Synthesis of (-)-lentiginosine, its 8a-epimer and dihydroxylated pyrrolizidine alkaloid from d-glucose

Article abstract of DOI:10.1016/j.tet.2006.02.074

The d-glucose derived α,β-unsaturated ester 5 on 1,2-acetonide deprotection, oxidative diol cleavage followed by treatment with N-benzylamine in the presence of NaBH₃CN undergoes reductive amination and a concomitant intramolecular conjugate ad

Full text of DOI:10.1016/j.tet.2006.02.074

Tetrahedron 62 (2006) 4349–4354
Synthesis of (L)-lentiginosine, its 8a-epimer and dihydroxylated
pyrrolizidine alkaloid from D-glucose
*
Vinod D. Chaudhari, K. S. Ajish Kumar and Dilip D. Dhavale
Department of Chemistry, Garware Research Centre, University of Pune, Pune 411 007, Maharashtra, India
Received 29 November 2005; revised 7 February 2006; accepted 23 February 2006
Available online 20 March 2006
Abstract—The D-glucose derived a,b-unsaturated ester 5 on 1,2-acetonide deprotection, oxidative diol cleavage followed by treatment with
N-benzylamine in the presence of NaBH3CN undergoes reductive amination and a concomitant intramolecular conjugate addition reaction
leading to the formation of dihydroxypyrrolidine-ester 6a and monohydroxypyrrolidine-g-lactone 6b. Intermediates 6a and 6b were
efficiently converted to (K)-lentiginosine 3a, its 8a-epimer 3b, and pyrrolizidine azasugar 4 in good overall yield.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
materials,3,5 however, the use of carbohydrate substrates has
received limited attention.6 While working in the area of
azasugars,7 we have recently exploited D-glucose derived
a,b-unsaturated ester 5 in the synthesis of trihydroxylated
pyrrolidine alkaloids A and B (Scheme 1). Thus, opening of
1,2-acetonide group in 5 followed by oxidative cleavage
afforded ethyl D-threo-hex-4-enoate, which on one pot
reductive amination and intramolecular conjugate addition
afforded hydroxy ester 6a and g-lactone 6b in the ratio
42:58 (81%) that were converted to A and B, respectively.7c
Now, we describe herein the utility of 6a/6b in the synthesis
of lentiginosine 3a, its 8a-epimer 3b and dihydroxylated
pyrrolizidine alkaloid 4.
Polyhydroxylated indolizidine alkaloids such as castanos-
permine 1, swainsonine 2 and lentiginosine 3a (Fig. 1) are
known to be the potential glycosidase inhibitors.1 Among
these, the least hydroxylated lentiginosine 3a, was found to
be the selective inhibitor (IC50 5 mg/mL) of amylogluco-
sidase enzyme and also exhibit anti-HIV activity.2,3 (K)-
Lentiginosine 3a was isolated from the leaves of Astragalus
lentiginous in 1990,3a however, its sign of rotation and the
stereochemical assignments raised controversy4 and there-
fore aroused synthetic interest in the past decade. The
known synthetic strategies mainly involve asymmetric
pathways starting from either chiral or achiral starting
HO
N
N
H
OH
HO
H
OH
OH
OH
OH
1
OH
2
5
3
N
H
N
8a
OH
OH
7
1
R
OH
4
3a R = Ha
3b R = Hb
Figure 1. Indolizidine and pyrrolizidine alkaloids.
Keywords: Alkaloids; Wittig olefination; Azasugars.
*
Corresponding author. Tel.: C91 20 25601225; fax: C91 20 25691728;
e-mail: ddd@chem.unipune.ernet.in
Scheme 1. Synthesis of pyrrolidine alkaloids.
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.074

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V. D. Chaudhari et al. / Tetrahedron 62 (2006) 4349–4354
2. Results and discussion
2.1. Synthesis of (L)-lentiginosine 3a
Bn
N
HO
a
6b
88%
HO
OBn
OBn
10
As shown in Scheme 2, treatment of hydroxy ester 6a with
hexamethyldisilazane in the presence of catalytic amount of
both TMSCl and ammonium thiocyanate afforded 3-O-TMS
protected ester 7.8 Reduction of the ester functionality in 7
with DIBAL-H followed by Wittig olefination (Ph3PZ
CHCOOEt) gave a,b-unsaturated ester 8a (E/ZZ4:1 based
on 1H NMR). Hydrogenation of 8a using ammonium
formate, 10% Pd/C afforded bicyclic lactam 9a. This one
pot four-step process involves reduction of the double bond,
hydrogenolysis of –OBn and –NBn groups, desilylation and
concomitant cyclization to give d-lactam 9a. The products 7,
8a and 9a were characterized by spectral and analytical
techniques, and the data was found to be in agreement with
the structures. In the next step, LAH reduction of 9a in THF
under reflux followed by column chromatography purifi-
cation gave (K)-lentiginosine 3a as white solid. This
compound [observed [a]D K3.5 (c 1.0, MeOH); lit.3b,5c,g,o,6d
K1.6, K2.6, K3.05, K2.0, K4.5] had spectral and
analytical data in agreement with that in the literature.3,5,6
95%
b
Bn
N
Bn
N
R1O
EtO
e
94%
O
R2O
BnO
OBn
11 R1 = TBDMS, R2 = H
c
82%
8b
93%
f
12 R1 = TBDMS, R2 = Bn
13 R1 = H, R2 = Bn
d
95%
O
N
g
N
H
OH
OH
91%
H
OH
OH
3b
9b
Scheme 3. Reagents and conditions: (a) LAH, THF, 0 8C, 30 min;
(b) TBSCl, imidazole, CH2Cl2, 25 8C, 3 h; (c) NaH, BnBr, THF, 0 8C,
6 h; (d) TBAF, THF, 25 8C, 4 h; (e) (i) (COCl)2, DMSO, NEt3, K78 8C,
2 h; (ii) PPh3CHCOOEt, CH2Cl2, 25 8C 1 h; (f) HCOONH4, 10% Pd/C,
MeOH, reflux, 1 h; (g) LAH, THF, reflux, 10 h.
Bn
N
Bn
N
EtO
EtO
b
a
2.3. Synthesis of dihydroxylated pyrrolizidine alkaloid 4
6a
H
O
88%
89%
OBn
O
TMSO
OBn
TMSO
The hydroxyl ester 6a was utilized in the synthesis of
dihydroxylated pyrrolizidine alkaloid 4 (Scheme 4). Thus,
hydrolysis of 6a with lithium hydroxide and activation of
carboxylate group using ethylchloroformate and triethyl
amine afforded mixed anhydride, which on treatment with
diazomethane in diethyl ether followed by Wolff rearrange-
ment using silver benzoate in methanol furnished one
carbon homologated methyl ester 14.7b Treatment of methyl
ester 14 with ammonium formate and 10% Pd/C afforded
bicyclic lactam 15 that was reduced with LAH to give
dihydroxylated pyrrolizidine alkaloid 4. The spectral data
and analytical data of 4 was found to be identical with that
reported5o [observed [a]D C6.5 (c 0.25, MeOH), lit.5o [a]D
C7.6 (c 1.3, MeOH)].
8a
7
94%
c
O
N
H
N
H
OH
d
OH
92%
OH
OH
3a
9a
Scheme 2. Reagents and conditions: (a) HMDS, cat. TMSCl, cat. NH4SCN,
CH2Cl2, 25 8C, 30 min; (b) (i) DIBAL-H, CH2Cl2, K50 8C, 2.5 h; (ii)
Ph3PCHCOOEt, CH2Cl2, 25 8C, 30 min; (c) HCOONH4, 10% Pd/C, cat.
AcOH, MeOH, reflux, 1 h; (d) LAH, THF, reflux, 8 h.
2.2. Synthesis of 1,2-epilentiginosine 3b
O
Bn
N
Similar methodology was attempted for the g-lactone 6b,
however, DIBAL-H reduction afforded lactol, which on the
Wittig olefination led to the formation of a diastereomeric
mixture of an unexpected product.9 As an alternative,
reduction of g-lactone 6b with LAH in THF afforded diol 10
(Scheme 3). The primary hydroxy group in 10 was
selectively protected using TBDMSCl to get 11 that on
benzylation afforded 12. Treatment of 12 with TBAF in
THF furnished alcohol 13, which on Swern oxidation and
Wittig olefination gave a,b-unsaturated ester 8b (E/ZZ4:1
based on 1H NMR). Hydrogenation of ester 8b using
ammonium formate and 10% Pd/C gave bicyclic lactam 9b.
Finally, reduction of 9b with LAH afforded 3b, an 8a-
epimer of 3a. This compound [observed [a]DC4.3 (c 0.5,
MeOH); lit.5kC3.4 (c 0.41, MeOH)] had spectral and
analytical data in agreement with that in the literature.5k,10
a
MeO
6a
H
71%
HO
OBn
14
b
70%
O
N
H
c
N
OH
OH
77%
OH
H
OH
4
15
Scheme 4. Reagents and conditions: (a) (i) LiOH, methanol–water,
0–25 8C, 4 h; (ii) ClCOOEt, NEt3, THF, 0–25 8C, 30 min; (iii) CH2N2,
diethyl ether, 25 8C, 1.5 h; (iv) PhCOOAg, NEt3, methanol, 25 8C, 3 h;
(b) HCOONH4, 10% Pd/C, methanol, reflux, 1 h; (c) LAH, THF, reflux,
10 h.

V. D. Chaudhari et al. / Tetrahedron 62 (2006) 4349–4354
4351
3. Conclusion
CDCl3) d 0.13 (s), 14.1, 36.6, 56.3, 58.3, 60.3, 66.9, 71.4,
80.9, 83.5, 126.8, 127.5, 127.6 (s), 128.1 (s), 128.2 (s), 128.6
(s), 138.0, 138.8, 171.9.
In conclusion, a new synthetic protocol for (K)-lentigino-
sine 3a, and its 8a-epi-analogue 3b and dihydroxylated
pyrrolizidine alkaloid 4 has been developed starting from
D-glucose derived a,b-unsaturated ester 5. With our
methodology the hydroxylated C-3/C-4 carbons of
D-glucose, both with the R configuration, are retained in
the target molecule 3a. It is therefore obvious that (K)-
lentiginosine 3a has (1R,2R,8aR) absolute configuration as
reported earlier.5c,o,6d
4.1.2. Ethyl(E)-4-((2R,3R,4R)-1-benzyl-4-benzyloxy-3-
trimethylsilyloxy-pyrrolidin-2-yl)but-2-enoate (8a). To
a solution of 7 (2.00 g, 4.50 mmol) in dichloromethane
(20 mL) was added DIBAL-H (6.43 mL, 5.42 mmol) at
K50 8C and stirred for 2.5 h. The reaction mixture was
quenched with saturated solution of NH4Cl (5 mL), filtered
through Celite to afford aldehyde. To a solution of aldehyde
(1.78 g, 4.29 mmol) in dichloromethane (10 mL) was added
PPh3CHCOOEt (1.17 g, 5.15 mmol) at 25 8C and stirred for
30 min. Reaction mixture was adsorbed on neutral alumina
and purified by column chromatography on neutral alumina
(10% ethyl acetate/n-hexane) afforded 8a (1.89 g, 89%) as a
thick oil; [found: C, 69.42; H, 7.88. C27H37NO4Si requires
C, 69.37; H, 7.97]; Rf (10% ethyl acetate/n-hexane) 0.43;
4. Experimental
4.1. General
Melting points were recorded with Thomas Hoover melting
point apparatus and are uncorrected. IR spectra were
recorded with Shimadzu FTIR-8400 as a thin film or in
Nujol mull or using KBr pellets and are expressed in
reciprocal centimetre (cmK1). 1H (300 MHz) and 13C
(75 MHz) NMR spectra were recorded with Varian Mercury
300 using CDCl3 or D2O as a solvent. Chemical shifts were
reported in d unit (ppm) with reference to TMS as an
internal standard and J values are given in Hertz. Elemental
analyses were carried out with Elemental Analyser Flash
1112. Optical rotations were measured using a Bellingham
Stanley-ADP digital polarimeter with sodium light
(589.3 nm) at 25 8C. Thin-layer chromatography was
performed on Merck pre-coated plates (0.25 mm, silica
gel 60 F254). Column chromatography was carried out with
silica gel (100–200 mesh). The reactions were carried out in
oven-dried glassware under dry N2. Methanol, DMF, THF
were purified and dried before use. Petroleum ether (PE)
that was used is a distillation fraction between 40–60 8C.
LAH, DIBAL-H, 10% Pd–C were purchased from Aldrich
and/or Fluka. After decomposition of the reaction with
water, the work-up involves—washing of combined organic
layer with water, brine, drying over anhydrous sodium
sulfate and evaporation of solvent at reduced pressure.
[a]D K36.4 (c 0.27, CHCl3); nmax (neat) 1718, 1259 cmK1
;
dH (300 MHz, CDCl3) d 0.18 (s, 9H), 1.25 (t, JZ7.1 Hz,
3H), 2.51–2.60 (m, 4H), 3.02 (br d, JZ12.0 Hz, 1H), 3.29
(br d, JZ13.1 Hz, 1H), 3.78 (dt, JZ5.7, 2.4 Hz, 1H), 4.01
(dd, JZ5.7, 3.2 Hz, 1H), 4.06 (d, JZ13.1 Hz, 1H), 4.23 (q,
JZ7.1 Hz, 2H), 4.44 (ABq, JZ11.2 Hz, 2H), 5.39 (d, JZ
15.6 Hz, 1H), 7.01–7.40 (m, 11H); dC (75 MHz, CDCl3) d
0.1 (s), 14.2, 33.4, 56.3, 58.0, 60.1, 68.8, 71.5, 81.0, 83.6,
123.1, 127.0, 127.5 (s), 127.7 (s), 128.2 (s), 128.3, 137.9,
138.4, 145.6, 166.2. Our attempt to isolate the Z-isomer in
pure form was unsuccessful and the 89% yield reflects the
total yield of E and Z mixtures.
4.1.3. (1R,2R,8aR)-Hexahydro-1,2-dihydroxyindolizidin-
5(1H)-one (9a). A solution of 8a (0.50 g, 1.10 mmol),
ammonium formate (0.22 g, 7.49 mmol), 10% Pd/C (0.20 g)
and acetic acid (0.02 mL, 0.34 mmol) in methanol (10 mL)
was refluxed for 1 h. The solution was filtered, concentrated
and purified by column chromatography (10% methanol/
chloroform) to afford 9a (0.17 g, 94%) as a white solid, mp
122–124 8C; [found: C, 56.21; H, 7.54. C8H13NO3 requires
C, 56.13; H, 7.65]; Rf (10% methanol/chloroform) 0.34;
[a]D C12.0 (c 0.25, MeOH); nmax (KBr) 3357, 1720,
1656.7, 1452, 1028 cmK1; dH (300 MHz, D2O) d 1.30–1.47
(m, 1H), 1.60–1.76 (m, 1H), 1.90–2.00 (m, 1H), 2.13–2.20
(m, 1H); 2.21–2.43 (m, 2H), 3.31 (dd, JZ12.6, 6.8 Hz, 1H),
3.39 (ddd, JZ15.3, 11.5, 3.5 Hz, 1H), 3.65–3.72 (m, 2H),
4.19 (dd, JZ15.3, 7.1 Hz, 1H); dC (75 MHz, D2O) d 19.3,
25.5, 29.8, 48.6, 61.5, 72.7, 79.7, 172.4.
4.1.1. Ethyl 2-((2R,3R,4R)-1-benzyl-4-benzyloxy-3-tri-
methylsilyloxy-pyrrolidin-2-yl)acetate (7). To a solution
of hydroxyester7c 6a (1.00 g, 2.71 mmol) in dichloro-
methane (10 mL) was added HMDS (0.34 mL,
1.60 mmol) followed by catalytic amount of both TMSCl
(0.04 mL, 0.30 mmol) and ammonium thiocyanate (0.01 g,
0.13 mmol) at 25 8C. The reaction mixture was stirred for
30 min and extracted with dichloromethane (2!30 mL).
The combined organic layer was concentrated, adsorbed on
neutral alumina and purification by column chromatography
on neutral alumina (7% ethyl acetate/n-hexane) afforded 7
(1.10 g, 88%) as thick oil; [found: C, 67.82; H, 7.90.
C25H35NO4Si requires C, 67.99; H, 7.99]; Rf (10% ethyl
acetate/n-hexane) 0.47; [a]D K4.0 (c 0.50, CHCl3); nmax
(neat) 1728, 1217 cmK1; dH (300 MHz, CDCl3) d 0.22 (s,
9H), 1.25 (t, JZ7.1 Hz, 3H), 2.38 (dd, JZ10.9, 6.3 Hz, 1H),
2.47 (d, JZ5.7 Hz, 2H), 2.73 (dd, JZ11.8, 5.7 Hz, 1H),
2.80 (dd, JZ10.9, 1.9 Hz, 1H), 3.14 (d, JZ13.1 Hz,
1H), 3.61–3.65 (m, 1H), 3.89 (d, JZ13.1 Hz, 1H), 3.98
(dd, JZ7.1, 4.6 Hz, 1H), 3.99 (q, JZ7.1 Hz, 2H), 4.27
(ABq, JZ11.8 Hz, 2H), 7.05–7.23 (m, 10H); dC (75 MHz,
4.1.4. (1R,2R,8aR)-(L)-1,2-Dihydroxyindolizidine (3a).
To an ice-cooled suspension of LAH (0.06 g, 1.50 mmol) in
THF (3 mL) was added lactam 9a (0.07 g, 0.41 mmol) in
THF (7 mL). The reaction mixture was warmed to room
temperature, refluxed for 8 h and quenched with ethyl
acetate (2 mL) and aq NH4Cl (0.3 mL). Filtration through
Celite, the filtrate was adsorbed on silica gel and column
chromatography (20% methanol/chloroform) gave 3a
(0.06 g, 92%) as a white solid, mp 106–108 8C; lit.3b,5g
106–107 8C; [found: C, 61.08; H, 9.59. C8H15NO2 requires
C, 61.12; H, 9.62]; Rf (20% methanol/chloroform) 0.30;
[observed [a]D K3.5 (c 1.0, MeOH); lit.3b,5c,g,o,6d K1.6,
K2.6, K3.05, K2.0, K4.5]; nmax (neat) 3578, 2929,
1134 cmK1; dH (300 MHz, D2O) d 1.14–1.25 (m, 2H),
1.34–1.41 (m, 1H), 1.52–1.60 (m, 1H), 1.73–1.74 (m, 1H);

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V. D. Chaudhari et al. / Tetrahedron 62 (2006) 4349–4354
1.85–1.91 (m, 2H), 1.98 (ddd, JZ14.0, 11.5, 2.7 Hz, 1H),
2.56 (dd, JZ11.2, 7.6 Hz, 1H), 2.76 (dd, JZ11.2, 1.6 Hz,
1H), 2.87 (d, JZ10.9 Hz, 1H), 3.56 (dd, JZ8.7, 3.8 Hz,
1H), 4.00 (ddd, JZ7.6, 3.8, 1.6 Hz, 1H); dC (75 MHz, D2O)
d 25.3, 26.3, 29.9, 54.9, 62.5, 70.8, 77.9, 85.2.
74.53; H, 8.53]; Rf (20% ethyl acetate/n-hexane) 0.75; [a]D
C48.6 (c 0.7, CHCl3); nmax (neat) 2926, 1456, 1252,
1092 cmK1; dH (300 MHz, CDCl3) d 0.02 (s, 6H), 0.88 (s,
9H), 1.69–1.91 (m, 2H), 2.02–2.09 (m, 1H), 2.18–2.56 (m,
1H), 2.91 (m, 1H), 3.43–3.48 (m, 1H), 3.54–5.56 (m, 1H),
3.67–3.74 (m, 1H), 3.90 (dd, JZ6.0, 2.1 Hz, 1H), 3.99 (ddd,
JZ7.6, 6.0, 2.1 Hz, 1H), 4.06 (d, JZ13.1 Hz, 1H), 4.44 (s,
2H), 4.45 (d, JZ12.0 Hz, 1H), 4.63 (d, JZ12.0 Hz, 1H),
7.25–7.38 (m, 15H); dC (75 MHz, CDCl3) d 18.2, 25.9 (s),
30.2, 57.3, 58.4, 60.7, 63.3, 71.4, 81.5, 82.9, 127.1, 127.6
(s), 127.7 (s), 128.0 (s), 128.2 (s), 128.3 (s), 128.4 (s), 129.3,
138.0.
4.1.5. (2S,3R,4R)-1-Benzyl-4-benzyloxy-2-(2-hydroxy-
ethyl)pyrrolidin-3-ol (10). To an ice-cooled suspension
of LAH (0.19 g, 4.76 mmol) in THF (4 mL) was added a
solution of g-lactone 6b (0.50 g, 2.46 mmol) in THF
(10 mL) and stirred for 30 min at 25 8C. Work up as
described for 3a and purification by column chromato-
graphy (30% ethyl acetate/n-hexane) afforded 10 (0.44 g,
88%) as thick oil; [found: C, 73.41; H, 7.71. C20H25NO3
requires C, 73.37; H, 7.70]; Rf (50% ethyl acetate/n-hexane)
0.43; [a]D C84.8 (c 0.33, CHCl3); nmax (neat) 3300–3600
(broad) cmK1; dH (300 MHz, CDCl3) d 1.90–1.97 (m, 2H),
2.18 (dd, JZ10.8, 6.4 Hz, 1H), 2.73–2.79 (m, 1H), 3.22 (d,
JZ12.8 Hz, 1H), 3.24 (dd, JZ10.8, 6.3 Hz, 1H), 3.56 (br s,
exchangeable with D2O, 2H), 3.67–3.75 (m, 1H), 3.81–3.86
(m, 1H), 3.89 (dt, JZ6.4, 2.6 Hz, 1H), 4.00 (d, JZ12.8 Hz,
1H), 4.19 (dd, JZ5.8, 2.6 Hz, 1H), 4.52 (ABq, JZ11.7 Hz,
2H), 7.22–7.36 (m, 10H); dC (75 MHz, CDCl3) d 28.9, 57.2,
58.3, 59.8, 66.4, 71.6, 76.7, 83.5, 127.2, 127.6, 127.7 (s),
128.3 (s), 129.0 (s), 137.7, 137.9.
4.1.8. 2-((2S,3R,4R)-1-Benzyl-3,4-bis(benzyloxy)pyrro-
lidin-2-yl)ethanol (13). To a solution of 12 (0.15 g,
0.29 mmol), in THF (10 mL) was added TBAF (0.18 g,
0.58 mmol) and stirred for 4 h at 25 8C. The reaction
mixture was concentrated under vaccum and extracted with
(3!15 mL) dichloromethane. The combined organic layers
were concentrated, adsorbed on silica gel and purified by
column chromatography (10% ethyl acetate/n-hexane)
afforded 13 (0.12 g, 95%) as thick oil; [found: C, 77.63;
H, 7.50. C27H31NO3 requires C, 77.67; H, 7.48]; Rf (20%
ethyl acetate/n-hexane) 0.19; [a]D C21.4 (c 0.28, CHCl3);
nmax (neat) 3494, 2922, 1377, 1217 cmK1; dH (300 MHz,
CDCl3CD2O) d 1.81–1.86 (m, 1H), 1.92–2.03 (m, 1H),
2.30–2.35 (m, 1H), 3.13–3.14 (m, 1H), 3.24 (dd, JZ10.4,
5.5 Hz, 1H), 3.39 (br d, JZ12.6 Hz, 1H), 3.68–3.75 (m,
1H), 3.81–3.88 (m, 1H), 4.02–4.11 (m, 3H), 4.46 (s, 2H),
4.35 (d, JZ11.8 Hz, 1H), 4.64 (d, JZ11.8 Hz, 1H), 7.22–
7.34 (m, 15H); dC (75 MHz, CDCl3) d 29.3, 55.4, 59.5, 61.4,
64.8, 71.8, 72.0, 82.3, 83.9, 127.2, 127.5 (s), 127.6 (s), 128.3
(s), 129.0 (s), 137.7, 137.8.
4.1.6. (2S,3R,4R)-1-Benzyl-4-benzyloxy-2-(2-tert-butyl-
dimethysilyloxyethyl)pyrrolidin-3-ol (11). To a solution
of diol 10 (0.40 g, 1.22 mmol), in dichloromethane (15 mL)
was added TBDMSCl (0.22 g, 1.46 mmol) followed by
imidazole (1.00 g, 1.46 mmol) and stirred for 3 h at 25 8C.
Water was added to the reaction mixture and extracted with
(3!10 mL) dichloromethane. The combined organic layer
was concentrated, adsorbed on silica gel and purified by
column chromatography (20% ethyl acetate/n-hexane)
afforded 11 (0.81 g, 95%) as thick oil; [found: C, 70.65;
H, 8.93. C26H39NO3Si requires C, 70.70; H, 8.90]; Rf (20%
ethyl acetate/n-hexane) 0.23; [a]D C65.5 (c 0.58, CHCl3);
nmax (neat) 3429, 2930, 1460, 1254 cmK1; dH (300 MHz,
CDCl3CD2O) d 0.20 (s, 6H), 0.82 (s, 9H), 1.90–2.15 (m,
2H), 2.25 (dd, JZ10.1, 6.5 Hz, 1H), 2.73–2.79 (m, 1H),
3.29 (d, JZ13.1 Hz, 1H), 3.32 (dd, JZ10.1, 6.8 Hz, 1H),
3.73 (ddd, JZ12.0, 9.3, 3.0 Hz, 1H), 3.91–3.99 (m, 2H),
4.03 (d, JZ13.1 Hz, 1H), 4.23 (dd, JZ5.7, 2.4 Hz, 1H), 4.6
(ABq, JZ11.8 Hz, 2H), 7.13–7.21 (m, 10H); dC (75 MHz,
CDCl3) d 18.1, 25.8 (s), 29.5, 57.5, 58.1, 61.2, 67.3, 71.6,
76.8, 83.3, 127.0, 127.5, 127.7 (s), 128.2 (s), 128.3 (s), 128.9
(s), 137.9, 138.1.
4.1.9. Ethyl (E)-4-((2S,3R,4R)-1-benzyl-3,4-bis(benzyl-
oxy)pyrrolidin-2-yl)but-2-enoate (8b). To a solution of
oxalyl chloride (0.03 mL, 0.31 mmol) in dichloromethane
(1 mL) at K78 8C was added slowly a solution of DMSO
(0.04 mL, 0.58 mmol) in dichloromethane (1 mL). After
10 min, a solution of alcohol 13 (0.11 g, 0.26 mmol) in
dichloromethane (2 mL) was added and the reaction was
stirred at K78 8C for 2 h. Triethylamine (0.18 mL,
1.31 mmol) was added and the mixture was stirred at
K78 8C for 30 min. Usual work up afforded aldehyde as a
thick liquid. To the solution of aldehyde (0.11 g,
0.30 mmol) in dichloromethane (10 mL) was added PPh3-
CHCOOEt (0.12 g, 0.36 mmol) and stirred for 1 h at 25 8C.
The reaction mixture was adsorbed on silica gel
and purification by column chromatography (10% ethyl
acetate/n-hexane) afforded 8b (0.12 g, 94%) as thick oil;
[found: C, 76.61; H, 7.18. C31H35NO4 requires C, 76.67; H,
7.26]; Rf (10% ethyl acetate/n-hexane) 0.73; [a]D C44.0 (c
0.25, CHCl3); nmax (neat) 1724, 1244 cmK1; dH (300 MHz,
CDCl3) d 1.20 (t, JZ7.1 Hz, 3H), 2.19 (dd, JZ9.9, 5.7 Hz,
1H), 2.36–2.41 (m, 1H), 2.56–2.58 (m, 1H), 2.80–2.81 (m,
1H), 3.19–3.27 (m, 2H), 3.82 (dd, JZ6.0, 2.4 Hz, 1H), 3.89
(d, JZ12.9 Hz, 1H), 3.87–3.89 (m, 1H), 4.08 (q, JZ7.1 Hz,
2H), 4.33 (s, 2H), 4.36 (d, JZ11.8 Hz, 1H), 4.51 (d, JZ
11.8 Hz, 1H), 5.75 (d, JZ15.6 Hz, 1H), 6.90 (dt, JZ15.6,
7.1 Hz, 1H), 7.19–7.25 (m, 15H); dC (75 MHz, CDCl3) d
14.4, 30.9, 57.3, 58.6, 60.1, 65.2, 71.4, 71.7, 81.4, 83.3,
122.5, 126.9, 127.4 (s), 127.5 (s), 127.6 (s), 127.9 (s), 128.1
(s), 137.7, 146.7, 166.3. Our attempt to isolate the Z-isomer
4.1.7. (2S,3R,4R)-1-Benzyl-3,4-bis(benzyloxy)-2-(2-tert-
butyldimethysilyloxyethyl)pyrrolidine (12). To a hexane
washed sodium hydride (0.03 g, 1.25 mmol) was added a
solution of alcohol 11 (0.43 g, 0.97 mmol) in THF (8 mL)
dropwise at 0 8C and stirred for 30 min. A solution of benzyl
bromide (0.13 mL, 1.07 mmol) in THF (2 mL) was added
dropwise, followed by addition of TBAI (0.02 g,
0.05 mmol) and stirred for 5 h at 25 8C. The reaction
mixture was neutralized with water concentrated under
vaccum, extracted using (3!10 mL) dichloromethane. The
combined organic layer was concentrated, adsorbed on
silica gel and purified using column chromatography (10%
ethyl acetate/n-hexane) afforded 12 (0.41 g, 82%) as a thick
liquid; [found: C, 74.52; H, 8.43. C33H45NO3Si requires C,

V. D. Chaudhari et al. / Tetrahedron 62 (2006) 4349–4354
4353
in pure form was unsuccessful, 94% yield reflects the total
yield of E and Z isomer.
4.1.13. (6R,7R,7aR)-Hexahydro-6,7-dihydroxypyrro-
lizin-3-one (15). The reaction of 14 (0.20 g, 0.54 mmol)
with 10% Pd/C (0.10 g) and ammonium formate (0.23 g,
3.70 mmol) as described for the synthesis of 9a afforded 15
(0.06 g, 70%) as a sticky gum; [found: C, 53.51; H, 7.03.
C7H11NO3 requires C, 53.49; H, 7.05]; Rf (10% methanol/
chloroform) 0.35; [a]D K15.3 (c 0.5, MeOH); nmax (neat)
3335, 1723, 1659, 1433, 1214 cmK1; dH (300 MHz, D2O) d
1.54–1.79 (m, 2H), 2.58 (dd, JZ10.7, 0.8 Hz, 1H), 3.16–
3.24 (m, 2H), 3.42–3.58 (m, 2H); 3.82 (dd, JZ5.7, 1.8 Hz,
1H), 4.12–4.16 (m, 1H); dC (75 MHz, D2O) d 32.4, 49.7,
58.3, 63.2, 74.1, 78.6, 180.5.
4.1.10. (1R,2R,8aS)-Hexahydro-1,2-dihydroxyindolizin-
5(1H)-one (9b). The reaction of 8b, (0.12 g, 0.25 mmol)
with 10% Pd/C (0.08 g) and ammonium formate (0.11 g,
1.73 mmol) as described for the synthesis of 9a afforded 9b
(0.04 g, 93%) as a white solid, mp 174–176 8C; [found: C,
56.10; H, 7.59. C8H13NO3 requires C, 56.13; H, 7.65]; Rf
(10% methanol/chloroform) 0.34; [a]D K19.0 (c 0.42,
MeOH); nmax (KBr) 3441, 2926, 1711, 1653, 1212 cmK1
;
dH (300 MHz, D2O) d 1.46 (m, 1H), 1.74–1.82 (m, 1H),
1.94–2.04 (m, 2H), 2.19–1.45 (m, 2H), 3.32 (d, JZ13.7 Hz,
1H), 3.74–3.84 (m, 2H), 4.08–4.09 (m, 1H), 4.23 (dd, JZ
4.9, 0.8 Hz, 1H); dC (75 MHz, D2O) d 20.0, 21.6, 30.1, 51.6,
60.8, 72.1, 76.1, 173.18.
4.1.14. (1R,2R,7aR)-(D)-1,2-Dihydroxypyrrolizidine (4).
The reaction of lactam 15 (0.10 g, 0.63 mmol) with LAH
(0.10 g, 2.54 mmol) as described for 3b afforded 4 (0.07 g,
77%) as thick oil; [found: C, 58.68; H, 9.19. C7H13NO2
requires C, 58.72; H, 9.15]; Rf (20% methanol/chloroform)
0.32; [observed [a]D C6.5 (c 0.25, MeOH), lit.5o [a]D C7.6
(c 1.3, MeOH)]; nmax (neat) 3300–3600 (broad) cmK1; dH
(300 MHz, D2O) d 1.76–1.91 (m, 1H); 1.95–2.16 (m, 1H),
2.18–2.27 (m, 2H), 2.86–2.98 (m, 2H), 3.11 (dd, JZ11.2,
4.9 Hz, 1H), 3.23 (dd, JZ11.2, 3.8 Hz, 1H), 3.35–3.41 (m,
1H), 3.92–4.04 (m, 1H), 4.17–4.25 (m, 1H); dC (75 MHz,
D2O) d 28.7, 32.4, 59.8, 62.2, 72.1, 80.2, 82.3.
4.1.11. (1R,2R,8aS)-(D)-1,2-Dihydroxyindolizidine (3b).
The reaction of lactam 15 (0.07 g, 0.04 mmol) with LAH
(0.06 g, 1.50 mmol) as described for the synthesis of 3a
afforded 3b (0.06 g, 91%) as a sticky solid; [found: C, 56.21;
H, 7.68. C8H15NO2 requires C, 56.13; H, 7.65]; Rf (20%
methanol/chloroform) 0.30; [observed [a]D C4.3 (c 0.5,
MeOH); lit.5k C3.4 (c 0.41, MeOH)]; nmax (neat) 3355,
2934, 1121 cmK1; dH (300 MHz, D2O) d 1.57–1.79 (m, 3H),
1.95–2.08 (m, 3H), 2.90 (dd, JZ13.2, 3.0 Hz, 1H), 3.02–
3.10 (m, 1H), 3.36 (d, JZ11.8 Hz, 1H), 3.66 (d, JZ12.1 Hz,
1H), 4.03 (dd, JZ12.1, 6.3 Hz, 1H), 4.18 (d, JZ3.0 Hz,
1H), 4.31 (dd, JZ6.3, 3.0 Hz, 1H); dC (75 MHz, D2O) d
22.9, 24.7, 25.2, 53.1, 62.2, 66.9, 77.8, 81.1.
Acknowledgements
We are thankful to the DST (SP/S1/G23-2000), New Delhi
for financial support and the UGC, New Delhi for the grant
to procure high field (300 MHz) NMR facility.
4.1.12. Methyl 3-((2R,3R,4R)-1-benzyl-4-benzyloxy-3-
hydroxypyrrolodin-2-yl)propanoate (14). To an ice-
cooled solution of 6a (0.63 g, 1.30 mmol) in methanol–
water (5 mL, 4/1) was added lithium hydroxide monohy-
drate (0.30 g, 5.22 mmol) and stirred for 4 h at 25 8C. The
solution was neutralized and worked up to afford the acid.
To a solution of an acid in THF (5 mL) was added
triethylamine (0.28 mL, 2.02 mmol) and ethylchlorofor-
mate (0.19 mL, 2.02 mmol). After 15 min, the suspension
was allowed to warm to 25 8C and filtered. The filtrate was
cooled to 0 8C and a freshly prepared solution of
diazomethane in diethyl ether (0.24 g, 5.80 mmol) was
added dropwise and stirred for 3 h at 25 8C. The solvent was
evaporated to afford thick oil. To a solution of diazoketone
in methanol (8 mL) was added dropwise a solution of silver
benzoate (0.11 g, 0.49 mmol) in triethylamine (0.50 mL)
and stirred for 3 h at 25 8C. The solvent was evaporated and
the residue was purified by column chromatography (20%
ethyl acetate/n-hexane) to give 14 (0.45 g, 71%) as a thick
liquid; [found: C, 71.46; H, 7.46. C22H27NO4 requires C,
71.52; H, 7.37]; Rf (25% ethyl acetate/n-hexane) 0.68; [a]D
K24.0 (c 0.5, CHCl3); nmax (neat) 3345, 1728, 1457,
1134 cmK1; dH (300 MHz, CDCl3CD2O): d 1.25–1.28 (m,
2H), 2.56–2.76 (m, 3H), 2.90–3.33 (m, 2H), 2.98 (br d, JZ
13.1 Hz, 1H), 3.72 (s, 3H), 3.87 (d, JZ6.8 Hz, 1H), 3.96 (br
d, JZ13.1 Hz, 1H), 4.11 (d, JZ3.8 Hz, 1H), 4.33 (ABq, JZ
12.0 Hz, 2H), 7.26–7.34 (m, 10H); dC (75 MHz, CDCl3) d
29.5, 36.7, 52.0, 57.0, 57.8, 67.1, 71.0, 82.5, 82.8, 127.2,
127.5, 127.7 (s), 128.3 (s), 128.6 (s), 128.8 (s), 137.7, 138.0,
173.9.
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Gurjar et al., starting from (R) and (S)-pipecolinic acid and
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istry. However, the subsequent report of Brandi et al. claim
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Bn
N
O
EtO
O
OBn
X
10. For enantiomer of 3b see: Paolucci, C.; Musiani, L.;
Venturelli, F.; Fava, V. Synthesis 1997, 1415.