Novel and stereoselective synthesis of (+)-lentiginosine

Article abstract of DOI:10.1016/j.tetasy.2003.12.017

The stereoselective synthesis of (+)-lentiginosine, a potent amyloglucosidase inhibitor, is disclosed exploiting the potential of the sulfinyl moiety as an internal nucleophile to regio- and stereoselectively functionalize an olefin.

Full text of DOI:10.1016/j.tetasy.2003.12.017

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 565–570
Novel and stereoselective synthesis of (+)-lentiginosineq
Sadagopan Raghavan* and T. Sreekanth
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 15 November 2003; accepted 5 December 2003
Abstract—The stereoselective synthesis of (+)-lentiginosine, a potent amyloglucosidase inhibitor, is disclosed exploiting the potential
of the sulfinyl moiety as an internal nucleophile to regio- and stereoselectively functionalize an olefin.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
attracted the attention of synthetic chemists as a popular
synthetic target due to its biological activity. Despite
significant advances in asymmetric synthesis, the vast
majorityof the reported enantioselective syntheses of
lentiginosine relyon chiral pool starting materials. We
Lentiginosine 1, a dihydroxy indolizidine alkaloid, was
first isolated in 1990 from the leaves of Astragalus
lentiginosus.1 Lentiginosine is a strong and selective
inhibitor of amyloglucosidase, an enzyme that hydro-
lyses 1,4- and 1,6-a-glucosidic linkages. The structure of
lentiginosine was deduced from its NMR spectrum and
was assigned as (1S,2S,8aS) absolute configuration
based on biosynthetic considerations. The isolated
compound was reported to be weaklyleavorotatory
3
recentlydisclosed a methodology wherein the sulfinyl
moietywas utilized as an intramolecular nucleophile to
functionalize b-hydroxy-c,d-unsaturated sulfoxides,
regio- and stereoselectively. As an extension of this
methodology,4 we herein report a novel and stereo-
selective synthesis of (+)-lentiginosine.
{½aŠ ¼ )3.3 in MeOH}. Various syntheses2 of all (S)-
D
lentiginosine, however, have led to samples with small
positive rotations. Based on the biological activitydata 2g
of both (+)- and ())-lentiginosine, it has been argued
that the natural product is dextrorotatoryand the neg-
ative rotation initiallyreported is due to impurities
present in the natural product, which is evident from the
published 1H NMR spectrum.1 Lentiginosine has
2. Results and discussion
By retrosynthetic analysis (Scheme 1), (+)-1 can be
derived from the retron 2, which in turn can be obtained
from the bromohydrin 3. The bromohydrin 3 can be
traced back to the unsaturated sulfoxide 4.
OH
OH
O
S
OH Br
HO
H
X
Tol
HO
H2N
OH
N
OP
2
3
(+)-1
X
O
S
OH
X = Nucleofuge
P = Protecting group
Me
OP
4
Scheme 1.
q IICT Communication No. 031010.
* Corresponding author. E-mail: sraghavan@iict.ap.nic.in
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.017

566
S. Raghavan, T. Sreekanth / Tetrahedron: Asymmetry 15 (2004) 565–570
O
S
O
S
O
Me
a
b
OBn
EtO2C
Me
Me
Tol
OBn
OP1 Br
7
5
6
O
S
4
2
Tol
OP2
3, P1 = P2 = H
9, P1, P2 = CMe2
H2O
O
S
OH
OBn
i
OH
S
ii
c
OBn
d
O i
Me
Br
ii
4
O
S
OH OH
OBn
Tol
Intermediate
Br
OBn
8
Scheme 2. Reaction conditions: (a) LDA, THF, )78 ꢁC, 70%; (b) DIBAL, ZnCl2, THF, )78 ꢁC, 91%; (c) NBS, H2O, toluene, rt, 85%; (d) 2,2-DMP,
acetone, CSA (cat.), rt, 87%.
The unsaturated sulfoxide 4, (P ¼ Bn) was readilyelab-
orated from the unsaturated ester 55 bycondensation
with the lithium anion of (R)-methyl p-tolyl sulfoxide6 6
out isolation was subjected to treatment with excess
triethylamine in dichloromethane to afford (+)-lentigi-
nosine after purification bypassing through a Dowex
column. The physical characteristics of (+)-lentiginosine
were in excellent agreement to those reported in the
literature.2e
7
followed bya diastereoselective reduction (dr > 95:<5)
of the resulting b-ketosulfoxide 7 (Scheme 2). At the
outset it was not clear if the bromohydration of 4 would
afford 1,2-diol 3 via a 5-exo nucleophilic attack (path-
way(i), Scheme 2) or 1,3-diol 8 via a 6-endo nucleophilic
attack (pathway(ii), Scheme 2). The electron with-
drawing inductive effect of the C2 hydroxy group and
the electron releasing inductive effect of the alkyl chain
at C4 was expected to promote the 6-endo nucleophilic
attack bythe sulfinyl group.
3. Conclusion
In summarywe have disclosed a novel snythesis of
lentiginosine, involving 12 steps in 10.7% overall yield
that exploits the potential of the sulfinyl group as a
nucleophile to functionalize an olefin stereo- and regio-
selectively.
Treatment of 4 with N-bromosuccinimide in toluene in
the presence of water afforded the bromohydrin 3, via
5-exo nucleophilic attack. The regio- and stereochemis-
tryof 3 was ascertained byits transformation into the
acetonide 9, whose 13C NMR revealed8 signals for the
methyl group at d 27.1, 27.4 and for the acetal carbon at
d 110. An overall trans-addition9 of the electrophile and
nucleophile across the double bond would predicate an
anti-orientation of the C3 hydroxy and C4 bromine
atom. Treatment of 3 with anhydrous potassium car-
bonate in methanol afforded the epoxide 10. Further
treatment of the epoxide 10 with sodium azide following
SharplessÕ protocol10 afforded the azidodiol 11 as the
onlyisolated product. Protection of the diol as its ace-
tonide 12,11 and its subsequent treatment under Pum-
merer reaction conditions12 afforded the intermediate 13.
One pot hydrolysis and reduction of the intermediate 13
afforded the alcohol 14. Treatment of 14 with Pd(OH)2/
C under a hydrogen atmosphere in the presence of
di-tert-butyl dicarbonate yielded the diol carbamate 15
bysequential reduction, carbamate formation and
hydrogenolysis (Scheme 3). Further elaboration of 15 to
the retron 2 required conversion of the diol into suitable
leaving groups and deprotection of the acetonide. Thus,
treatment of 15 with p-toluenesulfonyl chloride in the
presence of triethylamine afforded the ditosyl derivative
16, which upon further treatment with TFA/H2O (95:5)
overnight afforded the ammonium salt 17, which with-
4. Experimental section
All air or moisture sensitive reactions were carried out
under nitrogen atmosphere. Solvents were distilled
freshlyover Na/benzophenone ketyl for THF, over P O5
2
followed byCaH for DCM and over P2O5 for toluene.
2
Commerciallyavailable reagents were used without
further purification except NBS, which was freshly
recrystallized from hot water before use. Thin layer
chromatographywas performed with precoated silica
gel plates. Column chromatographywas carried out
using silica gel (60–120 mesh). NMR spectra were
1
recorded on a 200, 300 or 400 MHz spectrometer. H
NMR and 13C NMR samples were internallyreferenced
to TMS (0.00 ppm).
4.1. 8-Benzyloxy-1-(RS)-(4-methylbenzylsulfinyl)-
E-3-octen-2-one 7
A solution of (R)-(+)-methyl p-tolylsulfoxide (2.77 g,
18 mmol) in THF was added dropwise to a solution of

S. Raghavan, T. Sreekanth / Tetrahedron: Asymmetry 15 (2004) 565–570
567
O
S
OH
O
S
OH Br
a
b
Tol
Tol
O
OH
OBn
OBn
3
10
O
O
O
O
O
S
OP1 N3
HO
TolS
e
d
Tol
CF3C(O)O
N3
14
N3
OP2
11, P1 = P2 = H
OBn
13
c
OBn
OBn
12, P1, P2 = CMe2
O
O
OH
OH
HO
H
PO
TsO
-TFA+H3N
17
g
g
HO
N
BocHN
(i)
(ii)
(+)-1
15, P = H
16, P = Ts
f
OP
OTs
Scheme 3. Reaction conditions: (a) K2CO3, MeOH, 0 ꢁC, 83%; (b) NaN3, NH4Cl, MeOH/H2O (8:1), reflux, 85%; (c) 2,2-DMP, acetone, CSA (cat.),
rt, 87%; (d) TFAA, Et3N, CH2Cl2, 0 ꢁC then aq NaHCO3, NaBH4, 75% for two steps; (e) H2, Pd(OH)2, (Boc)2O, ethanol, rt, 82%; (f) TsCl, Et3N,
DMAP (cat.), DCM, 75%; (g) (i) TFA/H2O (95:5), DCM, 0 ꢁC to rt; (ii) Et3N, DCM, rt, 70% for two steps.
LDA (18.0 mmol), prepared from diisopropylamine
(2.5 mL, 18.0 mmol) and n-BuLi (11.3 mL, 1.6 M/hex-
anes, 18.0 mmol), in THF (25 mL) and cooled at )78 ꢁC.
The mixture was stirred at )78 ꢁC for 1 h and then added
dropwise via a canula to a solution of ester 5 (2.46 g,
9 mmol) in THF (56 mL) cooled at )78 ꢁC. After 3 h at
)78 ꢁC, the reaction mixture was decomposed with aq
saturated NH4Cl solution (100 mL). The reaction mix-
ture was diluted with ether (100 mL), the organic layer
separated and the aq layer extracted with EtOAc
(3 · 25 mL). The combined organic extracts were washed
with brine, dried over Na2SO4 and evaporated under
reduced pressure to yield a residue, which was purified
bycolumn chromatographyusing EtOAc/petroleum
ether (2:3 v/v) as the eluent to afford 7 (4.66 g,
10.5 mmol) added dropwise over a period of 10 min.
After 30 min of stirring at the same temperature, meth-
anol (70 mL) was added and the reaction mixture
allowed to return to rt. The solvent was evaporated
under reduced pressure and the residue diluted with 5%
aq HCl solution and extracted into CH2Cl2. The organic
layer was washed with 5% aq NaOH solution, brine and
dried over Na2SO4. The crude product was purified by
column chromatographyusing 40% EtOAc/petroleum
ether as the eluent to afford the hydroxysulfoxide 4
(2.34 g, 6.33 mmol) essentiallyas a single diastereomer in
91% yield as a pale yellow liquid. Rf : 0.27 (40% EtOAc/
petroleum ether). ½aŠ ¼ +90.5 (c 1, acetone). H NMR
(200 MHz, CDCl3) dD7.51 (d, J ¼ 8:2 Hz, 2H), 7.34–7.20
(m, 7H), 5.74 (dt, J ¼ 15:6, 6.7 Hz, 1H), 5.42 (dd,
J ¼ 15:6, 5.9 Hz, 1H), 4.75–4.66 (m, 1H), 4.44 (s, 2H),
3.56 (br s, 1H), 3.42 (t, J ¼ 6:9 Hz, 2H), 2.94 (dd,
J ¼ 13:0, 9.7 Hz, 1H), 2.70 (dd, J ¼ 13:0, 3.0 Hz, 1H),
2.41 (s, 3H), 2.14–1.96 (m, 2H), 1.62–1.40 (m, 4H). 13C
NMR (75 MHz, CDCl3) d 21.4, 25.5, 29.2, 31.8, 62.9,
69.4, 70.1, 72.8, 123.9, 127.4, 127.5, 128.2, 130.0, 130.2,
133.1, 137.5, 140.0, 141.8. m=z FAB: 373 [M+H]þ. Anal.
Calcd for C22H28O3S: C, 70.93; H, 7.58; S, 8.61. Found:
C, 70.72; H, 7.31; S, 8.56.
25
1
12.6 mmol) in 70% yield. Viscous liquid. Rf : 0.32 (40%
25
EtOAc/petroleum ether). ½aŠ ¼ +145.0 (c 1, acetone).
D
1H NMR (200 MHz, CDCl3) d 7.53 (d, J ¼ 8:2 Hz, 2H),
7.38–7.25 (m, 7H), 6.82 (dt, J ¼ 15:6, 6.7 Hz, 1H), 6.10
(d, J ¼ 15:6 Hz, 1H), 4.52 (s, 2H), 4.0 (d, J ¼ 13:0 Hz,
1H), 3.82 (d, J ¼ 13:0 Hz, 1H), 3.48 (t, J ¼ 5:6 Hz, 2H),
2.42 (s, 3H), 2.30–2.16 (m, 2H), 1.68–1.58 (m, 4H). 13C
NMR (75 MHz, CDCl3) d 21.2, 24.3, 28.9, 32.2, 69.5,
72.7, 123.9, 127.3, 127.34, 128.1, 129.8, 130.2, 138.2,
139.7, 141.8, 151.1, 190.5. m=z FAB: 371 [M+H]þ. Anal.
Calcd for C22H26O3S: C, 71.32; H, 7.07; S, 8.65. Found:
C, 70.91; H, 7.11; S, 8.46.
4.3. 8-Benzyloxy-4-bromo-1-(SS)-(4-methylphenyl-
sulfinyl)-(2R,3R,4S)-octane-2,3-diol 3
4.2. 8-Benzyloxy-1-(RS)-(4-methylphenylsulfinyl)-
(2R,3E)-3-octen-2-ol 4
To a solution of the sulfoxide 4 (2.24 g, 6.02 mmol) in
drytoluene (24 mL) was added water (216 mg,
12.04 mmol), followed by N-bromosuccinimide (1.27 g,
7.22 mmol) and the reaction mixture stirred at room
temperature for 15 min. The reaction was quenched by
the addition of aq saturated NaHCO3 solution. The
layers were separated and the aqueous layer extracted
with ethylacetate (3 · 25 mL). The combined organic
A solution of the b-ketosulfoxide 7 (2.59 g, 7 mmol) in
anhydrous THF (61.5 mL) was added to a solution of
ZnCl2 (1.14 g, 8.4 mmol) in anhydrous THF (8.5 mL)
and stirred at rt for 15 min. The reaction mixture was
cooled to )78 ꢁC and DIBAL-H (5.25 mL, 2 M/toluene,

568
S. Raghavan, T. Sreekanth / Tetrahedron: Asymmetry 15 (2004) 565–570
layers were successively washed with water, brine and
dried over Na2SO4. Evaporation of the solvent afforded
the crude product, which was purified bycolumn chro-
matographyusing EtOAc/hexane (2:3 v/v) as the eluent
to yield bromohydrin 3 (2.4 g, 5.11mmol) in 85% yield.
(m, 1H), 3.42 (t, J ¼ 5:6 Hz, 2H), 3.03–2.89 (m, 2H),
2.78–2.70 (m, 2H), 2.44 (s, 3H), 1.76–1.40 (m, 6H). 13C
NMR (75 MHz, CDCl3) d 21.4, 22.6, 29.6, 31.1, 55.9,
60.4, 65.7, 69.9, 72.9, 74.0, 123.9, 124.8, 127.6, 128.3,
130.1, 137.9, 139.6, 141.8. m=z FAB: 389 [M+H]þ. Anal.
Calcd for C22H28O4S: C, 68.01; H, 7.26; S, 8.25. Found:
C, 67.85; H, 7.21; S, 8.05.
Colourless solid. Mp 147–148 ꢁC. Rf : 0.27 (40% EtOAc/
25
petroleum ether). ½aŠ ¼ )58.5 (c 1.0, acetone). 1H NMR
D
(200 MHz, CDCl3) d 7.52 (d, J ¼ 8:2 Hz, 2H), 7.36–7.24
(m, 7H), 4.80 (br s, 1H), 4.50–4.46 (m, 3H), 4.0 (t,
J ¼ 6:8 Hz, 1H), 3.88–3.78 (m, 1H), 3.44 (m, 3H), 3.15
(m, 2H), 2.44 (s, 3H), 1.74–1.40 (m, 6H). 13C NMR
(75 MHz, CDCl3) d 21.4, 51.0, 61.1, 67.9, 71.4, 73.3,
74.7, 124.1, 127.7, 127.8, 128.4, 130.1, 137.4, 139.7,
142.0. m=z FAB: 471 [M+H]þ. Anal. Calcd for
C22H29O4BrS: C, 56.29; H, 6.23; S, 6.83. Found: C,
56.21; H, 6.15; S, 6.70.
4.6. 4-Azido-8-benzyloxy-1-(SS)-(4-methylphenylsulfinyl)-
(2R,3S,4S)-octane-2,3-diol 11
To a solution of the epoxide 10 (120 g, 3.1 mmol) in a
solvent mixture of MeOH/H2O (8:1, 18 mL) was added
NH4Cl (0.50 g, 9.3 mmol) followed byNaN (1.21 g,
3
18.6 mmol) and the mixture refluxed for 6 h. The reac-
tion mixture allowed to attain rt and the solvent then
evaporated under reduced pressure. The residue was
extracted with ethylacetate (2 · 30 mL), washed succes-
sivelywith water and brine and dried over Na 2SO4. The
solvent was evaporated under reduced pressure to yield
the crude product, which was purified bycolumn chro-
matographyusing EtOAc/hexane (2:3 v/v) to afford the
azidodiol 11 (1.13 g, 2.64 mmol) in 85% yield. White
4.4. 4-[5-Benzyloxy-1-bromo-(1S)-pentyl]-2,2-dimethyl-5-
(SS)-(4-methylphenylsulfinylmethyl)-(4R,5R)-1,3-
dioxolane 9
To a solution of the bromohydrin (0.093 g, 0.2 mmol) in
a mixture of acetone and 2,2-dimethoxypropane (3:1,
0.8 mL) was added a catalytic amount of CSA (3 mg)
and the reaction mixture then stirred at ambient tem-
perature for 1 h. Et3N, enough to neutralize CSA, was
added and the volatiles removed under reduced pres-
sure. The residue was purified bycolumn chromato-
graphyusing EtOAc/hexane (1:4 v/v) as the eluent to
yield acetonide 9 (0.088 g, 0.17 mmol) in 87% yield. Pale
yellow solid. Mp 96–97 ꢁC. Rf : 0.5 (30% EtOAc/petro-
solid. Mp 119–120 ꢁC. Rf : 0.28 (40% EtOAc/petroleum
25
ether). ½aŠ ¼ )90.5 (c 0.8, acetone). 1H NMR
D
(200 MHz, CDCl3) d 7.51 (d, J ¼ 8:2 Hz, 2H), 7.34–7.22
(m, 7H), 5.50 (br s, OH, 1H), 4.42 (s, 2H), 4.40 (m, 1H),
3.51–3.33 (m, 3H), 3.18 (dd, J ¼ 13.4, 10.0 Hz, 1H),
3.05–3.0 (m, 1H), 2.70 (d, J ¼ 13:4 Hz, 1H), 2.41 (s, 3H),
1.68–1.52 (m, 6H). 13C NMR (75 MHz, CDCl3) d 21.4,
22.5, 29.5, 31.0, 59.9, 63.7, 65.2, 70.0, 72.9, 74.8, 124.1,
127.5, 127.7, 128.4, 130.2, 138.5, 138.8, 142.0. m=z FAB:
432 [M+H]þ. Anal. Calcd for C22H29N3O4S: C, 61.23;
H, 6.77; N, 9.74; S, 7.43. Found: C, 61.0; H, 6.52; N,
9.60; S, 7.23.
25
D
1
leum ether). ½aŠ ¼ )116.5 (c 0.6, acetone). H NMR
(200 MHz, CDCl3) d 7.52 (d, J ¼ 8:2 Hz, 2H), 7.36–7.20
(m, 7H), 4.51–4.44 (m, 3H), 3.88 (m, 2H), 3.45 (t,
J ¼ 5:7 Hz, 2H), 3.35 (dd, J ¼ 13:2, 2.3 Hz, 1H), 2.80
(dd, J ¼ 13:2, 10.2 Hz, 1H), 2.42 (s, 3H), 2.16–2.04 (m,
1H), 1.80–1.56 (m, 5H), 1.44 (s, 3H), 1.43 (s, 3H). 13C
NMR (75 MHz, CDCl3) d 21.3, 23.5, 27.1, 27.4, 28.9,
34.9, 55.9, 63.7, 69.9, 72.8, 75.3, 82.9, 110.0, 123.9,
127.3, 127.5, 128.2, 129.9, 138.4, 139.4, 141.4. m=z FAB:
513 [M+H]þ. Anal. Calcd for C25H33BrO4S: C, 58.94; H,
6.53; S, 6.29. Found: C, 58.59; H, 6.32; S, 6.09.
4.7. 4-[1-Azido-5-benzyloxy-(1S)-pentyl]-2,2-dimethyl-5-
(SS)-(4-methylphenylsulfinylmethyl)-(4S,5R)-1,3-dioxo-
lane 12
To a solution of the azidodiol 11 (1.07 g, 2.5 mmol) in a
mixture of 2,2-dimethoxypropane and acetone (1:3,
10 mL) was added CSA (24 mg, 0.1 mmol) and the
reaction mixture stirred at ambient temperature for 1 h.
A few drops of Et3N were added to neutralize CSA and
the volatiles removed under reduced pressure to afford
the crude product, which was purified bycolumn chro-
matographyusing EtOAc/hexane (1:4 v/v) as the eluent
to yield acetonide 12 (1.02 g, 2.17 mmol) in 87% yield.
4.5. 1-[(3S)-(4-benzyloxybutyl(2S)-oxiranyl]-2-(SS)-
(4-methylphenylsulfinyl)-(1R)-ethan-1-ol 10
To a solution of 3 (1.88 g, 4.0 mmol) in methanol
(16 mL) was added K2CO3 (0.61g, 4.40 mmol) at 0 ꢁC.
The reaction mixture was stirred and graduallyallowed
to return to rt over a period of 45 min. After stirring for
another 1 h at rt, TLC revealed the complete conversion
of the starting material. Diethylether (15 mL) was added
to the reaction mixture, and after 10 min, when the
inorganic salts had settled, the reaction mixture was
filtered and the filtrate evaporated under reduced pres-
sure to afford the epoxide 10 (1.28 g, 3.32 mmol) in 83%
yield, which was taken ahead to the next step without
Viscous liquid. Rf : 0.48 (30% EtOAc/petroleum ether).
25
D
½aŠ ¼ )116.5 (c 0.6, acetone). 1H NMR (200 MHz,
CDCl3) d 7.52 (d, J ¼ 8:2 Hz, 2H), 7.36–7.20 (m, 7H),
4.50 (s, 2H), 4.44–4.38 (m, 1H), 3.56 (t, J ¼ 6:7, Hz, 1H),
3.50–3.36 (m, 3H), 3.01 (dd, J ¼ 13:4, 2.2 Hz, 1H), 2.73
(dd, J ¼ 13:4, 10.4 Hz, 1H), 2.41 (s, 3H), 1.58–1.32 (m,
12H). 13C NMR (75 MHz, CDCl3) d 21.2, 22.5, 26.6,
27.0, 29.1, 30.7, 62.8, 63.3, 69.6, 72.7, 72.8, 81.4, 110.1,
123.7, 127.3, 127.4, 128.1, 129.9, 138.3, 140.9, 141.6 m=z
FAB: 472 [M+H]þ. Anal. Calcd for C25H33N3O4S: C,
63.67; H, 7.05; N, 8.91; S, 6.80. Found: C, 63.51; H,
6.89; N, 8.80; S, 6.76.
further purification. White solid. Mp 124–125 ꢁC. Rf :
25
0.24 (40% EtOAc/petroleum ether). ½aŠ ¼ )102.0 (c 0.8,
D
acetone). 1H NMR (200 MHz, CDCl3) d 7.51 (d,
J ¼ 8:2 Hz, 2H), 7.40–7.24 (m, 7H), 4.46 (s, 2H), 4.18

S. Raghavan, T. Sreekanth / Tetrahedron: Asymmetry 15 (2004) 565–570
569
4.8. 5-[1-Azido-5-benzyloxy-(1S)-pentyl]-2,2-dimethyl-
(4S,5S)-1,3-dioxolan-4-ylmethanol 14
extracted with DCM (2 · 5 mL). The combined organic
layer was successively washed with water, brine and
dried over Na2SO4. Evaporation of the solvent afforded
the crude product, which was purified bycolumn chro-
matographyusing EtOAc/petroleum ether (3:7 v/v) as
the eluent to afford 16 (0.47 g, 0.75 mmol) in 75% yield.
To a solution of azido acetonide 12 (0.89 g, 1.9 mmol) in
dryDCM (9 mL) was added Et N (0.79 mL, 5.7 mmol)
3
followed byTFAA (0.79 mL, 5.7 mmol) under N at
2
25
1
0 ꢁC and stirred for 15 min. NaBH4 (0.28 g, 7.6 mmol)
dissolved in an aqueous solution of 5% NaHCO3
(12 mL) was then added to the reaction mixture at 0 ꢁC
and stirred for another 20 min at the same temperature.
The reaction mixture was then extracted into DCM. The
combined organic layers were washed successively with
water, brine and dried over anhydrous Na2SO4. The
solvent was evaporated in vacuo and the residue on
column chromatographyover silica gel using a mixture
of EtOAc/petroleum ether (1:4 v/v) as the eluent affor-
Solid. Mp 96–97 ꢁC. ½aŠ ¼ )14.3 (c 0.6, acetone). H
D
NMR (200 MHz, CDCl3) d 7.80 (m, 4H), 7.36–7.32 (m,
4H), 4.38 (d, J ¼ 9:4 Hz, 1H), 4.14–3.98 (m, 5H), 3.71–
3.64 (m, 2H), 2.47 (s, 6H), 1.72–1.62 (m, 4H), 1.48 (s,
9H), 1.33 (s, 3H), 1.30 (s, 3H), 1.28–1.25 (m, 2H). 13C
NMR (75 MHz, CDCl3) d 21.3, 21.6, 26.7, 26.9, 28.2,
28.4, 31.4, 52.7, 69.3, 70.1, 78.8, 79.8, 109.7, 127.8,
127.9, 129.8, 129.82, 132.7, 133.0, 144.7, 145.0, 155.6.
m=z FAB: 642 [M+H]þ. Anal. Calcd for C30H43NO10S2:
C, 56.14; H, 6.75; N, 2.18; S, 9.99. Found: C, 56.11; H,
6.69; N, 2.17; S, 9.89.
ded 14 (0.50 g, 1.42 mmol) in 75% yield. Viscous liquid.
25
D
Rf : 0.5 (25% EtOAc/petroleum ether). ½aŠ ¼ )30.5 (c
1
0.6, acetone). H NMR (200 MHz, CDCl3) d 7.38–7.22
(m, 5H), 4.50 (s, 2H), 4.04 (m, 1H), 3.90–3.72 (m, 2H),
3.66–3.41 (m, 4H), 1.76–1.48 (m, 6H), 1.45 (s, 3H), 1.41
(s, 3H). 13C NMR (75 MHz, CDCl3) d 22.9, 26.8, 27.1,
29.3, 30.8, 62.7, 63.9, 69.8, 72.8, 72.9, 78.2, 109.4, 127.5,
127.6, 128.3, 138.3. m=z FAB: 350 [M+H]þ. Anal. Calcd
for C18H27N3O4: C, 61.87; H, 7.79; N, 12.03. Found: C,
61.75; H, 7.68; N, 11.85.
4.11. (1S,2S,8aS)-Perhydro-1,2-indolizinediol 1
To a solution of the acetonide 16 (0.38 g, 0.6 mmol) in
DCM (0.6 mL) was added a solution of TFA/water
(95:5, 1.2 ml) at 0 ꢁC after which the mixture was grad-
uallyallowed to attain rt for 16 h. The solvent was
evaporated under reduced pressure with anytraces of
water in the residue removed as an azeotrope with
benzene. The residue was dissolved in DCM (3 mL) and
triethylamine (0.5 mL, 3.6 mmol) added. The reaction
mixture was stirred at rt for 6 h. The solvent was evap-
orated and the residue dissolved in the minimum
amount of water and purified byion-exchange chro-
matography(Dowex resin) using 2% ammonia solution
4.9. 5-[1-tert-Butyloxycarbonylamido-5-benzyloxy-(1S)-
pentyl]-2,2-dimethyl-(4S,5S)-1,3-dioxolan-4-ylmethanol
15
To a mixture of azido acetonide 14 (0.45 g, 1.3 mmol)
and (Boc)2O (0.56 g, 2.6 mmol) in absolute ethanol
(2.6 mL) was added Pd(OH)2 (45 mg, 10% bywt). The
reaction mixture was evacuated, subsequentlyfilled with
H2 and stirred for 16 h at atmospheric pressure. The
reaction mixture was filtered through a small pad of
Celite and repeatedlywashed with ethanol. Evaporation
of the solvent afforded the crude product, which was
purified bycolumn chromatographyusing EtOAc/
petroleum ether (4:6) as the eluent to yield 15 (0.35 g,
to afford 1 (65 mg, 0.42 mmol) in 70% yield. Solid. Mp
25
D
103–104 ꢁC. ½aŠ ¼ +2.9 (c 0.28, MeOH). 1H NMR
(300 MHz, D2O) d 4.02 (ddd, J ¼ 7:4, 4.0, 1.9 Hz, 1H),
3.57 (dd, J ¼ 8:8, 4.0 Hz, 1H), 2.90 (dd, J ¼ 11:2, 2.0Hz,
1H), 2.79 (dd, J ¼ 11:4, 2.0 Hz, 1H), 2.60 (dd, J ¼ 11:4,
7.4 Hz, 1H), 2.06 (dd, J ¼ 11:3, 2.9 Hz, 1H), 2.01–1.12
(m, 7H). 13C NMR (75 MHz, D2O dioxane internal
standard) d 23.8, 24.8, 28.4, 53.4, 61.1, 69.3, 76.4, 83.8.
m=z FAB: 158 [M+H]þ. HRMS-FAB (m=z) [M+H]þ
calcd for C8H15NO2 158.1180, found 158.1190.
1.06 mmol) in 82% yield. Solid. Mp 75–76 ꢁC.
25
½aŠ ¼ )6.9 (c 0.6, acetone). 1H NMR (200 MHz,
D
CDCl3) d 4.90 (d, J ¼ 9 Hz, 1H), 3.98 (m, 1H), 3.64–3.52
(m, 6H), 2.04 (d, J ¼ 3:4 Hz, 1H), 1.64–1.52 (m, 6H),
1.44 (s, 9H), 1.38 (s, 6H). 13C NMR (75 MHz, CDCl3) d
21.6, 26.9, 27.0, 28.3, 31.0, 32.2, 52.6, 62.3, 62.6, 79.4,
79.5, 79.6, 109.0, 156.0. m=z FAB: 334 [M+H]þ. Anal.
Calcd for C16H31NO6: C, 57.64; H, 9.37; N, 4.20;.
Found: C, 57.49; H, 9.19; N, 4.10.
Acknowledgements
S.R. is thankful to Dr. J. S. Yadav, Director, IICT, for
constant support and encouragement. T.S. is thankful to
CSIR, New Delhi for a fellowship. Financial assistance
from DST (New Delhi) is gratefullyacknowledged. We
thank Dr. A. C. Kunwar for the NMR spectra and Dr.
M. Vairamani for the mass spectra.
4.10. 4-[1-tert-Butyloxycarbonylamido-5-benzyloxy-(1S)-
pentyl]-2,2-dimethyl-5-(4-methylphenylsulfonyloxy-
methyl)-(4S,5S)-1,3-dioxolane 16
To a solution of diol 15 (0.33 g, 1.0 mmol) in dichloro-
methane (5 mL) was added triethylamine (0.62 mL,
4.5 mmol) followed by p-toluenesulfonyl chloride
(0.42 g, 2.2 mmol) and the mixture stirred under nitrogen
for 1 h. The reaction mixture was quenched with 10%
citric acid solution. The aqueous layer was then
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5. The ester 5 was readilyobtained in three steps from 1,5-
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1. NaH, BnBr, 80%
OBn
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