Novel asymmetric total synthesis of the natural (+)-6-epicastanospermine

Article abstract of DOI:10.1016/S0040-4020(02)01258-9

An efficient noncarbohydrate-based enantioselective synthesis of (+)-6-epicastanospermine has been developed utilizing the Sharpless asymmetric aminohydroxylation of furyl acrylate and oxidation of α-furfurylamine derivative 17 as key steps.

Full text of DOI:10.1016/S0040-4020(02)01258-9

Tetrahedron 59 (2003) 2015–2020
Novel asymmetric total synthesis of the natural
(1)-6-epicastanospermine
Hong-Xing Zhang,a Peng Xiab and Wei-Shan Zhouc
,
*
aDepartment of Chemistry, Medical Center of Fudan University, Shanghai 200032, People’s Republic of China
bDepartment of Medicinal Chemistry, School of Pharmacy, Medical Center of Fudan University, Shanghai 200032,
People’s Republic of China
cShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Received 5 September 2002; accepted 26 September 2002
Abstract—An efficient noncarbohydrate-based enantioselective synthesis of (þ)-6-epicastanospermine has been developed utilizing the
Sharpless asymmetric aminohydroxylation of furyl acrylate and oxidation of a-furfurylamine derivative 17 as key steps. q 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction
We have been interested in exploiting dihydropyridones 2,
which are produced by oxidation of a-furfuryl amines 1, as
key intermediates in the asymmetric total syntheses of a
variety of polyhydroxylated alkaloids (Scheme 1). The
application of this strategy has resulted in syntheses of (þ)-
Figure 1.
azimic acid, (þ)-desoxoprosophylline, prosophylline
swainsonine and azasugars.1 As an extension of this work,
powerful inhibitor of amyloglucosidase (an exo-1,4-a-
we were intrigued by the possibility of using this strategy to
glucosidase) but does not inhibit either a-mannosidase or
realize polyhydroxylated alkaloids of the indolizidine
b-glucosidase.11
family.2 Among the polyhydroxylated indolizidine alka-
loids, castanospermine 3 and its derivatives have been the
During the studies of structure–activity relationships, a
most popular targets for synthetic investigations. Casta-
number of natural and unnatural derivatives of casta-
nospermine 3 (Fig. 1), isolated from the seeds of the
nospermine have been synthesized,12 utilizing a common
Australian legume Castanospermum australe3 and the dried
synthetic approach in which appropriate carbohydrate
pod of Alexa leiopetala,4 has been shown to be a potent
precursors were used. With the advancement in tech-
competitive and reversible inhibitor of various glyco-
nologies for enantioselective synthesis, non-carbohydrate
sidases.5 It has potential for the treatment of diabetes,6
derived syntheses are becoming increasingly popular. We
obesity,7 cancer,6b,8 and viral infections.9,10 (þ)-6-Epi-
recently reported the use of a-furfurylamine as a precursor
castanospermine 4, coexisting with castanospermine in the
for the synthesis of 1-deoxy-6-epicastanospermine 5.13
Australian legume Castanospermum australe,11 is a
Recently, we have extended the approach to the synthesis
of 6-epicastanospermine14 by using b-hydroxy-a-furfuryl-
amine 9 as a precursor. Herein, we wish to report our result
in details.
As shown in the retrosynthetic analysis (Scheme 2), the key
intermediate of our approach is the enantiopure b-hydroxy-
a-furfurylamine 9 that could be prepared from the Sharpless
Scheme 1.
asymmetric aminohydroxylation of furyl acrylate.15 One of
the attractive features of this approach lay in its inherent
Keywords: total synthesis; castanospermine; 6-epicastanospermine;
dihydropyridone; a-furfurylamine.
flexibility since the stereoselectivity of Sharpless asym-
metric aminohydroxylation of furyl acrylate could be
controlled by employing different ligands.
*
Corresponding author. Tel.: þ86-21-6416-3300; fax: þ86-21-6416-6128;
e-mail: zhws@pub.sioc.ac.cn
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01258-9

2016
H.-X. Zhang et al. / Tetrahedron 59 (2003) 2015–2020
yield. Reaction of 12 with KCN in EtOH/H2O (3:2) at room
temperature gave probably an epoxide as a white solid and
then nitrile 13. After we failed to reduce nitrile 13 with
Raney Ni in the presence of Et3NHþH2PO22·1.5H2O17 to
give aldehyde 15, we turned to use diisobutylaluminum
hydride (DIBAL-H) as the reducing agent. The reduction of
nitrile 13 with an excess of DIBAL-H proceeded very
slowly at 2658C. Considering the likely complexation of
the naked hydroxyl group with DIBAL-H would retard the
reduction, we tried to protect the hydroxyl group with BnBr/
NaH, BnBr/Ag2O and MOMCl, but failed because of low
yield as well as the formation of complex byproducts. After
the hydroxyl group was protected by trimethylsilyl chloride
successfully, the silyl ether 14 was reduced smoothly with
DIBAL-H. Without further separation, the resulted alde-
hyde 15 was further reduced by sodium borohydride to give
the diol 16. It should be noted that reduction of nitrile 13
with DIBAL-H in toluene or THF failed because of low
solubility or low reactivity. Modification of the DIBAL-H
reduction conditions by changing the solvent to tert-butyl
methyl ether and working up with 30% HOAc–H2O18
increased the yield up to 70% for two steps. Working up
with 30% HOAc–H2O not only decomposed the aluminum
complex for a smooth extraction, but also deprotected the
trimethylsiyl group at the same time. The diol 16 was
protected by Ac2O to give diacetate 17.
Scheme 2.
Scheme 3.
2. Results and discussion
Construction of the piperidine ring of 4 began with the
oxidation of compound 17 by m-CPBA to give dihydro-
pyridone 18 (Scheme 5). After protecting the hydroxyl
group of 18 with triethyl orthoformate, the dihydropyridone
19 was stereoselectively reduced by sodium borohydride in
the presence of cerium chloride heptahydrate (CeCl3·7H2O)
to give 20, in which the configuration of the newly
formed stereocenter was assigned by NOESY spectroscopic
Asymmetric aminohydroxylation of furyl acrylate 10 by the
reported procedure15 using (DHQ)2PHAL as the chiral
ligand yielded b-hydroxy-a-furfurylamine 9 in 62% yield
and 87% ee (Scheme 3).15a Homologation of the side chain
of compound 9 began with its reduction with an excess of
sodium borohydride at room temperature to give diol 1116
(Scheme 4). Selective tosylation of the primary hydroxyl
group of 11 with TsCl in pyridine gave tosylate 12 in 94%
Scheme 4. Reagents and conditions: (a) NaBH4, EtOH, rt, 94%; (b) TsCl, pyridine, 94%; (c) KCN, EtOH, H2O, 96%; (d) Me3SiCl, Et3N, CH2Cl2, 99%; (e) (i)
DIBAL-H, (CH3)3COCH3, 2788C; (ii) HOAc/H2O; (f) NaBH4, MeOH, 70% from 14; (g) Ac2O, Et3N, DMAP, CH2Cl2, 95%.
˚
Scheme 5. Reagents and conditions: (a) m-CPBA, CH2Cl2, 16 h, 88%; (b) HC(OEt)3, BF3·OEt2, 4 A MS, THF, 08C, 94%; (c) NaBH4, CeCl3·7H2O, MeOH,
2788C, 99%; (d) PhCO2H, PPh3, DEAD, THF, 92%; (e) NaBH4, HCO2H, 88%; f) K3Fe(CN)6, (DHQ)2PHAL, K2CO3, K2OsO2(OH)4, CH3SO2NH2, t-BuOH,
H2O, 79%; g) (i) H2, 10% Pd–C, EtOH, 3 h; (ii) K2CO3, MeOH, rt 10 h; (h) Ph3P, CCl4, Et3N, DMF, 62% from 23.

H.-X. Zhang et al. / Tetrahedron 59 (2003) 2015–2020
2017
analysis to be of R-form, which is opposite to that in the
target molecule. Thus, Mitsunobu reaction19 was employed
to invert the configuration of this hydroxyl group and as a
result benzoate 21 was obtained. After reductive
deethoxylation of 21 by using NaBH4 in formic acid,1c
Sharpless asymmetric dihydroxylation20 was used to
introduce two hydroxyl groups which afforded 1,2-glycol
23 with indicatedconfiguration asdeduced by2D-1H NOESY
study.
pressure. The crude product was then purified by flash
chromatography on silica gel (hexane/AcOEt, 10:10) to
afford a colorless solid 11 (1.37 g, 94%). Mp 92–938C;
1
[a]1D7¼þ42.5 (c¼0.8, CHCl3); H NMR d: 2.48–2.56 (m,
2H, OH), 3.59 (m, 2H, H-1), 4.12 (s, 1H, NH), 5.02 (m, 1H,
H-2), 5.14 (m, 2H, CH2Ph), 5.48 (d, 1H, J¼7.16 Hz, H-3),
6.31 (s,01H, H-30), 6.35 (m, 1H, H-40), 7.33–7.38 (m, 6H,
Ph, H-5 ); IR: 3526 (OH), 3327 (NH), 1686 (CvO) cm21
;
MS m/z: 292 (Mþþ1), 230 (Mþ2CCHOHCH2OH), 91
(CH2Ph); Anal. calcd for C15H17NO5: C, 61.85; H, 5.88; N,
4.81. Found: C, 61.86; H, 5.80; N, 4.72.
Having introduced the three desirable hydroxyl groups to
the six-membered ring, all that remained was the construc-
tion of the final bicyclic skeleton of 4. The protecting groups
in 23 were removed by catalytic hydrogenation on 10% Pd–
C followed by hydrolysis (K2CO3, H2O). Treatment of 24
with 2 equiv. of PPh3/CCl4/Et3N (1:1:1)21 in anhydrous
DMF at room temperature in the darkness resulted in the
complete conversion of monocyclic 24 into the expected
bicyclic (þ)-6-epicastanospermine 4 in 87% yield (62%
yield from 23). The 1H and 13C NMR spectral data matched
those reported in the literature11,22 {[a]D26¼þ3.0 (c¼1.3,
MeOH); lit.,22 [a]2D0¼þ2.2 (c¼0.7, MeOH), lit.11 [a]2D4¼þ8
(c¼1.09, MeOH)}.
3.1.2. (2R,3R)-3-(Carbobenzoxyamino)-3-(20-furyl)-1-(p-
tolylsulfonyloxy)-2-propanol (12). To a solution of diol 11
(673 mg, 2.3 mmol) in dry pyridine (4 mL) at 08C was
added a solution of TsCl (529 mg, 2.8 mmol) in pyridine
(3 mL) dropwise. After the addition, the solution was stirred
at 08C for 4.5 h and then poured into a mixture of ethyl
acetate (100 mL) and cold water (20 mL). The layers were
separated, and the organic layer was washed with water
(20 mL), 2N HCl (20 mL) and saturated NaCl (20 mL) in
turn, dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The crude product was then purified by
flash chromatography on silica gel (hexane/AcOEt, 30:10–
10:10) to afford 12 (0.967 g, 94%) as a colorless oil.
In conclusion, the asymmetric total synthesis of the natural
(þ)-6-epicastanospermine 4 was achieved in 15 steps and
19% overall yield starting from b-hydroxy-a-furfurylamine
derivative. Most significantly, the generality of this
approach would allow us to synthesize other polyhydroxyl-
ated indolizidines.
1
[a]2D0¼þ18.3 (c¼0.9, CHCl3); H NMR d: 2.45 (s, 1H, Ts-
CH3), 2.74 (br s, 1H, OH), 4.08 (m, 2H, H-1), 4.28 (br s, 1H,
NH), 4.91 (dd, 1H, J¼4.00, 9.01 Hz, H-2), 5.10 (s, 2H,
CH2Ph), 5.43 (br s, 1H, H-3), 6.25 (d, 1H, J¼2.80 Hz, H-30),
6.32 (dd, 1H, J¼1.79, 3.21 Hz, H-40), 7.24–7.35 (m, 8H, H-50
and Ph), 7.79 (d, 2H, J¼8.14 Hz, Ph); IR: 3381 (NH, OH),
1702 (C¼O) cm-1; MS m/z: 354 (Mþ2CH2Ph), 257
(Mþ2OH–OTs), 230 (Mþ2CHOHCH2OTs), 91 (CH2Ph);
Anal. calcd for C22H23NO7S: C, 59.31; H, 5.20; N, 3.14.
Found: C, 59.21; H, 5.38; N, 2.86.
3. Experimental
3.1. General
3.1.3. (3S,4R)-4-(Carbobenzoxyamino)-4-(20-furyl)-3-
hydroxybutanenitrile (13). To a solution of 12 (6.85 g,
15.4 mmol) in ethanol (34 mL) was added water (23 mL).
The resulting suspension was cooled to 08C and KCN (5.0 g,
76.8 mmol) was added. After the solution was stirred at
room temperature for 10 min, the epoxide was formed as
white precipitate, which disappeared gradually to give a
purple solution. After 10 h, ethanol was evaporated in
vacuo, and water (50 mL) was added to the residue. The
resulting mixture was extracted with ethyl acetate
(3£100 mL). The combined organic layer was washed
with saturated NaCl (20 mL), dried over anhydrous Na2SO4
and concentrated under reduced pressure. The crude product
was then purified by flash chromatography on silica gel
(hexane/AcOEt, 20:10–10:10) to afford 13 (4.45 g, 96%) as
a pale yellow solid. Mp 105–1068C; [a]1D6¼þ22.6 (c¼1.3,
CHCl3); 1H NMR d: 2.55 (m, 2H, H-2), 3.03 (br s, 1H, OH),
4.36 (br s, 1H, NH), 4.91 (m, 1H, H-3), 5.14 (s, 2H, CH2Ph),
5.48 (m, 1H, H-4), 6.34 (m, 1H, H-30), 6.36 (m, 1H, H-40),
7.56 (m, 5H, Ph), 7.39 (m, 1H, H-50); IR: 3408 (OH), 3319
(NH), 2260 (CN), 1690 (CvO) cm21; MS m/z: 301
(Mþþ1), 230 (M22CH2OHCH2CN), 91 (CH2Ph); Anal.
calcd for C16H16N2O4: C, 63.99; H, 5.37; N, 9.33. Found: C,
64.19; H, 5.39; N, 9.37.
Melting points were determined with a Bu¨chi 535 melting
point apparatus and were uncorrected. Reactions were
monitored by using thin layer chromatography (TLC). The
silica gel H (10–40 mm) used in flash chromatography was
produced by Qingdao Chemical Plant, China. IR spectra
1
were measured on a Shimadzu IR 400 spectrometer. H
NMR and 13C NMR spectra were recorded on a Bruker AM-
300 (300 MHz) with CDCl3 as solvent and values were
reported in ppm using TMS or residual CHCl3 as internal
standard. MS spectra were conducted on a Finnigan 4021
GC-MS instrument and JMS-01U spectrometer. The optical
rotations, [a]2D0, were measured on a Perkin–Elmer 241 MC
automatic polarimeter in a 1-dm cell and recorded in units of
1021 deg cm2 g21. Element analysis were performed by the
Analytical Department of this institute. Dichloromethane
was distilled from calcium hydride. Tetrahydrofuran was
freshly distilled from Na-benzophenone.
3.1.1. (2R,3R)-3-(carbobenzoxyamino)-3-(20-furyl)-1,2-
propanediol (11). To a solution of 9 (1.67 g, 5.00 mmol)
in absolute EtOH (15 mL) was added NaBH4 (284 mg,
7.5 mmol) in small portions. After the solution was stirred at
room temperature for 30 min, the solvent was evaporated,
and water (10 mL) was added. The resulting solution was
extracted with ethyl acetate (3£30 mL). The combined
organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated under reduced
3.1.4. (3S,4R)-4-(Carbobenzoxyamino)-4-(20-furyl)-3-tri-
methylsilyloxybutanenitrile (14). To a solution of 13

2018
H.-X. Zhang et al. / Tetrahedron 59 (2003) 2015–2020
(2.23 g, 7.43 mmol) in CH2Cl2 (20 mL) and Et3N (4.14 mL,
29.7 mmol) at 08C was slowly added Me3SiCl (1.88 mL,
14.8 mmol). The resulting solution was allowed to warm to
room temperature and stirred for 3 h. The mixture was then
diluted with water (20 mL) and extracted with ethyl acetate
(3£50 mL). The combined organic extracts were washed
with saturated NaCl (20 mL), dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The crude
product was then purified by flash chromatography on silica
gel (hexane:AcOEt, 60:10) to afford 14 (2.75 g, 99%) as a
with ethyl acetate (3£30 mL). The combined organic layer
was washed with saturated NaCl (10 mL), dried over
anhydrous Na2SO4 and concentrated under reduced
pressure. The crude product was purified by flash chroma-
tography on silica gel (hexane/AcOEt, 40:10) to afford 17
(771 mg, 95%) as a yellow oil. [a]1D6¼þ15.1 (c¼1, CHCl3);
1H NMR d: 1.92 (m, 2H, H-2), 1.96 (s, 3H, Ac), 2.04 (s, 3H,
Ac), 4.08 (m, 2H, H-1), 5.04 (m, 1H, NH), 5.12 (m, 2H,
CH2Ph), 5.33 (d, 1H, J¼9.11 Hz, H-3), 5.41 (m, 1H, H-4),
6.23 (br s, 1H, H-30), 6.32 (br s, 1H, H-40), 7.36 (br s, 6H, H-
50 and Ph); IR: 3335 (NH), 1741 (C¼O) cm-1; MS m/z: 330
(Mþ2OAc), 230 (Mþ2CHOAcCH2CH2OAc), 91
(CH2Ph); Anal. calcd for C20H23NO7: C, 61.69; H, 5.95;
N, 3.60. Found: C, 61.80; H, 6.13; N, 3.49.
1
yellow oil. [a]1D9¼þ1.0 (c¼1, CHCl3); H NMR d: 20.02
(m, 9H, TMS), 2.57 (m, 2H, H-2), 4.45 (br s, 1H, NH), 4.89
(d, 1H, J¼9.47 Hz, H-3), 5.15 (s, 2H, CH2Ph), 5.48 (d, 1H,
J¼9.10 Hz, H-4), 6.20 (d, 1H, J¼3.27 Hz, H-30), 6.34 (dd,
1H, J¼2.02, 3.24 Hz, H-40), 7.38 (m, 6H, H-50 and Ph); IR:
3332 (NH), 2251 (CN), 1723 (CvO) cm21; MS m/z: 373
(Mþþ1), 230 (Mþ2CH2OTMSCH2CN), 91 (CH2Ph);
Anal. calcd for C19H24N2O4Si: C, 61.26; H, 6.49; N, 7.52.
Found: C, 60.99; H, 6.74; N, 7.45.
3.1.7. (2R,6j,10S)-2-((10,30-Diacetoxy)propyl)-1-carbo-
benzoxy-6-hydroxy-1,2,3,6-tetrahydropyridin-3-one
(18). To a solution of 17 (820 mg, 2.10 mmol) in CH2Cl2
(20 mL) was added 3-chloroperoxybenzoic acid (m-CPBA,
417 mg, 2.42 mmol). After the solution was stirred for 16 h
at room temperature, the solvent was evaporated under
reduced pressure to give a solid which was purified by flash
chromatography on silica gel (hexane/AcOEt, 40:10 and
20:10) to afford 18 (753 mg, 88%) as a yellow oil.
3.1.5. (3S,4R)-4-(Carbobenzoxyamino)-4-(20-furyl)-1,3-
butanediol (16). To a solution of 14 (1.26 g, 3.39 mmol)
in (CH3)3COCH3 (25 mL) at 2788C was added dropwise
the toluene solution of DIBAL-H (1.0 M, 7.5 mL) over 1 h,
maintaining the temperature between 278 and 2658C.
After the solution was stirred at 2788C for an additional
2.5 h, MeOH (0.2 mL) was added to terminate the reaction.
The mixture was poured into acetic acid solution (30%,
25 mL) and stirred for 0.5 h. The layers were separated, and
the aqueous layer was extracted with ether (5£30 mL). The
combined organic layers were washed with saturated
NaHCO3 (2£10 mL), saturated NaCl (20 mL), dried over
anhydrous Na2SO4 and concentrated under reduced pressure
to give aldehyde 15 (974 mg) as a colorless oil. To the
solution of the crude aldehyde 15 in MeOH (20 mL) at room
temperature was added NaBH4 (188 mg, 4.97 mmol) in
portions. After being stirred at room temperature for 20 min,
the mixture was concentrated. The residue was partitioned
between ethyl acetate (30 mL) and water (20 mL). The
aqueous layer was extracted with ethyl acetate (3£30 mL).
The combined organic layer was washed with saturated
NaCl (10 mL), dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The crude product was
purified by flash chromatography on silica gel (hexane/
AcOEt, 10:10) to afford 16 (727 mg, 70% from 14) as
colourless prisms. Mp 74–768C; [a]1D6¼þ37.1 (c¼1,
[a]1D6¼þ25.8 (c¼1.5, CHCl3); H NMR d: 1.85–2.00 (m,
1
5H, H-20 and Ac), 2.05 (s, 3H, Ac), 3.75–4.08 (m, 2H, H-
30), 4.97 (m, 1H, H-10), 5.24 (s, 2H, CH2Ph), 5.33–5.52 (m,
1H, H-2), 6.10 (m, 1H, H-6), 6.18 (d, 1H, J¼10.35 Hz, H-4),
6.95 (m, 1H, H-5), 7.37 (m, 5H, Ph); IR: 3458 (OH), 1741,
1709, 1692 (CvO), 1640 (CvC) cm21; MS m/z: 388
(Mþþ12H2O),
328
(Mþþ22H2O–OAc),
289
(Mþþ222OAc), 91 (CH2Ph); Anal. calcd for C20H23NO8:
C, 59.25; H, 5.72; N, 3.45. Found: C, 58.95; H, 5.91; N,
3.27.
3.1.8. (2R,6j,10)-2-((10,30-Diacetoxy)propyl)-1-carboben-
zoxy-6-ethoxy-1,2,3,6-tetrahydropyridin-3-one (19). To a
˚
suspension solution of 4 A molecular sieves (160 mg) in
THF (10 mL) at 08C were sequentially added 18 (930 mg,
2.29 mmol), triethylorthoformate (0.95 mL, 5.7 mmol) and
BF3·Et2O (50 ml). After 3 h at 08C, 10 mL of water was
added. The layers were separated, and the aqueous layer was
extracted with ethyl acetate (3£10 mL). The combined
organic layer was washed with brine, dried over anhydrous
Na2SO4 and concentrated under reduced pressure. The
crude product was purified by flash chromatography on
silica gel (hexane/AcOEt, 40:10) to afford 19 (0.940 g,
1
CHCl3); H NMR d: 1.70–1.90 (m, 2H, H-2), 2.17 (br s,
1
1H, OH), 2.93 (br s, 1H, OH), 3.88 (m, 2H, H-1), 4.29 (m,
1H, NH), 4.84 (d, 1H, J¼6.70 Hz, H-3), 5.13 (s, 2H,
CH2Ph), 5.55 (m, 1H, H-4), 6.27 (d, 1H, J¼2.90 Hz, H-30),
6.34 (dd, 1H, J¼2.02, 3.24 Hz, H-40), 7.37 (m, 6H, H-50 and
Ph); IR: 3343 (NH), 1689 (CvO) cm21; MS m/z: 306
(Mþþ1), 230 (Mþ2CH2OHCH2CH2OH), 91 (CH2Ph);
Anal. calcd for C16H19NO5: C, 62.94; H, 6.27; N, 4.59.
Found: C, 62.96; H, 6.24; N, 4.35.
94%) as an oil. [a]D15¼þ21.7 (c¼2, CHCl3); H NMR d:
1.20 (m, 3H, EtO–CH3), 1.85–2.00 (m, 5H, H-20and Ac),
2.05 (s, 3H, Ac), 3.74 (m, 2H, EtO–CH2), 4.11 (m, 2H,
H-30), 4.87–5.03 (m, 1H, H-10), 5.16 (m, 1H, H-2), 5.31 (m,
2H, CH2Ph), 5.96 (m, 1H, H-5), 6.11 (d, 1H, J¼10.29 Hz,
H-4), 6.96 (m, 1H, H-6), 7.33 (m, 5H, Ph); IR: 1745, 1710
(CvO) cm21; MS m/z: 434 (Mþþ1), 388 (Mþ2EtO), 374
(Mþ2OAc), 91 (CH2Ph); Anal. calcd for C22H27NO8: C,
60.96; H, 6.29; N, 3.23. Found: C, 60.96; H, 6.35; N,
3.05.
3.1.6. (3S,4R)-4-(Carbobenzoxyamino)-4-(20-furyl)-1,3-
butanediol, diacetate (17). To a solution of 16 (636 mg,
2.08 mmol), DMAP (20 mg) and Et3N (0.87 mL,
6.25 mmol) in CH2Cl2 (8 mL) was added Ac2O (0.29 mL,
3.12 mmol) slowly. The mixture was stirred at room
temperature for 1 h and then poured into ice water. The
layers were separated and the aqueous layer was extracted
3.1.9. (2R,3R,6j,10)-2-((10,30-Diacetoxy)propyl)-1-carbo-
benzoxy-6-ethoxy-3-hydroxy-1,2,3,6-tetrahydropyridine
(20). To a solution of 19 (531 mg, 1.22 mmol) in methanol
(12 mL) was added CeCl3·7H2O (228 mg, 0.61 mmol).
After the solution was cooled to 2788C, NaBH4 (46 mg,

H.-X. Zhang et al. / Tetrahedron 59 (2003) 2015–2020
2019
1.2 mmol) was added in small portions. The resulting
mixture was stirred for 10 min, and water (7 mL) was added
to quench the reaction. The layers were separated, and the
aqueous layer was extracted with ethyl acetate (3£10 mL).
The combined organic layer was washed with brine (5 mL),
dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by flash
chromatography on silica gel (hexane/AcOEt, 30:10) to
afford an oil 20 (531 mg, 99%). [a]1D5¼257.3 (c¼1.4,
Ac), 2.04 (m, 5H, H-200and Ac), 3.50–3.75 (m, 2H, EtO–
CH2), 4.12 (m, 2H, H-3 ), 4.24 (m, 1H, H-2), 4.30, (br s, 1H,
OH), 4.60 (m, 1H, H-3), 5.19 (m, 3H, H-10and CH2Ph), 5.59
(m, 2H, H-4 and H-5), 5.72 (m, 1H, H-6), 7.37 (m, 5H, Ph);
IR: 3456 (OH), 1740, 1709 (CvO) cm21; MS m/z: 390
(Mþ2EtO), 300 (Mþ2Cbz), 346 (Mþþ12OAc–Et), 91
(CH2Ph); Anal. calcd for C22H29NO8: C, 60.68; H, 6.71; N,
3.22. Found: C, 60.48; H, 6.71; N, 3.19.
3.1.12. (2R,3S,4R,5R,10S)-2-((10,30-Diacetoxy)propyl)-1-
carbobenzoxy-3-benzoyloxy-4,5-dihydroxypiperidine
(23). To a solution of 22 (124 mg, 0.25 mmol) in tert-
butyl alcohol (2 mL) and water (2 mL) at 08C were
added K3[Fe(CN)6] (247 mg, 0.75 mmol), (DHQ)2PHAL
(10 mg, 5% equiv.), K2CO3 (104 mg, 0.75 mmol), CH3-
SO2NH2 (24 mg, 0.25 mmol) and K2OsO2(OH)4 (5 mg,
5% equiv.). After the mixture was stirred at 08C for 2 h,
the reaction was quenched by addition of Na2SO3
(0.094 g). Water (10 mL) was added after 30 min and
the resulting mixture was extracted with ethyl acetate
(3£30 mL). The combined organic layer was washed with
brine (10 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product
was purified by flash chromatography on silica gel
(hexane/AcOEt, 10:10) to afford a colorless oil 23
(105 mg, 79%). [a]D14¼236.9 (c¼1, CHCl3); 1H NMR
d: 1.83 (s, 3H, A0c), 2.00 (s, 3H, Ac), 2.10 (m, 1H, H-20),
2.30 (m, 1H, H-2 ), 3.29 (m, 2H, H-6), 4.08–4.20 (m, 4H,
H-30 and H-2, H-4), 4.49 (m, 1H, H-5), 5.06–5.20 (m,
2H, CH2Ph), 5.39 (m, 1H, H-10), 5.82 (m, 1H, H-3),
7.10–7.1 (m, 2H, Ph), 7.32–7.43 (m, 4H, Ph), 7.58 (m,
2H, Ph), 7.90 (d, 2H, J¼7.35 Hz, Ph); IR: 1743, 1714
(CvO) cm21; MS m/z: 530 (Mþþ1), 470 (Mþ2OAc),
1
CHCl3); H NMR d: 1.14 (m, 3H, EtO–CH3), 1.95 (s, 3H,
3.1.10. (2R,3S,6j,10)-2-((10,30-Diacetoxy)propyl)-1-carbo-
benzoxy-6-ethoxy-3-benzoyloxy-1,2,3,6-tetrahydropyri-
dine (21). To a solution of 20 (483 mg, 1.11 mmol) in dry
THF (12 mL) at room temperature were added triphenyl
phosphine (582 mg, 2.22 mmol), benzoic acid (271 mg,
2.22 mmol)
and
diethylazodicarboxylate
(DEAD)
424 (Mþ2Bz), 91 (CH2Ph); IR: 3451, 1739, 1722 cm21
;
(0.35 mL, 2.22 mmol). After the mixture was stirred for
2 h, the solvent was evaporated under reduced pressure and
the residue was purified by flash chromatography on silica
gel (hexane/AcOEt, 50:10) to give 21 (550 mg, 92%) as a
Anal. calcd for C27H31NO10: C, 61.24; H, 5.90; N, 2.65.
Found: C, 61.24; H, 5.83; N, 2.50.
3.1.13. (1S,6R,7R,8S,8aR)-1,6,7,8-Tetrahydroxy-indolizi-
dine (6-epicastanospermine) (4). To a solution of 23
(120 mg, 0.23 mmol) in ethanol (3 mL) was added catalytic
amount of 10% Pd/C (12 mg). After being stirred under H2
atmosphere (1 atm) at room temperature for 5 h, the mixture
was filtered and the solvent was evaporated under reduced
pressure. The residue was dissolved in methanol (3 mL),
and then K2CO3 (96 mg, 0.69 mmol) was added. After the
resulting solution was stirred at room temperature for 24 h,
the solvent was evaporated under reduced pressure. The
residue was purified by chromatography on Dowex-50 (Hþ)
(first elution with MeOH, then with strong aqueous
ammonia) to afford 24 (41.5 mg). The crude 24 was
dissolved in dry DMF (0.5 mL), and then triphenyl
phosphine (3.5 mg) and CCl4 (0.033 mL) were added.
After 10 min, Et3N (0.044 mL) was added, and the mixture
was stirred at room temperature for 20 h. Methanol (0.3 mL)
was added to quench the reaction. The solvent was
evaporated, and the residue was purified by flash chroma-
tography on silica gel (CHCl3–MeOH, 2:1) to give a yellow
oil 4 (26.3 mg, 62%). [a]2D6¼þ3.0 (c 1.3, MeOH); 1H NMR
(D2O) d: 1.74 (m, 1H, H-2), 2.01 (dd, 1H, J¼4.20, 9.70 Hz,
H-8a), 2.21 (m, 1H, H-3), 2.31–2.40 (m, 2H, H-5 and H-2),
3.12 (m, 2H, H-3 and H-5), 3.54 (dd, 1H, J¼3.45, 9.52 Hz,
H-7), 3.89 (t, 1H, J¼9.65 Hz, H-8), 4.02 (m, 1H, H-6),
4.41 (m, 1H, H-1); 13C NMR (D2O) d: 35.3 (C2), 54.4 (C3),
57.9 (C5), 69.8 (C8), 71.4 (C6), 72.7 (C1), 74.4 (C8a), 77.9
(C7).
1
colourless oil. [a]D15¼þ152.4 (c¼1, CHCl3); H NMR d:
1.20 (m, 3H, EtO–CH3), 1.74 (m, 1H, H-20), 1.99 (s, 3H,
Ac), 2.05 (s, 3H, Ac), 2.25 (m, 1H, H-20), 3.49–3.70 (m, 2H,
EtO–CH2), 4.19 (m, 3H, H-30 and H-2), 4.87–5.00 (m, 1H,
H-10), 5.11 (m, 2H, CH2Ph), 5.48 (m, 1H, H-3), 5.63–5.78
(m, 1H, H-6), 6.16 (m, 2H, H-4 and H-5), 7.23–7.57 (m, 8H,
Ph), 7.94 (m, 2H, Ph); IR: 1743, 1713 (CvO) cm21; MS
m/z: 540 (Mþþ1), 494 (Mþ2EtO), 480 (Mþ2OAc), 450
(Mþþ12Et–OAc), 434 (Mþ2OBz), 91 (CH2Ph); Anal.
calcd for C29H33NO9: C, 64.55; H, 6.16; N, 2.60. Found: C,
64.51; H, 6.24; N, 2.75.
3.1.11. (2R,3S,10S)-2-((10,30-Diacetoxy)propyl)-1-carbo-
benzoxy-3-benzoyloxy-1,2,3,6-tetrahydropyridine (22).
To a solution of 21 (523 mg, 0.97 mmol) in 88% formic
acid (3 mL) was added NaBH4 (93 mg, 2.46 mmol) in
portions at 08C. After being stirred for 0.5 h at 08C, the
mixture was diluted with ethyl acetate (10 mL). The resulting
mixture was neutralized with saturated NaHCO3. The layers
wereseparated, and the aqueous layerwas extracted with ethyl
acetate (3£30 mL). The combined organic layer was washed
with brine (10 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was
purifiedbyflashchromatographyonsilicagel(hexane/AcOEt,
40:10) to afford an oil 22 (421 mg, 88%). [a]1D5¼þ22.6
(c¼1.2, CHCl3); 1H NMR d: 1.75 (m, 1H, H-20), 1.90 (s, 3H,
Ac), 2.05 (m, 4H, H-20 and Ac), 3.80 (m, 1H, H-2), 4.15 (m,
2H, H-30), 4.50 (m, 1H,0H-6), 4.76 (dd, 1H, J¼7.01, 32.80 Hz,
H-6), 5.20 (m, 3H, H-1 and CH2Ph), 5.50 (m, 1H, H-3), 5.98
(m, 1H, H-4), 6.15 (m, 1H, H-5), 7.23–7.57 (m, 8H, Ph), 7.93
(m, 2H, Ph); IR: 1743, 1714(CvO) cm21; MSm/z: 495 (Mþ),
436 (Mþ2OAc), 390 (Mþ2Bz), 91 (CH2Ph); Anal. calcd for
C27H29NO8: C, 65.44; H, 5.90; N, 2.83. Found: C, 65.43; H,
5.87; N, 2.69.
Acknowledgements
Project (29872046) supported by the National Natural
Science Foundation of China.

2020
H.-X. Zhang et al. / Tetrahedron 59 (2003) 2015–2020
Biochem. Biophys. Res. Commun. 1987, 148, 206–210.
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