Concise synthesis of two advanced intermediates for the asymmetric synthesis of polyhydroxylated indolizidine alkaloids

Article abstract of DOI:10.1007/s11426-010-4065-1

A concise five-step approach to indolizidinones 10 and 11, two advanced intermediates for the asymmetric synthesis of polyhydroxylated indolizidine alkaloids, has been developed by using N-Cbz pyrrolidin-2-yl pyridin-2-yl sulfide 13 as the chiral building

Full text of DOI:10.1007/s11426-010-4065-1

SCIENCE CHINA
Chemistry
September 2010 Vol.53 No.9: 1914–1920
doi: 10.1007/s11426-010-4065-1
• ARTICLES •
Concise synthesis of two advanced intermediates for the
asymmetric synthesis of polyhydroxylated indolizidine alkaloids
ZHENG Xiao1,2, ZHU WenFang1 & HUANG PeiQiang1*
1Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
2Key Laboratory of Synthetic Chemistry of Natural Substances; Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Received April 19, 2010; accepted May 31, 2010
A concise five-step approach to indolizidinones 10 and 11, two advanced intermediates for the asymmetric synthesis of poly-
hydroxylated indolizidine alkaloids, has been developed by using N-Cbz pyrrolidin-2-yl pyridin-2-yl sulfide 13 as the chiral
building block. The method features a SmI2-mediated coupling of sulfide 13 with functionalized aldehyde 14 and a tandem
N-deprotection-lactamization, which constitutes a stepwise “2 + 4” annulation method for the construction of the indolizidinone
ring system of 12a.
indolizidinone, samarium diiodide, -amidohydroxyalkylation, tandem reaction, chiral building block
1 Introduction
Polyhydroxylated indolizidine alkaloids have been consid-
ered as sugar mimics due to the structural similarity. Many
of them exhibit significant bioactivities and are investigated
as promising drug candidates [1–3]. For instance, (+)-cas-
tanospermine (1) (Figure 1) is a powerful inhibitor of  and
-glucosidases, and has been considered as a potential chemo-
therapeutic agent for cancers, diabetes, viral infections, and
immunosuppressive deficiencies [4]. Its 6-O-butanoyl de-
rivative, named celgosivir, is currently undergoing phase II
clinical trials for the treatment of HCV infection [5].
()-Swainsonine (2) is a potent inhibitor of -D-mannosidase
and mannosidase II [6], and the first glucosidase inhibitor
entering phase II clinical trials as an anticancer drug [7]. In
addition, based on the pharmacophore model research, some
unnatural indolizidinones have been designed and investi-
gated as medicinal agents. For example, indolizidinone 3
was designed as a mimic scaffold of baccatin core. On
Figure 1
the basis of this scaffold, two novel “taxoid-mimicking”
compounds have been synthesized, which demonstrated no-
table cytotoxicity against human breast cancer cell lines [8].
A number of synthetic strategies for the asymmetric syn-
thesis of polyhydroxylated indolizidine alkaloids and struc-
turally related molecules have been developed [9–11].
Among them, building block based approaches have
achieved much success [12]. For example, unsaturated in-
*Corresponding author (email: pqhung@xmu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2010
chem.scichina.com
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ZHENG Xiao, et al. Sci China Chem September (2010) Vol.53 No.9
1915
dolizidinones 4 [13] and 5 [14] have been used as key in-
termediates for the asymmetric total synthesis of
(+)-castanospermine and (+)-swainsonine, respectively.
In recent years, we have been engaged in the develop-
ment of flexible methods for the asymmetric synthesis of
azasugars, which are based on the key disconnection shown
in Scheme 1. To overcome the challenges associated with
the formation [15, 16] and stereoselective -hydroxyalky-
lation of carbanion A, both indirect and direct methods have
been investigated [17]. In this context, compounds 7 [18], 8
[19] and 9 [20] have been developed as key building blocks
for the synthesis of a variety of 2-hydroxyalkyl-3-pyrrolidi-
nols (6), and compound 9 has been used for the asymmetric
synthesis of castanospermine (1) [20].
As a continuation of the aforementioned studies, we report
herein the construction of two functionalized indolizidinone
derivatives 10 and 11 from an improved pyridin-2-yl sulfide-
type chiral building block 13 using the SmI2-mediated
-amidohydroxyalkylation methodology [18] as the key
step (Scheme 2). In this approach, the N-Cbz-protected
pyrrolidin-2-yl pyridin-2-yl sulfide 13 and functionalized
aldehyde 14 were designed as the synthetic equivalents of E
and F, respectively. According to the literature precedents,
the -lactam moiety in 12 can be used for the diastereose-
lective ,-dihydroxylation 10 (8-epi-B) [13, 21], which can
be easily available via the selenium-based method [22], on
the other hand of 12a, the pyrrolidinol moiety can either be
incorporated into target molecules, or be used for the dihy-
droxylation of C after dehydration of 11 via the Chugaev
reaction [14] or Martin sulfurane [12]. Thus, indolizidi-
nones 10 and 11 can be conceived as two advanced inter-
mediates for the asymmetric synthesis of polyhydroxylated
indolizidine alkaloids and related compounds.
2 Experimental
2.1 General experimental
Melting points were determined on a Yanaco MP-500 micro
melting point apparatus and are uncorrected. Infrared spec-
tra were measured with a Nicolet Avatar 360 FT-IR spec-
1
trometer using film KBr pellet technique. H NMR spectra
were recorded on a Varian unity +500 spectrometer or a
Bruker Avance DPX 400 MHz NMR spectrometer in
CDCl3 with tetramethylsilane as an internal standard.
Chemical shifts are expressed in  (ppm) units downfield
from TMS. Mass spectra were recorded by a Bruker Dalton
Esquire 3000 plus liquid chromatography–mass spectra
(direct injection). Optical rotations were measured with a
Perkin-Elmer 341 automatic polarimeter. Flash column
chromatography was carried out with silica gel (300–400
mesh). THF was distilled over sodium. Dichloromethane
was distilled over P2O5.
2.2 Synthesis of N,O-diprotected pyrrolidin-2-yl pyridin-
2-yl sulfide
(S)-1-Benzyloxycarbonyl-3-(tert-butyldimethylsilyloxy)-2-
pyrrolidinone (16)
To a suspension of NaH (60% in mineral oil, 774 mg, 19.4
mmol) in dry THF (50 mL) was added dropwise a solution
of (S)-3-(tert-butyldimethylsilyloxy)-2-pyrrolidinone 15 (3.78
g, 17.6 mmol) in anhydrous THF (20 mL) at 20 °C under
nitrogen atmosphere. After being stirred for 15 min, the
mixture was warmed to 0 °C, and then Cbz-Cl (3.0 mL, 21
mmol) was added dropwise. The resulting mixture was
stirred at 0 °C for 1 h, quenched with saturated aqueous
NH4Cl (10 mL) and extracted with Et2O (3 × 25 mL). The
combined organic phases were washed with brine (10 mL),
dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel (eluent:EtOAc/PE = 1:5) af-
fording lactam 16 (4.86 g, yield: 79%) as a colorless crystal.
mp 87–88 °C; []D20 45.3 (c 1.04, CHCl3). IR (film): 3066,
Scheme 1
1
2928, 1758, 1724, 1454, 1248, 1169 cm1; H NMR (500
MHz, CDCl3):  0.12 (s, 3H, SiCH3), 0.16 (s, 3H, SiCH3),
0.90 (s, 9H, SiC(CH3)3), 1.95 (dddd, J = 9.2, 9.2, 9.4, 12.6
Hz, 1H, H-4), 2.31 (dddd, J=2.3, 6.8, 7.8, 12.6 Hz, 1H, H-4),
3.54 (ddd, J = 6.8, 9.2, 10.8 Hz, 1H, H-5), 3.85 (ddd, J=2.3,
Scheme 2 Retrosynthetic analysis.

1916
ZHENG Xiao, et al. Sci China Chem September (2010) Vol.53 No.9
9.2, 10.8 Hz, 1H, H-5), 4.34 (dd, J = 7.8, 9.4 Hz, 1H, H-3),
5.28 (s, 2H, PhCH2), 7.28–7.50 (m, 5H, Ph-H) ppm; 13C
NMR (125 MHz, CDCl3):  5.2, 4.5, 18.3, 25.7, 28.4,
41.9, 68.1, 71.5, 128.2, 128.4, 128.6, 135.3, 151.7, 172.6
ppm; MS (ESI, m/z): 372 (M+Na+), 350 (M+H+). Anal.
calcd for C18H27NO4Si: C, 61.86; H, 7.79; N, 4.01. Found:
C, 62.12; H, 7.96; N, 3.58.
20 mL, 2.0 mmol) quickly with vigorous stirring. After the
addition, the cooled bath was removed and the mixture was
stirred for another 10 min. The reaction was quenched with
a saturated aqueous solution of NH4Cl (4.0 mL), and ex-
tracted with Et2O (3 × 15 mL). The combined organic
phases were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica
gel (EtOAc/PE = 1:4) to afford the desired product 18 as a
colorless oil in 50% yield. HPLC: Shim-pack CLC-SIL
(150  4.6), PE/EtOAc = 90:10, 1.5 mL/min,  = 254 nm, t1
35.5 min (48.6%), t2 40.3 min (51.4%). IR (film): 3033,
2954, 1784, 1738, 1701, 1409, 1353, 1255, 1104, 1049 cm1;
1H NMR (400 MHz, CDCl3):  0.04–0.08 (m, 6H, 2SiCH3),
0.84 (2s, 9H, SiC(CH3)3), 1.32–1.85 (m, 2H), 1.90–2.60 (m,
4H), 3.28–3.43 (m, 1H), 3.50–3.64 (m, 2H), 3.68–4.06 (m,
1H), 4.29–4.64 (m, 1H), 5.02–5.16 (m, 2H), 7.20–7.40 (m,
5H, Ph-H) ppm; 13C NMR (100 MHz, CDCl3):  4.9,
4.73, 4.69, 14.0, 17.8, 17.9, 22.6, 24.0, 25.1, 25.61, 25.63,
28.0, 28.2, 28.8, 29.0, 29.3, 29.6, 30.4, 31.9, 33.0, 33.7,
45.1, 46.1, 51.6, 51.8, 63.6, 66.9, 67.1, 69.2, 69.4, 72.1,
74.9, 77.2, 79.7, 80.6, 127.6, 127.9, 128.5, 136.6, 156.2,
157.2, 172.1, 172.6, 176.6, 177.0 ppm; MS (ESI, m/z): 420
(M+H+). HRMS calcd for [C22H33NO5Si+Na+]: 442.2026;
found: 442.2040.
(2R,3S)-1-Benzyloxycarbonyl-3-(tert-butyldimethylsilyloxy)-2-
(pyridin-2-ylthio)-1-pyrrolidine (13)
To a solution of lactam 16 (2.80 g, 8.0 mmol) in MeOH
(40 mL) was added NaBH4 (760 mg, 20 mmol) in one por-
tion at 20 °C. After being stirred at 20 °C for 15 min, the
reaction was quenched with saturated aqueous NaHCO3
(10 mL) and brine (8 mL), and extracted with Et2O (3 × 15
mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The crude hemiacetal (2.80 g, yield,
~100%) was obtained as a colorless oil, which can be used
for the next procedure without further purification. MS (ESI,
m/z): 374 (M+Na+), 369 (M++H2O).
A mixture of crude hemiacetal (4.44 g, 12.7 mmol),
2-mercaptopyridine (2.30 g, 20.8 mmol), p-toluenesulfonic
acid monohydrate (22 mg) and PPTS (22 mg) in 22 mL of
anhydrous CH2Cl2 was stirred at room temperature for 24 h.
After removal of the solvent in vacuo, the residue was puri-
fied by flash column chromatography (EtOAc/PE/Et3N =
1:15:0.1) to afford sulfide 13 (3.86 g, yield: 68%) as a pale
yellow oil. IR (film): 3038, 2953, 1710, 1578, 1404, 1347,
(1S,8R/S,8aR)-1-(tert-Butyldimethylsilyloxy)-8-hydroxy-5-
indolizidinone (12a + 12b)
To a mixture of 18 (100 mg, 0.24 mmol) and 10% Pd-C
(20 mg) in methanol (2.0 mL) was added Et3N (34 L, 0.24
mmol). The mixture was stirred at room temperature under
an atmosphere of H2 overnight. The mixture was filtered
over celite and concentrated under reduced pressure. Flash
chromatographic purification on silica gel (eluent: EtOAc/PE
= 10:1) provided 12a and 12b (inseparable mixture of
1
1095 cm1; H NMR (500 MHz, CDCl3):  0.08–0.10 (2s,
3H, SiCH3), 0.10–0.18 (2s, 3H, SiCH3), 0.70–0.90 (2s, 9H,
SiC(CH3)3), 1.80–1.88 (m, 1H, H-4), 2.20–2.38 (m, 1H,
H-4), 3.54–3.72 (m, 2H, H-5), 4.48–4.54 (m, 1H, H-3),
5.12–5.22 (m, 1H, H-2), 5.17 (d, J = 15.2 Hz, 1H, PhCH2),
5.72–5.82 (d, J = 15.2 Hz, 1H, PhCH2), 6.95–7.02 (m, 1H,
Py-H), 7.09–7.49 (m, 7H, Ph-H+Py-H), 8.36–8.44 (m, 1H,
Py-H) ppm; 13C NMR ( 125 MHz, CDCl3):  5.0, 4.6,
4.5, 18.0, 25.7, 31.1, 31.8, 44.8, 45.0, 66.8, 67.0, 69.6,
70.2, 77.6, 78.5, 119.8, 122.8, 122.9, 127.1, 127.5, 127.8,
127.9, 128.2, 128.4, 135.9, 136.8, 149.4, 154.7 ppm; MS
(ESI, m/z): 445 (M+H+). HRMS calcd for [C23H32N2O3SSi+
H+]: 445.1981; found: 445.1966.
1
diastereoisomers, ratio 12a:12b = 49:51 deduced by H
NMR) as a pale yellow oil (64 mg, yield: 93%). IR (film):
3367, 2953, 2929, 1625, 1471, 1254, 1128 cm1; minor
1
isomer 12a H NMR (500 MHz, CDCl3):  0.14 (s, 3H,
SiCH3), 0.18 (s, 3H, SiCH3), 0.92 (s, 9H, SiC(CH3)3),
1.68–1.84 (m, 2H, H-2), 2.06–2.20 (m, 2H, H-7), 2.30–2.56
(m, 2H, H-6), 2.80 (s br, 1H, OH), 3.25 (t, J = 8.3 Hz, 1H,
H-8a), 3.46–3.58 (m, 2H, H-3), 3.73–3.80 (m, 1H, H-8),
4.03–4.11(m, 1H, H-1) ppm; 13C NMR (125 MHz, CDCl3):
 4.97, 4.05, 17.8, 25.6, 29.2, 29.6, 31.1, 42.5, 67.0, 70.7,
2.3 Synthesis of the indolizidinones
1
(2R,3S,5’R/S)-1-Benzyloxycarbonyl-3-(tert-butyldimethylsi-
77.1, 168.6 ppm; major isomer 12b H NMR (500 MHz,
lyloxy)-2-(5-oxo-tetrahydrofuran-2-yl)-pyrrolidine (18)
CDCl3):  0.12 (s, 6H, 2SiCH3), 0.96 (s, 9H, SiC(CH3)3),
1.68–1.90 (m, 2H, H-2), 1.98 (s br, 1H, OH), 2.06–2.20 (m,
2H, H-7), 2.30–2.56 (m, 2H, H-6), 3.17 (dd, J=2.0, 8.14 Hz,
1H, H-8a), 3.46–3.58 (m, 2H, H-3), 4.23 (s br, 1H, H-8),
4.28–4.35(m, 1H, H-1) ppm; 13C NMR (125 MHz, CDCl3):
 4.85, 4.60, 18.0, 25.7, 26.2, 28.3, 31.2, 42.8, 61.7, 67.7,
70.8, 169.0 ppm; MS (ESI, m/z): 286 (M+H+). Anal. calcd
for C14H27NO3Si: C, 58.91; H, 9.53; N, 4.91. Found: C,
To a slurry of Sm powder (flame dried under Ar, 826 mg,
5.5 mol) in THF (50 mL) was added I2 (1.270 mg, 5.0 mmol)
at room temperature. The reaction mixture was stirred for
2 h at 45 °C to prepare the SmI2 (0.1 M in THF) reagent.
To an ice-bath cooled solution of sulfide 13 (222 mg, 0.5
mmol) and aldehyde 10 (116 mg, 1.0 mmol) in dry THF
(2.5 mL) was added freshly prepared SmI2 (0.1 M in THF,

ZHENG Xiao, et al. Sci China Chem September (2010) Vol.53 No.9
1917
58.48; H, 9.46; N, 4.63.
H-6), 2.56 (dt, J = 16.8, 7.4 Hz, 1H, H-6), 3.32–3.42 (m, 2H,
H-3+H-8a), 3.52–3.58 (m, 1H, H-3), 3.77–3.85 (m, 1H,
H-8), 4.03–4.09 (m, 1H, H-1), 4.55 (d, J = 11.8 Hz, 1H,
PhCH2), 4.63(d, J = 11.8 Hz, 1H, PhCH2), 7.30–7.40(m, 5H,
Ph-H) ppm; 13C NMR (125 MHz, CDCl3):  4.78, 4.54,
17.9, 25.4, 25.7, 29.0, 32.0, 42.5, 68.3, 70.5, 74.5, 74.8,
127.6, 127.7, 128.4, 137.9, 169.4 ppm; MS (ESI, m/z): 376
(M+H+), 398 (M+Na+). Anal. calcd for C21H33NO3Si: C,
67.16; H, 8.86; N, 3.73. Found: C, 67.07; H, 8.48; N, 4.05.
(1S,8R,8aR)-1-(tert-Butyldimethylsilyloxy)-8-hydroxy-5-indo-
lizidinone (12a)
To a suspension of PDC (1.90 g, 5.0 mmol) and 3 Å mole-
cule sieve (600 mg) in dry CH2Cl2 (5 mL) was added drop-
wise a solution of 12a and 12b (560 mg, 1.96 mmol) in
CH2Cl2 (5 mL). After being stirred at room temperature
for 8 h, the solvent was removed in vacuum, and then ether
(20 mL) was added to the residue. The mixture was filtered
over celite and concentrated in vacuum, the crude ketone 19
(487 mg, yield: ~84.5%) was obtained as a colorless oil.
This ketone was dissolved in methanol (10 mL), and cooled
to 60 °C. Solid NaBH4 (155 mg, 4.08 mmol) was added
portion-wise in 15 min. The mixture was stirred under 55 °C
for 30 min, quenched with saturated aqueous NaHCO3 (5.0
mL) and brine (5.0 mL), and extracted with EtOAc (3 × 30
mL). The combined organic phases were dried over anhy-
drous Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography
on silica gel (eluent: EtOAc/PE=10:1) affording (1S,8R,8aR)-
12a (385 mg, yield: 69% for two steps) as a white crystal.
Mp 63–64 °C; []D20 +36.1 (c 0.9, CHCl3). IR (film): 3303,
(1S,8R,8aR)-8-Benzyloxy-1-(tert-butyldimethylsilyloxy)-2,3,
8,8a-tetrahydroindolizin-5(1H)-one (10)
To the diisoproylamine (0.34 mL, 2.4 mmol) was added
dropwise n-BuLi (2.5 mol/L, 0.90 mL, 2.25 mmol) at 0 °C
under N2. After being stirred for 30 min, THF (2.4 mL) was
added and cooled to 78 °C. To this LDA solution was
slowly added a solution of 20 (600 mg, 1.6 mmol) in THF
(2.4 mL) at 78 °C. After being stirred for 2 h, a solution of
phenylseleneyl bromide (453 mg, 1.92 mmol) in THF (2.0 mL)
was added. The resulting mixture was stirred at 78 °C for
3 h, quenched with saturated aqueous NH4Cl (5.0 mL), and
extracted with EtOAc (3 × 10 mL). The organic phases were
washed with brine and dried over Na2SO4, filtered and con-
centrated under reduced pressure to afford a red oil. To a
solution of this residue in dry THF (16 mL) was added
AcOH (0.30 mL) and H2O2 (30%, 4.0 mL) subsequently at
0 °C. After being stirred for 1 h, the reaction was quenched
with cold saturated aqueous NaHCO3 (20 mL), and ex-
tracted with EtOAc (3 × 20 mL). The organic phases were
dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by flash column chromatograph
(eluent: EtOAc/PE = 4:1) to afford 10 (420 mg, yield: 70%)
2929, 1619, 1467, 1254, 1093 cm1; H NMR (500 MHz,
1
CDCl3):  0.14 (s, 3H, SiCH3), 0.18 (s, 3H, SiCH3), 0.92 (s,
9H, SiC(CH3)3 ), 1.70–1.88 (m, 2H, H-2), 2.06–2.18 (m, 2H,
H-7), 2.35 (ddd, J = 6.9, 11.8, 18.5 Hz, 1H, H-6), 2.53 (ddd,
J = 1.7, 6.8, 18.5 Hz 1H, H-6), 2.75 (s br, 1H, OH), 3.17 (t,
J = 8.3 Hz, 1H, H-8a), 3.53 (m, 2H, H-3), 3.77 (ddd, J=4.1,
8.3, 12.4 Hz, 1H, H-8), 4.65 (dt, J = 6.9, 8.3 Hz, 1H, H-1)
ppm; 13C NMR (125 MHz, CDCl3):  4.97, 4.05, 17.8,
25.6, 29.2, 29.7, 31.1, 42.5, 67.0, 70.8, 77.1, 168.5 ppm;
MS (ESI, m/z): 308 (M+Na+), 286 (M+H+). Anal. calcd for
C14H27NO3Si: C, 58.91; H, 9.53; N, 4.91. Found: C, 58.67;
H, 9.54; N, 5.13.
as a colorless oil. []20 +7.4 (c 1.1, CHCl3); IR (film):
D
3032, 2929, 2856, 1670, 1608, 1437, 1254, 1102, 1052 cm1;
1H NMR (500 MHz, CDCl3):  0.05 (s, 3H, SiCH3), 0.08 (s,
3H, SiCH3), 0.88 (s, 9H, SiC(CH3)3), 1.74–1.81 (m, 1H,
H-2), 1.91–2.00 (m, 1H, H-2), 3.45–3.52 (m, 1H, H-8a),
3.69–3.76 (m, 2H, H-3), 4.13–4.18 (ddd, J = 1.5, 2.3, 11.8
Hz, 1H, H-8), 4.23–4.28 (m, 1H, H-1), 4.59 (d, J=11.7 Hz,
1H, PhCH2), 4.72 (d, J = 11.7 Hz, 1H, PhCH2), 5.88 (dd, J=
2.3, 10.1 Hz, 1H, =CH), 6.53 (dd, J = 1.5, 10.1 Hz, 1H,
=CH), 7.28–7.42 (m, 5H, Ph-H) ppm; 13C NMR (125 MHz,
CDCl3):  4.80, 4.64, 17.8, 25.6, 33.5, 42.3, 68.0, 71.0,
75.6, 75.9, 125.0, 127.8, 128.0, 128.4, 137.3, 140.7, 161.9
ppm; MS (ESI, m/z): 374 (M+H+), 396 (M+Na+). Anal.
calcd for C21H31NO3Si: C, 67.52; H, 8.36; N, 3.75. Found:
C, 67.19; H, 8.68; N, 3.57.
(1S,8R,8aR)-8-Benzyloxy-1-(tert-butyldimethylsilyloxy)-5-
indolizidinone (20)
To a solution of 12a (310 mg, 1.09 mmol) in dry THF (4 mL)
was added a suspension of NaH (60% in mineral oil, 65 mg,
1.63 mmol) in 2 mL dry THF at 0 °C under N2. After being
stirred for 30 min, BnBr (0.22 mL, l.85 mmol) was added
dropwise. The mixture was warmed to 45 °C and stirred for
3 h, then quenched with saturated aqueous NH4Cl (4 mL) at
0 °C, and extracted with CH2Cl2 (3 × 10 mL). The combined
organic phases were washed with brine (5 mL), dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography
on silica gel (eluent: EtOAc) affording 20 (380 g, yield:
(1S,8R,8aR)-8-Benzyloxy-1-hydroxyhexahydro-5-indolizidin-
one (11)
93%) as colorless oil. []20 26.3 (c 0.97, CHCl3); IR
D
(film): 3031, 2930, 1655, 1454, 1255, 1115 cm1; H NMR
1
To a solution of 20 (330 mg, 0.88 mmol) in methanol (9.0
mL) was added dropwise AcCl (0.1 mL, 1.35 mmol) at 0 °C,
warmed to room temperature, and stirred overnight. To
quench the reaction, solid NaHCO3 was added portion-wise
(500 MHz, CDCl3):  0.04 (s, 3H, SiCH3), 0.08 (s, 3H,
SiCH3), 0.88 (s, 9H, SiC(CH3)3), 1.68–1.78 (m, 1H, H-2),
1.90–2.00 (m, 3H, H-2+H-7), 2.29 (dt, J = 16.8, 6.1 Hz, 1H,

1918
ZHENG Xiao, et al. Sci China Chem September (2010) Vol.53 No.9
till no gas was released. The mixture was filtered over celite
and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (eluent:
EtOAc/MeOH = 30:1) affording indolizidinone 11 (220 mg,
yield: 96%) as a white crystal. mp 91–93 °C; []20 90 (c
D
0.94, CHCl3); IR (film): 3363, 3030, 2921, 2887, 1622,
1
1455, 1414, 1099 cm1; H NMR (500 MHz, CDCl3): 
1.70–1.83 (m, 2H, H-2), 2.17–2.25 (m, 1H, H-7), 2.25–2.38
(m, 2H, H-6+H-7), 2.54–2.62 (m, 1H, H-6), 2.72 (s, br, 1H,
OH), 3.26 (t, J = 8.29 Hz, 1H, H-8a), 3.49–3.59 (m, 3H),
3.98–4.04 (m, 1H), 4.52 (d, J = 12.7 Hz, 1H, PhCH2), 4.76
(d, J = 12.7 Hz, 1H, PhCH2), 7.32–7.42 (m, 5H, Ph-H) ppm;
13C NMR (125 MHz, CDCl3):  25.8, 29.6, 30.0, 42.6, 66.1,
70.5, 75.8, 77.6, 127.8, 128.3, 128.8, 137.4, 168.1 ppm; MS
(ESI, m/z): 284 (M+Na+), 262 (M+H+). Anal. calcd for
C15H191NO3: C, 68.94; H, 7.33; N, 5.36. Found: C, 68.86; H,
7.15; N, 5.40.
Scheme 4
3 Results and discussion
in 50% yield, along with 33% of the reduction product 17
(Scheme 4). According to the previous studies [18], this
type of SmI2-mediated reductive coupling would give ex-
cellent 2,3-trans-diastereoselectivity at the pyrrolidine ring.
Thus, two diasteremers obtained are C-5’ epimers. The di-
astereomeric mixture of lactone 18 was subjected to hydro-
genolysis in the presence of triethylamine, which led to a
tandem N-deprotection-lactamization to produce the indol-
3.1 Synthesis of N,O-diprotected pyrrolidin-2-yl pyridin-
2-yl sulfide
As shown in Scheme 3, the starting N,O-diprotected pyr-
rolidin-2-yl pyridin-2-yl sulfide 13 was prepared from the
known lactam 15 [23]. Successive treatment of (S)-15 with
NaH and benzyl chloroformate provided the activated lac-
tam (S)-16 in 79% yield. Controlled regioselective reduction
of (S)-16 with NaBH4 in MeOH at 20 °C afforded a di-
astereomeric mixture of N,O-hemiacetal in quantitative
yield, which was treated with 2-mercaptopyridine in the
presence of 1% (w/w) of a 1:1 mixture of PPTS and p-TsOH
to yield the desired sulfide 13 in nearly diastereomerically
pure form with an overall yield of 68% from 16. According
to our previous studies [18], 2,3-trans stereochemistry was
tentatively assigned for 13.
1
izidinones 12a and 12b (ratio = 49:51, determined by H
NMR) in a combined yield of 93%. In the presence of the 3
Å molecular sieve, oxidation of the diastereomeric mixture
of 12a/b with PDC afforded only one ketone 19 in about
85% yield, which confirmed our assumption on the stereo-
chemistry of compounds 18 and 12a/b. Because the partial
epimerization at C-8a of ketone 19 occurred readily, the
crude oxidation product was directly reduced by NaBH4 to
give the desired indolizidinone 12a as the major diastereomer
(dr>20:1) in 69% yield over two steps.
The stereochemistry of 12a was determined by two di-
mensional NMR spectroscopy. The proton assignment was
3.2 Synthesis of the indolizidinones
1
confirmed by H–1H COSY. The NOESY experiments al-
With the building block 13 in hand, we then undertook its
reductive coupling with functionalized-aldehyde 14 [24] by
the method we previously developed for the N-Boc analogue
7 [18]. Thus, a mixture of sulfide 13 (1 equiv) and aldehyde
14 (2 equiv) was treated with a freshly prepared SmI2 solu-
tion (4 equiv) in THF at 0 °C. After stirring at rt for 10 min,
the desired lactone 18 was obtained as an inseparable di-
astereomeric mixture (dr = 49:51, determined by HPLC)
lowed the determination of the H-1/H-8a-trans relationship
and the H-8/H-8a-trans relationship (Figure 2).
The stereochemical course of NaBH4 reduction can be
understood on the basis of the conformer G (Figure 3). Both
the steric hindrance imposed by OTBS and the well known
preferential axial attack of nucleophiles in the cyclohexanone
Figure 2
Scheme 3

ZHENG Xiao, et al. Sci China Chem September (2010) Vol.53 No.9
1919
in five steps and with overall yields of 21% and 29%, respec-
tively. Another key feature of the method resides is a tan-
dem N-deprotection-lactamization that allowed efficient
stepwise “2 + 4” annulation for the construction of the
(1S,8R,8aR)-1,8-dihydroxyl-5-indolizidinone ring system of
12a. The functionalized indolizidinone derivatives 10 and
11 might serve as advanced intermediates for the asymmet-
ric synthesis of hydroxylated indolizidine alkaloids by the
known transformations.
The authors are grateful to the National Natural Science Foundation of
China (20832005) and the National Basic Research Program (973 Pro-
gram) of China (2010CB833200) for financial support.
Figure 3
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4
5
6
7
8
9
Indolizidinone 12a was benzylated (NaH, BnBr) to give
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phenylselenylated product, which, which was directly used
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Scheme 5
4 Conclusions
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1920
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