A common approach to pyrrolizidine and indolizidine alkaloids; Formal synthesis of (-)-isoretronecanol, (-)-trachelanthamidine and an approach to the synthesis of (-)-5-epitashiromine and (-)-tashiromine

Article abstract of DOI:10.1016/j.tetasy.2011.03.009

A common and short stereoselective route is described for the formal synthesis of pyrrolizidine alkaloids, (-)-isoretronecanol and (-)-trachelanthamidine. An approach to the synthesis of indolizidine alkaloids (-)-5-epitashiromine and (-)-tashiromine utilizing ring closing metathesis is also described starting from commercially available and inexpensive l-proline.

Full text of DOI:10.1016/j.tetasy.2011.03.009

Tetrahedron: Asymmetry 22 (2011) 662–668
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A common approach to pyrrolizidine and indolizidine alkaloids; formal
synthesis of (ꢀ)-isoretronecanol, (ꢀ)-trachelanthamidine and an approach
to the synthesis of (ꢀ)-5-epitashiromine and (ꢀ)-tashiromine
Kotha Kapu Sridhar Reddy a, Batchu Venkateswara Rao a, , Sagi Satyanarayana Raju b
⇑
a Organic Division III, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India
b Organic Division I (HPLC), Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A common and short stereoselective route is described for the formal synthesis of pyrrolizidine alkaloids,
(ꢀ)-isoretronecanol and (ꢀ)-trachelanthamidine. An approach to the synthesis of indolizidine alkaloids
(ꢀ)-5-epitashiromine and (ꢀ)-tashiromine utilizing ring closing metathesis is also described starting
Received 15 February 2011
Accepted 18 March 2011
Available online 4 May 2011
from commercially available and inexpensive
L
-proline.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
OH
OH
H
H
N
The pyrrolizidine1 and indolizidine2 alkaloids are important
classes of biologically active natural products and have attracted
considerable attention in organic synthesis. Over the past five dec-
ades, many studies aimed at the isolation and stereocontrolled
syntheses of these alkaloids have been carried out. Several pyrroli-
zine imides display amnesia-reversal activity.3 It should be noted
that pyrrolizidine N-oxide and indolizidine N-oxide have antineo-
plastic activity and are in clinical trials.4 Indolizidine alkaloids iso-
lated from plant sources and animal sources (frog’s skin) have
shown important biological properties.5 Therefore, these alkaloids
are popular targets and several efficient methods for the construc-
tion of the azabicyclo [3.3.0] and azabicyclo [4.3.0] skeletons have
been developed.
N
(-)-isoretronecanol 1
(-)-trachelanthamidine 2
OH
H
OH
H
N
N
(-)-tashiromine 4
Figure 1.
(-)-5-epitashiromine 3
Over the past few years, our laboratory has demonstrated the
merit and potency of ring-closing metathesis in the construction
of carbocycles, azasugars and oxygenated heterocycles from com-
mercially available starting materials.6 Herein we report a ring-
closing metathesis protocol for the construction of pyrrolizidine
and indolizidine skeletons in the form of formal synthesis of (ꢀ)-
isoretronecanol7 1, (ꢀ)-trachelanthamidine8 2, and an approach
to the synthesis of (ꢀ)-5-epitashiromine9 3 and (ꢀ)-thashiro-
mine10 4 from a common intermediate (Fig. 1).
10 by using ring-closing metathesis followed by stereoselective
hydrogenation. Intermediates 7 and 10 can be obtained from 11,
which in the turn can be prepared from Boc protected prolinol es-
ter 12 (Scheme 1)
Our synthetic strategy (Scheme 2) started from the N-Boc proline
ester 12. The reduction of the ester functionality in 12 with LAH
afforded alcohol 13, which was converted to olefin 14 by performing
a Swern oxidation followed by a one carbon Wittig homologation.11
Dihydroxylation of the olefin functionality gave a diastereomeric
mixture of diol 15. Regioselective benzylation of diol 15 with dibu-
tyltinoxide in toluene followed by the addition of benzyl bromide
in the presence of catalytic TBAI gave compound 16 in 88% yield.
The secondary alcohol was oxidized to ketone 17 using TEMPO, after
which the keto group was subsequently converted to olefin com-
pound 18 by a one carbon Wittig homologation.12 Deprotection of
Boc with TFA/DCM (1:1) followed by neutralization of the resultant
TFA salt with Et3N gave compound 11.
2. Results and discussion
It was envisaged that pyrrolizidine amides 5 and 6 and indolizi-
dine amides 8 and 9 could be generated from intermediates 7 and
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.03.009

K. K. S. Reddy et al. / Tetrahedron: Asymmetry 22 (2011) 662–668
OH
663
H
N
OBn
H
5
O
1, 2
N
OH
OH
OH
H
O
7
OBn
N
H
H
O
O
6
OMe
N
NH
Boc
H
12
11
OBn
H
N
N
O
8
H
O
10
N
9
O
Scheme 1. Retrosynthetic analysis.
OBn
OBn
b
c
a
H
OH
12
H
N
N
b
c
a
Boc
Boc
11
N
N
13
14
O
19
O
7
d
e
OBn
g
OBn
OH
OH
N
OH
N
N
OBz
H
Boc
Boc
Boc
H
OH
OH
O
ref 8c
d
17
16
15
1
N
N
O
O
f
20
5
OBn
OBn
N
H
N
+
Boc
OBz
H
H
11
18
ref 8c
d
Scheme 2. Reagents and conditions: (a) LiAlH4, THF, 0 °C to rt, 1 h, 95%; (b) (i)
DMSO, (COCl)2, Et3N, DCM, ꢀ78 °C, 1 h; (ii) Ph3P@CH2, THF, ꢀ10 °C, 3 h, for two
steps, 69%; (c) OsO4, NMO, monohydrate, acetone/H2O (3:1), 0 °C to rt, 6 h, 89%; (d)
(i) Bu2SnO, toluene, reflux, 8 h, (ii) BnBr, TBAI, reflux, 16 h, for two steps, 88%; (e)
TEMPO, NaBr, NaOCl, NaHCO3, toluene/EtAc/H2O (3:3:1) 0 °C, 1 h, 91%; (f)
Ph3P@CH2, THF, ꢀ10 °C, 4 h, 61%; (g) TFA/DCM (1:1), Et3N, 0 °C, 1 h; 99%.
2
N
N
O
O
21
6
Scheme 3. Reagents and conditions: (a) acryloyl chloride, Et3N, cat DMAP, DCM,
0 °C, 3 h, 65%; (b) 10 mol % Grubbs’ 2nd generation catalyst, benzene, 90 °C, 36 h,
76%; based on the recovery of starting material (c) (i) H2, Pd–C, MeOH, rt, 2 h, 95%,
(ii) benzoyl chloride, Et3N, cat DMAP, DCM, 0 °C, 2 h, 95%; (d) K2CO3, MeOH, rt, 2 h,
90%.
Acrylation of 11 with acryloyl chloride and Et3N in DCM affor-
ded compound 7,13 which underwent ring-closing metathesis with
a Grubbs’1st or 2nd catalyst under different conditions; better
yields were obtained when the reaction was performed in benzene
for 24 h at 100 °C with 10 mol % of 2nd generation catalyst to give
19. Hydrogenation of 19 in the presence of H2–Pd/C (10 mol %) fol-
lowed by the protection of the hydroxy group as its benzoate affor-
ded cis- and trans-diastereomers 20 and 21 in a 64:36 ratio,
whereas under H2–PtO2 conditions cis- and trans-isomers 20 and
21 were obtained in a 77:23 ratio (by HPLC).14 Attempts to sepa-
rate the diastereomers 5 and 6 and their derivatives (TBDPS ether,
acetate and benzoate) by column chromatography were unsuc-
cessful. Finally, we separated diastereomers 20 and 21 obtained
from Pd/C hydrogenation by preparative HPLC.14 Deprotection of
the Bz group with K2CO3 in MeOH at 0 °C gave compounds 5 and
6 (Scheme 3). The conversion of compounds 5 and 6 to compounds
1 and 2 has already been reported in the literature.16,8c The spec-
troscopic and analytical data of compounds 5 and 6 were in good
agreement with the reported values.8c
Acylation of 11 with 3-butenoic acid using ethylchloroformate
and NMM in THF afforded compound 10,15 which underwent
ring-closing metathesis with 1st generation Grubbs’ catalyst

664
K. K. S. Reddy et al. / Tetrahedron: Asymmetry 22 (2011) 662–668
(10 mol %) in DCM for 6 h at 50 °C to give 22 (Scheme 4). Hydroge-
nation in presence of H2–Pd/C (10 mol %) followed by protection of
the hydroxy group as its benzoate gave cis- and trans-diastreomers
23 and 24 in a 55:45 ratio14 (determined by HPLC). As aforemen-
tioned, when the hydrogenation was carried out with H2–PtO2, it
afforded cis- and trans-diastreomers 23 and 24 in a 74:26 ratio
(by HPLC)14 as inseparable isomers. The diastereomers obtained
from the Pd/C hydrogenation were separated by preparative
HPLC14 as their benzoate esters 23 and 24. Deprotection of the
Bz group with K2CO3 in MeOH at 0 °C gave compounds 8 and 9
(Scheme 4). The cis- and trans-diastereomers were confirmed by
DQF COSY and proton NMR spectroscopy.17
constant(s) J (Hz). 13C NMR chemical shifts are expressed in ppm.
Optical rotations were measured with JASCO P-2000 digital polar-
imeter. Accurate mass measurement was performed on Q STAR
mass spectrometer (Applied Biosystems, USA).
4.2. tert-Butyl 2-(hydroxymethyl) pyrrolidine-1-carboxylate 13
To a stirred suspension of LiAlH4 (1.80 g, 48.03 mmol) in THF
(40 mL) at 0 °C was added compound 12 (11 g, 48.03 mmol) in
THF (40 mL). After 1 h stirring at 0 °C the reaction mixture was
quenched with H2O (1.8 mL), 15% aqueous NaOH (1.8 mL) and
H2O (5.4 mL). The precipitate was filtered through a Celite pad
and washed with hot ethyl acetate (100 mL) and the filtrate was
concentrated in vacuo and purified by flash column chromatogra-
phy (ethyl acetate/hexane, 1:3) to give compound 13 as a liquid
OBn
OBn
(9.17 g, 95%). ½a D25
ꢁ
¼ ꢀ39:75 (c 1.2, CHCl3); lit.13
½
a 2D5
ꢁ
¼ ꢀ48:5 (c
H
N
H
N
1.68, CH2Cl2). IR (Neat): 3426, 2974, 2879, 1671, 1405, 1369,
a
c
b
1251, 1169, 1109, 1050, 773 cmꢀ1 1H NMR (300 MHz, CDCl3):
.
11
d = 3.81–4.16 (m, 2H), 3.28–3.58 (m, 3H), 1.71–2.14(m, 4H), 1.46
(br s, 9H), (because of the rotameric nature of the compound, the
NMR could not be resolved clearly). 13C NMR (300 MHz, CDCl3):
d = 156.56, 79.79, ⁄79.42, 66.54, ⁄63.70, 59.67, ⁄58.47, 47.18,
⁄46.46, 28.23, ⁄28.17, 23.68, ⁄22.83, (⁄rotamer). ESIMS: m/z = 202
[M++1], 224 [M++Na]; HRMS calcd for C10H19NO3Na 224.1262,
found 224.1266.
O
22
O
10
OBz
H
d
8
9
N
O
O
4.3. tert-Butyl 2-vinyl pyrrolidine-1-carboxylate 14
23
+
OBz
To a solution of DMSO (8.2 mL, 115.4 mmol) in DCM (30 mL)
was added oxalyl chloride (5 mL, 57.71 mmol) drop wise at -
78 °C. After stirring for 30 min, a solution of alcohol 13 (5.8 g,
28.85 mmol) in DCM (40 mL) was added over a period of 10 min.
After stirring for 30 min at ꢀ78 °C, the reaction mixture was
quenched with triethylamine (24 mL, 173.1 mmol). The reaction
mixture was slowly warmed to 0 °C, diluted with chloroform
(50 mL), washed with the water and brine, dried over Na2SO4
and concentrated under vacuum. The crude residue was dissolved
H
d
N
24
Scheme 4. Reagents and conditions: (a) 3-butenoic acid, ethylchloroformate, NMM,
THF, 0 °C to rt, 3 h, 89%; (b) 10 mol % Grubbs’ 1st generation catalyst, DCM, 50 °C,
6 h, 82%; (c) (i) H2, Pd–C, MeOH, rt, 2 h, 90%, (ii) benzoyl chloride, Et3N, cat DMAP,
DCM, 0 °C, 2 h, 95%; (d) K2CO3, MeOH, rt, 2 h, 90%.
in THF (30 mL),
A yellow solution of Ph3P@CH2 (8.34 g,
30.25 mmol) in THF (40 mL) was added at ꢀ10 °C After stirring
for 3 h, the reaction mixture was quenched with saturated aq
NH4Cl at 0 °C, THF was removed under reduced pressure and the
residue was extracted with ethyl acetate (3 ꢂ 100 mL). The com-
bined organic extracts were washed with H2O (50 mL) brine
(40 mL), dried over anhydrous Na2SO4, concentrated under re-
duced pressure and purified by silica gel column chromatography
(ethyl acetate/hexane, 1:20) to give compound 14 as a liquid
3. Conclusion
In conclusion, we have developed a versatile route to pyrrolizi-
dine and indolizidine skeletons from key intermediate 11, which
was prepared from easily available L-proline by using ring-closing
metathesis. Further improvements of the strategy and its applica-
tions to other analogues are currently in progress.
(3.92 g, 69%). ½a D25
¼ ꢀ11:5 (c 1, CHCl3). IR (Neat): 2974, 2878,
ꢁ
1695, 1393, 1169, 1114, 987, 914 cmꢀ1. 1H NMR (200 MHz, CDCl3):
d = 5.70–5.79 (m, 1 H), 5.00–5.13 (m, 2H), 4.17–4.37 (m, 1H), 3.38–
3.45 (m, 2H), 1.64–2.08 (m, 4H), 1.45 (s, 9H), (because of the rota-
meric nature of the compound, the NMR could not be resolved
clearly). 13C NMR (300 MHz, CDCl3): d = 154.54, ⁄154.38, 138.81,
⁄138.49, 113.58, 78.98, 59.03, ⁄46.39, 46.03, 31.89, ⁄31.29, 28.37,
⁄23.26, 22.65 (⁄rotamer). ESIMS: m/z = 198 [M++1], 220 [M++Na];
HRMS calcd for C11H19NO2Na 220.1313, found 220.1320.
4. Experimental
4.1. General
Moisture and oxygen sensitive reactions were carried out under
a nitrogen gas atmosphere. All solvents and reagents were purified
by standard techniques. TLC was performed on Merck Kiesel Gel
60, F254 plates (layer thickness 0.25 mm). Column chromatography
was performed on silica gel (60–120 and 100–200 mesh) using
ethyl acetate, hexane chloroform and methanol as eluents. Melting
points were determined on a Fisher John’s melting point apparatus
and are uncorrected. IR spectra were recorded on a Perkin–Elmer
RX-1 FT-IR system. 1H NMR (INOVA-400, AVANCE-300 and GEMINI
200-MHz) and 13C NMR (75 and 100 MHz) spectra were recorded
on corresponding MHz. 1H NMR data are expressed as chemical
shifts in ppm followed by multiplicity (s, singlet; d, doublet; t, trip-
let; q, quartet; m, multiplet), number of proton(s) and coupling
4.4. (S)-tert-Butyl 2-(1, 2-dihydroxyethyl) pyrrolidine-1-
carboxylate 15
To a stirred solution of compound 14 (4 g, 20.30 mmol) in ace-
tone: water (24 mL: 8 mL) was added NMO monohydrate (4.11 g,
30.45 mmol), followed by OsO4 (0.1 mL, 0.4 mmol) at 0 °C and stir-
red at room temperature for 6 h. After the addition of Na2SO3
(0.5 g), the acetone was removed under reduced pressure and the
reaction mixture was diluted with H2O and extracted with DCM
(3 ꢂ 50 mL). The combined organic layers were dried over Na2SO4

K. K. S. Reddy et al. / Tetrahedron: Asymmetry 22 (2011) 662–668
665
concentrated in vacuo and purified by column chromatography
4.7. (S)-tert-Butyl 2-(3-(benzyloxy) prop-1-en-2-yl) pyrrolidine-
(ethyl acetate/hexane, 1:1.5) to give compound 15 as a sirup
1-carboxylate 18
(4.17 g, 89%). ½a D25
ꢁ
¼ ꢀ38:3 (c 1.8, CHCl3). IR (Neat): 3418, 2974,
2881, 1748, 1666, 1400, 1166, 1110, 1063, 884, 772 cmꢀ1
.
1H
To a stirred solution of 17 (3 g, 9.45 mmol) in THF (30 mL), a
yellow coloured solution of Ph3P@CH2 (2.87 g, 10.40 mmol) in
THF (40 mL) was added at ꢀ10 °C. After stirring for 4 h, the reac-
tion mixture was quenched with saturated aq. NH4Cl at 0 °C, after
which THF was removed under reduced pressure and the residue
was extracted with ethyl acetate (3 ꢂ 80 mL). The combined or-
ganic extracts were washed with H2O (30 mL), brine (30 mL), dried
over anhydrous Na2SO4, concentrated under reduced pressure and
purified by silica gel column chromatography (ethyl acetate/hex-
NMR (300 MHz, CDCl3): d = 3.94–3.98 (m, 1 H), 3.77–3.82 (m,
1H), 3.46–3.57 (m, 3H), 3.13–3.33 (m, 2H), 2.83–2.95 (m, 1H),
1.67–2.15 (m, 4H), 1.46–1.47 (d, 9H) (because of the rotameric nat-
ure of the compound, the NMR could not be resolved clearly). 13C
NMR (300 MHz, CDCl3): d = 156.55, ⁄80.46, 80.20, ⁄75.71, 72.71,
64.12, ⁄62.86, ⁄59.18, 58.54, ⁄47.39, 47.01, 28.46, 28.23,⁄27.49,
⁄24.01, 23.16 (⁄rotamer). ESIMS: m/z = 232 [M++1], 254 [M++Na];
HRMS calcd for C11H21NO4Na 254.1368, found 254.1372.
ane, 1:20) to give compound 18 as
¼ ꢀ30:3 (c 1, CHCl3). IR (Neat): 2974, 2876, 1694, 1394,
1166, 1117, 1091, 1027, 911, 771, 699 cmꢀ1 1H NMR (500 MHz,
a liquid (1.81 g, 61%).
½ ꢁ
a 2D5
4.5. (S)-tert-Butyl 2-((R)-2-(benzyloxy)-1-hydroxyethyl)
pyrrolidine-1-carboxylate 16
.
CDCl3): d = 7.19–7.30 (m, 5 H), 5.07 (s, 1H), 4.93 (s, 1H), 4.26–
4.55 (m, 3H), 3.90–4.05 (m, 2H), 3.32–3.50 (m, 2H), 1.76–2.12
(m, 4H), 1.38 (s, 9H), (because of the rotameric nature of the com-
pound, the NMR could not be resolved clearly). 13C NMR (300 MHz,
CDCl3): d = 154.48, ⁄154.22, 146.64, ⁄145.90, 138.15, 128.58,
128.27, ⁄128.05, 127.48, ⁄111.16, 110.79, 79.1, ⁄78.54, 71.81,
⁄71.22, 59.26, ⁄46.78, 46.38, 31.60, ⁄30.86, 28.37, ⁄23.34, 22.62
(⁄rotamer). ESIMS: m/z = 318 [M++1], 340 [M++Na]; HRMS calcd
for C19H27NO3Na 340.1888, found 340.1887.
To a stirred solution of compound 15 (4 g, 17.30 mmol) in dry
toluene (80 mL) was added dibutyltin oxide (5.60 g, 22.49 mmol)
at room temperature. The reaction was slowly heated to 80 °C, stir-
red for 8 h, and then the reaction mixture was allowed to return to
room temperature. Benzyl bromide (2.27 mL, 19.03 mmol) and a
catalytic amount of TBAI were added to the cooled reaction mixture
and stirred for 16 h at 80 °C. The reaction mixture was cooled to
room temperature and the solvent evaporated under reduced pres-
sure. The residue was purified by silica gel column chromatography
(ethyl acetate/hexane, 1:9) to give compound 16 as a liquid (4.90 g,
4.8. (S)-2-(3-(Benzyloxy) prop-1-en-2-yl) pyrrolidine 11
88%). ½a 2D5
¼ ꢀ29:4 (c1.4, CHCl3). IR (Neat): 3421, 2973, 2874, 1688,
ꢁ
A solution of 18 (3 g,9.4 mmol) in DCM (8 mL) was treated with
trifluoroacetic acid (8 ml) at 0 °C and the mixture was stirred for
1 h at the same temperature. Next, DCM and TFA were removed
under vacuum, and the pH of the solution was adjusted to 7 using
saturated aqueous NaHCO3 solution. Crude product 11 was ex-
tracted with DCM (3 ꢂ 40 mL) and used for the next step without
further purification (2.03 g, 99%).
1669, 1392, 1165, 1111, 736, 697 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d = 7.22–7.37 (m, 5 H), 4.48–4.61 (m, 2H), 3.75–3.95 (m, H), 3.29–
3.51 (m, 4H), 1.72–2.15 (m, 4H), 1.46–1.47 (s, 9H) (because of the
rotameric nature of the compound, the NMR could not be resolved
clearly). 13C NMR (300 MHz, CDCl3): d = ⁄138.09, 137.89, ⁄128.36,
128.20, 127.88, ⁄127.68, 127.51, ⁄127.17, ⁄126.71, 79.62, ⁄78.72,
⁄73.31, 73.21, ⁄72.71, 71.91, 71.60, 60.45, ⁄60.06, ⁄59.57, 59.12,
47.40, ⁄46.74, 28.27, ⁄28.01, 27.12, ⁄26.72, 23.94, ⁄23.24 (⁄rotamer).
ESIMS: m/z = 322 [M++1], 344 [M++Na]; HRMS calcd for C18H27NO4-
Na 344.1837, found 344.1831.
4.9. (S)-1-(2-(3-(Benzyloxy) prop-1-en-2-yl) pyrrolidin-1-yl)
prop-2-en-1-one 7
To a solution of 11 (1 g, 4.60 mmol) in DCM (15 mL) were added
Et3N (2.56 mL, 18.4 mmol) and acryloylchloride (1.87 mL,
23.0 mmol) at 0 °C and the reaction mixture was stirred at rt for
3 h. After evaporation of volatile compounds, the reaction mixture
was extracted with DCM (3 ꢂ 50 mL) and H2O (30 mL). The com-
bined organic fractions were collected and washed with H2O
(25 mL) and brine (25 mL), and then dried (Na2SO4). Chromatogra-
phy of the residue on silica gel (ethyl acetate/hexane, 1:2.3) affor-
4.6. (S)-tert-Butyl 2-(2-(benzyloxy) acetyl) pyrrolidine-1-
carboxylate 17
To a stirred solution of 16 (3.2 g, 9.96 mmol) in ethyl acetate
and toluene (1:1, 6 mL) were added sodium bromide (1.02 g,
9.96 mmol), water (0.9 mL) and TEMPO free radical (31.1 mg,
0.19 mmol) at 0 °C simultaneously. A solution of NaHCO3 (2.09 g,
24.9 mmol) in aqueous NaOCl (20.3 mL, 10.95 mmol, 4% aqueous
solution) was added slowly to the above reaction mixture at 0 °C.
After completion of the reaction, the reaction mixture was diluted
with ethyl acetate (15 mL) and washed with an aqueous solution of
KI (7 mg), 10% KHSO4 (4 mL) and 10% sodium thiosulphate (15 mL)
followed by water and extracted with ethyl acetate (3 ꢂ 150 mL).
The organic layer was dried over Na2SO4 concentrated in vacuo
and purified by column chromatography (ethyl acetate/hexane,
ded 7 as a syrup (0.81 g, 65%). ½a D25
¼ ꢀ8:7 (c 1.2, CHCl3). IR (Neat):
ꢁ
3030, 2947, 2874, 1648, 1610, 1430, 1092, 742, 699 cmꢀ1. 1H NMR
(300 MHz, CDCl3): d = 7.26–7.38 (m, 5H), 6.27–6.55 (m, 2H), 5.53–
5.70 (m, 1H), 5.12–5.19 (2s, 1H), 4.90–4.94 (2s, 1H), 4.45–4.77 (m,
3H), 3.95–4.15(m, 2H), 3.54–3.69(m, 2H), 1.77–2.12(m, 4H), (be-
cause of the rotameric nature of the compound, the NMR could
not be resolved clearly). 13C NMR (300 MHz, CDCl3): d = 164.97,
⁄164.01, 145.98, ⁄145.02, ⁄138.21, 137.79, 128.85, ⁄128.61,
128.37, ⁄128.24, 127.78, 127.67, 127.44, ⁄127.16, 113.72, 111.50,
72.40, ⁄71.74, ⁄71.67, 71.24, 59.14, ⁄58.92, ⁄47.16, 46.34, 31.32,
⁄30.08, ⁄23.64, 21.45, (⁄rotamer). ESIMS: m/z = 272 [M++1], 294
[M++Na]; HRMS calcd for C17H21NO2Na 294.1469, found 294.1481.
1:12) to give compound 17 as a liquid (2.89 g, 91%). ½a D25
¼ ꢀ34:5
ꢁ
(c 1, CHCl3). IR (Neat):2975, 2927, 1731, 1692, 1393, 1163, 1118,
740, 698 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 7.14–7.20 (m, 5 H),
.
4.29–4.53 (m, 3H), 3.99–4.13 (m, 2 H), 3.23–3.37 (m, 2H), 1.94–
2.07 (m, 1H), 1.73–1.79 (m, 3H), 1.24–1.33 (d, 9H), (because of
the rotameric nature of the compound, the NMR could not be re-
solved clearly). 13C NMR (300 MHz, CDCl3): d = ⁄207.35, 207.00,
⁄154.46, 153.61, ⁄137.28, 136.98, 128.51, ⁄128.39, 128.04,
⁄127.91, 127.85, 80.10, ⁄79.79, ⁄73.45, 73.33, 73.31, ⁄72.71, 62.51,
⁄61.96, ⁄46.79, 46.61, ⁄29.96, ⁄28.81, 28.37, 28.21, ⁄24.36, 23.56
(⁄rotamer). ESIMS: m/z = 320 [M++1], 342 [M++Na]; HRMS calcd
for C18H25NO4Na 342.1681, found 342.1666.
4.10. (S)-7-(Benzyloxymethyl)-2, 3-dihydro-1H-pyrrolizin-5
(7aH)-one 19
To a solution of diene 7 (0.80 g, 2.95 mmol) in benzene
(300 mL), Grubbs’ second-generation catalyst (252 mg, 0.29 mmol)
was added at rt. The reaction mixture was refluxed for 36 h. Ben-
zene was removed under vacuum. Chromatography on silica gel

666
K. K. S. Reddy et al. / Tetrahedron: Asymmetry 22 (2011) 662–668
(ethyl acetate/hexane, 1:3) provided compound 19 as a liquid
2.55–2.64 (m, 2H), 2.00–2.13 (m, 2H), 1.40–1.52(m, 3H). 13C NMR
(300 MHz, CDCl3): d = 172.89, 166.15, 133.21, 129.61, 129.47,
128.44, 65.74, 65.20, 41.38, 41.14, 38.28, 31.47, 26.88. ESIMS: m/
z = 282 [M++Na]; HRMS calcd for C15H18NO3260.1286, found
260.1294.
(0.54 g, 76% based on the starting material recovery).
½
a 2D5
ꢁ
¼ ꢀ40:8 (c 1.8, CHCl3). IR (Neat): 3376, 2931, 1692, 1448,
1399, 1102, 746 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 7.25–7.35
.
(m, 5H), 5.86 (s, 1H), 4.54 (s, 2H), 4.28 (s, 2H), 4.16–4.21 (dd,
J = 6.04, 10.19 1H), 3.41–3.51 (m, 1H), 3.18–3.27 (m, 1H), 2.04–
2.37 (m, 3H), 1.09–1.30 (m, 1H). 13C NMR (300 MHz, CDCl3):
d = 175.26, 161.64, 137.13, 128.24, 127.66, 127.35, 122.70, 72.65,
67.19, 66.26, 41.63, 29.21, 28.86. ESIMS: m/z = 244 [M++1], 266
[M++Na]; HRMS calcd for C15H18NO2Na 244.1337, found 244.1346.
4.12. (1S,7aS)-1-(Hydroxymethyl) tetrahydro-1H-pyrrolizin-
3(2H)-one 5
To a stirred solution of 20 (25 mg, 0.096 mmol), in MeOH
(1.5 mL), was added K2CO3 at 0 °C. After 2 h water was added to
the reaction mixture. Methanol was removed under reduced pres-
sure and the residue was extracted with DCM (3 ꢂ 10 mL). The
combined organic extracts were washed with H2O (5 mL), brine
(5 mL), dried over anhydrous Na2SO4, concentrated under reduced
pressure and purified by silica gel column chromatography
(MeOH:CHCl3, 1:19) to give compound 5 as a liquid (13 mg, 90%)
4.11. ((1S,7aS)-3-Oxohexahydro-1H-pyrrolizin-1-yl) methyl
benzoate 20 and ((1R,7aS)-3-oxohexahydro-1H-pyrrolizin-1-yl)
methyl benzoate 21
Method I: To
a stirred solution of compound 19 (0.2 g,
0.823 mmol) in MeOH was added a catalytic amount of Pd/C
(10%), after which the flask was purged with H2 and the solution
hydrogenated for 2 h. The reaction mixture was filtered through
a Celite bed, and then the solution was concentrated under vac-
uum. The crude colourless liquid (0.121 g, 95%, 0.781 mmol) ob-
tained was dissolved in DCM (3 mL), after which were added
Et3N (0.10 mL, 0.781 mmol) and benzoylchloride (0.09 mL, 0.781.
mmol) at 0 °C and the reaction mixture was stirred at rt for 2 h.
After evaporation of the volatile compounds, the crude mixture
was extracted with DCM (3 ꢂ 10 mL) and H2O (5 mL). The com-
bined organic layers were collected and washed with H2O (5 mL)
and brine (5 mL), and then dried (Na2SO4). Chromatography on sil-
ica gel (ethyl acetate/hexane, 1:1.5) of the residue afforded a mix-
ture of 20 and 21 as a liquid (0.192 g, 95%). The diastereomers were
separated via preparative HPLC (mobile phase: 30% acetonitrile in
water).14 Major diastereomer 20 was afforded as a liquid (0.064 g,
64%), minor diastereomer 21 was also obtained as a liquid (0.026 g,
26%) with preparative HPLC of 0.100 g compound.
½
a 2D5
ꢁ
¼ ꢀ64:5 (c 1, EtOH); lit.16
½
a 2D5
ꢁ
¼ ꢀ69:6 (c 1.02, EtOH) IR
(Neat): 3438, 2925, 1654, 1456, 1042, 651 cmꢀ1
.
1H NMR
(300 MHz, CDCl3): d = 3.97–4.05 (ddd, J = 5.5, 7.1, 10.5, Hz, 1H),
3.65–3.74 (dd, J = 7.2, 10.6 Hz, 1H), 3.56–3.63 (dd, J = 6.3, 10.6 Hz,
1H), 3.45–3.54 (dd, J = 7.2, 10.6 Hz, 1H), 3.04–3.12 (m, 1H) 2.82–
2.90 (dd, J = 9.0, 17.0 Hz, 1H), 2.58–2.69 (m, 1H), 2.20–2.34 (dd,
J = 3.3, 17.0 Hz, 1H), 1.93–2.17 (m, 3H), 1.79–1.88 (m, 1H), 1.54–
1.68 (m, 1H). 13C NMR (300 MHz, CDCl3): d = 174.19, 63.84,
62.67, 40.87, 37.74, 36.39, 26.73, 25.42. ESIMS: m/z = 156 [M++1],
178 [M++Na]; HRMS calcd for C8H13NO2Na 178.0843, found
178.0842.
4.13. (1R,7aS)-1-(Hydroxymethyl) tetrahydro-1H-pyrrolizin-
3(2H)-one 6
To a stirred solution of 21 (10 mg, 0.038 mmol), in MeOH
(1 mL), was added K2CO3 at 0 °C. After 2 h, water was added to
the reaction mixture. Methanol was removed under reduced pres-
sure and the residue was extracted with DCM (3 ꢂ 10 mL). The
combined organic extracts were washed with H2O (5 mL), brine
(5 mL), dried over anhydrous Na2SO4, concentrated under reduced
pressure and purified by silica gel column chromatography
(MeOH/CHCl3, 1:19) to give compound 6 as a liquid (5 mg, 90%).
Method II: To
a stirred solution of compound 19 (0.2 g,
0.823 mmol) in MeOH was added a catalytic amount PtO2 (10%)
after which the flask was purged with H2 and the solution hydro-
genated for 2 h. The reaction mixture filtered through a Celite
bed and then the solution was concentrated under vacuum. The
crude colourless liquid (0.121 g, 95%, 0.781 mmol) obtained was
dissolved in DCM (3 mL), after which were added Et3N (0.10 mL,
0.781 mmol) and benzoylchloride (0.09 mL, 0.781. mmol) at 0 °C
and the reaction mixture was stirred at rt for 2 h. After evaporation
of volatile compounds, the crude mixture was extracted with DCM
(3 ꢂ 10 mL) and H2O (5 mL). The combined organic layers were
collected and washed with H2O (5 mL) and brine (5 mL), and then
dried (Na2SO4). Chromatography on silica gel (ethyl acetate/hex-
ane, 1:1.5) of the residue afforded a mixture of 20 and 21 as a li-
quid (0.192 g, 95%).
½
a 2D5
ꢁ
¼ þ15:5 (c 0.5, EtOH). Lit.16
½
a 2D5
ꢁ
¼ ꢀ13:2 (c 0.19, EtOH) (for
the enantiomer of this compound). IR (Neat): 3447, 2924, 1657,
1450, 1216, 1034, 759, 667 cmꢀ1 1H NMR (300 MHz, CDCl3):
.
d = 3.60–3.72 (m, 3H) 3.45–3.50 (m, 1H), 2.96–3.00 (m, 1H),
2.42–2.53 (m, 2H), 2.21–2.32 (m, 1H), 1.90–2.06 (m, 3H), 1.31–
1.39(m, 1H). 13C NMR (300 MHz, CDCl3): d = 173.99, 65.22, 64.07,
44.07, 41.10, 38.13, 31.64, 26.92. ESIMS: m/z = 156 [M++1], 178
[M++Na]; HRMS calcd for C8H13NO2Na 178.0843, found 178.0842.
4.14. (S)-1-(2-(3-(Benzyloxy) prop-1-en-2-yl) pyrrolidin-1-yl)
4.11.1. Data for compound 20
but-3-en-1-one 10
½
a 2D5
ꢁ
¼ ꢀ30:8 (c 1.5, CHCl3). IR (Neat): 2955, 2892, 1715, 1695,
1450, 1418, 1271, 114, 713 cmꢀ1 1H NMR (300 MHz, CDCl3):
.
To a solution of 11 (1 g, 4.60 mmol) in dry THF (15 mL) was
added N-methylmorpholine (0.5 mL, 4.60 mmol) at 0 °C followed
by ethylchloroformate (0.34 mL, 4.30 mmol). After 5 minutes, but-
enoic acid (0.39 mL, 5.06 mmol) and then N-methylmorpholine
(0.5 mL, 4.60 mmol) were added and stirring was continued for
3 h at the same temperature. The reaction mixture was quenched
with saturated aq NH4Cl at 0 °C, after which THF was removed un-
der reduced pressure and the residue was extracted with ethyl ace-
tate (3 ꢂ 50 mL). The combined organic extracts were washed with
H2O (25 mL) brine (30 mL), dried over anhydrous Na2SO4, concen-
trated under reduced pressure and purified by silica gel column
chromatography (ethyl acetate/hexane, 1:2.5) to afford 10 as a li-
d = 7.96–7.99 (m, 2H), 7.52–7.56 (m, 1H), 7.40–7.44 (m, 2H),
4.25–4.34 (1 m, 2H), 4.02–4.08 (m, 1H), 3.49–3.56 (m, 1H), 3.05–
3.11 (m, 1H), 2.88–2.95 (m, 2H), 2.29–2.36 (m, 1H), 1.95–2.17 (m,
2H), 1.83–1.88(m, 1H), 1.53–1.64 (m, 1H). 13C NMR (300 MHz,
CDCl3): d = 173.28, 166.19, 133.20, 129.58, 129.50, 128.46, 64.47,
63.48, 40.87, 37.84, 33.51, 26.73, 25.53. ESIMS: m/z = 282
[M++Na]; HRMS calcd for C15H18NO3 260.1286, found 260.1294.
4.11.2. Data for compound 21
½
a 2D5
ꢁ
¼ ꢀ11:7 (c 1, CHCl3). IR (Neat): 2924, 2887, 1717, 1418,
1272, 1111, 712 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 7.98–8.01
.
(m, 2H), 7.53–7.58 (m, 1H), 7.41–7.46 (m, 2H), 4.31–4.48 (m,
2H), 3.70–3.81 (m, 1H), 3.53–3.62 (m, 1H), 3.01–3.09 (m, 1H),
quid (1.16 g, 89%). ½a D25
ꢁ
¼ ꢀ18:2 (c 1.5, CHCl3). IR (Neat): 3448,
3079, 2974, 2874, 1643, 1414, 1093, 912, 742, 699 cmꢀ1
.
1H NMR

K. K. S. Reddy et al. / Tetrahedron: Asymmetry 22 (2011) 662–668
667
(300 MHz, CDCl3): d = 7.25–7.37 (m, 5H), 5.8–6.04 (m, 1H), 5.02–
4.16.1. Data for compound 23
¼ ꢀ7:4 (c 1.5, CHCl3). IR (Neat): 2950, 2882, 1717, 1635,
1457, 1272, 1115, 713 cmꢀ1 1H NMR (300 MHz, CDCl3): d = 7.99–
7.98 (m, 2H), 7.53–7.56 (m, 1H), 7.42–7.45 (m, 2H), 4.27–4.44
(m, 2H), 3.70–3.77 (m, 1H), 3.49–3.58 (m, 2H), 2.53–2.56 (m,
1H), 2.34–2.40 (m, 2H), 1.69–2.12 (m, 6H). 13C NMR (300 MHz,
CDCl3): d = 168.63, 166.36, 133.22, 129.78, 129.54, 128.51, 62.49,
60.35, 44.97, 33.37, 29.25, 27.94, 24.10, 22.28. ESIMS: m/z = 274
[M++1], 296 [M++Na]; HRMS calcd for C16H20NO3 274.1443, found
274.1448.
5.19 (m, 3H), 4.87–4.94 (2s, 1H), 4.43–4.69 (m, 3H), 3.95–4.12
(m, 2H), 3.43–3.62(m, 2H), 2.95–3.13 (m, 2H), 1.76–2.06(m, 4H).
13C NMR (300 MHz, CDCl3): d = 170.09, ⁄168.92, 145.83, ⁄145.11,
⁄138.11, 137.66, 131.76, ⁄131.21, 128.26, ⁄128.12, 127.66, 127.57,
127.36, ⁄117.74, 117.32, 112.90, ⁄111.20, 72.36,⁄71.59, ⁄71.50,
71.10, 59.16, ⁄58.55, ⁄47.05, 46.15, ⁄40.07, 39.26, 31.17, ⁄29.96,
⁄23.48, 21.34 (⁄rotamer). ESIMS: m/z = 286 [M++1], 308 [M++Na];
HRMS calcd for C18H23NO2Na 308.1626, found 308.1629.
½ ꢁ
a 2D5
.
4.15. (S)-8-(Benzyloxymethyl)-1,2,3,8a-tetrahydroindolizin-
5(6H)-one 22
4.16.2. Data for compound 24
½
a 2D5
ꢁ
¼ ꢀ20:1 (c 1.6, CHCl3). IR (Neat): 3442, 2926, 2855, 1644,
To a solution of diene 10 (0.60 g, 2.10 mmol) in DCM (200 mL),
Grubbs’ first-generation catalyst (89 mg, 0.10 mmol) was added at
rt. The reaction mixture was refluxed for 6 h at 50 °C. Next, DCM
was removed under vacuum. Chromatography on silica gel (ethyl
acetate/hexane, 1:3.5) provided compound 22 as a liquid (0.44 g,
1453, 1409, 1092, 742, 700 cmꢀ1 1H NMR (300 MHz, CDCl3):
.
d = 7.98–8.01 (m, 2H), 7.55–7.57 (m, 1H), 7.42–7.46 (m, 2H),
4.33–4.34 (m, 2H), 3.54–3.61 (m, 1H), 3.43–3.47 (m, 1H), 3.28–
3.33 (m, 1H), 2.49–2.56 (m, 1H), 2.26–2.40 (m, 2H), 1.98–2.06(m,
2H), 1.86–1.90 (m, 1H),1.66–1.81 (m, 2H), 1.51–1.59(m, 1H). 13C
NMR (300 MHz, CDCl3): d = 168.61, 166.28, 133.21, 129.70,
129.50, 128.47, 66.06, 61.39, 44.88, 40.03, 32.57, 30.80, 24.81,
22.22. ESIMS: m/z = 274 [M++1], 296 [M++Na]; HRMS calcd for
82%). ½a 2D5
¼ ꢀ4:4 (c 1.8, CHCl3). IR (Neat): 3442, 2926, 2855,
ꢁ
1644, 1453, 1409, 1092, 742, 700 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d = 7.25–7.35 (m, 5H), 5.74 (s, 1H), 4.41–4.51 (q, 2H), 3.92–4.12 (m,
3H), 3.59–3.76 (m, 1H)3.36–3.44 (m, 1H), 2.83–3.07 (m, 2H), 2.19–
2.26 (m, 1H), 1.98–2.08(m, 1H), 1.75–1.93 (m, 1H), 1.39–1.59(m,
1H). 13C NMR (300 MHz, CDCl3): d = 165.65, 137.23, 132.50,
127.85, 127.18, 127.14, 120.59, 71.75, 70.33, 59.31, 43.56, 32.69,
30.29, 21.7. ESIMS: m/z = 258 [M++1], 280 [M++Na]; HRMS calcd
for C16H19NO2Na 280.1313, found 280.1317.
C16H20NO3N 274.1443, found 274.1443.
4.17. (8R,8aS)-8-(Hydroxymethyl) hexahydroindolizin-5(1H)-
one 8
To a stirred solution of 23 (20 mg, 0.072 mmol), in MeOH
(1.5 mL), was added K2CO3 at 0 °C and stirring was continued for
2 h after which the reaction mixture was quenched with H2O.
Methanol was removed under reduced pressure and the residue
was extracted with DCM (3 ꢂ 10 mL). The combined organic ex-
tracts were washed with H2O (5 mL) brine (5 mL), dried over anhy-
drous Na2SO4, concentrated under reduced pressure and purified
by silica gel column chromatography (MeOH/CHCl3, 1:13.3) to give
4.16. ((8S,8aS)-5-Oxooctahydroindolizin-8-yl) methyl benzoate
23 and ((8R,8aS)-5-oxooctahydroindolizin-8-yl) methyl
benzoate 24
Method I: To
a stirred solution of compound 22 (0.3 g,
1.16 mmol) in MeOH was added a catalytic amount of Pd/C (10%)
after which the flask was purged with H2 and the solution hydro-
genated for 2 h. The reaction mixture was filtered through a Celite
bed and then the solution was concentrated under vacuum. The
crude colourless liquid (0.187 g, 95%, 1.108 mmol) was dissolved
in DCM (3 mL), after which were added Et3N (0.15 mL,
1.108 mmol) and benzoylchloride (0.13 mL, 1.108 mmol) at 0 °C
and the reaction mixture was stirred at rt for 2 h. After evaporation
of the volatiles, the crude was extracted with DCM (3 ꢂ 10 mL) and
H2O (5 mL). The combined organic fractions were collected and
washed with H2O (5 mL) and brine (5 mL) and then dried (Na2SO4).
Chromatography of the residue on silica gel (ethyl acetate/hexane,
1:1.5) afforded mixture of 23 and 24 as a liquid (0.286 g, 95%). The
diastereomers were separated through preparative HPLC (mobile
phase: 30% acetonitrile in water).14 Major diastereomer 23 was ob-
tained as a liquid (0.055 g, 55%), minor diastereomer 24 was ob-
tained as a liquid (0.045 g, 45%) yield with preparative HPLC of
0.100 g compound.
compound 8 as a liquid (10 mg, 90%). ½a D25
ꢁ
¼ ꢀ32:9 (c 1, CHCl3). IR
(Neat): 3368, 2922, 2878, 1613, 1471, 1417, 1323, 1048 cmꢀ1
.
1H
NMR (300 MHz, CDCl3): d = 3.72–3.75 (dd, J = 6.5, 10.6 Hz, 1H),
3.69 (ddd, J = 4.4, 4.4, 11.2 Hz, 1H) 3.51–3.55 (dd, J = 7.5, 10.6 Hz,
1H), 3.43–3.49 (m, 2H), 2.22–2.36 (m, 3H), 2.00–2.06 (m, 1H),
1.88–1.97 (m, 2H), 1.66–1.81 (m, 3H). 13C NMR (300 MHz, CDCl3):
d = 169.36, 60.71, 59.20, 44.95, 35.79, 28.91, 27.55, 23.24, 22.21.
ESIMS: m/z = 170 [M++1], 192 [M++Na]; HRMS calcd for C9H15NO2-
Na 192.1000, found 192.1004.
4.18. (8S,8aS)-8-(Hydroxymethyl) hexahydroindolizin-5(1H)-
one 9
To a stirred solution of 24 (10 mg, 0.036 mmol), in MeOH
(1 mL), was added K2CO3 at 0 °C and stirring was continued for
2 h after which the reaction mixture was quenched with H2O.
Methanol was removed under reduced pressure and the residue
was extracted with DCM (3 ꢂ 10 mL). The combined organic ex-
tracts were washed with H2O (5 mL) brine (5 mL), dried over anhy-
drous Na2SO4, concentrated under reduced pressure and purified
by silica gel column chromatography (MeOH/CHCl3, 1:13.3) to give
Method II: To
a stirred solution of compound 19 (0.2 g,
0.823 mmol) in MeOH was added a catalytic amount of PtO2
(10%), after which the flask was purged with H2 and the solution
hydrogenated for 2 h. The reaction mixture was filtered through
a Celite bed and then the solution was concentrated under vacuum.
The crude colourless liquid (0.121 g, 95%, 0.781 mmol) obtained
was dissolved in DCM (3 mL), after which were added Et3N
(0.10 mL, 0.781 mmol) and benzoylchloride (0.09 mL, 0.781.
mmol) at 0 °C and the reaction mixture was stirred at rt for 2 h.
After evaporation of volatile compounds, crude mixture was ex-
tracted with DCM (3 ꢂ 10 mL) and H2O (5 mL). The combined or-
ganic layers were collected and washed with H2O (5 mL) and
brine (5 mL), and then dried (Na2SO4). Chromatography on silica
gel (ethyl acetate/hexane, 1:1.5) of the residue afforded a mixture
of 20 and 21 as a liquid (0.192 g, 95%)
compound 9 as a liquid (5 mg, 90%) ½a D25
ꢁ
¼ ꢀ15:0 (c 0.5, CHCl3). IR
(Neat): 3369, 2923, 2882, 1614, 1471, 1416, 1057 cmꢀ1
.
1H NMR
(300 MHz, CDCl3): d = 3.74 (dd, J = 4.4, 10.8 Hz, 1H), 3.61–3.64
(dd, J = 5.3, 10.8 Hz, 1H), 3.53–3.61 (m, 1H), 3.41–3.46 (m, 1H),
3.24 (ddd, J = 5.0, 10.3, 10.3 Hz, 1H), 2.47–2.52 (m, 1H) 2.30–2.37
(m, 1H), 2.20–2.24 (m, 1H), 1.93–2.08 (m, 3H), 1.66–1.78(m, 1H),
1.52–1.62 (m, 2H), 1.40–1.49 (m, 1H). 13C NMR (300 MHz, CDCl3):
d = 169.17, 64.27, 61.17, 44.83, 42.72, 32.40, 30.95, 24.43, 22.27.
ESIMS: m/z = 170 [M++1], 192 [M++Na]; HRMS calcd for C9H15NO2-
Na 192.1000, found 192.1004.

668
K. K. S. Reddy et al. / Tetrahedron: Asymmetry 22 (2011) 662–668
2009, 131, 11640–11641; (d) Pohmakotr, M.; Prateeptongkum, S.;
Acknowledgements
Chooprayoon, S.; Tuchinda, P.; Reutrakul, V. Tetrahedron 2008, 64, 2339–
2347; (e) Belanger, G.; Larouche-Gauthier, R.; Menard, F.; Nantel, M.; Barabe, F.
J. Org. Chem. 2006, 71, 704–712. and references cited there in; (f) McElhinney,
A. D.; Marsden, S. P. Synlett 2005, 2528–2530; (g) Dieter, R. K.; Chen, N.;
Watson, R. T. Tetrahedron 2005, 61, 3221–3230; (h) Dieter, R. K.; Watson, R.
Tetrahedron Lett. 2002, 43, 7725–7728; (i) Bates, R. W.; Boonsombat, J. J. Chem.
K.S.R. thanks CSIR, New Delhi for the research fellowship. The
authors also thank Dr. J. S. Yadav and Dr. A. C. Kunwar for their sup-
port and encouragement. We also thank DST (SR/S1/OC-14/2007),
New Delhi for financial support.
Soc., Perkin Trans.
1 2001, 654–656; (j) Olivier, D.; Bellec, C.; Fargeau-
Bellassoued, M. C.; Lhommet, G. Heterocycles 2001, 55, 1689–1701; (k) Ha,
D.-C.; Park, S.-H.; Choi, K.-S.; Yun, C.-S. Bull. Korean Chem. Soc. 1998, 19, 728–
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4. Anderson, W. K.; Milowsky, A. S. J. Med. Chem. 1987, 30, 2144–2147.
5. For reviews on amphibian alkaloids, see: (a) Daly, J. W.; Spande, T. F. In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1986; Vol. 4, p 1. Chapter 1; (b) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In
The Alkaloids: Chemistry and Pharmacology; Cordell, G. A., Ed.; Academic Press:
San Diego, 1993; Vol. 43, p 185. Chapter 3.
6. (a) Bhaskar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44, 915–917; (b) Ramana, G.
V.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5103–5105; (c) Madhan, A.; Rao, B. V.
Tetrahedron Lett. 2003, 44, 5641–5643; (d) Chandrasekhar, B.; Madhan, A.; Rao,
B. V. Tetrahedron 2007, 63, 8746–8751; (e) Chandrasekhar, B.; Rao, B. V.; Rao, K.
V. M.; Jagadeesh, B. Tetrahedron: Asymmetry 2009, 20, 1217–1223; (f) Rao, J. P.;
Rao, B. V.; Swarnalatha, J. L. Tetrahedron Lett. 2010, 51, 3083–3087.
7. ( )-Isoretronecanol: (a) Despinoy, X. L. M.; McNab, H. Org. Biomol. Chem. 2009,
7, 4502–4511; (b) Kabata, M.; Suzuki, T.; Takabe, K.; Yoda, H. Tetrahedron Lett.
2006, 47, 1607–1611; (c) Dieter, R. K.; Chen, N.; Watson, R. T. Tetrahedron 2005,
61, 3221–3230; (d) Pereira, E.; Alves, C. F.; Boeckelmann, M. A.; Pilli, R. A.
Tetrahedron Lett. 2005, 46, 2691–2693; (e) Ishii, K.; Sone, T.; Shimada, Y.;
Shigeyama, T.; Noji, M.; Sugiyama, S. Tetrahedron 2004, 60, 10887–10898; (f)
Ledoux, S.; Marchalant, E.; Celerier, J.-P.; Lhommet, G. Tetrahedron Lett. 2001,
42, 5397–5399; (g) Lemaire, S.; Giambastiani, G.; Prestat, G.; Poli, G. Eur. J. Org.
Chem. 2004, 13, 2840–2847. and references cited therein.
14. The ratio of the diastereomers was determined by using RP-HPLC method
performed on Agilent 1100 series HPLC with DAD detector on water HR C18
300 ꢂ 3.9 mm, 6
l column with 30% acetonitrile in water as mobile phase at a
flow rate of 1.0 mL/min and elute was monitored at 225 nm and the retention
times of the two isomers are 7.04 min and 7.84 min.
The two isomers were separated by using an RP-HPLC method performed on
Dionex P680 HPLC with PDA detector on zorbax SBC18 50 ꢂ 9.4 mm, 5
l
column with 30% acetonitrile in water as mobile phase at 1.0 mL/min flow rate
and elute was monitored at 225 nm
15. Shashidhar, J.; Ghosh, S. Tetrahedron Lett. 2009, 50, 1177–1179.
16. Bertrand, S.; Hoffmann, N.; Jean-Pierre, P. Eur. J. Org. Chem. 2000, 2227–
2238.
17. The configuration of the newly created stereogenic centre in 8 and 9 was
confirmed by 1H NMR coupling constants and DQF COSY. The Ha proton in
compound 8 showed the following coupling constants JHa-Hb and JHa-Hc = 4.4 Hz
and JHa-Hd = 11.2 Hz which confirms that the relationship of Ha proton to Hb
and Hc is cis. In the case of Ha proton in compound 9 the following J values are
observed. JHa-Hb and JHa-Hd = 10.3 Hz and JHa-Hc = 5.0 Hz which confirms that the
relationship of the Ha proton to Hb and Hd is trans.
OH
OH
H
H
N
N
O
Hd
Hb
Ha
Hc
O
compound 8
8. ( )-Trachelanthamidine: (a) Ishibashi, H.; Sasaki, M.; Taniguchi, T. Tetrahedron
2008, 64, 7771–7773; (b) Craig, D.; Hyland, C. J. T.; Ward, S. E. Synlett 2006,
2142–2144; (c) Chang, M.-Y.; Wu, D.-C.; Chang, N.-C. Heterocycles 2005, 65,
2965–2971. and references cited therein.
9. ( )-5-Epitashiromine: (a) Dieter, R. K.; Chen, N.; Watson, R. T. Tetrahedron 2005,
61, 3221–3230; (b) Agami, C.; Dechoux, L.; Hebbe, S.; Menard, C. Tetrahedron
2004, 60, 5433–5438; (c) Dieter, R. K.; Watson, R. Tetrahedron Lett. 2002, 43,
7725–7728. and references cited therein; (d) Ha, D. C.; Park, S. H.; Choi, K. S.;
Yun, C. S. Bull. Korean Chem. Soc. 1998, 19, 728–730.
OH
H
Hb
N
H
O
Hd
N
OH
Ha
Hc
10. ( )-Tashiromine: (a) Amorde, S. M.; Jewett, I. T.; Martin, S. F. Tetrahedron 2009,
65, 3222–3231; (b) Garrido, N. M.; Blanco, M.; Cascón, I. F.; Díez, D.; Vicente, V.
M.; Sanz, F.; Urones, J. G. Tetrahedron: Asymmetry 2008, 19, 2895–2900; (c)
Conard, J. C.; Kong, J.; Laforteza, B. N.; MacMillan, D. W. C. J. Am. Chem. Soc.
O
compound 9