Synthesis of 1-homoaustraline

Article abstract of DOI:10.1016/j.carres.2006.05.003

The 1,3-dipolar cycloaddition of a five-membered cyclic nitrone derived from malic acid and unsaturated d-threo-hexonolactone leads to a single adduct, which was transformed into 1-homoaustraline via a reaction sequence involving rearrangement of the six-

Full text of DOI:10.1016/j.carres.2006.05.003

Carbohydrate Research 341 (2006) 2005–2011
Synthesis of 1-homoaustraline
a
a
a
b
´
Dariusz Socha, Konrad Pasniczek, Margarita Jurczak, Jolanta Solecka
and Marek Chmielewskia,*
aInstitute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
bNational Institute of Hygiene, 00-791 Warsaw, Poland
Received 8 February 2006; received in revised form 25 April 2006; accepted 4 May 2006
Available online 24 May 2006
Dedicated to Professor Janusz Jurczak on the occassion of his 65th birthday
Abstract—The 1,3-dipolar cycloaddition of a five-membered cyclic nitrone derived from malic acid and unsaturated D-threo-hexono-
lactone leads to a single adduct, which was transformed into 1-homoaustraline via a reaction sequence involving rearrangement of
the six-membered lactone ring into the five-membered one, removal of the terminal carbon atom from the sugar chain, reduction of
the lactone fragment into triol, protection of primary hydroxy groups, mesylation of the secondary one, cleavage of the N–O bond,
and the intramolecular alkylation of the nitrogen atom.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Keywords: Iminosugars; Homoaustraline; Nitrones; Aldono-1,5-lactone; 1,3-Dipolar cycloaddition; Glucosidases
1. Introduction
preferences leads, in many cases, to formation of a single
adduct or at least a high preponderance of a single ad-
duct.3 Particularly attractive are the exclusive formation
of adducts 6 and 7 from the nitrone 4 and the D-threo 4-
O-acetyl-lactone 2 and D-erythro 4-O-acetyl-lactone 3,
respectively.3
We have shown that application of the known meth-
odology4 to cycloadduct 8 offers a convenient approach
to the indolizidine alkaloids. This has been demon-
strated by the synthesis of 7-hydroxy-lentiginosine (9)
and the formal synthesis of lentiginosine (10).5
The straightforward access to adducts 6 and 7 enables
Recently, we have reported on the cycloaddition of 2,3-
unsaturated d-lactones 1–3 and the five-membered cyclic
nitrones 4 or 5, which proceeds exclusively in the exo
mode and results in a high preference for the anti addi-
tion 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 (syn either to acetoxymethyl or to 3-
tert-butoxy group), the 4-O-acetyl group of the lactone
assumes a decisive role in the control of the stereochem-
ical outcome of the cycloaddition. This stereochemical
t
-BuO
t-BuO
Ot-Bu
CH2OAc
R1
O
O
O
O
N
O
4
N
O
5
R2
1
2: R1 = OAc, R2 = H
3: R1 = H, R2 = OAc
*
Corresponding author. Tel.: +48 22 631 87 88; fax: +48 22 632 66 81; e-mail: chmiel@icho.edu.pl
0008-6215/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2006.05.003

2006
D. Socha et al. / Carbohydrate Research 341 (2006) 2005–2011
convenient entry to the corresponding pyrrolizidines
and indolizidines with an (R) or (S) configuration at
the bridgehead carbon atom.6
2. Results and discussion
Recently we have shown that the adduct 6 with identical
configurations at C-1a, 2, 5a, 5b, and 6 carbon atoms,
which is the same as in castanospermine (11) at C-7, 6,
8, 8a, and C-1 atoms, can be easily transformed into
the iminosugars related to 11, especially into 8-homo-
castanospermine (14).10 The same adduct 6 opens also
an easy access to australine 138 and related compounds
via intramolecular alkylation of the nitrogen atom by
the activated C-2 carbon atom. It should be stressed that
the configuration at C-2 of the adduct 6 undergoes
inversion during the nitrogen alkylation step, conse-
quently leading to the correct configuration at C-3 of
australine-related compounds. The present paper de-
scribes the synthesis of a derivative of australine in
which the 1-hydroxy group was replaced by the
hydroxymethyl substituent (1-homoaustraline; 15). Syn-
thesis of a number of 7-hydroxymethyl-indolizidines
using intramolecular 1,3-dipolar cycloaddition has been
reported recently by the Brandi’s group.9b
Aldehydo-lactone 16, the substrate for the synthesis,
was obtained from adduct 6 following a earlier reported
two-step procedure,10 which involves rearrangement of
the six-membered lactone ring into the five-membered
one by deacetylation of 6 followed by glycolic cleavage
of the terminal diol group. Subsequently, the alde-
hydo-lactone 16 was reduced to the triol 17 and both
primary hydroxy groups were protected with tert-buty-
ldiphenylsilyl ethers to afford 19. The remaining second-
ary hydroxy group was mesylated to give compound 21
(Scheme 1).
t-BuO
H
AcO
CH2OAc
2
O
4
O
3
5
N
5a
O
O
1a
5b
H
O
AcOH2C
O1
6
7
O
t-Bu
N
OAc
8
6
7
O
H
O
O
N
Ot-Bu
Ot-Bu
8
Both components of the cycloaddition, the nitrone
and the unsaturated lactone, carry over their own sub-
stituents (such as protected hydroxyl groups) with their
original configurations, whereas the configuration at
C-1a, C-5a, and C-5b of the cycloadduct is established
during the reaction. Adduct 6 is particularly interesting
because it has anti located tert-butoxy group and the
bridgehead proton H-5b,3 which corresponds to an anti
rearrangement of OH-1 and H-8a in indolizidines, or
OH-1 and H-7a in pyrrolizidines. Such a geometry,
found in many indolizidines and pyrrolizidines, for
example, castanospermine (11),6d swainsonine (12),7 or
australine (13),8 cannot be achieved by the cycloaddition
of simple olefins to the nitrone 4 or by its alkylation with
nucleophiles since this direction of approach is highly
hindered by the unfavorable steric interactions. In order
to force the syn approach of the dipolarophile to the
substituent at C-3 of the nitrone Brandi’s group9 per-
formed 1,3-dipolar cycloaddition as an intramolecular
process. In the case of cycloaddition of the nitrone 4
to the lactone 2, syn approach of 2 to the tert-butoxy
group was coerced by substituents in the lactone.
Hydrogenolysis of the N–O bond over Pd/C caused
prompt intramolecular alkylation of the nitrogen atom,
which proceeded with inversion of configuration at the
carbon atom bearing the mesyloxy group to afford 22,
which was characterized as the acetate 23. The configu-
1
ration of 23 was confirmed by H NMR spectroscopy.
The coupling constants J1,2 and J2,3 (both 8.2 Hz) con-
firmed the axial position of H-1, H-2, and H-3 protons.
NOEs measurements showed a spin–spin interaction be-
tween H-1 (d 2.59 ppm) and H-3 (d 2.90 ppm) protons.
OH
H
HO
HO
OH
OH
R
H
N
H
N
8
5
1
HO
HO
8a
7
6
2
OH
3
OH
N
4
9: R=OH
10: R=H
12
11
HOH2C
OH
H
OH
HOH2C
HO
HO
OH
H
N
H
1
3
7
5
7a
6
2
HO
HO
N
4
N
HO
HOH2C
HOH2C
14
13
15

D. Socha et al. / Carbohydrate Research 341 (2006) 2005–2011
2007
AcO
H
H
O
N
OR
N
CH2OAc
O
O
RO
CH2OR
H
H
O
a
b
H
H
H
H
O
H
H
O
O
O
t-Bu
Ot-Bu
O
N
O
t-Bu
16
17: R=H
18: R=Ac
6
Ot-Bu
R1OH2C
R1O
OR2
OR
TBDPSOH2C
RO
H
N
H
TBDPSO
CH2OTBDPS
b
d
e
H
H
H
N
O
Ot-Bu
N
R1OH2C
TBDPSOH2C
24: R1=H, R2=tBu
25: R1=Ac, R2=tBu
26: R1=R2=Ac
19: R=H
20: R=Ac
21: R=Ms
22: R=H
23: R=Ac
c
f
15: R1=R2=H
Scheme 1. Reagents and conditions: (a) LiBH4, THF, rt, 24 h, 68% after acetylation; (b) TBDPSiCl, Et3N, DMAP, 24 h, 58%; (c) MsCl, CH2Cl2,
Et3N, 2 h, ꢀ5 ꢁC, 89%; (d) 10% Pd/C, AcOEt, H2, 24 h, 65% after acetylation; (e) Bu4NF, THF, 24 h, 87% after acetylation; (f) TFA, 2 h, 67% after
acetylation.
Irradiation of the H-1 signal caused enhancement of the
H-3 signal by 2.5% and conversely, the signal due to H-1
was enhanced by 3.1% when H-3 was irradiated.
In order to get the free iminosugar 15, the stepwise
deprotection was carried out. Initially the two primary
hydroxy groups were desilylated and acetylated. Subse-
quently the tert-butyl group in 23 was removed using tri-
fluoroacetic acid and the resulting hydroxyl was
acetylated yielding the tetra-acetate of 1-homoaustraline
15.
ily available components of the 1,3-dipolar cycloaddi-
tion controls the absolute stereochemistry at all five
stereogenic centers present in the target molecule. The
reported synthesis demonstrated an exceptional effec-
tiveness of the 1,3-dipolar cycloaddition of nitrones
and sugar unsaturated d-lactones, which led to only
one diastereo-isomer with defined configuration at all
stereogenic centers.
The discrimination between hydroxymethyl groups at
earlier stage of the synthesis, followed by oxidative
decarboxylation of the carboxylic group derived from
the lactone should provide a simple way to australine 13.
The biological activity of 15 toward commercially
available a- and b-glucosidases was tested. Surprisingly,
15 showed only a weak inhibition of the a-glucosidase
activity at a concentration of 0.02 M and no inhibition
of b-glucosidase. Low biological activity of both 8-
homocastanospermine (14) and 1-homoaustraline (15)
is worth to note since the hydroxymethyl group at the
carbon atom next to the bridgehead junction occurs in
many natural iminosugars and related alkaloids, for
example: (ꢀ)-rosmarinecine (27),11 (+)-turneforcidine
(28),12 (ꢀ)-hastanecine (29),12a,13 lupinine (30),14 or
(+)-tashiromine (31).15
3. Experimental
3.1. General methods
1H NMR spectra were recorded on a Bruker DRX 500
Avance Spectrometer. IR spectra were obtained on an
FT-IR-1600 Perkin–Elmer spectrophotometer. The
optical rotations were measured with a JASCO Dip-
360 digital polarimeter. Mass spectra were recorded
using an AMD-604 instrument and HPLC-MS were re-
corded with Mariner and API 356 detectors. Column
chromatography was carried out using E. Merck Kiesel
Gel (230–400 mesh). Adduct 6 was obtained according
to known procedure.2,3
Enzymes and substrates were purchased from Sigma:
a-glucosidase from rice, type V, 63.43 U/mg, 1.34 mg/
HOH2C
HOH2C
HOH2C
HOH2C
HOH2C
OH
OH
OH
H
H
H
H
H
HO
N
N
N
N
N
27
28
29
30
31
In summary, we have reported the simple synthesis of
mL; b-glucosidase from almonds, 25.8 U/mg, 95.4%
1-homoaustraline 15 in which a proper selection of read-
protein.

2008
D. Socha et al. / Carbohydrate Research 341 (2006) 2005–2011
3.2. (10S,2S,3S,3aS,4S)-4-tert-Butoxy-2-(10,20-dihydr-
oxyethyl)-3-hydroxymethyl-pyrrolidino[1,2-b]isoxazol-
idine (17)
1H, J 5.8, 11.7, 13.3 Hz, H-60), 1.90 (m, 1H, H-5), 1.35
(m, 1H, H-50), 1.22, 1.19, 0.86 (3s, 27H, t-Bu); 13C
NMR without aromatic carbons (125 MHz, C6D6) d:
78.9, 73.3, 72.9, 72.1, 69.4, 65.5, 64.0, 52.9, 48.4, 32.4,
28.2, 27.2, 27.2, 19.6, 19.5; HRESIMS: calcd for
C45H62NO5Si2: 752.4161; found: 752.4191 [M+H]+.
The crude aldehyde 16 (0.12 g, 0.45 mmol), obtained by
the earlier reported procedure,10 was dissolved in dry
THF (15 mL) and reduced with 2 mol equiv of LiBH4.
After 24 h, 1 M HCl was added by drops until pH 7.
Then the mixture was diluted with THF, filtered
through Celite, and evaporated to afford crude triol 17
(0.09 g, 74% yield), which was used for the next steps
without purification. The triol 17 was characterized as
the triacetate 18, which was obtained by acetylation with
Ac2O–pyridine and a catalytic amount of DMAP. After
standard work up, the product was purified on a silica
gel column using 1:1 hexane–EtOAc as an eluent to af-
ford (10S,2S,3S,3aS,4S)-3-acetoxymethyl-4-tert-butoxy-
2-(10,20-diacetoxyethyl)-pyrrolidino[1,2-b]isoxazolidine
3.4. (10S,2S,3S,3aS,4S)-2-(10-Acetoxy-20-tert-butyldi-
phenylsiloxyethyl)-4-tert-butoxy-3-tert-butyldiphenylsil-
oxymethyl-pyrrolidino[1,2-b]isoxazolidine (20)
Disilyl derivative 19 (0.13 g, 0.173 mmol) was dissolved
in Et3N (15 mL), then Ac2O (15 mL) and DMAP
(0.02 mmol) were added. After 30 min the mixture was
washed with water, brine, and again with water. The
organic layer was dried over MgSO4 and evaporated.
Crude product was purified on silica gel column using
hexane–ethyl acetate 3:1 v/v as an eluent to afford 20
(0.115 g, 84% yield); [a]D +14.4 (c 1.4, CH2Cl2); IR
(18); [a]D +31.5 (c 1.0, CH2Cl2); IR (film): m 1746 cmꢀ1
;
1H NMR (500 MHz, C6D6) d: 5.65 (ddd, 1H, J 3.7, 6.2,
6.3 Hz, H-10), 4.59 (dd, 1H, J 3.7, 11.9 Hz, H-20a), 4.35
(dd, 1H, J 8.3, 11.1 Hz, CHHOAc), 4.32 (dd, 1H, J 5.6,
6.2 Hz, H-2), 4.30 (dd, 1H, J 6.3, 11.9 Hz, H-20b), 4.26
(dd, 1H, J 6.8, 11.1 Hz, CHHOAc), 3.60 (m, 1H, H-4),
3.32 (dd, 1H, J 2.7, 6.7 Hz, H-3a), 3.12 (m, 1H, H-6),
3.03 (dddd, 1H, J 2.7, 5.6, 6.8, 8.3 Hz, H-3), 2.99 (m,
1H, H-60), 1.78, 1.71, 1.70 (3s, 9H, OAc), 1.56 (m, 1H,
H-5), 1.43 (m, 1H, H-50), 0.94 (s, 9H, t-Bu); 13C NMR
(125 MHz, CDCl3) d: 170.7, 170.6, 170.2, 76.9, 74.2,
71.1, 70.9, 69.3, 63.5, 62.8, 54.1, 45.2, 33.1, 28.2, 21.1,
20.8, 20.7; HRESIMS: calcd for C19H31NO8Na:
424.1942; found: 424.1964 [M+Na]+.
(film): m 1744, 1112 cmꢀ1; H NMR (500 MHz, C6D6)
1
d: 7.80, 7.22 (2m, 20H, Ph), 5.70 (m, 1H, H-10), 4.86
(dd, 1H, J 4.8, 5.8 Hz, H-2), 4.08 (d, 2H, J 5.8 Hz, H-
20a, H-20b), 4.06 (dd, 1H, J 8.1, 9.9 Hz, CHHOSi),
4.00 (dd, 1H, J 7.8, 9.9 Hz, CHHOSi), 3.76 (m, 1H,
H-4), 3.68 (dd, 1H, J 3.5, 6.9 Hz, H-3a), 3.25 (m, 2H,
H-3, H-6), 3.00 (ddd, 1H, J 6.6, 7.6, 12.0 Hz, H-60),
1.71 (m, 1H, H-5), 1.62 (s, 3H, OAc), 1.50 (m, 1H, H-
50), 1.19, 1.18, 0.94 (3s, 27H, t-Bu); 13C NMR without
aromatic carbons (125 MHz, C6D6) d: 169.6, 77,0,
73.5, 72.3, 72.2, 70.6, 63.4, 63.3, 54.4, 49.3, 33.3, 28.3,
27.2, 27.1, 20.8, 19.5, 19.5; HRESIMS: calcd for
C47H64NO6Si2: 794.42667; found: 794.4273 [M+H]+.
3.3. (10S,2S,3S,3aS,4S)-4-tert-Butoxy-2-(20-tert-butyldi-
phenylsiloxy-10-hydroxyethyl)-3-tert-butyldiphenylsil-
oxymethyl-pyrrolidino[1,2-b]isoxazolidine (19)
3.5. (10S,2S,3S,3aS,4S)-2-(20-tert-Butyldiphenylsiloxy-
10-methanesulfonyloxyethyl)-4-tert-butoxy-3-tert-butyldi-
phenylsiloxymethyl-pyrrolidino[1,2-b]isoxazolidine (21)
The crude triol 17 (0.082 g, 0.30 mmol) was dissolved in
Et3N (15 mL), then tert-butyl(chloro)diphenylsilane
(0.20 g, 0.72 mmol) and DMAP (0.06 mmol) were
added. The soln was left under argon, at room temper-
ature for 24 h and subsequently refluxed for 3 h. The
mixture was then cooled, washed with water, brine,
and again with water. The organic layer was dried over
MgSO4 and evaporated. The residue was purified on a
silica gel column using 4:1 hexane–ethyl acetate as eluent
to afford 19 (0.13 g, 58% yield); [a]D +16.5 (c 1.1,
A soln of alcohol 19 (0.13 g, 0.173 mmol), dry CH2Cl2
(15 mL), and Et3N (0.04 g, 0.4 mmol) was cooled to
ꢀ5 ꢁC. Subsequently mesyl chloride (0.027 g,
0.24 mmol) was added and the temperature of the mix-
ture was allowed to rise to room temperature. After
2 h the mixture was washed with brine (10 mL) and
water (10 mL), dried over MgSO4, and evaporated.
The crude product was purified on a silica gel column
using hexane–ethyl acetate 1:1 v/v as an eluent to afford
21 (0.13 g, 89% yield); [a]D +15.9 (c 1.9, CH2Cl2); IR
CH2Cl2); IR (film): m 3468, 1112 cmꢀ1
;
1H NMR
(film): m 1112 cmꢀ1 1H NMR (500 MHz, C6D6) d:
;
(500 MHz, C6D6) d: 7.85, 7.25 (2m, 20H, Ph), 5.05 (d,
1H, J 7.7 Hz, H-2), 4.61 (dd, 1H, J 5.2, 9.1 Hz, H-10),
4.45 (dd, 1H, J 9.8, 10.5 Hz, CHHOSi), 4.22 (dd, 1H,
J 9.1, 9.2 Hz, H-20a), 4.14 (dd, 1H, J 5.2, 9.2 Hz, H-
20b), 4.00 (dd, 1H, J 5.7, 9.8 Hz, CHHOSi), 3.68 (dddd,
1H, J 5.7, 6.0, 7.7, 10.5 Hz, H-3), 3.54 (ddd, 1H, J 6.7,
7.8, 8.0 Hz, H-4), 3.14 (ddd, 1H, J 2.6, 6.9, 13.3 Hz,
H-6), 2.98 (dd, 1H, J 6.0, 7.8 Hz, H-3a), 2.42 (ddd,
7.90–7.18 (m, 20H, Ph), 5.36 (m, 1H, H-10), 4.84 (dd,
1H, J 5.9, 7.0 Hz, H-2), 4.28–4.21 (m, 2H, H-20a, H-
20b), 4.16 (dd, 1H, J 8.3, 10.4 Hz, CHHOSi), 3.92 (dd,
1H, J 6.6, 10.4 Hz, CHHOSi), 3.68 (m, 1H, H-4), 3.56
(dd, 1H, J 3.5, 7.0 Hz, H-3a), 3.22 (dddd, 1H, J 3.5,
5.9, 6.6, 8.3 Hz, H-3), 3.14 (m, 1H, H-6), 2.95 (ddd,
1H, J 6.5, 8.4, 12.3 Hz, H-60), 2.60 (s, 3H, Ms), 1.65
(m, 1H, H-5), 1.46 (m, 1H, H-50), 1.20, 1.13, 0.89 (3s,

D. Socha et al. / Carbohydrate Research 341 (2006) 2005–2011
2009
27H, t-Bu); 13C NMR without aromatic carbons
3.8. (1S,2S,3R,7S,7aS)-2,7-Diacetoxy-1,3-diacetoxy-
methyl-pyrrolizidine (26)
(125 MHz, C6D6) d: 81.4, 77.8, 73.6, 72.0, 70.1, 64.8,
63.0, 54.6, 48.7, 38.8, 33.3, 28.2, 27.2, 27.1, 19.6, 19.4;
HRESIMS: calcd for C46H64NO7Si2S: 830.3937; found:
830.3942 [M+H]+.
Compound 23 (0.034 g, 0.088 mmol) was dissolved in
TFA (8 mL) and stirred for 5.5 h. Subsequently the sol-
vent was carefully evaporated. The crude product was
dissolved in Et3N (5 mL), Ac2O (5 mL), and DMAP
was added. After 1 h the solvents were evaporated and
the residue was purified by chromatography (1:1 hex-
ane–EtOAc) to afford 26 (0.022 g, 67% yield); [a]D
3.6. (1S,2S,3R,7S,7aS)-2-Acetoxy-1,3-bis-(tert-butyldi-
phenylsiloxymethyl)-7-tert-butoxy-pyrolizidine (23)
To a soln of 21 (0.138 g, 0.154 mmol) in AcOEt (10 mL),
a catalytic amount of 10% Degussa Pd/C was added and
the mixture was held under hydrogen atmosphere. After
24 h, the catalyst was filtered and the solvent evapo-
rated. The crude 22 was dissolved in Et3N (10 mL)
and Ac2O (10 mL) and DMAP (0.02 mmol) were added.
After 1 h, solvents were evaporated and a crude product
was purified on a silica gel column (1:1 hexane–EtOAc)
to afford 23 (0.11 g, 91% yield); [a]D ꢀ15.9 (c 0.22,
+10.7 (c 0.61, CH2Cl2); IR (film): m 1734 cmꢀ1 1H
;
NMR (500 MHz, C6D6) d: 5.34 (t, 1H, J 8.8 Hz, H-2),
5.10 (ddd, 1H, J 1.3, 4.1, 4.1 Hz, H-7), 4.32 (dd, 1H, J
4.4, 11.3 Hz, C-3CHHOAc), 4.31 (dd, 1H, J 5.1,
11.2 Hz, C-1CHHOAc), 4.09 (dd, 1H, J 5.6, 11.3 Hz,
C-3CHHOAc), 3.97 (dd, 1H, J 7.7, 11.2 Hz, C-
1CHHOAc), 3.22 (dd, 1H, J 4.1, 8.4 Hz, H-7a), 2.98
(m, 2H, H-3, H-5), 2.58 (dddd, 1H, J 5.1, 7.7, 8.4,
8.8 Hz, H-1), 2.49 (ddd, 1H, J 6.1, 9.3, 11.5 Hz, H-50),
1.76 (m, 1H, H-6), 1.74, 1.71, 1.65, 1.62 (4s, 12H,
4 · OAc), 1.66 (m, 1H, H-60); 13C NMR (125 MHz,
C6D6) d: 170.0, 169.8, 169.5, 169.2, 77.2, 73.6, 69.1,
68.9, 65.3, 64.3, 52.0, 42.1, 34.7, 20.5, 20.4, 20.4, 20.3;
HRESIMS: calcd for C17H26NO8: 372.16529; found:
372.1650 [M+H]+.
CHCl3); IR (film): m 1741, 1112 cmꢀ1
;
1H NMR
(500 MHz, CDCl3) d: 7.42–7.31 (m, 20H, Ph), 5.27 (t,
1H, J 8.2 Hz, H-2), 3.90 (m, 1H, H-7), 3.67 (dd, 1H, J
4.9, 10.5 Hz, C-3CHHOSi), 3.66 (dd, 1H, J 6.5,
10.5 Hz, C-3CHHOSi), 3.64 (m, 2H, C-1CH2OSi), 3.38
(dd, 1H, J 5.1, 7.9 Hz, H-7a), 3.08 (m, 1H, H-5), 2.90
(ddd, 1H, J 4.9, 6.5, 8.2 Hz, H-3), 2.78 (m, 1H, H-50),
2.59 (m, 1H, H-1), 1.89 (s, 3H, Ac), 1.85 (m, 2H, H-
6,60), 1.09, 1.04, 1.03 (3s, 27H, 3t-Bu); 13C NMR
(125 MHz, CDCl3) d: 170.0, 135.7, 135.7, 135.7, 135.7,
133.8, 133.8, 133.7, 133.5, 129.5, 129.5, 129.5, 129.4,
127.6, 127.6, 127.6, 127.5, 77.6, 73.3, 72.3, 71.5, 67.6,
67.1, 62.9, 52.8, 44.7, 35.5, 28.4, 26.9, 26.8, 21.1, 19.2,
19.2; HRESIMS: calcd for C47H64NO5Si2: 778.4318;
found: 778.4352 [M+H]+.
3.9. (1S,2S,3R,7S,7aS)-1,3-Dihydroxymethyl-2,7-dihydr-
oxy-indolizidine (1-homoaustraline, 15)
Compound 26 (0.022 g, 0.059 mmol) was dissolved in
1.3% soln of ammonia in MeOH (8 mL) and left for
24 h at room temperature. Subsequently, MeOH was
evaporated and the residue was purified by chromato-
graphy (MeOH) to afford 15 (0.01 g, 83% yield); [a]D
3.7. (1S,2S,3R,7S,7aS)-2-Acetoxy-1,3-diacetoxymethyl-
7-tert-butoxy-pyrrolizidine (25)
ꢀ3.7 (c 0.44, CH3OH); IR (film): m 3402 cmꢀ1
;
1H
NMR (500 MHz, CD3OD) d: 4.15 (ddd, 1H, J 2.3,
4.1, 4.2 Hz, H-7), 3.88 (dd, 1H, J 4.2, 10.8 Hz, C-
1CHHOH), 3.77 (t, 1H, J 9.0 Hz, H-2), 3.74 (dd, 1H,
J 3.4, 11.1 Hz, C-3CHHOH), 3.58 (dd, 1H, J 7.2,
10.8 Hz, C-1CHHOH), 3.53 (dd, 1H, J 6.4, 11.1 Hz,
C-3CHHOH), 3.24 (dd, 1H, J 4.2, 8.7 Hz, H-7a), 3.14
(ddd, 1H, J 2.4, 7.3, 10.0 Hz, H-5), 2.80 (ddd, 1H, J
6.2, 10.0, 11.0 Hz, H-50), 2.68 (ddd, 1H, J 3.4, 6.4,
9.0 Hz, H-3), 2.41 (dddd, 1H, J 4.2, 7.2, 8.7, 9.0 Hz,
H-1), 2.00 (dddd, 1H, J 2.3, 2.4, 6.2, 13.0 Hz, H-6),
1.93 (dddd, 1H, J 4.1, 7.3, 11.0, 13.0 Hz, H-60); 13C
NMR (125 MHz, CD3OD) d: 76.6, 75.4, 71.7, 71.2,
64.3, 63.0, 53.3, 46.8, 37.2; HRESIMS: calcd for
C9H18NO4: 204.12303; found: 204.1240 [M+H]+.
To compound 23 (0.078 g, 0.100 mmol) in THF
(10 mL), 1 equiv of Bu4NF was added. After 24 h, pyr-
idine (1.5 mL) and Ac2O (1 mL) were added to the mix-
ture. After 3 h, the reaction mixture was concentrated
and a crude product was purified on a silica gel (1:1 hex-
ane–EtOAc) to afford 25 (0.034 g, 87% yield); [a]D +9.61
(c 1.05, CH2Cl2); IR (film): m 1743, 1237 cmꢀ1; 1H NMR
(500 MHz, C6D6) d: 5.53 (t, 1H, J 8.6 Hz, H-2), 4.37 (dd,
1H, J 4.6, 11.3 Hz, C-3CHHOAc), 4.27 (dd, 1H, J 5.6,
11.2 Hz, C-1CHHOAc), 4.21 (dd, 1H, J 7.27, 11.2 Hz,
C-1CHHOAc), 4.19 (dd, 1H, J 7.1, 11.3 Hz, C-
3CHHOAc), 3.55 (m, 1H, H-7), 3.16 (dd, 1H, J 4.6,
8.0 Hz, H-7a), 3.06 (m, 2H, H-3, H-5), 2.89 (m, 1H,
H-1), 2.67 (m, 1H, H-50), 1.72, 1.71, 1.66 (3s, 9H,
3 · Ac), 1.67 (m, 1H, H-6), 1.57 (m, 1H, H-60), 0.98 (s,
9H, t-Bu); 13C NMR (125 MHz, C6D6) d: 170.0, 169.9,
169.6, 77.6, 73.5, 71.1, 69.3, 68.5, 65.3, 64.0, 52.1, 41.7,
36.2, 28.3, 20.5, 20.5, 20.4; HRESIMS: calcd for
C19H32NO7: 386.21733; found: 386.2179 [M+H]+.
3.10. Biological tests
The b-glucosidase activity of pyrrolizidine 15 was mea-
sured by modification of procedures described previ-
ously.16,17 The reaction mixture consisted of: 100 lL of
0.014 M p-nitrophenyl b-D-glucopyranoside, 250 lL of

2010
D. Socha et al. / Carbohydrate Research 341 (2006) 2005–2011
Tetrahedron: Asymmetry 2000, 11, 1645–1680; (c) Carbo-
hydrate Mimics; Chapleur, Y., Ed.; Wiley-VCH: Wein-
heim, 1998; (d) Iminosugars as Glycosidase Inhibitors;
0.2 M acetate buffer (pH 4.6), 50 lL of inhibitor soln
(either water or MeOH), and 100 lL of enzyme soln
(3 lg/mL). After incubation for 15 min at 30 ꢁC, the
reaction was terminated by addition of 1 mL of 2%
sodium carbonate. The absorbance of liberated p-nitro-
phenol was measured at 405 nm.
The a-glucosidase activity of 15 was measured by
modification of the procedures described previously.18,19
The reaction mixture consisted of: 25 lL of 0.0165 M p-
nitrophenyl a-D-glucopyranoside, 403 lL of 0.1 M ace-
tate buffer (pH 4.0), 50 lL of inhibitor soln (either water
or MeOH), and 22 lL of enzyme soln (10 · diluted).
After incubation for 15 min at 37 ꢁC, the reaction was
terminated by addition of 1 mL of 2% sodium carbon-
ate. The absorbance of liberated p-nitrophenol was
measured at 405 nm.
}
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Acknowledgements
This work was supported by the Ministry of Education
and Science, Grant # 3 T09A 025 28.
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