A facile synthesis of 1,4-dideoxy-1,4-imino-l-ribitol (LRB) and (-)-8a-epi-swainsonine from d-glutamic acid

Article abstract of DOI:10.1016/j.tet.2011.04.075

A facile synthesis of (-)-8a-epi-swainsonine 2 and 1,4-dideoxy-1,4-imino-l- ribitol (LRB) 4 has been achieved by using the versatile building block 3, which was available from cheap d-glutamic acid. The new forming stereogenic center in synthesis of 2 was constructed by highly selective reduction of the ketone 13 with Li(t-BuO)₃AlH in THF (dr=95:5).

Full text of DOI:10.1016/j.tet.2011.04.075

Tetrahedron 67 (2011) 4919e4923
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A facile synthesis of 1,4-dideoxy-1,4-imino-
swainsonine from -glutamic acid
L-ribitol (LRB) and (ꢀ)-8a-epi-
D
,
a
,
a,b
Xiao-Ling Wang a, Wen-Feng Huang a, Xin-Sheng Lei b , Bang-Guo Wei , Guo-Qiang Lin
*
*
a Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China
b School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthesis of (ꢀ)-8a-epi-swainsonine 2 and 1,4-dideoxy-1,4-imino-
L
-ribitol (LRB) 4 has been
Received 19 April 2011
Accepted 21 April 2011
Available online 29 April 2011
achieved by using the versatile building block 3, which was available from cheap
D-glutamic acid. The
new forming stereogenic center in synthesis of 2 was constructed by highly selective reduction of the
ketone 13 with Li(t-BuO)3AlH in THF (dr¼95:5).
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloid
Lactam
Asymmetric synthesis
Swainsonine
LRB
1. Introduction
OH
HO
OH
HO
H
N
(ꢀ)-Swainsonine 1 (see Fig.1) was firstly isolated from the fungus
Rhizoctonia leguminicola1 and subsequently found in the Australian
plant Swainsona canescens2 and also other plant3 and fungi.4
(ꢀ)-Swainsonine 1 exhibits lysosomal R-mannosidase and man-
nosidaseIIinhibitory properties5 andshows tobeapotentinhibitorof
cancer, HIV, and immunological disorders.6 Currently, (ꢀ)-swainso-
nine 1 is under phase II clinical trials as an anticancer drug.7 Due to its
promising biological activities and intriguing structure, the study for
(ꢀ)-swainsonine 1 has attracted considerable attention, and a num-
ber of synthetic approaches have been reported.8 Additionally, the
relative analogues have been confirmed to exhibit different activities
compared withswainsonine 1.9 Forexample, (ꢀ)-8a-epi-swainsonine
has also been demonstrated to be an effective inhibitor of lysosomal
HO
O
N
Boc
Lactam 3
OTBS
(-)-Swainsonine 1
HO
OH
OH
HO
H
N
HO
N
H
OH
(-)-8a-epi-Swainsonine 2
LRB 4
Fig. 1. The structures of (ꢀ)-swainsonine and (ꢀ)-8a-epi-swainsonine.
(hydroxymethyl)pyrrolidine lactam3 and its application forsynthesis
of ceramide sphingolipid have been reported by our group.12 As part
of this program aiming at the synthesis of polyhydroxylated indoli-
zidine alkaloids, azasugars and their analogues, we have developed
a concise approach for stereoselective synthesis of (ꢀ)-8a-epi-
R-
-mannosidase, with 93% potency of swainsonine 1.9b Thus,
D
unnatural diastereomers of swainsonine have become attractive
synthetic targets and several synthetic routes for preparation of 8a-
epi-swainsonine have been published.10
Among these synthetic approaches for swainsonine and its ana-
logues, the most challenging part is the asymmetric construction of
indolizidine unit bearing four chiral centers. Recently, we have been
devoted to exploring some multifunctional building blocks and uti-
lizing them in the asymmetric synthesis of some natural products,
including bioactive piperidine alkaloids and depsipeptides.11 In 2010,
an efficient method for preparation of (2S,3S,4S)-3,4-dihydroxy-5-
swainsonine 2 and 1,4-dideoxy-1,4-imino-
-ribitol 4.13,14 Herein we
L
describe this convenient method for synthesis of these two com-
pounds using lactam 3 as a chiral building block (Scheme 1).
2. Results and discussion
As shown in Scheme 2, the lactam 3 would be a desirable building
block for the synthesis of (ꢀ)-8a-epi-swainsonine 2 and LRB 4. Pro-
tection of the two hydroxyl groups of lactam 3 with 2,2-dimethox-
ypropane (DMP) afforded the compound 7 in 96% yield. Then, the
* Corresponding authors. E-mail address: bgwei1974@fudan.edu.cn (B.-G. Wei).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.075

4920
X.-L. Wang et al. / Tetrahedron 67 (2011) 4919e4923
HO
OH
HO
OH
OH
HO
H
N
O
O
O
O
O
O
c
a
b
O
HO
O
N
10
N
H
Boc
OTBS
OH
N
N
N
Boc
N
Boc
Boc
O
OH
O
(-)-8a-epi-Swainsonine 2
Lactam 3
LRB 4
11
12
13
Ref 12
previous work
Scheme 3. Asymmetric synthesis of 13. Reagents and conditions: a. TBAF, THF, 0 ꢁC to
rt, 2 h, 90%; b. (i) NaIO4, RuCl3$xH2O, CH3CN, H2O, rt, 5 h; (ii) MeO(Me)NH$HCl, EDCI,
HOBt, i-Pr2NEt, DCM, rt, 16 h, 74% two steps; c. Allylmagnesium chloride, THF, ꢀ78 ꢁC
to rt, 5 h, 76%.
D
-Glutamic Acid
Scheme 1. Synthetic strategy of (ꢀ)-8a-epi-swainsonine 2 and LRB 4.
Table 1
HO
OH
O
O
O
O
The anti diastereoselective reduction of 13
a
b
c
O
N
O
HO
OTBS
O
O
O
O
N
N
Boc
OTBS
Boc
7
Boc
8
OTBS
[H-]
H
3
N
N
Boc
13
Boc
14
O
OH
O
N
O
HO
OH
O
O
d
e
Entrya
Solvent
T
ꢁC
[Hꢀ
]
Yb
%
anti/cisc
AcO
N
N
HHCl
OH
Boc
1
EtOH
EtOH
THF
PhMe
EtOH
THF
20
NaBH4
NaBH4
LiEt3BH
DIBAL-H
Li(t-BuO)3AlH
Li(t-BuO)3AlH
82
71
73
84
76
81
53:47
64:36
71:29
67:33
78:22
95:5
OTBS
Boc
OTBS
2
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
3d
4
9
LRB 4
10
5e
6f
Scheme 2. Asymmetric synthesis of LRB 4. Reagents and conditions: a. p-TsOH, DMP,
acetone, 0 ꢁC to rt, 3 h, 96%; b. LiEt3BH, THF, ꢀ78 ꢁC, 30 min; c. DMAP, Et3N, acetic
anhydride, DCM, 0 ꢁC to rt, 10 h, 94% two steps; d. Triethylsilane, BF3$Et2O, DCM,
ꢀ78 ꢁC, 5 h, 85%; e. (COCl)2, MeOH, rt, 2 days, 59%.
a
The reaction was performed with 2.0 mmol reductive reagents and 1 mmol
ketone 13.
b
c
d
e
f
Combined yield of cis/trans products.
All the diastereoselectivity was examined by HPLC.
THF, ꢀ78 ꢁC, 0.5 h.
regioselective reduction of carbonyl was examined. While BH3$SMe2
was used as reducing agent, the reduction of compound 7 only gave
a small quantity of corresponding amide 10 in 23% yield. Therefore, an
indirect approach for selective reduction of carbonyl was examined.
Although the imide of piperidine was easily converted to the corre-
sponding alcohol in NaBH4/MeOH system,11b this reductive condition
was not effective for the reduction of the imide 7. Gratefully, when
LiBEt3H was used, the imide 7 was easily converted to alcohol 8 at
ꢀ78 ꢁC in quantitative yield as diastereomers. The following re-
duction of alcohol 8 with Et3SiH in the presence of BF3$Et2O gave
compound 10 in a low yield (41%). However, acetylation (Ac2O, TEA,
EtOH, ꢀ78 ꢁC, 4 h.
THF, ꢀ78 ꢁC, 4 h.
(entry 1), even at low temperature (entry 2). LiEt3BH and DIBAL-H
were also screened and the results showed that the reaction oc-
curred smoothly under all these conditions, while the diaster-
eoselectivity of product 14 were not significantly increased (entries
3 and 4). Although the diastereoselective chelation-controlled re-
duction of the ketone by using Li(t-OBu)3AlH19 could produce high
diastereoselectivity, the result 14 was dissatisfying (entry 5) when
the reaction took place in EtOH. Interestingly, when THF was used
under the same condition, the reaction gave an encouraging result
with high diastereoselectivity (anti/cis¼95:5, entry 6).
DMAP) of compound 8 and subsequent reduction (BF3$Et2O, Et3SiH)
could give the corresponding protective LRB 10 {[
25
a
]
D
þ66.2 (c 1.0,
CHCl3); lit.15
[a]
þ60.2 (c 0.3, CHCl3)} in 81% overall yield. Finally,
25
D
removal of protective group by (COCl)2/MeOH system gave 1,4-
dideoxy-1,4-imino-
ꢀ50.9 (c 0.52, H2O); lit.14l
25
D
L
-ribitol 4$HCl {[
a
]
25
D
[a]
ꢀ52 (c 0.41, H2O) } in 59% yield. The spectroscopic and physi-
Finally, we turned our attention to explore the asymmetric
synthesis of (ꢀ)-8a-epi-swainsonine 2. Protection of secondary al-
cohol 14 as its TBS ether (TBSOTf, 2,6-lutidine) gave compound 15
in 75% yield. Next, hydroboration of compound 15 with BH3$SMe2
in tetrahydrofuran at room temperature followed by oxidation of
resulting intermediate with H2O2 smoothly gave primary alcohol 16
in 64% overall yield. Then treatment of compound 16 with meth-
anesulfonyl chloride in the presence of pyridine gave crude product
without further purification. Removal of protective group with
TMSOTf/2,6-lutidine and subsequent cyclization of the resulting
crude product gave the protective (ꢀ)-8a-epi-swainsonine in one-
pot manner, which was not easily purified due to the minor
caldataof thesyntheticLRB4wereidenticalwiththereporteddata.14l
Thus, a very concise method for the asymmetric synthesis of LRB 4
was established based on the lactam 3.
To synthesize (ꢀ)-8a-epi-swainsonine 2 in an asymmetric way,
the following synthetic route was explored. Removal (TBAF, THF) of
the protective group of amide 10 gave primary alcohol 11 in 90%
yield. Then, the oxidation of compound 11 with NaIO4 and
RuCl3$xH2O,16 followed by subsequent treatment of the resulting
compound with N-methoxymethanamine hydrochloride in the
presence of HOBt and EDCI gave Weinreb amide17 12 as a colorless
oil in 74% overall yield. Treatment of compound 12 with allylmag-
nesium chloride at ꢀ78 ꢁC generated the corresponding ketone 13
in 76% yield18 (Scheme 3).
In seeking a method for the diastereoselective reduction of
carbonyl for compound 13, various conditions were tested, and the
results were summarized in Table 1. The table showed that when
NaBH4 was used, the reaction smoothly occurred and produced
secondary alcohol 14 in 82% yield with low diastereoselectivity
2,6-lutidine. In the end, the removal of protective (ꢀ)-8a-epi-
25
swainsonine with MeOH/(COCl)2 gave 2 {[
a
]
[
ꢀ63.4 (c 1.02,
D
MeOH); lit.10f
[a
]
ꢀ64 (c 1, MeOH); lit.10g
a
]
ꢀ63 (c 0.95,
25
25
D
D
MeOH)} in 76% overall yield according to the references.10 The
spectroscopic and physical data of the synthetic (ꢀ)-8a-epi-
swainsonine 2 were identical with the reported data.10f,g Thus,
a novel convenient method for the asymmetric synthesis of (ꢀ)-8a-

X.-L. Wang et al. / Tetrahedron 67 (2011) 4919e4923
4921
epi-swainsonine 2 was also established based on the versatile
building block 3 (Scheme 4).
ꢀ5.6 ppm; MS (ESI): 424 (MþNaþ); HRMS (MALDI/DHB) calcd for
[C19H35NO6SiþNaþ]: 424.2131, found: 424.2141.
4.1.2. (3aS,6S,6aS)-tert-Butyl 4-acetoxy-6-((tert-butyldimethylsily-
loxy)methyl)-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-
carboxylate 9. To a solution of 7 (220 mg, 0.55 mmol) in THF
(15 mL) was stirred at ꢀ78 ꢁC, then a solution of LiEt3BH (1.65 mL,
1 M in THF) was slowly dropped and the reaction was stirred for
30 min. Absolute MeOH (4 mL) was carefully dropped and stirred
for 5 min. The mixture was treated with saturated NaHCO3 aqueous
solution and warmed to room temperature. Then the solvent was
removed in vacuo and the residue was diluted with EtOAc and
separated. The aqueous layer was extracted with EtOAc for three
times and the combined organic layers were washed with brine.
Dried and concentrated gave crude compound 8 as a mixture of
diastereomers without further purification. The crude 8 and DMAP
(37 mg, 0.30 mmol) were dissolved in dry DCM (15 mL) and stirred
at 0 ꢁC. Then a solution of TEA (0.23 mL, 1.64 mmol) and acetic
anhydride (0.15 mL,1.65 mmol) was dropped. After being stirred for
10 h, the reaction mixture was quenched with saturated NaHCO3
aqueous solution and extracted with DCM for three times. The
combined organic layers were washed with brine, dried, and con-
O
O
OH
O
O
b
c
a
H
H
14
2
Ref 11
OTBS
N
N
Boc
15
OTBS
Boc
16
Scheme 4. Asymmetric synthesis of (ꢀ)-8a-epi-swainsonine 2. Reagents and condi-
tions: a. 2,6-lutidine, TBSOTf, DCM, 0 ꢁC to rt, 4 h, 75%; b. BH3$SMe2, THF, 0 ꢁC to rt, 8 h,
then NaOH (3 M), H2O2 (30%), 0 ꢁC, 1 h, 64%. c. (i) MsCl, Py, rt, 1 h (ii) 2,6-lutidine,
TMSOTf, DCM, 24 h (iii) (COCl)2, MeOH, 0 ꢁC to rt, 12 h, 76% three steps.
3. Conclusions
In summary, an efficient approach for synthesis of (ꢀ)-8a-epi-
swainsonine 2 has been developed based on the versatile building
block 3. In addition, a convenient method for synthesis of 1,4-
dideoxy-1,4-imino- -ribitol 4 has also been described. All these
L
results display again promising synthetic application of glutamic
acid (Scheme 1). Continuation of the exploration and application of
building block 3 in total synthesis of other active natural products
are now in progress in our laboratory.
centrated. The residue was purified by chromatography on silica gel
20
to give 9 (232 mg, 94%), the major 9 as a white foam. [
a]
þ89.5 (c
D
1.0, CHCl3); IR (film): nmax 2986, 2933, 1747, 1712, 1379, 1257, 1207,
1120 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
: 6.18 (d, J¼6.0 Hz, 1H), 4.72
(dd, J¼5.0, 5.8 Hz, 1H), 4.55 (d, J¼5.4 Hz, 1H), 4.17e4.11 (m, 2H),
3.61e3.58 (m, 1H), 2.10 (br s, 3H), 1.52e1.36 (m, 15H), 0.87 (s, 9H),
4. Experimental section
4.1. General
0.02 (s, 3H), 0.01 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
d: 169.3,
153.0, 112.2, 81.6, 81.2, 80.7, 77.9, 61.9, 61.3, 28.2, 25.8, 25.5, 25.4,
20.9, 18.1, ꢀ5.5, ꢀ5.6 ppm; MS (ESI): 468 (MþNaþ); HRMS (MALDI/
DHB) calcd for [C21H39NO7SiþNaþ]: 468.2394, found:468.2386.
THF was distilled from sodium/benzophenone. All reactions
were monitored by thin layer chromatography (TLC) on glass
plates coated with silica gel with fluorescent indicator (Huanghai
HSGF254). Flash chromatography was performed on silica gel
(Huanghai 300e400) with petroleum/EtOAc as eluent. Melting
points were recorded on a Mel-Temp apparatus and uncorrected.
Optical rotations were measured on a JASCO P-1030 polarimeter
with a sodium lamp. Mass spectra were recorded on an HP-5989
instrument and HRMS (MALDI/DHB) were measured on an
LCMS-IT-TOF (Shimazu Corporation) apparatus. IR spectra were
recorded using KBr disks or film, on a Fourier Transform Infrared
Spectrometer, Type: Avatar 360 E.S.P, manufactured by Thermo
Nicolet Corporation, USA. NMR spectra were recorded on a Varian
or a Bruker spectrometer (300 or 400 MHz), and chemical shifts
are reported in d (ppm) referenced to an internal TMS standard for
1H NMR and CDCl3 (77.0 ppm) for 13C NMR.
4.1.3. (3aS,4S,6aR)-tert-Butyl 4-((tert-butyldimethylsilyloxy)methyl)-
2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate
10. To a solution of 9 (100 mg, 0.22 mmol) and Et3SiH (0.35 mL) in
DCM (15 mL) were stirred at ꢀ78 ꢁC under argon atmosphere, then
a solution of BF3$Et2O (0.08 mL, 0.66 mmol) in dry DCM (2 mL) was
slowly dropped. After stirring for 5 h at ꢀ78 ꢁC, the mixture was
quenched with saturated NaHCO3 aqueous solution and diluted
with DCM. The organic layer was separated and the aqueous layer
was extracted with DCM for three times. The combined organic
layers were washed with brine, dried, and concentrated. The resi-
due was purified by chromatography on silica gel to give 10 (74 mg,
20
85%) as a colorless oil. [
a]
þ66.2 (c 1.0, CHCl3); IR (film): nmax
D
2957, 2933, 1701, 1405, 1382, 1376, 1255, 1176, 1123 cmꢀ1; 1H NMR
(300 MHz, CDCl3) : 4.71e4.67 (m, 2H), 4.01 (br s, 1/2H), 3.95e3.92
(m,1H), 3.74e3.48 (m, 7/2H),1.44 (br s,12H),1.23 (br s, 3H), 0.92 (br
s, 9H), 0.02 (s, 3H), 0.01 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
d
d
:
4.1.1. (3aS,4S,6aS)-tert-Butyl 4-((tert-butyldimethylsilyloxy)methyl)-
2,2-dimethyl-6-oxo-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carbox-
ylate 7. To a solution of compound 3 (359 mg, 0.99 mmol) and
p-TsOH (30 mg, 0.17 mmol) were stirred in dry acetone (14 mL),
then DMP (1.2 mL) was dropped under argon atmosphere. After
stirring for 3 h at room temperature, the mixture was quenched
with saturated NaHCO3 aqueous solution and extracted with EtOAc
for three times. The combined organic layers were washed with
brine and dried over anhydrous Na2SO4. Filtered and concentrated,
154.1, 111.2, 83.2, 82.6, 79.6, 64.7, 63.5, 53.8, 28.4, 27.0, 25.8, 25.0,
18.0, ꢀ5.7 ppm; MS (ESI): 410 (MþNaþ); HRMS (MALDI/DHB) calcd
for [C19H37NO5SiþHþ]: 388.2519, found: 388.2541.
4.1.4. (2S,3S,4R)-2-(Hydroxymethyl)pyrrolidine-3,4-diol hydrochlo-
ride (LRB) 4. To a solution of 10 (74 mg, 0.19 mmol) in absolute
MeOH (10 mL) were stirred at ꢀ10 ꢁC under argon atmosphere,
then a solution of (COCl)2 (1.3 mL, 18 mmol) was slowly dropped.
After stirring for 2 days at room temperature, the mixture was
concentrated and the residue was triturated with absolute Et2O at
the residue was purified by chromatography on silica gel to give 7
20
D
(382 mg, yield 96%) as a colorless oil. [
a
]
þ92.6 (c 1.0, CHCl3); IR
ꢀ78 ꢁC to rt for three times to give LRB 4 (19 mg, 59%) as a white
25
(film): nmax 2988, 2938, 1783, 1373, 1298, 1258, 1158, 1116 cmꢀ1; 1H
NMR (300 MHz, CDCl3)
solid. Mp 125e127 ꢁC [lit.14m 128e130 ꢁC]; [
a]
ꢀ50.9 ꢁC (c 0.52,
D
25
d
: 4.65 (d, J¼5.7 Hz, 1H), 4.52 (d, J¼5.4 Hz,
H2O) [lit.14m
[
a]
ꢀ52 ꢁC (c 0.41, H2O)]; IR (film): nmax 3407, 1619,
D
1H), 4.23 (br s, 1H), 3.99 (dd, J¼2.1, 10.5 Hz, 1H), 3.77 (dd, J¼1.2,
1407, 1142, 1065 cmꢀ1 1H NMR (400 MHz, D2O):
; d 4.40e4.34 (m,
10.5 Hz, 1H), 1.54 (s, 9H), 1.46 (s,3H), 1.38 (s,3H), 0.85 (s, 9H), 0.03 (s,
1H); 4.21 (dd, J¼4.1, 8.2 Hz, 1H), 3.95 (dd, J¼3.4, 12.3 Hz, 1H), 3.83
3H), 0.01 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3)
d: 170.9, 149.9,
(dd, J¼5.7, 12.3 Hz, 1H), 3.65e3.61 (m, 1H), 3.47 (dd, J¼4.0, 12.5 Hz,
111.8, 83.5, 78.2, 75.7, 61.9, 61.8, 27.9, 27.1, 25.8, 25.6, 18.1, ꢀ5.7,
1H), 3.39e3.35 (m, 1H) ppm; 13C NMR (D2O, 100 Hz):
d 71.6, 69.7,

4922
X.-L. Wang et al. / Tetrahedron 67 (2011) 4919e4923
62.1, 58.8, 49.6 ppm; HRMS (MALDI/DHB) calcd for
38.6, 30.2, 28.4, 26.7, 25.0 ppm; MS (ESI): 334 (MþNaþ); HRMS
(MALDI/DHB) calcd for [C16H25NO5þNaþ]: 334.1631, found:
334.1639.
[C5H11NO3þHþ]: 134.0817, found: 134.0831.
4.1.5. (3aS,4S,6aR)-tert-Butyl 4-(hydroxymethyl)-2,2-dimethyl-tetra-
hydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate 11. To a solution of 10
(507 mg, 1.31 mmol) in dry THF (10 mL) was stirred at 0 ꢁC under
argon atmosphere, then a solution of TBAF (2.6 mL, 1 M) in THF was
slowly dropped. After stirring for 2 h at room temperature, the
mixture was quenched with saturated NaHCO3 aqueous solution and
the resulting mixture was extracted with EtOAc for three times. The
combined organic layers were washed with brine, dried, and con-
4.1.8. (3aS,4S,6aR)-tert-Butyl
methyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate
4-((R)-1-hydroxybut-3-enyl)-2,2-di-
14. To
a solution of (Ot-Bu)3AlH (360 mg, 1.46 mmol) in dry THF (10 mL)
was dropped a solution of compound 13 (226 mg, 0.72 mmol) in dry
THF (4 mL) at ꢀ78 ꢁC under argon atmosphere. After being stirred
for 5 h at the same condition, the reaction mixture was quenched
with saturated NaHCO3 aqueous solution and warmed to room
temperature. The resulting mixture was extracted with EtOAc for
three times and the combined organic layers were washed with
brine, dried, and concentrated. The residue was purified by chro-
centrated. The residue was purified by chromatography on silica gel
24
D
to give 11 (321 mg, 90%) as a colorless oil. [
a]
þ29.4 (c 1.04, CHCl3);
IR (film): nmax 3440, 2979, 1674, 1479, 1417, 1162, 1056, 858 cmꢀ1; 1H
NMR (400 MHz, CDCl3) : 4.74e4.50 (m, 2H), 4.13e4.01 (m, 1H),
3.83e3.66 (m, 3H), 3.51e3.48 (m, 2H) 1.46 (br s, 9H), 1.32 (br s,
6H) ppm; 13C NMR (100 MHz, CDCl3)
: 155.5, 111.8, 82.9, 82.1, 80.3,
d
matography on silica gel to give 14 (182 mg, 81%) as a colorless oil.
24
D
[a
]
þ46.6 (c 0.675, CHCl3); IR (film): nmax 3445, 2979, 1697, 1673,
d
1415, 1367, 1163, 1055 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d:
65.2, 63.3, 63.0, 52.7, 28.4, 27.1, 25.1, 14.4 ppm; MS (ESI): 296
(MþNaþ); HRMS (MALDI/DHB) calcd for [C13H23NO5þNaþ]:
296.1474, found: 296.1477.
5.89e5.82 (m, 1H), 5.24e5.18 (m, 2H), 4.73e4.64 (m, 2H),
3.96e3.82 (m, 1H), 3.54e3.48 (m, 1H), 3.42e3.34 (m, 2H), 1.46 (s,
9H), 1.50e1.41 (m, 2H), 3.34e1.26 (m, 6H) ppm; 13C NMR (100 MHz,
CDCl3) d: 204.9, 154.6, 129.4, 119.6, 112.5, 81.6, 80.8, 79.7, 78.8, 71.4,
4.1.6. (3aS,4R,6aR)-tert-Butyl 4-(methoxy(methyl)carbamoyl)-2,2-
dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate 12. To
a solution of 11 (130 mg, 0.476 mmol) in CCl4 (3 mL) and CH3CN
(3 mL) was stirred at 0 ꢁC, and then water (6 mL) was dropped.
NaIO4 (405 mg,1.90 mmol) was added in one portion and stirred for
15 min. The mixture was treated with a catalytic amount of
RuCl3$xH2O and stirred for 5 h at room temperature. Et2O (5 mL)
was poured and stirred for 2 h until the color of the mixture turn to
white. The mixture was diluted with water and extracted with
EtOAc for three times. The combined organic layers were washed
with brine for one time, dried, and concentrated to give the crude
acid without further purification. To a mixture of above crude acid
and HOBt (109 mg, 0.809 mmol) in dry DMF (6 mL) were stirred at
70.7, 52.5, 45.4, 30.2, 28.3, 26.9 ppm; HRMS (MALDI/DHB) calcd for
[C16H27NO5þNaþ]: 336.1786, found: 336.1794.
4.1.9. (3aS,4R,6aR)-tert-Butyl 4-((R)-1-(tert-butyldimethylsilyloxy)
but-3-enyl)-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-
carboxylate 15. To
a solution of compound 14 (126 mg,
0.403 mmol) and 2,6-lutidine (0.01 mL, 0.984 mmol) in dry DCM
(4 mL) was stirred at 0 ꢁC under argon atmosphere. After stirring for
15 min, the reaction mixture was slowly treated with TMSOTf
(186 mg, 0.86 mmol) and stirred for 4 h at room temperature. The
resulting mixture was quenched with saturated NaHCO3 aqueous
solution and extracted with EtOAc for three times. The combined
organic layers were washed with brine, dried, and concentrated.
0
ꢁC, then EDC (100 mg, 0.524 mmol) was added in one portion.
The residue was purified by chromatography on silica gel to give 15
24
After stirring for 30 min, the resulting mixture was treated with
MeO(Me)NH$HCl (56 mg, 0.571 mmol) and i-Pi2NEt (0.33 mL,
1.90 mmol) and stirred for 16 h. The reaction mixture was diluted
with water and extracted with EtOAc for three times. The combined
organic layers were washed with brine, dried, and concentrated.
The residue was purified by chromatography on silica gel to give 12
(129 mg, 75%) as a colorless oil. [
a
]
þ19.83 (c 0.42, CHCl3); IR
1H NMR
: 5.88e5.76 (m, 1H), 5.19e5.05 (m, 2H),
D
(film): nmax 2930, 1699, 1403, 1367, 1175, 1119 cmꢀ1
(400 MHz, CDCl3)
;
d
4.68e4.60 (m, 2H), 4.25e4.15 (m, 1H), 4.02e3.91 (m, 2H),
3.57e3.46 (m, 1H), 2.38e2.27 (m, 1H), 2.12e2.08 (m, 1H), 1.49e1.28
(m, 12H), 1.03e0.82 (m, 12H), 0.25e0.07 (m, 6H) ppm; 13C NMR
D25
(111 mg, 74%) as a yellow foam. [
(film): nmax 2987, 1797, 1697, 1663, 1396, 1371, 1295, 1152,
1001 cmꢀ1 1H NMR (300 MHz, CDCl3)
: 4.78e4.69 (m, 2H),
4.67e4.46 (m, 1H), 3.89 (br s, 3H), 3.74 (br s, 3H), 3.28e3.21 (m, 2H),
1.46 (br s, 9H), 1.42 (br s, 6H) ppm; 13C NMR (75 MHz, CDCl3)
a
]
þ20.27 (c 1.04, CHCl3); IR
(100 MHz, CDCl3) d: 154.7, 134.7, 117.2, 111.2, 82.7, 79.4, 74.1, 73.0,
67.8, 54.9, 38.5, 28.5, 26.9, 25.9, 25.7, 25.3, 24.9, 17.9, ꢀ4.4,
ꢀ4.6 ppm; HRMS (MALDI/DHB) calcd for [C22H41NO5SiþNaþ]:
450.2652, found: 450.2669.
;
d
d:
154.9, 112.2, 83.4, 82.6, 80.1, 64.4, 61.5, 53.3, 32.3, 28.4, 27.0, 26.9,
25.8 ppm; MS (ESI): 331 (MþHþ); HRMS (MALDI/DHB) calcd for
[C15H26N2O6þHþ]: 331.1869, found: 331.1872.
4.1.10. (3aS,4R,6aR)-tert-Butyl 4-((R)-1-(tert-butyldimethylsilyloxy)-
4-hydroxybutyl)-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-
5-carboxylate 16. To
a solution of compound 15 (119 mg,
0.279 mmol) in dry THF (8 mL) was treated with a solution of
BH3$SMe2 (0.1 mL) at 0 ꢁC under argon atmosphere. After stirring
for 8 h at room temperature, the reaction mixture was cooled to
0 ꢁC again, and an aqueous solution of NaOH (1.15 mL, 3 M in water)
was slowly dropped. Then, a solution of H2O2 (1.15 mL, 30% in
water) was carefully dropped due to the formation of much bubble.
The reaction mixture was stirred for 1 h and quenched with water.
The resulting mixture was extracted with EtOAc for three times,
and the combined organic layers were washed with brine. Dried
4.1.7. (3aS,4R,6aR)-tert-Butyl 4-but-3-enoyl-2,2-dimethyl-tetrahy-
dro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate
13. To
a
cooled
(ꢀ78 ꢁC) solution of 12 (360 mg, 1.09 mmol) in dry THF (10 mL) was
treated with a solution of allylmagnesium chloride (1.92 mL, 1.7 M
in THF) under argon atmosphere. After stirring for 30 min at ꢀ78 ꢁC,
the mixture was warmed to room temperature and stirred for 5 h.
Then the resulting mixture was quenched with saturated NH4Cl
aqueous solution and extracted with EtOAc for three times. The
combined organic layers were washed with brine, dried, and con-
and concentrated, the residue was purified by chromatography on
24
centrated. The residue was purified by chromatography on silica gel
silica gel to give 16 (77 mg, 64%) as a colorless oil. [
a]
þ29.93 (c
D
24
D
to give 13 (258 mg, 76%) as a colorless oil. [
a
]
þ122.06 (c 1.05,
0.42, CHCl3); IR (film): nmax 3400, 2922, 1179, 1109 cmꢀ1
;
1H NMR
CHCl3); IR (film): nmax 2980, 2937, 1701, 1456, 1395, 1212, 1168,
(400 MHz, CDCl3) : 4.69e4.64 (m, 2H), 4.29e4.11 (m, 1H),
d
1053 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
: 5.94e5.88 (m, 1H),
3.91e3.81 (m, 2H), 3.73e3.65 (m, 2H), 3.56e3.51 (m, 2H), 1.75e1.75
(m, 2H),1.69e1.64 (m, 2H),1.48 (s, 9H),1.53e1.36 (m, 3H),1.32e1.26
(m, 3H), 0.90 (s, 9H), 0.11e0.01 (m, 6H) ppm; 13C NMR (100 MHz,
5.23e5.14 (m, 2H), 4.65 (br s, 3H), 3.89e3.77 (m, 1H), 3.49e3.28 (m,
3H), 1.44 (br s, 9H), 1.35e1.28 (m, 6H) ppm; 13C NMR (100 MHz,
CDCl3)
d
: 204.7, 134.6, 119.0, 111.3, 83.8, 80.1, 72.4, 67.8, 60.6, 53.8,
CDCl3) d: 154.6,111.2, 83.3, 80.0, 77.2, 66.1, 62.2, 54.7, 30.1, 28.4, 27.0,

X.-L. Wang et al. / Tetrahedron 67 (2011) 4919e4923
4923
6. (a) Dennis, J. W. Cancer Res. 1986, 46, 5131; (b) White, S. L.; Schweitzer, K.;
Humphries, M. J.; Olden, K. Biochem. Biophys. Res. Commun. 1988, 150, 615; (c)
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Elson, P.; Knox, J.; Winquist, E.; Bukowski, R. Invest. New Drugs 2005, 23, 577.
8. For the first syntheses, see: (a) Mezher, H. A.; Hough, L.; Richardson, A. C. J.
Chem. Soc., Chem. Commun. 1984, 447; (b) Fleet, G. W. J.; Gough, M. J.; Smith, P.
W. Tetrahedron Lett. 1984, 25, 1853 For more recent syntheses, see: (c) El Nemr,
A. Tetrahedron 2000, 56, 8579; (d) Zhao, H.; Hans, S.; Cheng, X.; Mootoo, D. R. J.
Org. Chem. 2001, 66, 1761; (e) Pearson, W. H.; Ren, Y.; Powers, J. D. Heterocycles
2002, 58, 421; (f) Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774; (g)
Buschmann, N.; Rueckert, A.; Blechert, S. J. Org. Chem. 2002, 67, 4325; (h) Song,
L.; Duesler, E. N.; Mariano, P. S. J. Org. Chem. 2004, 69, 7284; (i) Lindsay, K. B.;
Pyne, S. G. Aust. J. Chem. 2004, 57, 669; (j) Pyne, S. G. Curr. Org. Synth. 2005, 2,
39; (k) Ceccon, J.; Greene, A. E.; Poisson, J. F. Org. Lett. 2006, 8, 4739; (l) Au, C.
W. G.; Pyne, S. G. J. Org. Chem. 2006, 71, 7097; (m) Guo, H.; O’Doherty, G. A. Org.
Lett. 2006, 8, 1609; (n) Dechamps, I.; Pardo, D.; Cossy, J. ARKIVOC 2007, 5, 38; (o)
Guo, H.; O’Doherty, G. A. Tetrahedron 2008, 64, 304; (p) Dechamps, I.; Pardo, D.
G.; Cossy, J. Tetrahedron 2007, 63, 9082; (q) Tian, Y.-S.; Joo, J.-E.; Kong, B.-S.;
Pham, V.-T.; Lee, K.-Y.; Ham, W.-H. J. Org. Chem. 2009, 74, 3962; (r) Bates, R. W.;
Dewey, M. R. Org. Lett. 2009, 11, 3706; (s) Oxenford, S. J.; Moore, S. P.; Carbone,
G.; Barker, G.; O’Brine, P.; Shipton, M. R.; Gilday, J.; Campos, K. R. Tetrahedron:
Asymmetry 2010, 21, 1563; (t) Chio, H. G.; Kwon, J. H.; Kim, J. C.; Lee, W. K.; Eum,
H.; Ha, H.-J. Tetrahedron Lett. 2010, 51, 3284.
9. (a) Cenci di Bello, I.; Fleet, G. W. J.; Namgoong, S. K.; Tadano, K.; Winchester, B.
Biochem. J. 1989, 259, 855; (b) Davis, B.; Bell, A. A.; Nash, J. R.; Watson, A. A.;
Griffiths, R. C.; Jones, M. G.; Smith, C.; Fleet, W. J. Tetrahedron Lett. 1996, 37,
8565.
10. (a) Tadano, K.; Hotta, Y.; Morita, M.; Suami, T.; Winchester, B.; Cenci di Bello, I.
Chem. Lett. 1986, 2105; (b) Tadano, K.; Hotta, Y.; Morita, M.; Suami, T.; Win-
chester, B.; Cenci di Bello, I. Bull. Chem. Soc. Jpn. 1987, 60, 3667; (c) Kim, Y. G.;
Cha, J. K. Tetrahedron Lett. 1989, 30, 5721; (d) Dudot, B.; Micouin, L.; Baussanne,
I.; Royer, J. Synthesis 1999, 688; (e) Keck, G. E.; Romer, D. R. J. Org. Chem. 1993,
58, 6083; (f) Bi, J.; Aggarwal, V. K. Chem. Commun. 2008, 120; (g) Abrams, J. N.;
Badu, R. S.; Guo, H.-B.; Le, D.; Le, J.; Osbourn, J. M.; O’Doherty, G. A. J. Org. Chem.
2008, 73, 1935; (h) Coral, J. A.; Guo, H.-B.; Shan, M.; O’Doherty, G. A. Hetero-
cycles 2009, 79, 521.
25.8, 24.9, 17.8, ꢀ4.3, ꢀ4.6 ppm; HRMS (MALDI/DHB) calcd for
[C22H43NO6SiþNaþ]: 468.2757, found: 468.2755.
4.1.11. (ꢀ)-8a-epi-Swainsonine 2. To a solution of compound 16
(75 mg, 0.168 mmol) in dry pyridine (4 mL) was stirred at 0 ꢁC, then
MsCl (40 mg, 0.336 mmol) was slowly dropped. After stirring for
1 h, the resulting mixture was concentrated and the residue yellow
oil was diluted with EtOAc and water. Separated, the aqueous layer
was extracted with EtOAc for three times. The combined organic
layers were washed with an aqueous solution of KHSO4 and brine.
The dried solution was concentrated to give crude compound
without further purification. To a solution of above crude com-
pound in dry DCM (10 mL) and 2,6-lutidine (0.12 mL) were cooled
to ꢀ78 ꢁC, then TMSOTf (0.20 mL) was slowly dropped. After stir-
ring for 24 h at ꢀ78 ꢁC to room temperature, the resulting mixture
was quenched with water and extracted with DCM for three times.
The combined organic layers were dried and concentrated to give
crude product, which was easily separated from the minor of 2,6-
lutidine by chromatography on silica gel. The above crude product
was dissolved in absolute MeOH (4 mL) and stirred at ꢀ10 ꢁC, then
(COCl)2 (0.25 mL) was slowly dropped. After stirring for 12 h at
ꢀ10 ꢁC to room temperature, the mixture was concentrated in
vacuo to dryness. The resulting crude product was applied to ion-
exchange chromatography (Dowex 50X8, Hþ form) eluting with
aqueous ammonium hydroxide solution to give (ꢀ)-8a-epi-swain-
sonine 2 (22 mg, 76%) as a white powder. Mp 115e117 ꢁC [lit.10f
116e118 ꢁC; lit.10g 117e119 ꢁC]; [
a
]
ꢀ63.4 ꢁC (c 1.02, MeOH)
D25
25
25
[lit.10f
[
a]
ꢀ64 ꢁC (c 0.95, MeOH); lit.10g
[
a
]
D
ꢀ63 ꢁC (c 1.0,
D
MeOH)]; IR (film): nmax 3352, 2946, 1641, 1331, 1162, 1007 cmꢀ1; 1H
NMR (400 MHz, D2O):
d
4.26 (m, 1H); 4.08 (m, 1H), 3.88 (dd, J¼6.64,
11. (a) Liu, R.-C.; Wei, J.-H.; Wei, B.-G.; Lin, G.-Q. Tetrahedron: Asymmetry 2008, 19,
2731; (b) Liu, R.-C.; Huang, W.; Ma, J.-Y.; Wei, B.-G.; Lin, G.-Q. Tetrahedron Lett.
2009, 50, 4046; (c) Ma, J.-Y.; Xu, L.-F.; Huang, W.-F.; Wei, B.-G.; Lin, G.-Q. Synlett
2009, 1307.
9.06 Hz, 1H), 3.37 (m, 1H), 2.91 (m, 1H), 2.09e2.06 (m, 3H),
1.89e1.85 (m, 1H), 1.74e1.65 (m, 1H), 1.542e1.46 (m, 2H) ppm; 13C
NMR (D2O, 100 Hz):
d 71.2, 70.4, 68.3, 64.8, 62.1, 53.7, 31.4,
20.9 ppm; HRMS (MALDI/DHB) calcd for [C8H15NO3þNaþ]:
12. Huang, W.-F.; Li, Q.-R.; Chao, L.-M.; Lei, X.-S.; Wei, B.-G. Tetrahedron Lett. 2010,
51, 4317.
196.0950, found: 196.0942.
13. (þ)-4 (DRB) was found in Morus alba, which is a potent inhibitor of glucosidase
and of eukaryotic DNA polymerases. The enantiomer (ꢀ)-4 of 1,4- dideoxy-1,4-
Acknowledgements
imino-
years.
D-ribitol was been widely synthesized extensively studied in past thirty
14. For the syntheses of 1,4-dideoxy-1,4-imino-
L
-ribitol (LRB) (ꢀ)-4, see: (a) Setoi,
We thank the National Natural Science Foundation of China
(21072034, 20832005, 20702007) and the National Basic Research
Program (973 program) of China (grant no. 2010CB912600) for fi-
nancial support.
H.; Kayakiri, H.; Takeno, H.; Hashimoto, M. Chem. Pharm. Bull. 1987, 35, 3995;
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