Synthesis of pyrrolizidine alkaloids via 1,3-dipolar cycloaddition involving cyclic nitrones and unsaturated lactones

Article abstract of DOI:10.1016/j.carres.2008.04.029

The 1,3-dipolar cycloaddition of cyclic nitrone derived from tartaric acid and (S)-5-hydroxymethyl-2(5H)-furanone leads to a single adduct which was transformed into 2,6-dihydroxyhastanecine via reaction sequence involving reduction of the lactone moiety, glycolic cleavage of the terminal diol, and the N-O hydrogenolysis followed by the intramolecular alkylation of the nitrogen atom.

Full text of DOI:10.1016/j.carres.2008.04.029

Carbohydrate Research 343 (2008) 2215–2220
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Carbohydrate Research
journal homepage: http://www.elsevier.com/locate/carres
Synthesis of pyrrolizidine alkaloids via 1,3-dipolar cycloaddition involving
cyclic nitrones and unsaturated lactones
a
a
a
b
´
Sebastian Stecko , Margarita Jurczak , Zofia Urbanczyk-Lipkowska , Jolanta Solecka ,
Marek Chmielewski a,
*
a Institute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
b National Institute of Hygiene, 00-791 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1,3-dipolar cycloaddition of cyclic nitrone derived from tartaric acid and (S)-5-hydroxymethyl-2(5H)-
furanone leads to a single adduct which was transformed into 2,6-dihydroxyhastanecine via reaction
sequence involving reduction of the lactone moiety, glycolic cleavage of the terminal diol, and the N–O
hydrogenolysis followed by the intramolecular alkylation of the nitrogen atom.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 14 January 2008
Accepted 21 April 2008
Available online 27 April 2008
Keywords:
Nitrone
Necine bases
Iminosugars
1,3-Dipolar cycloaddition
1. Introduction
ones due to the possible formation of endo adducts.7 A single
adduct is formed only in the case of the matching pair when the
A large number of structurally different polyhydroxylated alka-
loids have been isolated from natural sources such as plants or
microorganisms. An apparent common structural feature of this
group is a nitrogen-containing four- (azetidine), five- (pyrrolidine),
or six-membered (piperidine) ring, or related fused ring systems
(pyrrolizidine, indolizidine, and quinolizidine) built up from the
above monocycles, substituted with one or more hydroxyl
groups.1,2 The structural similarity of these compounds to mono-
saccharides, reflected in fact that they are also called iminosugars,
results in an interesting biological activity as selective inhibitors of
glycosidases. Consequently, the iminosugars show antibacterial,
antiviral, antitumor, or antidiabetic activities.3 For these reasons,
the synthesis of the iminosugars and their analogues has attracted
attention of many academic and pharmaceutical laboratories
including our group.3–6
Recently, we have reported that the 1,3-dipolar cycloaddition of
five-membered cyclic nitrones to the a,b-unsaturated d-lactones
provides an attractive entry to the pyrrolizidine and indolizidine
iminosugars.6 We found that the cycloadditions involving d-lac-
tones proceed exclusively in the exo mode, and therefore in many
cases only a single product is formed. The corresponding transfor-
mations involving c-lactones proceed with a lower diastereoselec-
tivity, as compared with the cycloaddition to the six-membered
endo approach of reactants is hindered. Cycloadducts 4 and 5 read-
ily available from the -glycero lactone 1 and nitrones of -(+)-
tartaric acid 2 and -(+)-malic acid 3, respectively, are particularly
attractive. In the present paper, we demonstrate that the adduct 4,
easily accessible from the relatively inexpensive substrates, is a
convenient starting material for the synthesis of necine alkaloids
6–9 which have 1(S) and 7a(S) configuration. Both of these stereo-
genic centers cannot be easily epimerized, and therefore have to be
established at the cycloaddition step (see Chart 1).
D
L
D
O
O
Ot-Bu
O
O
Ot-Bu
N
N
HO
Ot-Bu
2
1
3
O
O
O
O
HO
HO
H
H
H
H
H
H
O
O
Ot-Bu
Ot-Bu
N
N
Ot-Bu
4
5
* Corresponding author. Fax: +48 22 632 66 81.
E-mail address: chmiel@icho.edu.pl (M. Chmielewski).
Chart 1.
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.04.029

2216
S. Stecko et al. / Carbohydrate Research 343 (2008) 2215–2220
HO
HO
HO
HO
HO
OH
OH
6
OH
6
H
N
H
N
H
N
H
H
(S)
(S)
(S)
(S)
1
7
5
1
7
5
7a
7a
HO
HO
HO
OH
2
2
4
4
3
N
3
N
(-)-hastanecine 6
(-)-croalbinecine 7
(+)-laburnine 9
(+)-macronecine 8
10
Chart 2.
The present paper describes the synthesis of dihydroxy-hasta-
necine 10 from adduct 4. In comparison with the parent compound
6, the pyrrolizidine 10 bears two additional hydroxy groups at the
C-2 and C-6 carbon atoms. All secondary hydroxyls in 10, however,
can be easily removed and/or configurations of the adjacent carbon
atoms can be inverted. Therefore, the adduct 4 can be treated as an
entry not only to hydroxypyrrolizidine 10, but also to other necine
bases of several alkaloids such as (ꢀ)-hastanecine (6),8 (ꢀ)-croalbi-
necine (7),8b,9 (+)-macronecine (8),10 and (+)-laburnine (9).11 All
ation of the substrate. The primary hydroxyl group in 12 was then
selectively protected with pivaloyl chloride to give 13. In turn, the
compound 13 was subjected to the sequence of three reactions
involving desilylation with tetrabutylammonium fluoride and
NaIO4-mediated diol cleavage followed by the reduction of alde-
hyde with NaBH4 affording alcohol 14. After mesylation of the
hydroxy group followed by the hydrogenolysis of the N–O bond,
the intramolecular N-alkylation afforded the pyrrolizidine 16.
The deprotection–acetylation sequence (pivaloyl protection was
removed by the LiAlH4 reduction and t-butyl protecting groups
were removed by treatment with trifluoroacetic acid) provided
peracetylated derivative 17 of target compound. The structure
and configuration of 17 was confirmed by X-ray structure analysis
(Fig. 1).12 The final deprotection was performed by the treatment
of 17 with 1% solution of ammonia in methanol to afford pyrroli-
zidine 10.
these compounds display
a variety of interesting biological
activities8–11 (see Chart 2).
2. Results and discussion
The synthesis of 10 is depicted in Scheme 1. The free hydroxy
group in 4 was protected with t-BuPh2Si yielding 11. Subsequently,
the lactone moiety was reduced with BH3–Me2S complex to give
diol 12. The same reduction performed with LiAlH4 led to desilyl-
Since the hydroxymethyl group stemming from lactone 1 was
removed at the later stage of the synthesis of 10, one could con-
OH
O
OH
OH
O
OPiv
2
t-BuPh2SiO
RO
t-BuPh2SiO
H
H
H
H
H
2
c
H
3
1a 4a
4b
b
H
H
H
O
O
O
3a
Ot-Bu
Ot-Bu
Ot-Bu
N
4
N
5
N
6
5
6
Ot-Bu
Ot-Bu
Ot-Bu
13
4
R = H
12
a
11 R = SiPh2t-Bu
d-f
RO
OPiv
PivO
AcO
Ot-Bu
OAc
H
H
N
H
j-m
h-i
O
g
AcO
Ot-Bu
AcO
Ot-Bu
OAc
N
N
16
17
Ot-Bu
n
14 R = H
HO
OH
H
15 R = Ms
HO
OH
N
10
Scheme 1. Reagents and conditions: (a) t-BuPh2SiCl, imidazole, CH2Cl2, ꢀ15 °C to rt; (b) BH3–Me2S, THF, rt; (c) PivCl, DMAP, CH2Cl2, ꢀ15 °C to rt; (d) TBAF, THF, rt; (e) NaIO4,
MeOH, rt; (f) NaBH4, MeOH, rt; (g) MsCl, Et3N, CH2Cl2, ꢀ15 °C to rt; (h) H2, 10% Pd/C, EtOAc–MeOH (4:1), rt; (i) Ac2O, Et3N, rt; (j) LiAlH4, Et2O, rt; (k) Ac2O, Et3N, rt; (l)
CF3COOH, rt; (m) Ac2O, Et3N, rt; (n) 1% NH3 in MeOH, rt.

S. Stecko et al. / Carbohydrate Research 343 (2008) 2215–2220
2217
amounted to 4:1.5:1 (HPLC), respectively, whereas that of
23:26:27 amounted to 5:1.5:1 (HPLC). The assignment of gross
structure of compounds 24–27 was based on HRMS spectra. The
low stereoselectivity of the 21 monoprotection practically pre-
cludes the use of the adduct 19 as the substrate for the synthesis
leading to 10, as well as to 6–9.
Compound 10 was tested on bovine kidney a-
bovine liver b- -galactosidase, bovine liver b- -glucuronidase, rice
a- -glucosidase, almond b- -glucosidase, and jack bean a- -man-
nosidase inhibition. Under procedures described previously,13–16
L-fucosidase,
D
D
D
D
D
compound 10 displayed only low activity against the a-D-gluco-
sidase, 37% in concentration 7.26 mM.
3. Experimental
3.1. General methods
Melting points were determined using Köfler hot-stage appara-
tus with microscope and were uncorrected. Proton and carbon
NMR spectra were recorded on a Bruker DRX 500 Avance Spec-
trometer at 500 MHz and 125 MHz, respectively, using deuterated
solvents and TMS as an internal standard. Chemical shifts are
reported as d values in ppm and coupling constants are in Hertz.
Infrared spectra were obtained on an FT-IR-1600 Perkin–Elmer
spectrophotometer. The optical rotations were measured with a
JASCO J-1020 digital polarimeter. High resolution mass spectra
were recorded on ESI-TOF Mariner spectrometer (Perspective Bio-
system). X-ray analyses were performed on Nonius MACH3
difractometer.
Thin layer chromatography (TLC) was performed on aluminum
sheets Silica Gel 60 F254 (20 ꢁ 20 ꢁ 0.2) from Merck. Column chro-
matography was carried out using Merck silica gel 230–400 mesh.
The TLC spots were visualized in UV (254 nm) and by treatment
with alcoholic solution of ninhydrine.
Figure 1. ORTEP drawing of X-ray structure of 17 (salt with CF3COOH).12
sider the use of a non-chiral furanone 18 as the component of the
1,3-cycloaddition with nitrone 2. In such a case, the preferred ap-
proach of reactants should be exo and anti to the 3-Ot-Bu of the nit-
rone, and the resulting configuration at C-1a and C-4a of both
adducts should be the same. It has been reported, however, that
the cycloaddition of 18 and 2 leads to the mixture of two exo ad-
ducts 19 and 20 (Scheme 2) in a ratio of about 9:1.7 Moreover,
the reduction of lactone 19 gave diol 21 with two difficult to dis-
criminate primary hydroxyl groups. Silylation of 21 with equimo-
lar amount of t-BuPh2SiCl, or its acylation with equimolar
amount of PivCl led in both cases to the mixture of substrate 21,
double-substituted compound 22 (23) and two mono-substituted
24 and 25 (26 and 27), which could not be easily separated into
pure regioisomers (Scheme 2). The ratio of products 22:24:25
All solvents were dried and purified applying standard tech-
niques.17 Cycloadduct 4 was prepared following our previous
procedure.7
O
O
O
O
O
O
H
H
H
H
H
H
+
2
+
O
O
Ot-Bu
Ot-Bu
N
N
18
Ot-Bu
Ot-Bu
20
19
OR2
R1O
OH
HO
H
H
H
H
H
H
O
O
Ot-Bu
Ot-Bu
N
N
Ot-Bu
Ot-Bu
22: R1=R2=t-BuPh2Si
23: R1=R2=Piv
21
24: R1=t-BuPh2Si; R2=H
25: R1=H; R2=t-BuPh2Si
26: R1=Piv; R2=H
27: R1=H; R2=Piv
Scheme 2.

2218
S. Stecko et al. / Carbohydrate Research 343 (2008) 2215–2220
3.2. (1aS,2R,4aR,4bS,5S,6S)-5,6-Di-tert-butoxy-2-tert-
butyldiphenylsilyloxymethyl-hexahydrofuro[3,4-d]pyrrolo-
[1,2-b]isoxazol-1(3H)-one (11)
(hexane–ethyl acetate 9:1?4:1 v/v) affording 1.19 g of 13
(80%); colorless oil; [a]D ꢀ4.1 (c 1.5, CH2Cl2); IR (film, CH2Cl2) m:
1730 cmꢀ1
;
1H NMR (500 MHz, C6D6) d: 7.90–7.10 (10H, m,
2 ꢁ Ph), 4.70 (1H, dd, J 11.1, 5.2 Hz, CHHOPiv), 4.42 (1H, dd, J
11.1, 7.9 Hz, CHHOPiv), 4.31 (1H, dd, J 9.0, 5.5 Hz, H-2), 4.06 (1H,
dd, J 10.2, 3.0 Hz, CHHOSi), 3.98 (1H, ddd, J 9.0, 6.3, 3.0 Hz, CH(OH)-
CH2OSi), 3.88 (1H, dd, J 10.2, 6.3 Hz, CHHOSi), 3.82–3.75 (2H, m,
H-4, H-5), 3.68 (1H, m, H-3a), 3.52 (1H, dd, J 11.6, 5.0 Hz, H-6),
3.09–3.03 (1H, dddd, J 7.9, 5.5, 5.2, 2.0 Hz, H-3), 2.97 (1H, dd, J
11.6, 6.0 Hz, H-60), 2.67 (1H, br s, OH), 1.22 (9H, s, t-Bu), 1.14
(9H, s, t-Bu), 1.13 (9H, s, t-Bu), 0.97 (9H, s, t-Bu); 13C NMR
(125 MHz, C6D6) d: 177.8, 135.9, 130.1, 128.1, 81.9, 76.5, 76.4,
73.8, 73.4, 73.1, 69.7, 67.1, 63.3, 61.5, 48.9, 38.8, 29.2, 28.5, 27.4,
27.1, 19.5; HRMS (ESI) m/z calcd for C38H59NO7SiNa: 692.3924
[M+Na+], found: 692.3924.
To a cooled (ꢀ15 °C) solution of 1.0 g (2.9 mmol) of the adduct 4
and 0.3 g (4.4 mmol) of imidazole in dichloromethane (50 mL),
0.9 mL (0.9 g, 3.2 mmol) of t-BuPh2SiCl was added. The progress
of reaction was monitored by TLC (hexane–ethyl acetate 2:1 v/v).
After disappearance of substrate, reaction mixture was diluted
with dichloromethane (50 mL), washed with water (2 ꢁ 25 mL),
brine (25 mL), and dried over anhydrous Na2SO4. After removal
of solvent residue was chromatographed on silica gel (hexane–
ethyl acetate 9:1 then 4:1 v/v) affording 1.68 g (99%) of 11 as a col-
orless oil; [a]D +48.1 (c 1.34, CH2Cl2); IR (film, CH2Cl2) m: 1779,
;
1113 cmꢀ1 1H NMR (500 MHz, C6D6) d: 7.72–7.20 (10H, m,
2 ꢁ Ph), 4.75 (1H, d, J 6.2 Hz, H-1a), 4.24 (1H, dd, J 2.8, 1.9 Hz,
H-2), 4.14 (1H, dd, J 2.7, 2.2 Hz, H-4b), 4.02 (1H, dd, J 4.2, 3.4 Hz,
H-5), 3.82 (1H, ddd, J 5.8, 5.5, 4.2 Hz, H-6), 3.77 (1H, dd, J 6.2,
2.7 Hz, H-4a), 3.57 (1H, dd, J 11.5, 2.8 Hz, CHHOSi), 3.53 (1H, dd, J
12.1, 5.8 Hz, H-7), 3.23 (1H, dd, J 11.5, 1.9 Hz, CHHOSi), 2.97
(1H, dd, J 12.1, 5.5 Hz, H-70), 1.18 (9H, s, t-Bu), 1.08 (9H, s,
t-Bu), 1.00 (9H, s, t-Bu); 13C NMR (125 MHz, C6D6) d: 176.3,
136.0, 135.8, 133.3, 132.4, 130.3, 130.2, 128.5, 128.35, 82.9, 82.1,
80.1, 76.9, 75.8, 74.3, 73.8, 64.2, 61.2, 55.9, 28.8, 28.4, 26.9, 19.3;
HRMS (ESI): calcd for C33H48NO6Si: 582.32676 [M+H+], found:
582.3268.
3.5. (2S,3S,3aS,4S,5S)-4,5-Di-tert-butoxy-2-hydroxymethyl-3-
pivaloyloxymethyl-hexahydropyrrolo[1,2-b]isoxazol (14)
A solution of 0.50 g (0.75 mmol) of 13 and TBAF (0.26 g,
0.83 mmol) in THF (25 mL) was stirred under argon atmosphere.
The progress of reaction was monitored by TLC (hexane–ethyl ace-
tate 4:1 v/v). After disappearance of the substrate, solvent was
evaporated and the residue was dissolved in methanol (20 mL),
treated with NaIO4 (0.32 g, 1.5 mmol), and stirred at room temper-
ature for 1 h (TLC, CH2Cl2–MeOH 9:1 v/v). Subsequently, the reac-
tion mixture was filtered and the solution was treated with NaBH4
(29 mg, 0.75 mmol). The progress of the reaction was monitored by
TLC (hexane–ethyl acetate 1:1 v/v). The mixture was then acidified
by 5% HCl aq and then neutralized with triethylamine. Solvents
were evaporated in vacuo. The oily residue was purified on silica
gel (hexane–ethyl acetate 1:1 v/v) to afford 0.25 g (83%) of 14; col-
orless oil; [a]D +72.6 (c 0.85, CH2Cl2); IR (film, CH2Cl2) m: 3256,
3.3. (R)-2-(tert-Butyldiphenylsilyloxy)-1-((2S,3S,3aS,4S,5S)-4,5-
di-tert-butoxy-3-(hydoxymethyl)hexahydropyrrolo[1,2-b]-
isoxazol-2-yl)ethanol (12)
A 2 M solution of BH3–Me2S in THF (7 mL) was added to a solu-
tion of 1.68 g (2.9 mmol) of lactone 11 in 25 mL THF under argon.
The progress of reaction was monitored by IR spectra. After con-
sumption of the lactone, excess of borane was destroyed by addi-
tion of methanol (ca. 20 mL). Solvents were evaporated in
vacuum and the residue was dissolved in 30 mL of 7 N ammonia
solution in methanol and stirred overnight. Subsequently, solvent
was removed under diminished pressure and the oil residue was
purified on silica gel (hexane–ethyl acetate 1:1 v/v) affording
1.3 g (77%) of diol 12 as a colorless oil; [a]D +25.0 (c 4.6, CH2Cl2);
1728 cmꢀ1 1H NMR (500 MHz, C6D6) d: 4.35 (2H, m, CH2OPiv),
;
4.24 (1H, m, H-2), 3.85 (2H, m, H-4, H-5), 3.78 (2H, m, CH2OH),
3.56 (1H, m, H-6), 3.50 (1H, m, H-3a), 3.20 (1H, br s, OH), 3.08
(1H, m, H-60), 2.92 (1H, m, H-3), 1.15 (9H, s, t-Bu), 1.14 (9H, s,
t-Bu), 1.03 (9H, s, t-Bu); 13C NMR (125 MHz, C6D6) d: 177.5, 81.7,
78.9, 77.9, 74.1, 73.9, 73.6, 63.1, 61.8, 61.7, 48.5, 38.7, 28.9, 28.5,
27.3; HRMS (ESI): calcd for C21H39NO6Na: 424.2670 [M+Na+],
found: 424.2671.
IR (film, CH2Cl2) m: 3369, 1112 cmꢀ1 1H NMR (500 MHz, CDCl3–
;
D2O) d: 7.70–7.33 (10H, m, 2 ꢁ Ph), 4.24 (1H, dd, J 9.1, 6.3 Hz,
H-2), 3.96 (1H, ddd, J 9.1, 6.5, 3.3 Hz, CH(OH)CH2OSi), 3.93–3.86
(2H, m, CHHOH, CHHOSi), 3.86–3.81 (2H, m, H-4, H-5), 3.71 (1H,
dd, J 10.4, 6.5 Hz, CHHOSi), 3.63 (1H, dd, J 11.6, 3.9 Hz, CHHOH),
3.43 (1H, dd, J 12.0, 5.6 Hz, H-6), 3.09 (1H, dd, J 4.2, 3.8 Hz,
H-3a), 2.94 (1H, m, H-3), 2.82 (1H, dd, J 12.0, 6.0 Hz, H-60), 1.19
(9H, s, t-Bu), 1.14 (9H, s, t-Bu), 1.07 (9H, s, t-Bu); 13C NMR
(125 MHz, C6D6) d: 135.9, 133.8, 130.0, 128.3, 82.2, 77.6, 77.1,
74.1, 73.8, 73.4, 70.1, 66.7, 62.0, 61.2, 28.9, 28.4, 27.1, 19.6; HRMS
(ESI) m/z calcd for C33H51NO6SiNa: 608.3378 [M+Na+], found:
608.3380.
3.6. (2S,3S,3aS,4S,5S)-4,5-Di-tert-butoxy-2-mesyloxymethyl-3-
pivaloyloxymethyl-hexahydropyrrolo[1,2-b]isoxazol (15)
A mesyl chloride (72 lL, 0.11 g, 0.93 mmol) was added to a
cooled solution of alcohol 14 (0.25 g, 0.62 mmol) and Et3N
(0.26 mL, 0.19 g, 1.86 mmol) in CH2Cl2 (5 mL). The progress of reac-
tion was controlled by TLC (hexane–ethyl acetate 1:1 v/v). After
dilution with dichloromethane (20 mL), the post-reaction mixture
was washed with water (2 ꢁ 10 mL), brine (10 mL), and dried over
Na2SO4. After evaporation of the solvent, the residue was purified
on silica gel (hexane–ethyl acetate 1:1 v/v) affording 0.27 mg
(92%) of mesylate 15; colorless oil; [a]D +84.2 (c 0.11, CH2Cl2); IR
3.4. (2S,3S,3aS,4S,5S)-4,5-Di-tert-butoxy-2-((R)-20-tert-
butyldiphenylsilyloxy-10-hydroxyethyl)-3-pivaloyloxymethyl-
hexahydropyrrolo[1,2-b]isoxazol (13)
(film, CH2Cl2) m: 1730 cmꢀ1 1H NMR (500 MHz, C6D6) d: 4.38–
;
4.28 (3H, m, H-2, CH2OMs), 4.02 (1H, dd, J 11.7, 5.5 Hz, CHHOPiv),
3.96 (1H, dd, J 11.4, 7.7 Hz, CHHOPiv), 3.77 (1H, ddd, J 5.4, 5.1,
3.6 Hz, H-5), 3.73 (1H, dd, J 3.6, 3.3 Hz, H-4), 3.49 (1H, dd, J 12.4,
5.4 Hz, H-6), 3.37 (1H, dd, J 4.6, 3.3 Hz, H-3a), 3.02 (1H, dd, J
12.4, 5.1 Hz, H-60), 2.72 (1H, dddd, J 7.7, 6.3, 5.5, 4.6 Hz, H-3),
2.39 (3H, s, Ms), 1.15 (9H, s, t-Bu), 1.09 (9H, s, t-Bu), 0.99 (9H, s,
t-Bu); 13C NMR (125 MHz, C6D6) d: 177.4, 82.0, 77.7, 75.8, 74.0,
73.9, 73.7, 67.9, 62.0, 61.9, 48.7, 37.0, 28.8, 28.4, 27.2; HRMS
The PivCl (0.3 mL, 0.30 g, 2.5 mmol) was added to cooled (0 °C)
solution of diol 12 (1.3 g, 2.2 mmol) and DMAP (0.54 g, 4.4 mmol)
in CH2Cl2 (30 mL). The progress of reaction was controlled by TLC
(hexane–ethyl acetate 4:1 v/v). Subsequently, the post-reaction
mixture was diluted with dichloromethane (20 mL), washed with
sodium carbonate (30 mL), water (30 mL), brine (30 mL), and then
organic layer was dried over anhydrous sodium sulfate. After
evaporation of the solvent, the residue was purified on silica gel
(ESI): calcd for
502.2470.
C
22H41NO8NaS: 502.2445 [M+Na+], found:

S. Stecko et al. / Carbohydrate Research 343 (2008) 2215–2220
2219
3.7. (1S,2S,6S,7S,7aS)-2-Acetoxy-6,7-di-tert-butoxy-1-
(pivaloyloxymethyl)hexahydro-pyrrolizine (16)
H-7a), 2.88–2.81 (2H, m, H-30, H-50), 2.24 (1H, m, H-7); 13C NMR
(125 MHz, CD3OD) d: 82.8, 79.7, 74.9, 73.7, 63.1, 62.9, 60.5,
54.3; HRMS (ESI): calcd for C8H16NO4: 190.1074 [M+H+], found:
190.1066.
A solution of mesylate 15 (0.27 g, 0.57 mmol) in AcOEt–MeOH
(4:1 v/v, 10 mL) was hydrogenated over 10% Pd on charcoal
(25 mg) under atmospheric pressure. Reaction was monitored by
TLC (hexane–ethyl acetate 1:1 v/v). Subsequently, the post-reac-
tion mixture was filtered through Celite and concentrated in vacuo.
Residue was dissolved in Et3N (3 mL) and 0.5 mL of Ac2O was
added. After 30 min of stirring at room temperature reaction
mixture was concentrated and product was isolated on a silica
gel column (hexane–ethyl acetate 2:1 v/v) to afford 0.22 g (89%)
of 16 as a colorless oil; [a]D ꢀ2.1 (c 4.8, CH2Cl2); IR (film, CH2Cl2)
3.10. (2S,3S,3aS,4S,5S)-2,3-Bis(hydroxymethyl)-4,5-di-tert-
butoxy-hexahydropyrrolo[1,2-b]isoxazol (21)
A 2 M solution of BH3–Me2S in THF (2 mL) was added to a solu-
tion of 100 mg (0.319 mmol) of lactone 19 in 10 mL THF under
argon. The progress of reaction was monitored by IR spectra. After
consumption of the lactone, the excess of borane was destroyed by
addition of methanol (ca. 20 mL). Solvents were evaporated in
vacuum and the residue was dissolved in 30 mL of 7 N ammonia
solution in methanol and stirred overnight. Subsequently solvent
was removed under diminished pressure and the oil residue was
purified on silica gel (CH2Cl2–MeOH 30:1 v/v) affording 76 mg
(75%) of diol 21 as a colorless oil; [a]D +32.0 (c 3.0, CH2Cl2); IR (film,
CH2Cl2) m: 3341, 1098 cmꢀ1; 1H NMR (500 MHz, CDCl3-D2O) d: 4.55
(1H, ddd, J 5.7, 5.5, 4.5 Hz, H-2), 4.12–4.00 (2H, m, H-5, C3CHHOH),
3.96 (1H, dd, J 12.6, 5.5 Hz, C2CHHOH), 3.92–3.82 (3H, C2CHHOH,
H-4, H-6), 3.70 (1H, dd, J 11.2, 5.0 Hz, C3CHHOH), 3.60 (1H, dd, J
4.9, 3.1 Hz, H-3a), 3.26 (1H, dd, J 12.2, 7.1 Hz, H-60), 2.95–2.85
(1H, m, H-3), 1.21 (9H, s, t-Bu), 1.19 (1H, s, t-Bu); 13C NMR
(125 MHz, CDCl3) d: 81.3, 81.0, 80.9, 68.6, 60.7, 59.4, 51.0, 28.7,
28.3; HRMS (ESI) m/z calcd for C16H32NO5: 318.2280 [M+H+],
found: 318.2277.
m: 1732 cmꢀ1 1H NMR (500 MHz, C6D6) d: 5.31 (1H, ddd, J 5.7,
;
5.4, 4.7 Hz, H-6), 4.30 (1H, dd, J 11.5, 4.8 Hz, CHHOPiv), 4.08 (1H,
dd, J 11.5, 6.4 Hz, CHHOPiv), 4.00–3.92 (1H, m, H-1, H-2), 3.50
(1H, dd, J 11.4, 5.7 Hz, H-5), 3.38–3.32 (2H, m, H-3, H-7a), 2.93
(1H, dd, J 11.4, 4.7 Hz, H-50), 2.77 (1H, m, H-7), 2.72 (1H, dd, J
10.4, 5.7 Hz, H-30), 1.61 (3H, s, CH3C@O), 1.20 (9H, s, t-Bu), 1.16
(9H, s, t-Bu), 1.04 (9H, s, t-Bu); 13C NMR (125 MHz, C6D6) d:
177.7, 169.6, 81.4, 79.1, 77.5, 73.8, 73.5, 70.7, 63.4, 59.7, 58.7,
48.2, 38.9, 29.0, 28.5, 27.3, 20.5; HRMS (ESI): calcd for
C
23H42NO6: 428.3007 [M+H+], found: 428.3027.
3.8. (1S,2S,6S,7S,7aS)-2,6,7-Triacetoxy-1-acetoxymethyl-
hexahydropyrrolizine (17)
To a 1 M solution of LiAlH4 (0.76 mL) in Et2O (20 mL) compound
16 (0.22 g, 0.51 mmol) in Et2O (10 mL) was added. After disappear-
ance of the substrate (TLC), 100 lL of saturated solution of Na2SO4
was added and the mixture was stirred in ultrasound bath for
5 min. After filtration through Celite and evaporation of the sol-
vent, the residue was dissolved in Et3N (2 mL) and treated with
Ac2O (0.3 mL). After 45 min solvents were removed under dimin-
ished pressure and the residue was purified on a silica gel column
(hexane–ethyl acetate 1:2 v/v). Subsequently, the product was dis-
solved in CF3COOH (5 mL) and stirred overnight. After evaporation
of the solvent the residue was acetylated with Ac2O (0.3 mL) in
Et3N (2 mL). The solvents were then removed under diminished
pressure and the crude product was purified on silica gel (hex-
ane–ethyl acetate 1:3 v/v) to afford 0.12 g (68%) of 17; mp of salt
with CF3COOH: 146–147 °C (benzene–CH2Cl2 2:1 v/v); For free
amine: colorless oil; [a]D: +2.1 (c 0.6, CH2Cl2); IR (film, CH2Cl2) m:
3.11. Monoprotection of diol 21
3.11.1. Method A
To a cooled (ꢀ15 °C) solution of 18 mg (57 lmol) of the diol 21
and 7.8 mg (114 lmol) of imidazole in dichloromethane (2 mL),
16 lL (17 mg, 62 lmol) of t-BuPh2SiCl was added. After disappear-
ance of the substrate, reaction mixture was diluted with dichloro-
methane (5 mL), washed with water (2 mL), brine (2 mL), and dried
over anhydrous Na2SO4. The ratio of products 22:26:27 amounted
to 4:1.5:1, respectively (HPLC). After column chromatography on a
silica gel column (hexane–ethyl acetate 4:1 v/v), 13.5 mg (24%) of
22 and a mixture of 24 and 25 (4 mg; 19%; characterized by MS
only) were isolated.
3.11.2. (2S,3S,3aS,4S,5S)-2,3-Bis(tert-butyldiphenylsilyloxy-
methyl)-4,5-di-tert-butoxy-hexahydropyrrolo[1,2-b]-
isoxazol (22)
1739, 1230 cmꢀ1 1H NMR (500 MHz, C6D6) d: 5.36 (1H, m, H-2),
;
5.30 (1H, m, H-1), 5.12 (1H, m, H-6), 4.28 (1H, dd, J 11.3, 5.5 Hz,
CHHOAc), 4.15 (1H, dd, J 11.3, 6.1 Hz, CHHOAc), 3.37 (1H, dd, J
11.7, 5.7 Hz, H-3), 3.32 (1H, dd, J 11.0, 6.0 Hz, H-5), 3.24 (1H, m,
H-7a), 2.78 (1H, dd, J 11.7, 4.9 Hz, H-30), 2.70 (1H, dd, J 11.0,
5.5 Hz, H-50), 2.64 (1H, m, H-7), 1.70 (3H, s, CH3C@O), 1.59 (3H, s,
CH3C@O), 1.58 (3H, s, CH3C@O), 1.57 (3H, s, CH3C@O); 13C NMR
(125 MHz, C6D6) d: 170.0, 169.8, 169.5, 169.2, 81.5, 79.0, 76.8,
71.4, 63.4, 58.6, 57.1, 48.6, 20.37, 20.30, 20.27, 20.25; HRMS
(ESI): calcd for C16H23NO8Na: 380.1316 [M+Na+], found: 380.1331.
[a]D +7.7 (c 2.0, CH2Cl2); 1H NMR (500 MHz, C6D6) d: 7.81–7.20
(20H, 4 ꢁ Ph), 4.41 (1H, m, H-2), 4.24 (1H, d, J 6.7 Hz, H-3a), 4.21–
4.12 (2H, H-5, C3CHHOSi), 4.06–3.96 (3H, H-6, C2CHHOSi, C3CHHO-
Si), 3.92 (1H, dd, J 11.6, 5.0 Hz, C2CHHOSi), 3.68 (1H, t, J 6.7, 6.7 Hz,
H-4), 3.12 (1H, dd, J 11.6, 9.1 Hz, H-60), 2.73 (1H, m, H-3), 1.15 (9H,
s, t-Bu), 1.14 (9H, s, t-Bu), 1.10 (9H, s, t-Bu), 0.99 (9H, s, t-Bu); 13C
NMR (125 MHz, C6D6) d: without aromatic signals, 81.2, 80.9, 79.3,
74.7, 74.3, 67.8, 51.3, 29.3, 28.3, 27.1, 27.0, 19.2; HRMS (ESI) m/z
calcd for C48H68NO5Si2: 794.4636 [M+H+], found: 794.4632. A mix-
ture of 24 and 25 HRMS (ESI) m/z calcd for C32H49NO5SiNa:
578.3278 [M+Na+], found: 578.3274.
3.9. (1S,2S,6S,7S,7aS)-2,6,7-Trihydroxy-7-
(hydroxymethyl)hexahydropyrrolizine (10)
The 58 mg (0.16 mmol) of 17 was dissolved in 15 mL of 1% solu-
tion of NH3 in methanol and stirred at room temperature for 17 hr
under argon atmosphere. Then the solvent was removed and resi-
due was purified on Florisil (ethyl acetate–methanol 1:1, then
methanol) affording 28 mg (93%) of compound 1 as a colorless
3.11.3. Method B
To a cooled (0 °C) solution of diol 21 (13.5 mg; 43 lmol) and
4.6 mg (38 lmol) of DMAP in dichloromethane (2 mL), PivCl
(5.3 lL, 5.2 mg, 45 lmol) was added. The progress of reaction was
monitored by TLC (hexane–ethyl acetate 1:1 v/v). After disappear-
ance of substrate, reaction mixture was diluted with dichlorometh-
ane (5 mL), washed with sat. Na2CO3 (1 mL), brine (1 mL), and
dried over anhydrous Na2SO4. The ratio of products 23:26:27
amounted to 5:1.5:1 (HPLC). After column chromatography on
oil; [a]D ꢀ3.6 (c 0.5, MeOH); IR (film, CH2Cl2) m: 3357, 3194 cmꢀ1
;
1H NMR (500 MHz, CD3OD) d: 4.12–4.01 (3H, m, H-1, H-2, H-6),
3.69 (1H, dd, J 10.9, 5.5 Hz, CHHOH), 3.58 (1H, dd, J 10.9, 6.6 Hz,
CHHOH), 3.27–3.15 (2H, m, H-3, H-5), 3.09 (1H, dd, J 7.5, 4.2 Hz,

2220
S. Stecko et al. / Carbohydrate Research 343 (2008) 2215–2220
A. Synthesis of Naturally Occurring Nitrogen Heterocycles from Carbohydrates;
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mixture 26 and 27 (3 mg, 18%, characterized by MS only) were
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3.11.4. (2S,3S,3aS,4S,5S)-2,3-Bis(pivaloyloxymethyl)-4,5-di-tert-
butoxy-hexahydropyrrolo[1,2-b]isoxazol (23)
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[a]D +37.8 (c 0.95, CH2Cl2); IR (film) m: 1730 cmꢀ1 1H NMR
;
(500 MHz, C6D6) d: 4.54 (1H, dd, J 11.6, 3.5 Hz, C2CHHOPiv), 4.46
(1H, ddd, J 7.6, 6.3, 3.5 Hz, H-2), 4.27 (1H, dd, J 11.6, 7.6 Hz,
C2CHHOPiv), 4.22–4.12 (2H, C3CH2OPiv), 3.85–3.78 (2H, m, H-4,
H-5), 3.60 (1H, dd, J 11.9, 5.1 Hz, H-6), 3.50 (1H, dd, J 3.9, 3.7 Hz,
H-3a), 3.06 (1H, dd, J 11.9, 5.0 Hz, H-60), 2.82–2.73 (1H, m, J 7.2,
6.3, 6.3, 3.9 Hz, H-3), 1.23 (9H, s, t-Bu), 1.19 (9H, s, t-Bu), 1.14
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177.4, 177.3, 81.8, 77.0, 75.2 73.6, 73.4, 73.3, 62.5, 62.4, 61.6,
58.7, 48.7, 38.6, 38.5, 28.7, 28.2, 27.0, 26.9; HRMS (ESI) m/z calcd
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Acknowledgment
This work was supported by the Ministry of Science and High
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