Asymmetric syntheses of (8R,8aS)- and (8R,8aR)-8-hydroxy-5-indolizidinones: Two promising oxygenated indolizidine building blocks

Article abstract of DOI:10.1007/s11426-011-4256-4

Starting from the oxygenated piperidine building block 20, two synthetic approaches to new building blocks (8R,8aS)- and (8R,8aR)-8-hydroxy-5- indolizidinones 19a/19b and 15a/15b have been developed, respectively. The first one is based on the trans-diastereoselective reductive alkylation (dr = 93:7), followed by a four-step procedure; and the second one called for the RCM reaction on the N,O-acetal derived from a vinylation, which was followed by a pyrrole formation, and a stereocontrolled cis-selective (dr = 91:9) catalytic hydrogenation. Reduction of the diastereomer 15a produced (8R,8aR)-8- indolizidinol (18). Science China Press and Springer-Verlag Berlin Heidelberg 2011.

Full text of DOI:10.1007/s11426-011-4256-4

SCIENCE CHINA
Chemistry
May 2011 Vol.54 No.5: 737–744
doi: 10.1007/s11426-011-4256-4
• ARTICLES •
Asymmetric syntheses of (8R,8aS)- and (8R,8aR)-
8-hydroxy-5-indolizidinones: Two promising oxygenated
indolizidine building blocks
ZHANG HongKui*, LI Xin, HUANG Huang & HUANG PeiQiang*
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen. China
Received January 10, 2011; accepted February 11, 2011
Starting from the oxygenated piperidine building block 20, two synthetic approaches to new building blocks (8R,8aS)- and
(8R,8aR)-8-hydroxy-5-indolizidinones 19a/19b and 15a/15b have been developed, respectively. The first one is based on the
trans-diastereoselective reductive alkylation (dr = 93:7), followed by a four-step procedure; and the second one called for the
RCM reaction on the N,O-acetal derived from a vinylation, which was followed by a pyrrole formation, and a stereocontrolled
cis-selective (dr = 91:9) catalytic hydrogenation. Reduction of the diastereomer 15a produced (8R,8aR)-8-indolizidinol (18).
indolizidines, building blocks, diastereoselective synthesis, RCM reaction, catalytic hydrogenation
3-hydroxyglutarimides 8-based synthetic methodologies
[14–16]. The value of this chiral building block is being
demonstrated by our group [17–24], and also by other re-
search groups [25–28].
1 Introduction
Piperidine is a nucleus widely found in alkaloids and phar-
maceutical interesting compounds [1, 2]. The building block
[3] (chiron)-based strategy has enjoyed great success in the
stereocontrolled synthesis of piperidine ring-containing het-
erocycles [4–12] (Figure 1). In this context, Meyers’ semi-
nal chiral bicyclic lactam 1 [4] and Husson’s “CN R,S”
synthon 2 [5] have became two classical building blocks,
which have been further extended by Bosch [6], Kibayashi
[7], and Hu [8], respectively. Bosch bicyclic lactams 3 [6],
Toyooka building block 4 [9], Ciufolini/Zhou building
block 5 [10, 11], and Comins dihydropiridones 6 [12], allow
the access to 3- and 4-hydroxylated piperidines, respectively.
More recently, TpMo(CO)2(3-pyridinyl) complexes 7 is
being developed by Liebeskind and co-workers as or-
ganometallic enantiomeric scaffolds [13]. In recent years,
we have been engaged in the development of protected
Indolizidine nucleus is also present in many alkaloids [29]
including poison-frog alkaloids pumiliotoxins (PTXs) [30].
At present, over 30 alkaloids are considered to be pumilio-
toxins (9–12) (Figure 2). The structure diversity and re-
markable biological activities possessed by the indolizidine
alkaloids make them attractive synthetic targets, which re-
sulted in a number of ingenious total syntheses [31], and also
the development of several enantiopure oxygenated indol-
izidine building blocks such as 13 [32], 14 [33], 15a [34],
and 16a/16b [35]. On the other hand, N-protected
8-aminoindolozidines 17a/17b [36] have been synthesized
in view of the synthesis of bioactive alkaloids; and both
8-indolizidinol (18) [35–37] and its diastereomer have been
synthesized for purpose of probing the proposed biogenetic
origin of secu’amaine A [38]. As a continuation of our
study on the development of indolizidine building blocks
[39], we now report the asymmetric synthesis of (8R,8aS)-
*Corresponding author (email: hkzhang@xmu.edu.cn; pqhuang@xmu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2011
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parts per million () relative to internal Me4Si. IR spectra
were recorded on a Nicolet Avatar 360 RT-IR spectropho-
tometer. Mass spectra were recorded by a Bruker Dalton
Esquire 3000 plus or a Finnigan Mat-LCQ (ESI direct injec-
tion) apparatus. HRFABMS spectra were recorded on a
Bruker APEX-FTMS apparatus. Elemental analyses were
performed using a Vario RL analyzer. Melting points were
determined on a Yanaco MP-500 melting point apparatus
and are uncorrected.
Tetrahydrofuran was distilled prior to use from sodium
benzophenone ketyl. Methylene chloride was distilled from
phosphorus pentoxide. Dimethylformamide was distilled
from calcium hydride. Silica gel (Zhifu, 300–400 mesh)
from Yantai silica gel factory (China) was used for column
chromatography, eluting (unless otherwise stated) with ethyl
acetate/petroleum ether (60–90 °C) (EtOAc/PE) mixture.
2.2 Synthesis of (R)-1-allyl-3-benzyloxy-2,6-piperidined-
ione (20)
Figure 1 Structures of some oxygenated piperidine building blocks.
Following our previously established procedure for prepar-
ing (S)-1-allyl-3-benzyloxy-2,6-piperidinedione [40] but
using D-glutamic acid as starting material, (R)-1-allyl-3-
benzyloxy-2,6-piperidinedione (20) was obtained as a col-
orless oil in an overall yield of 35% (3 steps). []2D0 +78.9 (c
2.3, CHCl3) {lit. [40] []2D0 72.2 (c 1.0, CHCl3) for the
enantiomer}; IR (film) max 2941, 2859, 1731, 1681, 1416,
1
1357, 1333, 1238, 1128 cm1; H NMR (400 MHz, CDCl3,
ppm)  2.06–2.15 (m, 2H), 2.61 (dt, J = 17.8, 6.2 Hz, 1H),
2.93 (ddd, J = 17.8, 7.8, 6.2 Hz, 1H), 4.07 (dd, J = 6.0, 4.8
Hz, 1H), 4.34–4.36 (m, 2H), 4.67 (d, J=12.0 Hz, 1H), 4.87
(d, J = 12.0 Hz, 1H), 5.12–5.19 (m, 2H), 5.74–5.84 (m, 1H,
CHCH2), 7.28–7.41 (m, 5H, Ph-H); 13C NMR (100 MHz,
CDCl3, ppm)  24.1, 28.9, 41.6, 72.4, 73.6, 117.3, 127.8,
127.9, 128.4, 131.8, 137.1, 171.0, 171.2. MS (ESI) m/z
260.3 (M+H+), 282.2 (M+Na+); Anal. calcd for C15H17NO3:
C, 69.48; H, 6.61; N, 5.40. Found: C, 69.04; H, 6.75; N,
5.31.
Figure 2 Structures of some pumiliotoxins and oxygenated indolizidine
building blocks
2.3 Synthesis of (5R,6S)-1-allyl-5-(benzyloxy)-6-(3-hy-
droxypropyl)piperidin-2-one (24)
and (8R,8aR)-8-hydroxy-5-indolizidinones (19a/19b and
15a/15b), as well as (8R,8aR)-8-indolizidinol (18) starting
from the 3-benzyloxyglutarimides building block 20 [40].
A 0.4 M solution of TBSO(CH2)3MgBr [41] (21) in THF
(58.0 mL, 23.2 mmol) was added to a cooled solution (0 °C)
of compound 20 (1.504 g, 5.8 mmol) in CH2Cl2 (58 mL).
After being stirred at 0 °C for 1 h, saturated aqueous NH4Cl
(25 mL) was added, and the aqueous layer was extracted
with CH2Cl2 (5 × 20 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, fil-
tered and concentrated under reduced pressure. The residue
was purified by flash chromatograph on silica gel (EtOAc/
PE = 1:5) to give a mixture of diastereomeric and tautameric
isomers (2.325 g, 96%) as a colorless oil. The mixture was
used for the next reaction without further separation.
2 Experimental
2.1 General
Optical rotations were recorded on a Perkin-Elmer 341
1
automatic polarimeter. H and 13C NMR spectra were re-
corded on a Bruker 400 spectrometer. 1H NMR spectra were
registered in CDCl3, and chemical shifts are expressed in

Zhang HK, et al. Sci China Chem May (2011) Vol.54 No.5
739
HRESIMS calcd for [C15H21NO3+H]+: 264.1599; found:
264.1591.
Et3SiH (13.0 mL, 82.5 mmol) and BF3OEt2 (4.2 mL,
33.0 mmol) were added dropwise successively to a cooled
solution (60 °C) of the above mixture (2.325 g, 5.6 mmol)
in CH2Cl2 (55 mL). The mixture was stirred at 60 °C for
3 h, and then was allowed to warm slowly to room tem-
perature and stirred for 2 d. The reaction was quenched with
a saturated aqueous NaHCO3 solution (25 mL), and the
aqueous layer was extracted with CH2Cl2 (5 × 15 mL). The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure to give the crude product (0.88 g, 52 %). The crude
2.5 Synthesis of 3-[(2S,3R)-3-(benzyloxy)-6-oxopiperidin-
2-yl]propyl-4-methylbenzenesulfonate (27)
p-TsCl (210 mg, 1.08 mmol) was added to a cooled solution
(0 °C) of 26 (190 mg, 0.72 mmol), DMAP (20 mg) and
triethylamine (0.2 mL, 1.44 mmol) in dry CH2Cl2 (3 mL).
The mixture was stirred at room temperature overnight.
After completion of the reaction (monitored by TLC), H2O
(5 mL) was added, and the aqueous layers were extracted
with CH2Cl2 (4 × 15 mL). The combined organic layers
were washed with brine, dried over anhydrous Na2SO4 fil-
tered and concentrated under reduced pressure. The residue
was purified by flash chromatograph on silica gel (EtOAc/
PE = 2:1) to give 27 (266 mg, 89%) as a colorless oil. []D20
1
product (24 and 25 with a ratio of 93:7, determined by H
NMR) was separated by flash chromatograph on silica gel
(EtOAc/PE = 5:1) to give compound 24 (0.82 g, yield: 48%)
and diastereomer 25 (0.06 g, yield: 4%). Major diastereomer
24: colorless oil; []2D0 57.3 (c 1.6, CHCl3); IR (film) vmax
1
3388, 2941, 2869, 1619, 1478, 1453, 1413, 1062 cm1; H
38.5 (c 1.3, CHCl3); IR (film) vmax 2924, 2863, 1661, 1452,
1356, 1174, 1096 cm1; 1H NMR (400 MHz, CDCl3, ppm) 
1.46–1.52 (m, 1H), 1.58–1.72 (m, 3H), 1.86–2.02 (m, 2H),
2.21–2.29 (m, 1H), 2.44 (s, 3H, ArCH3), 2.47–2.55 (m, 1H),
3.37–3.46 (m, 2H), 4.00 (td, J = 6.0, 1.2 Hz, 2H), 4.47 (d, J
= 11.6 Hz, 1H, PhCH), 4.60 (d, J = 11.6 Hz, 1H, PhCH),
6.85 (s, 1H), 7.29–7.37 (m, 7H, Ar-H), 7.76–7.78 (m, 2H,
Ar-H); 13C NMR (100 MHz, CDCl3, ppm)  21.6, 22.8, 24.7,
27.5, 30.4, 55.9, 69.9, 70.5, 73.6, 127.6, 127.8, 127.9, 128.5,
129.8, 132.8, 137.7, 144.8, 171.9; MS (ESI, m/z): 418.5
(M+H+), 440.4 (M+Na+); Anal. Calcd for C22H27NO5S: C,
63.29; H, 6.52; N, 3.35. Found: C, 62.84; H, 6.08; N, 3.65.
NMR (400 MHz, CDCl3, ppm)  1.41–1.59 (m, 3H),
1.75–1.82 (m, 1H), 1.96–2.03 (m, 3H), 2.11 (br s, 1H), 2.34
(ddd, J = 18.3, 5.7, 3.9 Hz, 1H), 2.59 (ddd, J = 18.3, 10.3,
8.1 Hz, 1H), 3.41 (dd, J = 15.6, 6.8 Hz, 1H), 3.47–3.50 (m,
1H), 3.59–3.62 (m, 1H), 3.69 (dd, J = 6.0, 3.2 Hz, 1H), 4.54
(s, 2H), 4.61 (dt, J = 15.6, 2.2 Hz, 1H), 5.14 (dd, J = 10.0,
1.6 Hz, 1H), 5.23 (dt, J = 16.0, 1.6 Hz, 1H), 5.73–5.77 (m,
1H), 7.28–7.36 (m, 5H, Ph-H); 13C NMR (100 MHz, CDCl3,
ppm)  21.1, 26.8, 28.7, 29.0, 47.4, 59.5, 61.6, 69.9, 72.0,
116.8, 127.2, 127.5, 128.3, 132.9, 137.9, 169.5; MS (ESI,
m/z): 304.3 (M+H+), 326.3 (M+Na+); Anal. calcd for
C18H25NO3: C, 71.26; H, 8.31; N, 4.62. Found: C, 71.04; H,
7.98; N, 4.69.
2.6 Synthesis of (8R,8aS)-8-(benzyloxy)-5-indolizidinone
(19b)
2.4 Synthesis of (5R,6S)-5-(benzyloxy)-6-(3-hydroxy-
propyl) piperidin-2-one (26)
To a cooled solution (50 °C) of compound 27 (247 mg,
0.59 mmol) in THF (25 mL) was added slowly a solution of
NaH (48 mg, 1.18 mmol) in THF (10 mL). The mixture was
stirred for 1 h at 50 °C, then allowed to warm up to room
temperature and stirred overnight. The reaction was quenched
by addition of a saturated aqueous NH4Cl (20 mL). The
aqueous layer was extracted with CH2Cl2 (4 × 10 mL). The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatograph
(EtOAc/PE = 2:1) on silica gel to give compound 19b (135
mg, 95%) as a colorless oil. []2D0 100.3 (c 1.4, CHCl3); IR
RhCl3·3H2O (43 mg, 10% weight) was added to a solution
of compound 24 (428 mg, 1.41 mmol) in n-propanol (8 mL)
and the mixture was stirred at 115 °C for 3.5 h. Then, the
reaction was allowed to cool down to room temperature.
Water and CH2Cl2 (1:1, 10 mL) were added. The organic
phase was separated, and the aqueous layers were extracted
with CH2Cl2 (5 × 5 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4 filtered
and concentrated under reduced pressure. The residue was
purified by flash chromatograph on silica gel (MeOH/
EtOAc = 1:20) to give 26 (244 mg, 66%) as a colorless oil.
[]2D0 57.8 (c 0.93, CHCl3); IR (film) vmax 3295, 2934, 2867,
(film) vmax 2947, 2879, 1639, 1453, 1414, 1274, 1123 cm1;
1H NMR (400 MHz, CDCl3, ppm)  1.42–1.53 (m, 1H),
1.68–1.80 (m, 2H), 1.90–1.98 (m, 1H), 2.20–2.26 (m, 1H),
2.30–2.39 (m, 2H), 2.57 (m, 1H), 3.31–3.56 (m, 4H), 4.53
(d, J=11.8 Hz, 1H, PhCH), 4.68 (d, J=11.8 Hz, 1H, PhCH),
7.28–7.38 (m, 5H, Ph-H); 13C NMR (100 MHz, CDCl3, ppm)
 22.2, 26.6, 29.9, 32.0, 45.3, 62.5, 71.0, 77.8, 127.6, 127.8,
128.4, 137.9, 168.2; MS (ESI, m/z): 268.1 (M+Na+, 100).
HRESIMS calcd for [C15H19NO2+H]+: 246.1490; found:
1650, 1452, 1408, 1357, 1059 cm1; H NMR (400 MHz,
1
CDCl3, ppm)  1.51–1.71 (m, 4H), 1.86–2.02 (m, 2H),
2.21–2.30 (m, 1H), 2.47–2.55 (m, 1H), 3.40–3.70 (m, 4H),
3.88 (s, 1H), 4.50 (d, J = 12.0 Hz, 1H, PhCH), 4.61 (d, J =
12.0 Hz, 1H, PhCH), 7.28–7.37 (m, 5H, Ph-H), 7.55 (s, 1H,
CONH); 13C NMR (100 MHz, CDCl3, ppm)  22.8, 27.5,
28.1, 30.8, 56.2, 61.7, 70.5, 74.0, 127.6, 127.7, 128.4, 137.8,
172.4; MS (ESI, m/z): 264.2 (M+H+), 286.2 (M+Na+);

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Zhang HK, et al. Sci China Chem May (2011) Vol.54 No.5
246.1487.
2H), 2.58 (dt, J = 17.5, 4.0 Hz, 1H), 4.53 (s, 2H, PhOCH2),
3.00 (m, 1H), 4.65 (dd, J=3.5, 3.5 Hz, 1H), 6.28 (dd, J=3.2,
3.3 Hz, 1H), 6.31 (dd, J = 3.2, 1.6 Hz, 1H), 7.27–7.35 (m,
5 H, Ph-H), 7.36 (dd, J = 3.3, 1.6 Hz, 1H); 13C NMR (100
MHz, CD3CN, ppm)  27.8, 28.2, 67.2, 69.4, 112.1, 112.2,
116.8, 117.3, 127.5, 127.6, 128.3, 138.7, 168.2; MS (ESI,
m/z): 264.2 (M+Na+); HRESIMS calcd for [C15H15NO2+
Na]+: 264.1001; found: 264.1006.
2.7 Synthesis of (8R,8aS)-8-hydroxy-5-indolizidinone
(19a)
To a mixture of 19b (105 mg, 0.43 mmol) and 10% Pd/C
(82 mg) was added methanol (12 mL). The mixture was
stirred at room temperature and under an atmosphere of H2
for 3 d. The mixture was filtered through a celite pad and
washed with methanol. The solvent was removed under
reduced pressure. The residue was purified by flash chro-
matograph on silica gel (EtOAc/PE = 1:1) to provide 19a
(60 mg, 91%) as a white solid. mp: 104–105 C (ethyl ace-
tate) (lit. [42] 99–101 C); []2D0 35.7 (c 0.70, EtOH) {lit.
2.9 Synthesis of (8R,8aR)-8-(benzyloxy)-5-indolizidinone
(15b)
To a mixture of 32 (100 mg, 0.41 mmol), AcONH4 (35 mg,
0.44 mmol) and 10% Pd/C (50 mg) was added EtOAc (6
mL). The mixture was stirred at room temperature and un-
der an atmosphere of H2 (1 atm) for 24 h. The mixture was
filtered through a Celite pad and washed with methanol.
The solvent was removed under reduced pressure. The
residue was purified by flash chromatograph on silica gel
(EtOAc/PE = 1:2) to provide compound 15b (70 mg, 73%)
and compound 19b (7 mg, 7%) (combined yield: 80%,
15b/19b = 10:1). The major diastereomer 15b is a colorless
oil with []2D0 1.5 (c 1.2, CHCl3); IR (film) vmax 2949,
[42] []2D0 37.7 (c 1.27, EtOH)}; IR (film) vmax 3373, 2963,
1
2875, 1605, 1462, 1420, 1250, 1084 cm1; H NMR (400
MHz, CDCl3, ppm)  1.50–1.60 (m, 1H), 1.71–1.85 (m, 2H),
1.96–2.03 (m, 1H), 2.07–2.13 (m, 1H), 2.31–2.46 (m, 2H),
2.53–2.60 (ddd, J = 18.0, 7.3, 1.7 Hz, 1H), 3.28–3.32 (ddd, J
= 15.3, 10.3, 5.3 Hz, 1H), 3.43–3.61 (m, 3H); 13C NMR
(100 MHz, CDCl3, ppm)  22.3, 30.1, 30.4, 31.7, 45.6, 64.0,
71.4, 168.4; MS (ESI, m/z): 178.1 (M+Na+, 100); Anal. calcd
for C8H13NO2: C, 61.91; H, 8.44; N, 9.03. Found: C, 61.35;
H, 8.51; N, 9.00.
1
2878, 1618, 1458, 1097 cm1; H NMR (400 MHz, CDCl3,
ppm)  1.69–1.78 (m, 3H), 1.93–1.96 (m, 1H), 2.02–2.10
(m, 1H), 2.23–2.29 (m, 1H), 2.32–2.38 (m, 1H), 2.41–2.46
(m, 1H), 3.45 (td, J = 9.6, 2.0 Hz, 1H), 3.51–3.61 (m, 2H),
3.81–3.83 (m, 1H), 4.46 (d, J=12.0 Hz, 1H, PhCH), 4.66 (d,
J = 12.0 Hz, 1H, PhCH), 7.27–7.37 (m, 5H, Ph-H); 13C
NMR (100 MHz, CDCl3, ppm)  22.0, 24.4, 26.4, 27.4, 45.1,
62.3, 70.1, 70.4, 127.4, 127.6, 128.3, 138.1, 168.7; MS (ESI,
m/z): 268.2 (M+Na+, 100). Anal. calcd for C15H19NO2: C,
73.44; H, 7.81; N, 5.71. Found: C, 73.12; H, 8.10; N, 5.70.
2.8 Synthesis of (R)-8-(benzyloxy)-7,8-dihydroindolizin-
5(6H)-one (32)
A 0.7 M THF solution of vinylmagnesium bromide (4.3 mL,
3.0 mmol) was added to a cooled solution (20 °C) of
compound 20 (389 mg, 1.5 mmol) in CH2Cl2 (15 mL). The
mixture was stirred at 20 °C for 1 h. The reaction was
quenched with a saturated aqueous NH4Cl solution (5 mL),
and the aqueous layer was extracted with CH2Cl2 (5 × 10
mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by flash
chromatograph on silica gel (EtOAc/PE = 1:2) to give com-
pound 29 as a diastereomeric mixture (366 mg, 88%) as
colorless oil, which was used as such in the next step. The
diastereomeric mixture 29 (366 mg, 1.27 mmol) in CH2Cl2
(127 mL) was added a solution of the 2nd generation Grubbs
catalyst (6% mol, 65 mg, 0.076 mmol) in anhydrous di-
chloromethane (3 mL). The reaction mixture was heated to
reflux with stirring overnight. After completion of the reac-
tion (monitored by TLC), the solvent was removed under
reduced pressure at 25 °C. Then, 2 g of silica gel was added,
and the mixture was stirred for 3 h. The reaction mixture
was subjected to the flash chromatographic purification on
silica gel (EtOAc/PE = 1:30) to provide product 32 (221 mg,
72%) as a colorless oil. []2D0 14.2 (c 0.59, CHCl3); IR
(film) vmax 2922, 2859, 1719, 1404, 1364, 1315, 1298, 1063
2.10 Synthesis of (8R,8aR)-8-hydroxy-5-indolizidinone
(15a)
The compound 15b (78 mg, 0.32 mmol) and 10% Pd/C (45
mg) was added ethanol (6 mL). The mixture was stirred at
room temperature and under an atmosphere of H2 for 2 d. The
mixture was filtered through a Celite pad and washed with
methanol. The solvent was removed under reduced pressure.
The residue was purified by flash chromatograph on silica
gel (EtOAc/MeOH = 15:1) to provide 15a (44 mg, 91%) as
a white solid. mp: 101–103 C (ethyl acetate) (lit. [34a]
100–102 C); []D20 +35.6 (c 0.8, CHCl3) {lit. [34a] []D28
+38.0 (c 2.4, CHCl3)}; IR (film) max 3383, 2923, 2870,
1
1597, 1485 cm1; H NMR (400 MHz, CDCl3, ppm) 
1.70–2.01 (m, 5H), 2.02–2.07 (m, 1H), 2.31 (br dd, J=18.0,
7.6 Hz, 1H), 2.51 (ddd, J = 18.0, 12.0, 7.6 Hz, 1H),
3.42–3.55 (m, 3H), 3.90–4.04 (m, 1H), 4.08–4.16 (m, 1H);
13C NMR (100 MHz, CDCl3, ppm)  21.9, 26.1, 27.5, 28.3,
45.2, 62.6, 63.1, 169.3. MS (ESI, m/z): 178.2 (M+Na+, 100).
1
cm1; H NMR (400 MHz, CD3CN, ppm)  2.16–2.35 (m,

Zhang HK, et al. Sci China Chem May (2011) Vol.54 No.5
741
1
2.11 Synthesis of (8R,8aR)-8-indolizidinol (18)
mixture (24:25 = 93:7, determined by H NMR) in a com-
bined yield of 52% (from 20). The major diastereomer 24
was tentatively assigned as trans based on our previous
conclusion [16], which was confirmed by its conversion
into the known bicyclic lactam 19a (vide infra) [42].
Borane-methyl sulfide complex (0.11 mL, 1.14 mmol) was
added dropwise to a cooled solution (0 °C) of compound
15a (44 mg, 0.28 mmol) in anhydrous THF (3 mL) over a
period of 10 min. After being stirred at 0 °C for 30 min, the
solution was warmed to room temperature and stirred for
another 4 h. The reaction was quenched by ethanol. Evapo-
ration of the solvent gave a viscous oil, which was dissolved
in ethanol (4 mL) and heated to reflux for 2 h. After cooling
to room temperature and evaporation of the solvent under
reduced pressure, the residue was purified by flash chroma-
tography (EtOAc/PE = 1:3) to give 18 as a white solid (26
mg, 66%). mp 101–103 C (EtOAc) (lit. [34a] 101–103 C);
[]D20 +16.6 (c 1.1, CHCl3) {lit. [34a] []2D8 +19.9 (c 1.2,
CHCl3)}; IR (film) vmax 3422, 2962, 2887, 2371, 2323, 1591,
Deprotection of the N-allyl group in lactam 24 by treat-
ment with RhCl33H2O in propanol [43] produced lactam 26
in 66% yield (Scheme 2). Chemoselective tosylation of
amido alcohol 26 gave the corresponding tosylate 27 in
90% yield. Amido tosylate 27 was treated with NaH in THF
to provide the indolizidinone derivative 19b in 95% yield.
Debenzylation of 19b under catalytic hydrogenolytic condi-
tions (10% Pd/C, EtOH, H2, 1 atm, rt) let to (8R,8aS)-8-
hydroxy-5-indolizidinone (19a) in a yield of 91%. Com-
pound 19a is a white solid with mp 104–105 C (lit. [42]
mp 99–101 C), and []2D0 = 35.7 (c 0.70, EtOH) {lit. [42]
1
1462, 1180 cm1; H NMR (400 MHz, CDCl3, ppm) 
[]2D0 37.7 (c 1.27, EtOH)}. The spectroscopic data of
(8R,8aS)-8-hydroxy-5-indolizidinone 19a is identical with
those reported in ref. [42]. Thus, the stereochemical out-
come of the trans-diastereoselective reductive dehydroxyla-
tion (22/23 to 24) is confirmed.
1.46–1.58 (m, 1H), 1.62–1.70 (m, 1H), 1.79–1.87 (m, 1H),
1.90–2.02 (m, 3H), 2.05–2.24 (m, 3H), 2.58 (td, J = 12.0,
3.2 Hz, 1H), 2.78 (dt, J = 12.0, 4.0 Hz, 1H), 3.04–3.15 (m,
1H), 3.16–3.33 (m, 1H), 3.30–3.40 (m, 1H), 4.43 (dt, J =
10.4, 4.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, ppm) 
18.9, 19.9, 22.4, 26.4, 51.8, 64.1, 65.2, 68.8; MS (ESI, m/z):
142 (M+H+); HRESIMS calcd for C8H15NO: 141.1153;
found: 141.1152.
To access the (8R,8aR)-diastereomer 15a of lactam 19a,
an alternative approach was envisioned. In view of the
widespread use of the ring-closing-metathesis (RCM) as a
powerful method in the synthesis of N-containing hetereo-
cycles [44], a synthetic route featuring the use of RCM was
designed (Scheme 3). Thus, the precursor 29 for the RCM
was prepared by addition of vinylmagnesium bromide to the
building block 20, which provided the adduct 29 in a yield
of 88%. Exposure of the diastereomeric mixture of the diene
29 to the Grubbs’ second-generation catalyst 30 (6 mol%)
in CH2Cl2 at 35 °C let to the formation of the desired bicy-
clical lactam 31. Without further purification, labile com-
pound 31 was treated with silica gel in CH2Cl2 at rt for 4 h
to give the dehydration product 32 in 72% yield from 29.
For the hydrogenation of substituted pyrrole rings to the
corresponding pyrrolidines, Pd/C, Pd(OH)2/C, Pt, PtO2, and
5% Rh/Al2O3 have been used as the catalysts under either
acidic or non-acidic conditions [45]. However, it has been
reported that the hydrogenation of chiral pyrroles bearing
3 Results and discussion
The synthesis started with the known (R)-1-allyl-3-benzyloxy-
2,6-piperinedione 20 [40] and C3 Grignard reagent 21 [41]
(Scheme 1). Addition of Grignard reagent 21 to imide 20 in
THF/CH2Cl2 (1:1) at 0 °C afforded a mixture of N,O-acetal
22 (as a diastereomeric mixture) and the ring opening
tautomer 23. Following our previous reported protocol [19],
without further separation, the mixture of 22 and 23 was
directly treated with BF3OEt2/Et3SiH (CH2Cl2, 60 °C to rt)
to give the reductive dehydroxylated, and concomitantly
desilylated alcohols 24 and 25 as a separable diastereomeric
Scheme 2 Synthesis of the (8R,8aS)-8-hydroxy-5-indolizidinone building
blocks 19b and 19a.
Scheme 1 Synthesis of lactams 24 and 25

742
Zhang HK, et al. Sci China Chem May (2011) Vol.54 No.5
Scheme 5 Synthesis of (8R,8aR)-8-indolizidinol (18)
[34a] afforded (8R,8aR)-8-indolizidinol 18 in 66% yield
(Scheme 5). The physical data {mp 101–103C (lit. [34a]
101–103 C); []D20 +16.6 (c 1.1, CHCl3), lit. [34a] []D28
+19.9 (c 1.2, CHCl3); lit. [35] – 17.4 (c 1.15, CHCl3) for the
enantiomer} and spectroscopic data of the indolizidinol 18
were identical with those reported in the literature [34a].
Scheme 3 Synthesis of compound 32 via the RCM.
4 Conclusions
stereocenters at the benzylic position generally gave poor
diastereoselectivities [37, 39, 46].
In our case, in view of obtaining a good diastereoselec-
tivity, less reactive non-acidic condition was used. In the
event, catalytic hydrogenation of 32 (10% Pd/C, EtOH, H2,
1 atm, rt, 3 d) afforded the diastereomeric lactams 15a and
19a in an appreciable ratio of 3.5:1 (Scheme 4). The corre-
lation of both the physical and spectral data of the di-
astereomer 15a with those reported for 15a {(white solid,
m.p. 101–103 C (lit. [34a] 100–102 C); []2D0 +35.6 (c 0.8,
In summary, starting from the 3-benzyloxyglutarimides
building block 20, we have developed two distinguished
routes to (8R,8aS)- and (8R,8aR)- 8-hydroxy-5-indolizidinone
building blocks 19a/19b and 15a/15b, respectively. Reduc-
tion of the building block 15a led to (8R,8aR)-8-indolizidinol
(18). These functionalized indolizidinone building blocks
would find applications in the synthesis of the various types
of indolizidine alkaloids. In addition, the findings gained
during the synthesis of (8R,8aR)-8-hydroxy-5-indolizidi-
none 15a via the ring-closing-metathesis (RCM) and the
subsequent highly cis-diastereoselective heterogeneous
catalytic hydrogenation of the fused pyrrole will be useful
for other synthetic applications.
CHCl3) (lit. [34a] []D28 +38.0 (c 2.4, CHCl3)) allowed to
confirm its stereochemistry as 8R,8aR. To improve the
stereoselectivity of the hydrogenation, milder conditions
were envisioned. It has been reported that chemoselectivity
of Pd/C-catalyzed hydrogenation could be achieved using a
nitrogen-containing compound as a catalyst poison [47].
Thus, we selected to use NH4OAc as an additive, and
change the solvent from ethanol to ethyl acetate. Gratify-
ingly, in such a manner, catalytic hydrogenation (10% Pd/C,
NH4OAc, EtOAc, H2, 1 atm, rt, 24 h) let to indolizidinones
15b and 19b in 10:1 ratio with a combined yield of 80%.
Further subjection of the major diastereomer 15b to cata-
lytic hydrogenation conditions (10% Pd/C, EtOAc, H2, 1
atm, rt, 24 h) gave the indolizidinone 15a in 91% yield.
Reduction of 15a with borane-dimethylsulfide complex
The authors are grateful to the NSF of China (20672089, 20832005), the
NFFTBS (J1030415), and the National Basic Research Program of China
(973 Program, 2010CB833200) for financial support.
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