Synthesis of 8-homocastanospermine

Article abstract of DOI:10.1139/V06-032

The 1,3-dipolar cycloaddition of a five-membered cyclic nitrone derived from malic acid (4) and unsaturated D-threo-hexaldonolactone (1) leads to a single adduct 6, which can be transformed into the 8-homocastanospermine (13) via a sequence involving rear

Full text of DOI:10.1139/V06-032

534
Synthesis of 8-homocastanospermine1
Konrad PaÑniczek, Dariusz Socha, Margarita Jurczak, Jolanta Solecka, and
Marek Chmielewski
Abstract: The 1,3-dipolar cycloaddition of a five-membered cyclic nitrone derived from malic acid (4) and unsaturated
D-threo-hexaldonolactone (1) leads to a single adduct 6, which can be transformed into the 8-homocastanospermine
(13) via a sequence involving rearrangement of the six-membered lactone ring into the five-membered one, removal of
the terminal carbon atom from the sugar chain, cleavage of the N—O bond, and the intramolecular alkylation of the ni-
trogen atom. The iminosugar (13) does not show any interesting inhibitory activity towards α- and β-glucosidases.
Key words: iminosugars, homocastanospermine, nitrones, aldono-1,5-lactone, 1,3-dipolar cycloaddition, glucosidases.
Résumé : La cycloaddition 1,3-dipolaire d’une nitrone cyclique à cinq chaînons dérivée de l’acide malique (4) et de la
D-thréo-hexaldonolactone insaturée (1) conduit à la formation d’un seul adduit qui peut être transformé en 8-
homocastanospermine (13), par le biais d’une séquence impliquant le réarrangement de la lactone à six chaînons en
une lactone à cinq chaînons, l’élimination de l’atome de carbone terminal de la chaîne du sucre, le clivage de la liaison
N—O et d’une alkylation intramoléculaire de l’atome d’azote. L’iminosucre (13) ne présente pas d’activité inhibitrice
intéressante vis-à-vis des α- et des β-glucosidases.
Mots clés : iminosucres, homocatanospermine, nitrones, aldono-1,5-lactone, cycloaddition 1,3-dipolaire, glucosidases.
[Traduit par la Rédaction] PaÑniczek et al. 539
Introduction
an (R) or (S) configurations at the bridgehead carbon atom,
which are closely related to the castanospermine (11) and
swainsonine (12) (Chart 3) (6).
Recently, we have reported that the cycloaddition of 2,3-
unsaturated aldono-1,5-lactones (1 or 2) and the five-
membered cyclic nitrones (3 or 4) (Chart 1) proceeds exclu-
sively in the exo mode and results in a high preference for
the anti addition to both the acetoxymethyl group of the
lactone and the 3-tert-butoxy group of the nitrone (1–3). In
the case of mismatched pairs, the 4-acetoxy group of the
lactone assumes a decisive role in the control of the stereo-
chemical pathway of cycloaddition. The stereochemical
preferences are the underlying reason that, in many cases, a
single adduct or at least a high preponderance of a single
adduct is observed. This observation has been well-
illustrated by the exclusive formation of adducts 6 and 7
from D-threo 4-O-acetyl-lactone (1) and D-erythro 4-O-
acetyl-lactone (2), respectively (Chart 2) (3).
Both components of the cycloaddition, the nitrone and the
unsaturated lactone, carry over their own substituents (pro-
tected hydroxyls) with their original configuration, whereas
the configurations at C-1a, C-4a, and C-4b of the cyclo-
adduct are established during the reaction. Adduct 6 is par-
ticularly interesting because it can be easily transformed into
the compounds related to the castanospermine (11) and
especially the 8-homocastanospermine (13). The castano-
spermine (11) (7) itself displays a range of interesting thera-
peutic properties (8), however, it is very toxic, therefore its
use has a limited value. The present paper describes the syn-
thesis of imino sugar 13 from adduct 6.
We have shown that application of the known methodol-
ogy (4) to cycloadduct 8 offers a convenient approach to the
indolizidine alkaloids. This has been demonstrated by the
synthesis of 7-hydroxylentiginosine (9) and the formal syn-
thesis of lentiginosine (10) (5). The easy access to adducts 6
and 7 opens an entry to the corresponding indolizidines with
Results and discussion
Adduct 6 (2, 3) was deacetylated with sodium methoxide
in methanol to afford compound 14. The reaction proceeds
with rearrangement of the six-membered lactone ring into a
five-membered one. The glycolic cleavage of the terminal
diol group in 14 with NaIO4 followed by the reduction of the
aldehyde group with sodium triacetoxyborohydride gave
compound 16 in 83% yield. The use of sodium borohydride
resulted in the reduction of both carbonyl functions of the al-
dehyde 15, whereas the sodium cyanoborohydride gave the
desired product 16 in a low yield (Scheme 1).
The activation of the terminal hydroxymethyl group by
the introduction of a halogen or sulfonyl as a leaving group,
followed by the direct alkylation of the isoxazolidine nitro-
gen atom, led to an unattractive mixture of products. There-
fore, we decided to form the indolizidine skeleton in a
stepwise manner. First, the hydroxymethyl group was pro-
Received 30 August 2005. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 21 April 2006.
K. PaÑniczek, D. Socha, M. Jurczak, and M. Chmielewski.2
Institute of Organic Chemistry of the Polish Academy of
Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
J. Solecka. National Institute of Hygiene, 00-791 Warsaw,
Poland.
1This article is part of a Special Issue dedicated to Professor
Walter A. Szarek.
2Corresponding author (e-mail: chmiel@icho.edu.pl).
Can. J. Chem. 84: 534–539 (2006)
doi:10.1139/V06-032
© 2006 NRC Canada

PaÑniczek et al.
535
Chart 1.
Chart 3.
HO
OH
OH
t-BuO
Ot-Bu
CH2OAc
OH
H
N
H
N
R1
HO
HO
R
O
OH
O
N
O
3
R2
9: R = OH
10: R = H
11
1: R1= OAc, R2=H
2: R1= H, R2=OAc
HOH2C
HO
OH
H
H
N
HO
t-BuO
OH
N
HO
O
N
O
12
13
O
Note that the oxidation of the hydroxymethyl group in
suitably protected 13 or 23 to the carboxylic function fol-
lowed by an oxidative decarboxylation, for example, by the
methodology recently reported by us for the other
indolizidine (5), should provide 11.
5
4
Chart 2.
AcO
t-BuO
CH2OAc
O
The biological activity of compound 13 toward commer-
cially available α- and β-glucosidases was tested and
compared with the corresponding data measured for com-
mercially available 11. Surprisingly, compound 13 showed
only a trace inhibition of α-glucosidase activity in a concen-
tration of 0.02 mol/L and no inhibition of β-glucosidase.
In summary, we have reported the simple synthesis of 8-
homocastanospermine (13) in which a proper selection of
readily available components of the 1,3-dipolar cyclo-
addition controls the absolute stereochemistry at all five
stereogenic centers present in the target molecule. The re-
ported synthesis demonstrated an exceptional effectiveness
of the 1,3-dipolar cycloaddition of nitrones and sugar unsat-
urated δ-lactones, which led to formation of only one
diastereomer with a fully defined configuration at all
stereogenic centers.
H
O
N
O
O
O
H
AcOH2C
O
N
Ot-Bu
OAc
7
6
O
H
O
O
N
Ot-Bu
Ot-Bu
8
tected as a tert-butyldiphenylsilyl derivative 17 and lactone
was reduced with sodium borohydride to give diol 18. Both
hydroxy groups in 18 were masked by the formation of an
isopropylidene moiety. The desilylation of 19 with tetra-
butylammonium fluoride led to alcohol 20. Due to the low
stability of the isopropylidene fragment and the tendency of
the terminal mesyloxymethyl group to undergo intramole-
cular alkylation, the next three steps were performed with
only a partial purification of intermediary products. Alcohol
20 was mesylated to afford 21, the isopropylidene protection
was removed using 80% acetic acid, and the sequence was
completed by the hydrogenolysis of the N—O bond over
Pd/C and intramolecular alkylation of the nitrogen atom.
The final product of this reaction sequence (indolizidine 22)
was acetylated and characterized as the triacetate 23. The
tert-butyl protection in 23 was subsequently removed with
trifluoroacetic acid and the liberated hydroxy group was
acetylated affording tetraacetate 24. The complete de-
acetylation of 24 with ammonia in methanol furnished the
13. Synthesis of a number of 8-hydroxymethylindolizidines
using intramolecular 1,3-dipolar cycloaddition has been re-
ported recently by Brandi’s group (9).
Experimental
1H NMR spectra were recorded on a Bruker DRX 500
Avance spectrometer. IR spectra were obtained on a
PerkinElmer FT-IR 1600 spectrophotometer. The optical ro-
tations were measured with a JASCO Dip-360 digital
polarimeter. Mass spectra were recorded using an AMD-604
instrument and HPLC–MS were recorded with Mariner and
API 356 detectors. Column chromatography was performed
with E. Merck Kiesel Gel (230–400 mesh).
Adduct 6 was obtained according to the known procedure
(2, 3).
Enzymes and substrates were purchased from Sigma-
Aldrich: α-glucosidase from rice, type V, 63.43 U/mg,
1.34 mg/mL; β-glucosidase from almonds, 25.8 U/mg,
95.4% protein.
(1aS,2R,4aR,4bS,5S,1′R)-5-tert-Butoxy-2-(1′,2′-dihy-
droxyethyl)-4-oxo-pyrrolidino[1,2-b]isoxazolidino[4,5-c]-
tetrahydrofurane (14)
Adduct 6 was dissolved in methanol, treated with 1 molar
equiv. of sodium carbonate, and stirred at room temperature
© 2006 NRC Canada

536
Can. J. Chem. Vol. 84, 2006
Scheme. 1. (a) Na2CO3, MeOH (88%); (b, c) NaIO4, MeOH–H2O; NaBH(OAc)3, CH2Cl2 (74%); (d) tert-butyldiphenylchlorosilane,
DMAP, CH2Cl2 (76%); (e) NaBH4, MeOH (60%); ( f ) 2,2-dimethoxypropane, p-TsOH (87%); (g) Bu4NF, THF (94%); (h) MsCl, Et3N,
CH2Cl2 (96%); (i) 80% AcOH; H2, 10% Pd/C, MeOH; Ac2O, Et3N, DMAP (55%); (j) MeOH–NH3 (91%).
H
H
O
H
O
O
O
O
O
RO
O
RO
H
H
H
b
H
H
a
c
RO
H
H
H
H
6
O
O
Ot-Bu
O
Ot-Bu
N
Ot-Bu
N
N
14: R = H
14Ac: R = Ac
15
16: R=H
16Ac: R=Ac
H
O
H
OR
N
O
H
OR
TBDPSO
O
N
TBDPSO
O
f
TBDPSO
H
H
H
e
H
H
d
H
H
H
H
O
O
Ot-Bu
Ot-Bu
N
O
Ot-Bu
18: R=H
18Ac: R=Ac
19
17
OR2
H
OR1
O
N
O
RO
H
R2O
R2O
i
g
j
H
H
H
O
13
N
Ot-Bu
22: R1=t-Bu, R2=H
23: R1=t-Bu, R2=Ac
24: R1=R2=Ac
20: R=H
21: R=Ms
h
until the disappearance of the substrate (1 h). Subsequently,
the solution was neutralized with Amberlite IR-1200 [H+],
diluted with dichloromethane, filtered through Celite, and
evaporated. The crude product was purified by chromatogra-
phy using CH2Cl2–MeOH (20:1 v/v) as the eluent to afford
14 in 88% yield. [α]D +5.3° (c 0.5, CH2Cl2). IR (film, cm–1):
H-5), 3.94 (bd, 1H, J = 7.3 Hz, H-4b), 3.83 (dd, 1H, J = 0.8,
6.7 Hz, H-4a), 3.35 (ddd, 1H, J = 3.5, 7.7, 13.6 Hz, H-7).
2.92 (ddd, 1H, J = 7.2, 10.4, 13.6 Hz, H-7′), 2.10, 2.09 (2s,
6H, 2Ac), 2.06 (ddt, 1H, J = 3.5, 13.1, 7.2, 7.2 Hz, H-6),
1.90 (dddd, 1H, J = 5.5, 7.2, 10.4, 13.1 Hz, H-6′′), 1.22 (s,
9H, t-Bu). 13C NMR (125 MHz, CDCl3) δ: 176.0, 170.5,
169.8, 80.1, 77.9, 74.6, 73.3, 71.1, 70.0, 62.7, 53.9, 52.0,
34.3, 28.4, 20.9, 20.7. HRMS (ESI) m/z calcd. for
C18H28NO8: 386.1809 [M + H]+; found: 386.1827.
1
3392, 1773. H NMR (500 MHz, CDCl3) δ: 4.90 (dd, 1H,
J = 6.3, 8.1 Hz, H-1a), 4.64 (dd, 1H, J = 2.8, 6.3 Hz, H-2),
4.23 (dt, 1H, J = 5.8, 7.3, 7.5 Hz, H-5), 4.20 (ddd, 1H, J =
2.8, 5.0, 6.4 Hz, CHOH), 3.93 (bd, 1H, J = 7.3 Hz, H-4b),
3.90 (dd, 1H, J = 0.9, 8.1 Hz, H-4a), 3.81 (dd, 1H, J = 6.4,
11.1 Hz, CHHOH), 3.72 (dd, 1H, J = 5.0, 11.1 Hz,
CHHOH), 3.47 (ddd, 1H, J = 2.6, 7.8, 14.0 Hz, H-7), 2.90
(dddd, 1H, J = 0.6, 7.4, 10.8, 14.0 Hz, H-7′), 2.12 (ddt, 1H,
J = 2.6, 7.4, 7.5, 13.1 Hz, H-6), 1.99 (dddd, 1H, J = 5.8, 7.8,
10.8, 13.1 Hz, H-6′), 1.21 (s, 9H, t-Bu). 13C NMR
(125 MHz, CDCl3) δ: 176.4, 82.5, 78.5, 74.6, 73.5, 71.2,
69.4, 63.9, 53.1, 50.7, 34.0, 28.4. HRMS (ESI) m/z calcd.
for C14H23NO6Na: 324.1418 [M + Na]+; found: 324.1430.
(1aS,2S,4aR,4bS,5S)-5-tert-Butoxy-2-hydroxymethyl-4-
oxo-pyrrolidino[1,2-b]isoxazolidino[4,5-c]tetrahydro-
furane (16)
Compound 14 (0.051 g, 0.17 mmol) was dissolved in
methanol–water (6:1 v/v, 5 mL) and treated at room tempera-
ture with 2 molar equiv. of sodium metaperiodate (0.072 g).
After 1 h the reaction was completed. The crude product
(15) was passed through a short silica gel column using di-
chloromethane–methanol (20:1 v/v) as the eluent. After
evaporation of the solvent, the product was dissolved in dry
CH2Cl2 (15 mL) and reduced with 2 molar equiv. of
NaBH(OAc)3. Standard work up provided a product that was
purified on a silica gel column (hexane – ethyl acetate, 1:2
v/v) to afford 16 (0.034 g, 74%). [α]D +11.0° (c 0.4,
(1aS,2R,4aR,4bS,5S,1′R)-2-(1′,2′-Diacetoxyethyl)-5-tert-
butoxy-4-oxo-pyrrolidino[1,2-b]isoxazolidino[4,5-c]-
tetrahydrofurane (14Ac)
Melting point 81–83 °C. [α]D –4.7° (c 0.3, CH2Cl2). IR
1
1
(film, cm–1): 1781, 1745. H NMR (500 MHz, CDCl3) δ:
CH2Cl2). IR (film, cm–1): 3409, 1774. H NMR (500 MHz,
5.49 (ddd, 1H, J = 2.9, 3.7, 8.8 Hz, CHOAc), 4.75 (dd, 1H,
J = 4.6, 6.7 Hz, H-1a), 4.66 (dd, 1H, J = 4.6, 8.8 Hz, H-2),
4.54 (dd, 1H, J = 2.9, 12.6 Hz, CHHOAc), 4.31 (dd, 1H, J =
3.7, 12.6 Hz, CHHOAc), 4.21 (dt, 1H, J = 5.5, 7.2, 7.3 Hz,
CDCl3) δ: 4.90 (dd, 1H, J = 6.1, 7.9 Hz, H-1a), 4.66 (ddd,
1H, J = 3.7, 4.9, 6.0 Hz, H-2), 4.23 (dt, 1H, J = 5.7, 7.3,
7.5 Hz, H-5), 4.06 (dd, 1H, J = 3.7, 12.4 Hz, CHHOH), 3.96
(dd, 1H, J = 5.0, 12.4 Hz, CHHOH), 3.95 (d, 1H, J =
© 2006 NRC Canada

PaÑniczek et al.
537
7.5 Hz, H-4b), 3.89 (d, 1H, J = 7.9 Hz, H-4a), 3.46 (ddd,
1H, J = 2.8, 7.8, 14.0 Hz, H-7), 2.93 (ddd, 1H, J = 7.4,
10.6 14.0 Hz, H-7′), 2.13 (ddt, 1H, J = 2.8, 13.2, 7.3,
7.4 Hz, H-6), 1.98 (dddd, 1H, J = 5.7, 7.8, 10.6, 13.2 Hz, H-
6′), 1.22 (s, 9H, t-Bu). 13C NMR (125 MHz, CDCl3) δ:
176.5, 82.5, 78.4, 74.5, 73.6, 71.3, 60.3, 53.3, 51.1, 34.1,
28.3. HRMS (ESI) m/z calcd. for C13H22NO5: 272.1492
[M + H]+; found: 272.1486.
6.5, 11.2 Hz, CHHOH), 3.94 (dd, 1H, J = 1.2, 7.1 Hz, H-
4b), 3.76 (dd, 1H, J = 1.2, 6.3 Hz, H-4a), 3.22 (ddd, 1H, J =
4.5, 7.5, 13.0 Hz, H-7), 2.92 (ddd, 1H, J = 6.9, 9.3, 13.0 Hz,
H-7′), 1.97 (dddd, 1H, J = 4.5, 6.9, 7.0, 13.0 Hz, H-6), 1.83
(dddd, 1H, J = 5.6, 7.5, 9.3, 13.0 Hz, H-6′), 1.20, 1.06 (2s,
18H, 2t-Bu). 13C NMR (125 MHz, CDCl3) δ: 177.1, 135.62,
135.61, 133.4, 133.2, 129.72, 129.70, 127.7, 127.6, 82.8,
77.8, 74.4, 72.9, 71.1, 61.7, 53.7, 52.0, 34.0, 28.4, 26.8,
19.2. HRMS (ESI) m/z calcd. for C29H39NO5NaSi: 532.2490
[M + H]+; found: 532.2516.
(1aS,2S,4aR,4bS,5S)-2-Acetoxymethyl-5-tert-butoxy-4-
oxo-pyrrolidino[1,2-b]isoxazolidino[4,5-c]tetrahydro-
furane (16Ac)
(1aS,2S,3S,3aS,4S)-2-(2′-tert-Butyldiphenylsiloxymethyl-
[α]D –8.7° (c 0.4, CH2Cl2). IR (film, cm–1): 1779, 1742.
1H NMR (500 MHz, CDCl3) δ: 4.81 (dd, 1H, J = 4.8,
6.8 Hz, H-1a), 4.72 (ddd, 1H, J = 3.8, 4.8, 8.3 Hz, H-2),
4.56 (dd, 1H, J = 3.8, 12.4 Hz, CHHOAc), 4.41 (dd, 1H, J =
8.3, 12.4 Hz, CHHOAc), 4.23 (dt, 1H, J = 5.3, 7.1, 7.3 Hz,
H-5), 3.95 (d, 1H, J = 7.3 Hz, H-4b), 3.82 (d, 1H, J =
6.8 Hz, H-4a), 3.40 (ddd, 1H, J = 3.5, 7.7, 13.6 Hz, H-7),
2.94 (ddd, 1H, J = 7.3, 10.0, 13.6 Hz, H-7′), 2.13 (s, 3H,
Ac), 2.10 (dddd, 1H, J = 3.5, 7.1, 7.3, 13.1 Hz, H-6), 1.95
(dddd, 1H, J = 5.3, 7.7, 10.0, 13.1 Hz, H-6′), 1.24 (s, 9H, t-
Bu). 13C NMR (125 MHz, C6D6) δ: 176.2, 169.9, 80.1, 77.6,
73.8, 73.7, 71.6, 63.0, 53.4, 51.6, 34.5, 28.2, 20.2. HRMS
(ESI) m/z calcd. for C15H24NO6: 314.15981 [M + H]+;
found: 314.1613.
1 -hydroxy)-4-tert-butoxy-3-hydroxymethyl-pyrrolidino-
′
[1,2-b]isoxazolidine (18)
Lactone 17 (0.10 g, 0.2 mmol) was dissolved in methanol
(25 mL), treated in portions with NaBH4 (0.015 g,
0.4 mmol), and left for 4 h. Subsequently, 2 drops of water
were added and the mixture was filtered through Celite. The
solution was evaporated and the residue was purified on a
silica gel column using hexane – ethyl acetate (1:3 v/v) as the
eluent to afford 15 (0.062 g, 60%); mp 108.0–109.5 °C. [α]D
1
+38.2° (c 1.23, CH2Cl2). IR (film, cm–1): 3392. H NMR
(500 MHz, C6D6) δ: 7.78 (m, 4H, Ph), 7.22 (m, 6H, Ph),
4.57 (d, 1H, J = 8.0 Hz, H-1a), 4.06 (dd, 1H, J = 8.6,
9.5 Hz, CHHOTBDPS), 4.01 (dd, 1H, J = 5.2, 9.5 Hz,
CHHOTBDPS), 3.95 (dd, 1H, J = 5.2, 8.6 Hz, H-2), 3.89
(dd, 1H J = 5.3, 11.1 Hz, CHHOH), 3.83 (dd, 1H, J = 5.8,
11.1 Hz, CHHOH), 3.69 (q, 1H, J = 7.5, 7.5, 7.6 Hz, H-4),
3.57 (dd, 1H, J = 5.6, 7.6 Hz, H-3a), 3.26 (m, 1H, J = 5.3,
5.6, 5.8, 7.9 Hz, H-3), 3.09 (ddd, 1H, J = 2.9, 7.1, 13.3 Hz,
H-6), 2.51 (ddd, 1H, J = 6.0, 11.0, 13.3 Hz, H-6′), 1.82 (m,
1H, H-5), 1.39 (m, 1H, H-5′), 1.15, 0.97 (2s, 18H, 2t-Bu).
13C NMR (125 MHz, CDCl3) δ: 135.5, 135.5, 133.3, 133.3,
129.7, 129.7, 127.7, 127.7, 78.8, 74.7, 71.4, 71.3, 70.4, 64.6,
60.6, 53.5, 47.6, 31.8, 28.2, 26.8, 19.2. HRMS (ESI) m/z
calcd. for C29H44NO5Si: 514.2983 [M + H]+; found: 514.3003.
(1aS,2R,4aR,4bS,5S)-5-tert-butoxy-2-formyl-4-oxo-pyr-
rolidino[1,2-b]isoxazolidino[4,5-c]tetrahydrofurane (15)
A small sample of 15 was partially purified by chroma-
tography using hexane – ethyl acetate (1:2 v/v) as the eluent;
mp 60.5–63.5 °C. [α]D +29.1° (c 0.4, CH2Cl2). IR (film, cm–1):
1
1773, 1728. H NMR (500 MHz, C6D6) δ : 9.57 (d, 1H, J =
2.2 Hz, CHO), 4.29 (bt, 1H, J = 6.3, 7.4 Hz, H-1a), 3.94 (dd,
1H, J = 2.2, 6.3 Hz, H-2), 3.51 (bd, 1H, J = 7.6 Hz, H-4b),
3.42 (dt, 1H, J = 5.8, 7.2, 7.6 Hz, H-5), 3.23 (dd, 1H, J =
1.0, 7.4 Hz, H-4a), 3.04 (ddd, 1H, J = 2.2, 7.8, 13.9 Hz, H-
7), 2.26 (dddd, 1H, J = 0.7, 7.4, 11.0, 13.9 Hz, H-7′), 1.60
(m, 1H, H-6), 1.35 (m, 1H, H-6′), 0.90 (s, 9H, t-Bu). HRMS
(ESI) m/z calcd. for C14H23NO6Na: 324.14176 [M +
MeOH + Na]+; found: 324.1408. HRMS (ESI) m/z calcd. for
C15H25NO6Na: 338.15741 [M + EtOH + Na]+; found:
338.1590.
(1aS,2S,3S,3aS,4S)-2-(1 -Acetoxy-2 -tert-butyldiphenyl-
′
′
siloxymethyl)-3-acetoxymethyl-4-tert-butoxy-pyrroli-
dino[1,2-b]isoxazolidine (18Ac)
1
[α]D +21.1° (c 1.8, CH2Cl2). IR (film, cm–1): 1744. H
NMR (500 MHz, C6D6) δ: 7.82 (m, 4H, Ph), 7.23 (m, 6H,
Ph), 5.61 (dt, 1H, J = 4.4, 6.1, 6.1 Hz, H-1a), 4.67 (dd, 1H,
J = 4.4, 5.9 Hz, H-2), 4.35 (dd, 1H, J = 8.2, 10.9 Hz,
CHHOAc), 4.32 (dd, 1H, J = 7.1, 10.9 Hz, CHHOAc), 4.07
(d, 2H, J = 6.1 Hz, CH2OTBDPS), 3.68 (q, 1H, J = 6.0, 6.0,
6.0 Hz, H-4), 3.40 (dd, 1H, J = 2.8, 6.8 Hz, H-3a), 3.20 (dt,
1H, J = 11.7, 7.1, 7.1 Hz, H-6), 3.14 (m, 1H, J = 2.9, 5.9,
7.1, 8.2 Hz, H-3), 3.02 (dt, 1H, J = 11.7, 6.8, 6.8 Hz, H-6′),
1.76, 1.71 (2s, 6H, 2Ac), 1.64 (m, 1H, H-5), 1.50 (m, 1H, H-
5′), 1.18, 0.97 (2s, 18H, 2t-Bu). 13C NMR (125 MHz, CDCl3)
δ: 170.6, 170.1, 135.6, 135.5, 133.1, 133.0, 129.8, 129.8,
127.8, 127.7, 76.4, 73.7, 71.7, 71.6, 71.4, 63.6, 63.4, 54.1,
45.6, 33.5, 28.1, 27.0, 20.8, 20.4, 19.5. HRMS (ESI) m/z
calcd. for C33H48NO7Si: 598.31946 [M + H]+; found: 598.3195.
(1aS,2S,4aR,4bS,5S)-5-tert-Butoxy-2-tert-butyldiphenyl-
siloxymethyl-4-oxo-pyrrolidino[1,2-b]isoxazolidino[4,5-c]-
tetrahydrofurane (17)
Alcohol 16 (0.043 g, 0.16 mmol) was dissolved in di-
chloromethane (15 mL), and treated with tert-butyldiphenyl-
chlorosilane (0.057 g, 0.2 mmol) and DMAP (0.2 mmol).
The solution was left under argon at room temperature for
24 h and then it was refluxed for 3 h. Subsequently, the mix-
ture was cooled, washed with water, brine, and water again.
The organic layer was dried and evaporated. The residue was
purified on a silica gel column using hexane – ethyl acetate
(4:1 v/v) as the eluent to afford 17 (0.062 g, 76% yield). [α]D
–0.9° (c 0.5, CH2Cl2). IR (film, cm–1): 1779. 1H NMR
(500 MHz, CDCl3) δ: 7.69 (m, 4H, Ph), 7.39 (m, 6H, Ph),
4.70 (dd, 1H, J = 4.2, 6.3 Hz, H-1a), 4.61 (ddd, 1H, J = 4.2,
5.8, 6.5 Hz, H-2), 4.17 (dt, 1H, J = 5.6, 7.0, 7.1 Hz, H-5),
4.04 (dd, 1H, J = 5.8, 11.2 Hz, CHHOH), 4.02 (dd, 1H, J =
(1aS,2S,6aS,6bS,7S)-2-(tert-Butyldiphenylsiloxymethyl)-
7-tert-butoxy-4,4-dimethyl-3,5-dioxa-pyrrolidino[1,2-b]-
isoxazolidino[4,5]cycloheptane (19)
Compound 15 (0.051 g, 0.1 mmol) was dissolved in 2,2-
dimethoxypropane (25 mL), treated with a catalytic amount
© 2006 NRC Canada

538
Can. J. Chem. Vol. 84, 2006
of p-TsOH, and kept under reflux for 1 h. Subsequently, the
solution was cooled, neutralized with triethylamine, and
evaporated. The residue was purified by chromatography af-
fording 19 (0.048 g) in 87% yield. [α]D +4.3° (c 1.3,
69.6, 68.4, 61.7, 54.5, 48.5, 36.4, 34.0, 28.1, 25.0, 24.1.
HRMS (ESI) m/z calcd. for C17H32NO7S: 394.1894 [M +
H]+; found: 394.1913.
1
CH2Cl2). H NMR (500 MHz, C6D6) δ: 7.81 (m, 4H, Ph),
(1S,6S,7S,8S,9S)-6,7-Diacetoxy-8-acetoxymethyl-1-tert-
butoxyindolizidine (23)
7.20 (m, 6H, Ph), 4.43 (bd, 1H, J = 4.6 Hz, H-1a), 4.35 (t,
1H, J = 6.9, 7.2 Hz, H-2), 4.23 (t, 1H, J = 11.8, 12.3 Hz, H-
6), 4.12 (dd, 1H, J = 6.9, 9.9 Hz, CHHOTBDPS), 4.07 (dd,
1H, J = 7.2, 9.9 Hz, CHHOTBDPS), 3.57 (dt, 1H, J = 6.5,
5.2, 5.2 Hz, H-7), 3.42 (dd, 1H, J = 4.9, 11.8 Hz, H-6′), 3.17
(m, 1H, H-9), 3.07 (m, 1H, H-9′), 3.00 (d, 1H, J = 6.5 Hz,
H-6b), 2.89 (dt, 1H, J = 12.3, 4.6, 4.9 Hz, H-6a), 1.56 (m,
1H, H-8), 1.47 (m, 1H, H-8′), 1.36, 1.33 (2s, 6H, C(CH3)2),
1.20, 0.96 (2s, 18H, 2t-Bu). 13C NMR (125 MHz, CDCl3) δ:
135.6, 133.5, 129.6, 127.7, 101.5, 77.0, 74.2, 70.9, 70.1,
69.5, 64.0, 61.1, 54.4, 47.3, 33.9, 28.3, 26.8, 24.8, 23.9,
19.1. HRMS (ESI) m/z calcd. for C32H48NO5Si: 554.32963
[M + H]+; found: 554.3314.
Compound 21 (0.04 g, 0.1 mmol) was dissolved in 80%
acetic acid (15 mL) and kept at room temperature for 1 h.
Subsequently, the solvent was evaporated, the residue was
dissolved in methanol (20 mL) and treated with a catalytic
amount of 10% Degussa Pd/C under hydrogen. After 24 h,
the catalyst was filtered and the solvent was evaporated. The
residue was dissolved in triethylamine (10 mL) and treated
with acetic anhydride (10 mL) and DMAP (2 mg). After 2 h,
the solvents were evaporated and a crude product was puri-
fied on a silicagel column using hexane – ethyl acetate
(1:1 v/v) as the eluent to afford 23 (0.021 g, 55%). [α]D
1
+103° (c 0.1, CHCl3). IR (film, cm–1): 1746, 1231. H NMR
(500 MHz, CDCl3) δ: 5.14 (t, 1H, J = 9.6, 10.5 Hz, H-7),
5.08 (dt, 1H, J = 5.0, 9.6, 10.0 Hz, H-6), 4.21 (dd, 1H, J =
2.7, 11.7 Hz, CHHOAc), 4.15 (ddd, 1H, J = 2.1, 5.3, 6.8 Hz,
H-1), 4.12 (dd, 1H, J = 2.6, 11.7 Hz, CHHOAc), 3.35 (dd,
1H, J = 5.0, 10.3 Hz, H-5), 3.12 (dt, 1H, J = 1.6, 8.8,
9.0 Hz, H-3), 2.33 (m, 1H, H-8), 2.29 (dd, 1H, J = 5.3,
10.8 Hz, H-8a), 2.16 (dddd, 1H, J = 1.5, 6.8, 8.8, 13.4 Hz,
H-2), 2.07, 2.05, 1.99 (3s, 9H, 3Ac), 2.04 (m, 1H, H-3′),
1.95 (m, 1H, H-5′), 1.90 (dddd, 1H, J = 2.0, 9.0, 9.1,
13.3 Hz, H-2′), 1.20 (s, 9H, t-Bu). 13C NMR (125 MHz,
CDCl3) δ: 171.0, 170.5, 170.1, 74.1, 72.3, 71.9, 70.2, 66.8,
59.8, 53.7, 52.7, 38.3, 35.1, 28.8, 20.89, 20.85, 20.85.
HRMS (ESI) m/z calcd. for C19H32NO7: 386.2173 [M + H]+;
found: 386.2189.
(1aS,2S,6aS,6bS,7S)-7-tert-Butoxy-4,4-dimethyl-3,5-
dioxa-2-hydroxymethylpyrrolidino[1,2-b]isoxazolidino-
[4,5]cycloheptane (20)
Compound 19 (0.11 g, 0.2 mmol) was dissolved in THF
(20 mL), treated with tetrabutylammonium fluoride (0.26 g,
1 mmol), and left overnight. Subsequently, the solvent was
evaporated and the mixture was partially purified on a silica
gel column to afford alcohol 20 (0.059 g, 94%). [α]D +39.5°
1
(c 0.7, CH2Cl2). IR (film, cm–1): 3417. H NMR (500 MHz,
C6D6) δ: 4.17 (t, 1H, J = 11.8, 12.2 Hz, H-6), 4.12 (dd, 1H,
J = 4.3, 8.6 Hz, H-2), 4.04 (d, 1H, J = 4.8 Hz, H-1a), 3.94
(dd, 1H, J = 8.6, 11.2 Hz, CHHOH), 3.62 (dd, 1H, J = 4.3,
11.2 Hz, CHHOH), 3.53 (q, 1H, H-7), 3.37 (dd, 1H, J = 5.1,
11.8 Hz, H-6′), 3.07 (m, 1H, H-9), 3.03 (m, 1H, H-9′), 2.94
(d, 1H, J = 6.7 Hz, H-6b), 2.84 (ddd, 1H, J = 4.8, 5.1,
12.2 Hz, H-6a), 1.50 (m, 1H, H-8), 1.44 (m, 1H, H-8′), 1.34,
1.32 (2s, 6H, C(CH3)2), 0.90 (s, 9H, t-Bu). 13C NMR
(125 MHz, C6D6) δ: 101.4, 78.4, 73.3, 71.4, 70.9, 69.3, 64.0,
61.6, 54.3, 48.5, 33.8, 27.9, 25.0, 24.2. HRMS (ESI) m/z
calcd. for C16H29NO5Na: 338.1938 [M + Na]+; found:
338.1952.
(1S,6S,7S,8S,9S)-8-Acetoxymethyl-1,6,7-triacetoxy-
indolizidine (24)
Compound 23 (0.02 g, 0.052 mmol) was dissolved in
trifluoroacetic acid (5 mL) and stirred for 2 h. Subsequently,
the solvent was carefully evaporated and the residue was dis-
solved in triethylamine (1 mL) and treated with acetic anhy-
dride (1 mL) and DMAP (1 mg). After 1 h, the mixture was
evaporated and the residue purified by chromatography us-
ing hexane – ethyl acetate (1:1 v/v) as the eluent to afford 24
(0.012 g, 62%). [α]D +64.5° (c 0.18, CHCl3). IR (film, cm–1):
(1aS,2S,6aS,6bS,7S)-7-tert-Butoxy-4,4-dimethyl-3,5-
dioxa-2-mesyloxymethylpyrrolidino[1,2-b]isoxazolidino-
[4,5]cycloheptane (21)
1
1745. H NMR (500 MHz, C6D6) δ: 5.28 (dt, 1H, J = 5.1,
9.6, 10.0 Hz, H-6), 5.20 (dd, 1H, J = 9.6, 10.8 Hz, H-7),
5.12 (ddd, 1H, J = 1.3, 4.6, 7.2 Hz, H-1), 4.30 (dd, 1H, J =
4.8, 11.8 Hz, CHHOAc), 3.97 (dd, 1H, J = 3.1, 11.8 Hz,
CHHOAc), 3.11 (dd, 1H, J = 5.1, 10.3 Hz, H-5), 2.63 (m,
1H, H-3), 2.36 (m, 1H, J = 3.1, 4.8, 10.4, 10.8 Hz, H-8),
1.92 (m, 1H, H-2), 1.77, 1.75, 1.70, 1.66 (4s, 12H, 4Ac),
1.74–1.70 (m, 2H, H-5′, H-8a), 1.60 (m, 1H, H-2′), 1.54 (m,
1H, H-3′). 13C NMR (125 MHz, C6D6) δ: 169.9, 169.9,
169.7, 169.5, 73.2, 72.5, 71.9, 66.6, 61.0, 53.4, 51.6, 39.3,
32.6, 20.5, 20.42, 20.38, 20.36. HRMS (ESI) m/z, calcd. for
C17H25NO8Na: 394.1472 [M + Na]+; found: 394.1486.
Alcohol 20 (0.063 g, 0.2 mmol) was dissolved in dry di-
chloromethane (20 mL), treated with triethylamine (0.040 g,
0.4 mmol), and cooled to –5 °C. Subsequently, mesyl chlo-
ride (0.027 g, 0.24 mmol) was added and the temperature of
the mixture was allowed to rise to room temperature. After
2 h, the mixture was washed with brine (15 mL) and water
(15 mL), dried and evaporated to get crude 21 (0.0755 g,
1
96%). [α]D –2.0° (c 0.45, CH2Cl2). H NMR (500 MHz,
C6D6) δ: 4.35 (dd, 1H, J = 8.8, 10.5 Hz, CHHOMs), 4.22
(ddd, 1H, J = 1.0, 3.8, 8.8 Hz, H-2), 4.09 (t, 1H, J = 11.8,
12.3 Hz, H-6), 4.08 (dd, 1H, J = 3.9, 10.5 Hz, CHHOMs),
3.93 (d, 1H, J = 4.9 Hz, H-1a), 3.54 (q, 1H, H-7), 3.33 (dd,
1H, J = 5.3, 11.8 Hz, H-6′), 3.05 (m, 1H, H-9), 3.00 (m, 1H,
H-9′), 2.91 (d, 1H, J = 6.7 Hz, H-6b), 2.82 (ddd, 1H, J =
4.9, 5.3, 12.3 Hz, H-6a), 2.19 (s, 3H, Ms), 1.49 (m, 2H, H-
8,8′), 1.31, 1.27 (2s, 6H, C(CH3)2), 1.06 (s, 9H, t-Bu). 13C
NMR (125 MHz, C6D6) δ: 101.8, 77.9, 73.6, 71.6, 71.0,
(1S,6S,7S,8S,9S)-8-Hydroxymethyl-1,6,7-trihydroxy-
indolizidine (8-homocastanospermine, 13)
Compound 23 (0.013 g, 0.035 mmol) was dissolved in
1.3% of ammonia in methanol (5 mL) and left for 24 h at
room temperature. Subsequently, the solvent was evaporated
© 2006 NRC Canada

PaÑniczek et al.
539
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and the residue was purified by chromatography using
methanol – ethyl acetate (1:1 v/v) as the eluent to afford 24
(5.8 mg, 82%). [α]D +35.8° (c 0.55, CH3OH). IR (KBr, cm–1):
1
3380. H NMR (500 MHz, CD3OD) δ: 4.32 (m, 1H, H-1),
3.90 (dd, 1H, J = 2.2, 10.9 Hz, CHHOH), 3.76 (ddd, 1H, J =
2.3, 5.1, 10.8 Hz, CHHOH), 3.58 (ddd, 1H, J = 5.0, 8.8,
10.4 Hz, H-6), 3.26 (dd, 1H, J = 8.8, 10.1 Hz, H-7), 3.18
(dd, 1H, J = 5.0, 10.6 Hz, H-5), 3.08 (ddd, 1H, J = 2.0, 9.0,
9.1 Hz, H-3), 2.25 (dddd, 1H, J = 2.0, 5.5, 9.0, 13.9 Hz, H-
2), 2.08 (ddd, 1H, J = 9.1, 9.1, 9.1 Hz, H-3′), 1.91 (dd, 1H,
J = 10.2, 10.9 Hz, H-5′), 1.86 (m, 2H, H-8,8a), 1.75 (dddd,
1H, J = 1.7, 9.0, 9.1, 13.8 Hz, H-2′). 13C NMR (125 MHz,
CD3OD) δ: 75.8, 73.2, 71.8, 71.6, 61.1, 58.0, 53.5, 43.9,
34.2. HRMS (ESI) m/z calcd. for C9H18NO4: 204.1230 [M +
H]+; found: 204.1227.
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The β-glucosidase activity of 13 was measured by the
modification of the procedures described previously (10,
11). The reaction mixture consisted of 100 µL of
0.014 mol/L p-nitrophenyl β-D-glucopyranoside, 250 µL of
0.2 mol/L acetate buffer (pH 4.6), 50 µL of inhibitor solu-
tion (either water or methanol), and 100 µL of enzyme solu-
tion (3 µg/mL). After incubation for 15 min at 30 °C, the
reaction was terminated by the addition of 1 mL of 2% so-
dium carbonate. The absorbance of liberated p-nitrophenol
was measured at 405 nm.
The α-glucosidase activity of 13 was measured by modifi-
cation of the procedures described previously (12, 13). The
reaction mixture consisted of 25 µL of 0.0165 mol/L p-
nitrophenyl α-D-glucopyranoside, 403 µL of 0.1 mol/L ace-
tate buffer (pH 4.0), 50 µL of inhibitor solution (either water
or methanol), and 22 µL of enzyme solution (10 times di-
luted). After incubation for 15 min at 37 °C, the reaction
was terminated by the addition of 1 mL of 2% sodium car-
bonate. The absorbance of liberated p-nitrophenol was mea-
sured at 405 nm.
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Acknowledgements
This work was supported by the Ministry of Science and
Information Grant No. 3 T09A 025 28.
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© 2006 NRC Canada