A divergent and stereoselective approach for the syntheses of some polyhydroxylated indolizidine and pyrrolizidine iminosugars

Article abstract of DOI:10.1002/ejoc.201201342

A common, divergent, and efficient approach to the syntheses of (+)-steviamine (9), (-)-1-deoxy-8a-epi-castanospermine (10), (+)-trihydroxyindolizidine (11), (+)-3,7a-di-epi-hyacinthacine A1 (12), and (-)-2-epi-lentiginosine (4) was achieved by starting from D-ribose-derived intermediate 13. The key steps involved in these syntheses are a highly diasteroselective Grignard addition to a ribosylimine, a one-pot stereoselective intramolecular reductive amination, a selectve deprotection of a silyl ether, and a ring-closing metathesis (RCM) reaction. A divergent approach to synthesize small molecules is a challenging task for synthetic chemists, but it is needed for examining structure-activity relationships. We report the syntheses of (+)-steviamine (9), (-)-1-deoxy-8a-epi-castanospermine (10), (+)-trihydroxyindolizidine (11), (+)-3,7a-di-epi-hyacinthacine A1 (12), and (-)-2-epi-lentiginosine (4) from D-ribose-derived N-glycosylamine 13. Copyright

Full text of DOI:10.1002/ejoc.201201342

FULL PAPER
DOI: 10.1002/ejoc.201201342
A Divergent and Stereoselective Approach for the Syntheses of Some
Polyhydroxylated Indolizidine and Pyrrolizidine Iminosugars
Anugula Rajender,[a] Jalagam Prasada Rao,[a] and Batchu Venkateswara Rao*[a]
Keywords: Natural products / Azasugars / Nitrogen heterocycles / Total synthesis / Diastereoselectivity
A common, divergent, and efficient approach to the synthe-
ses of (+)-steviamine (9), (–)-1-deoxy-8a-epi-castanosperm-
The key steps involved in these syntheses are a highly di-
asteroselective Grignard addition to a ribosylimine, a one-
ine (10), (+)-trihydroxyindolizidine (11), (+)-3,7a-di-epi-hya- pot stereoselective intramolecular reductive amination, a
cinthacine A1 (12), and (–)-2-epi-lentiginosine (4) was
achieved by starting from D-ribose-derived intermediate 13.
selectve deprotection of a silyl ether, and a ring-closing
metathesis (RCM) reaction.
Introduction
Iminosugars (azasugars or iminocyclitols) are small mo-
lecules of both synthetic and natural origin that mimic
carbohydrates in biological systems. Structurally, they are
the nitrogen analogues of monosaccharides, in which the
oxygen atom in the ring is replaced by a nitrogen atom.
Iminosugars are important in their ability to inhibit glyco-
processing enzymes,[1] which play an important role in sev-
eral metabolic processes.[2] The polyhydroxylated indolizid-
ines and pyrrolizidines (see Figure 1) belong to a class of
iminosugars that are known for their interesting therapeutic
applications.[3]
The natural product (–)-steviamine (1) is the first exam-
ple of this new class of indolizidine alkaloids that inhibits
the α-galactosaminidase (GalNAcase) enzyme[4] and may
be used for the treatment of Schindler/Kanzaki disease.[5]
Interestingly, the synthetic compound (+)-steviamine (9)
was found to inhibit the α-rhamnosidase enzyme.[4] In-
hibitiors of this enzyme are potential therapeutic agents for
the treatment of bacillary dysentery, cancer,[6a] tuberculosis,
and leprosy.[6b]
Figure 1. Some naturally occurring polyhydroxylated indolizidine
and pyrrolizidine alkaloids.
(+)-Castanospermine (2) and its congeners play a pivotal
role in inhibiting the progression of multiple sclerosis,[7]
cancer,[8] and diabetes.[9] (+)-Hyacinthacine A1 (5),[10] (–)-
swainsonine (3), and its isomers[11] are known for their gly-
cosidase inhibitory activity. (–)-Swainsonine (3) has also
been screened for the treatment of life-threatening diseases
such as HIV, cancer, and immunological disorders.[12]
(–)-2-epi-Lentiginosine (4) is a potent inhibitor of α-man-
nosidase and has an IC50 value of 4.6 μm.[13] The synthetic
compound (–)-trihyroxyindolizidine (11) was found to be a
selective inhibitor of rat intestinal sucrase.[14] Because of the
interesting biological activities of these iminosugars, numer-
ous synthetic approaches have been developed, thus far,
that use different strategies.[15,16] Herein, we present a diver-
gent and highly stereoselective approach for the syntheses
of various polyhydroxylated indolizidine and pyrrolizidine
iminosugars (see Figure 2). A divergent approach to synthe-
size small molecules is a challenging task for the synthetic
chemists. This approach provides a number of diverse mo-
lecules in a few short steps, which is a great help for a drug
discovery program.
[a] Organic and Biomolecular Chemistry Division, CSIR – Indian
Institute of Chemical Technology,
Hyderabad 500607, India
Fax: +91-040-27193003
E-mail: venky@iict.res.in
drb.venky@gmail.com
Homepage: http://www.iictindia.org/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201342.
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A. Rajender, J. P. Rao, B. V. Rao
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the (E) isomer of α,β-unsaturated ketone 17 (see Scheme 2).
Next, we successfully carried out a one-pot stereoselective
intramolecular reductive amination[20] and selective depro-
tection of the triethylsilyl (TES) group[21] by using 10% Pd/
C and ammonium formate in methanol at reflux to give
piperidine derivative 18.[22] The secondary alcohol in 18 was
treated with MsCl and pyridine to give a mesylated com-
pound, which then underwent an intramolecular SN2 reac-
tion to afford indolizidine 19 in 70% yield.[23] The synthesis
of steviamine (9) was achieved by treatment of compound
19 with aqueous HCl in methanol, which was followed by
Figure 2. Iminosugars synthesized from 14.
In the course of developing synthetic approaches towards
these biologically active compounds,[17] we recently commu-
nicated a flexible and highly stereoselective method for the
syntheses of erythro isomers 14[18] and 15[19] (see Scheme 1)
through a Grignard addition to N-glycosylamine 13. In this
publication, we present some logical functional group ma-
nipulations of 14 and 15 to construct different indolizidine
and pyrrolizidine rings (see Figure 2).
Scheme 1. Synthesis of key intermediates 14 and 15 from d-ribose
(TBS = tert-butyldimethylsilyl).
Results and Discussion
We envisaged the syntheses of steviamine (9), 1-deoxy-
8a-epi-castanospermine (10), indolizidine 11, 3,7a-di-epi-
Scheme 2. Synthesis of compounds 9, 10, and 12 starting from 14.
Reagents and conditions: (a) see ref.[18]; (b) (i) O3, CH2Cl2, –78 °C
hyacinthacine A1 (12), and 2-epi-lentiginosine (4) to start and then Me2S, 0 °C, 2 h; (ii) Ph3P=CHCOCH3, toluene, reflux,
85% (over two steps); (c) HCOONH4, 10% Pd/C, MeOH, reflux,
3 h, 80%; (d) pyridine, MsCl, room temp., 3 h, 70%; (e) HCl (6 m),
from intermediate 14 and an alternative synthesis of 12 to
start from key intermediate 15.
MeOH, r.t. for 9 and reflux for 10, 12 h, 90% for 9 and 90% for
For the synthesis of steviamine (9, see Figure 2), the
10; (f) CbzCl, NaHCO3, MeOH, 0 °C to r.t., 2 h, 90%; (g) MOMCl
amino functionality in 14 was converted to N(Bn)Cbz de-
rivative 16 (Cbz = benzyloxycarbonyl) by using our earlier
procedure.[18] The ozonolysis of the terminal olefin in 16
afforded an aldehyde. The crude aldehyde was subjected to
a Wittig olefination by treating with Ph3P=CHCOCH3 in
(MOM = methoxymethyl), N,N-diisopropylethylamine (DIPEA),
4-(dimethylamino)pyridine (DMAP), CH2Cl2, 0 °C to r.t., 95%;
(h) BH3·Me2S, tetrahydrofuran (THF), 0 °C to r.t., 2 h, then
NaOH, H2O2, 0 °C, 2 h, 86% for 22 and 80% for 25; (i) Bu4NF,
THF, r.t., 10 min, 95%; (j) (i) MsCl, NEt3, CH2Cl2, DMAP, 0 °C,
15 min, (ii) 10% Pd/C, H2, MeOH, 12 h, 90% for 24 and 86% for
toluene and heating the reaction mixture at reflux to afford 26 (over two steps).
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Polyhydroxylated Indolizidines and Pyrrolizidines
purification by ion-exchange chromatography. The analyti-
cal data of compound 9 was in good accordance with the
reported values.[4]
1-Deoxy-8a-epi-castanospermine (10) is a synthetically
known analogue of castanospermine (2).[24] To synthesize
compound 10, compound 14 was treated with CbzCl and
NaHCO3 in MeOH to furnish carbamate 20 in 90% yield.
Masking of the secondary alcohol in 20 as a MOM ether
by using MOMCl and DIPEA in CH2Cl2 afforded 21 in
95% yield. Hydroboration/oxidation of the terminal olefin
in 21 was carried out by treatment with BH3·Me2S in THF
and then treatment with NaOH/H2O2 to provide the de-
sired primary alcohol 22 in 86% yield. Cleavage of the silyl
ether in 22 by using Bu4NF afforded diol 23 in a good yield.
Mesylation of the diol functionality in 23 by treatment with
MsCl, NEt3, and DMAP in CH2Cl2 provided the dimesyl
product, which upon hydrogenolysis with 10% Pd/C in
methanol gave indolizidine derivative 24 in 90% yield. Fi-
nally, the removal of the isopropylidene acetal and MOM
ether group in 24 was accomplished by adding aqueous HCl
in methanol and heating at reflux. Purification of the result-
ant salt by an ion-exchange resin afforded the desired final
product 10 in 90% yield. The spectral and physical data
for 10 were in good agreement with the reported values.[24]
Compound 20 was treated with BH3·Me2S in THF, which
was followed by treatment with NaOH/H2O2 to afford diol
25 in 80% yield. Mesylation of diol 25 with MsCl and pyr-
idine gave the dimesyl derivative, which was immediately
subjected to hydrogenolysis with H2 in presence of 10% Pd/
C in methanol to give the desired pyrrolizidine 26 in 86%
yield. The conversion of pyrrolidine 26 into 3,7a-di-epi-hya-
cinthacine A1 (12) is reported in the literature.[25]
Scheme 3. Syntheses of compounds 4 and 11 from 14 and com-
pound 12 from 15. Reagents and conditions: (a) allyl bromide,
K2CO3, CH3CN, reflux, 12 h, 75% for 27, 70% for 32; (b) 10 mol-
% Grubbs first-generation catalyst, CH2Cl2, reflux, 12 h, 80% for
28, 85% for 33; (c) (i) 10% Pd/C, H2, MeOH, cat. NaHCO3, 12 h;
(ii) MsCl, pyridine, r.t., 2 h, 74% for 29, 68% for 26 (over two
steps); (d) HCl (6 m), r.t., 12 h, 85%; (e) Bu4NF, THF, r.t., 1 h,
85%; (f) (i) SiO2/NaIO4, CH2Cl2/H2O (4:1), 0 °C, 30 min; (ii) 10%
Our next goal was to synthesize compounds 11, 12, and
4 under ring-closing metathesis (RCM)[26] conditions (see
Scheme 3). To obtain the diene precursors for the prepara- Pd/C, H2, MeOH, 12 h, 55% (over two steps).
tion of the pyrrolizidine and indolizidine rings, the amino
group in 14 and 15 underwent a chemoselective allylation
by using allyl bromide and K2CO3 in CH3CN and heating
at reflux to furnish diene precursors 27 and 32 in 75 and
70% yield, respectively. Diene 27 and 32 were then sub-
jected to an olefin metathesis by using 10 mol-% of the first-
generation Grubbs catalyst in CH2Cl2 and heating at reflux
to afford 28 and 33 in 80 and 85% yield, respectively. Hy-
drogenolysis of 28 and 33 by using 10% Pd/C in MeOH and
then mesylation with MsCl in pyridine gave compounds 29
and 26, respectively, in good yields. Finally, compound 29
was globally deprotected by treatment with aqueous HCl.
Filtration of the resultant reaction mixture through ion-ex-
change chromatography gave indolizidine 11. The spectral
and physical data for 11 were in good agreement with the
reported values.[14]
pound 31 were in good agreement with the reported val-
ues.[28] The conversion of the compound 31 into (–)-2-epi-
lentiginosine (4) is reported in the literature.[28]
Conclusions
We have successfully demonstrated our aforementioned
strategy for the syntheses of different bicyclic iminosugars
(see Figure 2) by using inexpensive and readily available d-
ribose as the starting material. The key features of this
strategy are its high diastereoselectivity, the stereocontrolled
nucleophilic Grignard addition to a N-glycosylamine, a
one-pot stereoselective intramolecular reductive amination,
a selective silyl ether deprotection, a selective mesylation, a
cyclization, and a RCM. This strategy provides the desired
products in good yields and is also useful for building a
library of compounds with improved therapeutic activities.
To synthesize (–)-2-epi-lentiginosine (4, see Scheme 3),
compound 28 was treated with Bu4NF in THF to afford
diol 30 in 85% yield. The oxidative cleavage of diol 30 by
using silica-supported sodium periodate[27] in CH2Cl2/H2O
(4:1) gave an aldehyde, which upon hydrogenation with
catalytic 10% Pd/C in MeOH afforded bicyclic indolizidine
Experimental Section
General Methods: The moisture- and oxygen-sensitive reactions
31 in 55% yield. The spectral and physical data of com- were carried out under nitrogen in flame- or oven-dried glassware
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A. Rajender, J. P. Rao, B. V. Rao
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with magnetic stirring. Standard techniques were used to purify the
solvents and reagents prior to use. Solutions were dried with
Na2SO4 and then concentrated under reduced pressure. TLC was
performed with Merck Kiesel gel 60, F254 plates (layer thickness
0.25 mm). Column chromatography was performed with silica gel
(60–120 and 100–200 mesh), and ethyl acetate and hexane were
used as the eluents. Melting points were determined with a Fisher
Johns melting point apparatus. IR spectra were recorded with a
Perkin–Elmer RX-1 FTIR system. The 1H NMR (300 and
reflux for 2 h. The solvent was removed under reduced pressure to
give the crude product, which was purified by silica gel column
chromatography (8% ethyl acetate in hexane) to yield the (E) iso-
mer of α,β-unsaturated ketone 17 (0.9 g, 85% yield) as a thick col-
orless syrup. [α]2D6 = –8.6 (c = 0.23, CHCl ). IR (neat): νmax = 2985,
˜
3
2932, 1697 (NCOOCH2Ph), 1497, 1370, 1251, 1067, 985, 836, 748,
1
698 cm–1. H NMR (500 MHz, CDCl3, major rotamer): δ = 7.45–
7.10 (m, 10 H, 2 Ph), 6.65 (m, 1 H, -CH=CHCOCH3), 5.70 (d, J
= 15.8 Hz, 1 H, -CH=CHCOCH3 ), 5.41–4.79 (m, 2 H,
500 MHz) and 13C NMR (75 and 100 MHz) spectroscopic data NCOOCH2Ph), 4.77–4.48 (m, 2 H, -NCH2Ph), 4.36–4.15 (m, 3 H,
were recorded with Bruker Avance-300 and Varian-400 instru-
ments. Chemical shifts were reported in ppm with respect to TMS
as the internal standard. 1H NMR spectroscopic data are reported
as chemical shifts in ppm, which is followed by multiplicity [singlet
5-H and -CH2OTBS), 4.08–3.52 (m, 3 H, 4-H, -CHOTES, and
NCHCH2CH=CH), 2.62–2.32 (m, 2 H, -CH2CH=CH), 2.09 (s, 3
H, COCH3), 1.44 (s, 3 H, CH3), 1.22 (s, 3 H, CH3), 1.02–0.88 [m,
9 H, Si(CH2CH3)3], 0.89 (s, 9 H, tBuSi), 0.75–0.50 [m, 6 H,
(s), doublet (d), triplet (t), quartet (q), and multiplet (m)], number Si(CH2)3], 0.10–0.01 (m, 6 H, SiMe2) ppm. 13C NMR (75 MHz,
of proton(s), and coupling constants (J, in Hz). Optical rotations
were measured with a JASCO digital polarimeter. Accurate mass
measurements were performed with a Q STAR mass spectrometer
(Applied Biosystems, USA).
CDCl3, major rotamer): δ = 198.5 (COCH3), 156.7 (NCOOPh),
146.1 (-CH=CHCOCH3), 139.5 (Cq-Ph), 136.4 (Cq-Ph), 132.8
(-CH=CHCOCH3), 128.4, 128.2, 128.0, 127.7, 127.3, 126.7 (Ph),
107.7 [(CH3)2C(O)2], 79.5 (C-5), 76.8 (C-4), 72.1 (-CH2OTBS), 67.1
(-CHOTES), 64.7 (NCOOCH2Ph), 55.7 (NCHCH2CH=CH), 46.7
(NCH2Ph), 33.2 (CH2CH=CH), 26.1 (COCH3), 25.9 (CH3), 24.4
(CH3), 18.2 [SiC(CH3)3], 6.8 [Si(CH2CH3)3], 4.9 [Si(CH2CH3)3],
–5.5 (SiCH3) ppm. MS (ESI): m/z = 748 [M + Na]+. HRMS (ESI):
calcd. for C40H63NO7NaSi2 [M + H]+ 748.40353; found 748.40426.
(R)-1-{(4R,5S)-5-[(S)-1-(Benzylamino)allyl]-2,2-dimethyl-1,3-di-
oxolan-4-yl}-2-(tert-butyldimethylsilyloxy)ethanol (15): To a solu-
tion of N-glycosylamine 13 (2 g, 4.75 mmol) in dry THF (10 mL)
was added dropwise vinylmagnesium bromide (1.0 m solution in
THF, 23.7 mL) at –78 °C under nitrogen. The reaction mixture was
warmed to room temp., and after stirring at r.t. for 2 h, the mixture
was quenched with a saturated solution of NH4Cl. The resulting
solution was extracted with ethyl acetate (2ϫ50 mL). The com-
bined organic layers were washed with brine, dried with anhydrous
Na2SO4, and concentrated in vacuo. The resulting crude material
was purified by silica gel column chromatography (10% ethyl acet-
ate in hexane) to give compound 15 (1.54 g, 72% yield) as a syrup.
(R)-2-(tert-Butyldimethylsilyloxy)-1-{(4R,5S)-2,2-dimethyl-5-
[(2S,6S)-6-methylpiperidin-2-yl]-1,3-dioxolan-4-yl}ethanol (18): To a
solution of α,β-unsaturated ketone 17 (0.50 g, 0.68 mmol) in
MeOH (10 mL) were added 10% Pd/C (10 mg) and ammonium
formate (0.17 g, 2.72 mmol), and the resulting solution was heated
at reflux for 3 h. After completion of the reaction, the mixture was
filtered through a pad of Celite, which was then washed with
MeOH (2ϫ10 mL). The filtrate was concentrated by using a rotary
evaporator, and purification of the crude residue by silica gel col-
[α]2D6 = –12.6 (c = 1.3, CHCl ). IR (neat): ν
= 2931, 2857, 1459,
˜
3
max
1379, 1214, 1068, 916, 836, 750, 667 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 7.36–7.17 (m, 5 H, Ph), 5.69 (m, 1 H, -CH=CH2), 5.36 umn chromatography (30% ethyl acetate in hexane) afforded 18
(d, J = 10.1 Hz, 1 H, -CH=CH2), 5.18 (d, J = 17.2 Hz, 1 H, (0.2 g, 80% yield) as a thick colorless syrup. [α]2D6 = +35.8 (c = 0.66,
-CH=CH2), 4.16 (dd, J = 5.5, 9.6 Hz, 1 H, 5-H), 3.91 (dd, J = 5.5,
9.6 Hz, 1 H, 4-H), 3.85 (dd, J = 2.0, 10.5 Hz, 1 H, CH2OTBS),
3.82 (d, J = 12.1 Hz, 1 H, NCH2Ph), 3.72 (dd, J = 2.0, 10.5 Hz, 1
CHCl ). IR (neat): νmax = 3437, 2924, 1450, 1379, 1215, 1066, 868,
˜
3
769, 667 cm–1. 1H NMR (500 MHz, CDCl3): δ = 3.98 (dd, J = 4.9,
10.3 Hz, 1 H, 5-H), 3.79–3.71 (m, 2 H, -CH2OTBS), 3.59 (dd, J =
H, -CH2OTBS), 3.60 (d, J = 12.1 Hz, 1 H, NCH2Ph), 3.60 [m, 1 4.9, 10.3 Hz, 1 H, 4-H), 3.52 [m, 1 H, -CH(OH)CH2OTBS], 2.82
H, -CH(OH)CH2OTBS], 3.32 (t, J = 9.6 Hz, 1 H, -NCHCH=CH2), (ddd, J = 1.9, 10.3 Hz, 1 H, NCHCH2CH2-), 2.60 [m, 1 H,
1.35 (s, 3 H, CH3), 1.28 (s, 3 H, CH3), 0.92 (s, 9 H, tBuSi), 0.09 (s, NCH(CH3)], 1.91–1.76 [m, 2 H, NCH(CH3)CH2- and NCHCH2-],
6 H, SiMe2) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.1
(-CH=CH2), 136.3 (Cq-Ph), 128.8, 128.6, 127.5 (Ph), 118.6
1.62 (m, 1 H, NCHCH2CH2-), 1.40 [m, 1 H, NCH(CH3)CH2-],
1.27 (s, 3 H, CH3), 1.20 (s, 3 H, CH3), 1.05 (m, 1 H, NCHCH2CH2-),
(-CH=CH2), 108.5 [(CH3)2C(O)2], 79.2 (C-5), 77.2 (C-4), 69.4 1.01 (d, J = 6.4 Hz, 3 H, 10-H), 0.96–0.86 (m, 1 H, NCHCH2-),
(-CH2OTBS), 65.0 [-CH(OH)CH2OTBS], 60.7 (NCHCH=CH2), 0.83 (s, 9 H, tBuSi), 0.01 (s, 6 H, SiMe2) ppm. 13C NMR (75 MHz,
50.6 (-NCH2Ph), 27.8 (-CH3), 26.0 [-SiC(CH3)3], 25.6 (-CH3), 18.5 CDCl3): δ = 107.7 [(CH3)2C(O)2], 80.5 (C-5), 77.3 (C-4), 69.9
[-SiC(CH3)3], –5.2 (-SiCH3), –5.3 (-SiCH3) ppm. MS (ESI): m/z =
422 [M + H]+. HRMS (ESI): calcd. for C23H40NO4Si [M + H]+
422.27102; found 422.2711.
[-CH(OH)CH2OTBS], 65.3 (CH2OTBS), 56.1 [NCH(CH3)CH2-],
5 1 . 7 ( N C H C H 2 C H 2 - ) , 3 4 . 4 [ N C H ( C H 3 ) C H 2 - ] , 2 9 . 5
(NCHCH2CH2-), 27.9 (NCHCH2CH2-), 26.0 [SiC(CH3)3], 25.3
(CH3), 24.0 (CH3), 22.5 [NCH(CH3)], 18.6 [SiC(CH3)3], –5.2
(SiCH3) ppm. MS (ESI): m/z = 374 [M + H]+. HRMS (ESI): calcd.
for C19H40NO4Si [M + H]+ 374.27177; found 374.27211.
Benzyl Benzyl[(S,E)-1-{(4S,5S)-5-[(R)-3,3-diethyl-8,8,9,9-tetra-
methyl-4,7-dioxa-3,8-disiladecan-5-yl]-2,2-dimethyl-1,3-dioxolan-4-
yl}-5-oxohex-3-enyl]carbamate (17): Through a solution of terminal
olefin 16 (1.0 g, 1.46 mmol) in CH2Cl2 (15 mL) at –78 °C was
passed ozone gas for 20 min (until the solution changed to light
blue). The reaction mixture was treated with dimethyl sulfide
(0.52 mL, 7.3 mmol) at –78 °C and then stirred for another 30 min.
The reaction mixture was extracted with CH2Cl2 (2ϫ50 mL), and
the combined organic layers were washed with brine and dried with
the anhydrous Na2SO4. The organic layers were concentrated under
reduced pressure to obtain the crude aldehyde, which was used in
the next step without purification. To the solution of the crude
aldehyde in dry toluene (10 mL) was added Ph3P=CHCOCH3
(0.69 g, 2.19 mmol) at r.t., and the reaction mixture was heated at
(3aR,4S,6S,9aS,9bS)-4-[(tert-Butyldimethylsilyloxy)methyl]-2,2,6-tri-
methyloctahydro[1,3]dioxolo[4,5-a]indolizidine (19): To a stirred
solution of compound 18 (0.1 g, 0.26 mmol) in pyridine (5 mL) was
added dropwise MsCl (0.03 mL, 0.40 mmol), and the reaction mix-
ture was stirred at r.t. for 12 h. The solvent was evaporated under
reduced pressure, and the resulting crude material was purified by
column chromatography (20% ethyl acetate in hexane) to give bicy-
clic indolizidine 19 (0.068 g, 70% yield). [α]2D6 = +16.9 (c = 1.88,
CHCl ). IR (neat): ν
= 2920, 2851, 1464, 1214, 743, 667 cm–1.
max
˜
3
1H NMR (500 MHz, CDCl3): δ = 4.69 (dd, J = 5.4, 7.3 Hz, 1 H,
1-H), 4.20 (dd, J = 5.4, 7.3 Hz, 1 H, 2-H), 3.89 (m, 1 H,
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Eur. J. Org. Chem. 2013, 1749–1757

Polyhydroxylated Indolizidines and Pyrrolizidines
-CH2OTBS), 3.75–3.63 (m, 2 H, -CH2OTBS and 3-H), 2.88 (m, 1 (1.51 mL, 8.40 mmol), MOMCl (0.34 mL, 4.20 mmol), and a cata-
H, 8a-H), 2.62 (m, 1 H, 5-H), 2.00 (m, 1 H, 6-Ha), 1.72 (m, 1 H, lytic amount of DMAP at 0 °C. The resulting mixture was warmed
6-Hb), 1.66–1.51 (m, 2 H, 8-Ha and 8-Hb), 1.45 (s, 3 H, CH3), 1.30 to r.t. and then stirred overnight. After completion of reaction,
(s, 3 H, CH3), 1.29–1.0 (m, 2 H, 7-Ha and 7-Hb), 1.17 (d, J =
5.8 Hz, 3 H, 5a-H), 0.90 (s, 9 H, tBuSi), 0.06 (s, 6 H, SiMe2) ppm.
water and brine solution were added to the reaction mixture. The
organic layer was separated, dried with anhydrous NaSO4, and
13C NMR (75 MHz, CDCl3): δ = 113.6 [(CH3)2C(O)2], 84.3 (C-1), then concentrated in vacuo. The residue was purified by silica gel
77.9 (C-2), 63.1 (C-8a), 61.4 (C-3), 58.1 (-CH2OTBS), 52.6 (C-5),
column chromatography (3 % ethyl acetate and hexane) to give
34.4 (C-7), 30.3 (C-8), 25.9 [SiC(CH3)3 and CH3], 24.5 (CH3), 23.9 MOM ether 21 (0.82 g, 95% yield) as a thick, syrupy liquid. [α]2D6
(C-7), 20.7 (C-5a), 18.2 [SiC(CH3)3], –5.5 (SiCH3) ppm. MS (ESI):
m/z = 356 [M + H]+. HRMS (ESI): calcd. for C19H38NO3Si [M +
H]+ 356.26203; found 356.26155.
= –20.1 (c = 0.12, CHCl ). IR (neat): ν
= 2929, 2855, 1697
˜
3
max
(NCOOCH2Ph), 1458, 1369, 1214, 1102, 770, 667 cm–1. H NMR
(300 MHz, CDCl3, major rotamer): δ = 7.47–7.05 (m, 10 H, 2 Ph),
5.72 (m, 1 H, -CH=CH2), 5.06 (s, 2 H, NCOOCH2Ph), 5.01–4.74
(m, 6 H, -CH=CH2, -NCH2Ph, and -OCH2OCH3), 4.48–4.20 (m,
3 H, and 5-H, 4-H, and CH2OTBS), 4.10–3.62 (m, 2 H, and
NCHCH2CH=CH2), 3.45 (s, 3 H, OCH2OCH3), 3.22 (s, 1 H,
-CHOMOM), 2.50–2.01 (m, 2 H, -CH2CH=CH2), 1.42 (s, 3 H,
CH3), 1.22 (s, 3 H, CH3), 0.90 (s, 9 H, tBuSi), 0.07 (s, 6 H,
SiMe2) ppm. 13C NMR (75 MHz, CDCl3, major rotamer): δ =
157.0 (NCOOCH2Ph), 139.7 (Cq-Ph), 136.4 (-CH=CH2), 135.2
(Cq-Ph), 128.5, 128.3, 128.2, 127.6, 127.1, 126.5 (Ph), 116.9
(-CH=CH2), 108.0 [(CH3)2C(O)2], 96.9 (OCH2OCH3), 79.6 (C-5),
77.4 (C-4), 74.8 (-CHOMOM), 67.6 (NCOOCH2Ph), 62.7
(-CH2OTBS), 55.9 (OCH2OCH3), 55.4 (NCHCH2CH=CH2), 46.8
(NCH2Ph), 33.6 (-CH2CH=CH2), 26.1 (CH3), 25.8 [SiC(CH3)3],
24.3 (CH3), 18.3 [SiC(CH3)3], –5.5 (SiCH3) ppm. MS (ESI): m/z =
614 [M + H]+. HRMS (ESI): calcd. for C34H52NO7Si [M + H]+
614.35361; found 614.35076.
1
(1S,2R,3S,5R,8aS)-Octahydro-3-(hydroxymethyl)-5-methylindol-
izidine-1,2-diol (9): Aqueous HCl (6 m solution, 1 mL) was added
to compound 19 (0.05 g, 014 mmol) in MeOH (2 mL) at room
temp. The reaction mixture was stirred for 12 h and then concen-
trated in vacuo. The residue was dissolved in a small amount of
distilled water, and the resulting solution was neutralized with
aqueous NaOH (2 m solution). The crude product was purified by
an acid resin column [DOWEX 50WX8, 100–200 mesh, distilled
water and then NH4OH (1 m solution)] to give 9 (0.025 g, 90%
yield) as a yellow oil. [α]2D6 = –32.4 (c = 1.0, MeOH); ref.[4] [α]2D2
–34.0 (c = 1.0, MeOH). IR (neat): ν = 3316, 2943, 2831, 1449,
=
˜
max
1
1219 cm–1. H NMR (300 MHz, D2O): δ = 4.27 (t, J = 7.2 Hz, 1
H, 1-H), 3.98–3.80 (m, 2 H, -CH2OTBS), 3.73 (t, J = 6.6 Hz, 1 H,
2-H), 3.48 (m, 1 H, 3-H), 2.82 (m, 1 H, 5-H), 2.65 (m, 1 H, 8a-H),
1.92 (m, 1 H, 8-Ha), 1.79–1.60 (m, 2 H, 6-Ha and 7-Ha), 1.40–1.14
(m, 3 H, 6-Hb, 8-Hb, and 7-Hb), 1.09 (d, J = 6.0 Hz, 3 H, 5a-
H) ppm. 13C NMR (75 MHz, D2O): δ = 73.2 (C-1), 68.5 (C-2), 66.2
(C-3), 60.7 (-CH2OTBS), 56.0 (C-5), 52.4 (C-8a), 32.5 (C-6), 28.4
(C-8), 22.9 (C-7), 18.5 (C-5a) ppm. MS (ESI): m/z = 202
[M + H]+. HRMS (ESI): calcd. for C10H20NO3 [M + H]+
202.14479; found 202.14377.
Benzyl Benzyl[(S)-1-{(4S,5S)-2,2-dimethyl-5-[(R)-8,8,9,9-tetra-
methyl-2,4,7-trioxa-8-siladecan-5-yl]-1,3-dioxolan-4-yl}-4-
hydroxybutyl]carbamate (22): To a solution of olefin 21 (0.70 g,
1.14 mmol) in dry THF was added BH3·Me2S (0.16 mL,
1.71 mmol) dropwise at 0 °C, and the stirring was continued for 2 h
at room temp. The resulting solution was quenched by the addition
of NaOH (10% aqueous solution, 3 mL) and then by H2O2 (30%
solution, 2 mL) at 0 °C, and the resulting mixture was stirred for
another 2 h. Water (10 mL) was added to the reaction mixture, and
the resulting mixture was extracted with ethyl acetate (20 mL). The
organic layer was washed with brine, and the solvent was evapo-
rated on a rotary evaporator. The crude product was purified by
silica gel column chromatography (15% ethyl acetate in hexane) to
afford 22 (0.62 g, 86% yield) as a syrup. [α]2D6 = –31.8 (c = 1.33,
Benzyl Benzyl[(S)-1-{(4S,5R)-5-[(R)-2-(tert-butyldimethylsilyloxy)-
1-hydroxyethyl]-2,2-dimethyl-1,3-dioxolan-4-yl}but-3-enyl]carb-
amate (20): To a stirred suspension of N-benzyl compound 14
(1.0 g, 2.30 mmol) in MeOH (10 mL) were added NaHCO3 (0.77 g,
9.20 mmol) and CbzCl (0.39 mL, 2.76 mmol) at 0 °C. The reaction
mixture was warmed to r.t., was stirred for 2 h, and then was fil-
tered through a pad of Celite. The filtrate was concentrated in
vacuo. The residue was purified by column chromatography (5%
ethyl acetate in hexane) to afford 20 (1.18 g, 90% yield) as a thick
CHCl ). IR (neat): νmax = 3457, 2935, 2856, 1695 (NCOOCH2Ph),
˜
3
colorless liquid. [α]2D6 = +2.1 (c = 0.59, CHCl ). IR (neat): ν
=
1256, 1102, 835, 699 cm–1. 1H NMR (300 MHz, CDCl3, major rot-
amer): δ = 7.44–7.07 (m, 10 H, 2 Ph), 5.12 (s, 2 H, NCOOCH2Ph),
4.73–4.43 (m, 3 H, OCH2OCH3 and 5-H), 4.33 (s, 2 H, -NCH2Ph),
4.03 (m, 1 H, 4-H) 3.86–3.33 (m, 5 H, -CH2OTBS, -CH2OH, and
-CHOMOM) 3.45 (s, 3 H, -OCH3), 3.24 (m, 1 H, NCHCH2-),
1.72–1.20 [m, 4 H, -(CH2)2CH2OH], 1.39 (s, 3 H, CH3), 1.19 (s, 3
H, CH3), 0.86 (s, 9 H, tBuSi), 0.06–0.01 (m, 6 H, SiMe2) ppm.
1 3 C NMR (75 MHz, CDCl3 , major rotamer): δ = 157.2
(NCOOCH2Ph), 139.8 (Cq-Ph), 136.2 (Cq-Ph), 128.4, 128.3, 128.1,
127.9, 127.4, 126.8, 126.6 (Ph), 108.0 [(CH3)2C(O)2], 96.8
(OCH2OCH3), 79.9 (C-5), 77.2 (C-4), 74.9 (-CHOMOM), 67.1
(NCOOCH2Ph), 62.7 (-CH2OH), 62.3 (-CH2OTBS), 55.9
(OCH2 OCH3 ), 55.6 (NCHCH2-), 46.6 (-NCH2 Ph), 28.7
(NCHCH2-), 26.1 (CH3), 25.8 [SiC(CH3)3], 25.2 (NCHCH2CH2-),
24.5 (CH3), 18.2 [SiC(CH3)3], –5.5 (SiCH3) ppm. MS (ESI): m/z =
632 [M + H]+. HRMS (ESI): calcd. for C34H54NO8Si [M + H]+
632.36400; found 632.36132.
˜
3
max
3483, 2930, 1692 (NCOOCH2Ph), 1456, 1369, 1213, 1059, 910, 834,
751, 696 cm–1. 1H NMR (500 MHz, CDCl3, major rotamer): δ =
7.49–7.01 (m, 10 H, 2 Ph), 5.84–5.48 (m, 1 H, -CH=CH2), 5.25–
4.74 (m, 5 H, -CH=CH2, NCOOCH2Ph, and 5-H), 4.69–4.40 (m,
2 H, -NCH2Ph), 4.27 (m, 1 H, 4-H), 3.98–3.52 [m, 4 H, -CH2OTBS,
-CH(OH)CH2OTBS, and NCHCH2CH=CH2], 2.75 (br. s, 1 H,
OH), 2.50–2.10 (m, 2 H, NCHCH2CH=CH2), 1.37 (s, 3 H, CH3),
1.22 (s, 3 H, CH3), 0.90 (s, 9 H, tBuSi), 0.07 (s, 6 H, SiMe2) ppm.
13C NMR (125 MHz, CDCl3): δ = 157.1 (NCOOPh), 139.5
(Cq-Ph), 135.1 (-CH=CH2), 127.9, 127.7, 127.1, 126.5 (Ph), 116.7
(-CH=CH2), 108.1 [(CH3)2C(O)2], 79.6 (C-5), 69.1 (C-4), 67.1
[NCOOCH2Ph and -CH(OH)CH2OTBS], 64.6 (-CH2OTBS), 54.7
(NCHCH2), 46.8 (NCH2Ph), 33.6 (CH2CH=CH2), 26.8 (CH3),
25.8 [SiC(CH3)3], 24.6 (CH3), 18.2 [SiC(CH3)3], –5.4 (SiCH3), –5.4
(SiCH3) ppm. MS (ESI): m/z = 570 [M + H]+. HRMS (ESI): calcd.
for C32H48NO6Si [M + H]+ 570.32699; found 570.32454.
Benzyl Benzyl[(S)-1-{(4S,5S)-2,2-dimethyl-5-[(R)-8,8,9,9-tetra-
Benzyl Benzyl[(S)-4-hydroxy-1-{(4S,5S)-5-[(R)-2-hydroxy-1-(meth-
methyl-2,4,7-trioxa-8-siladecan-5-yl]-1,3-dioxolan-4-yl}but-3-enyl]- oxymethoxy)ethyl]-2,2-dimethyl-1,3-dioxolan-4-yl}butyl]carbamate
carbamate (21): To the solution of alcohol 20 (0.80 g, 1.40 mmol) in
dichloromethane (10 mL) were added N,N-diisopropylethylamine
(23): To a stirred solution of 22 (0.5 g, 0.79 mmol) in THF (5 mL)
was added Bu4NF (1.0 m solution in THF, 0.79 mL) at room temp.
Eur. J. Org. Chem. 2013, 1749–1757
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1753

A. Rajender, J. P. Rao, B. V. Rao
FULL PAPER
The reaction mixture was stirred for 1 h and then was concentrated.
The resulting crude compound was purified by column chromatog-
raphy (60% ethyl acetate in hexane) to provide diol 23 (0.39 g, 95%
yield) as a thick colorless liquid. [α]2D6 = –1.77 (c = 0.33, CHCl3).
(m, 1 H, 8a-H), 2.61 (m, 1 H, 5-Hb), 2.54 (m, 1 H, 3-Hb), 2.03 (m,
1 H, 1-Ha), 1.89–1.70 (m, 2 H, 2-Ha and 1-Hb), 1.47 (m, 1 H, 2-
Hb) ppm. 13C NMR (75 MHz, D2O): δ = 74.0 (C-8), 73.7 (C-7),
70.0 (C-6), 64.8 (C-8a), 55.7 (C-5), 52.6 (C-3), 29.3 (C-1), 23.3 (C-
2) ppm. MS (ESI): m/z = 174 [M + H]+. HRMS (ESI): calcd. for
C8H16NO3 [M + H]+ 174.11285; found 174.11247.
IR (neat): ν
= 3447, 2927, 1691 (NCOOCH2Ph), 1454, 1211,
˜
max
1112, 1067, 700 cm–1 1H NMR (300 MHz, CDCl3, major rot-
.
amer): δ = 7.51–7.15 (m, 10 H, 2 Ph), 5.16 (s, 2 H, NCOOCH2Ph),
4.80–4.51 (m, 4 H, -NCH2Ph and -OCH2OCH3), 4.29 (dd, J = 3.0,
6.7 Hz, 1 H, 5-H), 4.03 (dd, J = 3.0, 6.7 Hz, 1 H, 4-H), 3.91 (m, 1
H, -CHOMOM), 3.73 (m, 1 H, -CH2OH), 3.68–3.47 [m, 3 H,
-CH(MOM)CH2OH and -CH2OH], 3.44 (s, 3 H, OCH2OCH3),
3.35 (m, 1 H, NCHCH2-), 1.80–1.20 [m, 4 H, -(CH2)2CH2OH],
1.42 (s, 3 H, CH3), 1.22 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
CDCl3, major rotamer): δ = 157.4 (NCOOCH2Ph), 139.8 (Cq-Ph),
136.2 (Cq-Ph), 128.7, 128.4, 128.0, 127.4, 126.9 (Ph), 108.4
[(CH3)2C(O)2], 97.3 (OCH2OCH3), 80.7 (C-5), 79.6 (C-4), 76.2
(-CHOMOM), 67.6 (NCOOCH2Ph), 64.3 [-CH(MOM)CH2OH],
62.4 (-CH2OH), 55.9 (OCH2OCH3), 55.2 (NCHCH2-), 46.5
(NCH2Ph), 29.0 (NCHCH2-), 26.2 (CH3), 25.4 (NCHCH2CH2-),
24.4 (CH3) ppm. MS (ESI): m/z = 540 [M + Na]+. HRMS (ESI):
calcd. for C28H39NO8Na [M + Na]+ 540.25853; found 540.25679.
Benzyl Benzyl[(S)-1-{(4S,5R)-5-[(R)-2-(tert-butyldimethylsilyloxy)-
1-hydroxyethyl]-2,2-dimethyl-1,3-dioxolan-4-yl}-4-hydroxybutyl]-
carbamate (25): Compound 25 was prepared using the procedure
developed for the preparation of compound 22. The crude product
was purified by silica gel chromatography (17% ethyl acetate in
hexane) to yield 25 (80% yield). [α]2D6 = –18.14 (c = 2.76, CHCl3).
IR (neat): ν
= 3445, 2929, 2857, 1681 (NCOOCH2Ph), 1460,
˜
max
1374, 1254, 1058, 836, 775, 697 cm–1. 1H NMR (500 MHz, CDCl3,
major rotamer): δ = 7.49–7.01 (m, 10 H, 2 Ph), 5.28–4.91 (m, 3 H,
NCOOCH2Ph and OH), 4.65 (s, 2 H, CH2Ph), 4.30 (m, 1 H, 5-H),
3.96 (m, 1 H, 4-H), 3.81–3.56 (m, 4 H, -CH2OH, and -CH2OTBS),
3.55–3.29 [m, 2 H, -CH(OH)CH2OTBS and NCHCH2-], 1.84–1.38
[m, 4 H, -(CH2)2CH2OH], 1.36 (s, 3 H, CH3), 1.10 (s, 3 H, CH3),
0.90 (s, 9 H, tBuSi), 0.08 (s, 6 H, SiMe2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 157.3 (NCOOCH2Ph), 139.5 (Cq-Ph), 136.2 (Cq-Ph),
128.2, 128.0, 127.9, 127.8, 127.1, 126.5 (Ph), 108.0 [(CH3)2C(O)2],
80.0 (C-5), 76.1 (C-4), 69.0 (-NCOOCH2Ph), 67.3 [-CH(OH)-
CH2OTBS], 64.1 (-CH2OTBS), 61.3 (-CH2OH), 53.7 (NCHCH2-),
46.5 (-NCH2Ph), 28.3 (-CH2CH2OH), 27.0 (CH3), 25.8 [SiC-
(CH3)3], 24.6 (CH3), 23.9 (NCHCH2-), 18.2 [SiC(CH3)3], –5.5
(SiCH3), –5.4 (SiCH3) ppm. MS (ESI): m/z = 588 [M + H]+.
HRMS (ESI): calcd. for C32H50NO7Si [M + H]+ 588.33435; found
588.33511.
(3aR,4R,9aS,9bS)-4-(Methoxymethoxy)-2,2-dimethyloctahydro-
[1,3]dioxolo[4,5-g]indolizidine (24): To a solution of diol 23 (0.3 g,
0.58 mol) in dry CH2Cl2 (4 mL) were added NEt3 (0.20 mL,
1.45 mmol), MsCl (0.06 mL, 0.87 mmol), and a catalytic amount
of DMAP at 0 °C. The reaction mixture was stirred for 15 min
at 0 °C. The organic layer was washed with brine, separated, and
concentrated in vacuo. The crude dimesylated product was sub-
jected to hydrogenation by using 10 % Pd/C (30 mg) in MeOH
(5 mL), as the reaction mixture was stirred for 12 h. The mixture
was filtered through a pad of Celite, which was then washed with
MeOH (2ϫ10 mL). The filtrate was concentrated, and the crude
residue was purified by silica gel column chromatography (80%
ethyl acetate in hexane) to give bicyclic indolizidine 24 (0.145 g,
90% yield) as a colorless liquid. [α]2D6 = +20.05 (c = 0.71, CHCl3).
(3aR,4S,8aS,8bS)-4-[(tert-Butyldimethylsilyloxy)methyl]-2,2-di-
methylhexahydro-3aH-[1,3]dioxolo[4,5-a]pyrrolizidine (26): Com-
pound 26 was prepared using the procedure developed for the prep-
aration of compound 24. The crude product was purified by col-
umn chromatography (20% ethyl acetate in hexane) to give com-
pound 26 as a yellow oil (86% yield). [α]2D6 = +26.90 (c = 1.44,
IR (neat): ν
= 2932, 2822, 1217, 1041, 755 cm–1 1H NMR
.
˜
max
CHCl3); ref.[25] [α]2D5 = +29.7 (c = 0.209, CHCl ). IR (neat): ν
=
˜
3
max
(300 MHz, CDCl3): δ = 4.78 (s, 2 H, OCH2OCH3), 4.42 (dd, J =
4.5, 8.3 Hz, 1 H, 8-H), 4.04 (ddd, J = 5.3, 10.2 Hz, 1 H, 6-H), 3.87
(dd, J = 4.5, 8.3 Hz, 1 H, 7-H), 3.42 (s, 3 H, OCH2OCH3), 3.10
(dd, J = 5.3, 10.2 Hz, 1 H, 5-Ha), 3.05 (ddd, J = 2.6, 10.2 Hz, 1 H,
3-Ha), 2.39–2.00 (m, 4 H, 8a-H, 5-Hb, 1-Ha, and 2-Ha), 1.93–1.67
(m, 2 H, 3-Hb and 2-Hb), 1.46 (m, 1 H, 1-Hb), 1.55 (s, 3 H, CH3),
1.40 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 109.6
[(CH3)2C(O)2], 96.2 (OCH2OCH3), 79.0 (C-7), 74.6 (C-8), 73.0 (C-
6), 64.8 (OCH2OCH3), 55.5 (C-8a), 53.4 (C-3), 51.7 (C-5), 28.5 (C-
1), 28.3 (CH3), 26.3 (CH3), 21.5 (C-2) ppm. MS (ESI): m/z = 258
[M + H]+. HRMS (ESI): calcd. for C13H24NO4 [M + H]+
258.17109; found 258.16998.
2932, 2858, 1464, 1378, 1078, 1254, 837 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 4.74 (dd, J = 5.0, 5.8 Hz, 1 H, 2-H), 4.50 (d, J =
5 . 8 H z , 1 H , 1 - H ) , 3 . 9 3 ( d d , J = 7 . 1 , 9 . 9 H z , 1 H ,
-CH2OTBS), 3.67 (dd, J = 5.8, 9.9 Hz, 1 H, -CH2OTBS), 3.43 (dd,
J = 2.2, 11.9 Hz, 1 H, 5-Ha), 3.02–2.86 (m, 2 H, 3-H and 7a-H),
2.72 (dd, J = 5.7, 11.9 Hz, 1 H, 5-Hb), 1.95–1.80 (m, 2 H, 7-Ha and
6-Ha), 1.68 (m, 1 H, 7-Hb), 1.51 (s, 3 H, CH3), 1.36 (m, 1 H, 6-
Hb), 1.28 (s, 3 H, CH3), 0.89 (s, 9 H, tBuSi), 0.07 (s, 6 H,
SiMe2) ppm. 13C NMR (75 MHz, CDCl3): δ = 110.9 [(CH3)2-
C(O)2], 83.1 (C-1), 81.7 (C-2), 72.2 (-CH2OTBS), 68.5 (C-3), 63.0
(C-7a), 53.1 (C-5), 28.2 (C-7), 26.5 (CH3), 25.9 [SiC(CH3)3], 24.7
(CH3), 24.1 (C-6), 18.3 [SiC(CH3 )3 ], –5.4 (SiCH3 ), –5.3
(SiCH3) ppm. MS (ESI): m/z = 328 [M + H]+. HRMS (ESI): calcd.
for C17H34NO3Si [M + H]+ 328.22964; found 328.23025.
(6R,7R,8S,8aS)-Octahydroindolizine-6,7,8-triol (10): To the stirred
suspension of compound 24 (0.1 g, 0.39 mmol) in MeOH (2 mL)
was added aqueous HCl (6 m solution, 2 mL), and the reaction
mixture was stirred and heated at reflux for 12 h. The solvent was
(R)-1-[(4R,5S)-5-{(S)-1-[Allyl(benzyl)amino]but-3-enyl}-2,2-di-
evaporated on a rotary evaporator. Distilled water (1 mL) was methyl-1,3-dioxolan-4-yl]-2-(tert-butyldimethylsilyloxy)ethanol (27):
added to the crude residue, and the resulting solution was neutral-
ized with aqueous NaOH (2 m solution). The solution was concen-
trated in vacuo. The residue was purified by an acid resin column
[DOWEX 50WX8, 100–200 mesh, distilled water and then NH4OH
(1 m solution)] to give 10 (0.06 g, 90% yield) as a white solid. M.p.
165–167 °C; ref.[24] m.p. 166–168 °C. [α]2D6 = –36.1 (c = 1.0, H2O);
To amino compound 14 (1.5 g, 3.44 mmol) in acetonitrile (15 mL)
were added allyl bromide (0.58 mL, 6.89 mmol) and K2CO3 (1.42 g,
10.3 mmol) at 0 °C. The reaction mixture was warmed to r.t. and
then heated at reflux for 12 h. The resulting mixture was filtered
through a pad of Celite, and the filtrate was concentrated in vacuo.
The crude residue was dissolved in water, and the resulting solution
was extracted with ethyl acetate (2ϫ50 mL). The combined or-
ref.[24] [α]2D2 = –36.3 (c = 1.0, H O). IR (neat): ν
= 3415, 2922,
˜
2
max
1
2853, 1459, 1388, 1046, 770 cm–1. H NMR (500 MHz, D2O): δ = ganic extracts were concentrated in vacuo. Purification of the crude
3.99 (br. s, 1 H, 7-H), 3.82 (br. d, J = 8.9 Hz, 1 H, 6-H), 3.50 (d, J
residue by column chromatography (5% ethyl acetate in hexane)
= 10 Hz, 1 H, 8-H), 3.16 (m, 1 H, 3-Ha), 3.03 (m, 1 H, 5-Ha), 2.75 afforded 27 (1.23 g, 75% yield) as yellow oil. [α]2D6 = +25.6 (c =
1754
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1749–1757

Polyhydroxylated Indolizidines and Pyrrolizidines
1.66, CHCl ). IR (neat): ν = 2929, 2856, 1460, 1250, 1064,
(c = 2.75, CHCl ). IR (neat): ν
= 2929, 2855, 1464, 1375, 1254,
˜
˜
3
max
3
max
778 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.40–7.16 (m, 5 H,
1086, 839 cm–1 1H NMR (300 MHz, CDCl3): δ = 4.62 (t, J =
.
Ph), 6.00 (m, 1 H, NCH2CH=CH2), 5.80 (m, 1 H, -CH=CH2), 5.57 6.0 Hz, 1 H, 1-H), 4.14 (dd, J = 1.1, 6.0 Hz, 1 H, 2-H), 3.80 (dd,
(br. s, 1 H, OH), 5.22–5.11 (m, 2 H, NCH2CH=CH2), 5.09–4.97
(m, 2 H, -CH=CH2), 4.35 (dd, J = 6.1, 8.3 Hz, 1 H, 5-H), 4.15 (dd,
J = 6.1, 9.4 Hz, 1 H, 4-H), 3.83 (d, J = 13.2 Hz, 1 H, -NCH2Ph),
J = 4.9, 10.5 Hz, 1 H, -CH2OTBS), 3.67 (dd, J = 6.0, 10.5 Hz, 1
H, -CH2OTBS), 3.24 (dd, J = 5.6, 11.3 Hz, 1 H, 5-Ha), 3.15 (m, 1
H, 3-H), 2.99 (dd, J = 1.8, 11.3 Hz, 1 H, 5-Hb), 2.80 (m, 1 H, 8a-
3.75 (dd, J = 2.2, 10.5 Hz, 1 H, -CH2OTBS), 3.64 (dd, J = 4.5, H), 1.79 (m, 1 H, 8-Ha), 1.69–1.08 (m, 5 H, 6-Ha, 7-Ha, 8-Hb, 6-
10.5 Hz, 1 H, -CH2OTBS), 3.55 (d, J = 13.2 Hz, 1 H, -NCH2Ph), Hb, and 7-Hb), 1.44 (s, 3 H, CH3), 1.26 (s, 3 H, CH3), 0.89 (s, 9 H,
3.38 [m, 1 H, -CH(OH)CH2 OTBS], 3.32–3.14 (m, 2 H, tBuSi), 0.06 (s, 6 H, SiMe2) ppm. 13C NMR (75 MHz, CDCl3): δ
NCH2CH=CH2 and NCHCH2-), 3.08 (dd, J = 7.9, 13.9 Hz, 1 H, = 111.2 [(CH3)2C(O)2], 83.4 (C-1), 79.4 (C-2), 63.8 (-CH2OTBS),
NCH2CH=CH2), 2.54–2.31 (m, 2 H, -CH2CH=CH2), 1.36 (s, 3 H, 62.0 (C-3), 61.7 (C-8a), 46.6 (C-5), 25.9 (CH3), 25.8 [SiC(CH3)3],
CH3), 1.28 (s, 3 H, CH3), 0.91 (s, 9 H, tBuSi), 0.08 (s, 6 H,
25.0 (C-6), 24.4 (C-8), 24.2 (CH3), 19.7 (C-7), 18.0 [SiC(CH3)3],
SiMe2) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.0 (Cq-Ph), 137.4
–5.5 (SiCH3) ppm. MS (ESI): m/z = 342 [M + H]+. HRMS (ESI):
(NCH2CH=CH2), 134.9 (-CH2CH=CH2), 129.8, 128.3, 127.4 (C- calcd. for C18H36NO3Si [M + H]+ 342.24536; found 342.24590.
Ph), 119.0 (NCH2CH=CH2), 115.8 (-CH2CH=CH2), 107.7
(1S,2R,3S,8aS)-3-(Hydroxymethyl)-octahydroindolizidine-1,2-diol
[(CH3)2C(O)2], 77.4 (C-5), 77.1 (C-4), 69.1 (-CH2OTBS), 65.0
(11): To compound 29 (0.05 g, 0.14 mmol) in MeOH (2 mL) was
[-CH(OH)CH2OTBS], 58.1 (NCH2Ph), 54.7 (NCH2CH=CH2),
added aqueous HCl (6 m solution, 1 mL), and the resulting solution
was stirred at room temp for 12 h. The reaction mixture was con-
centrated in vacuo to obtain the crude product, which was dis-
54.1 (NCHCH2-), 31.2 (CH2CH=CH2), 27.6 (CH3), 26.0 [SiC-
(CH3)3], 25.2 (CH3), 18.2 [SiC(CH3)3], –5.2 (SiCH3), –5.1
(SiCH3) ppm. MS (ESI): m/z = 476 [M + H]+. HRMS (ESI): calcd.
solved in distilled water (1 mL). The resulting solution was neutral-
for C27H46NO4Si [M + H]+ 476.31763; found 476.31906.
ized with aqueous NaOH (2 m solution) and then was concen-
(R)-1-{(4R,5S)-5-[(S)-1-Benzyl-1,2,3,6-tetrahydropyridin-2-yl]-
2,2-dimethyl-1,3-dioxolan-4-yl}-2-(tert-butyldimethylsilyloxy)-
ethanol (28): To a solution of diene 27 (0.92 g, 1.93 mmol) in dry
CH2Cl2 (250 mL) was added Grubbs’ first-generation catalyst
(0.16 g, 0.19 mmol), and the resulting purple solution turned to
brown after 10 min. The reaction mixture was stirred and heated
at reflux for another 12 h, and then the solvent was removed under
reduced pressure. The resulting residue was purified by column
chromatography (3% ethyl acetate in hexane) to give compound 28
(0.69 g, 80% yield) as a light brown oil. [α]2D6 = +12.9 (c = 1.18,
trated. Purification by an acid resin column [DOWEX 50WX8,
100–200 mesh, distilled water and then aqueous NH4OH (2 m solu-
tion)] gave 11 (0.023 g, 85% yield) as a yellow oil. [α]2D6 = +7.1 (c
= 1.0, H2O); ref.[14] [α]2D2 = –8.7 (c = 1.2, H O). IR (neat): ν
=
˜
2
max
3315, 2943, 2831, 1449, 1019, 771 cm–1. 1H NMR (500 MHz, D2O):
δ = 4.34 (t, J = 6.2 Hz, 1 H, 1-H), 3.82 (t, J = 5.8 Hz, 1 H, 2-H),
3.78–3.65 (m, 2 H, -CH2OH), 3.37 (m, 1 H, 5-Ha), 3.04–2.90 (m, 2
H, 5-Hb, 3-H), 2.80 (ddd, J = 3.7, 9.4 Hz, 1 H, 8a-H), 1.73 (m, 1
H, 8-Ha), 1.62 (m, 1 H, 6-Ha), 1.57–1.37 (m, 2 H, 7-Ha and 8-Hb),
1.35–1.13 (m, 2 H, 6-Hb and 7-Hb) ppm. 13C NMR (75 MHz,
D2O): δ = 73.6 (C-1), 69.7 (C-2), 64.6 (-CH2OH), 64.2 (C-2), 57.8
(C-8a), 48.0 (C-5), 24.6 (C-6), 20.9 (C-7), 20.7 (C-8) ppm. MS
(ESI): m/z = 188 [M + H]+. HRMS (ESI): calcd. for C9H18NO3
[M + H]+ 188.12798; found 188.12812.
CHCl ). IR (neat): ν
= 2927, 2854, 1458, 1249, 751, 666 cm–1.
max
˜
3
1H NMR (300 MHz, CDCl3): δ = 7.40–7.20 (m, 5 H, Ph), 5.88 (br.
d, J = 10.5 Hz, 1 H, NCH2CH=CH-), 5.55 (br. d, J = 10.5 Hz, 1
H, NCH2CH=CH-), 4.33 (dd, J = 5.6, 10.2 Hz, 1 H, 5-H), 4.19
(dd, J = 5.6, 9.4 Hz, 1 H, 4-H), 3.85 (dd, J = 2.2, 10.5 Hz, 1 H,
-CH2OTBS), 3.78 (d, J = 12.4 Hz, 1 H, CH2Ph), 3.73 (m, 1 H,
-CH2OTBS), 3.71 (d, J = 12.4 Hz, 1 H, CH2Ph), 3.63 [m, 1 H,
-CH(OH)CH2OTBS], 3.26 (m, 1 H, NCH2CH=CH-), 3.14–3.05
(m, 2 H, NCHCH2CH=CH- and NCH2CH=CH-), 2.47–2.22 (m,
2 H, NCHCH2CH=CH-), 1.36 (s, 3 H, CH3), 1.30 (s, 3 H, CH3),
0.93 (s, 9 H, tBuSi), 0.10 (s, 6 H, SiMe2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 136.8 (Cq-Ph), 129.5, 128.5, 127.5 (C-Ph), 124.5
(NCHCH2 CH=CH-), 122.7 (NCHCH2 CH=CH-), 107.8
[(CH3)2C(O)2], 77.6 (C-5), 76.6 (C-4), 69.8 [-CH(OH)CH2OTBS],
65.3 (-CH2OTBS), 55.5 (-NCH2Ph), 54.7 (NCH2CH=CH2-), 45.2
(NCHCH2CH=CH-), 28.0 (NCHCH2CH=CH-), 26.0 [SiC(CH3)3],
25.5 (CH3), 21.1 (CH3), 18.6 [SiC(CH3)3], –5.1 (SiCH3) ppm. MS
(ESI): m/z = 448 [M + H]+. HRMS (ESI): calcd. for C25H42NO4Si
[M + H]+ 448.28610; found 448.28776.
(R)-1-{(4R,5S)-5-[(S)-1-Benzyl-1,2,3,6-tetrahydropyridin-2-yl]-
2,2-dimethyl-1,3-dioxolan-4-yl}ethane-1,2-diol (30): To a stirred
solution of compound 28 (0.2 g, 0.447 mmol) in THF (2 mL) was
added Bu4NF (1.0 m solution in THF, 0.44 mL) at r.t., and the
resulting mixture was stirred for 1 h. After evaporation of the
solvent in vacuo, the crude product was purified by column
chromatography (25% ethyl acetate in hexane) to afford diol 30
(0.127 g, 85% yield) as a yellow oil. [α]2D6 = +25.70 (c = 0.5, CHCl3).
IR (neat): ν
= 3422, 2929, 2855, 1452, 1376, 1218, 1065,
˜
max
743 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.40–7.20 (m, 5 H,
Ph), 5.91 (br. d, J = 10.2 Hz, 1 H, NCH2CH=CH-), 5.58 (br. d, J
= 10.2 Hz, 1 H, NCH2CH=CH-), 4.42 (dd, J = 5.6, 9.8 Hz, 1 H,
5-H), 4.21 (dd, J = 5.6, 8.6 Hz, 1 H, 4-H), 3.88–3.67 [m, 5 H,
-CH2OH, -CH(OH)CH2OH, and NCH2Ph], 3.32 (m, 1 H,
NCH2CH=CH-), 3.14–3.05 (m, 2 H, NCH2CH=CH- and
NCHCH=CH-), 2.55–2.24 (m, 2 H, NCHCH2CH=CH-), 1.40 (s,
3 H, CH3), 1.34 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 136.4 (Cq-Ph), 129.3, 128.4, 127.5 (Ph), 124.4 (NCH2CH=CH-),
122.2 (NCH2CH=CH-), 107.9 [(CH3)2C(O)2], 78.3 (C-5), 77.0
(C-4), 68.6 [-CH(OH)CH2OH], 64.3 (-CH2OH), 55.8 (-NCH2Ph),
54.2 (NCH2 CH=CH-), 45.0 (NCHCH2 CH=CH-), 29.5
(NCHCH2CH=CH-), 27.7 (CH3), 25.2 (CH3) ppm. MS (ESI): m/z
= 334 [M + H]+. HRMS (ESI): calcd. for C19H28NO4 [M + H]+
334.20262; found 334.20128.
(3aR,4S,9aS,9bS)-4-[(tert-Butyldimethylsilyloxy)methyl]-2,2-di-
methyloctahydro-[1,3]dioxolo[4,5-a]indolizidine (29): To a solution
of compound 28 (0.16 g, 0.35 mmol) in MeOH (3 mL) were added
10% Pd/C (20 mg) and NaHCO3 (5 mg), and the reaction mixture
was stirred under an atmosphere of H2 for 12 h. The reaction mix-
ture was filtered through a pad of Celite, which was then washed
with MeOH (2 ϫ 10 mL), and the filtrate was concentrated in
vacuo. To a solution of the crude residue in pyridine (5 mL) was
added MsCl (0.04 mL, 0.53 mmol) dropwise at room temp. The
resulting mixture was stirred overnight, and the pyridine was evap-
orated in vacuo. The residue was purified by silica gel chromatog-
raphy (20% ethyl acetate in hexane) to give the protected bicyclic
indolizidine 29 (0.09 g, 74% yield) as a colored oil. [α]2D6 = +37.70
(3aR,9aS,9bS)-2,2-Dimethyloctahydro-[1,3]dioxolo[4,5-a]indol-
izidine (31): Silica-supported NaIO4 (0.128 g, 0.60 mmol) was
added to diol 30 (0.1 g, 0.30 mmol) in CH2Cl2/H2O (2 mL/0.5 mL)
Eur. J. Org. Chem. 2013, 1749–1757
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1755

A. Rajender, J. P. Rao, B. V. Rao
FULL PAPER
at 0 °C, and the resulting mixture was stirred for 30 min. The reac-
tion mixture was then filtered through a pad of Celite, and the
filtrate was concentrated in vacuo. The resulting crude aldehyde
was then subjected to hydrogenation with 10% Pd/C (18 mg) in
MeOH (2 mL) for 12 h. Again, the reaction mixture was filtered
through a pad of Celite, which was then washed with MeOH
127.4 (Ph and NCH2CH=CH-), 108.8 [(CH3)2C(O)2], 78.8 (C-4),
76.9 (C-5), 71.4 [-CH(OH)CH2OTBS], 69.6 (-CH2OTBS), 65.0
(NCH2CH=CH-), 60.6 (NCH2Ph), 56.5 (NCHCH=CH-), 28.3
(CH3), 25.9 [SiC(CH3)3], 25.7 (CH3), 18.4 [SiC(CH3)3], –5.3
(SiCH3), –5.2 (SiCH3) ppm. MS (ESI): m/z = 434 [M + H]+.
HRMS (ESI): calcd. for C24H40O4NSi [M + H]+ 434.27094; found
(2ϫ5 mL). The filtrate was concentrated in vacuo, and the residue 434.27211.
was purified by column chromatography (80% ethyl acetate in hex-
Supporting Information (see footnote on the first page of this arti-
ane) to provide bicyclic indolizidine 31 (0.033 g, 55% yield) as a
1
cle): H and 13C NMR spectra for all compounds synthesized.
colorless oil. [α]2D6 = –47.50 (c = 0.5, CHCl3); ref.[28] [α]2D5 = –49.7
(c = 0.49, CHCl ). IR (neat): ν
= 2929, 2856, 1462, 1254,
max
˜
3
750 cm–1 1H NMR (300 MHz, CDCl3): δ = 4.65 (dd, J = 6.7,
.
Acknowledgments
11.8 Hz, 1 H, 2-H), 4.18 (t, J = 6.7 Hz, 1 H, 1-H), 3.36 (dd, J =
6.7, 9.8 Hz, 1 H, 3-Ha), 2.96 (br. d, J = 11.8 Hz, 1 H, 5-Ha), 2.31
(dd, J = 5.0, 9.8 Hz, 1 H, 3-Hb), 2.23–2.00 (m, 2 H, 5-Hb and 8a-
H), 1.91 (m, 1 H, 8-Ha), 1.75 (m, 1 H, 7-Ha), 1.63–1.20 (m, 4 H,
6-Ha, 8-Hb, 7-Hb, and 6-Hb), 1.46 (s, 3 H, CH3), 1.27 (s, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 114.0 [(CH3)2C(O)2],
84.1 (C-1), 77.2 (C-2), 68.8 (C-8a), 59.6 (C-3), 52.4 (C-5), 28.4 (C-
6), 27.1 (CH3), 25.0 (C-8), 24.3 (CH3), 23.7 (C-7) ppm. MS (ESI):
m/z = 220 [M + Na]+. HRMS (ESI): calcd. for C11H19NO2Na [M
+ Na]+ 220.1323; found 220.1325.
A. R. thanks the University Grants Commission (UGC), New
Delhi, and J. P. R. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi for the fellowship. We also thank the
Director of CSIR-IICT for the constant support and encourage-
ment.
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(R)-1-[(4R,5S)-5-{(S)-1-[Allyl(benzyl)amino]allyl}-2,2-dimethyl-
1,3-dioxolan-4-yl]-2-(tert-butyldimethylsilyloxy)ethanol (32): By
using the same procedure as described for 27, compound 15 was
used as the starting material to afford compound 32 (70% yield).
[α]2D6 = –20.0 (c = 0.10, CHCl ). IR (neat): νmax = 3075, 2931, 2856,
˜
3
1250, 1065, 837, 777 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.36–
7.16 (m, 5 H, Ph), 6.05 (br. s, 1 H, OH), 5.92–5.69 (m, 2 H,
NCH2CH=CH2 and NCHCH=CH2), 5.45 (dd, J = 1.7, 10.2 Hz, 1
H, NCHCH=CH2), 5.23–5.11 (m, 3 H, NCHCH=CH2 and
NCH2CH=CH2), 4.39 (dd, J = 5.5, 9.5 Hz, 1 H, 5-H), 4.23 (dd, J
= 5.5, 9.5 Hz, 1 H, 4-H), 3.91 (d, J = 12.8 Hz, 1 H, NCH2Ph), 3.75
(dd, J = 2.1, 10.8 Hz, 1 H, -CH2OTBS), 3.64 (dd, J = 4.5, 10.7 Hz,
1 H, -CH2OTBS), 3.51 [dd, J = 2.1, 10.8 Hz, 1 H, -CH(OH)-
C H 2 O T B S ] , 3 . 3 7 – 3 . 2 7 ( m , 2 H , N C H C H = C H 2 a n d
NCH2CH=CH2), 3.24 (d, J = 12.8 Hz, 1 H, NCH2Ph), 2.86 (dd, J
= 9.0, 13.4 Hz, 1 H, NCH2CH=CH2), 1.29 (s, 3 H, CH3), 1.26 (s,
3 H, CH3), 0.92 (s, 9 H, tBuSi), 0.09 (s, 3 H, SiMe2), 0.08 (s, 3 H,
SiMe2) ppm. 13C NMR (75 MHz, CDCl3): δ = 136.9 (Cq-Ph), 134.6
(NCHCH=CH2), 131.6 (NCH2CH=CH2), 129.9, 128.5, 127.6 (Ph),
121. 0 (NCH2 CH=CH2 ), 119.6 (NCHCH=CH2 ), 108.7
[(CH3)2C(O)2], 77.5 (C-5), 76.2 (C-4), 69.0 [-CH(OH)CH2OTBS],
65.0 (-CH2OTBS), 61.8 (NCH2Ph), 54.6 (NCH2CH=CH2), 53.4
(NCHCH=CH2), 27.7 (CH3), 26.0 [SiC(CH3)3], 25.6 (CH3), 18.5
[SiC(CH3)3], –5.2 (SiCH3), –5.1 (SiCH3) ppm. MS (ESI): m/z = 462
[M + H]+. HRMS (ESI): calcd. for C26H44NO4Si [M + H]+
462.30162; found 462.30341.
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dimethyl-1,3-dioxolan-4-yl}-2-(tert-butyldimethylsilyloxy)ethanol
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yield). [α]2D6 = –6.6 (c = 1.82, CHCl ). IR (neat): νmax = 2988, 2931,
˜
3
1455, 1253, 771 cm–1. H NMR (300 MHz, CDCl3): δ = 7.40–7.18
1
(m, 5 H, Ph), 6.01 (dd, J = 2.2, 5.3 Hz, 1 H, NCH2CH=CH-), 5.86
(br. d, J = 5.3 Hz, 1 H, NCH2CH=CH-), 4.18 (dd, J = 5.2, 9.0 Hz,
1 H, 5-H), 3.98–3.86 (m, 3 H, 4-H, -CH2OTBS and NCH2Ph),
3.83–3.70 [m, 3 H, -CH2OTBS, -CH(OH)CH2OTBS, and
NCHCH=CH-], 3.46 (d, J = 12.8 Hz, 1 H, -NCH2Ph), 3.43 (d,
J = 12.8 Hz, 1 H, NCH2CH=CH-), 3.29 (d, J = 12.8 Hz, 1 H,
NCH2CH=CH-), 1.45 (s, 3 H, CH3), 1.30 (s, 3 H, CH3), 0.93 (s, 9
H, tBuSi), 0.11 (s, 6 H, SiMe2) ppm. 13C NMR (75 MHz, CDCl3):
δ = 137.4 (Cq-Ph), 130.1 (NCH2CH=CH-), 129.7, 128.4, 127.6,
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1749–1757

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Received: October 10, 2012
Published Online: February 11, 2013
Eur. J. Org. Chem. 2013, 1749–1757
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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