An expedient total synthesis of optically active piperidine and indolizidine alkaloids (-)-β-conhydrine and (-)-lentiginosine

Article abstract of DOI:10.1016/j.tet.2010.11.011

Attempts directed toward the stereocontroled total synthesis of piperidine and indolizidine alkaloids resulted in the synthesis of (-)-β-conhydrine 1 and (-)-lentiginosine 3. The synthesis of 1 and 3 were developed from protected d-mannitol as the chiral

Full text of DOI:10.1016/j.tet.2010.11.011

Tetrahedron 67 (2011) 1341e1347
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An expedient total synthesis of optically active piperidine and indolizidine
alkaloids (ꢀ)-
Ahmed Kamal , Saidi Reddy Vangala
b
-conhydrine and (ꢀ)-lentiginosine
*
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 August 2010
Received in revised form 29 October 2010
Accepted 2 November 2010
Available online 5 November 2010
Attempts directed toward the stereocontroled total synthesis of piperidine and indolizidine alkaloids
resulted in the synthesis of (ꢀ)-
b
-conhydrine 1 and (ꢀ)-lentiginosine 3. The synthesis of 1 and 3 were
developed from protected -mannitol as the chiral precursor, which involved nucleophilic addition and
D
azide nucleophilic substitution, Barbier allylation, ring closing metathesis, and Sharpless asymmetric
dihydroxylation as the key steps.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Conhydrine
Lentiginosine
Mannitol
Ring closing metathesis
Sharpless asymmetric dihydroxylation
1. Introduction
formation processes.6 In view of their enormous biological impor-
tance of this class of compounds, a number of auxiliary supported
Exploiting natural products to ascertain a lead has always been
an important technique in drug discovery.1 The piperidine and
indolizidine moieties are found as core structures in many struc-
turally diverse and stereochemically interesting alkaloids. Many of
these alkaloids also possess potent and therapeutically interesting
or chiral pool approaches have been reported for (þ)-
b-conhydrine
27 and (þ)-lentiginosine 4.8 However not much attention has been
given to the enantioselective syntheses for the preparation of
(ꢀ)-
b
-conhydrine 19 and (ꢀ)-lentiginosine 3.10, 17
As part of our research program aimed at developing enantio-
selective syntheses of naturally occurring alkaloids and lacto-
nes,7c,11 we became interested in developing a general route
capable of providing not only the target molecules 1 and 3 but also
their other stereoisomers. Herein, we would like to report an effi-
biological activities. Particularly, those that are
a-substituted by
1-hydroxy alkyl side chain constitutes a framework, that is, fre-
quently encountered in natural alkaloids, such as conhydrine and
lentiginosine (Fig. 1) and have attracted much attention due to their
antiviral, antitumor, and anti-HIV properties.2 (ꢀ)-
b
-Conhydrine 1
cient total synthesis of (ꢀ)-
b
-conhydrine 1 and (ꢀ)-lentiginosine 3
is one of the alkaloids of the hemlock, isolated from the seeds and
leaves of the poisonous alkaloids plant Conium maculatum L., whose
extracts were used in the Greece for the execution of criminals in
18563 and its structure was elucidated in 1933.4 The poly-
hydroxylated indolizidine alkaloid (ꢀ)-lentiginosine 3 is the trans-
dihydroxylated indolizidine alkaloid isolated from the leaves of
Astrayalus lentiginousus in 1990.5 Polyhydroxylated indolizidine
alkaloids with glycosidase inhibitory properties have been the
subject of an intense research effort during the last two decades.
Such inhibitors are not only useful as potential drugs for the
treatment of viral infections, cancer, autoimmune pathologies, di-
abetes, and other metabolic disorders but can also provide a new
insight into the widespread and important glycoside cleavage/
employing an entirely different approach. This strategy involves
NH
NH
OH
OH
(–)-β-conhydrine 1
(+)-β-conhydrine 2
N
N
OH
OH
OH
OH
(–)-lentiginosine 3
(+)-lentiginosine 4
* Corresponding author. E-mail address: ahmedkamal@iict.res.in (A. Kamal).
Fig. 1. 1-Hydroxy piperidine molecules.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.011

1342
A. Kamal, S.R. Vangala / Tetrahedron 67 (2011) 1341e1347
practically simple and high yielding reactions for the synthesis of
both (ꢀ)- -conhydrine 1 and (ꢀ)-lentiginosine 3 starting from
-mannitol.
511a and 1412 could be prepared from optically active
using known protocols. This could be an effective route for the
preparation of (ꢀ)- -conhydrine 1 and (ꢀ)-lentiginosine 3.
D-mannitol by
b
D
b
2. Result and discussions
2.2. Synthesis of (L)-
b-conhydrine (Scheme 2)
2.1. Retrosynthetic analysis
Our journey for the synthesis of (ꢀ)-b-conhydrine 1 began with
(2R,3S)-3-(benzyloxy)-4-pentene-1,2-diol 5, which was obtained by
using a known protocol.11a Compound 5 was exposed to Lindlar’s
catalyst that results in the saturation of double bond in EtOAc to
provide diol 6 in quantitative yield. The oxirane formation was ach-
ieved by the selective tosylation of the primary hydroxyl group in 6
using Martinelli standard conditions13 employing p-toluenesulfonyl
chloride, dibutyltin oxide, and trimethylamine in CH2Cl2 to afford the
monoprotected tosylate of 6. Then the crude tosylate was taken up for
the cyclization step using K2CO3 in methanol to afford the epoxide 716
in an excellent yield. This epoxide 7, on treatment with 2-(2-propy-
nyloxy)tetrahydro-2H-pyran (25) in the presence of n-BuLi and
BF3$Et2O in THF at ꢀ78 ꢁC for 3 h, afforded 8. Compound 8 was ex-
posed to Lindlar’s catalyst that results in the saturation of triple bond
in EtOAc to provide 9 in 95% yield. The secondary alcohol of the
compound 9 was converted to the corresponding tosylated com-
pound 10 by using p-toluenesulfonyl chloride and pyridine. The crude
compound 10 was then subjected to nucleophilic displacement with
NaN3 in DMF at 60 ꢁC to furnish the corresponding azide 11 in 72%
yield (for two steps). Deprotection of the THP group in compound 11
was carried out by using PTSA to afford 12. The primary alcohol in 12
wasconverted totosylate using p-toluenesulfonyl chloride and TEA to
give the corresponding tosylate compound 13. Finally, the target
molecule was achieved by the reduction of azide and deprotection of
benzyl group using PdeC/H2 in EtOAc and added one drop 30%
methanolic NaOH solution in the reaction mixture to give the desired
As per our retrosynthetic analysis (Scheme 1), the (ꢀ)-
b-conhy-
drine 1 could be easily obtained from the precursor 11, which inturn
could be synthesized from intermediate 5 via epoxide (7) and also
the (ꢀ)-lentiginosine 3 could be easily obtained from the precursor
22. Compound 22 could be prepared from 19 involving ring closing
metathesis and PdeC/H2 reduction for saturation of double bond
and compound 197c is expected to be obtained from 14. Whereas,
3
1
N3
NBoc
OTHP
OH
OBn
OH
11
22
NBoc
O
O
O
OBn
OH
19
7
(ꢀ)-
b-conhydrine 1 in 82% yield. The physical and spectroscopic data
of 1 were in agreement with those reported in the literature. How-
O
ever, this method has provided good overall yield with enhanced
HO
O
H
stereoselectivity of the target molecule, (ꢀ)-b-conhydrine 1.
O
OBn
5
14
2.3. Synthesis of (L)-lentiginosine 3 (Scheme 3)
D-Mannitol
Synthesis of (ꢀ)-lentiginosine 3 began with the Barbier allyla-
tion reaction on R-2,3-O-isopropylidene glyceraldehyde 14, using
Scheme 1. Retrosynthetic approach for (ꢀ)-
b-conhydrine 1 and (ꢀ)-lentiginosine 3.
OH
OH
O
c
b
a
D-Mannitol
OBn OH
OBn
d
OBn OH
7
5
6
OR
OH
N3
b
f
OTHP
OTHP
OTHP
OBn
OBn
OBn
8
11
9 R= H
e
10 R= OTs
g
N3
N3
i
h
HN
OH
OTs
OBn
12
OBn
OH
13
1
Scheme 2. Reaction conditions: (a) Ref. 11a; (b) Lindlar’s catalyst-H2, ethanol, rt, 4 h, 95%; (c) p-toluenesulfonyl chloride, dibutyltin oxide, triethylamine, dry CH2Cl2, 0 ꢁC to rt, 4 h,
then K2CO3, MeOH, rt, 3 h, 92%; (d) 25, n-BuLi, BF3$Et2O, dry THF, ꢀ78 ꢁC, 3 h, 78%; (e) p-toluenesulfonyl chloride, pyridine, 0 ꢁC to rt, 16 h; (f) NaN3, DMF, 60 ꢁC, 14 h, 72% (for two
steps); (g) PTSA, MeOH, rt, 5 h, 96%; (h) p-toluenesulfonyl chloride, TEA, dry CH2Cl2, rt, 92%; (i) 10% PdeC/H2, EtOAc, one drop 30% NaOH, rt, 6 h, 85%.

A. Kamal, S.R. Vangala / Tetrahedron 67 (2011) 1341e1347
1343
N3
O
OR
Ref-12
D-Mannitol
a
b(2)
H
O
O
O
O
O
O
17
15 R=H
16 R=Ts
14
b(1)
c
NBoc
O
NBoc
O
NBoc
NHBoc
f
e
d
O
O
O
O
O
O
19
20
21
18
g
O
NBoc
N
NBoc
N
h
j
OH
i
OH
OEt
OH
OH
OH
OH
24
23
22
3
O
Scheme 3. Reaction conditions: (a) Zn, allyl bromide, THF, saturated aq NH4Cl, 0 ꢁC to rt, 8 h, 65%; (b) (1) p-toluenesulfonyl chloride, pyridine, 0 ꢁC to rt, 91% (2) NaN3, DMF,
60 ꢁC, 14 h, 85%; (c) (1) LiAlH4, THF, 0 ꢁC to rt, 1 h (2) 15% NaOH, (Boc)2O, 0 ꢁC to rt, 4 h, 88%; (d) NaH, allyl bromide, THF, saturated aq NH4Cl, 0 ꢁC to rt, 18 h, 85%; (e) first
generation Grubb’s catalyst, dry CH2Cl2, reflux, 8 h, 91%; (f) 10% PdeC/H2, EtOAc, rt, 6 h, 96%; (g) PTSA, MeOH, rt, 5 h, 85%; (h) (1) NaIO4, saturated aq NaHCO3, CH2Cl2, rt; (2)
Ph3P]CHCO2Et, dry C6H6, 50 ꢁC; (i) (1) AD-mix-
12 h, 84%.
b
, CH3SO2NH2, H2O:t-BuOH¼1:1, 0 ꢁC, 24 h; (2) TFA, rt, 10 h; (3) EtOH, reflux, 6 h, 62% (for three steps); (j) LiAlH4, THF, reflux,
Zn-allyl bromide at 0 ꢁC to give the homoallylic alcohol 157c with
good diastereoselectivity (syn-anti¼ 5:95). This alcohol was con-
verted to the corresponding tosylate 16 in excellent yield (91%) by
using p-toluenesulfonyl chloride and pyridine. This tosylated
compound 16 was then subjected to nucleophilic displacement
with NaN3 in DMF at 60 ꢁC to furnish the corresponding azide 17
in good yield (85%). Compound 17 was treated with LiAlH4, which
results in the reduction of the azide functionality to its corre-
sponding amine. The reaction mixture was then quenched with
10% NaOH solution and (Boc)2O was added immediately to convert
the amine to its N-Boc derivative 187c in 88% yield. This on ally-
lation with allyl bromide and NaH in THF at 0 ꢁC gave N-allyl
compound 19. The RCM of 19 in the presence of Grubb’s first
generation catalyst10hej,14 Cl2Ru(]CHPh)(Cy3)2 (5 mol %) in dry
CH2Cl2 at reflux condition proceeds to give compound 20, which
was exposed to PdeC/H2 that results in the saturation of double
bond in EtOAc to provide compound 21 in quantitative yield.
Deprotection of the primary acetonide in compound 21 with PTSA
in MeOH furnished the diol 2215 in good yield. This was treated
with NaIO4 in the presence of saturated NaHCO3 to give piperidine
carboxaldehyde, which on in situ Wittig olefination by using sta-
3. Conclusion
In conclusion, we report the asymmetric total synthesis of
(ꢀ)-
b
-conhydrine 1 and (ꢀ)-lentiginosine 3 from the commercially
available starting material
D
-mannitol in good overall yields. The
present method not only involves simple and high yielding re-
actions like reduction, nucleophilic addition, nucleophilic dis-
placement but could also provide an easy practical access to the
synthesis of a variety of structural analogues of (ꢀ)-
b-conhydrine 1
and (ꢀ)-lentiginosine 3 for evaluating their biological properties.
4. Experimental
4.1. General experimental
All reagents were purchased from Aldrich (SigmaeAldrich, St.
Louis, MO, USA). Reactions were monitored by TLC, performed on
silica gel glass plates containing 60 F-254. Column chromatography
was performed with Merck 60e120 mesh silica gel. IR spectra were
recorded on a PerkineElmer RX-1 FT-IR system. 1H NMR spectra
were recorded on a Bruker UXNMR/XWIN-NMR-300 MHz spec-
trometer. 13C NMR (75 MHz) spectra were recorded on Bruker
bilized ylide (Ph3P]CHCO2Et) gives a,b-unsaturated N-Boc piper-
idine 23 in good yield. The geometry of the newly formed double
bond was assigned by the detection of the Jtrans coupling constant
Avance-300 MHz spectrometer. Chemical shifts (d) are reported in
parts per million downfield from internal TMS standard. Peaks are
labeled as singlet (s), doublet (d), triplet (t), quartet (q), doublet
doublet (dd), doublet doublet doublet (ddd), triplet doublet (td),
and multiplet (m). ESI spectra were recorded on Micro mass,
Quattro LC using ESIþ software with capillary voltage 3.98 kV and
ESI mode positive ion trap detector. Optical rotations were mea-
sured with Horiba-SEPA-300 digital polarimeter.
(15.86 Hz between the protons at
d 5.73 and 6.81, respectively).
This was then taken up for the stereoselective incorporation of
hydroxyl groups via a Sharpless asymmetric dihydroxylation. The
enantioselective Sharpless asymmetric dihydroxylation of
a,b-
unsaturated N-Boc piperidine 23 with ADmix , in t-BuOH/H2O
b
(1:1) provided the diol. This was further treated with TFA without
purification for deprotection of Boc group, followed by refluxing
the crude compound in EtOH to furnish indolizidinone 2417 in 62%
yield (for three steps). The reduction of the carbonyl group in
indolizidinone 24 was carried out by using LiAlH4 to give 3 in 84%
yield. The physical and spectroscopic data of 3 were in agreement
with those reported in the literature. However, this method has
provided good overall yield with enhanced stereoselectivity of the
target molecule, (ꢀ)-lentiginosine 3.
4.1.1. (2R,3S)-3-(Benzyloxy)pentane-1,2-diol (6). A mixture of com-
pound 5 (2 g, 9.62 mmol) and Lindlar’s catalyst (50 mg) in dry
ethanol (20 mL) was stirred under hydrogen atmosphere at room
temperature for 4 h. The reaction mixture was filtered through
Celite and the solvent evaporated in vacuo to give the crude
product, which was purified by column chromatography (hexane/
EtOAc, 7:3) to give compound 6 (1.92 g, 95%) as a syrup. [
a
]
27 þ21 (c
D

1344
A. Kamal, S.R. Vangala / Tetrahedron 67 (2011) 1341e1347
1, CHCl3); 1H NMR (300 MHz, CDCl3):
d
7.39e7.25 (5H, m, AreH),
reaction, the reaction mixture was filtered through Celite and the
4.72e4.45 (2H, m, PhCH2), 3.79e3.55 (3H, m, CH2OH, and CHOH),
3.54e3.39 (1H, m, CHOBn), 2.74e2.04 (2H, br s, OH), 1.82e1.50 (2H,
m, CH2CH3),1.00 (3H, t, J 7.5 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3):
solvent evaporated in vacuo to give the crude product, which was
purified by column chromatography (hexane/EtOAc, 94:6) to afford
compound 9 (1.93 g, 95%) as colorless oil. [
a
]
35 þ4.9 (c 1.5, CHCl3);
D
d
138.22, 128.45, 127.91, 127.72, 82.32, 72.65, 72.22, 63.63, 23.05,
1H NMR (300 MHz, CDCl3):
d
7.45e7.25 (5H, m, AreH), 4.72e4.46
9.62; IR (CHCl3, cmꢀ1): nmax 3410, 2966, 2931, 2877, 1713, 1455,
1274, 1070, 1024, 701 cmꢀ1; ESI: m/z 233.2 (MþþNa); HRMS (ESI):
m/z calcd for C12H18O3Na: 233.1153; found: 233.1158.
(3H, m, PhCH2, and THP-H), 3.92e3.73 (2H, m, OCH2CH2),
3.52e3.36 (2H, m, THP-H), 3.32e3.25 (1H, m, CHOH), 3.24e3.19
(1H, m, CHOBn), 1.96e1.33 (14H, m, OCH2(CH2)3CH, CH2CH3, and
THP-H), 1.05e0.93 (3H, q, J 7.38 Hz, CH2CH3); 13C NMR (75 MHz,
4.1.2. (R)-2-((S)-1-(benzyloxy)propyl)oxirane (7). To a stirred solu-
tion of compound 6 (2 g, 9.52 mmol), dibutyltin oxide (35 mg,
0.05 mmol), and Et3N (1.37 mL, 9.52 mmol) in dry CH2Cl2, p-tolue-
nesulfonyl chloride (1.82 g, 9.52 mmol) was added at 0 ꢁC under N2
atmosphere. On completion of reaction after stirring for 4 h at room
temperature, water was added and the reaction mixture was
extracted with CH2Cl2. The organic extract was washed with water,
brine, and dried over anhydrous Na2SO4. Removal of solvent under
reduced pressure afforded a crude mass, which was used for next
step without any purification. To the monotosylate derivative of 6 in
dry MeOH (25 mL), anhydrous K2CO3 (3.94 g, 28.57 mmol) was added
under N2 atmosphere and stirred for 3 h. On completion of reaction,
MeOH was evaporated under reduced pressure keeping the tem-
perature below 30 ꢁC. The residue was redissolved in CH2Cl2, washed
with water, brine, and dried over anhydrous Na2SO4. Removal of
solvent under reduced pressure afforded a residue, which on puri-
fication with silica gel column chromatography (hexane/EtOAc, 9:1)
CDCl3): d 128.31, 127.83, 127.77, 127.62, 98.82, 83.69, 72.03, 71.55,
67.45, 62.27, 31.74, 30.72, 29.71, 25.43, 22.89, 21.62, 19.63, 10.24; IR
(CHCl3, cmꢀ1): nmax 3467, 2941, 2871, 1454, 1119, 1075, 1027, 904,
754, 698, 666 cmꢀ1; MS (ESI) m/z: 359 (MþþNa); HRMS (ESI): m/z
calcd for C20H32O4Na: 359.2198; found: 359.2192.
4.1.5. 2-((5S,6S)-5-Azido-6-(benzyloxy)octyloxy)-tetrahydro-2H-py-
ran (11). To a stirred solution of compound 9 (1 g, 2.97 mmol) in
dry CH2Cl2 (10 mL), excess of pyridine (6 mL) was added at room
temperature and the reaction mixture was cooled to 0 ꢁC. p-Tol-
uenesulfonyl chloride (0.57 g, 2.97 mmol) was added and the re-
action mixture was stirred for 16 h at room temperature. After
completion of the reaction, the solvent was removed under reduced
pressure to obtain crude tosylate 10. To the crude tosylate 10 (3 g,
9.2 mmol) in dry DMF (10 mL) was added NaN3 (0.24 g, 3.57 mmol).
This heterogeneous mixture was stirred at 60 ꢁC for 14 h, and then
it was cooled to room temperature followed by addition of water
(20 mL), and extraction with ether (3ꢂ30 mL). The combined or-
ganic layer was washed with brine solution and dried over anhy-
drous Na2SO4, evaporated, and the residue obtained was purified by
silica gel column chromatography (hexane/EtOAc, 96:4) to afford
afforded epoxide 7 (1.68 g, 92%) as a colorless liquid. [
a
]
35 þ5.6 (c 1.5,
D
CHCl3); 1H NMR (300 MHz, CDCl3):
d
7.42e7.25 (5H, m, AreH),
4.66e4.48 (2H, m, PhCH2), 3.22e3.18 (1H, m, CHOBn), 2.95e2.92 (1H,
m, OCH), 2.79e2.77 (1H, m, OCH2CH), 2.72e2.69 (1H, m, OCH2CH),
1.81e1.54 (2H, m, CH2CH3), 1.1 (3H, t, J 7.2 Hz, CH2CH3); 13C NMR
azide 11 (0.80 g, 72%) as a colorless liquid. [
a
]
35 ꢀ21.6 (c 1.5, CHCl3);
D
(75 MHz, CDCl3):
d
129.81, 128.21, 127.77, 127.65, 82.23, 72.42, 70.21,
1H NMR (300 MHz, CDCl3):
d
7.41e7.26 (5H, m, AreH), 4.68e4.53
63.92, 23.45, 9.62; IR (CHCl3, cmꢀ1): nmax 2966, 2924, 2361, 1455,
1071, 1028, 847, 737, 698 cmꢀ1; MS (ESI) m/z: 215(MþþNa); HRMS
(ESI): m/z calcd for C12H16O2Na: 215.1047; found: 215.1047.
(3H, m, PhCH2, and THP-H), 3.89e3.83 (1H, m, CHOBn), 3.83e3.71
(1H, m, CHN3), 3.56e3.26 (4H, m, OCH2CH2, and THP-H), 1.91e1.34
(14H, m, OCH2(CH2)3CH, CH2CH3, and THP-H), 1.02e0.91 (3H, q, J
7.18 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3):
d 128.31,127.79,127.73,
4.1.3. (3S,4R)-3-(Benzyloxy)-8-(tetrahydro-2H-pyran-2-yloxy)oct-6-
yn-4-ol (8). To a stirred solution of 25 (1.28 g, 9.98 mmol) in dry THF
(40 mL), n-BuLi (5.96 mL, 9.98 mmol, 1.6 N hexane solution) was
added drop wise under N2 atmosphere at ꢀ78 ꢁC and stirred for
30 min. To this reaction mixture, BF3.OEt2 (1.17 mL, 8.33 mmol) was
added, followed by a solution of compound 7 (1.6 g, 8.33 mmol) in
dry THF (10 mL) after 10 min interval and the resulting solution
stirred for an additional 3 h at ꢀ78 ꢁC. After completion of reaction,
the reaction was quenched with saturated NaHCO3 solution (20 mL)
and saturated NH4Cl solution (20 mL) at ꢀ78 ꢁC and allowedtowarm
to room temperature. The reaction mixture was extracted with
EtOAc (3ꢂ50 mL), washed with water (2ꢂ20 mL), dried over Na2SO4,
evaporated, and the residue obtained was purified by silica gel col-
umn chromatography (EtOAc/hexane, 1.5:8.5) to furnish 8 (2.1 g,
127.58, 98.88, 82.44, 72.51, 67.21, 64.13, 62.32, 30.69, 30.07, 29.45,
25.3, 23.51, 23.22, 19.62, 9.57; IR (CHCl3, cmꢀ1): nmax 2941, 2869,
2101, 1454, 1262, 1120, 1077, 1033, 736, 697 cmꢀ1; MS (ESI) m/z: 384
(MþþNa); HRMS (ESI): m/z calcd for C20H31N3O3Na: 384.2263;
found: 384.2251.
4.1.6. (5S,6S)-5-Azido-6-(benzyloxy)octan-1-ol (12). A mixture of
compound 11 (0.5 g, 1.38 mmol) and PTSA (12 mg, 5 mol %) in
MeOH (10 mL) was stirred at room temperature for 5 h. After
completion of reaction saturated NaHCO3 solution was added and
stirred for additional 15 min followed by removal of the solvent
under reduced pressure. The residual compound was redissolved in
CH2Cl2 and the organic layer was washed with water, brine and
dried over anhydrous Na2SO4. Removal of the solvent under re-
duced pressure followed by column chromatographic purification
78%) as a yellow liquid. [
a
]
35 þ7.5 (c 1.5, CHCl3); 1H NMR (300 MHz,
D
CDCl3):
d
7.41e7.25 (5H, m, AreH), 4.86e4.76 (1H, m, THP-H),
(hexane/EtOAc, 9:1) afforded a pure compound 12 (0.37 g, 96%) as
35
4.72e4.51 (2H, m, PhCH2), 4.32e4.18 (2H, m, OCH2C), 3.94e3.72 (2H,
m, THP-H), 3.59e3.39 (2H, m, CHOH, and CHOBn), 2.59e2.46 (1H, m,
CCH2CH), 2.46e2.41 (1H, m, CCH2CH), 1.94e1.54 (8H, m, CH2CH3,
and THP-H), 0.99e0.92 (3H, q, J 7.18 Hz, CH2CH3); 13C NMR (75 MHz,
a colorless thick liquid. [
(300 MHz, CDCl3):
a]
ꢀ22.1 (c 1.5, CHCl3); 1H NMR
D
d
7.36e7.25 (5H, m, AreH), 4.65e4.53 (2H, m,
PhCH2), 3.67e3.59 (2H, m, CH2OH), 3.45e3.25 (2H, m, CHOBn, and
CHN3), 1.71e1.34 (8H, m, CH(CH2)3OH, and CH2CH3), 0.99e0.92 (3H,
CDCl3):
d
128.32, 127.82, 127.77, 127.62, 96.84, 81.86, 81.25, 78.35,
q, J 7.36 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3):
d
128.28, 127.80,
72.25, 70.49, 61.96, 54.51, 30.22, 25.25, 23.03, 22.16, 19.02, 9.45; IR
(CHCl3, cmꢀ1): nmax 3423, 2941, 2875, 2203, 1454, 1116, 1074, 1023,
927, 902, 749, 698 cmꢀ1; MS (ESI) m/z: 355(MþþNa);HRMS (ESI): m/
z calcd for C20H28O4Na: 355.1885; found: 355.1879.
127.75, 127.59, 82.35, 72.47, 64.14, 62.45, 32.31, 29.96, 23.46, 22.65,
9.54; IR (CHCl3, cmꢀ1): nmax 3410, 2931, 2103, 1216, 1069, 758 cmꢀ1
;
MS (ESI) m/z: 300 (MþþNa); HRMS (ESI): m/z calcd for
C15H23N3O2Na: 300.1687; found: 300.1682.
4.1.4. (3S,4R)-3-(Benzyloxy)-8-(tetrahydro-2H-pyran-2-yloxy)octan-
4-ol (9). A mixture of compound 8 (2 g, 6.02 mmol) and Lindlar’s
catalyst (50 mg) in dry ethanol (20 mL) was stirred under a hy-
drogen atmosphere at room temperature for 4 h. On completion of
4.1.7. (5S,6S)-5-Azido-6-(benzyloxy)octyl 4-methylbenzenesulfonate
(13). To a stirred solution of compound 12 (0.250 g, 0.9 mmol) in
dry CH2Cl2 (5 mL) was added TEA (2 mL) at room temperature and
cooled to 0 ꢁC. p-Toluenesulfonyl chloride (0.19 g, 1 mmol) was

A. Kamal, S.R. Vangala / Tetrahedron 67 (2011) 1341e1347
1345
added and reaction mixture was stirred for 4 h at room tempera-
ture. After removal of the solvent under reduced pressure a residue
was obtained, which was purified by column chromatography
4.13e4.07 (1H, q, J 6.7 Hz, OCH2CH), 4.00e3.95 (1H, t, J 6.1 Hz, OCH),
3.79e3.74 (1H, q, J 6.7 Hz, OCH2CH), 3.22e3.16 (1H, q, J 6.7 Hz,
CHN3), 2.36e2.32 (2H, t, J 7.5 Hz, CHCH2CH), 1.45 (3H, s, CH3), 1.34
(hexane/EtOAc, 94:6) to give the tosylate compound 13 (350 mg,
(3H, s, CH3); 13C NMR (75 MHz, CDCl3):
d 133.3, 118.5, 109.9, 77.7,
35
92%) as a colorless liquid. [
a
]
ꢀ20.2 (c 1.5, CHCl3); 1H NMR
66.3, 62.5, 35.2, 26.4, 25.3; IR (CHCl3, cmꢀ1): nmax 2987, 2929, 2109,
1382, 1372, 1262, 1216, 1158, 1110, 1069, 995, 968, 923, 855, 814,
617 cmꢀ1; MS (ESI) m/z: 197 (Mþ); HRMS (ESI): m/z calcd for
C9H15N3O2Na: 220.1061; found: 220.1071.
D
(300 MHz, CDCl3):
d
7.81e7.75 (2H, d, J 8.31 Hz, AreH), 7.33e7.21
(7H, m, AreH), 4.64e4.49 (2H, m, PhCH2), 4.04e3.96 (2H, t, J
6.23 Hz, 0OCH2CH2), 3.36e3.25 (1H, m, CHOBn), 3.21e3.12 (1H, m,
CHN3), 2.45 (3H, s, PhCH3), 1.74e1.22 (8H, m, CH(CH2)3OH, and
CH2CH3), 1.01e0.89 (3H, q, J 7.36 Hz, CH2CH3); 13C NMR (75 MHz,
4.1.11. tert-Butyl (R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl) but-3-
enylcarbamate (18). To a stirred solution of compound 17 (1.40 g,
7.1 mmol) in THF (10 mL) was cooled to 0 ꢁC and added to LiAlH4
(0.27 g, 7.1 mmol). The reaction mixture was stirred for 1 h at room
temperature after which the reaction was quenched with 15%
NaOH solution at 0 ꢁC and (Boc)2O (1.55 g, 7.1 mmol) was imme-
diately added, then the reaction mixture was stirred for 4 h to
convert the amine into the N-Boc derivative 18. The resulting re-
action mixture filtered through a pad of Celite, and the solvent was
removed under reduced pressure. The residue was purified by
column chromatography (hexane/EtOAc, 9:1) to give compound 18
CDCl3):
d 144.71, 138.14, 132.99, 129.81, 128.32, 127.81, 127.69,
127.52, 82.26, 72.46, 70.12, 63.93, 29.55, 28.57, 23.41, 22.42, 21.58,
9.52; IR (CHCl3, cmꢀ1): nmax 2941, 2133, 1217, 1069, 778, 698 cmꢀ1
;
MS (ESI) m/z: 454 (MþþNa); HRMS (ESI): m/z calcd for
C22H29N3O4SNa: 454.1687; found: 454.1682.
4.1.8. (S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)but-3-en-1-ol
(15). To a stirred suspension of Zn (4.5 g, 69 mmol) in dry THF
(30 mL), a solution of R-2,3-O-isopropylidene glyceraldehyde 14
(3 g, 23 mmol) in dry THF (15 mL) was added and cooled to 0 ꢁC
under nitrogen atmosphere. After stirring at 0 ꢁC for 15 min, allyl
bromide (6 mL, 69 mmol) was added and the reaction mixture was
stirred for 8 h at room temperature. The reaction mass quenched
with saturated aq NH4Cl at 0 ꢁC and resulting reaction mixture was
filtered through a pad of Celite, followed by removal of the solvent
under reduced pressure. The residue was purified by column
(1.69 g, 88%) as a thick brown liquid. [
NMR (300 MHz, CDCl3):
a
]
27 þ29.7 (c 0.51, CHCl3); 1H
D
d
5.86e5.71 (1H, m, CH]CH2), 5.12e5.05
(2H, m, CH]CH2), 4.62e4.59 (1H, br s, NH), 4.16e4.08 (1H, t, J
9.4 Hz, OCH2CH), 3.97e3.93 (1H, t, J 6.6 Hz, OCH), 3.71e3.61 (2H, m,
OCH2CH, and CHNH), 2.33e2.27 (2H, t, J 7.1 Hz, CHCH2CH), 1.43 (9H,
s, C(CH3)3), 1.41 (3H, s, CH3), 1.32 (3H, s, CH3); 13C NMR (75 MHz,
chromatography (hexane/EtOAc, 9:1) to give compound 15 (2.85 g,
CDCl3): d 155.9, 134.7, 118.3, 109.2, 79.3, 76.4, 66.3, 50.2, 38.1, 28.4,
27
72%) as a pale yellow liquid. [
(300 MHz, CDCl3):
a
]
þ10.8 (c 0.5, CHCl3); 1H NMR
26.4, 25.2; IR (CHCl3, cmꢀ1): nmax 3415, 3078, 2971, 2925, 1665,
1460, 1410, 1365, 1254, 1164, 1040 cmꢀ1; MS (ESI) m/z: 294
(MþþNa); HRMS (ESI): m/z calcd for C14H25NO4Na: 294.1681;
found: 294.1687.
D
d
5.09e5.75 (1H, m, CH]CH2), 5.16e5.06 (2H, m,
CH]CH2), 3.99e3.83 (3H, m, OCH2CH, and OCH), 3.73e3.66 (1H, m,
CHOH), 2.35e2.31 (2H, m, CHCH2CH), 1.93 (1H, br s, OH), 1.39 (3H, s,
CH3), 1.32 (3H, s, CH3); 13C NMR (CDCl3):
d 134.5, 118.6, 109.5, 78.6,
70.5, 65.7, 38.1, 27.0, 25.7; IR (CHCl3, cmꢀ1): nmax 3688, 2989, 2936,
2360, 1376, 1217, 1066, 920 cmꢀ1; MS (ESI) m/z: 172 (Mþ).
4.1.12. tert-Butyl allyl((R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl) but-
3-enyl)carbamate (19). To a stirred suspension of NaH (0.26 g,
11 mmol) in dry THF (10 mL), a solution of 18 (1.5 g, 5.5 mmol) in dry
THF (5 mL) was added drop wise at 0 ꢁC under a nitrogen atmo-
sphere. The resulting solution was stirred for 15 min at room tem-
perature, allyl bromide (1.38 g,11 mmol) was added, and the reaction
mixture was stirred for 18 h. After completion of reaction, the re-
action mixture quenched with saturated aq NH4Cl at 0 ꢁC and
extracted with EtOAc (3ꢂ20 mL). The combined organic extracts
were washed with brine and dried over anhydrous Na2SO4, con-
centrated under reduced pressure, and purified by column chro-
matography (hexane/EtOAc, 95:5) to afford pure 19 (1.56 g, 91%) as
4.1.9. (S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)but-3-enyl 4-meth-
ylbenzenesulfonate (16). To a solution of compound 15 (2 g,
11.6 mmol) taken in dry CH2Cl2 (10 mL), were added p-toluene-
sulfonyl chloride (2.47 g, 13 mmol) and excess of pyridine (6 mL) at
room temperature. The reaction mixture then stirred for 16 h fol-
lowed by removal of the solvent under reduced pressure to give
a residue, which was purified by column chromatography (hexane/
EtOAc, 94:6) to give compound 16 (3.448 g, 91% yield) as a thick
yellow liquid. [
a
]
27 þ32.1 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3):
D
d
7.77e7.75 (2H, d, J 8.3 Hz, AreH), 7.33e7.28 (2H, d, J 8.3 Hz, AreH),
a thick yellow liquid. [
a
]
27 þ34.8 (c 0.55, CHCl3); 1H NMR (300 MHz,
D
5.75e5.53 (1H, m, CH]CH2), 5.15e4.96 (2H, m, CH]CH2),
4.58e4.46 (1H, q, J 6.7 Hz, CHOTs), 4.14e4.01 (1H, m, OCH2CH),
3.97e3.91 (1H, m, OCHCH), 3.77e3.71 (1H, m, OCH2CH), 2.45 (3H, s,
PhCH3), 2.41(2H, t, J 6.1, CHCH2CH), 1.30 (3H, s, CH3), 1.27 (3H, s,
CDCl3):
d
5.98e5.68 (2H, m, CH]CH2), 5.16e5.03 (4H, m, CH]CH2),
4.26e4.08 (2H, m, CHN, and OCH2CH), 4.01e3.96 (1H, q, J 6.7 Hz,
OCH), 3.83 (2H, d, J 5.2 Hz, CH2N), 3.63 (1H, t, J 8.3 Hz, OCH2CH),
2.53e2.04 (2H, m, CHCH2CH), 1.43 (9H, s, C(CH3)3), 1.40 (3H, s, CH3),
CH3); 13C NMR (75 MHz, CDCl3):
d
144.5, 131.7, 129.6, 127.8, 119.1,
1.32 (3H, s, CH3); 13C NMR (75 MHz, CDCl3):
d 154.6, 136.4, 134.9,
109.6, 96.1, 81.2, 75.1, 66.4, 35.6, 26.6, 25.2, 21.6; IR (CHCl3, cmꢀ1):
nmax 2986, 2934, 1642, 1598, 1453, 1367, 1256, 1215, 1178, 1069, 996,
902, 851, 814, 777, 668 cmꢀ1; MS (ESI) m/z: 349 (MþþNa); HRMS
(ESI): m/z calcd for C16H22O5NaS: 349.1085; found: 349.1076.
117.3, 115.7, 115.3, 79.5, 76.7, 67.2, 66.6, 48.2, 34.0, 28.3, 26.4, 25.2; IR
(CHCl3, cmꢀ1): nmax 3079, 2981, 2930, 1693, 1642, 1453, 1403, 1367,
1251, 1154, 1067, 993 cmꢀ1; MS (ESI) m/z: 312(MþþH); HRMS (ESI):
m/z calcd for C17H29NO4Na: 334.1994; found: 334.2010.
4.1.10. (S)-4-((R)-1-Azidobut-3-enyl)-2,2-dimethyl-1,3-dioxolane
(17). To a stirred solution of tosylate 16 (3 g, 9.2 mmol) in dry DMF
(15 mL) was added NaN3 (0.72 g, 11 mmol). This heterogeneous
mixture was stirred for 14 h at 60 ꢁC, cooled to room temperature
followed by addition of water (20 mL), and extraction with diethyl
ether (3ꢂ30 mL). The combined organic layer was washed with
brine solution and dried over anhydrous Na2SO4, evaporated, and
the residue obtained was purified by silica gel column chroma-
tography (hexane/EtOAc, 96:4) to give the azide 17 (1.54 g, 85%) as
4.1.13. (R)-tert-Butyl 6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-5,6-di-
hydropyridine-1(2H)-carboxylate (20). To a stirred solution of diene
19 (0.8 g, 2.57 mmol) in dry CH2Cl2 (20 mL) was added Grubbs’s first
generation catalyst (90 mg, 0.11 mmol, 0.1 equiv), the resulting
purple solution turned brown after 10 min. The reaction mixture
stirred for 8 h at reflux temperature, and concentrated in vacuo
obtained residue. The residue was purified by column chromatog-
raphy (hexane/EtOAc, 94:6) afford a pure compound 20 (0.67 g,
27
93%) as a dark brown oil. [
a
]
þ5.9 (c 0.2, CHCl3); 1H NMR
D
a pale yellow liquid. [
CDCl3):
a]
27 þ5.6 (c 0.05, CHCl3); 1H NMR (300 MHz,
(300 MHz, CDCl3):
d
5.85e5.68 (2H, m, CH]CH), 4.42e4.19 (3H, m,
D
d
5.9e5.75 (1H, m, CH]CH2), 5.23e5.13 (2H, m, CH]CH2),
OCH, OCH2CH, and CH2N), 4.18e3.99 (1H, t, J 8.1 Hz, CHN),

1346
A. Kamal, S.R. Vangala / Tetrahedron 67 (2011) 1341e1347
3.79e3.48 (2H, br s, OCH2CH, and CH2N), 2.51e2.42 (1H, dd, J 10.9,
5.1 Hz, CHCH2CH), 1.79e1.71 (1H, d, J 7..3 Hz, CHCH2CH), 1.47 (9H, s,
C(CH3)3), 1.43 (3H, s, CH3), 1.32 (3H, s, CH3); 13C NMR (75 MHz,
OCH2CH3), 3.99 (1H, d, J 10.8 Hz, CH2N), 2.82e2.7 (1H, t, J 12.6 Hz,
CH2N), 1.85e1.56 (6H, m, piperidine-H),1.44 (9H, s, C(CH3)3), 1.25e1.16
(3H, t, J 7.2 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3):
d 166.2. 154.9,
CDCl3):
d
155.1, 124.4, 122.1, 109.2, 79.3, 74.4, 67.2, 51.6, 40.8, 28.2,
147.4, 121.9, 79.7, 60.4, 51.6, 39.9, 28.8, 28.3, 25.2, 19.8, 14.2; IR (CHCl3,
cmꢀ1): nmax 2977, 2938, 1720, 1695, 15,882, 1408, 1306, 1266, 1163,
1043, 868, 771 cmꢀ1; MS (ESI) m/z: 306 (MþþNa); HRMS (ESI): m/z
calcd for C15H25NO4Na: 306.1681; found: 306.1669.
26.5, 25.8, 25.3; IR (CHCl3, cmꢀ1): nmax 2975, 1695, 1676, 1457, 1414,
1391, 1366, 1307, 1256, 1229, 1173, 1051, 1026, 977, 961 cmꢀ1; MS
(ESI) m/z: 306 (MþþNa); HRMS (ESI): m/z calcd for C15H25NO4Na:
306.1681; found: 306.1672.
4.1.17. (1R,2S,8aR)-1,2-Dihydroxy-hexahydroindolizin-3(5H)-one
4.1.14. (R)-tert-Butyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)piperidine-
1-carboxylate(21). A mixture of compound 20 (0.5 g,1.76 mmol) and
10% palladium on charcoal (0.04 g) in dry EtOAc (5 mL) was stirred
under a hydrogen atmosphere at room temperature for 6 h. The
reaction mixture was filtered through Celite and the solvent evap-
orated in vacuo to give the crude product, which was purified by
(24). To a solution of AD-mix-b (3.5 g) and CH3SO2NH2 (235 mg,
2.47 mmol) in t-BuOH/H2O¼1:1 (5 mL) was stirred for 10 min at
room temperature then cooled to 0 ꢁC and alkene 23 (0.7 g,
2.47 mmol) was added and stirred at 0 ꢁC. After 24 h, the reaction
mixture was quenched with sodiumsulfite, it was diluted with
EtOAc (20 mL), filtered through Celite and the filtrate was con-
centrated under reduced pressure to give a diol. This crude diol was
stirred in 10 mL of TFA for (Boc deprotection) 10 h and evaporated
TFA in vacuo followed by refluxing this mixture in ethanol for 6 h
gave indolizidinone, which was purified by flash column chroma-
flash chromatography (hexane/EtOAc, 95:5) to afford compound 21
27
(0.48 g, 95%) as colorless oil. [
a
]
þ4.8 (c 0.2, CHCl3); 1H NMR
D
(300 MHz, CDCl3):
d
4.39e4.33 (1H, q, J 7.5 Hz, OCH), 4.19e3.95 (3H,
m, OCH2CH, and CHN), 3.58 (1H, t, J 7.7 Hz, CH2N), 2.96 (1H, t, J
10.4 Hz, CH2N), 1.79e1.48 (6H, m, piperidine-H), 1.44 (9H, s, C(CH3)3),
tography (CHCl3/MeOH/Et3N, 30:68:2) to give pure indolizidinone
1.39 (3H, s, CH3), 1.32 (3H, s, CH3); 13C NMR (75 MHz, CDCl3):
d
155.3,
24 (0.24 g, 62%). [
a
]
D
ꢀ58.7 (c 0.5, MeOH); 1H NMR (300 MHz,
27
109.3, 79.2, 77.2, 74.9, 67.4, 39.9, 28.4, 26.6, 26.5, 25.6, 25.2, 19.8; IR
(CHCl3, cmꢀ1): nmax 3009, 2977, 2937, 2869, 1667, 1424, 1366, 1275,
1166, 1063, 1040, 869, 756 cmꢀ1; MS (ESI) m/z: 308 (MþþNa); HRMS
(ESI): m/z calcd for C15H27NO4Na: 308.1837; found: 308.1828.
CDCl3): d 5.30 (2H, br s, OH), 4.41e4.17 (1H, m, CHC]O), 4.12e4.07
(1H, t, J 7.2 Hz, COCHOH), 3.63e3.29 (1H, m, CHN), 2.76e2.54 (1H,
m, piperidine-H), 2.27e2.14 (1H, m, piperidine-H), 2.11e1.61 (4H,
m, piperidine-H), 1.49e1.21(2H, m, piperidine-H); 13C NMR
(75 MHz, CDCl3):
d 172.2, 80.1, 73.4, 58.8, 39.8, 25.6, 24.5, 22.9; IR
4.1.15. (R)-tert-Butyl 2-((S)-1,2-dihydroxyethyl)piperidine-1-carbox-
ylate (22). A mixture of compound 21 (1.0 g, 4.08 mmol) and PTSA
(40 mg, 5 mol %) in MeOH (10 mL) was stirred at room temperature
for 5 h. After completion of reaction saturated NaHCO3 solution was
added and stirred for additional 15 min followed by removal of the
solvent under reduced pressure. The residual compound was
redissolved in CH2Cl2 and the organic layer was washed with water,
brine and, dried over anhydrous Na2SO4. Removal of the solvent
under reduced pressure followed by column chromatographic pu-
(CHCl3, cmꢀ1): nmax 3352, 2987, 2950, 1682, 1474, 1457, 1203, 1182,
1132, 1035, 833, 801, 721 cmꢀ1; MS (ESI) m/z: 194 (MþþNa); HRMS
(ESI): m/z calcd for C8H13NO3Na: 194.0555; found: 194.0562.
4.1.18. (ꢀ)-
b-Conhydrine (1). To a solution of 13 (0.2 g, 0.464 mmol)
in ethanol (10 mL) was added 20 mg of 10% Pd/C and mixture was
stirred under a hydrogen atmosphere for 6 h then added one drop
30% methanolic NaOH solution in the reaction mixture. After
completion of reaction, the solution was filtered through Celite pad
and the filtrate was concentrated under reduced pressure. The
crude product was purified by column chromatography (CHCl3/
rification (hexane/EtOAc, 8:2) afford a pure compound 22 (0.73 g,
27
85%) as a light brown viscous liquid. [
a
]
þ27.1 (c 1, CHCl3); 1H
D
NMR (300 MHz, CDCl3):
d
4.23e4.05 (2H, br s, OH), 4.09e3.95 (1H,
MeOH, 97:3) to give the (ꢀ)-
b-conhydrine 1 as a white solid
27
q, J 7.2 Hz, OCH), 3.91e3.78 (2H, br s, OCH2CH, and CHN), 3.71e3.58
(1H, d, J 10.56 Hz, OCH2CH), 3.56e3.40 (1H, m, CH2N), 2.95e2.75
(1H, m, CH2N), 1.78e1.51 (6H, m, piperidine-H), 1.41 (9H, s, C
(0.056 g, 85%). Mp: 67e68 ꢁC {lit.9b mp 67 ꢁC} [
a
]
D
ꢀ34.5 (c 1,
20
CHCl3) {lit.9b
[
a]
¼ ꢀ34.1(c 0.4, CHCl3)}; 1H NMR (300 MHz,
D
CDCl3): d 3.18 (1H, td, J 7.8, 3.5 Hz, CHOH), 3.0e3.08 (1H, m, CHNH),
(CH3)3); 13C NMR (75 MHz, CDCl3):
d
157.1, 79.7, 70.8, 63.9, 51.6,
2.52 (1H, td, J 11.5, 2.7 Hz, CH2NH), 2.3 (1H, ddd, J 10.2, 7.5, 2.5 Hz,
CH2NH), 1.04e1.55 (8H, m, CH2CH3, and piperidine-H), 0.93 (3H, t, J
40.5, 28.2, 25.7, 24.9, 19.4; IR (CHCl3, cmꢀ1): nmax 3387, 2931, 2868,
1667, 1423, 1366, 1275, 1167, 1039, 925, 870, 770 cmꢀ1; MS (ESI) m/
z: 268 (MþþNa); HRMS (ESI): m/z calcd for C12H23NO4Na:
268.1524; found: 268.1529.
7.5 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3):
d 76.1, 61.3, 47, 29.7,
26.9. 25.0, 10.4; IR (Neat, cmꢀ1): nmax 3285, 2928, 2855, 1726, 1635,
1455, 1269, 1114, 976 cmꢀ1; MS (ESI) m/z: 144(Mþþ1); HRMS (EI):
m/z calcd for C8H18NO: 144.1025; found: 144.1022.
4.1.16. (R,E)-tert-Butyl 2-(3-ethoxy-3-oxoprop-1-enyl)piperidine-1-car-
boxylate (23). To a stirred solution of compound 22 (0.7 g, 2.85 mmol)
in CH2Cl2 (20 mL) was cooled to 0 ꢁC and sequentially added saturated
aq NaHCO3 (0.2 mL) and NaIO4 (0.73 g, 3.42 mmol) portion wise. The
reaction mixture stirred for 1 h at room temperature, after completion
of reaction the reaction mass was filtered through anhydrous Na2SO4
bed. The filtrate was concentrated under reduced presser to afford the
corresponding crude aldehyde, which was subjected to Witting ole-
fination without purification. To a solution of aldehyde in dry benzene
(20 mL) was added Ph3P]CHCO2Et (1 g, 3.0 mmol) and the reaction
mixture was stirred at 50 ꢁC for 6 h. After completion of the reaction,
reaction mixture was cooled to 25 ꢁC, extracted with EtOAc
(3ꢂ50 mL), washed with water, brine and dried over anhydrous
Na2SO4, and concentrated under reduced pressure to give the crude
product, which was then purified by column chromatography (hex-
4.1.19. (ꢀ)-Lentiginosine 3. To
a stirred solution of (100 mg,
0.584 mmol) of indolizidinone 24 in THF (10 mL) at 0 ꢁC was added
LiAlH4 (44 mg, 1.16 mmol). The suspended mixture was stirred at
reflux temperature for 12 h, cooled to 0 ꢁC, diluted with 2 mL of
THF, and then carefully treated successively with water and 10% aq
NaOH. The resulting mixture was stirred for 1 h and filtered
through pad Celite; filtrate was dried with anhydrous Na2SO4, and
concentrated under reduced pressure. The crude residue was then
purified by column chromatography on silica gel (CHCl3/MeOH,
8:2) to give 76 mg of pure target molecule 3 as a colorless solid 84%.
Mp 106e108 ꢁC [lit.10f mp 106e107 ꢁC]; [
1H NMR (300 MHz, D2O):
a
]
D
27 ꢀ3.1 (c 0. 5, MeOH);
d
4.07e4.03 (1H, ddd, J 7.1, 3.5, 2.4 Hz,
CHCHCH), 3.63e3.57 (1H, dd, J 8.4, 3.5 Hz, OCHCH2), 2.95e2.77 (2H,
br d, J 10.5 Hz, CHCH2N), 2.71e2.61 (1H, dd, J 7.1, 3.5 Hz, CHN),
2.07e1.96 (1H, m, piperidine-H), 1.94e1.76 (2H, m, piperidine-H),
1.71e1.53 (2H, m, piperidine-H), 1.47e1.25 (2H, m, piperidine-H),
ane/EtOAc, 9:1) over to give the unsaturated ester 23 (0.72 g, 90% for
27
two steps) as a gum. [
a
]
þ3.7 (c 0.25, CHCl3); 1H NMR (300 MHz,
D
CDCl3):
d
6.84e6.77 (1H, dd, J 15.8, 3.9 Hz, olefin), 5.76e5.69 (1H, dd, J
1.22e1.09 (1H, m, piperidine-H); 13C NMR (75 MHz, D2O):
d
82.2,
15.8, 2.7 Hz, olefin), 4.80 (1H, s, CHN), 4.16e4.07 (2H, q, J 7.2 Hz,
75.0, 68.1, 59.7, 52.2, 27.1, 23.5, 26.6; IR (CHCl3, cmꢀ1): nmax 3351,

A. Kamal, S.R. Vangala / Tetrahedron 67 (2011) 1341e1347
1347
3113, 2930, 2852, 1557, 1442, 1141, 1115, 1042, 995 cmꢀ1; MS (ESI)
m/z: 158 (MþþH); HRMS (ESI): m/z calcd for C8H16NO2: 158.0942;
found: 158.0944.
Xie, J.-H.; Li, W.; Kong, W.-L.; Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2009, 11,
4994e4997.
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2008, 19, 746e750; (b) Angle, S. R.; Bensa, D.; Belanger, D. S. J. Org. Chem. 2007,
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