The synthesis of (1S,8aS)-1-hydroxyindolizidine using a stereoselective Grignard addition to an N-benzyl-3-deoxy sugar imine derived from D-Glucose

Article abstract of DOI:10.1016/j.tetasy.2010.08.001

A highly stereoselective approach to 1-hydroxyindolizidine is described using a Grignard reaction on N-benzyl imine derived from 3-deoxy-1,2-O- isopropylidine-α-d-xylo-pentodialdofuranose and reductive cyclization as key steps.

Full text of DOI:10.1016/j.tetasy.2010.08.001

Tetrahedron: Asymmetry 21 (2010) 2314–2318
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The synthesis of (1S,8aS)-1-hydroxyindolizidine using a stereoselective
Grignard addition to an N-benzyl-3-deoxy sugar imine derived from D-Glucose
⇑
Y. Jagadeesh, B. Chandrasekhar , B. Venkateswara Rao
Organic Division III, Indian institute of Chemical Technology, 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 highly stereoselective approach to 1-hydroxyindolizidine is described using a Grignard reaction on N-
Received 20 July 2010
Accepted 29 July 2010
Available online 9 September 2010
benzyl imine derived from 3-deoxy-1,2-O-isopropylidine-
a
-
D-xylo-pentodialdofuranose and reductive
cyclization as key steps.
Ó 2010 Elsevier Ltd. All rights reserved.
OH
1. Introduction
N
N
N
HO
HO
Polyhydroxylated indolizidine alkaloids are frequently encoun-
tered in nature in a variety of sources. Some of the important mem-
bers of this family are castanospermine 1, swainsonine 2,
lentiginosine 3, and slaframine 4. Compounds 1–3 are specific
inhibitors of glycosidases and have shown activity against HIV,
cancer, and diabeties.1,2 Slaframine 4 is a neurotoxin fungus
metabolite that has potent use in the treatment of diseases involv-
ing cholinergic dysfunction.3 Due to their interesting biological
activity and structural features, these indolizidine alkaloids have
attracted the attention of both biologists and synthetic chemists.4
As part of an ongoing program for the synthesis of azasugars,5,6
we recently developed an approach for the synthesis of (5, 6),
(6, 6), (6, 7) bicyclic iminosugars using a highly stereoselective
Grignard addition onto a sugar imine.6 Herein we report an exten-
sion of this methodology for the stereoselective synthesis of
(1S,8aS)-1-hydroxyindolizidine 5, which is a key precursor in the
biosynthesis of indolizidine alkaloids, such as swainsonine 2 and
OH
N
H
H
H
HO
NH2
HO
HO
OH
OH
2
1
3
N
H
H
HO
H3COCO
5
4
Figure 1.
ence of 4 Å molecular sieves afforded chiral imine 7, which was
used as such without any purification for the next step. Treatment
of imine 7 with homoallyl magnesium bromide in THF at 0 °C gave
syn-amino olefin 8 as the exclusive isomer by 1H NMR. The abso-
lute configuration of the newly created stereogenic center was
not known at this stage (Scheme 1). However, based on our earlier
observation we presumed it to be a syn isomer, because the ring
oxygen chelates with the Grignard reagent and helps the nucleo-
phile to undergo addition with high stereoselectivity.6,10 It was
thought that the presence of an alkoxy group at the C-3 position
also helped in getting exclusive stereoselectivity, however the for-
mation of 8 clearly shows that the chelation of ring oxygen is the
only essential factor for the selectivity (Fig. 2).
In order to construct the piperidine ring, the amino compound 8
was treated with benzyloxy carbonyl chloride in the presence of
NaHCO3 in MeOH to afford compound 9 in 92% yield. Hydrobora-
tion of 9 with BH3ꢀDMS at 0 °C gave amino alcohol 10. Both 9
and 10 exist as rotational isomers as seen by the 1H and 13C
NMR because of the hindered rotation of N–C bond of the N-Cbz
group.5b,11 Debenzylation of 10 with Pd/C in the presence of
ammonium formate in methanol for 3 h at 60 °C gave the free
amine, which was immediately protected as the Cbz derivative
slaframine
4
in the fungus Rhizoctonia legumniola (Fig. 1).7
Although several approaches are known in the literature for 5, to
the best of our knowledge none of them have utilized carbohy-
drates as the starting materials.8 The key aspect of the present syn-
thesis is to find the stereoselectivity in the Grignard addition to an
N-benzyl-3-deoxy sugar imine derived from D-glucose (Scheme 1).
2. Results and discussions
Our synthesis starts from aldehyde 6, which can be prepared
from commercially available D-glucose using a literature proce-
dure.9 Condensation of aldehyde 6 with benzylamine in the pres-
⇑
Corresponding author. Tel./fax: + 91 40 27193003.
E-mail address: chanduiict@gmail.com (B. Chandrasekhar).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.08.001

Y. Jagadeesh et al. / Tetrahedron: Asymmetry 21 (2010) 2314–2318
2315
O
NHBn
NBn
O
O
O
a
b
O
O
O
O
O
O
6
8
7
Scheme 1. Reagents and conditions: (a) BnNH2, 4 Å molecular sieves, DCM; (b) homoallyl magnesium bromide, THF, 0 °C, 12 h.
R
utilized for the synthesis of 1-hydroxyindolizidine. This approach
is also helpful for the preparation of other indolizidine and quino-
lizidine alkaloids. Work is currently in progress in our laboratory.
Br
R
Mg
Br
BnN
Mg
O
NBn
O
O
4. Experimental
4.1. General
H
O
Nu
H
O
O
TLC was performed on Merck Kiesel Gel 60, F254 plates (layer
thickness 0.25 mm). Column chromatography was performed on
silica gel (60–120 mesh) using ethyl acetate and hexane mixture
as eluent. Melting points were determined on a Fisher John’s melt-
ing point apparatus and are uncorrected. IR spectra were recorded
on a Perkin–Elmer RX-1 FT-IR system. 1H NMR and 13C NMR spec-
tra were recorded using Bruker Avance-300 MHz, Varian-400 MHz
spectrometer. 1H NMR data are expressed as chemical shifts in
ppm followed by multiplicity (s—singlet; d—doublet; t—triplet;
q—quartet; m—multiplet), number of proton(s) and coupling con-
stant(s) J (Hz). 13C NMR chemical shifts are expressed in ppm. Opti-
cal rotations were measured with Horiba-SEPA-300 digital
polarimeter. Accurate mass measurement was performed on Q
STAR mass spectrometer (Applied Biosystems, USA). Due to the
isomerization by the restricted rotation around C@N with the pres-
ence of N-Cbz group, the 1H and 13C NMR spectra’s of compounds 9
and 10 showed doubling of the signals and were thus assigned as
rotamers.5b,11
H
H
Nu
I
Figure 2.
11 in 86% yield. For the construction of the piperidine ring, com-
pound 11 was treated with MsCl and Et3N in CH2Cl2 at 0 °C to give
the mesyl derivative, which was used as such without purification.
The cyclization was carried out on the crude mesyl derivative using
KOtBu in THF to yield compound 12 in 80% yield. The next stage
was to construct the pyrrolidine unit; for this the acetonide moiety
in 12 was removed using TFA–H2O to give hemiacetal 13 in 85%
yield. Oxidative cleavage of 13 with NaIO4 in methanol-water gave
the eliminated
a,b-unsaturated aldehyde 14 in 82% yield. The
formation of 14 can be explained through b-formyloxy elimination
of the aldehyde derived from 13 during oxidative cleavage
(Scheme 2).12
To circumvent the elimination problem, hemiacetal 13 was
treated with NaBH4 in methanol to give triol 15 in 80% yield. The
subsequent oxidative degradation of compound 15 with NaIO4
gave the aldehyde, which was used as such in the next step with-
out any purification. Deprotection of Cbz and simultaneous reduc-
tive amino cyclization under Pd/C and an H2 atmosphere in
methanol gave 1-hydroxyindolizidine 5 in 73% yield, whose NMR
and physical properties were in perfect agreement with the re-
ported values (Scheme 3).8j,l,13
4.1.1. (S)-N-Benzyl-1-((3aR,5S,6aR)-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)pent-4-en-1-amine (8)
To a solution of aldehyde 6 (1.60 g, 9.3 mmol) in dry CH2Cl2
(20 mL) and molecular sieves 4 Å (200 mg) was added benzyl-
amine (1 mL, 9.3 mmol) at room temperature and kept at 0 °C for
4 h. The reaction mixture was filtered and concentrated to give
crude imine 7, which was used as such for the next step. To the
solution of homoallyl magnesium bromide prepared from Mg
(1.11 g, 46.3 mmol) and homoallyl bromide (4.6 mL, 46.3 mmol)
in THF (30 mL) was added a solution of chiral imine 7 (2.42 g,
9.3 mmol) in THF over 10 min at 0 °C under nitrogen. After stirring
overnight at room temperature, the mixture was poured into
3. Conclusion
In conclusion, a highly stereoselective Grignard addition reac-
tion onto a 3-deoxy sugar imine derived from
D-glucose was
NRR1
NBnCbz
d
O
O
a
b
O
O
8
HO
R=Bn, R1=Cbz
O
O
9
10
11
c
R= H, R1=Cbz
NCbz
O
NCbz
NCbz
O
e
f
O
OH
OH
CHO
O
12
14
13
Scheme 2. Reagents and conditions: (a) CbzCl, NaHCO3, MeOH, rt, 4 h; (b) BH3.DMS, THF, 0 °C, 2 h; (c) (i) Pd/C, ammonium formate, 60 °C, 2 h, (ii) CbzCl, NaHCO3, MeOH, rt,
4 h; (d) (i) MsCl, TEA, DMAP, CH2Cl2, 30 min, (ii) KOtBu, THF, 0 °C to rt, 3 h; (e) TFA: H2O (3:2), rt, 3 h; (f) NaIO4, MeOH–H2O, 2 h.

2316
Y. Jagadeesh et al. / Tetrahedron: Asymmetry 21 (2010) 2314–2318
NCbz
NCbz
N
a
O
b
OH
OH
OH
OH
OH
H
OH
5
13
15
Scheme 3. Reagents and conditions: (a) NaBH4, MeOH, rt, 1 h; (b) NaIO4, MeOH–H2O, 2 h, then H2, Pd/C, MeOH, 12 h.
saturated NH4Cl (50 mL) and extracted into ethyl acetate
(3 ꢁ 50 mL). The collected organic layers were combined, washed
with water, brine, then dried over Na2SO4, concentrated under re-
duced pressure, and purified through column chromatography
(hexane/ethyl acetate = 8:2) to afford the corresponding amino
4.06–4.30 (m, 2H), 4.33–4.66 (m, 3H), 5.09–5.22 (br d, 2H,
J = 16.9 Mz), 5.36–5.5 (m, 1H), 7.10–7.42 (m, 10H); 13C NMR
(75 MHz, CDCl3) d 22.3 and 22.4*, 26.1, 26.6, 29.1, 29.6, 32.2,
*
*
*
36.3, 42.5, 62.3, 67.3 and 67.4 , 78.7 and 79.0 , 80.1 and 80.2 ,
104.7 and 104.8*, 110.9, 126.7, 127.3, 127.7, 128.1, 128.2, 128.4,
136.3, 139.2, 157.5; ESI/MS (m/z) 470 (M++H); HRMS calcd for
olefin 8 as a yellow oil (2.1 g, 72% for two steps). ½a D28
¼ ꢃ9:6 (c
ꢂ
1.51, CHCl3); IR (neat) mmax 2983, 2933, 1640, 1453, 1375, 1214,
C27H35NO6Na 492.2362, found 492.2333.
1062, 1021, 736 cmꢃ1
;
1H NMR (300 MHz, CDCl3) d 1.28 (s, 3H,
Rotamers.
*
CH3), 1.47 (s, 3H), 1.5–1.67 (m, 2H), 1.67–1.8 (m, 1H), 1.98 (dd,
1H, J = 4.15, 12.84 Hz), 2.06–2.25 (m, 2H), 2.5–2.6 (m, 1H), 3.72
(d, 1H, J = 13.2 Hz), 3.85 (d, 1H, J = 13.2 Hz), 4.15–4.25 (m, 1H),
4.66 (dd, 1H, J = 4.1 Hz), 4.9–5.03 (m, 2H), 5.69–5.84 (m, 1H),
5.72 (d, 1H, J = 3.4 Hz), 7.12–7.23 (m, 5H); 13C NMR (75 MHz,
CDCl3) d 26.1, 26.7, 29.6, 29.8, 35.6, 51.2, 58.9, 80.0, 80.4, 105.2,
110.8, 114.6, 126.7, 128.1, 128.2, 138.5, 140.7; ESI/MS (m/z) 318
(M++H); HRMS calcd for C19H28NO3 318.2069, found 318.2057.
4.1.4. Benzyl(S)-1-((3aR,5S,6aR)-2,2-dimethyl-tetrahydrofuro-
[2,3-d][1,3]dioxol-5-yl)-5-hydrox-ypentylcarbamate (11)
A solution of 10 (2.2 g, 4.7 mmol) in dry methanol (20 mL) was
hydrogenated in the presence of 10% Pd–C and ammonium formate
(0.9 g, 14.1 mmol) at 60 °C for 3 h. The catalyst was filtered
through a Celite pad and the collected filtrate was concentrated
to give the free amine. This crude amine was dissolved in dry
DCM and to it were added sodium bicarbonate (1.13 g, 13.5 mmol)
and benzyloxycarbonyl chloride (1.12 mL, 6.7 mmol) at 0 °C and
stirred at rt for overnight. The reaction mixture was washed with
saturated NH4Cl (100 mL) and extracted with CH2Cl2 (3 ꢁ 50 mL).
The organic layers were combined and washed with brine then
dried over Na2SO4 and concentrated in vacuo and purified through
silica gel column chromatography (hexane/ethyl acetate = 8:2) to
4.1.2. Benzyl((S)-1-((3aR,5S,6aR)-2,2-dimethyl-tetrahydrofuro-
[2,3-d][1,3]dioxol-5-yl)pent-4-eny-l)carbamate (9)
To a stirred solution of 8 (1.9 g, 6 mmol) in dry methanol was
added sodium bicarbonate (1 g, 12 mmol) followed by benzyloxy-
carbonyl chloride (1.5 mL, 9 mmol) at 0 °C. The mixture was stirred
at rt for 3 h. Methanol was evaporated under reduced pressure and
reaction mixture was extracted with ethyl acetate and water. The
collected organic layer was dried over Na2SO4, concentrated, and
purified by column chromatography (hexane/ethyl acetate = 9:1)
give 11 (1.45 g) in 86% as a syrup. ½a D28
¼ ꢃ40:2 (c 0.55, CHCl3);
ꢂ
IR (neat) mmax 3441, 2936, 1704, 1528, 1455, 1376, 1299, 1219,
1161, 1051, 1018, 847, 754, 699 cmꢃ1 1H NMR (300 MHz, CDCl3)
;
to give 9 (2.5 g, 92%) as a thick liquid. ½a D28
ꢂ
¼ ꢃ23:33 (c 0.9, CHCl3);
d 1.28 (s, 3H), 1.47 (s, 3H), 1.34–1.73 (m, 7H), 2.0 (dd, 1H, J = 4.2,
13.2 Hz), 3.48–3.65 (m, 2H), 3.65–3.8 (m, 1H), 4.13–4.23 (m, 1H),
4.62 (dd, 1H, J = 4.2 Hz), 4.79 (d, 1H, J = 10.2 Hz), 5.03 (d, 1H,
J = 12.5 Hz), 5.08 (d, 1H, J = 12.5 Hz), 5.69 (d, 1H, J = 3.8 Hz), 7.25–
7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) d 22.2, 26.0, 26.7, 32.3,
33.7, 35.1, 42.6, 62.5, 66.8, 79.3, 80.3, 105.2, 111.2, 128.0, 128.1,
128.5, 136.3, 156.6; ESI/MS (m/z) 380 (M++H); HRMS calcd for
IR (neat) mmax 2982, 2934, 1697, 1454, 1415, 1216, 1162, 1020, 914,
848, 699 cmꢃ1 1H NMR (300 MHz, CDCl3) d 1.23 (s, 3H), 1.38 (s,
;
3H), 1.28–1.63 (m, 4H), 1.68–2.06 (m, 3H), 4.08–4.3 (m, 1H), 4.3–
4.71 (m, 3H), 4.75–4.94 (m, 2H), 5.07–5.25 (m, 2H), 5.31–5.73
(m, 2H), 7.1–7.4 (m, 10H); 13C NMR (75 MHz, CDCl3) d 26.1, 26.6,
28.3 and 28.8*, 29.0 and 29.6*, 30.2 and 30.3*, 36.2, 67.2 and
*
*
*
67.4 , 78.6, 78.9, 80.1 and 80.2 , 104.7 and 104.8 , 110.8, 115.0,
126.6, 127.2, 127.9, 128.1, 128.2, 128.3, 136.3, 137.4, 139.1,
157.4; ESI/MS (m/z) 452 (M++H); HRMS calcd for C27H33NO5Na
474.2256, found 474.2265.
C20H29NO6Na 402.1892, found 402.1881.
4.1.5. (S)-Benzyl 2-((3aR,5S,6aR)-2,2-dimethyl-tetrahydrofuro-
[2,3-d][1,3]dioxol-5-yl)piperidine-1-carboxylate (12)
* Rotamers.
To a solution of 11 (1.2 g, 3.2 mmol) in CH2Cl2 (15 mL) at 0 °C
was added methanesulphonylchloride (0.3 mL, 3.8 mmol) followed
by triethylamine (1.34 mL, 9.6 mmol). After 30 min stirring at this
temperature, the reaction mixture was poured into water (25 mL)
and the layers were separated. The aqueous layer was extracted
with CH2Cl2 (2 ꢁ 25 mL), and the combined organic layers were
dried with Na2SO4, filtered, and concentrated in vacuo. To this
mesylate derivative in dry THF (15 mL) was added KOtBu (1.06,
9.5 mmol) and the resulting yellow solution was stirred at room
temperature for 3 h. The reaction mixture was quenched with
NH4Cl (20 mL) and extracted with ethyl acetate (3 ꢁ 50 mL). The
combined organic layers were dried over Na2SO4 and concentrated
in vacuo. The crude product was purified by column chromatogra-
phy (hexane/ethyl acetate = 9:1) to give the title compound 12 as a
4.1.3. Benzyl((S)-1-((3aR,5S,6aR)-2,2-dimethyl-tetrahydrofuro-
[2,3-d][1,3]dioxol-5-yl)-5-hydroxy-pentyl)carbamate (10)
To a solution of 9 (2.4 g, 5.3 mmol) in dry THF (30 mL), BH3ꢀDMS
(1.5 mL, 16 mmol) was added at 0 °C. Stirring was continued for 3 h
at room temperature. The reaction mixture was quenched by the
addition of 10% NaOH (8.16 mL) followed by 30% H2O2 (2.4 mL)
at 0 °C and stirring was continued at room temperature for another
1 h. The reaction mixture was extracted with ethyl acetate and
water and the combined organic layers were washed with brine
dried over anhydrous Na2SO4, concentrated, and purified by col-
umn chromatography (hexane/ethyl acetate = 7:3) to give alcohol
10 (2.3) in 93% yield as a thick liquid. ½a D28
¼ ꢃ27:7 (c 1.55, CHCl3);
ꢂ
IR (neat) mmax 3452, 2936, 1693, 1454, 1417, 1242, 1214, 1161,
colorless oil (0.9 g) in 80% yield. ½a D28
¼ ꢃ60:7 (c 2.57, CHCl3); IR
ꢂ
1055, 1019, 848, 737, 699 cmꢃ1
;
1H NMR (400 MHz, CDCl3) d
(neat) mmax 2938, 1696, 1426, 1376, 1318, 1249, 1214, 1163,
1.24 (s, 3H), 1.38 (s, 3H), 1.3–2.05 (m, 8H), 3.29–3.54 (m, 2H),
1077, 1021, 908, 848, 761, 698 cmꢃ1 1H NMR (300 MHz, CDCl3)
;

Y. Jagadeesh et al. / Tetrahedron: Asymmetry 21 (2010) 2314–2318
2317
d 1.28 (s, 3H), 1.47 (s, 3H), 1.57–1.8 (m, 7H), 1.9–2.1 (m, 1H), 3.06
(dd, 1H, J = 12.5 Hz), 4.01–4.31 (m, 2H), 4.32–4.48 (m, 1H), 4.62
(dd, 1H, J = 3.97 Hz), 5.04 (d, 1H, J = 12.5 Hz), 5.15 (d, 1H,
J = 12.5 Hz), 5.67–5.77 (br s, 1H), 7.23–7.36 (m, 5H); 13C NMR
(100 MHz, CDCl3) d 19.7, 25.0, 25.9, 26.5, 26.8, 36.5, 40.3, 52.8,
66.8, 77.3, 79.9, 105.0, 110.6, 127.5, 127.6, 128.2, 136.7, 155.6;
ESI/MS (m/z) 362 (M++H); HRMS calcd for C20H27NO5Na
384.1786, found 384.1767.
128.4, 136.5, 157.1; ESI/MS (m/z) 346 (M++Na); HRMS calcd for
17H25NO5Na 346.1630, found 346.1624.
C
4.1.9. (1S,8aS)-Octahydroindolizin-1-ol (5)
To a stirred solution of compound triol 15 (0.17 g, 0.53 mmol) in
methanol (5 mL) was added NaIO4 (0.224 g, 1.05 mmol in 3 mL
water) and stirring was continued for 1 h. After completion of
the reaction, methanol was evaporated under reduced pressure
and the crude slurry was dissolved in ethyl acetate, organic layer
was washed with NaHCO3 and brine then dried over Na2SO4, and
concentrated to give the crude aldehyde (0.1 g), which was used
as such for the next reaction immediately without any purification.
A solution of the aldehyde in methanol (5 mL) was added to 10%
Pd/C (0.01 g) and then the flask was purged with H2 and the solu-
tion hydrogenated for 24 h. The catalyst was filtered and washed
with methanol and the filtrate was concentrated to give a crude
product, which upon purification by column chromatography
(chloroform/methanol = 7:3) gave 5 (0.035 g, 73%) as a liquid.
4.1.6. (S)-Benzyl 2-((2S,4R)-4,5-dihydroxy-tetrahydrofuran-2-
yl)piperidine-1-carboxylate (13)
The cyclic compound 12 (0.8 g) was treated with 2 mL of TFA/
H2O (3:2) at 0 °C; then the reaction mixture was warmed to room
temperature and stirred for 3 h. The solvents were removed by
three co-evaporations with toluene (3 ꢁ 10 mL), and the residual
product was dissolved in water and neutralized with NaHCO3 ex-
tracted with ethyl acetate. The organic layer was dried over Na2SO4
and concentrated in vacuo and the crude product purified by col-
umn chromatography (hexane/ethyl acetate = 6:4) to give the lac-
½
a 2D8
ꢂ
¼ þ23:5 (c 0.80, EtOH), {lit.8j, ½a D25
¼ þ22:5 (c 1, EtOH)}; IR
ꢂ
tol in 85% yield as a syrup. ½a D28
¼ ꢃ47:6 (c 1.48, CHCl3); IR (neat)
ꢂ
(neat) mmax 3359, 2926, 2854, 1653, 1547, 1447, 1264, 1133,830,
754 cmꢃ1; The NMR spectroscopic values are in good agreement
with the earlier reports.8j,l 1H NMR (400 MHz, CDCl3) d 1.20–1.3
(m, 2H), 1.46–1.75 (m, 5H), 1.80–2.0 (m, 3H), 2.17 (m, 1H), 2.5
(br s, OH, 1H), 3.13 (m, 2H), 4.05 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 23.8, 25.0, 25.1, 33.2, 52.7, 53.5, 69.0, 72.8; ESI/MS (m/z)
142 (M++H); HRMS calcd for C8H16NO 142.1231, found 142.1239.
mmax 3399, 2931, 1671, 1433, 1353, 1260, 1145, 1071, 1030, 955,
856, 757, 698 cm-1; 1H NMR (300 MHz, CDCl3): d 1.28–2.1 (m,
10H), 3.0 (m, 1H), 3.95–4.32 (m, 3H), 4.55–4.67 (m, 1H), 4.97–
5.27 (m, 3H), 7.20–7.40 (m, 5H); 13C NMR (75 MHz, CDCl3) d
18.9, 19.3, 24.9, 25.0, 25.9, 36.0, 39.9, 57.4, 67.0, 67.3, 75.1,
102.6, 127.7, 127.8, 127.9, 128.0, 128.4, 128.5, 136.6, 157.6; ESI/
MS (m/z) 344 (M++Na); HRMS calcd for C17H23NO5Na 344.1473,
found 344.1472.
Acknowledgments
The authors thank the CSIR, New Delhi, for research fellowship.
We also thank Dr. J. S. Yadav and Dr. A.C. Kunwar for their support
and encouragement. DST (SR/S1/OC-14/2007)-New Delhi for finan-
cial support.
4.1.7. (S,E)-Benzyl 2-(3-oxoprop-1-enyl)piperidine-1-
carboxylate (14)
Lactol 13 (0.2 g, 0.73 mmol) was dissolved in methanol (5 mL)
and was added to NaIO4 (0.31 g, 1.46 mmol in 3 mL H2O) at 0 °C.
The reaction mixture was stirred at rt for 1 h. After completion of
the reaction, methanol was removed under reduced pressure and
extracted with ethyl acetate. The combined organic layers were
washed with aq NaHCO3, dried, concentrated, and purified by col-
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2. Harris, C. M.; Schneider, M. J.; Ungemach, F. S.; Hill, J. E.; Harris, T. M. J. Am.
Chem. Soc. 1988, 110, 940. and references therein.
umn chromatography (hexane/ethyl acetate = 8:2) to give
unsaturated aldehyde 14 (0.14 g) in 82% yield as a colorless oil.
¼ ꢃ21:5 (c 0.58, CHCl3); IR (neat) mmax 2923, 2854, 1696,
1460, 1420, 1262, 1173, 1083, 970 cmꢃ1 1H NMR (300 MHz,
a,b-
½ ꢂ
a 2D8
3. Broquist, H. P. Ann. Rev. Nutr. 1985, 5, 391.
;
4. (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139; (b) Michael, J. P. Nat. Prod. Rep.
2007, 24, 191; (c) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603. and references
cited therein.
5. (a) Madhan, A.; Rao, B. V. Tetrahedron Lett. 2003, 5641; (b) Chandrasekhar, B.;
Madhan, A.; Rao, B. V. Tetrahedron 2007, 8746.
6. Chandrasekhar, B.; Rao, B. V.; Rao, K. V. M.; Jagadeesh, B. Tetrahedron:
Asymmetry 2009, 20, 1217.
7. (a) Guengerich, F. P.; Synder, J. J.; Broquist, H. P. Biochemistry 1973, 12, 4264; (b)
Clevenstine, E. C.; Walter, P.; Harris, T. M.; Broquist, H. P. Biochemistry 1979, 18,
3663.
CDCl3) d 1.36–1.55 (m, 2H), 1.68 (m, 2H), 1.77–1.95 (m, 2H), 2.86
(t, 1H, J = 12.5 Hz), 4.10 (d, 1H, J = 12.8 Hz), 5.14 (s, 2H), 5.07–
5.23 (m, 1H), 6.06–6.17 (ddd, 1H, J = 2.2, 7.5, 15.8 Hz), 6.75 (dd,
1H, J = 4.0, 15.8 Hz), 7.28–7.40 (m, 5H), 9.58 (d, 1H, J = 7.7 Hz);
13C NMR (75 MHz, CDCl3) d 19.7, 25.1, 28.6, 40.7, 52.2, 67.4,
127.9, 128.1, 128.5, 133.0, 136.4, 155.6, 156.2, 193.0; ESI/MS (m/
z) 296 (M++Na).
8. (a) Harris, C. M.; Harris, T. M. Tetrahedron Lett. 1987, 28, 2559; (b) Sibi, M. P.;
Christensen, J. W. Tetrahedron Lett. 1990, 31, 5689; (c) Shono, T.; Kise, N.;
Tanabe, T. J. Org. Chem. 1988, 53, 1364; (d) Takahata, H.; Banba, Y.; Momose, T.
Tetrahedron: Asymmetry 1990, 1, 763; (e) Takahata, H.; Takamatsu, T.;
Yamazaki, T. J. Org. Chem. 1989, 54, 4812; (f) Takahata, H.; Tajima, M.; Banba,
Y.; Momose, T. Chem. Pharm. Bull. 1989, 37, 2550; (g) Nukui, S.; Sodeoka, M.;
Sasai, H.; Shibasaki, M. J. Org. Chem. 1995, 60, 398; (h) Green, D. L. C.; Kiddle, J.
J.; Thompson, C. M. Tetrahedron 1995, 51, 2865; (i) Sibi, M. P.; Christensen, J. W.
J. Org. Chem. 1999, 64, 6434; (j) Pourashraf, M.; Delair, P.; Rasmussen, M. O.;
Greene, A. E. J. Org. Chem. 2000, 65, 6966; (k) Batey, R. A.; MacKay, D. B.;
Santhakumar, V. J. Am. Chem. Soc. 1999, 121, 5075; (l) Wee, A. G. H.; Fan, G. –J.;
Bayirinoba, H. M. J. Org. Chem. 2009, 74, 8261; (m) Klitzke, C. F.; Pilli, R. A.
Tetrahedron Lett. 2001, 42, 5605.
4.1.8. (S)-Benzyl 2-((1S,3R)-1,3,4-trihydroxybutyl)piperidine-1-
carboxylate (15)
The lactol 13 (0.35 g, 1.1 mmol) was dissolved in dry methanol
(10 mL) and to it was added NaBH4 (0.082 g, 2.2 mmol) at 0 °C and
stirred for 1 h. The reaction mixture was quenched by adding satd
NH4Cl and MeOH was removed in vacuo and extracted with ethyl
acetate. The organic layer was dried over Na2SO4, concentrated,
and purified by column chromatography (hexane/ethyl ace-
tate = 3:7) to afford the triol 15 (0.23 g) in 80% yield as a liquid.
½
a 2D8
ꢂ
¼ ꢃ43:33 (c 0.40, CHCl3); IR (neat) mmax 3391, 2935, 1672,
9. (a) Iacono, S.; Rasmussen, J. R. Org. Synth. 1986, 64, 57; (b) Manna, S.; Viala, J.;
Yadagiri, P.; Falck, J. R. Tetrahedron Lett. 1986, 24, 2679.
1432, 1351, 1262, 1174, 1081, 1035, 741, 698 cmꢃ1 1H NMR
;
10. (a) Bloch, R. Chem. Rev. 1998, 98, 1407; (b) van Delft, F. L.; de Kort, M.; Vander
Marel, G. A.; van Boom, J. H. J. Org. Chem. 1996, 61, 1883; (c) Kobayashi, Y.;
Matsumoto, T.; Takemoto, Y.; Nakatani, K.; Ito, Y.; Kamijo, T.; Harada, H.;
Terashima, S. Chem. Pharm. Bull. 1991, 39, 2550; (d) van Delft, F. L.; de Kort, M.;
van der Marel, G. A.; van Boom, J. H. Tetrahedron: Asymmetry 1994, 5, 2261; (e)
Cativiela, C.; Diaz-de-Villegas, M. D.; Gálvez, J. A. Tetrahedron: Asymmetry 1996,
7, 529; (f) Veith, U.; Schwardt, O.; Jäger, V. Synlett 1996, 1181; (g) Cram, D. J.;
(300 MHz, CDCl3): d 1.32–1.80 (m, 8H), 2.92–3.12 (m, 1H), 3.43
(dd, 1H, J = 6.0, 11.1 Hz), 3.56 (dd, 1H, J = 2, 11.1 Hz), 3.78–4.2 (m,
4H), 4.34 (br s, 1H), 5.06 (d, 1H, J = 12.5 Hz), 5.1 (d, 1H,
J = 12.5 Hz), 7.22–7.35 (m, 5H); 13C NMR (75 MHz, CDCl3) d 19.5,
25.0, 25.7, 36.5, 40.4, 56.5, 66.5, 67.3, 69.7, 71.8, 127.6, 127.9,

2318
Y. Jagadeesh et al. / Tetrahedron: Asymmetry 21 (2010) 2314–2318
Elhafez, A. A. J. Am. Chem. Soc. 1952, 74, 5828; (h) Cram, D. J.; Kopecky, K. R. J.
Am. Chem. Soc. 1959, 81, 2748.
13. The NMR spectral pattern of synthetic compound 5 is superimposable with the
spectra available in the Supplementary data given by Wee et al.8l
11. (a) Jagadeesh, Y.; Reddy, J. S.; Rao, B. V.; Swarnalatha, J. L. Tetrahedron 2010, 66,
1202; (b) Dhavale, D. D.; Jachak, S. M.; Karche, N. P.; Trombini, C. Tetrahedron
2004, 60, 3009; (c) Shu, H.; Noble, A. R.; Zhang, S.; Miao, L.; Trudell, M. L.
Tetrahedron 2010, 66, 4428; (d)Applications of NMR Spectroscopy in Organic
Chemistry; Jackman, L. M., Sternhell, S., Eds.; Pergamon: Elmsford, NY, 1978. p
361.
12. Formation of 14:
NCbz
NCbz
O
NCbz
H
H
NaIO4
O
OH
OH
MeOH-H2O
CHO
CHO
13
14
H
O