Total synthesis of (-)-lentiginosine

Article abstract of DOI:10.1016/j.tetasy.2014.04.011

A simple and practical synthesis of (-)-lentiginosine 2 with good overall yield has been achieved from the commercially available diethyl d-tartarate. The key steps are a highly stereoselective Grignard reaction on an aldehyde and a Staudinger reduction.

Full text of DOI:10.1016/j.tetasy.2014.04.011

Tetrahedron: Asymmetry 25 (2014) 860–863
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of (À)-lentiginosine
Macha Lingamurthy, Anugula Rajender, Batchu Venkateswara Rao
⇑
Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and practical synthesis of (À)-lentiginosine 2 with good overall yield has been achieved from the
Received 20 March 2014
Accepted 14 April 2014
Available online 28 May 2014
commercially available diethyl D-tartarate. The key steps are a highly stereoselective Grignard reaction on
an aldehyde and a Staudinger reduction.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Since these results were highly encouraging, analogues of com-
pound 2 should have the potential to generate new anti cancer
drugs.6 Due to its biological importance, several approaches have
been developed for the synthesis of (+)-lentiginosine 17,8b and its
enantiomer (À)-lentiginosine 2.8 A good yielding approach which
Polyhydroxylated indolizidine alkaloids, such as (+)-lentigino-
sine 1, (À)-lentiginosine 2, (À)-swainsonine 3 and (+)-castanosper-
mine 4, belong to the important class of iminosugars or azasugars
(Fig. 1). They are mimics of monosaccharides in biological systems
and are also excellent glycosidase inhibitors.1 Glycosidases are
enzymes which are involved in a wide range of metabolic path-
ways such as digestion, post-translational processing of glycopro-
teins and lysosomal catabolism of glycoconjugates.2 Therefore
iminosugars or azasugars are useful for the treatment of diabetes
and viral infections, as well as being anticancer, anti-HIV and
lysosomal storage disorder agents.3
gives enantiomerically pure
2 is still desirable for further
evaluation of its activity and preparation of analogues.
In continuation of our efforts in developing synthetic routes for
iminosugars from nucleophilic additions on N-glycoslylamine
derivatives,9 we herein report a simple and practical synthesis
of 2 using a highly stereoselective Grignard addition on an
aldehyde.
(+)-Lentiginosine 1, isolated in 1990 from the leaves of Astraga-
lus lentiginosus,4 is a well known selective inhibitor of natural
amyloglucosidase,4 and also found to be an inhibitor of ATPase
and Heat shock protein 90 (Hsp90), which is a promising binding
site for new classes of Hsp90 inhibitors with multi target antican-
cer potential.5 (À)-Lentiginosine 2, a synthetic iminosugar, acts as
apoptosis inducer in U937 cells, naturally deficient in P53. Recent
studies by Minutolo et al. on different tumour cell lines using com-
pound 2, showed interesting results. This compound exhibited gly-
cosidase inhibitor activity and unexpected pro apoptotic activity.
2. Results and discussion
As per the retrosynthetic analysis shown in Scheme 1, (À)-len-
tiginosine 2 can be obtained by intramolecular dialkylation of the
amino derivative, which in turn can be prepared by reduction
of the azido compound 5. Compound 5 can be obtained by
stereoselective nucleophile addition of 4-bromo-1-butene on
aldehyde 6 followed by simple transformations. Compound 6 can
easily be synthesised from diethyl
D-tartarate 7 using literature
methods.9a,10
OH
OH
(À)-Diethyl
D-tartrate 7 was converted into alcohol 8 using lit-
erature methods.9a,10 Swern oxidation of alcohol 8 gave aldehyde
6, which was subjected to a chelation controlled Grignard reaction
(Fig. 2) using 4-bromo-1-butene and Mg in THF to give alcohols 9
and 10 (9:1) in 80% yield (over two steps),11 which were separated
by column chromatography. Hydroboration/oxidation of the termi-
nal olefin in 9 using BH3ÁDMS followed by NaOH and H2O2 fur-
nished diol 11 in 85% yield.
N
N
N
N
OH
OH
HO
OH
HO
OH
HO
(-)-swainsonine 3
Figure 1.
OH
OH
(+)-castanospermine
(+)-lentiginosine 1
2
(-)-lentiginosine
4
The selective tosylation of the primary hydroxy group in 11
using TsCl, Et3N in the presence of catalytic Bu3SnO in dry DCM
gave the tosylated compound which upon treatment with NaN3
in DMF at 60 °C without any purification afforded the azido com-
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail address: drb.venky@gmail.com (B.V. Rao).
http://dx.doi.org/10.1016/j.tetasy.2014.04.011
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

M. Lingamurthy et al. / Tetrahedron: Asymmetry 25 (2014) 860–863
861
OMOM
OMOM
N
N3
O
D
MsO
MOMO
diethyl -tartrate
TBDPSO
OMs
OMOM
HO
OH
7
5
6
2
Scheme 1.
M
O
H
OMOM
OMOM
OH
chelation controlled
H
TBDPSO
MOMO
R
nucleophile
(homoallyl unit)
9
6
M = metal
Figure 2. Chelation controlled addition of aldehyde 6.
pound 12 in 80% yield. Cleavage of the silyl ether in 12 using TBAF
yielded the primary alcohol 13 in 95% yield.
overall yield. The key steps involved in this synthesis are the highly
diastereoselective Grignard addition on aldehyde 6 and a Stauding-
er reduction followed by in situ cyclisation to give the indolizidine
ring. This strategy helps in making large quantities of compound 2
for further evaluation of its activity and in making analogues.
Compound 13 was treated with MsCl and Et3N in DCM to afford
the dimesylated compound 5, which without further purification
was subjected to a Staudinger protocol12 (TPP, THF, H2O) to afford
the desired indolizidine ring 14 in 80% yield (over two steps) as
shown in Scheme 2. Finally, treatment of 14 with 6 M HCl under
reflux conditions followed by work-up gave the required final
product (À)-lentiginosine 2 in 90% yield, whose spectroscopic
and physical data were in good agreement with the reported
values.8j The same strategy can be applied for the synthesis of
4. Experimental
Moisture and oxygen sensitive reactions were carried out under
a nitrogen gas atmosphere in flame or oven dried glassware with
magnetic stirring. All solvents and reagents were purified by stan-
dard techniques. Solutions were dried over Na2SO4 before concen-
tration under reduced pressure. TLC was performed on Merck
Kiesel gel 60, F254 plates (layer thickness 0.25 mm). Column chro-
matography was performed on silica gel (60–120 or 100–200
mesh) using ethyl acetate and hexane as eluants. Melting points
were determined on a Fisher John’s melting point apparatus and
(+)-lentiginosine 1 from diethyl L-tartarate.
3. Conclusion
In conclusion, we have synthesised (À)-lentiginosine 2 from the
commercially available starting material diethyl
D
-tartarate in 32%
OMOM
O
OH
OMOM
DMSO, (COCl)2, Et3N,
DCM, -78 oC
Br
OH
O
OEt
ref 10a
96%
TBDPSO
TBDPSO
EtO
Mg, THF, 0 oC to r.t
80% (over two steps)
OMOM
OMOM
OH
O
8
7
6
OMOM
OMOM
OMOM
1. TSCl, Et3N, Bu3SnO,
DCM, 0 oC to r.t,
2. NaN3, DMF, 60 oC,
12 h, 80% (over two steps)
BH3·DMS, THF,
NaOH, H2O2,
N3
OH
TBDPSO
MOMO
TBDPSO
MOMO
TBDPSO
MOMO
R1
R2
OH
OH
11
0 oC to r.t, 2 h, 85%
12
9. R1 = OH, R2 = H
10
. R1 = H, R2 = OH
9:1 (syn:anti)
OMOM
MsCl, Et3N, DCM, 0 oC,
30 min
TPP, THF, H2O, 50 oC,
16 h, 80% (over two steps)
OMOM
N3
TBAF, THF, r.t,
95%
N3
MsO
MOMO
HO
MOMO
OMs
OH
5
13
N
N
6 M HCl, MeOH, reflux,
2 h, 90%
HO
OH
MOMO
OMOM
2
14
Scheme 2.

862
M. Lingamurthy et al. / Tetrahedron: Asymmetry 25 (2014) 860–863
are uncorrected. IR spectra were recorded on a Perkin–Elmer RX-1
FT-IR system. 1H NMR in Bruker Avance-300 and Varian-400,
500 MHz and 13C NMR spectra in 75 and 100 MHz were recorded.
Chemical shifts were reported in ppm with respect to TMS as an
internal standard. 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-
stants (J) which are quoted in Hz. Optical rotations were measured
with JASCO digital polarimeter. Accurate mass measurements were
performed on Q STAR mass spectrometer (Applied Biosystems,
USA).
4.3. (5S,6R,7R)-8-(tert-Butyldiphenylsilyloxy)-6,7-bis(methoxy-
methoxy)octane-1,5-diol 11
To a stirred solution of 9 (2.0 g, 3.98 mmol) in dry THF (20 mL),
BH3ÁMe2S (0.7 mL, 8.76 mmol) was added dropwise at À10 °C. Stir-
ring was then continued for 3 h at room temperature. The reaction
mixture was quenched by the addition of 10% NaOH (10 mL) fol-
lowed by 30% H2O2 (15 mL) at 0 °C and allowed to warm to room
temperature, and stirred for another 2 h. The reaction mixture
was extracted with ethyl acetate (2 Â 100 mL). The combined
organic layers were washed with brine, separated and dried over
anhydrous Na2SO4. The solvent was removed on rotary evaporator.
The residue was purified by column chromatography on silica gel
using ethyl acetate/hexane (3:2) as the eluant to give pure com-
4.1. (2R,3R,4S)-1-(tert-Butyldiphenylsilyloxy)-2,3-bis(methoxy-
methoxy)oct-7-en-4-ol 9
pound 11 (1.76 g, 85%) as a colourless oil. [
a
]
25 = À2.1 (c 0.9,
D
To a stirred solution of oxalyl chloride (1.94 mL, 22.2 mmol) in
dry DCM (20 mL) under a nitrogen atmosphere, was added DMSO
(3.2 mL, 44.6 mmol) slowly at À78 °C and stirred for 30 min at the
same temperature. Next, alcohol 8 (5.0 g, 11.1 mmol) in dry DCM
(20 mL) was added slowly over 10 min and stirring was continued
further for 2 h at À78 °C after which Et3N (9.4 mL, 66.96 mmol)
was added at À78 °C. The temperature was slowly raised to room
temperature over 20 min and the reaction mixture was diluted with
DCM (50 mL). The organic layer was sequentially washed with satu-
rated aq NH4Cl solution and brine, and dried over anhydrous Na2SO4.
The solvent was removed on a rotary evaporator to give crude alde-
hyde 6, which was used in the next step without purification.
To a stirred solution of aldehyde 6 (3 g, 6.73 mmol) in dry THF
(20 mL) at 0 °C, were added dropwise homoallyl magnesium bro-
mide [prepared in situ from Mg (0.64 g, 26.9 mmol) and homoallyl
bromide (1.02 g, 10.0 mmol)] in dry THF (5 mL) over a period of
5 min. The solution was then gradually allowed to room tempera-
ture, and stirring was continued for another 5 h after which the reac-
tion mixture was quenched by adding saturated aq NH4Cl solution
at 0 °C. The mixture was extracted with ethyl acetate (3 Â 50 mL)
and the combined organic extracts were washed with water and
brine, and dried over anhydrous Na2SO4. The solvent was removed
on a rotary evaporator and the residue was purified through silica
gel column chromatography (ethyl acetate/hexane = 1:9) to give
CHCl3); IR (neat): 3435, 2927, 2855, 1466, 1427, 1213, 1108,
1028 cmÀ1 1H NMR (500 MHz, CDCl3): d 7.69–7.63 (m, 4H), 7.47–
;
7.37 (m, 6H), 4.71, 4.69 (ABq, JAB = 6.7 Hz, 2H), 4.62 (d, J = 6.7 Hz,
1H), 4.54 (d, J = 6.7 Hz, 1H), 3.85–3.75 (m, 4H), 3.67 (t, J = 5.9 Hz,
1H), 3.62 (dd, J = 5.6 Hz, 2.8 Hz, 1H), 3.40 (s, 3H), 3.29 (s, 3H), 3.25
(m, 1H), 1.68–1.46 (m, 6H), 1.06 (s, 9H); 13C NMR (125 MHz, CDCl3):
d 135.56, 135.50, 133.0, 132.9, 129.8, 127.74, 127.72, 98.7, 96.6,
82.9, 77.6, 70.2, 62.69, 62.62, 56.2, 55.8, 32.59, 32.56, 26.7, 21.6,
19.1; ESIMS (m/z): 543 [M+Na]+; HRMS (ESI) [M+Na]+: Anal. Calcd
for C28H44O7NaSi 543.27485 Found 543.27436.
4.4. (2R,3R,4S)-8-Azido-1-(tert-butyldiphenylsilyloxy)-2,3-bis-
(methoxymethoxy) octan-4-ol 12
To a stirred solution of 11 in DCM (1.5 g, 6.7 mmol) were added
Et3N (0.4 mL, 2.88 mmol), Bu2SnO (0.71 g, 2.88 mmol) and p-tolu-
enesulfonylchloride in DCM (0.54 g, 2.88 mmol) at 0 °C under a
nitrogen atmosphere. After stirring for 1 h at room temperature,
the reaction mixture was extracted with CHCl3 (100 mL). The
organic extract was washed with water (30 mL) and brine (30 mL)
and dried over anhydrous Na2SO4. Evaporation of the solvent under
reduced pressure afforded the tosylated compound as a liquid,
which was used in the next step without further purification.
To the above tosylated derivative in dry DMF (20 mL) was
added NaN3 (1.12 g, 17.28 mmol) under a nitrogen atmosphere at
room temperature. The reaction was slowly heated to 90 °C and
stirred for 12 h, after which the reaction mixture was allowed to
cool to room temperature, poured into ice cold water (40 mL)
and extracted with diethyl ether (3 Â 80 mL). The combined
organic extracts were washed with water (50 mL) and brine
(30 mL), dried over anhydrous Na2SO4, concentrated under
reduced pressure and purified by column chromatography (ethyl
acetate/hexane 1:8) to afford 12 (1.25 g, 80% for two steps) as a
compound 9 (2.70 g, 80%) as a colourless oil. [
a
]
25 = À11.3 (c 0.7,
D
CHCl3); IR (neat): 3472, 3071, 2927, 2892, 2855, 1468, 1427, 1107,
1025 cmÀ1 1H NMR (300 MHz, CDCl3): d 7.74–7.60 (m, 4H), 7.49–
;
7.39 (m, 6H), 5.87 (m, 1H), 5.06 (dd, J = 16.9 Hz, 1.1 Hz, 1H), 4.98
(dd, J = 9.8 Hz, 1.8 Hz, 1H), 4.71, 4.69 (ABq, JAB = 6.7 Hz, 2H), 4.63
(d, J = 6.7 Hz, 1H), 4.55 (d, J = 6.7 Hz, 1H), 3.88–3.74 (m, 4H), 3.63
(m, 1H), 3.40 (s, 3H), 3.28 (s, 3H), 3.14 (d, J = 4.1 Hz, 1H), 2.39–2.11
(m, 2H), 1.75–1.50 (m, 2H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3):
d 138.4, 135.59, 135.53, 133.0, 129.8, 127.75, 127.71, 114.7, 98.7,
96.6, 82.6, 77.6, 69.8, 62.8, 56.2, 55.8, 32.6, 29.8, 26.8, 19.1; ESIMS
(m/z): 525 [M+Na]+; HRMS (ESI) [M+Na]+: Anal. Calcd for
liquid. [
a]
25 = À6.5 (c 1.1, CHCl3); IR (neat): 2923, 2853, 2094,
D
1465, 1428, 1108, 1028 cmÀ1 1H NMR (300 MHz, CDCl3): d 7.71–
;
C
28H42O6NaSi 525.26429 Found 525.26417.
7.61 (m, 4H), 7.47–7.35 (m, 6H), 4.71, 4.69 (ABq, JAB = 6.7 Hz, 2H),
4.62 (d, J = 6.7 Hz, 1H), 4.54 (d, J = 6.7 Hz, 1H), 3.85–3.73 (m, 4H),
3.61 (dd, J = 5.6 Hz, 2.6 Hz, 1H), 3.40 (s, 3H), 3.33–3.23 (m, 2H),
3.29 (s, 3H), 1.68–1.46 (m, 6H), 1.06 (s, 9H); 13C NMR (125 MHz,
CDCl3): d 135.56, 135.51, 132.9, 129.8, 127.76, 127.73, 98.7, 96.6,
82.9, 77.5, 70.0, 62.6, 56.2, 55.8, 51.3, 32.5, 28.8, 26.7, 22.7, 19.1;
ESIMS (m/z): 568 [M+Na]+; HRMS (ESI) [M+Na]+: Anal. Calcd for
4.2. (2R,3R,4R)-1-(tert-Butyldiphenylsilyloxy)-2,3-bis(methoxy-
methoxy)oct-7-en-4-ol 10
[
a]
25 = À4.4 (c 0.9, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.72–
D
7.63 (m, 4H), 7.47–7.36 (m, 6H), 5.83 (m, 1H), 5.05 (dd, J = 17.0 Hz,
1.6 Hz, 1H), 4.96 (dd, J = 10.2 Hz, 1.8 Hz, 1H), 4.75 (d, J = 6.7 Hz,
1H), 4.67 (d, J = 6.7 Hz, 1H), 4.65, 4.63 (ABq, JAB = 7.0 Hz, 2H), 3.93
(m, 1H), 3.81–3.74 (m, 3H), 3.59 (dd, J = 6.4 Hz, 3.2 Hz, 1H), 3.50
(d, J = 5.6 Hz, 1H), 3.36 (s, 3H), 3.28 (s, 3H), 2.34 (m, 1H), 2.15 (m,
1H), 1.75–1.50 (m, 2H), 1.05 (s, 9H); 13C NMR (125 MHz, CDCl3):
d 138.6, 135.56, 135.54, 133.05, 133.01, 129.7, 127.7, 114.6, 98.1,
97.6, 81.8, 78.3, 70.0, 63.6, 56.1, 32.1, 30.0, 26.7, 19.1; ESIMS
(m/z): 525 [M+Na]+; HRMS (ESI) [M+Na]+: Anal. Calcd for
C28H43O6N3NaSi 568.28133 Found 568.28086.
4.5. (2R,3R,4S)-8-Azido-2,3-bis(methoxymethoxy)octane-1,4-
diol 13
To a stirred solution of compound 12 (1.0 g, 1.83 mmol) in dry
THF (10 mL) was added TBAF (3.7 mL, 1 M solution in THF) at room
temperature and stirred for 1 h. The solvent was removed on a
rotary evaporator and the residue was purified by column
C28H42O6NaSi 525.26429 Found 525.26411.

M. Lingamurthy et al. / Tetrahedron: Asymmetry 25 (2014) 860–863
863
chromatography on silica gel (ethyl acetate/hexane, 3:2) to
financial support as part of XII Five Year plan programme under
title ORIGIN (CSC-0108) and Director, CSIR-IICT for the constant
support and encouragement.
give pure compound 13 (0.53 g, 95%) as a colourless liquid.
[a]
25 = +8.7 (c 1.2, CHCl3); IR (neat): 3415, 2922, 2852, 2093,
D
1459, 1213, 1149, 1021 cmÀ1 1H NMR (300 MHz, CDCl3): d 4.80–
;
4.68 (m, 4H), 3.88–3.73 (m, 4H), 3.56 (m, 1H), 3.44 (s, 3H), 3.43
(s, 3H), 3.30 (t, J = 6.4 Hz, 2H), 2.79 (br s, 1H), 1.71–1.46 (m, 6H);
13C NMR (75 MHz, CDCl3): d 98.2, 97.0, 81.1, 79.8, 69.5, 61.3,
56.2, 55.9, 51.3, 33.5, 28.7, 23.0; ESIMS (m/z): 330 [M+Na]+; HRMS
(ESI) [M+Na]+: Anal. Calcd for C12H25O6N3NaSi 330.16356 Found
330.16331.
References
1. (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139; (b) Michael, J. P. Nat. Prod. Rep.
2007, 24, 191; (c) Cardona, F.; Goti, A.; Brandi, A. Eur. J. Org. Chem. 2007, 1551.
and references cited therein.
2. (a) Cipolla, L.; La Ferla, B.; Gregori, M. Comb. Chem. High Throughput Screening
2006, 9, 571; (b) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash,
R. J. Phytochemistry 2001, 56, 265.
3. (a) Mehta, A.; Ziztmann, N.; Rudd, P. M.; Block, T. M.; Dwek, R. A. FEBS Lett.
1998, 430, 17; (b) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645; (c) Asano, N. Glycobiology 2003, 13,
93R.
4.6. (1R,2R,8aR)-1,2-Bis(methoxymethoxy)octahydroindolizine
14
4. Pastuszack, I.; Molyneux, R. J.; James, L. F.; Elbein, A. D. Biochemistry 1990, 29,
1886.
To an ice-cold solution of 13 (0.5 g, 1.63 mmol) in dry DCM
(10 mL) was added Et3N (0.4 mL, 2.45 mmol) under a nitrogen
atmosphere. After stirring for 5 min methane sulfonylchloride
(0.2 mL, 1.79 mmol) and catalytic DMAP were added to the reac-
tion mixture and allowed to stir at room temperature for 30 min.
The reaction mixture was then extracted with CHCl3 (2 Â 50 mL).
The organic extract was washed with brine (20 mL), separated
and dried over anhydrous Na2SO4. Evaporation of the solvent under
reduced pressure afforded the dimesylated compound 5 as a liquid,
which was used in the next step without further purification. To
the crude mesylated compound 5 in THF (10 ml), triphenyl phos-
phine (0.64 g, 2.45 mmol) and water (0.2) were added at room
temperature. The reaction mixture was stirred for 16 h at 50 °C.
After completion of the reaction (by monitoring TLC) the solvent
was removed on a rotary evaporator and the residue was purified
by column chromatography on silica gel (dichloromethane/metha-
nol 40:1) to give pure compound 14 (0.32 g, 80%) as a colourless
5. From Piaz, F.; Vassallo, A.; MG, Chini; Cordero, FM; Cardona, F.; Pisano, C.;
Bifulco, G.; De Tommasi, N.; Brandi, A. PLoS ONE 2012, 7, e43316.
6. (a) Cordero, M. F.; Bonanno, P.; Khairnar, B. B.; Cardona, F.; Brandi, A.; Macchi,
B. Chem Plus Chem 2012, 77, 9; (b) Minutolo, A.; Grelli, S.; Marino-Merlo, F.;
Cordero, F. M.; Brandi, A.; Macchi, B.; Mastino, A. Cell Death Dis. 2012, 3, e358;
(c) Macchi, B.; Minutolo, A.; Grelli, S.; Mastino, A.; Cardona, F.; Cordero, F. M.;
Brandi, A. Glycobiology 2010, 20, 500.
7. (a) Alam, M. A.; Vankar, Y. D. Tetrahedron Lett. 2008, 49, 5534. Recent
publications of (+)-lentinginosine: For more details see review Ref.1c;; (b)
Prasad, K. R.; Pawar, A. B. ARKIVOC 2010, 39; (c) Lauzon, S.; Tremblay, F.;
Gagnon, D.; Godbout, C.; Chabot, C.; Mercier-Shanks, C.; Perreault, S.; DeSève,
H.; Spino, C. J. Org. Chem. 2008, 73, 6239; (d) Chen, M.-J.; Tsai, Y.-M. Tetrahedron
Lett. 2007, 48, 6271; (e) Raghavan, S.; Sreekanth, T. Tetrahedron: Asymmetry
2004, 15, 565.
8. (a) Ansari, A. A.; Vankar, Y. D. RSC Adv. 2014, 4, 12555; (b) Kim, G.-W.; Jin, T.;
Kim, J.-S.; Park, S.-H.; Lee, K.-H.; Kim, S.-S.; Myeong, I.-S.; Ham, W.-H.
Tetrahedron: Asymmetry 2014, 25, 87; (c) Shao, J.; Yang, J.-S. J. Org. Chem.
2012, 77, 7891; (d) Kamal, A.; Reddy, V. S. Tetrahedron 2011, 67, 1341; (e) Liu,
S.-W.; Hsu, H.-C.; Chang, C.-H.; Tsai, H.-H. G.; Hou, D.-R. Eur. J. Org. Chem. 2010,
4771; (f) Chandrasekhar, S.; Vijaykumar, B. V. D.; Pratap, T. V. Tetrahedron:
Asymmetry 2008, 19, 746; (g) Azzouz, R.; Fruit, C.; Bischoff, L.; Marsais, F. J. Org.
Chem. 2008, 73, 1154; (h) Angle, S. R.; Bensa, D.; Belanger, D. S. J. Org. Chem.
2007, 72, 5592; (i) Kim, I. S.; Zee, O. P.; Jung, Y. H. Org. Lett. 2006, 8, 4101; (j)
Chaudhari, V. D.; Kumar, K. S. A.; Dhavale, D. D. Tetrahedron 2006, 62, 4349; (k)
Ayad, T.; Genisson, Y.; Baltas, M. Org. Biomol. Chem. 2005, 3, 2626; (l) Nukui, S.;
Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1995, 60, 398; (m) Ichikawa,
Y.; Ito, T.; Isobe, M. Chem. Eur. J. 2005, 11, 1949; (n) Ayad, T.; Génisson, Y.;
Baltas, M.; Gorrichon, L. Chem. Commun. 2003, 582; (o) Chandra, K. L.;
Chandrashekhar, M.; Singh, V. K. J. Org. Chem. 2002, 67, 4630; (p) Azzouz, R.;
Fruit, C.; Bischoff, L.; Marsais, F. J. Org. Chem. 2002, 67, 1154; (q) Cardona, F.;
Goti, A.; Picasso, S.; Vogel, P.; Brandi, A. J. Carbohydr. Res. 2000, 19, 585; (r)
McCaig, A. E.; Meldrum, K. P.; Wightman, R. H. Tetrahedron 1998, 54, 9429; (s)
Brandi, A.; Cicchi, S.; Cordero, F. M.; Frignoli, R.; Goti, A.; Picasso, S.; Vogel, P. J.
Org. Chem. 1995, 60, 6806; (t) Gurjar, M. K.; Ghosh, L.; Syamala, M.; Jayasree, V.
Tetrahedron Lett. 1994, 35, 8871.
liquid. [
a]
25 = +27.7 (c 0.8, CHCl3); IR (neat): 2925, 2853, 1515,
D
1213, 1035 cmÀ1
;
1H NMR (600 MHz, CDCl3): d 4.80–4.65 (m,
4H), 4.01 (dd, J = 5.6 Hz, 1.8 Hz, 1H), 3.77 (dd, J = 7.9 Hz, 1.8 Hz,
1H), 3.39 (s, 6H), 3.05–2.98 (m, 2H), 2.42 (dd, J = 9.7 Hz, 6.0 Hz,
1H), 2.01–1.19 (m, 8H); 13C NMR (75 MHz, CDCl3): d 95.8, 95.2,
87.4, 79.5, 68.7, 59.6, 55.5, 55.4, 53.2, 28.9, 24.6, 24.0; ESIMS (m/
z): 246 [M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd for C12H24O4N
246.16998 Found 246.16971.
4.7. (1R,2R,8aR)-Octahydroindolizine-1,2-diol 2
9. (a) Lingamurthy, M.; Rajender, A.; Rao, B. V. Tetrahedron Lett. 2013, 54, 6189;
(b) Rajender, A.; Rao, J. P.; Rao, B. V. Eur. J. Org. Chem. 2013, 1749; (c) Rajender,
A.; Rao, B. V. Tetrahedron Lett. 2013, 54, 2329; (d) Chandrasekhar, B.; Rao, B. V.
Tetrahedron: Asymmetry 2009, 20, 1217; (e) Jagadeesh, Y.; Chandrasekhar, B.;
Rao, B. V. Tetrahedron: Asymmetry 2010, 21, 2314; (f) Rao, J. P.; Rao, B. V.;
Swarnalatha, J. L. Tetrahedron Lett. 2010, 51, 3083; (g) Rajender, A.; Rao, J. P.;
Rao, B. V. Tetrahedron: Asymmetry 2011, 22, 1306; (h) Rao, M. V.;
Chandrasekhar, B.; Rao, B. V. Tetrahedron: Asymmetry 2011, 22, 1342; (i) Rao,
G. S.; Rao, B. V. Tetrahedron Lett. 2011, 52, 4861; (j) Rao, G. S.; Chandrasekhar,
B.; Rao, B. V. Tetrahedron: Asymmetry 2012, 23, 564; (k) Rao, G. S.; Rao, B. V.
Tetrahedron Lett. 2011, 52, 6076.
10. (a) Lee, J.; Kim, K.-H.; Jeong, S. Bioorg. Med. Chem. Lett. 2011, 21, 4203; (b)
Zhong, H. M.; Suhn, J.-H.; Rawal, V. H. J. Org. Chem. 2007, 72, 386; (c) Suhn, J.-
H.; Waizumi, N.; Zhong, H. M.; Rawal, V. H. J. Am. Chem. Soc. 2005, 127, 7290;
(d) Dulphy, H.; Gras, J.-L.; Lejon, T. Tetrahedron 1996, 52, 8517.
11. (a) Iida, H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1985, 36, 3255; (b)
Gautam, D.; Rao, B. V. Tetrahedron Lett. 2010, 51, 4199.
To compound 14 (0.1 g, 0.41 mmol), in MeOH (2 mL) was added
6 M HCl, and the resulting solution was stirred for 12 h at room
temperature. The solvent was concentrated in vacuo, the crude
product obtained was neutralised with 2 M NaOH and purified
by an acid resin column (DOWEX 50 W X 8, 100–200 mesh), by
eluting with 1 N NH4OH to give 2 as a white solid (0.057 g, 90%).
Observed [
a]
25 = À2.9 (c 0.5, MeOH), mp 105–108 °C (dec);
D
{lit.8j,n,r,t À3.05, À2.0, À2.6, À3.5, mp 106–108 °C (dec)}; IR (neat):
3315, 2943, 2831, 1449, 1414, 1020 cmÀ1 1H NMR (300 MHz,
;
D2O): d 4.00 (m, 1H), 3.56 (dd, J = 8.6 Hz, 3.9 Hz, 1H), 2.87 (d,
J = 11.3 Hz, 1H), 2.76 (dd, J = 11.3 Hz, 1.7 Hz, 1H), 2.56 (dd,
J = 11.3 Hz, 7.5 Hz, 1H), 2.05–1.81 (m, 3H), 1.73 (m, 1H), 1.56 (m,
1H), 1.37 (m, 1H), 1.24–1.14 (m, 2H); 13C NMR (125 MHz, D2O): d
85.1, 77.9, 70.9, 62.5, 54.9, 29.7, 26.2, 25.3; ESIMS (m/z): 158
[M+H]+; HRMS (ESI) [M+H]+: Anal. Calcd for C8H16O2N 158.11756
Found 158.11752.
12. Takahata, H.; Kubota, M.; Takahashi, S.; Mamose, T. Tetrahedron: Asymmetry
1996, 7, 3047.
Acknowledgments
M.L.M. thanks the CSIR-New Delhi and A.R. thanks the UGC-
New Delhi for fellowship. Authors also thank CSIR-New Delhi for