Synthesis of a protected trihydroxyindolizidine 3-carboxylate via a hetero-Diels-Alder addition of ethyl 2-nitrosoacrylate to a d-ribose-derived exo-glycal

Article abstract of DOI:10.1016/j.carres.2010.12.022

A protected trihydroxyindolizidine 3-carboxylate was prepared by a 6-endo epoxide cleavage, which in turn was intermediately formed from the hetero-Diels-Alder adduct of ethyl 2-nitrosoacrylate to a d-ribose-derived exo-glycal.

Full text of DOI:10.1016/j.carres.2010.12.022

Carbohydrate Research 346 (2011) 508–511
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Synthesis of a protected trihydroxyindolizidine 3-carboxylate
via a hetero-Diels–Alder addition of ethyl 2-nitrosoacrylate
to a D-ribose-derived exo-glycal
⇑
Zoe S. Massen, Evdoxia Coutouli-Argyropoulou, Vassiliki C. Sarli, John K. Gallos
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
A protected trihydroxyindolizidine 3-carboxylate was prepared by a 6-endo epoxide cleavage, which
Received 9 December 2010
Received in revised form 28 December 2010
Accepted 29 December 2010
Available online 3 January 2011
in turn was intermediately formed from the hetero-Diels–Alder adduct of ethyl 2-nitrosoacrylate to a
D
-ribose-derived exo-glycal.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Polyhydroxylated indolizidine alkaloids
Ethyl bromopyruvate
Ethyl 2-nitrosoacrylate
Hetero-Diels–Alder cycloaddition
exo-Glycals
Catalytic hydrogenation
Alkaloids mimicking the structures of monosaccharides are
widespread in plants and microorganisms; among them, those
with nitrogen in the ring (also called aza-sugars) can be classified
into five structural classes: pyrrolidines, piperidines, pyrrolizi-
dines, indolizidines and nortropanes.1 Many of them exhibit spe-
cific glycosidase and glycosyltranferase inhibition, being thus
potential therapeutical agents.2 Glycosidases and glycosyltrans-
ferases are involved in a variety of important biological processes,
such as intestinal digestion, post-translational processing of glyco-
proteins and the lysosomal catabolism of glycoconjugates, and it
has been shown that their inhibition is related to many diseases,
such as viral and microbial infection, cancer metastasis, diabetes
and other metabolic disorders.
Among the plethora of pyrrolizidine alkaloids, the members of
hyacinthacine family3 such as hyacinthacine B1 [(5R)-1] and hyacin-
thacine B2 [(5S)-1] (Scheme 1), with a carbon branch both at C-3
and C-5 positions, were isolated from the bulbs of Muscari armen-
icum and Hyacinthoides non-scripta, and some of them act as inhib-
itors against a variety of glycosidases. Because of their current
interest as potential drugs, pyrrolizidine alkaloids have become
popular synthetic targets4 and a number of new synthetic ana-
logues have been prepared. Also, polyhydroxylated indolizidine
alkaloids,5 such as the well known (ꢀ)-swainsonine and (+)-cast-
anospermine, exhibit effective glycosidase inhibition and potential
therapeutic applications as antidiabetic, antiviral, anticancer and
antimetastatic immunoregulating agents. In addition, aza-glycu-
ronic acid mimetics and related compounds have been found to
show glycosidase inhibitory activities.6
Inspired from these structures, we considered that hyacintha-
cines B1 and B2 (1) and the indolizidine analogues 2 could be
prepared from D-ribose via epoxide 3 as the crucial reactive inter-
mediate. Intramolecular 5-exo epoxide opening7 could lead to hya-
cinthacines 1, whereas a 6-endo process will afford the respective
indolizidine 2 precursors. Compound 3, in turn, could be prepared
from D-ribose-derived exo-glycal 5 by adding ethyl 2-nitrosoacry-
late (in situ generated from the oxime of ethyl bromopyruvate)
to give 4 and further proper manipulation. Some years ago, we effi-
ciently synthesised enantiomerically pure unnatural hydroxylated
pyrrolizidines8 by stereoselective hetero-Diels–Alder addition of
ethyl 2-nitrosoacrylate to easily prepared pent-4-enofuranosides
and further manipulations of adducts.
In a recent publication we reported the addition of ethyl
2-nitrosoacrylate to exo-glycal 59 as indicated in Scheme 2. The
resulting cycloadduct 4 was then firstly reduced by NaCNBH3 to
give a mixture of 6 and its epimer in very good yield, but with poor
diastereoselectivity, and then this mixture was epimerised by Et3N
to the thermodynamically more stable isomer 6. In fact, the oxa-
zine ring of this epimer adopts a chair-like conformation that
brings the CO2Et group equatorial and the ribose O-substituent ax-
ial, the latter being favoured by the anomeric effect. N–O Bond
scission in this compound by hydrogenation with H2 over Raney
⇑
Corresponding author. Tel.: +30 2310 997714; fax: +30 2310 997679.
E-mail address: igallos@chem.auth.gr (J.K. Gallos).
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.12.022

Z. S. Massen et al. / Carbohydrate Research 346 (2011) 508–511
509
HO
HO
OH
N
H
5
5-exo
CO2Et
TBSO
N
TBSO
O
CO2Et
O
O
HN
O
HO
1
H
R
O
O
O
O
O
O
6-endo
HO
HO
N
4
5
3
H
OH
, R = CH2OH, CO2H
2
Scheme 1. Retrosynthetic analysis of hyacinthacines 1 and indolizidines 2.
H
CO2Et
CO2Et
H
TBSO
TBSO
N
TBSO
N
TBSO
HO
O
CO2Et
O
X
O
O
O
N
ii, iii
i
iv, v
H
O
O
O
O
O
O
O
O
4
5
6
7
, X = H
8, X = Cbz
CO2Et
CO2Et
CO2Et
CO2Et
TBSO
MsO
Cbz
Cbz
Me
HN
HO
HO
N
N
3
N
O
6
viii or ix
vi
vii
8a
7
1
or
8
H
O
H
O
H
H
O
O
O
O
O
O
10
11
9
12
Scheme 2. Reagents and conditions: (i) BrCH2C(NOH)CO2Et (2 equiv), Na2CO3 (5 equiv), CH2Cl2, 20 °C, 24 h, 64%; (ii) NaCNBH3 (4 equiv), AcOH glacial, 20 °C, 24 h; (iii) CHCl3,
Et3N (cat.), reflux, 30 min, 80% from 4; (iv) Raney Ni, H2, MeOH, H3BO3, reflux, 75%; (v) Cbz-Cl, Et3N, MeOH, 0–20 °C, 8 h, 50% (35% of 7 recovered); (vi) MsCl, DMAP, pyridine,
0 °C, 90 min, 74%; (vii) TBAF, THF, 0 °C, 12 h, 80%; (viii) Pd/C, 1,4-cyclohexadiene, EtOH, 20 °C, 1 h, 73% to 11; (ix) Pd/C, H2, MeOH, 20 °C, 2 h, 86% to 12.
Ni in MeOH in the presence of boric acid10 gave in a highly stere-
oselective manner the proline derivative 7 in 75% yield. In the next
step, the amino group was protected with Cbz (50% yield and 35%
of 7 recovered) and the free hydroxyl group was mesylated to give
9 in 74% yield. Removal of the TBS group with TBAF in THF afforded
spontaneously the epoxide 10 with inversion of C-4 configuration
(ribose numbering).
through space interaction with an endo 1-H that of d 1.65. The
other 1-H is hidden in multiplet centred at d 2.05. An exo 6-H
should be far off both 1-H.
Our attention was then turned to efforts for converting epoxide
10 into a pyrrolizodine ring. However, despite our attempts, we
could not find experimental conditions leading to 5-exo products,
probably because the C-4 (ribose numbering) is strongly hindered
by the acetonide group. In a different way leading to epi-hyacinth-
cine B2, we attempted cyclisation of 9. Removal, however, of the
Cbz group with H2 over Pd/C gave a complex mixture of products,
where no pyrrolizidine ring was identified. Taking into account the
possibility that the overcrowded environment of the mesyloxy
group did not allow approach of the amino group, we attempted
to remove the TBS and acetonide protecting groups. By treatment,
however, of 9 with PPTS at rt, the TBS group was firstly removed,
but under reflux, compound was decomposed.
Considering, finally, that mesyloxy was not a good leaving
group, compound 9 was treated with TBAI in refluxing acetonitrile
or benzene in order to substitute this group by iodide in a SN2 reac-
tion, but without success. Alternatively, the free hydroxyl group in
compound 8 was triflated and then iodide was successfully intro-
duced upon treatment with TBAI. Surprisingly, however, we were
then unable to deprotect the amino group of this product although
several hydrogenation conditions were applied.
Deprotection of amino group, which activates the pyrrolidine
nitrogen towards nucleophilic substitution, was found to be quite
tricky. Removal of Cbz group by hydrogenation with H2 over Pd/
C caused the epoxide reduction and compound 12 was prepared
in 86% yield. After several attempts, we found that hydrogenation
over Pd/C with cyclohexadiene as a hydrogen donor, afforded ind-
olizidine 11 by a 6-endo mode as the sole product in 73% yield.
The proton signal assignment of compound 11 was made by
H,H-COSY and decoupling experiments. The proposed stereochem-
istry of compound 11 was supported by NOE measurements per-
formed in CDCl3/C6D6 5/1 solution, where some of the signals
useful for stereochemical assignment could appear separately. Sig-
nificant NOE enhancements were observed between the bridged
8a-H (d 2.46) and the 3-H (d 3.19) of the indolizidine frame (5%
enhancement of 3-H upon saturation of the bridged proton and
4% enhancement of the 8a-H upon saturation of the 3-H). A
remarkable through space interaction was also noted between
one of the 1-H protons (d 1.65) and 6-H proton (d 4.06) (2%
enhancement of 6-H upon saturation of the 1-H and 1.5% enhance-
ment of 1-H upon saturation of 6-H). These findings are in accor-
dance with the proposed structure bearing the bridgehead and
the 3-H pyrrolidine protons in cis-arrangement and the three rings
in a concave disposition, which allows the approach of 1-H and 6-H
protons. As it comes out from molecular models, in the concave
arrangement of the three rings only an endo 6-H can have a
In conclusion, we have successfully applied the hetero-
Diels–Alder 2-nitrosoacrylate cycloaddition reaction to
a
D-ribose-derived exo-glycal in order to prepare a new protected tri-
hydroxyindolizidine derivative (11) by a 6-endo epoxide opening,
intermediately formed. Several attempted 5-exo openings of this
epoxide were unsuccessful. In addition, interesting proline deriva-
tives branched with polyhydroxylated chains like 7 and 12 were
formed.

510
Z. S. Massen et al. / Carbohydrate Research 346 (2011) 508–511
stirred at the same temperature for 90 min, the solvent was re-
1. Experimental
1.1. General
moved azeotropically with toluene on a rotary evaporator and
the residue was chromatographed on a column of silica gel with
hexane/ethyl acetate (5:1) as the eluent to give 102 mg of 9
(74%) as an oil. ½a D25
ꢂ
+7.6 (c 1.77, CHCl3); FTIR (film) 2934, 2857,
Optical rotations were determined at room temperature on an
A. Krüss P3000 Automatic Digital Polarimeter. The 1H and 13C
NMR spectra were recorded at 300 and 75 MHz, respectively, on
a Bruker 300 AM spectrometer, with tetramethylsilane (TMS) as
internal standard. High-resolution mass spectra (HRMS) were ob-
tained on a VG ZAB-ZSE mass spectrometer under fast-atom bom-
bardment (FAB) conditions with nitrobenzyl alcohol (NBA) as the
matrix or on an IONSPEC FTMS spectrometer (matrix-assisted la-
ser-desorption ionisation, MALDI) with 2,5-dihydroxybenzoic acid
(DHB) as matrix. Compounds 4, 5 and 6 were prepared according to
published procedures.9
1744, 1705, 1463, 1409, 1358, 1177, 1112, 920, 838, 777 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 7.33 (m, 5H), 5.12 (s, 2H), 5.03
(m, 1H), 4.40–4.10 (m, 6H), 3.98 (d, J = 5.1 Hz, 2H), 3.16 (s, 3H),
2.25 (m, 1H), 2.15 (m, 2H), 1.95 (m, 1H), 1.41 (s, 6H), 1.26
(t, J = 7.2 Hz, 3H), 0.9 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 172.2, 155.3, 136.2, 128.3, 128.0, 127.9, 110.0,
80.2, 78.5, 78.0, 67.6, 61.3, 61.2, 61.0, 60.3, 38.6, 28.9, 27.1, 26.9,
26.5, 25.8, 18.3, 14.0, ꢀ5.5, ꢀ5.6; HRMS (m/z) calcd for
C
29H48NO10SSi [(M+H)+] 630.27627, found 630.27565.
1.5. (2S,5R)-1-Benzyl 2-ethyl 5-((4S,5S)-2,2-dimethyl-5-((S)-
oxiran-2-yl)-1,3-dioxolan-4-yl)pyrrolidine-1,2-dicarboxylate (10)
1.2. (2S,5R)-Ethyl 5-((4S,5R)-5-((R)-2-(tert-
butyldimethylsilyloxy)-1-hydroxyethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)pyrrolidine-2-carboxylate (7)
To a stirred solution of 9 (100 mg, 0.16 mmol) in THF (7 mL) were
added dropwise 0.25 mL TBAF 1.0 M in THF (1.5 equiv) at 0 °C under
argon atmosphere and the stirring was continued for 1 h. An addi-
tional amount of 0.25 mL TBAF 1.0 M in THF (1.5 equiv) were added,
the mixture was allowed to warm at room temperature, and stirred
for 12 h. Then CH2Cl2 (10 mL) and brine (5 mL) were added, the or-
ganic layer was dried over Na2SO4, the solvent was evaporated off,
and the residue was chromatographed on a column of silica gel with
hexane/ethyl acetate (2:1) as the eluent to give 55 mg of 10 (80%) as
To a stirred solution of 6 (0.67 g, 1.55 mmol) in MeOH (40 mL)
were added H3BO3 (1.92 g, 31 mmol), MgSO4 (2.0 g) and catalytic
amount of Raney Ni, and the mixture was refluxed under H2 atmo-
sphere for 4 h. The H3BO3 was then neutralised by saturated aque-
ous Na2CO3, the mixture was extracted with CH2Cl2 (3 ꢁ 50 mL),
and the organic layer was dried over Na2SO4. The solvent was then
removed on a rotary evaporator and the residue was chromato-
graphed on a column of silica gel with hexane/ethyl acetate as
an oil. ½a 2D5
ꢂ
+1.7 (c 1.12, CHCl3); FTIR (film) 2986, 2864, 1748, 1706,
the eluent to give 485 mg of 7 (75%) as an oil. ½a D25
ꢂ
+3.3 (c 3.2,
1455, 1405, 1351, 1296, 1183, 1104, 1056 cmꢀ1; 1H NMR (300 MHz,
CDCl3) d 7.32 (m, 5H), 5.17 (d, J = 12.2 Hz, 1H), 5.04 (d, J = 12.2
Hz, 1H), 4.40–4.15 (m, 4H), 4.09 (q, J = 7.3 Hz, 2H), 3.05
(q, J = 3.7 Hz, 1H), 2.68 (d, J = 3.7 Hz, 2H), 2.40–1.90 (m, 4H), 1.40
(s, 6H), 1.38 (s, 9H), 1.15 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 172.4, 155.1, 136.0, 128.4, 128.1, 127.7, 109.1, 78.7, 78.2, 67.3, 61.3,
61.1, 60.2, 51.8, 44.7, 28.6, 27.5, 27.1, 26.5, 13.9; HRMS (m/z) calcd
for C22H30NO7 [(M+H)+] 420.20223, found 420.20211.
CHCl3), FTIR (film) 3442, 2924, 2852, 1742, 1460, 1377, 1250,
1219, 1048, 830, 783 cmꢀ1 1H NMR (CDCl3) d 4.17 (q, J = 7.0 Hz,
;
2H), 3.85 (m, 3H), 3.75 (m, 2H), 3.62 (m, 1H), 3.55 (br, 2H, OH,
NH), 3.35 (m, 1H), 2.00 (m, 4H), 1.36 (s, 3H), 1.35 (s, 3H), 1.27 (t,
J = 7.0 Hz, 3H), 0.91 (s, 9H), 0.09 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 174.2, 108.5, 83.1, 79.6, 73.5, 65.0, 61.5, 61.0, 60.2, 29.9, 29.3,
27.0, 26.9, 26.0, 18.5, 14.1, ꢀ5.3, ꢀ5.4; HRMS (m/z) calcd for
C
20H40NO6Si [(M+H)+] 418.26249, found 418.26254.
1.3. (2S,5R)-1-Benzyl 2-ethyl 5-((4S,5R)-5-((R)-2-(tert-
butyldimethylsilyloxy)-1-hydroxyethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)pyrrolidine-1,2-dicarboxylate (8)
1.6. (3aR,4S,7S,9aR,9bS)-Ethyl 4-hydroxy-2,2-dimethyl-
octahydro-[1,3]dioxolo[4,5-g]indolizine-7-carboxylate (11)
To a solution of 10 (30 mg, 0.07 mmol) and 1,4-cyclohexadiene
(0.07 mL, 10 equiv) in absolute EtOH (5 mL) catalytic amount of 5%
Pd/C was added and the mixture was stirred at room temperature
under argon atmosphere for 1 h. The solids then were filtered off,
the solvent was removed on a rotary evaporator, and the residue
was chromatographed on a column of silica gel with hexane/ethyl
acetate (2:1) as the eluent to give 15 mg of 11 (73%) as a colorless
To a stirred solution of 7 (0.25 g, 0.60 mmol) and dry Et3N
(0.68 ml, 8 equiv) in MeOH (8 mL) were added dropwise 0.256 ml
Cbz-Cl (3 equiv) at 0 °C under argon atmosphere. The mixture
was then stirred at room temperature for 8 h, the volatiles were re-
moved on a rotary evaporator, and the residue was chromato-
graphed on a column of silica gel with hexane/ethyl acetate (5:1)
as the eluent to give 160 mg of 8 (50%) as an oil. FTIR (film) 3471,
2929, 2856, 1730, 1708, 1453, 1412, 1350, 1252, 1211, 1108, 836,
oil. ½a 2D5
ꢂ
+19.1 (c 0.18, MeOH); FTIR (film) 3355, 2978, 2935, 2879,
1733, 1451, 1371, 1227, 1147, 1088, 1046, 840 cmꢀ1
;
1H NMR
776 cmꢀ1; ½a 2D5
ꢂ
+4.3 (c 0.62, CHCl3); 1H NMR (300 MHz, CDCl3) d
(300 MHz, CDCl3) d 4.18 (q, J = 7.3 Hz, 1H), 4.10 (m, 1H), 3.35
(m, 3H), 3.21 (dd, J = 9.8, 6.4 Hz, 1H), 2.51 (m, 1H), 2.31 (br, 1H,
OH), 2.15 (m, 2H), 2.03 (m, 2H), 1.65 (m, 1H), 1.46 (s, 3H), 1.45
(s, 3H), 1.28 (t, J = 7.0 Hz, 3H); 1H NMR (300 MHz, CDCl3/C6D6, 5/1)
d 4.17 (q, J = 7.6 Hz, 2H), 4.06 (m, 1H), 3.32 (m, 3H), 3.19 (dd,
J = 9.4, 6.2 Hz, 1H), 2.46 (m, 1H), 2.05 (m, 4H), 1.86 (d, J = 3.6 Hz,
1H), 1.65 (m, 1H), 1.43 (s, 3H), 1.42 (s, 3H), 1.26 (t, J = 7.6 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 173.1, 109.7, 84.6, 79.0, 68.8, 65.0,
63.3, 60.8, 54.2, 29.8, 28.6, 26.8, 26.7, 14.2; HRMS (m/z) calcd for
7.35 (br s, 5H), 5.15 (d, J = 12.3 Hz, 1H), 5.11 (d, J = 12.3 Hz, 1H),
4.40–3.60 (m, 7H), 3.35 (d, J = 3.1 Hz, 1H, OH), 2.20 (m, 3H), 1.90
(m, 1H), 1.39 (s, 3H), 1.36 (s, 3H), 1.33 (s, 2H), 1.27 (t, J = 7.0 Hz,
3H), 0.91 (s, 9H), 0.09 (s, 6H). 13C NMR (75 MHz, CDCl3) d 172.8,
155.0, 136.3, 128.3, 127.9, 127.8, 109.3, 80.6, 78.5, 73.8, 67.3,
64.6, 61.0, 60.6, 60.1, 29.4, 27.5, 27.2, 25.9, 18.3, 14.0, ꢀ5.3. HRMS
(m/z) calcd for C28H46NO8Si [(M+H)+] 552.29872, found 552.29817.
1.4. (2S,5R)-1-Benzyl 2-ethyl 5-((4S,5R)-5-((R)-2-(tert-
butyldimethylsilyloxy)-1-mesyloxyethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)pyrrolidine-1,2-dicarboxylate (9)
C
14H24NO5 [(M+H)+] 286.16545, found 286.16538.
1.7. (2S,5R)-Ethyl 5-((4S,5R)-5-((S)-1-hydroxyethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)pyrrolidine-2-carboxylate (12)
To a stirred solution of 8 (120 mg, 0.22 mmol) and DMAP (17 mg,
0.5 equiv) in pyridine (4 mL) were added 0.033 ml MeSO2Cl
(1.5 equiv) at 0 °C under argon atmosphere. The mixture was
To a solution of 10 (60 mg, 0.14 mmol) in MeOH (2 mL) catalytic
amount of 5% Pd/C was added and the mixture was stirred at room

Z. S. Massen et al. / Carbohydrate Research 346 (2011) 508–511
511
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temperature under H2 atmosphere for 2 h. The solids then were fil-
tered off, the solvent was removed on a rotary evaporator, and the
residue was chromatographed on a column of silica gel with hex-
ane/ethyl acetate (2:1) as the eluent to give 35 mg of 12 (86%) as
a thick oil. ½a 2D5
ꢂ
+15.2 (c 0.23, MeOH); FTIR (film) 3335, 2984,
2935, 1733, 1455, 1379, 1241, 1211, 1181, 1098, 1067, 882 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 4.18 (q, J = 7.3 Hz, 2H), 3.98 (ddd,
J = 9.8, 6.7, 3.1 Hz, 1H), 3.85 (m, 3H), 3.28 (m, 1H), 2.86 (br s, 2H,
OH, NH), 2.12 (m, 1H), 1.95 (m, 3H), 1.41 (s, 3H), 1.39 (s, 3H),
1.28 (t, J = 7.3 Hz, 3H), 1.26 (d, J = 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 174.5, 108.7, 83.6, 78.8, 66.6, 61.7, 61.1, 60.3, 29.9, 29.2.
27.3, 27.2, 18.7, 14.2; HRMS (m/z) calcd for
C14H25NO5Na
4. For a recent review: Wardrop, D. J.; Waidyarachchi, S. L. Nat. Prod. Rep. 2010, 27,
1431–1468.
[(M+Na)+] 310.16249, found 310.16255.
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Casiraghi, G. Eur. J. Org. Chem. 1999, 1395–1400.
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7. Van Ameijde, J.; Horne, G.; Wormald, M. R.; Dwek, R. A.; Nash, R. J.;
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This work was co-funded by European Union and National fund
PYTHAGORAS—EPEAEK II.
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