Contribution to the synthesis of polyhydroxylated indolizidines starting from sugar isothiocyanates

Article abstract of DOI:10.1016/j.tetasy.2016.02.011

A straightforward stereoselective route towards castanospermine analogues starting from the corresponding d-gluco- and l-ido-hexofuranose isothiocyanates (5S)-2 and (5R)-2 is described. The key transformations of this approach rely on ring-closing metathe

Full text of DOI:10.1016/j.tetasy.2016.02.011

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Contribution to the synthesis of polyhydroxylated indolizidines
starting from sugar isothiocyanates
⇑
ˇ
Ján Elecko, Jozef Gonda , Miroslava Martinková, Mária Vilková
Department of Organic Chemistry, Institute of Chemical Sciences, P. J. Šafárik University, Moyzesova 11, Sk-040 01 Košice, Slovak Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward stereoselective route towards castanospermine analogues starting from the corre-
sponding D-gluco- and L-ido-hexofuranose isothiocyanates (5S)-2 and (5R)-2 is described. The key trans-
formations of this approach rely on ring-closing metathesis and reductive amination to form the final
polyhydroxylated indolizidines 10–13 in good overall yields.
Received 12 February 2016
Accepted 19 February 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
bond. In continuation of our studies, we were interested in inves-
tigating the use of the rearranged products (5R)-2 and (5S)-2,
Polyhydroxylated indolizidine alkaloids have attracted consid-
erable attention from synthetic chemists due to their unique struc-
tures and remarkable biological properties, such as anticancer,
antiviral, and antidiabetic activities as well as their impressive gly-
cosidase inhibitory profile.1 The latter activity is due to their ability
to mimic the transition state included in the substrate hydrolysis.2
Members of the aforementioned class of alkaloids have been found
in various plant and fungi sources, and castanospermine 1 (Fig. 1)
is one of the most representative examples. Recent investigations
revealed that 1 has potential use as a therapeutic agent against
viral infections,3 various cancer types,4 and diabetes.5 Moreover,
castanospermine has displayed antiinflammatory6 and immuno-
suppressant potency.7 The source of this significant plethora of
the biological activity has been ascribed to its selective glycosidase
inhibitory properties, which are important in the carbohydrate-
mediated cell adhesion and signalling.8 For these promising rea-
sons, a number of synthetic methodologies towards polyhydrox-
yindolizidines have been developed.9,10 In particular, the
construction of the unnatural epimeric congeners and the other
related structural analogues has stimulated extensive synthetic
efforts because structural modifications in iminosugars based on
the number, position and stereochemistry of the hydroxyl func-
tionalities in the parent skeletons can induce significant changes
in their activities.11
which were effectively prepared on a multigram scale, for the gen-
eral preparation of tri- and pentahydroxylated indolizidine alka-
loids. In keeping with our earlier work,13 we herein report
modifications into 1-deoxycastanospermine 11 and its congeners
via ring-closing metathesis and reductive amination to create the
required bicyclic unit.
2. Results and discussion
The key aspect of our strategy is the use of the isothiocyanate
scaffolds (5S)-2 and (5R)-2 to accomplish the construction of target
compounds 10, 11, 12 and 13 based on the retrosynthetic analysis
outlined in Figure 1. The starting diastereoisomers (5S)-2 and (5R)-
2 were built up according to our previous work via the thermal
aza-Claisen rearrangement of the corresponding thiocyanate13
derived from D-glucose. At first, we pursued the conversion of both
derivatives (5S)-2 and (5R)-2 into amines (5S)-4 and (5R)-4. This
was achieved by the following sequence. Compound (5S)-2 to
sodium methoxide in MeOH and subsequent replacement of the
sulfur atom to oxygen with mesitylnitrile oxide in the generated
thiourethane resulted in the formation of carbamate (5S)-3 in
88% yield over two steps (Scheme 1). In a parallel fashion, isothio-
cyanate (5S)-2 was converted into the corresponding derivative
(5R)-3 (86%). The desired amines (5S)-4 and (5R)-4 were then
obtained by treatment of both (5S)-3 and (5R)-3 with 6 M NaOH
in EtOH in 85% and 84% yields, respectively. With the allylic amines
(5S)-4 and (5R)-4 in hand, we were now in a position to explore the
ring-closing metathesis (RCM) conditions required for the
formation of a new dihydropyrrole core. However, in most cases
it was found necessary to have the amino function protected
with the acyl or benzyl moieties during the RCM reaction leading
Our previous success with the total synthesis of biologically
active a-substituted a
-amino acid scaffolds12 from sugar templates
suggested that the [3,3]-sigmatropic rearrangements on struc-
turally appropriate allylic substrates effectively installed the CAN
⇑
Corresponding author.
E-mail address: jozef.gonda@upjs.sk (J. Gonda).
http://dx.doi.org/10.1016/j.tetasy.2016.02.011
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
ˇ
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J. Elecko et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
2
Reductive amination
RCM/dihydroxylation
aza-Claisen rearrangement
N=C=S
NCbz
5
OH
7
HO
N
6
7
R2
O
O
2
8a
6
5
O
O
1
4
1
2
4
1
2
8
3
OH
3
HO
H
H
H
R1
O
O
OH
BnO
BnO
(5S)-2
1, (1S,8aR), R1 = OH, R2 = H, castanospermine
11, (8aR), R1 = R2 = H, 1-deoxycastanospermine
12, (8aS), R1 = R2 = H, 8a-epi-1-deoxycastanospermine
10
13
9
, (5R,6S,7R)
, (5S,6R,7S)
2
(5R)-
10
, (1S,2R,8aR), R1 = R2 = OH
, (1R,2S,8aS), R1 = R2 = OH
Figure 1. Structures of several indolizidines and applied retrosynthesis.
to N-heterocycles.14–16 Thus, the liberated amines (5S)-4 and (5R)-
4 were immediately treated with benzyloxycarbonyl chloride to
furnish N-benzyloxy carbamates (5S)-5 and (5R)-5 in 98% and
97% yields, respectively. Their subsequent allylation step realized
under standard conditions (allyl bromide, NaH, DMF) afforded
alkenes (5S)-6 (86%) and (5R)-6 (82%).
The key metathesis of (5S)-6 and (5R)-6 was conducted in
CH2Cl2 in the presence of Grubbs’ first-generation catalyst and
led to the production of the corresponding heterocyclic ring17 on
the sugar moiety to afford (5S)-7 and (5R)-7 in 92% and 90% yields.
We tested different conditions to enhance the efficiency in RCM
reaction; both Grubbs I and II catalysts were tested, and the reac-
tions were carried out in toluene and CH2Cl2 at various tempera-
tures. Ultimately, the use of Grubbs I catalyst (10% mol) in dry
CH2Cl2 was found to be the most optimal (Scheme 1).
In order to further verify the configuration of the prepared
structures, we collected complete data sets (1H, 13C, COSY, HSQC)
including 1D-NOESY spectra for both molecules 10 and 13 in
D2O. In some cases spectral overlap hinders the detailed analysis
of the specific NMR resonances. This situation was especially
noticeable in compounds 10 and 13, where the signals of the
protons H-5a and H-8a in 10 and the signals of H-7 and H-8 in
13 overlapped (Supplementary data).
To enhance the structural diversity, two further analogues of
castanospermine 1 were derived from the common precursor
molecules (5S)-7 and (5R)-7 as well. Their exposure to the acid
hydrolysis (TFA) followed by hydrogenolysis resulted in the forma-
tion of 1-deoxycastanospermine 11 and 8a-epi-1-deoxycas-
tanospermine 12 in 65% and 62% yields over two steps,
respectively (Scheme 2). It should be noted that indolizidines
10–13 are known compounds and their structures were further
assigned by comparison of our data with those reported in the lit-
erature.24–28
O
NCS
5
NH2
5
HN
5
O
O
O
O
1
c
O
b
O
a
O
3. Conclusions
H
BnO
H
BnO
H
O
O
O
BnO
In conclusion, we have developed an efficient route towards
1-deoxycastanospemine 11 and its analogues (compounds 10, 12
and 13) from the appropriate sugar isothiocyanates (5S)-2 and
(5R)-2. The key transformations are the ring-closing metathesis
to create the new dihydropyrrole skeleton and reductive amination
to establish the required indolizidine backbone. The final products
10–13 were constructed via six- or seven-step sequences in good
overall yields (30–36%).
(5R)-213
(5S)-213
(5R)-4, 84%
(5S)-4, 85%
(5R)-3, 86%
(5S)-3, 88%
Cbz
H
5`
3`
Cbz
O
Cbz
N
HN
5
N
4`
2`
O
O
d
e
O
5
O
O
1
2
4
3
H
H
BnO
H
O
O
O
BnO
BnO
(5R)-6, 82%
(5R)
-
, 97%
, 98%
5
(5R)
,
-7 90%
(5S)-5
(5S)-6, 86%
(5S)
-7, 92%
4. Experimental
4.1. General
Scheme 1. Reagents and conditions: (a) (i) NaH, MeOH, 0 °C?rt, 4 h; (ii) mesityl-
nitrile oxide, MeCN, rt; (b) 6 M NaOH, EtOH, reflux; (c) CbzCl, NaHCO3, EtOH/H2O
(1:1), 0 °C?rt; (d) allyl bromide, NaH, DMF, 0 °C?rt; (e) Grubbs I, DCM, 0 °C?rt.
All commercial reagents were used in the highest available pur-
ity from Aldrich, Merck and Acros Organics without further purifi-
cation. Solvents were dried and purified before use according to
standard procedures. For flash column chromatography on silica
gel, Kieselgel 60 (0.040–0.063 mm, 230–400 mesh, Merck) was
used. Solvents for chromatography (n-hexane, ethyl acetate,
methanol, dichloromethane) were distilled before use. Thin layer
chromatography was run on Merck silica gel 60 F254 analytical
plates; detection was carried out with either ultraviolet light
(254 nm), or spraying with a solution of phosphomolybdic acid, a
basic potassium permanganate solution, or a solution of concen-
trated H2SO4, with subsequent heating. 1H NMR and 13C NMR spec-
tra were recorded in CDCl3, CD3OD and C6D6 on a Varian Mercury
Plus 400 FT NMR (400.13 MHz for 1H and 100.6 MHz for 13C) or on
With the synthesis of (5S)-7 and (5R)-7 established, our next
task was to accomplish the modification of each olefin into the
final indolizidines 10–13. For this purpose, alkene (5R)-7 was con-
verted via an Upjohn dihydroxylation (K2OsO4,18–20 NMO) into diol
8 (76%), which after treatment with 60% TFA was submitted to
subsequent catalytic hydrogenation (10% Pd/C) to provide the
pentahydroxylated indolizidine 10 in 78% yield over two steps.
The spectroscopic data, melting point and specific rotation of 10
matched the values published in the literature for the same pro-
duct mp 170–173 °C, Ref. 27 mp 171–173 °C, Ref. 28 170–172 °C,
Ref. 29 174–178 °C, {[
a
]
25 = ꢀ4.0 (c 0.15, MeOH, Ref. 27
D
[a
]
D
25 = ꢀ5.2 (c 0.40, H2O), Ref. 28 [
a]
25 = ꢀ10.0 (c 0.67, MeOH),
D
Ref. 29 [
a
]
D = ꢀ4.4 (c 1.2, H2O), temperature not reported}. In the
same way, diastereoisomer (5S)-7 was then elaborated into indoli-
zidine 13 in 75% overall yield (Scheme 2). The [ value for 13
{[
25 = +20.1 (c 0.17, MeOH), Ref. 26 [ 25 = +19.4 (c 0.0026,
MeOH), Ref. 27 [
were in agreement with those previously reported.
a
Varian Premium COMPACT 600 (599.87 MHz for 1H and
a]
D
150.84 MHz for 13C) spectrometer using TMS as internal reference.
For 1H, d are given in parts per million (ppm) relative to TMS
(d = 0.0), CD3OD (d = 4.84) and C6D6 (d = 7.15) and for 13C relative
a]
a]
D
D
a]
25 = +21.7 (c 0.35, H2O)} and spectroscopic data
D
ˇ
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3
Cbz
Cbz
N
N
HO
HO
5
O
O
(S)
H
(R)
a
a
O
O
7
7
(5S)-
(5R)-
HO
HO
HO
H
O
O
BnO
BnO
8, 76%
9, 74%
b
b
b
b
OH
OH
OH
OH
OH
OH
OH
N
N
N
6
7
N
8a
6
7
6
7
6
7
2
2
HO
8a
8a
8a
1
1
1
1
8
8
8
8
OH
H
H
H
H
HO
HO
OH
OH
12, 62%
OH
OH
13, 75%
10, 78%
11
, 65%
Scheme 2. Reagents and conditions: (a) K2OsO4, NMO, t-BuOH/H2O (1:1), 40 °C; (b) (i) 60% TFA, rt (ii) H2, 10% Pd/C, MeOH, rt.
to CDCl3 (d = 77.0), CD3OD (d = 49.05) and C6D6 (d = 128.02). The
multiplicity of the 13C NMR signals concerning the 13C–1H coupling
was determined by the DEPT method. Chemical shifts (in ppm) and
coupling constants (in Hz) were obtained by first-order analysis;
assignments were derived from COSY and H/C correlation spectra.
Infrared (IR) spectra were measured with a Nicolet 6700 FT-IR
spectrometer and expressed in v values (cmꢀ1). Optical rotations
were measured on a P-2000 Jasco polarimeter and reported as fol-
3H, OCH3), 3.99 (d, 1H, J3,4 = 3.3 Hz, H3), 4.19 (m, 1H, H4), 4.47 (d,
1H, JH,H = 11.5 Hz, CH2Ph), 4.57 (d, 1H, J1,2 = 3.9 Hz, H2), 4.65 (d,
1H, JH,H = 11.5 Hz, CH2Ph), 4.75 (m, 1H, H5), 5.16 (ddd, 1H,
J6,7cis = 10.4 Hz, J5,7cis = 1.2 Hz, J7cis,7trans = 1.2 Hz, H7cis), 5.29 (ddd,
1H, J6,7trans = 17.1 Hz, J5,7trans = 1.2 Hz, J7cis,7trans = 1.2 Hz, H7trans),
5.71 (m, 1H, NH), 5.77 (ddd, 1H, J6,7trans = 17.1 Hz, J6,7cis = 10.4 Hz,
J5,6 = 5.5 Hz, H6), 5.96 (d, 1H, J1,2 = 3.9 Hz, H1), 7.40–7.31 (m, 5H,
Ph); 13C NMR (100 MHz, CDCl3): d 26.2 (CH3), 26.7 (CH3), 52.0
(OCH3), 52.8 (C5), 72.2 (CH2Ph), 79.8 (C4), 81.5 (C2), 82.8 (C3),
104.9 (C1), 111.6 (Cq), 116.5 (C7), 128.1 (2 ꢁ CHPh), 128.3 (CHPh),
128.6 (2 ꢁ CHPh), 134.9 (C6), 136.6 (Ci), 156.7 (C@O). Anal. Calcd
for C19H25NO6: C, 62.80; H, 6.93; N, 3.85. Found: C, 62.68; H,
6.81; N, 3.70.
lows: [a] (c in grams per 100 mL, solvent). Melting points were
D
recorded on a Kofler hot block and are uncorrected. Microwave
reactions were carried out on the focused microwave system
(CEM Discover). The temperature content of the vessel was moni-
tored using a calibrated infrared sensor mounted under the vessel.
At the end of all reactions, the contents of vessel were cooled
rapidly using a stream of compressed air. Small quantities of
reagents (lL) were measured with appropriate syringes (Hamil-
ton). All reactions were performed under an atmosphere of nitro-
gen, unless otherwise noted.
Diastereoisomer (5S)-3: [a]
25 = +19.3 (c 0.25, CHCl3). 1H NMR
D
(400 MHz, CDCl3): d 1.32 (s, 3H, CH3), 1.48 (s, 3H, CH3), 3.62 (s,
3H, OCH3), 3.90 (d, 1H, J3,4 = 3.2 Hz, H3), 4.06 (dd, 1H, J3,4 = 3.2 Hz,
J4,5 = 7.6 Hz, H4), 4.47 (d, 1H, JH,H = 11.6 Hz, CH2Ph), 4.54–4.61 (m,
1H, H5), 4.62 (d, 1H, J1,2 = 3.8 Hz, H2), 4.66 (d, 1H, JH,H = 11.6 Hz,
CH2Ph), 5.00–5.05 (m, 1H, NH), 5.16 (ddd, 1H, J5,7cis
J7cis,7trans = 1.3 Hz, J6,7cis = 10.4 Hz, H7cis), 5.29 (ddd, 1H, J5,7trans
=
=
4.1.1. 3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-(meth-
oxycarbonylamino)-
O-benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-(methoxycar-
bonylamino)-b- -ido-hept-6-enfuranose (5S)-3
a
-
D
-gluco-hept-6-enfuranose (5R)-3 and 3-
J7cis,7trans = 1.3 Hz, J6,7trans = 17.0 Hz, H7trans), 5.75 (ddd, 1H,
J5,6 = 5.9 Hz, J6,7cis = 10.4 Hz, J6,7trans = 17.0 Hz, H6), 5.95 (d, 1H,
J1,2 = 3.8 Hz, H1), 7.29–7.38 (m, 5H, Ph); 13C NMR (100 MHz, CDCl3):
d 26.2 (CH3), 26.7 (CH3), 52.0 (OCH3), 52.6 (C5), 71.9 (CH2Ph), 81.1
(C4), 81.8 (C2), 81.9 (C3), 104.9 (C1), 111.6 (Cq), 116.8 (C7), 127.8
(2 ꢁ CHPh), 128.1 (CHPh), 128.5 (2 ꢁ CHPh), 135.3 (C6), 137.0 (Ci),
156.5 (C@O). Anal. Calcd for C19H25NO6: C, 62.80; H, 6.93; N,
3.85. Found: C, 62.65; H, 6.96; N, 3.73.
L
To a solution of isothiocyanate (5R)-2 (0.2 g, 0.484 mmol) in dry
MeOH (4.9 mL) was added sodium methoxide (28.6 mg,
0.53 mmol) at room temperature. After 6.5 h, no starting material
was detected (judged by TLC) in the reaction mixture. The solvent
was evaporated in vacuo, and the residue was partitioned between
CH2Cl2 (10 mL) and water (2 mL). The aqueous layer was extracted
with further portions of CH2Cl2 (2 ꢁ 5 mL). The combined organic
extracts were dried over Na2SO4, the solvent was evaporated, and
the residue was purified through a short column of silica gel
(n-hexane/ethyl acetate, 11:1) to give 0.174 g (81%) of thiocarba-
mate as a colourless oil, which was used immediately in the
subsequent reaction without spectral characterization.
4.1.2. 3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-amino-
a-D-gluco-hept-6-enfuranose (5R)-4 and 3-O-benzyl-5,6,7-tride-
oxy-1,2-O-isopropylidene-5-amino-b-
L-ido-hept-6-enfuranose
(5S)-4
A solution of carbamate (5R)-3 (1.05 g, 2.89 mmol) in EtOH
(20 mL) was treated with a 6 M aq NaOH solution (20 mL), and
the resulting mixture was stirred and heated at reflux for 26 h.
After cooling to room temperature, the mixture was then extracted
with Et2O (3 ꢁ 50 mL). The combined organic layers were dried
over Na2SO4, the solvent was evaporated, and the residue was
chromatographed on silica gel (n-hexane/ethyl acetate/Et3N,
1:5:0.05) to furnish 0.741 g (84%) of amine (5R)-4 as a colourless
oil.
To
a
solution of the obtained thiocarbamate (0.17 g,
0.381 mmol) in dry MeCN (3.4 mL) was added mesitylnitrile oxide
(68 mg, 0.42 mmol), and the resulting mixture was stirred for 3 h
at room temperature. Evaporation of solvent and chromatography
of the residue on silica gel (n-hexane/ethyl acetate, 9:1) afforded
0.147 g (86%) of carbamate (5R)-3 as a colourless oil.
The reaction of (5S)-2 (0.5 g, 1.44 mmol) with sodium methox-
ide (86 mg, 1.59 mmol) in dry MeOH (10 mL) and subsequent reac-
tion of the crude thiocarbamate with mesitylnitrile oxide (0.255 g,
1.58 mmol) using the same procedure as described for the prepara-
tion of (5R)-3 provided carbamate (5S)-3 (0.523 g, 88%, colourless
oil).
The reaction of (5S)-3 (0.950 g, 2.62 mmol) with 6 M aq NaOH
solution (16 mL) in EtOH (16 mL) under the same reaction condi-
tions as described for the preparation of (5R)-4, afforded amine
(5S)-4 (0.680 g, 85%, colourless oil).
Diastereoisomer (5R)-4: [
(400 MHz, CDCl3): d 1.19 (s, 2H, NH2), 1.32 (s, 3H, CH3), 1.47 (s,
a
]
25 = ꢀ53.2 (c 0.13, CHCl3). 1H NMR
D
Diastereoisomer (5R)-3: [
a]
D
25 = +44.2 (c 0.33, CHCl3). 1H NMR
(400 MHz, CDCl3): d 1.32 (s, 3H, CH3), 1.48 (s, 3H, CH3), 3.64 (s,
3H, CH3), 3.69–3.74 (m, 1H, H5), 3.92 (dd, 1H, J3,4 = 3.3 Hz,
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4
J4,5 = 8.6 Hz, H4), 4.02 (d, 1H, J3,4 = 3.3 Hz, H3), 4.49 (d, 1H,
JH,H = 11.6 Hz, CH2Ph), 4.63 (d, 1H, J1,2 = 3.9 Hz, H2), 4.73 (d, 1H,
JH,H = 11.8 Hz, CH2Ph), 4.70 (d, 1H, J1,2 = 3.9 Hz, H2), 5.01–5.13 (m,
3H, COOCH2Ph, NH), 5.15 (dd, 1H, J7cis,7trans = 1.3 Hz, J6,7cis = 10.4 Hz,
H7cis), 5.28 (dd, 1H, J7cis,7trans = 1.4 Hz, J6,7trans = 17.2 Hz, H7trans),
5.79 (ddd, 1H, J5,6 = 6.0 Hz, J6,7cis = 10.5 Hz, J6,7trans = 17.2 Hz, H6),
5.94 (d, 1H, J1,2 = 3.9 Hz, H1), 7.27–7.40 (m, 10H, Ph); 13C NMR
JH,H = 11.6 Hz, CH2Ph), 5.14 (ddd, 1H, J7cis,7trans = 1.4 Hz, J5,7cis
=
1.4 Hz, J6,7cis = 10.5 Hz, H7cis), 5.27 (ddd, 1H, J7cis,7trans = 1.5 Hz,
J5,7trans = 1.5 Hz, J6,7trans = 17.3 Hz, H7trans), 5.95 (d, 1H, J1,2 = 3.8 Hz,
H1), 5.99 (ddd, 1H, J5,6 = 6.1 Hz, J6,7cis = 10.5 Hz, J6,7trans = 17.2 Hz,
H6), 7.28–7.40 (5H, m, Ph); 13C NMR (100 MHz, CDCl3): d 26.2
(CH3), 26.7 (CH3), 52.2 (C5), 71.7 (CH2Ph), 81.6 (C3), 81.7 (C2),
83.7 (C4), 105.1 (C1), 111.5 (Cq), 115.0 (C7), 128.0 (2 ꢁ CHPh),
128.1 (CHPh), 128.6 (2 ꢁ CHPh), 137.1 (Ci), 137.5 (C6). Anal. Calcd
for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C, 66.84; H,
7.61; N, 4.55.
(100 MHz, CDCl3): d 26.3 (CH3), 26.9 (CH3), 52.8 (C5), 66.7 (CCbz
)
72.1 (CH2Ph), 81.2 (C4), 82.2 (C2), 82.3 (C3), 105.1 (C1), 111.8 (Cq),
116.7 (C7), 128.0 (2 ꢁ CHPh), 128.1 (CHPh), 128.2 (2 ꢁ CHPh), 128.2
(CHPh), 128.6 (2 ꢁ CHPh), 128.7 (2 ꢁ CHPh), 135.7 (C6), 137.0 (Ci),
137.0 (Ci), 156.0 (C@O). Anal. Calcd for C17H23NO4: C, 68.32; H,
6.65; N, 3.19. Found: C, 68.43; H, 6.59; N, 3.22.
Diastereoisomer (5S)-4: [
a
]
25 = ꢀ44.4 (c 0.11, CHCl3). 1H NMR
4.1.4. 3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-[allyl-
D
(400 MHz, CDCl3): d 1.32 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.63 (s,
2H, NH2), 3.81–3.86 (m, 1H, H5), 3.87 (d, 1H, J3,4 = 3.1 Hz, H3),
3.91 (dd, 1H, J3,4 = 3.1 Hz, J4,5 = 8.6 Hz, H4), 4.46 (d, 1H,
JH,H = 11.6 Hz, CH2Ph), 4.63 (d, 1H, J1,2 = 3.8 Hz, H2), 4.66 (d, 1H,
(benzyloxycarbonyl)amino]-
6 and 3-O-benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-[allyl-
(benzyloxycarbonyl)amino]-b- -ido-hept-6-enfuranose (5S)-6
a-D-gluco-hept-6-enfuranose (5R)-
L
To a solution of (5R)-5 (1.0 g, 2.28 mmol) in dry DMF (25 mL)
that had been pre-cooled to 0 °C was added NaH (0.109 g,
4.54 mmol, 60% dispersion in mineral oil), and the resulting sus-
pension was stirred for 30 min at 0 °C before the addition of allyl
bromide (0.50 mL, 5.78 mmol). The mixture was allowed to warm
to room temperature and then it was continued for another 1.5 h.
After cautious addition of NH4Cl (5 mL), the reaction mixture was
extracted with Et2O (3 ꢁ 70 mL), and the combined organic layers
were dried over Na2SO4. Evaporation of solvent and chromatogra-
phy of the residue on silica gel (n-hexane/ethyl acetate, 5:1)
afforded 0.895 g (82%) of derivative (5R)-6 as a colourless oil.
The reaction of (5S)-5 (0.960 g, 2.18 mmol) with NaH (0.105 g,
4.36 mmol) and allyl bromide (0.47 mL, 5.45 mmol) using the same
procedure as described for the preparation of (5R)-6 gave product
(5S)-6 (0.899 g, 86%, colourless oil).
JH,H = 11.6 Hz, CH2Ph), 5.12 (ddd, 1H, J7cis,7trans = 1.4 Hz, J5,7cis
=
1.4 Hz, J6,7cis = 10.5 Hz, H7cis), 5.30 (ddd, 1H, J7cis,7trans = 1.5 Hz,
J5,7trans = 1.5 Hz, J6,7trans = 17.2 Hz, H7trans), 5.76 (ddd, 1H,
J5,6 = 6.1 Hz, J6,7cis = 10.5 Hz, J6,7trans = 17.3 Hz, H6), 5.95 (d, 1H,
J1,2 = 3.8 Hz, H1), 7.27–7.39 (5H, m, Ph); 13C NMR (100 MHz, CDCl3):
d 26.3 (CH3), 26.7 (CH3), 52.3 (C5), 72.0 (CH2Ph), 82.0 (C3), 82.1 (C2),
84.4 (C4), 104.9 (C1), 111.7 (Cq), 116.3 (C7), 127.7 (2 ꢁ CHPh), 128.0
(CHPh), 128.5 (2 ꢁ CHPh), 137.2 (Ci), 137.6 (C6). Anal. Calcd for
C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C, 66.81; H, 7.65;
N, 4.62.
4.1.3. 3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-(benz-
yloxycarbonylamino)-
3-O-benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-(benzyloxy-
carbonylamino)-b- -ido-hept-6-enfuranose (5S)-5
a-D-gluco-hept-6-enfuranose (5R)-5 and
L
Diastereoisomer (5R)-6: [
a]
25 = ꢀ44.2 (c 0.15, CHCl3). 1H NMR
D
To a solution of amine (5R)-4 (0.741 g, 2.43 mmol) in a mixture
of 1:1 EtOH/H2O (25 mL) that had been pre-cooled to 0 °C were
successively added NaHCO3 (0.551 g, 6.56 mmol) and CbzCl
(0.52 mL, 3.64 mmol). The resulting mixture was stirred at 0 °C
for 10 min and then for 1.5 h at room temperature before the addi-
tion of H2O (10 mL). After extraction with CH2Cl2 (3 ꢁ 70 mL), the
combined organic layers were dried over Na2SO4, the solvent was
evaporated, and the residue was purified by flash chromatography
on silica gel (n-hexane/ethyl acetate, 3:1) to afford 1.0 g (97%) of
compound (5R)-5 as a colourless oil.
(400 MHz, CDCl3): d 1.29 (s, 3H, CH3), 1.42 (s, 1H, CH3), 3.61 (dd,
1H, J8,9 = 7.4 Hz, J8,8 = 15.6 Hz, H8), 3.93 (d, 1H, J3,4 = 3.3 Hz, H3),
4.07–4.21 (m, 1H, H8), 4.47 (d, 1H, JH,H = 11.7 Hz, CH2Ph), 4.53 (d,
1H, J1,2 = 3.9 Hz, H2), 4.55–4.65 (m, 3H, H4, H5, CH2Ph), 5.00–5.10
(m, 3H, COOCH2Ph, 2 ꢁ H10), 5.12–5.23 (m, 3H, COOCH2Ph,
2 ꢁ H7), 5.74 (m, 1H, H9), 5.91 (d, 1H, J1,2 = 3.8 Hz, H1), 6.03–6.17
(m, 1H, H6), 7.27–7.36 (m, 10H, Ph); 13C NMR (100 MHz, CDCl3):
d 26.6 (CH3), 27.0 (CH3), 50.4 (C8), 58.5 (C5), 67.5 (CCbz), 72.2
(CH2Ph), 80.4 (C4), 82.1 (C2), 82.5 (C3), 105.3 (C1), 111.9 (Cq),
2 ꢁ 117.2 (C7, C10), 128.0 (2 ꢁ CHPh), 128.1 (CHPh), 128.2
(2 ꢁ CHPh), 128.3 (2 ꢁ CHPh), 128.6 (3 ꢁ CHPh), 2 ꢁ 135.1 (C6, C9),
136.9 (Ci), 137.7 (Ci), 156.2 (C@O). Anal. Calcd for C28H33NO6: C,
70.13; H, 6.94; N, 2.92. Found: C, 70.14; H, 6.97; N, 2.96.
The reaction of (5S)-4 (0.680 g, 2.23 mmol) with NaHCO3
(0.506 g, 6.02 mmol) and CbzCl (0.48 mL, 3.35 mmol) in a mixture
of 1:1 EtOH/H2O (25 mL) according to the same procedure
described for the preparation of (5R)-5 gave carbamate (5S)-5
(0.960 g, 98%, colourless oil).
Diastereoisomer (5S)-6: [
a]
25 = ꢀ4.07 (c 0.11, CHCl3). 1H NMR
D
(400 MHz, CDCl3): d 1.31 (s, 3H, CH3), 1.44 (s, 1H, CH3), 3.79–3.95
(m, 2H, H8, H3), 4.08 (dd, 1H, J8,9 = 5.6 Hz, J8,8 = 16.1 Hz, H8), 4.45
(d, 1H, JH,H = 11.6 Hz, CH2Ph), 4.58 (d, 1H, J1,2 = 3.8 Hz, H2), 4.62
(d, 1H, JH,H = 11.6 Hz, CH2Ph), 4.66–4.80 (m, 1H, H5), 5.02–5.27
(m, 6H, 2 ꢁ H7, 2 ꢁ H10, COOCH2Ph), 5.80–6.01 (m, 3H, H1, H6,
H9), 7.27–7.38 (m, 10H, Ph); 13C NMR (100 MHz, CDCl3): d 26.6
(CH3), 27.0 (CH3), 49.6 (C8), 59.3 (C5), 67.1 (CCbz), 72.1 (CH2Ph),
78.6 (C4), 81.9 (C2), 82.1 (C3), 105.1 (C1), 111.8 (Cq), 116.3 (C7),
118.9 (C10), 127.8 (2 ꢁ CHPh), 127.9 (3 ꢁ CHPh), 128.0 (1 ꢁ CHPh),
128.5 (2 ꢁ CHPh), 128.6 (2 ꢁ CHPh), 133.3 (C6), 135.6 (C9), 137.0
(Ci), 137.4 (Ci), 156.2 (C@O). Anal. Calcd for C28H33NO6: C, 70.13;
H, 6.94; N, 2.92. Found: C, 70.10; H, 6.86; N, 2.93.
Diastereoisomer (5R)-5: [
a]
25 = ꢀ10.9 (c 0.11, CHCl3). 1H NMR
D
(400 MHz, CDCl3): d 1.32 (s, 3H, CH3), 1.48 (s, 3H, CH3), 4.01 (d, 1H,
J3,4 = 3.4 Hz, H3), 4.21 (dd, 1H, J3,4 = 3.4 Hz, J4,5 = 6.0 Hz, H4), 4.48
(d, 1H, JH,H = 11.5 Hz, CH2Ph), 4.55 (d, 1H, J1,2 = 3.9 Hz, H2), 4.62 (d,
1H, JH,H = 11.5 Hz, CH2Ph), 4.71–4.81 (m, 1H, H5), 5.08–5.12 (m,
2H, COOCH2Ph), 5.17 (dd, 1H, J7cis,7trans = 1.5 Hz, J6,7cis = 10.4 Hz,
H7cis), 5.28 (dd, 1H, J7cis,7trans = 1.5 Hz, J6,7trans = 17.2 Hz, H7trans),
5.66 (s, 1H, NH), 5.83 (ddd, 1H, J5,6 = 5.5 Hz, J6,7cis = 10.4 Hz,
J6,7trans = 17.2 Hz, H6), 5.94 (d, 1H, J1,2 = 3.8 Hz, H1), 7.27–7.39 (m,
10H, Ph); 13C NMR (100 MHz, CDCl3): d 26.3 (CH3), 26.8 (CH3), 53.0
(C5), 66.5 (CCbz) 72.4 (CH2Ph), 80.2 (C4), 81.9 (C2), 83.1 (C3), 105.1
(C1), 111.7 (Cq), 116.3 (C7), 128.0 (2 ꢁ CHPh), 128.2 (CHPh), 128.2
(2 ꢁ CHPh), 128.3 (CHPh), 128.5 (2 ꢁ CHPh), 128.8 (2 ꢁ CHPh), 135.3
(C6), 136.9 (Ci), 137.0 (Ci), 156.0 (C@O). Anal. Calcd for C17H23NO4:
C, 68.32; H, 6.65; N, 3.19. Found: C, 68.40; H, 6.63; N, 3.25.
4.1.5. (20R,4R)-4-C-[10-(Benzyloxycarbonyl)-20,50-dihydro-10H-
pyrrol-20-yl]-3-O-benzyl-1,2-O-isopropylidene-
a-D-gluco-fura-
nose (5R)-7 and (20S,4R)-4-C-[10-(benzyloxycarbonyl)-20,50-dihy-
Diastereoisomer (5S)-5: [
a
]
25 = ꢀ52.1 (c 0.13, CHCl3). 1H NMR
dro-10H-pyrrol-20-yl]-3-O-benzyl-1,2-O-isopropylidene-b-
furanose (5S)-7
L-threo-
D
(400 MHz, CDCl3): d 1.32 (s, 3H, CH3), 1.48 (s, 3H, CH3), 3.92
(d, 1H, J3,4 = 3.3 Hz, H3), 4.08–4.13 (m, 1H, H4), 4.48 (d, 1H,
JH,H = 11.7 Hz, CH2Ph), 4.56–4.61 (m, 1H, H5), 4.64 (d, 1H,
To a solution of (5R)-6 (0.895 g, 1.87 mmol) in dry CH2Cl2
(55 mL) that had been pre-cooled to 0 °C was added Grubb’s
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J. Elecko et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
first-generation catalyst (0.154 g, 0.187 mmol). After stirring at
4.1.7. (6S,7R,8R,8aS)-6,7,8-Trihydroxyindolizidine (8a-epi-1-de-
oxycastanospermine) 12
The reaction of (5S)-7 (0.160 g, 0.35 mmol) with 60% TFA (2 mL)
and subsequent hydrogenation in dry MeOH (5 mL) using 10% Pd/
C/20% Pd(OH)2/C (110 mg/10 mg) mixture following the same pro-
cedure as described for the preparation of compound 11 gave 8a-
room temperature for 30 min, the solvent was evaporated, and
the residue was subjected to flash chromatography on Al2O3 (n-
hexane/ethyl acetate, 6:1) to afford 0.758 g (90%) of (5R)-7 as a
colourless oil.
The reaction of (5S)-6 (0.898 g, 1.87 mmol) with Grubbs I
(0.154 g, 0.187 mmol) in dry CH2Cl2 (55 mL) using the same reac-
tion conditions as described for the preparation of (5R)-7 gave
derivative (5S)-7 (0.777 mg, 92%, colourless oil).
epi-1-deoxycastanospermine 12 (colourless foam, 38 mg, 62%);
25
mp 147–149 °C, (Ref. 22 149–150 °C, Ref. 25 190–192 °C); [
+42.2 (c 0.15, MeOH), {(Ref. 25 [
22 = +41.8 (c 0.0057, MeOH), Ref. 24 [ 20 = +23.0 (c 0.72, MeOH),
a]
D
a
]
=
D
a]
20 = +44.4 (c 1.3, H2O), Ref. 22
D
Diastereoisomer (5R)-7: [
a]
D
25 = +68.7 (c 0.11, CHCl3). 1H NMR
[
a
]
D
(400 MHz, CDCl3): d 1.31 (s, 3H, CH3), 1.44 (s, 3H, CH3), 4.06–4.34
(m, 3H, 2 ꢁ H8, H3), 4.56 (d, 1H, J1,2 = 3.8 Hz, H2), 4.58–4.71 (m,
3H, CH2Ph, H4), 4.80–4.96 (m, 1H, H5), 5.11 (d, 1H, JH,H = 12.4 Hz,
COOCH2Ph), 5.21 (d, 1H, JH,H = 12.4 Hz, COOCH2Ph), 5.77–5.84 (m,
1H, H7), 5.86 (d, 1H, J1,2 = 3.9 Hz, H1), 5.86–5.94 (m, 1H, H6),
7.27–7.39 (m, 10H, Ph); 13C NMR (100 MHz, CDCl3): d 26.5 (CH3),
26.9 (CH3), 53.5 (C8), 63.9 (C5), 66.9 (CCbz), 72.3 (CH2Ph), 81.2
(C4), 82.6 (C2), 83.6 (C3), 105.0 (C1), 111.8 (Cq), 125.8 (C7), 127.7
(CHPh), 127.9 (2 ꢁ CHPh), 128.0 (2 ꢁ CHPh), 128.3 (CHPh), 128.5
(2 ꢁ CHPh), 128.6 (2 ꢁ CHPh), 128.8 (C6), 137.0 (Ci), 137.7 (Ci),
155.0 (C@O). Anal. Calcd for C26H29NO6: C, 69.16; H, 6.47; N,
3.10. Found: C, 69.30; H, 6.43; N, 3.15.
Ref. 6 [a]
26 = +40.9 (c 0.00042, MeOH)}. 1H NMR (400 MHz,
D
CD3OD): d 1.70–1.87 (m, 3H, H1, 2 ꢁ H2), 1.90–1.98 (m, 1H, H1),
2.36 (m, 1H, H5), 2.60–2.70 (m, 2H, H8a, H3), 3.02–3.14 (m, 2H,
H3, H5), 3.72–3.78 (m, 2H, H6, H8), 3.85 (t, 1H, J6,7 = J7,8 = 3.2 Hz,
H7); 13C NMR (100 MHz, CD3OD): d 21.3 (C2), 24.7 (C1), 55.1 (C3),
55.4 (C5), 53.9 (C8a), 70.9 (C6), 70.9 (C8), 71.0 (C7). Anal. Calcd for
C8H15NO3: C, 55.47; H, 8.73; N, 8.09. Found: C, 55.38; H, 8.84; N,
8.08.
4.1.8. (4R)-4-C-[(20R,30S,40R)-10-(Benzyloxycarbonyl)-30,40-dihy-
droxypyrrolidin-20-yl]-3-O-benzyl-1,2-O-isopropylidene-
a-D-gluco-
furanose 8 and (4R)-4-C-[(20S,30R,40S)-10-(benzyloxycarbonyl)-
30,40-dihydroxypyrrolidin-20-yl]-3-O-benzyl-1,2-O-isopropylidene-
Diastereoisomer (5S)-7: [
a
]
D
25 = ꢀ0.9 (c 0.11, CHCl3). 1H NMR
(400 MHz, CDCl3): d 1.31 (s, 3H, CH3), 1.45 (s, 3H, CH3), 3.88
(d, 1H, J3,4 = 3.3 Hz, H3), 3.97–4.07 (m, 1H, H8), 4.18–4.28 (m,
1H, H4), 4.29–4.38 (m, 1H, H8), 4.42 (d, 1H, JH,H = 11.8 Hz,
CH2Ph), 4.52 (d, 1H, J1,2 = 3.8 Hz, H2), 4.64 (d, 1H, JH,H = 11.8
Hz, CH2Ph), 5.02–5.16 (m, 2H, COOCH2Ph, H5), 5.23 (d, 1H,
JH,H = 12.5 Hz, COOCH2Ph), 5.63–5.70 (m, 1H, H7), 5.71–5.78
(m, 1H, H6), 5.92–6.02 (m, 1H, H1), 7.27–7.43 (m, 10H, Ph);
13C NMR (100 MHz, CDCl3): d 26.5 (CH3), 27.0 (CH3), 54.3 (C8),
63.8 (C5), 67.2 (CCbz), 72.0 (CH2Ph), 81.8 (C4), 82.2 (C2), 83.0
(C3), 105.4 (C1), 111.7 (Cq), 126.9 (C7), 127.9 (CHPh), 127.9
(2 ꢁ CHPh), 128.1 (CHPh), 128.3 (2 ꢁ CHPh), 128.5 (2 ꢁ CHPh),
128.6 (2 ꢁ CHPh), 128.8 (C6), 137.3 (Ci), 137.6 (Ci), 155.5
(C@O). Anal. Calcd for C26H29NO6: C, 69.16; H, 6.47; N, 3.10.
Found: C, 69.23; H, 6.53; N, 3.05.
b-L
-threofuranose 9
To a solution of (5R)-7 (0.20 g, 0.44 mmol) in a mixture of 1:1
t-BuOH/H2O (4 mL) were added NMO (77 mg, 0.57 mmol) and
K2OsO4ꢂ2H2O (8 mg, 0.02 mmol), and the resulting mixture was
stirred at 40 °C for 4 h. After the cautious addition of H2O (3 mL),
the mixture was extracted with ethyl acetate (3 ꢁ 15 mL), and
the combined organic layers were successively washed with a sat-
urated Na2S2O3 solution (15 mL), then with brine (5 ml) and finally
dried. The solvent was subsequently evaporated and the residue
was subjected to flash chromatography on silica gel (n-hexane/
ethyl acetate, 1:1) to give 0.158 g (76%) of diol 8 as a colourless oil.
The reaction of (5S)-7 (0.230 g, 0.51 mmol) with K2OsO4ꢂ2H2O
(8 mg, 0.02 mmol) in the presence of NMO (89 mg, 0.66 mmol) in
a mixture of 1:1 t-BuOH/H2O (5 mL) using the same procedure as
described for the preparation of 8 gave compound 9 (0.184 g,
74%, colourless oil).
4.1.6. (6S,7R,8R,8aR)-6,7,8-Trihydroxyindolizidine (1-deoxycast-
anospermine) 11
Diastereoisomer 8:
[a]
25 = +23.8 (c 0.16, CHCl3). 1H NMR
D
To a solution of (5R)-7 (0.20 g, 0.44 mmol) in CH2Cl2 (2 mL)
that had been pre-cooled to 0 °C was added 60% TFA (5 mL). After
stirring at room temperature for 5 h, the solvent was co-evapo-
rated three times with toluene. The obtained crude product was
dissolved in dry MeOH (5 mL), 10% Pd/C/20% Pd(OH)2/C
(120 mg/10 mg) mixture was added, and the resulting suspension
was stirred at room temperature for 20 h under an atmosphere of
hydrogen. The catalyst was filtered through a small pad of Celite
and washed with MeOH. The filtrate was concentrated under
reduced pressure, and the residue was chromatographed on silica
gel (chloroform/methanol, 3:2) to furnish 50 mg (65%) of product
11 as white crystals; mp 177–179 °C (Ref. 21 mp 178–181 °C, Ref.
22 mp 177–179.5 °C, Ref. 23 mp 179–180 °C, Ref. 24 mp 176–
(400 MHz, CDCl3): d 1.32 (s, 3H, CH3), 1.44 (s, 3H, CH3), 2.55 (s,
1H, OH), 3.06 (s, 1H, OH), 3.50 (dd, 1H, J7,8 = 4.6 Hz, J8,8 = 11.8 Hz,
H8), 3.61–3.71 (m, 1H, H8), 3.99–4.05 (m, 1H, H5), 4.23–4.29 (m,
1H, H7), 4.45–4.50 (m, 1H, H6), 4.50–4.58 (m, 1H, CH2Ph), 4.63 (d,
1H, J1,2 = 3.9 Hz, H2), 4.72 (d, 1H, JH,H = 11.2 Hz, CH2Ph), 4.75–4.88
(m, 1H, H4), 5.08 (d, 1H, JH,H = 12.0 Hz, COOCH2Ph), 5.15 (d, 1H,
JH,H = 12.0 Hz, COOCH2Ph), 5.92 (d, 1H, J1,2 = 3.9 Hz, H1), 7.26–
7.43 (m, 10H, Ph); 13C NMR (100 MHz, CDCl3): d 26.3 (CH3), 26.8
(CH3), 51.3 (C8), 62.3 (C5), 66.9 (CCbz), 70.4 (C7), 71.2 (C6), 72.5
(CH2Ph), 79.4 (C4), 81.9 (C2), 83.9 (C3), 104.8 (C1), 112.0 (Cq),
127.8 (CHPh), 127.9 (CHPh), 128.2 (2 ꢁ CHPh), 128.4 (2 ꢁ CHPh),
128.6 (2 ꢁ CHPh), 128.8 (2 ꢁ CHPh), 136.1 (Ci), 136.5 (Ci), 155.4
(C@O). Anal. Calcd for C26H31NO8: C, 64.32; H, 6.44; N, 2.88. Found:
C, 64.40; H, 6.44; N, 2.83.
178 °C); [
MeOH), Ref. 22 [
(c 1.2, MeOH), Ref. 24 [
a
]
25 = +50.2 (c 0.1, MeOH), {(Ref. 1 [
a
]
D = +50.6 (c 0.2,
D
a]
22 = +47.8 (c 0.006, MeOH), Ref. 23 [ 29 = +50
a]
D
Diastereoisomer 9:
[a
]
D
25 = ꢀ52.9 (c 0.18, CHCl3). 1H NMR
D
a]
D = +50.1 (c 0.7, MeOH)}. 1H NMR
(400 MHz, CDCl3): d 1.33 (s, 3H, CH3), 1.46 (s, 3H, CH3), 2.62 (s,
1H, OH), 2.69 (s, 1H, OH), 3.22 (dd, 1H, J7,8 = 3.8 Hz, J8,8 = 12.1 Hz,
H8), 3.65–3.76 (m, 1H, H8), 3.90–4.01 (m, 1H, H5), 4.02–4.07 (m,
1H, H3), 4.17–4.23 (m, 1H, H7), 4.35 (d, 1H, JH,H = 11.5 Hz, CH2Ph),
4.54–4.51 (m, 2H, H2, CH2Ph), 4.63–4.71 (m, 1H, H6), 4.81–4.97
(m, 1H, H4), 5.10 (d, 1H, JH,H = 12.3 Hz, COOCH2Ph), 5.17 (d, 1H,
JH,H = 12.2 Hz, COOCH2Ph), 6.00 (d, 1H, J1,2 = 3.7 Hz, H1), 7.20–7.42
(10H, m, Ph); 13C NMR (100 MHz, CDCl3): d 26.3 (CH3), 26.8
(CH3), 52.9 (C8), 60.7 (C5), 67.2 (CCbz), 69.9 (C7), 72.2 (C6), 74.1
(CH2Ph), 78.9 (C4), 82.1 (C2), 83.6 (C3), 105.2 (C1), 112.1 (Cq),
(400 MHz, D2O): d 1.43–1.56 (m, 1H, H1), 1.72–1.87 (m, 2H,
2 ꢁ H2), 1.98–2.08 (m, 1H, H1), 2.09–2.22 (m, 2H, H8a, H5), 2.34
(1H, dt, J3,3 = 9.1 Hz, J2,3 = 9.2 Hz, H3), 2.95–3.05 (m, 1H, H3),
3.17 (dd, 1H, J5,6 = 5.3 Hz, J5,5 = 11.1 Hz, H5), 3.19–3.28 (m, 2H,
H7, H8), 3.6 (ddd, 1H, J5,6 = 5.3 Hz, J6,7 = 8.8 Hz, J5,6 = 10.9 Hz, H6);
13C NMR (100 MHz, CD3OD): d 22.7 (C2), 29.2 (C1), 54.6 (C3),
57.4 (C5), 69.3 (C8a), 72.1 (C6), 76.4 (C8), 80.8 (C7). Anal. Calcd
for C8H15NO3: C, 55.47; H, 8.73; N, 8.09. Found: C, 55.53; H,
8.75; N, 8.01.
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J. Elecko et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
6
127.6 (3 ꢁ CHPh), 128.0 (CHPh), 128.1 (2 ꢁ CHPh), 128.5 (2 ꢁ CHPh),
128.6 (2 ꢁ CHPh), 136.7 (Ci), 137.1 (Ci), 155.3 (C@O). Anal. Calcd for
References
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10
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mp 170–172 °C, Ref. 29 mp 174–178 °C); [
a
]
D
MeOH), {(Ref. 27 [
a]
25 = ꢀ5.2 (c 0.40, H2O), Ref. 28 [
a]
25 = ꢀ10
D
D
(c 0.67, MeOH), Ref. 29 [
a
]
D = ꢀ4.4 (c 1.2, H2O), temperature not
reported}. 1H NMR (600 MHz, CD3OD):
J1,8a = 7.1 Hz, J8,8a = 9.2 Hz, H8a), 2.08 (t, 1H, J5a,5b = J5a,6 = 10.5 Hz,
5a), 2.24 (dd, 1H, J2,3 = 6.2 Hz, J3a,3b = 9.5 Hz, H3b), 3.05 (dd, 1H,
d
2.04 (dd, 1H,
H
J5b,6 = 5.3 Hz, J5a,5b = 10.6 Hz, H5b), 3.17 (t, 1H, J6,7 = J7,8 = 8.9 Hz,
H7), 3.23–3.36 (m, 2H, H3a, H8), 3.50 (ddd, 1H, J5b,6 = 5.3 Hz,
J6,7 = 8.9 Hz, J5a,6 = 10.3 Hz, H6), 3.85 (t, 1H, J1,2 = J1,8a = 7.1 Hz, H1),
4.13 (q, 1H, J1,2 = J2,3a = J2,3b = 6.9 Hz, H2); 13C NMR (125 MHz,
CD3OD): d 57.3 (C5), 61.0 (C3), 69.8 (C2), 71.8 (C6), 72.7 (C8a), 75.1
(C8), 75.8 (C1), 80.9 (C7). Anal. Calcd for C8H15NO5: C, 46.82; H,
7.37; N, 6.38. Found: C, 46.77; H, 7.46; N, 6.39.
4.1.10. (1S,2R,6S,7R,8R,8aS)-1,2,6,7,8-Pentahydroxyindolizidine
13
The reaction of 9 (0.140 g, 0.29 mmol) with 60% TFA (2 mL) and
subsequent hydrogenation in dry MeOH (4 mL) using 10%
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procedure as described for the preparation of compound 10 gave
pentahydroxylated indolizidine derivative 13 (colourless oil,
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D
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25 = +20.1 (c 0.17, MeOH), {(Ref. 26 [ 25 = +19.4
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ˇ
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J5a,6 = 1.8 Hz, J5a,5b = 11.6 Hz, H5a), 2.89 (dd, 1H, J5b,6 = 1.8 Hz,
J5a,5b = 11.7 Hz, H5b), 3.36 (dd, 1H, J2,3b = 6.2 Hz, J3a,3b = 9.9 Hz,
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H
3b), 3.67–3.71 (m, 1H, H6), 3.81–3.88 (m, 2H, H7, H8), 4.00–4.12
(m, 2H, H1, H2); 13C NMR (100 MHz, CD3OD): d 55.5 (C5), 62.6
(C3), 67.1 (C8a), 68.3 (C2), 69.9 (C7), 70.3 (C8), 70.4 (C1), 71.2 (C6).
Anal. Calcd for C8H15NO5: C, 46.82; H, 7.37; N, 6.38. Found: C,
46.85; H, 7.39; N, 6.32.
Acknowledgements
The present work was supported by the Grant Agency (Grant
No. 1/0398/14) of the Ministry of Education, Slovak Republic. It
was also supported by the Slovak Research and Development
Agency (Grant No. APVV-14-0883).
Supplementary data
29. Matsumura, T.; Kasai, M.; Hayashi, T.; Arisawa, M.; Momose, Y.; Arai, I.;
Amagaya, S.; Komatsu, Y. Pharm. Biol. 2000, 38, 302–307.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.02.
011.
ˇ
Please cite this article in press as: Elecko, J.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.02.011