Hetero-Diels-Alder additions to pent-4-enofuranosides: Concise synthesis of hydroxylated pyrrolizidines

Article abstract of DOI:10.1016/S0040-4020(02)01251-6

A new facile method for the synthesis of hydroxylated pyrrolizidines of the alexine family has been developed, which involves hetero-Diels-Alder addition of ethyl 2-nitrosoacrylate to pent-4-enofuranosides and a further two-step reductive ring opening-ring closure treatment of the cycloadduct.

Full text of DOI:10.1016/S0040-4020(02)01251-6

Tetrahedron 58 (2002) 9351–9357
Hetero-Diels–Alder additions to pent-4-enofuranosides:
concise synthesis of hydroxylated pyrrolizidines
*
John K. Gallos, Vassiliki C. Sarli, Christos I. Stathakis, Theocharis V. Koftis,
Victoria R. Nachmia and Evdoxia Coutouli-Argyropoulou
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 540 06, Greece
Received 30 July 2002; revised 9 September 2002; accepted 3 October 2002
Abstract—A new facile method for the synthesis of hydroxylated pyrrolizidines of the alexine family has been developed, which involves
hetero-Diels–Alder addition of ethyl 2-nitrosoacrylate to pent-4-enofuranosides and a further two-step reductive ring opening-ring closure
treatment of the cycloadduct. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Alkaloids mimicking the structures of monosaccharides are
widespread in plants and microorganisms; among them,
those with a nitrogen in the ring can be classified into five
structural classes:1 pyrrolidines, piperidines, pyrrolizidines,
indolizidines and nortropanes. Many of them exhibit
specific glycosidase inhibition, being thus potential thera-
peutical agents.2 Glycosidases and glycosyltranferases are
involved in a variety of important biological processes, such
as intestinal digestion, post-translational processing of
glycoproteins and the lysosomal catabolism of glycoconju-
gates. It has been shown that their inhibition is related to
many diseases, such as viral and microbial infection,
metastasis, diabetes and other metabolic disorders.
Figure 1.
2. Results and discussion
Natural pyrrolizidine alkaloids constitute a structurally
diverse group of compounds.3 Further to necines (with a
Retrosynthetic analysis in Scheme 1 shows that pyrroli-
hydroxymethyl group at the C-1 position), there are two
zidines of the general structure 1 could be prepared by
more recently discovered families: that of alexine, austra-
reductive condensation of an intermediate amino-keto-
line, casuarine and related compounds, possessing a
aldehyde 2, generated in situ by reduction of species 3,
hydroxymethyl group at the C-3 carbon of the pyrrolizidine
which in turn is the hetero-Diels–Alder adduct of ethyl
skeleton and the hyacinthacine family with a carbon branch
2-nitrosoacrylate 5 with the pent-4-enofuranoside 4. Hetero-
both at C-3 and C-5 positions (Fig. 1). Because of their
diene 5, easily prepared in situ from the oxime of ethyl
current interest as potential drugs, pyrrolizidine alkaloids
bromopyruvate,6,7 reacts with electron-rich alkenes (enol
have become popular synthetic targets4 and a number of
ethers, enamines, allylsilanes, etc) to give highly versatile
new synthetic analogs have been prepared. We now report
oxazines.7,8
an efficient synthesis of enantiomerically pure hydroxylated
pyrrolizidines structurally related to the alexine, which
The requisite pent-4-enofuranoside 6 (Scheme 2) was easily
represents a novel route to this family of alkaloids.5
prepared from D-ribose in three steps.9 Treatment of 6 with
two equivalents of the oxime of ethyl bromopyruvate at
room temperature in the presence of aqueous sodium
Keywords: pyrrolizidines; carbohydrates; carbohydrate mimetics; Diels–
Alder reactions; hydrogenation.
carbonate afforded in fairly good yield cycloadduct 7 as a
single diastereoisomer. Although the absolute configuration
*
Corresponding author. Tel.: þ30-310-997714; fax: þ30-310-997679;
e-mail: igallos@chem.auth.gr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01251-6

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J. K. Gallos et al. / Tetrahedron 58 (2002) 9351–9357
Although the transformation of 8 to a pyrrolizidine could be
attempted in one step,7 it was expected that the overall
process would be of low diastereoselectivity.
Thus, the CvN double bond of 7 was easily reduced by
7a
NaCNBH3 to give a mixture of 8 and its epimer in very
good yield, but the diastereoselectivity was poor. In fact,
repeated experiments gave varying mixtures of the two
epimers depending upon the reaction time. Chromato-
graphic separation of the mixture gave only the fast-moving
product (8) in pure form, the slow-moving one (epi-8) being
always contaminated by the former, apparently because of
partial isomerisation of the kinetic to the thermodynamic
product either upon standing or in the column. Indeed,
reflux of a solution of the mixture in CHCl3 in the presence
of Et3N for 30 min caused quantitative conversion of the
slow-moving to the fast-moving product.
Scheme 1. Retrosynthetic analysis of pyrrolizidines 1.
The absolute configuration of the newly formed stereocenter
in product 8 was assigned in the next step. Having
determined that the isolated product had the structure of 8,
this explained the easy conversion of epi-8 to 8, in which
the oxazine ring adopts a chair-like conformation (Scheme3)
with two equatorial C-substituents and an axial O-substituent,
the latter being favoured by the anomeric effect.
Among several attempts for conversion of 8 to 9 in the
following step, the Raney Ni hydrogenation of 8 in MeOH
in the presence of excess of H3BO3 was found to be the most
suitable. Under these reaction conditions, compound 9 was
the exclusive product in 64% yield (Scheme 2). It is
apparent that the N–O bond cleavage by the hydrogenation
led to the formation of the expected amino-keto-aldehyde,
which was further transformed to 9 by a sequence of tandem
condensation–hydrogenation reactions. Finally, reduction
of the ester group in 9 with LiBH4 in THF and further
treatment with methanolic HCl yielded the unprotected
pyrrolizidine as its hydrochloride 10.
Comparing the structures of 6 and 10, it becomes evident
that the chirality of C-2 and C-3 (ribose numbering) in 6,
which have an erythro relative configuration, has been
transferred to the C-6 and C-7 (pyrrolizidine numbering) of
10. To obtain a pyrrolizidine with threo-stereochemistry,
structurally more relative to casuarine, pent-4-enofurano-
side 13 (Scheme 4) was used as a dienophile. This
Scheme 2. Reagents and conditions: (i) BrCH2C(NOH)CO2Et (2 equiv.),
Na2CO3 (5 equiv.), CH2Cl2, 208C, 24 h, 64%. (ii) NaCNBH3 (4 equiv.),
AcOH glacial, 208C, 24 h. (iii) CHCl3, Et3N (cat.), reflux, 30 min, 80%. (iv)
Raney Ni, H2, 1 atm., H3BO3 (100 equiv.), MeOH, MgSO4, 208C, 24 h,
64%. (v) LiBH4 (5 equiv.), THF, 208C, 24 h, then MeOH, HCl, 69%.
of the spiro-carbon in 7 could not be unequivocally assigned
by the existing spectroscopic data, the structure proposed is
the most probable, resulting from the addition of the diene
from the less hindered face of the double bond. Analogous
structures have been assigned for the nitrile oxide
cycloadducts to 6.10
To access the target molecule, two further steps were
needed: diastereocontrolled hydrogenation of the CvN
double bond followed by reductive N–O bond cleavage.
The later was expected to triger a sequence of reactions with
intermediate formation of an amino-keto-aldehyde of the
general structure 2 (Scheme 1), which under suitable
reduction conditions could generate the pyrrolizidine ring.
Scheme 3.

J. K. Gallos et al. / Tetrahedron 58 (2002) 9351–9357
9353
and 4.51 (t, J¼5.1 Hz), respectively, whereas the 5-Ha, 5-Hb
and 7a-H protons resonanced at d 2.52 (dd, J¼10.1, 5.1 Hz),
2.97 (dd, J¼10.1, 2.3 Hz) and 2.83 (m), respectively. The
strong NOE enhancements of both 7a-H (12%) and 6-H
(13%) protons, when irradiating the 7-H signal disclose the
cis-disposition of 7-H and 7a-H protons. In addition, the
significant mutual NOE enhancements of 3-H, 5-Ha and 7a-
H protons (6% of the 5-Ha and 9% of the 7a-H signals upon
irradiation of the 3-H, 4% of each of 3-H and 7a-H signals
when irradiating the 5-Ha and 4% of each of 3-H and 5-Ha
signals when irradiating the 7a-H) are indicative of their
proximity, and strongly support the proposed structure. The
unequivocal assignment of the stereochemistry of 9
confirms therefore the structure of its precursors 7 and 8.
For compound 16, the signals of 3-H and 7-H overlap in a
multiplet at d 3.74. The signals of 5-Ha, 5-Hb, 6-H and 7a-H
appeared at d 2.75 (dd, J¼10.7, 6.1 Hz), 3.29 (dd, J¼10.7,
6.8 Hz), 4.37 (ddd, J¼6.8, 6.1, 5.8 Hz) and 3.47 (ddd as q,
J¼7.0 Hz), respectively. As in the case of pyrrolizidine 9,
the proton assignements were made on the basis of their
expected chemical shifts and successive decouplings.
Despite the limitations of the overlapping signals of the
two crucial protons, NOE measurements support the
proposed structure 16. Thus, upon saturation of the 5-Ha
proton, a 5% enhancement of the multiplet at d 3.74 (3-H
and 7-H) is observed and mutually irradiation at d 3.74
caused a 7% enhancement of the 5-Ha signal. This fact
indicates that the 5-Ha proton is in proximity to 3-H one,
taking into account the trans-disposition of 5-Ha and 7-H.
Given the configuration of C-3, the strong signal enhance-
ment of 7a-H (10%) when irradiating the 3-H and 7-H signal
as well as the lack of any substantial mutual enhancement
between 7a-H and 5-Ha or 6-H indicates a cis-arrangement
of the 7-H and 7a-H protons.
Scheme 4. Reagents and conditions: (i) Ph3P, I2, imidazole, toluene, reflux,
˚
2 h, 89%. (ii) DBU, DMSO, molecular sieves 3 A, reflux, 3 h, 87%.
(iii) BrCH2C(NOH)CO2Et (7 equiv.), aqueous Na2CO3 (5 equiv.), CH2Cl2,
208C, 72 h, 62%. (iv) NaCNBH3 (4 equiv.), AcOH glacial, 208C, 24 h.
(v) CHCl3, Et3N (cat.), reflux, 2 h, 60%. (vi) Pd(OH)2/C, H2, 1 atm.,
MeOH, 208C, 24 h, 66%.
compound was prepared from 11, which in turn was
accessible from 1,2:5,6-diacetone-D-glucose,11 applying
the literature methods.
Again, the addition of ethyl 2-nitrosoacrylate 5 to the pent-
4-enofuranoside 13 proceeded highly diastereoselectively to
give adduct 14 as the only product isolated. The mutual
strong signal enhancements between the 3-H (d 3.92, ribose
numbering) and the close CH2 group of the oxazine ring (d
1.95) confirm the proximity of these protons, verifying thus
the configuration of the spiro-carbon center. Apparently, the
addition of the ethyl 2-nitrosoacrylate to 13 occurred again
from the same face of the double bond, the diastereo-
selection being determined by the steric hindrance induced
by the acetonide group of 13. Compound 14 was treated in
the same manner as 7 to give 15 in very good yield, with
intermediate formation of both 15 and epi-15. However, the
Raney Ni method failed to convert 15 to the desired
pyrrolizidine 16. After attempting a number of procedures
we were able to achieve this transformation, by using
Pd(OH)2/C as a hydrogenation catalyst.
In the sequence of reactions converting compounds 6 and 13
to pyrrolizidines 9 and 16, respectively, two new chiral
centers (C-3, C-7a) were created in each case. The chirality
of the C-3 center was generated in 8 and 15, as already
discussed, by the NaCNBH3 reduction of 7 and 14,
respectively, and the subsequent epimerisation with Et3N,
the later being determined by the diastereocontrolled
addition of the diene to 6 and 13. The C-7a chiral center,
which was made in the catalytic hydrogenation step, has
opposite absolute configuration in pyrrolizidines 9 and 16,
apparently its formation being determined by the exocyclic
a-chiral center of the likely intermediate imines 17 and 18
(Fig. 3).
The absolute configuration of the C-3 and C-7a stereo-
centers in compounds 9 and 16 (Fig. 2) was deduced from
their 1H NMR spectra and the observed NOE enhancements.
The proton assignment in compound 9 was easily made by
successive proton decouplings starting from the easily
distinguishable signals of 3-H, 6-H and 7-H protons, which
appeared at d 3.22 (t, J¼8.0 Hz), 4.86 (dt, J¼5.1, 2.3 Hz)
It was expected that starting from a hex-5-enopyranoside,
the same reaction sequence could result in the formation of
an indolizine derivative. So, addition of ethyl 2-nitroso-
acrylate 5 to the hex-5-enopyranoside 19, derived from
Figure 2.
Figure 3.

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J. K. Gallos et al. / Tetrahedron 58 (2002) 9351–9357
1
an A. Kru¨ss P3000 Automatic Digital Polarimeter. The H
and 13C NMR spectra were recorded at 300 and 75 MHz,
respectively, on a Bruker 300 AM spectrometer, with
tetramethylsilane (TMS) as internal standard. Micro-
analyses were performed on a Perkin–Elmer 2400-II
Element analyser and high-resolution mass spectra
(HRMS) were obtained on a VG ZAB-ZSE mass spec-
trometer under fast-atom bombardment (FAB) conditions
with nitrobenzyl alcohol (NBA) as the matrix or on an
IONSPEC FTMS spectrometer (matrix-assisted laser-
desorption ionisation, MALDI) with 2,5-dihydroxybenzoic
acid (DHB) as matrix.
4.1.1. Ethyl (2R,3R,4S,5R)-3,4-isopropylidenedioxy-2-
methoxy-1,6-dioxa-7-azaspiro[4.5]dec-7-ene-8-carboxyl-
ate (7). To a solution of the oxime of ethyl bromopyruvate
(1.56 g, 7.43 mmol) in CH2Cl2 (100 mL) were added 6
(1.38 g, 7.43 mmol) and Na2CO3 (3.9 g, 37 mmol) and the
mixture was stirred at room temperature for 12 h. The same
amount of the oxime of ethyl bromopyruvate (1.56 g,
7.43 mmol) was added again and the mixture was stirred at
room temperature for another 12 h. H2O (100 mL) was then
added, the organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3£100 mL). The
combined organic layer was dried over Na2SO4, the solvent
was evaporated off and the resulting mixture was chro-
matographed on a column of silica gel with hexane/ethyl
acetate 5:1 as the eluent to give adduct 7 (1.49 g, 64%) as a
colorless oil. [a]D¼þ10.5 (c 1.7, CHCl3); IR (neat) 1720,
Scheme 5. Reagents and conditions: (i) BrCH2C(NOH)CO2Et (2.5 equiv.),
aqueous Na2CO3 (5.5 equiv.), CH2Cl2, 208C, 5 days, 72% on the consumed
17. (ii) NaCNBH3 (4 equiv.), AcOH glacial, 208C, 4 h. (iii) CHCl3, Et3N
(cat.), reflux, 90 min, 62%.
D-glucose,10 led to the formation of the hetero-Diels–Alder
adduct 20 as a single diastereoisomer, which was further
converted to 21 by using the established procedures
(Scheme 5). All methods, however, used to convert 21
into the indolizidine 22 (Raney Ni/H2, Pd/C/H2, Pd(OH)2/
H2, Zn in CH3CO2H, etc) were unsuccessful. In all cases
compound 21 was decomposed to a plethora of unidentified
products.
Again, the absolute configuration of the spiro-carbon in 20
could not be unequivocally assigned by the existing
spectroscopic data, the structure proposed being the most
probable, resulting by the addition of the diene from the less
hindered face of the double bond. Analogous structures have
been assigned for the nitrile oxide cycloadducts to 19.10
Similarly, the absolute configuration of the newly formed
stereocenter in 21 was not determined, its structure assigned
by analogy to that of compounds 8 and 15.
1
1600 cm21; H NMR (CDCl3) d 1.34 (s, 3H), 1.36 (t, 3H,
J¼6.7 Hz), 1.49 (s, 3H), 1.86 (ddd, 1H, J¼13.3, 11.6,
7.4 Hz), 2.17 (ddd, 1H, J¼13.3, 7.3, 3.2 Hz), 2.57 (ddd, 1H,
J¼14.7, 11.6, 3.2 Hz), 2.70 (ddd, 1H, J¼14.7, 7.4, 7.3 Hz),
3.30 (s, 3H), 4.33 (two dq as m, 2H), 4.73 (d, 1H, J¼5.9 Hz),
4.93 (d, 1H, J¼5.9 Hz), 5.06 (s, 1H); 13C NMR (CDCl3) d
14.0, 18.4, 21.8, 24.7, 26.0, 55.1, 61.9, 83.3, 84.7, 108.1,
109.0, 112.9, 150.7, 163.2; HRMS (MALDI-FTMS) calcd
(C14H21NO7Na) 338.1210 (MþNa), found 338.1220, s
3.0 ppm.
3. Conclusion
4.1.2. Ethyl (2R,3R,4S,5R,8R)-3,4-isopropylidenedioxy-
2-methoxy-1,6-dioxa-7-azaspiro[4.5]decane-8-carboxyl-
ate (8). To a solution of 7 (630 mg, 2 mmol) in glacial acetic
acid (14 mL) was added NaCNBH3 (503 mg, 8 mmol) and
the mixture was stirred at room temperature for 24 h. The
acetic acid was then neutralized by saturated aqueous
Na2CO3, the mixture was extracted with CH2Cl2
(3£100 mL) and the organic layer was dried over Na2SO4.
The solvent was then removed on a rotary evaporator and
the residue was disolved in CHCl3 (20 mL). After adding a
drop of Et3N, this solution was refluxed for 30 min, the
volatiles were then evaporated off and the residue was
chromatographed on a column of silica gel with hexane/
ethyl acetate 5:1 as the eluent to give 8 (509 mg, 80%) as a
colorless oil. [a]D¼þ46.3 (c 1.7, CHCl3); IR (neat) 3350,
In conclusion, a new facile method for the synthesis of
hydroxylated pyrrolizidines of the alexine family has been
developed, which however failed to be applied to the
synthesis of a hydroxylated indolizidine. Starting from
easily available pent-4-enofuranosides, utilising cheap and
commercial reagents, applying simple and convenient
procedures, hydroxylated pyrrolizidines were prepared in
three steps: (i) hetero-Diels–Alder addition of the in situ
generated ethyl 2-nitrosoacrylate, (ii) CvN bond reduction
by NaCNBH3 followed by epimerisation of the product
mixture to the thermodynamically more stable isomer, and
(iii) reductive cyclisation reaction trigered by the N–O bond
cleavage by catalytic hydrogenation. It is worth noting that
all steps were highly diastereoselective and only one
product was isolated in each step.
1
1735 cm21; H NMR (CDCl3) d 1.28 (t, 3H, J¼7.2 Hz),
1.31 (s, 3H), 1.46 (s, 3H), 1.95 (m, 4H), 3.50 (s, 3H), 3.84
(br, 1H), 4.19 (q, 2H, J¼7.2 Hz), 4.51 (d, 1H, J¼6.0 Hz),
4.69 (d, 1H, J¼6.0 Hz), 5.04 (s, 1H), 5.79 (br, 1H); 13C
NMR (CDCl3) d 14.1, 23.5, 24.8, 26.2, 27.2, 56.4, 58.5,
61.1, 83.6, 84.6, 108.5, 110.5, 112.7, 171.0; Anal. calcd for
C14H23NO7 C, 52.99, H, 7.31, N, 4.41. Found: C, 53.06, H,
7.46, N, 4.27.
4. Experimental
4.1. General
Optical rotations were determined at room temperature on

J. K. Gallos et al. / Tetrahedron 58 (2002) 9351–9357
9355
4.1.3. Ethyl (3S,6R,7S,7aR)-6,7-isopropylidenedioxy-
pyrrolizidine-3-carboxylate (9). To a solution of 8
(120 mg, 0.38 mmol) in MeOH (10 mL) were added
H3BO3 (2.4 g, 38.7 mmol), catalytic amount of Raney Ni
and MgSO4 (200 mg) and the mixture was stirred under H2
atmosphere at room temperature for 24 h. The H3BO3 was
then neutralized by saturated aqueous 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 chromatographed on a
column of silica gel with hexane/ethyl acetate 2:1 as the
eluent to give 9 (62 mg, 64%) as a colorless oil.
2.9 Hz), 4.58 (d, 1H, J¼11.2 Hz), 4.62 (d, 1H, J¼3.6 Hz),
4.69 (d, 1H, J¼11.2 Hz), 5.95 (d, 1H, J¼3.6 Hz), 7.33 (m,
5H); 13C NMR (CDCl3) d 21.1, 26.2, 26.8, 72.6, 81.1, 81.6,
82.0, 105.7, 111.9, 127.9, 128.0, 128.4, 137.2; Anal. calcd
for C15H19IO4 C, 46.17, H, 4.91. Found: C, 46.02, H, 4.88.
4.1.6. (3aR,6R,6aR)-6-(Benzyloxy)-2,2-dimethyl-5-
methylenetetrahydrofuro[2,3-d][1,3]dioxole (13). A sol-
ution of 12 (500 mg, 1.28 mmol) in dry DMSO (7 mL) and
˚
DBU (0.4 mL) was refluxed for 3 h in the presence of 3 A
molecular sieves. H2O (10 mL) was then added and the
mixture was extracted with ethyl ether (30 mL). The organic
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 20:1 as the eluent to give 13
(292 mg, 87%) as a colorless oil. [a]D¼<0.0 (c 0.5,
CHCl3); IR (neat) 1620 cm21; 1H NMR (CDCl3) d 1.37 (s,
3H), 1.43 (s, 3H), 4.24 (d, 1H, J¼2.0 Hz), 4.26 (s, 1H), 4.49
(d, 1H, J¼11.7 Hz), 4.58 (d, 1H, J¼3.4 Hz), 4.66 (d, 1H,
J¼2.0 Hz), 4.69 (d, 1H, J¼11.7 Hz), 6.01 (d, 1H,
J¼3.4 Hz), 7.33 (m, 5H); 13C NMR (CDCl3) d 27.1, 27.9,
70.3, 80.5, 83.3, 88.7, 106.8, 113.7, 127.9, 128.3, 128.5,
137.2, 158.6; Anal. calcd for C15H18O4 C, 68.69, H, 6.92.
Found: C, 68.77, H, 6.83.
[a]D¼þ26.3 (c 0.34, CHCl3); IR (neat) 1725 cm21
;
1H
NMR (CDCl3) d 1.28 (t, 3H, J¼7.1 Hz), 1.34 (s, 3H), 1.55
(s, 3H), 1.63 (m, 1H), 1.94 (m, 1H), 2.26 (m, 2H), 2.52 (dd,
1H, J¼10.1, 5.1 Hz), 2.83 (m, 1H), 2.97 (dd, 1H, J¼10.1,
2.3 Hz), 3.22 (t, 1H, J¼8.0 Hz), 4.19 (q, 2H, J¼7.1 Hz),
4.51 (t, 1H, J¼5.1 Hz), 4.86 (dt, 1H, J¼5.1, 2.3 Hz); 13C
NMR (CDCl3) d 14.2, 21.2, 25.7, 26.5, 30.1, 53.6, 60.6,
61.4, 70.5, 77.6, 84.3, 112.7, 172.2; HRMS (MALDI-
FTMS) calcd (C13H22NO4) 256.1543 (MþþH), found
256.1550, s 2.7 ppm.
4.1.4. (1R,2S,5R,7aS)-1,2-Dihydroxy-5-(hydroxymethyl)-
pyrrolizidinium chloride (10). To a solution of 9 (100 mg,
0.392 mmol) in THF (3.5 mL) was added LiBH4 (44 mg,
2.04 mmol) and the mixture was stirred at room temperature
for 24 h. CH2Cl2 (20 mL) and 10% H3PO4 (1.6 mL) were
added dropwise, followed by addition of H2O (50 mL). The
mixture was then extracted with CH2Cl2 (3£40 mL) and the
organic layer washed with brine (50 mL), dried and
concentrated on a rotary evaporator. The residue was
subsequently dissolved in MeOH (4 mL), concentrated HCl
(0.15 mL) was added and after standing at room temperature
for 1 h, the volatiles were evaporated off to give 10 as a
colorless oil (57 mg, 69%). [a]D¼227.6 (c 0.4, MeOH); IR
(neat) 3400 (br) cm21; 1H NMR (D2O) d 1.53 (m, 1H), 1.83
(m, 2H), 2.05 (m, 1H), 2.97 (t, 1H, J¼11.0 Hz), 3.27 (dd,
1H, J¼9.9, 6.1, Hz), 3.54 (m, 2H), 3.73 (d, 1H, J¼11.0 Hz),
4.04 (m, 1H), 4.13 (m, 2H); 1H NMR (CDCl3/DMSO-d6) d
1.67 (m, 1H), 1.86 (m, 2H), 2.16 (m, 1H), 3.07 (m, 1H), 3.20
(m, 1H), 3.60 (m, 3H), 4.05 (m, 3H), 5.40 (br, 1H), 5.53 (br,
2H), 10.80 (br, 1H); 13C NMR (DMSO-d6) d 23.1, 26.6,
47.3, 57.9, 65.0, 68.5, 69.4, 70.7; HRMS (MALDI-FTMS)
calcd (C8H16NO3) 174.1125 (Mþ), found 174.1127, s
1.1 ppm.
4.1.7. Ethyl (2S,3R,4R,5R)-4-(benzyloxy)-2,3-isopropyl-
idenedioxy-1,6-dioxa-7-azaspiro[4.5]dec-7-ene-8-car-
boxylate (14). To a solution of the oxime of ethyl
bromopyruvate (1.13 g, 5.76 mmol) in CH2Cl2 (50 mL)
were added 13 (500 mg, 1.92 mmol) and Na2CO3 (1.0 g,
8.5 mmol) and the mixture was stirred at room temperature
for 24 h. Additional amounts of the oxime of ethyl
bromopyruvate (753 g, 3.84 mmol) were then added twice
again after two 24 h periods. H2O (50 mL) was then added,
the organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3£50 mL). The combined organic
layer was dried over Na2SO4, the solvent was evaporated off
and the resulting mixture was chromatographed on a column
of silica gel with hexane/ethyl acetate 10:1 as the eluent to
give adduct 14 (463 mg, 62%) as a colorless oil.
[a]D¼210.6 (c 1.2, CHCl3); IR (neat) 1720, 1600 cm21
;
1H NMR (CDCl3) d 1.36 (t, 3H, J¼6.8 Hz), 1.44 (s, 3H),
1.48 (s, 3H), 1.95 (m, 2H), 2.60 (m, 2H), 3.92 (d, 1H,
J¼3.4 Hz), 4.31 (two dq as m, 2H), 4.61 (d, 1H,
J¼12.7 Hz), 4.84 (d, 1H, J¼12.7 Hz), 4.93 (dd, 1H,
J¼4.4, 3.4 Hz), 5.95 (d, 1H, J¼4.4 Hz), 7.31 (m, 5H); 13C
NMR (CDCl3) d 14.0, 18.2, 23.9, 27.7, 28.0, 62.0, 72.3,
85.4, 86.8, 103.0, 104.4, 115.2, 128.0, 128.4, 128.6, 136.8,
4.1.5. (3aR,5S,6S,6aR)-6-(Benzyloxy)-5-(iodomethyl)-
2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (12).
A
150.4,
163.0;
HRMS
(MALDI-FTMS)
calcd
mixture of 11 (1.0 g, 3.57 mmol), Ph3P (2.36 g, 9 mmol),
I2 (1.016 g, 4 mmol) and imidazole (517 mg, 7.6 mmol) in
toluene (20 mL) was refluxed for 2 h and then decanted into
saturated aqueous NaHCO3 (200 mL) and diluted with
CH2Cl2 (50 mL). The unreacted Ph3P was oxidised by I2
and its excess was removed by adding Na2S2O3. The
organic layer was separated and the aqueous solution was
extracted with CH2Cl2 (50 mL). The combined organic
layers were dried over Na2SO4, the solvent was evaporated
off and the residue was chromatographed on a column of
silica gel with hexane/ethyl acetate 7:1 as the eluent to give
12 (1.245 g, 89%) as a colorless oil. [a]D¼274.1 (c 1.2,
CHCl3); 1H NMR (CDCl3) d 1.33 (s, 3H), 1.52 (s, 3H), 3.33
(m, 2H), 4.09 (d, 1H, J¼2.9 Hz), 4.47 (ddd, 1H, J¼8.8, 5.9,
(C20H25NO7Na) 414.1523 (MþNa), found 414.1527, s
1.0 ppm.
4.1.8. Ethyl (2S,3R,4R,5R,8R)-4-(benzyloxy)-2,3-isopro-
pylidenedioxy-1,6-dioxa-7-azaspiro[4.5]decane-8-car-
boxylate (15). To a solution of 14 (319 mg, 0.82 mmol) in
glacial acetic acid (7 mL) was added NaCNBH3 (206 mg,
3.28 mmol) and the mixture was stirred at room temperature
for 24 h. The acetic acid was then neutralized by saturated
aqueous 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 dissolved in CHCl3 (10 mL). After adding a
drop of Et3N, this solution was refluxed for 2 h, the volatiles

9356
J. K. Gallos et al. / Tetrahedron 58 (2002) 9351–9357
were then evaporated off and the residue was chromato-
graphed on a column of silica gel with hexane/ethyl acetate
5:1 as the eluent to give 15 (195 mg, 60%) as a colorless oil.
[a]D¼þ61.5 (c 0.7, CHCl3); IR (neat) 3350, 1735 cm21; 1H
NMR (CDCl3) d 1.26 (t, 3H, J¼6.8 Hz), 1.43 (s, 3H), 1.46
(s, 3H), 1.60 (m, 1H), 1.95 (m, 3H), 3.76 (d, 1H, J¼3.4 Hz),
3.86 (dd as t, 1H, J¼7.0 Hz), 4.18 (q, 2H, J¼6.8 Hz), 4.63
(d, 1H, J¼11.7 Hz), 4.80 (dd, 1H, J¼4.4, 3.4 Hz), 4.85 (d,
1H, J¼11.7 Hz), 5.80 (br, 1H), 5.89 (d, 1H, J¼4.4 Hz), 7.35
(m, 5H); 13C NMR (CDCl3) d 14.1, 23.7, 27.7, 28.0, 29.2,
58.5, 61.1, 72.3, 85.4, 87.0, 103.6, 103.9, 115.1, 128.0,
128.1, 128.4, 136.8, 171.1; HRMS (MALDI-FTMS) calcd
(C20H27NO7Na) 416.1680 (MþNa), found 416.1681, s
0.2 ppm.
4.1.11. Ethyl (3R,6R,8S,9R,10R,11S)-9,10,11-tris(benzyl-
oxy)-8-methoxy-1,7-dioxa-2-azaspiro[5.5]undecane-3-
carboxylate (21). To a solution of 20 (45 mg, 0.078 mmol)
in glacial acetic acid (2 mL) was added NaCNBH3 (20 mg,
0.32 mmol) and the mixture was stirred at room temperature
for 4 h. The acetic acid was then neutralized by saturated
aqueous Na2CO3, the mixture was extracted with CH2Cl2
(3£10 mL) and the organic layer was dried over Na2SO4.
The solvent was then removed on a rotary evaporator and
the residue was dissolved in CHCl3 (5 mL). After adding a
drop of Et3N, this solution was refluxed for 1.5 h, the
volatiles were then evaporated off and the residue was
chromatographed on a column of silica gel with hexane/
ethyl acetate 5:1 as the eluent to give 21 (28 mg, 62%) as a
colorless oil. [a]D¼þ36.5 (c 0.85, CHCl3); IR (neat) 3350,
1
4.1.9. Ethyl (3R,6S,7S,7aS)-7-(benzyloxy)-6-hydroxy-
pyrrolizidine-3-carboxylate (16). To a solution of 15
(100 mg, 0.254 mmol) in MeOH (2 mL) was added catalytic
amount of Pd(OH)2/C and the mixture was stirred under H2
atmosphere at room temperature for 24 h. The solids were
then filtered off, the organic layer was concentrated on a
rotary evaporator and the residue was chromatographed on a
column of silica gel with hexane/ethyl acetate 1:1 as the
eluent to give 16 (52 mg, 66%) as a colorless oil.
1735 cm21; H NMR (CDCl3) d 1.27 (t, 3H, J¼7.1 Hz),
1.98 (m, 2H), 2.20 (m, 2H), 3.42 (d, 1H, J¼9.1 Hz), 3.52 (s,
3H), 3.63 (dd, 1H, J¼9.1, 3.8 Hz), 3.82 (br, 1H), 3.85 (dd as
t, 1H, J¼9.1 Hz), 4.18 (q, 2H, J¼7.1 Hz), 4.63 (d, 1H,
J¼11.2 Hz), 4.67 (d, 1H, J¼12.0 Hz), 4.69 (d, 1H,
J¼3.8 Hz), 4.77 (d, 1H, J¼11.2 Hz), 4.79 (s, 2H), 4.82 (d,
1H, J¼12.0 Hz), 6.05 (br, 1H), 7.32 (m, 15H); 13C NMR
(CDCl3) d 14.0, 22.8, 27.1, 57.5, 58.8, 61.0, 73.8, 74.8, 75.4,
77.5, 78.9, 83.1, 99.0, 100.9, 127.5, 127.6, 127.8, 127.9 (two
overlapping peaks), 128.1, 128.2 (two overlaping peaks),
128.4, 138.1, 138.2, 138.5, 170.7; HRMS (MALDI-FTMS)
calcd (C33H39NO8Na) 600.2568 (MþNa), found 600.2557,
s 1.8 ppm.
[a]D¼þ22.2 (c 0.5, CHCl3); IR (neat) 1725 cm21
;
1H
NMR (CDCl3) d 1.27 (t, 3H, J¼6.8 Hz), 1.87 (m, 1H), 2.07
(m, 3H), 2.75 (dd, 1H, J¼10.7, 6.1 Hz), 2.90 (br, 1H) 3.29
(dd, 1H, J¼10.7, 6.8 Hz), 3.47 (ddd as t, 1H, J¼7.0 Hz),
3.74 (two dd overlaping as m, 2H), 4.17 (q, 2H, J¼6.8 Hz),
4.37 (ddd, 1H, J¼6.8, 6.1, 5.8 Hz), 4.62 (s, 2H), 7.32
(m, 5H); 13C NMR (CDCl3) d 14.1, 28.9, 31.7, 53.5, 60.9,
63.4, 68.9, 72.0, 79.0, 89.9, 127.6, 128.4 (two overlaping
peaks), 138.3, 174.4; HRMS (MALDI-FTMS) calcd
(C17H24NO4) 306.1700 (MþþH), found 306.1694, s
2.0 ppm.
Acknowledgements
We are grateful to Dr Alexandros E. Koumbis for the high
resolution mass spectra and to the ‘Leonidas Zervas’
Foundation for a fellowship to T. V. Koftis.
4.1.10. Ethyl (6R,8S,9R,10R,11S)-9,10,11-tris(benzyl-
oxy)-8-methoxy-1,7-dioxa-2-azaspiro[5.5]undec-2-ene-3-
carboxylate (20). To a solution of the oxime of ethyl
bromopyruvate (233 mg, 1.1 mmol) in CH2Cl2 (25 mL)
were added 19 (446 mg, 1.0 mmol) and Na2CO3 (583 mg,
5.5 mmol) and the mixture was stirred at room temperature
for 24 h. Additional amount of the oxime of ethyl
bromopyruvate (233 mg, 1.1 mmol) was then added four
times again every 24 h. H2O (25 mL) was then added, the
organic layer was separeted and the aqueous layer was
extracted with CH2Cl2 (3£25 mL). The combined organic
layer was dried over Na2SO4, the solvent was evaporated off
and the resulting mixture was chromatographed on a column
of silica gel with hexane/ethyl acetate 10:1 as the eluent to
give unchanged 19 firstly (213 mg, 48%), followed by
adduct 20 (217 mg, 38%, 72% on the consumed 19) as a
colorless oil. [a]D¼225.0 (c 1.0, CHCl3); IR (neat) 1720,
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