursor for
2-epilentiginosine, as they have the identically configured vicinal
diol structure.
The isopropylidene-protected chiral heterocyclic enaminoester
7, namely (3S,4R)-3,4-isopropylidenedioxypyrrolidin-2-ylidene
acetate, was prepared in six steps from commercially available
D
-erythronic acid g-lactone based on the literature method.15
-Erythronic acid g-lactone can also be prepared in a large scale by
D
oxidation of the very cheap
D
-(ꢀ)-isoascorbic acid.16
In our previous work,14 we have shown the efficient synthesis of
octahydroindolizinone-8-carboxylate 8 from the annulation re-
action of 7 with methyl acrylate followed by highly diastereo-
selective hydrogenation (Scheme 1). The stereochemistry of C-1,
C-2, and C-8a of octahydroindolizinone 8 resembled that of the
natural (ꢀ)-swainsonine. The challenge now is to convert the
8-methoxycarbonyl group into the 8-hydroxyl group stereospecif-
ically. The ‘conventional’ transformation of an ester into a hydroxyl
group involves lengthy and tedious multistep reactions, which
give low overall yield. Apparently, a successful synthesis of
(ꢀ)-swainsonine requires an efficient and short functional group
transformation.
In 1965, Denney and Sherman17a reported a straightforward
transformation from a carboxyl group to a hydroxyl group, so-called
carboxy-inversion reaction.17 The reaction was proposed to proceed
via a diacyl peroxide intermediate, which afforded alcohol product
through thermolytic rearrangement followed by basic hydrolysis.
Despite its simplicity in operation, surprisingly, the straightforward
carboxy inversion has been overlooked. Its application has only
To further demonstrate the synthetic potential of heterocyclic
secondary enamine chiral building block 7, we then attempted the
synthesis of (ꢀ)-swainsonine analogues, which have an alkyl group
at 7-position. We have known that the annulation reaction of 7
O
O
CC6H4Cl
O
H
CO2CH3
O
CO2H
O
O
H
O
O
H
N
O
DCC,
H2C CHCO2CH3
MCPBA
O
O
O
NaOH
O
N
CH2Cl2,
N
N
H
ref. 14
0 °C to rt
CO2CH3
O
O
O
Toluene
reflux
O
7
8
9: 89%
10
O
OH
O
C6H4Cl
O
O
C6H4Cl
OH
O
HO
H
H
N
O
O
H
H
N
O
O
HO
N
N
O
O
11A
11B
12B: no observed
NaOH,
CH3OH, rt
OH
H
O
OH
HO
OH
H
N
OH
1. BH3-THF
2. HCl
H
O
HO
N
O
OH
N
3: 71%
12A: 49% from 9
(-)-swainsonine
Scheme 1. Synthesis of (ꢀ)-swainsonine from enaminoester 7 and methyl acrylate.

G.-F. Shi et al. / Tetrahedron 64 (2008) 5005–5012
5007
with methyl crotonate and the subsequent hydrogenation gave rise
to the two diastereoisomeric (7S)- and (7R)-methylindolizinones
13A and 13B (13A:13Bw3:2), and the major product 13A has a cis
relationship between the methyl and dioxy substituents.14 Thus,
indolizinones 13A and 13B were prepared from 7 and methyl
crotonate, and were converted, respectively, into acids 14A and 14B
by basic hydrolysis. Carboxy-inversion reaction of 14A or 14B under
identical conditions as that for acid 9 produced alcohols 15A or 15B
in 54% or 56% yield, respectively. The configuration of 15B was
determined by X-ray diffraction analysis (Fig. 3),22 which demon-
strated unambiguously that the conversion of the carboxy to the
hydroxyl group has once again been accompanied with the in-
version of the configuration. The stereochemistry of 15B further
supported our assumption that, to avoid steric hindrance, the
rearrangement of diacyl peroxide to m-chlorobenzoate took place
predominantly from the opposite face of isopropylidenedioxy
substituent (convex face). Reduction of 7-methyl-8-hydroxyl-
indolizinones 15A and 15B with borane followed by acidic hy-
drolysis gave two isomeric (ꢀ)-7-methyl swainsonines 16A and 16B
in 88% and 78% yields, respectively (Scheme 2).
O
O
N
H
CO2CH3
ref. 14
7
CO2CH3
CO2CH3
O
O
H
H
CH3
CH3
O
O
+
N
N
O
O
13B
13A
(3:2)
NaOH
CO2H
NaOH
CO2H
O
O
H
H
N
CH3
CH3
O
O
N
O
O
14B: 84%
14A: 88%
DCC,
MCPBA
DCC,
MCPBA
Since the annulation reaction of enaminoester 7 with methyl
crotonate gave two isomeric hexahydroindolizinones with low
diastereoselectivity, a highly selective synthesis of 7-alkyl swain-
sonines was then explored by taking the advantage of highly
diastereoselective hydrogenation reaction. Thus, tetrahydro-5-
indolizinone 17 or 18 was prepared in 88% or 85% yield from the
reaction of 7 with methyl 4-ethyl or 4-isopropyl allenoate. Hydro-
genation of 17 or 18 afforded the fully cis-substituted octa-
hydroindolizinone 19 in 93% or 20 in 97% yield as a single
diastereoisomer. Through a series of reactions, including hydrolysis,
carboxy inversion, reduction of the amide, and deprotection, the
indolizinone 19 and 20 were transformed into 7-propyl swainso-
nine 25 and 7-isobutyl swainsonine 26, respectively (Scheme 3).
After the successful synthesis of swainsonine and 7-alkyl
swainsonine derivatives from enaminoester 7, we then turned our
attention to the synthesis of epi-lentiginosine. The synthesis re-
quired the removal of the 8-carboxylate group of indolizinone 8,
however, the excision with aqueous HBr (40%) under refluxing was
found inefficient. Since decarboxylation of an aromatic acid is
generally more efficient than an aliphatic one. Therefore, tetrahy-
droindolizinone-8-carboxylate 27 was prepared in 83% yield from
the reaction of enaminoester 7 with methyl propiolate catalyzed by
OH
OH
O
O
H
H
N
CH3
CH3
O
O
N
O
O
15A: 54%
15B: 56%
1. BH3-THF
2. HCl
1. BH3-THF
2. HCl
OH
OH
HO
H
HO
H
CH3
CH3
HO
N
HO
N
16A: 88%
16B: 78%
Scheme 2. Synthesis of (7S) and (7R)-7-methyl swainsonines 16A and 16B from
enaminoester 7 and methyl crotonate.
NaOMe, and then was decarboxylated in refluxing aqueous HBr
(40%) to form 1,2-dihydroxyl-1,2,3,5-tetrahydro-5-indolizinone 28
in 79% yield (Scheme 4). Protection of 1,2-dihydroxyl-5-indolizi-
none 28 followed by PtO2-catalyzed hydrogenation of 1,2-iso-
propylidenedioxy-5-indolizinone 29 under 10–15 atm of H2
afforded 90% yield of octahydroindolizinone 30. Reduction of 30
using fresh prepared borane and deprotection with acidic hydro-
lysis gave 2,8a-diepilentiginosine 31 in 74% yield (Scheme 4).
In conclusion, on the basis of our previous work,14 we have
provided the concise and stereoselective synthesis of (ꢀ)-swain-
sonine, (ꢀ)-7-alkyl swainsonines, and (ꢀ)-2,8a-diepilentiginosine
from a chiral heterocyclic enaminoester intermediate in five steps,
which was readily prepared from commercially available D-eryth-
ronic acid g-lactone in six steps. The highly efficient annulation
reaction of heterocyclic enaminoester with various a,b-unsaturated
carboxylates and a straightforward carboxy-inversion reaction
constituted the key features of the synthetic pathway for
(ꢀ)-swainsonine and its 7-alkylated analogues. The easy availabil-
ity of chiral heterocyclic enaminoester, very cheap reagents and
reactants, and simple chemical manipulations render our approach
powerful and practical in the synthesis of diverse natural and
unnatural polyhydroxylated indolizidines.
3. Experimental section
3.1. General
Melting points are uncorrected. 1H NMR (500, 400 or 300 MHz)
and 13C NMR (125 or 100 MHz) spectra were recorded in the
Figure 3. The ORTEP drawing of single crystal structure of 15B.

5008
G.-F. Shi et al. / Tetrahedron 64 (2008) 5005–5012
CO2CH3
O
CO2CH3
O
H
N
O
O
CH2R
CH2R
O
O
RHC
C
CHCO2CH3
NaH
H2/10-15 atm
N
Pd-C
N
H
O
O
CO2CH3
17: R = CH2CH3, 88%
19: R = CH2CH3, 93%
20: R = CH(CH3)2, 97%
7
18: R = CH(CH3)2, 85%
NaOH,
CH3OH
CO2H
OH
O
H
N
O
H
N
OH
CH2R
CH2R
HO
H
DCC,
MCPBA
1. BH3-THF
2. HCl
O
O
CH2R
HO
N
O
O
23: R = CH2CH3, 61%
24: R = CH(CH3)2, 60%
21: R = CH2CH3, 93%
22: R = CH(CH3)2, 95%
25: R = CH2CH3, 86%
26: R = CH(CH3)2, 66%
Scheme 3. Synthesis of (7S)-7-propyl or 7-iso-butyl substituted swainsonine 25 or 26 from enaminoester 7 and methyl 4-ethyl or 4-iso-propylallenoate.
solvent as indicated. THF was distilled from sodium benzophenone
ketyl. Petroleum ether refers to that of bp 60–90 ꢁC. The
key intermediate, cis-(3S,4R)-3,4-isopropylidenedioxypyrrolidin-2-
ylidene acetate 7, was synthesized following the Buchanan’s
3.2.1.1. Methyl (1S,2R)-1,2-O-isopropylidenedioxy-7-propyl-1,2,3,5-
tetrahydro-5-indolizinone-8-carboxylate 17. Yield 88%, mp 66–
67 ꢁC, [a]D20 ꢀ191.9 (c 0.59, CHCl3). IR v (cmꢀ1) 1714, 1668; 1H NMR
(500 MHz, CDCl3): 6.40 (s, 1H), 5.90 (d, J¼5.3 Hz, 1H), 4.94 (br s, 1H),
4.46 (d, J¼14.0 Hz, 1H), 4.09 (br d, J¼10.6 Hz, 1H), 3.90 (s, 3H), 2.84–
2.90 (m, 1H), 2.56–2.62 (m, 1H), 1.55–1.59 (m, 2H), 1.42 (s, 3H), 1.24
(s, 3H), 0.97 (t, J¼7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3): 165.8,
161.0, 155.7, 151.7, 118.9, 112.6, 109.6, 82.6, 74.7, 52.8, 52.1, 35.5, 27.2,
26.0, 23.0, 13.8. MS (EI): 43 (100), 202 (62), 218 (50), 250 (55), 275
(47), 307 (Mþ, 33%). Anal. Calcd for C16H21NO5: C 62.53, H 6.89, N
4.56; Found: C 62.14, H 7.29, N 4.40.
method15 from 2,3-O-isopropylidene-
pared from
-erythronic acid g-lactone.16
D-erythrose that was pre-
D
3.2. Total synthesis of swainsonine 3, 7-alkyl swainsonines
16A, 16B, 25, and 26
3.2.1. General procedure for the reaction of heterocyclic enamine 7
with methyl 4-alkylallenic carboxylates
3.2.1.2. Methyl (1S,2R)-1,2-O-isopropylidenedioxy-7-isobutyl-1,2,3,5-
tetrahydro-5-indolizinone-8-carboxylate 18. Yield 85%, mp 128–
129 ꢁC, [a]D20 ꢀ232 (c 0.4, CHCl3). IR v (cmꢀ1) 1731, 1661; 1H NMR
(500 MHz, CDCl3): 6.35 (s, 1H), 5.90 (d, J¼5.5 Hz, 1H), 4.94 (t,
J¼4.9 Hz, 1H), 4.46 (d, J¼14.3 Hz, 1H), 4.09 (dd, J¼14.3, 4.5 Hz, 1H),
3.89 (s, 3H), 2.95 (dd, J¼13.1, 6.0 Hz, 1H), 2.33 (dd, J¼13.0, 8.1 Hz,
1H), 1.73–1.78 (m, 1H), 1.41 (s, 3H), 1.24 (s, 3H), 0.95 (d, J¼6.6 Hz,
3H), 0.88 (d, J¼6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): 165.9, 160.8,
154.7, 151.7, 119.9, 112.6, 109.8, 82.6, 74.7, 52.8, 52.1, 42.6, 29.0, 27.2,
26.0, 22.7, 22.0. MS (TOF-EI): 232 (80), 264 (95), 274 (90), 289 (100),
321 (Mþ, 85%). Anal. Calcd for C17H23NO5: C 63.54, H 7.21, N 4.36;
Found: C 63.43, H 7.51, N 4.64.
Under nitrogen atmosphere and at 0 ꢁC, a solution of hetero-
cyclic enamine 715a (1 mmol) in dry THF (10 mL) was added drop-
wise to the suspension of NaH (0.5 mmol, 50% in mineral oil) in THF
(10 mL), and the resulting mixture was stirred until no evolution of
hydrogen gas. To this mixture, the solution of allenic carboxylate
(methyl 4-ethyl or 4-isopropylallenic carboxylate) (1.5 mmol) in
THF (10 mL) was added dropwise at 0 ꢁC. The reaction mixture was
stirred for 1 h at 0 ꢁC and for another 4 h at ambient temperature.
After removal of the solvent, the residue was chromatographed on
a silica gel column eluting with a mixture of petroleum ether and
ethyl acetate (4:1 to 1:1) to give tetrahydro-5-indolizinones 17 and
18, respectively.
3.2.2. General procedure for hydrogenation of the tetrahydro-5-
indolizinones 17 and 18
CO2CH3
O
O
O
The tetrahydro-5-indolizinone 17 or 18 (1 mmol) was mixed
with palladium on activated carbon (10%, 0.5 g) in methanol
(20 mL). The reaction mixture was stirred under hydrogen atmo-
sphere (10–15 atm) for 30–72 h at 40–50 ꢁC. After removal of the
catalyst and solvent, the octahydro-5-indolizinone 19 or 20 was
isolated by chromatography on a silica gel column eluting with
ethyl acetate and acetone (9:1).
HC CCO2CH3
MeOH/reflux
NaOMe
O
N
N
H
O
CO2CH3
7
27: 83%
40% HBr
O
reflux
HO
O
(CH3)2C(OCH3)2
TsOH
N
HO
HO
N
3.2.2.1. Methyl (1S,2R,7S,8S,8aR)-1,2-O-isopropylidenedioxy-7-pro-
pyl-octahydro-5-indolizinone-8-carboxylate 19. Yield 93%, mp 200–
202 ꢁC, [a]2D0 ꢀ67.4 (c 0.38, CHCl3) [lit.14 mp 204–205 ꢁC, [a]2D0 ꢀ68.2
(c 0.245, CHCl3)].
O
O
29: 89%
H2/10-15 atms
PtO2
28: 79%
HO
H
N
O
H
1. BH3-THF
2. HCl
3.2.2.2. Methyl (1S,2R,7S,8S,8aR)-1,2-O-isopropylidenedioxy-7-iso-
butyl-octahydro-5-indolizinone-8-carboxylate 20. Yield 97%, mp
180–182 ꢁC, [a]D20 ꢀ61.7 (c 0.235, CHCl3). IR v (cmꢀ1) 1731, 1638,
1629; 1H NMR (500 MHz, CDCl3): 4.76–4.80 (m, 2H), 4.14 (d,
J¼13.6 Hz, 1H), 3.68–3.70 (m, 1H), 3.67 (s, 3H), 3.28 (dd, J¼13.6,
4.7 Hz, 1H), 3.00 (t, J¼3.8 Hz, 1H), 2.56 (dd, J¼17.5, 12.2 Hz, 1H), 2.40
(dd, J¼17.7, 6.2 Hz, 1H), 2.18–2.23 (m, 1H), 1.69–1.74 (m, 1H), 1.40 (s,
O
N
31: 74%
2,8a-diepilentiginosine
O
30: 90%
Scheme 4. Synthesis of (ꢀ)-2,8a-diepilentiginosine from enaminoester 7 and methyl
propiolate.

G.-F. Shi et al. / Tetrahedron 64 (2008) 5005–5012
5009
3H), 1.30 (s, 3H), 1.13–1.22 (m, 2H), 0.90 (d, J¼6.4 Hz, 3H), 0.89 (d,
J¼6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3): 170.9, 169.5, 112.7, 80.8,
77.3, 62.9, 51.2, 50.3, 42.3, 34.7, 34.4, 25.4, 24.6, 24.4, 22.7, 22.3. MS
(EI): 250 (61), 326 (Mþ1, 100%). Anal. Calcd for C17H27NO5: C 62.75,
H 8.36, N 4.30; Found: C 63.27, H 8.32, N 4.29.
3.2.3.5. (1S,2R,7S,8S,8aR)-1,2-O-Isopropylidenedioxy-7-isobutyl-octa-
hydro-5-indolizinone-8-carboxylic acid 22. Yield 95%, mp 202–
204 ꢁC, [a]2D0 ꢀ17.8 (c 0.325, CHCl3). IR v (cmꢀ1) 2543–2750 (br),
1719, 1605; 1H NMR (500 MHz, CDCl3): 4.76 (t, J¼5.4 Hz,1H), 4.69 (t,
J¼4.4 Hz, 1H), 4.25 (d, J¼13.6 Hz, 1H), 3.77 (dd, J¼10.3, 4.0 Hz, 1H),
3.17 (dd, J¼13.6, 4.9 Hz, 1H), 2.67–2.75 (m, 2H), 2.21–2.23 (m, 1H),
2.04 (dd, J¼17.5, 12.0 Hz, 1H), 1.64–1.69 (m, 1H), 1.44 (s, 3H), 1.33 (s,
3H), 1.31–1.34 (m, 2H), 0.93 (d, J¼6.5 Hz, 3H), 0.86 (d, J¼6.5 Hz, 3H);
13C NMR (125 MHz, CDCl3): 175.5, 169.0, 112.3, 79.7, 77.4, 62.7, 50.3,
46.2, 42.8, 36.3, 33.8, 26.4, 24.69, 24.68, 24.0, 21.0. HRMS (TOF-ESI):
312.1805, C16H26NO5 required 312.1811 (Mþ1).
3.2.3. Hydrolysis of methyl octahydro-5-indolizinone-8-
carboxylates 8, 13A, 13B, 19, and 20.
The octahydro-5-indolizinone-8-carboxylate 8,14 13A,14 13B,14
19 or 20 (1 mmol) was mixed with aqueous sodium hydroxide (20%,
2 mL) in ethanol (95%, 15 mL). The mixture was stirred for 6 h at
room temperature and then was acidified with HCl (6 M) to pH
w3–4. After evaporating the solvents under vacuum, the residue
was chromatographed on a silica gel column to give acid 9,14A,14B,
21 or 22 (eluting solvents: from pure ethyl acetate to ethyl acetate/
methanol¼9:1).
3.2.4. Conversion of acids 9, 14A, 14B, 21, and 22 to alcohols 12A,
15A, 15B, 23, and 24 via carboxy-inversion reaction
At 0 ꢁC and under nitrogen atmosphere, the acid 9, 14A, 14B, 21
or 22 (1 mmol) was mixed with m-chloroperbenzoic acid
(1.8 mmol) in CH2Cl2 (15 mL) (note: 2 mL of DMF was used as co-
solvent for acid 9), and then the solution of dicyclohex-
ylcarbodiimide (1.8 mmol) in CH2Cl2 (15 mL) was added dropwise
to the reaction mixture. The mixture was stirred at 0 ꢁC for 2 h
and then at room temperature for 4 h. After removal of the in-
soluble by-product dicyclohexyl urea (DCU) and the solvent
dichloromethane, the residue was added toluene (20 mL) and was
heated in refluxing toluene for 12 h. The toluene was evaporated
under vacuum and the residue was dissolved in ethanol (20 mL)
and was treated with aqueous NaOH (20%, 2 mL) for 4 h. After
removal of the solvents, the product 12A, 15A, 15B, 23 or 24 was
isolated by chromatography on a silica gel column eluting with
ethyl acetate.
3.2.3.1. (1S,2R,8S,8aR)-1,2-O-Isopropylidenedioxy-octahydro-5-indol-
izinone-8-carboxylic acid 9. Yield 89%, mp >250 ꢁC, [a]D20 ꢀ21.4 (c
0.21, DMSO). IR v (cmꢀ1) 2730–3250 (br), 1724, 1619; 1H NMR
(500 MHz, DMSO-d6): 4.70 (t, J¼1.9 Hz, 2H), 3.92 (d, J¼13.3 Hz, 1H),
3.65 (dd, J¼10.4, 2.8 Hz, 1H), 3.02 (dd, J¼13.0, 2.4 Hz, 1H), 2.70 (dt,
J¼10.2, 3.2 Hz, 1H), 2.24–2.29 (m, 2H), 2.09–2.13 (m, 1H), 1.80–1.85
(m, 1H), 1.30 (s, 3H), 1.25 (s, 3H); 13C NMR (125 MHz, DMSO-
d6þCD3OD): 173.8, 169.0, 111.2, 80.3, 77.5, 61.6, 49.7, 39.1, 30.4, 25.6,
24.6, 23.7; MS (EI): 45 (100), 55 (83), 256 (Mþ1, 20%). Anal. Calcd for
C
12H17NO5: C 56.46, H 6.71, N 5.49; Found: C 56.52, H 7.15, N 5.55.
3.2.3.2. (1S,2R,7S,8S,8aR)-1,2-O-Isopropylidenedioxy-7-methyl-octa-
hydro-5-indolizinone-8-carboxylic acid 14A. Yield 88%, mp 216–
218 ꢁC, [a]2D0 ꢀ18.1 (c 0.215, CHCl3). IR v (cmꢀ1) 2730–3250 (br),
1720, 1614; 1H NMR (500 MHz, CDCl3): 4.77 (s, 1H), 4.70 (t,
J¼4.6 Hz, 1H), 4.26 (d, J¼13.5 Hz, 1H), 3.77 (dd, J¼10.4, 3.9 Hz, 1H),
3.16 (dd, J¼13.6, 4.8 Hz, 1H), 2.68 (dt, J¼10.9, 3.3 Hz, 1H), 2.61 (dd,
J¼17.4, 4.5 Hz, 1H), 2.25 (br, 1H), 2.14 (dd, J¼17.3, 12.2 Hz, 1H), 1.44
(s, 3H), 1.33 (s, 3H), 1.15 (d, J¼4.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3): 175.4,168.7,112.3, 79.7, 77.5, 62.7, 50.3, 46.6, 39.0, 31.4, 26.4,
24.7, 19.1. MS (EI): 166 (47), 270 (Mþ1, 100%). Anal. Calcd for
3.2.4.1. (1S,2R,8R,8aR)-1,2-O-Isopropylidenedioxy-8-hydroxyl-octa-
hydro-5-indolizinone 12A. Yield 49%, mp 123–125 ꢁC, [a]D20 þ12.8 (c
0.305, CHCl3). IR v (cmꢀ1) 3373 (br), 1606; 1H NMR (500 MHz,
CDCl3): 4.84 (t, J¼5.5 Hz, 1H), 4.77 (t, J¼5.3 Hz, 1H), 4.22 (d,
J¼13.9 Hz, 1H), 4.16–4.18 (m, 1H), 3.36 (dd, J¼8.0, 4.5 Hz, 1H), 3.16
(dd, J¼13.5, 4.6 Hz, 1H), 2.54 (dd, J¼17.2, 5.0 Hz, 1H), 2.42–2.49 (m,
1H), 2.14–2.17 (m, 1H), 2.04 (br, 1H), 1.87–1.93 (m, 1H), 1.45 (s, 3H),
1.36 (s, 3H); 13C NMR (125 MHz, CDCl3): 168.3,112.2, 79.8, 77.6, 66.1,
65.6, 50.6, 29.74, 29.69, 26.3, 24.6. HRMS (FT-ICR): 228.1226,
C
13H19NO5: C 57.98, H 7.11, N 5.20; Found: C 57.64, H 7.07, N 5.01.
C11H18NO4 required 228.1230 (Mþ1).
3.2.3.3. (1S,2R,7R,8S,8aR)-1,2-O-Isopropylidenedioxy-7-methyl-octa-
hydro-5-indolizinone-8-carboxylic acid 14B. Yield 84%, mp 283–
284 ꢁC, [a]2D0 ꢀ17.6 (c 0.295, CH3OH). IR v (cmꢀ1) 2750–3250 (br),
1724, 1625; 1H NMR (500 MHz, CDCl3): 4.87 (t, J¼5.8 Hz, 1H), 4.77
(t, J¼5.2 Hz, 1H), 4.34 (d, J¼13.5 Hz, 1H), 3.75 (dd, J¼11.3, 4.1 Hz,
1H), 3.18 (dd, J¼10.8, 3.6 Hz, 1H), 3.12 (dd, J¼13.6, 4.6 Hz, 1H), 2.75
(br, 1H), 2.64 (dd, J¼17.4, 5.5 Hz, 1H), 2.36 (d, J¼17.4 Hz, 1H), 1.42 (s,
3H), 1.34 (s, 3H), 1.07 (d, J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3):
175.2, 167.9, 111.9, 80.5, 77.7, 57.5, 50.2, 42.5, 38.3, 29.3, 26.4, 24.7,
15.6. MS (EI): 69 (100), 108 (82), 142 (69), 166 (94), 194 (95), 211
(70), 254 (65), 269 (Mþ, 44%). Anal. Calcd for C13H19NO5: C 57.98, H
7.11, N 5.20; Found: C 57.99, H 7.50, N 5.17.
3.2.4.2. (1S,2R,7S,8R,8aR)-1,2-O-Isopropylidenedioxy-8-hydroxyl-7-
methyl-octahydro-5-indolizinone 15A. Yield 54%, mp 189–190 ꢁC,
[a]D20 ꢀ7.2 (c 0.195, CHCl3). IR v (cmꢀ1) 3360, 1624; 1H NMR
(500 MHz, CDCl3): 4.83 (t, J¼4.7 Hz, 1H), 4.78 (t, J¼5.6 Hz, 1H), 4.20
(d, J¼13.6 Hz, 1H), 3.74 (t, J¼9.2 Hz, 1H), 3.37 (dd, J¼8.7, 4.5 Hz, 1H),
3.17 (dd, J¼13.5, 4.9 Hz, 1H), 2.58 (dd, J¼17.0, 4.8 Hz, 1H), 2.12 (dd,
J¼16.9, 12.1 Hz, 1H), 1.92 (br, 1H), 1.46 (s, 3H), 1.36 (s, 3H), 1.13 (d,
J¼6.1 Hz, 3H); 13C NMR (125 MHz, D2O): 171.5, 112.2, 79.2, 77.6,
69.2, 65.2, 50.2, 37.3, 33.9, 25.4, 23.7, 15.9. HRMS (FT-ICR): 242.1388,
C12H20NO4 required 242.1387 (Mþ1).
3.2.4.3. (1S,2R,7R,8R,8aR)-1,2-O-Isopropylidenedioxy-8-hydroxyl-7-
methyl-octahydro-5-indolizinone 15B. Yield 54%, mp 167–168 ꢁC,
[a]D20 ꢀ24 (c 0.225, CHCl3). IR v (cmꢀ1) 3440, 1626; 1H NMR
(300 MHz, DMSO-d6): 4.65–4.71 (m, 2H), 3.94 (dd, J¼7.2, 3.6 Hz,
1H), 3.86 (d, J¼13.1 Hz, 1H), 3.27 (dd, J¼6.9, 4.6 Hz, 1H), 2.96 (dd,
J¼12.6, 2.2 Hz, 1H), 2.25 (dd, J¼18.2, 6.1 Hz, 1H), 2.03–2.10 (m,
2H), 1.27 (s, 3H), 1.25 (s, 3H), 0.92 (d, J¼6.7 Hz, 3H); 13C NMR
(125 MHz, CDCl3) 168.2, 112.1, 80.0, 77.7, 67.1, 62.3, 50.4, 36.9,
32.6, 26.4, 24.7, 13.5. HRMS (TOF-EI): 241.1317, C12H19NO4 required
241.1314.
3.2.3.4. (1S,2R,7S,8S,8aR)-1,2-O-Isopropylidenedioxy-7-propyl-octa-
hydro-5-indolizinone-8-carboxylic acid 21. Yield 93%, mp 189–
191 ꢁC, [a]D20 ꢀ15.6 (c 0.32, CHCl3). IR v (cmꢀ1) 2877–3250 (br),1720,
1608; 1H NMR (500 MHz, CDCl3): 4.76 (t, J¼5.2 Hz, 1H), 4.68 (t,
J¼5.2 Hz, 1H), 4.25 (d, J¼13.6 Hz, 1H), 3.75 (dd, J¼10.3, 3.9 Hz, 1H),
3.16 (dd, J¼13.6, 5.0 Hz, 1H), 2.78 (t, J¼10.7 Hz, 1H), 2.65 (dd, J¼17.2,
4.5 Hz, 1H), 2.18–2.22 (m, 1H), 2.09 (dd, J¼17.1, 11.8 Hz, 1H), 1.55–
1.58 (m, 1H), 1.48–1.52 (m, 1H), 1.45 (s, 3H), 1.34 (s, 3H), 1.28–1.36
(m, 2H), 0.94 (t, J¼7.2 Hz, 1H); 13C NMR (125 MHz, CDCl3): 175.7,
168.8, 112.3, 79.8, 77.5, 62.7, 50.3, 45.7, 36.2, 35.8, 35.5, 26.4, 24.7,
19.2,14.0. MS (EI): 84 (100), 96 (70), 141 (55),195 (55), 221 (55), 297
(Mþ, 20%). Anal. Calcd for C15H23NO5: C 60.59, H 7.80, N 4.71;
Found: C 60.39, H 7.81, N 4.69.
3.2.4.4. (1S,2R,7S,8R,8aR)-1,2-O-Isopropylidenedioxy-8-hydroxyl-7-
propyl-octahydro-5-indolizinone 23. Yield 61%, mp 141–143 ꢁC,
[a]20 þ21.8 (c 0.165, CHCl3). IR v (cmꢀ1) 3338, 1606; 1H NMR

5010
G.-F. Shi et al. / Tetrahedron 64 (2008) 5005–5012
(500 MHz, CDCl3): 4.83 (t, J¼5.8 Hz, 1H), 4.77 (t, J¼5.2 Hz, 1H), 4.20
(d, J¼13.5 Hz, 1H), 3.80 (t, J¼9.5 Hz, 1H), 3.36 (dd, J¼8.6, 4.4 Hz, 1H),
3.17 (dd, J¼13.5, 4.8 Hz, 1H), 2.64 (dd, J¼17.5, 5.1 Hz, 1H), 2.06 (dd,
J¼17.3, 11.8 Hz, 1H), 1.94–1.96 (m, 1H), 1.81–1.88 (m, 1H), 1.81 (br,
1H), 1.48–1.51 (m, 1H), 1.45 (s, 3H), 1.36 (s, 3H), 1.28–1.32 (m, 1H),
1.16–1.22 (m, 1H), 0.96 (t, J¼7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3): 168.4, 112.2, 79.8, 77.7, 69.5, 65.8, 50.5, 39.1, 36.0, 33.5, 26.4,
24.7, 19.3, 14.2. MS (EI) 68 (100), 84 (72), 269 (Mþ, 22%). Anal. Calcd
for C14H23NO4: C 62.43, H 8.61, N 5.20; Found: C 61.98, H 8.85, N
4.95.
3.2.5.3. (7R)-7-Methyl swainsonine 16B. Yield 78%, mp 180–181 ꢁC,
[a]D20 ꢀ80 (c 0.145, CH3OH). IR v (cmꢀ1) 3425, 3378; 1H NMR
(500 MHz, D2O): 4.21–4.24 (m,1H), 4.05 (dd, J¼5.8, 3.5 Hz,1H), 3.85
(dd, J¼10.1, 5.2 Hz, 1H), 2.73 (dd, J¼11.1, 2.2 Hz, 1H), 2.56 (br dd,
J¼11.4, 2.0 Hz, 1H), 2.48 (dd, J¼10.9, 8.1 Hz, 1H), 2.14 (dd, J¼10.1,
3.1 Hz, 2H), 2.09–2.11 (m, 1H), 1.64 (tt, J¼13.4, 4.5 Hz, 1H), 1.45 (dd,
J¼14.0, 2.0 Hz, 1H), 0.82 (d, J¼7.2 Hz, 3H); 13C NMR (125 MHz, D2O):
69.5, 68.7, 68.1, 64.9, 59.9, 45.7, 31.4, 29.3, 10.2. HRMS (TOF-ESI):
188.1316, C9H18NO3 required 188.1287 (Mþ1).
3.2.5.4. (7S)-7-Propyl swainsonine 25. Yield 86%, mp 119–122 ꢁC,
[a]2D0 ꢀ12.1 (c 0.865, CH3OH). IR v (cmꢀ1) 3423; 1H NMR (500 MHz,
D2O): 4.22–4.25 (m, 1H), 4.12 (dd, J¼5.8, 3.6 Hz, 1H), 3.33 (t,
J¼9.7 Hz, 1H), 2.83 (br d, J¼10.5 Hz, 1H), 2.77 (d, J¼11.5 Hz, 1H), 2.47
(br t, J¼9.0 Hz, 1H), 1.92–1.97 (m, 2H), 1.71 (br d, J¼11.0 Hz, 1H),
1.53–1.59 (m, 1H),1.26–1.32 (m, 1H),1.17–1.22 (m, 1H),1.02–1.13 (m,
3H), 0.75 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, D2O): 72.3, 69.9,
69.5, 69.0, 60.2, 51.4, 41.9, 33.2, 28.4, 19.0, 13.6. HRMS (TOF-EI):
215.1523, C11H21NO3 required 215.1521.
3.2.4.5. (1S,2R,7S,8R,8aR)-1,2-O-Isopropylidenedioxy-8-hydroxyl-7-
isobutyl-octahydro-5-indolizinone 24. Yield 60%, mp 170–173 ꢁC,
[a]20 þ12.9 (c 0.34, CHCl3). IR v (cmꢀ1) 3322, 1606; 1H NMR
(500 MHz, CDCl3): 4.83 (t, J¼5.4 Hz, 1H), 4.78 (t, J¼5.4 Hz, 1H), 4.20
(d, J¼13.5 Hz, 1H), 3.76 (t, J¼9.0 Hz, 1H), 3.38 (dd, J¼8.4, 4.3 Hz, 1H),
3.18 (dd, J¼13.5, 4.6 Hz, 1H), 2.63–2.67 (m, 1H), 2.16 (br, 1H), 2.01–
2.06 (m, 2H), 1.66–1.70 (m, 2H), 1.45 (s, 3H), 1.36 (s, 3H), 1.11 (t,
J¼9.3 Hz,1H), 0.97 (d, J¼5.8 Hz, 3H), 0.89 (d, J¼5.7 Hz, 3H); 13C NMR
(125 MHz, CDCl3): 168.3, 112.2, 79.8, 77.7, 69.7, 65.8, 50.5, 40.9, 37.1,
36.1, 26.4, 24.7, 24.1, 21.1. MS (EI): 168 (90), 208 (94), 284 (Mþ,
100%). Anal. Calcd for C15H25NO4: C 63.58, H 8.89, N 4.94; Found: C
63.29, H 9.06, N 4.98.
3.2.5.5. (7S)-7-Isobutyl swainsonine 26. Yield 66%, mp 114–116 ꢁC,
[a]2D0 ꢀ21.3 (c 0.32, CH3OH). IR v (cmꢀ1) 3396; 1H NMR (500 MHz,
D2O): 4.20–4.24 (m, 1H), 4.11 (dd, J¼5.9, 3.6 Hz, 1H), 3.26 (t,
J¼9.7 Hz,1H), 2.79 (br d, J¼11.2 Hz, 1H), 2.75 (dd, J¼11.1, 2.2 Hz, 1H),
2.42 (dd, J¼10.9, 8.0 Hz, 1H), 1.90 (br d, J¼11.5 Hz, 1H), 1.85 (dd,
J¼9.5, 3.3 Hz, 1H), 1.73 (br d, J¼12.0 Hz, 1H), 1.52–1.57 (m, 1H), 1.38
(dt, J¼13.3, 2.9 Hz,1H),1.20–1.26 (m,1H), 0.93–1.01 (m, 2H), 0.76 (d,
J¼6.6 Hz, 3H), 0.69 (d, J¼6.5 Hz, 3H); 13C NMR (125 Hz, D2O): 72.2,
70.3, 69.4, 68.9, 60.1, 51.3, 40.8, 40.1, 28.6, 24.4, 23.6, 20.6. HRMS
(TOF-EI): 229.1681, C12H23NO3 required 229.1678.
3.2.5. Preparation of swainsonine and 7-alkyl swainsonines from
reduction of 8-hydroxyl-octahydro-5-indolizinone
At 0 ꢁC and under nitrogen atmosphere, the solution of borane
THF complex (3 mmol, 1 M in THF) was added dropwise to the 8-
hydroxyl-octahydro-5-indolizinone 12A, 15A, 15B, 23 or 24
(0.5 mmol) in THF (20 mL). The reaction mixture was stirred at 0 ꢁC
for 1 h and then at room temperature for 2–5 h. The reaction was
quenched by adding methanol (5 mL) until no hydrogen evolution.
After removal of the solvent, the residue was dissolved in methanol
(20 mL) and refluxed for 6 h to decompose the boron complex of
product. The volatiles were removed again under vacuum, and the
3.3. Total synthesis of 2,8a-diepilentiginosine from
heterocyclic enaminoester 7 and ethyl propiolate
3.3.1. Preparation of tetrahydro-5-indolizinone-8-carboxylate 27
from the reaction of enaminoester 7 with methyl propiolate
pure
1,2-O-isopropylidenedioxy-8-hydroxyoctahydroindolizine
(isopropylidene-protected swainsonine or 7-alkyl swainsonine)
was isolated by chromatography on a neutral aluminum oxide
column eluting with ethyl acetate. Deprotection procedure was
furnished with 6 N HCl (1 mL) in THF (2 mL) within 10 h at room
temperature. The acidic reaction mixture was basified using
Na2CO3 powder to pH w8–9, and then concentrated under vacuum
to dryness. The (ꢀ)-swainsonine or (ꢀ)-7-alkyl swainsonine was
isolated from repeating extraction of inorganic salts with
dichloromethane (10ꢂ5 mL) and acetone (10ꢂ5 mL) and purified
by recrystallization.
The solution of enaminoester 7 (1 mmol) and methyl propiolate
(4 mmol) in methanol (20 mL) was heated to reflux in a sealed
thick-wall tube for 16 h. To this solution, NaOMe (100 mg) was
added and the mixture was then refluxed for another 1 h. After
removal of methanol, the product tetrahydro-5-indolizinone-8-
carboxylate 27 was isolated by chromatography on a silica gel
column eluting with petroleum ether and ethyl acetate (2:1).
3.3.1.1. Methyl (1S,2R)-1,2-O-isopropylidenedioxy-1,2,3,5-tetrahydro-
5-indolizinone-8-carboxylate 27. Yield 83%, oil, [a]2D0 ꢀ63.8 (c 1.2 g/
100 ml, CHCl3). IR v (cmꢀ1) 1719, 1665; 1H NMR (400 MHz, CDCl3):
7.94 (d, J¼9.5 Hz, 1H), 6.53 (d, J¼9.5 Hz, 1H), 6.07 (d, J¼6.1 Hz, 1H),
5.00–5.04 (m, 1H), 4.42 (dd, J¼14.4, 1.2 Hz, 1H), 4.15 (dd, J¼14.4,
5.5 Hz,1H), 3.90 (s, 3H),1.45 (s, 3H),1.31 (s, 3H); 13C NMR (100 MHz,
CDCl3): 164.1, 161.5, 153.4, 140.6, 119.2, 112.4, 107.4, 82.5, 74.1, 54.0,
52.0, 26.9, 25.4. HRMS (TOF-ESI): 266.1019, C13H16NO5 required
266.1028 (Mþ1).
3.2.5.1. (ꢀ)-Swainsonine 3. Yield 71%, mp 133–134 ꢁC, [a]D20 ꢀ71.7
(c 0.12, CH3OH) [lit.4 mp 136–139 ꢁC, [a]D20 ꢀ74.9 (c 1.15, CH3OH)].
IR v (cmꢀ1) 3407 (br); 1H NMR (500 MHz, D2O): 4.23–4.25 (m,
1H), 4.14 (dd, J¼5.6, 3.7 Hz, 1H), 3.69 (td, J¼10.2, 4.2 Hz, 1H), 2.78–
2.83 (m, 2H), 2.50 (t, J¼9.4 Hz, 1H), 1.88–1.95 (m, 3H), 1.61(br d,
J¼13.8 Hz, 1H), 1.40 (qt, J¼13.3, 4.3 Hz, 1H), 1.13 (qd, J¼12.4,
4.3 Hz, 1H); 13C NMR (125 MHz, D2O): 72.5, 69.3, 68.7, 66.0, 60.3,
51.3, 32.1, 22.8. HRMS (TOF-EI): 173.1053, C8H15NO3 required
173.1052.
3.3.2. Decarboxylation of 5-indolizinone-8-carboxylate 27
The tetrahydro-5-indolizinone-8-carboxylate 27 (1 mmol) was
dissolved in hydrobromic acid (40%, 15 mL), and the solution was
refluxed at 130–135 ꢁC for 44 h. After evaporation the hydrobromic
acid under vacuum, the residue was chromatographed on a silica
gel column (ethyl acetate/methanol¼9:1) to give (1S,2R)-1,2-dihy-
droxy-1,2,3,5-tetrahydro-5-indolizinone 28 in 79%.
3.2.5.2. (7S)-7-Methyl swainsonine 16A. Yield 88%, mp 146–148 ꢁC,
[a]2D0 ꢀ60 (c 0.155, CH3OH). IR v (cmꢀ1) 3430; 1H NMR (500 Hz,
D2O): 4.23–4.26 (m, 1H), 4.13 (dd, J¼5.7, 3.7 Hz, 1H), 3.25 (t,
J¼9.7 Hz, 1H), 2.74–2.78 (m, 2H), 2.43 (dd, J¼10.8, 8.0 Hz, 1H), 1.91
(dt, J¼12.6, 2.2 Hz, 1H), 1.84 (dd, J¼9.4, 3.6 Hz, 1H), 1.60 (br d,
J¼13.3 Hz, 1H), 1.26–1.31 (m, 1H), 1.15 (qd, J¼12.8, 4.1 Hz, 1H), 0.92
(d, J¼6.3 Hz, 3H); 13C NMR (125 MHz, D2O): 72.0, 71.5, 69.4, 69.0,
60.2, 51.2, 37.4, 31.6, 17.0. HRMS (TOF-ESI):188.1260, C9H17NO3 re-
quired 188.1287 (Mþ1).
3.3.2.1. (1S,2R)-1,2-Dihydroxy-1,2,3,5-tetrahydro-5-indolizinone
28. Yield 79%, mp 164–166 ꢁC, [a]D20 þ53.3 (c 0.105, H2O). IR v
(cmꢀ1) 3237 (br), 1656, 1572; 1H NMR (500 MHz, DMSO-d6): 7.46 (t,
J¼7.8 Hz, 1H), 6.25 (d, J¼7.9 Hz, 2H), 4.93 (d, J¼3.8 Hz, 1H), 4.30 (s,

G.-F. Shi et al. / Tetrahedron 64 (2008) 5005–5012
5011
1H), 3.92 (d, J¼13.1 Hz, 1H), 3.84 (dd, J¼13.0, 3.3 Hz, 1H); 13C NMR
(125 MHz, CD3ODþD2O): 163.1, 151.0, 142.6, 117.1, 104.7, 73.9, 69.2,
53.7. HRMS (TOF-EI): 167.0584, C8H9NO3 required 167.0582.
3.3.5.1. 2,8a-Diepilentiginosine 31. Yield 74%, mp 104–106 ꢁC, [a]D20
ꢀ34.4 (c 0.38, CH3OH) [lit.23 mp 109–111 ꢁC, [a]2D4 ꢀ37.1 (c 0.55,
CH3OH)]. IR v (cmꢀ1) 3430 (br); 1H NMR (500 MHz, D2O): 4.21–4.24
(m, 1H), 3.94 (dd, J¼5.9, 3.9 Hz, 1H), 2.90 (br d, J¼10.9 Hz, 1H), 2.75
(dd, J¼11.3, 2.0 Hz, 1H), 2.39 (dd, J¼11.1, 7.9 Hz, 1H), 1.93–2.00 (m,
2H), 1.70 (br d, J¼12.9, 1H), 1.59 (br d, J¼12.7 Hz, 1H), 1.51 (br d,
J¼13.5 Hz, 1H), 1.32–1.38 (m, 2H), 1.14–1.20 (m, 1H); 13C NMR
(125 MHz, CDCl3): 72.3, 69.5, 68.1, 62.3, 53.1, 24.8, 24.7, 23.6. HRMS
(TOF-EI): 157.1105, C8H15NO2 required 157.1103.
3.3.3. Protection of 1,2-dihydroxy-5-indolizinone 28
The 1,2-dihydroxy-5-indolizinone 28 (0.5 mmol) and p-tolue-
nesulfonic acid monohydrate (10 mg) were dissolved in dime-
thoxypropane (4 mL) and dry dichloromethane (15 mL). The
reaction mixture was stirred at room temperature for 36 h. The p-
toluenesulfonic acid was neutralized with triethylamine (1 mL) and
was filtered. After removal of solvent,1,2-O-isopropylidenedioxy-5-
indolizinone 29 was isolated in 89% yield by chromatography on
a silica gel column eluting with ethyl acetate and petroleum ether
(1:1).
Acknowledgements
This work was supported by the National Natural Science
Foundation of China for Distinguished Young Scholars (No.
20525207), National Natural Science Foundation of China (No.
20472010), Beijing Natural Science Foundation (No. 2052013) and
the Research Fund for the Doctoral Program of Higher Education
(No. 20050027003).
3.3.3.1. (1S,2R)-1,2-O-Isopropylidenedioxy-1,2,3,5-tetrahydro-5-indol-
izinone 29. Yield 89%, mp 128–130 ꢁC, [a]D20 ꢀ4.7 (c 0.34, CH2Cl2). IR
v (cmꢀ1) 1647, 1594, 1577; 1H NMR (500 MHz, CDCl3): 7.44 (dd,
J¼8.8, 7.1 Hz, 1H), 6.55 (d, J¼9.1 Hz, 1H), 6.37 (d, J¼6.6 Hz, 1H), 5.53
(d, J¼5.6 Hz, 1H), 4.98 (t, J¼5.2 Hz, 1H), 4.44 (d, J¼14.4 Hz, 1H), 4.14
(dd, J¼14.4, 4.9 Hz,1H), 1.44 (s, 3H),1.32 (s, 3H); 13C NMR (125 MHz,
CDCl3): 161.8, 148.6, 140.5, 119.7, 113.1, 103.0, 81.4, 75.0, 53.1, 27.3,
25.9. MS (EI): 150 (100), 192 (25), 207 (Mþ, 40%). Anal. Calcd for
References and notes
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C
11H13NO3: C 63.76, H 6.32, N 6.76; Found: C 63.53, H 6.11, N 6.68.
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3.3.4. Hydrogenation of 1,2-O-isopropylidenedioxy-1,2,3,5-
tetrahydro-5-indolizinone 29
The tetrahydro-5-indolizinone 29 (0.5 mmol) was mixed with
PtO2 (100 mg) in methanol (20 mL). The reaction mixture was
stirred under hydrogen atmosphere (10–15 atm) for 48 h at 40 ꢁC.
The catalyst was filtered off and washed with methanol (2ꢂ10 mL).
The filtrate was concentrated under vacuum, and the residue was
purified on a silica gel column eluting with ethyl acetate and ace-
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zinone 30 in 90% yield.
´
´
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none 30. Yield 90%, mp 59–61 ꢁC, [a]D20 þ59.5 (c 0.19, CHCl3). IR v
(cmꢀ1): 1643, 1470, 1449; 1H NMR (500 MHz, CDCl3): 4.75 (t,
J¼5.6 Hz, 1H), 4.63 (t, J¼5.1 Hz, 1H), 4.24 (d, J¼13.6 Hz, 1H), 3.41–
3.45 (m, 1H), 3.11 (dd, J¼13.6, 5.1 Hz, 1H), 2.42 (br d, J¼17.3 Hz, 1H),
2.28–2.35 (m, 1H), 1.96–2.03 (m, 2H), 1.86 (q, J¼13.0 Hz, 1H), 1.72–
1.75 (m, 1H), 1.43 (s, 3H), 1.34 (s, 3H); 13C NMR (125 MHz, CDCl3):
169.3, 111.8, 81.1, 77.6, 61.2, 50.3, 31.3, 26.5, 24.8, 22.5, 21.0. HRMS
(TOF-EI): 211.1206, C11H17NO3 required 211.1208.
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At 0 ꢁC and under nitrogen atmosphere, the solution of borane
THF complex (1 M, 3 mL) was added dropwise to the solution of
octahydro-5-indolizinone 30 (0.5 mmol) in THF (15 mL). The re-
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