The chemistry of castanospermine. Direct oxidation of the tetraacetate to the corresponding γ-lactam

Article abstract of DOI:10.1016/j.carres.2004.05.006

From the products of oxidation of tetra-O-acetylcastanospermine (2) with N-bromosuccinimide, only the γ-lactam 11 was isolated (19%). Treatment of this lactam with DBU in dichloromethane afforded the elimination product 12, while deacetylation with sodium methoxide in methanol gave tetraol 13 together with diene 14. The X-ray crystal structure of compound 13 is reported.

Full text of DOI:10.1016/j.carres.2004.05.006

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 1747–1751
The chemistry of castanospermine. Direct oxidation of
the tetraacetate to the corresponding c-lactamq
Richard H. Furneaux, Graeme J. Gainsford, Jennifer M. Mason* and Peter C. Tyler
Industrial Research Ltd, PO Box 31-310, Lower Hutt, New Zealand
Received 29 February 2004; accepted 13 May 2004
Available online 10 June 2004
Abstract—From the products of oxidation of tetra-O-acetylcastanospermine (2) with N-bromosuccinimide, only the c-lactam 11 was
isolated (19%). Treatment of this lactam with DBU in dichloromethane afforded the elimination product 12, while deacetylation
with sodium methoxide in methanol gave tetraol 13 together with diene 14. The X-ray crystal structure of compound 13 is reported.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Keywords: Castanospermine; Lactam; Oxidation
1. Introduction
by invoking participation of the nitrogen atom to gen-
erate tricyclic aziridinium species that undergo nucleo-
philic attack at each of the carbon atoms of the three-
membered rings. In this way, for example, the C-6 alco-
hol 3 reacts with diethylaminosulfur trifluoride (DAST)
to give 6-fluoride 5 (49%) and the ring-contracted aus-
traline derivative 6 (19%) following attack by fluoride at
C-6 and C-5, respectively, of intermediate 4.3 Likewise,
with this reagent, C-8 alcohol 7 gives compounds 9 and
10 via the aziridinium ion 8, nucleophilic attack in this
case occurring at C-8 and C-8a, respectively.4
Castanospermine (1) is a polyhydroxy indolizidine
alkaloid found in the seeds of Castanospermum australe
and the pods of Alexa leiopetala. It and its derivatives
show potent inhibitory effects on a range of glycosid-
ases, and the consequences of these effects conceivably
account for its activities against cancer and viruses as
well as its anti-malarial, -diabetic, -inflammatory, and
immunosuppressant properties.2
In previous parts of this series1 the preparations of a
large number of castanospermine derivatives from the
natural product were reported, and the profound
importance of the nitrogen atom on the chemical reac-
tivities of compounds of this type was revealed. In par-
ticular, this atom has a major influence on nucleophilic
displacement reactions undergone by compounds with a
good leaving group at C-6 or C-8. As illustrated in
Scheme 1 these reactions give products derived by
nucleophilic displacement with retention of configura-
tion at these centres, together with products of rear-
rangement reactions. These findings can be accounted for
2. Results and discussion
In consequence of the findings illustrated in Scheme 1, it
was of interest to us to obtain derivatives of castano-
spermine containing functionality that would alter the
nucleophilicity of the nitrogen atom, and with this
objective, we turned attention to the possibility of
making lactam analogues by direct oxidation of tetra-
acetate 2. c-Lactams of castanospermine have been re-
ported on several occasions as intermediates in the
synthesis of the alkaloid and its derivatives,5 and d-lac-
tam analogues have been similarly encountered,6 but we
are not aware of such compounds having been obtained
previously by direct oxidation procedures.
qPart VI in a series. For Part V see Ref. 1.
* Corresponding author. Tel.: +64-4-931-3239; fax: +64-4-931-3055;
e-mail: j.mason@irl.cri.nz
0008-6215/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.05.006

1748
R. H. Furneaux et al. / Carbohydrate Research 339 (2004) 1747–1751
OR
OR
H
RO
1 R = H
2 R = Ac
N
RO
OAc
AcO
AcO
AcO
H
N
+
N
N
AcO
AcO
AcO
AcO
+
AcO
F
F
4
6
5
a
R
1
2
8
3 R = R1= R2 = OAc, R3 = OH
7 R = R2 = R3= OBn, R1 = OH
8a
R1
R2
N
3
7
6
5
R3
b
F
BnO
BnO
BnO
H
N
OBn
+
N
N
F
+
BnO
BnO
BnO
BnO
BnO
9
8
10
Scheme 1. Reagents and conditions: (a) DAST, CH2Cl2, 40 ꢁC, 2 h; (b) DAST, CH2Cl2, rt, 50 h.
Oxidations of cyclic tertiary amines to amides with
halogen-based reagents, including N-bromosuccini-
mide,7 are well established,8 if not commonly used
conversions, and we now report that the crystalline c-
lactam 11 was obtained directly from castanospermine
tetraacetate (2) in 19% yield, and as the only isolated
product, following oxidation with N-bromosuccinimide
in aqueous dioxane. The observed apparent selective
reaction at C-3 of castanospermine tetraacetate would
be expected whether carbenium-ion or free-radical for-
mation controls the rate of its oxidation, since the gen-
eration of both species is favoured at carbon atoms
bonded to heteroatoms within five- relative to six-
membered rings.9;10
When lactam 11 was treated with DBU in dichlo-
romethane the diene 12, derived by loss of two molecules
of acetic acid, was obtained in high yield, whereas
treatment of product 11 with sodium methoxide in
methanol gave the deacetylated tetraol 13 in 37% yield
and, in addition, the diene 14, isolated in 23% yield
(Scheme 2).
The crystal structure of the castanospermine lactam 13
is shown in Figure 1 and the unit cell in Figure 2. Inde-
pendent molecules are bound into a three-dimensional
lattice by classical hydrogen bonds utilising all four hy-
ꢀ
droxyl protons (Hꢀ ꢀ ꢀO 1.96–2.02 A, O–Hꢀ ꢀ ꢀO 163–
174ꢁ).11;12 Acceptor atoms are O-3 (with bonds from HO-7
and HO-1 of different molecules), O-6 and O-8 (with bonds
to HO-8 and HO-6, of different molecules, respectively).
The five-membered ring (N-4, C-8a, C-1–3) adopts a flat-
ꢀ
tened envelope conformation [Qð2Þ 0.247(3)A,
/
113.0(6)ꢁ]13 with the flap atom C-1 0.393(4) A from the
plane of the other four, and the six-membered ring (N-4,
C-5–8a) adopts a regular chair conformation with N-4,
ꢀ
ꢀ
C-5, C-7, C-8 coplanar [ 0.004(1) A] and C-8a and C-6
ꢀ
)0.569(3) and 0.693(3) A from the plane; Q, h and /
13
ꢀ
are 0.535(3) A, 9.1(3) and 124(2)ꢁ, respectively. The
substituents on this ring all adopt equatorial orientations.
For the tetraacetate 11 of compound 13, this ring con-
formation is retained in solution as is indicated by the large
vicinal proton NMR coupling constants exhibited by H-50,
H-6, H-7, H-8 and H-8a.
OR
H
OR
RO
a
RO
2
N
N
RO
RO
O
O
b
12 R = Ac
11 R = Ac
c
14 R = H
13 R = H
+
Scheme 2. Reagents and conditions: (a) NBS, dioxane, H2O, rt, 20 min; (b) DBU, CH2Cl2, rt, 24 h; (c) NaOMe, MeOH, rt, 30 min.

R. H. Furneaux et al. / Carbohydrate Research 339 (2004) 1747–1751
1749
Figure 1. Crystal structure of compound 13 (C8H13NO5).17 Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms have
arbitrary radii.
uncorrected. Elemental analyses were determined in the
Campbell Microanalytical Laboratory of the University
of Otago, Dunedin, New Zealand. Aluminum-backed
silica gel sheets (E. Merck or Reidel de Haen) were used
for thin-layer chromatography, and column chroma-
tography was performed on silica gel (230–400 mesh, E.
Merck). Chromatography solvents were distilled prior
to use; ‘hexanes’ refers to a petroleum fraction boiling
near 68 ꢁC. Castanospermine was extracted from the
dried seeds of C. australe.4 All other chemicals were
commercially available and were used without further
purification.
3.2. (1S,6S,7R,8R,8aR)-1,6,7,8-Tetraacetoxyhexahydro-
indolizin-3-one (11)
A solution of tetra-O-acetylcastanospermine (2)3 (5.0 g,
14.2 mmol) in 9:1 dioxane–water (22 mL) was stirred
rapidly at room temperature while N-bromosuccinimide
(6.3 g, 35.4 mmol) was added with the temperature being
kept below 40 ꢁC. After the addition was complete, the
mixture was allowed to cool to room temperature. It
was partitioned between CH2Cl2 (50 mL) and aq 1 M
Na2S2O3 (50 mL), and the organic phase was washed
with satd aq NaHCO3, dried (MgSO4) and concentrated
Figure 2. Unit cell contents of compound 13 viewed down the b-axis
(approx); dashed lines represent hydrogen bonds. For clarity, only cell
edges and the O, N and hydroxyl H atoms of the unique molecule are
labelled.11
3. Experimental
3.1. General methods
under reduced pressure. Column chromatography with
2:3 fi 0:1 hexanes–EtOAc as eluant gave the crystalline
title c-lactam (1.1 g, 19%). Recrystallised from hexanes–
EtOAc it had mp 184–185 ꢁC. 1H NMR (CDCl3): d 5.56
(t, 1H, J 5.7 Hz, H-1), 5.28 (t, 1H, J 9.6 Hz, H-8), 5.21 (t,
1H, J 9.3 Hz, H-7), 4.97 (m, 1H, H-6), 4.42 (dd, 1H, J
5.9, 12.8 Hz, H-5), 3.80 (dd, 1H, J 5.2, 9.3 Hz, H-8a),
2.78 (dd, 1H, J 5.8, 18.1 Hz, H-2), 2.68 (t, 1H, J 11.4 Hz,
H-50), 2.43 (d, 1H, J 18.1 Hz, H-20), 2.08, 2.06, 2.04, 2.01
(4s, 12H, CH3). 13C NMR (CDCl3): d 171.2 (C-3), 170.1,
NMR spectra were recorded on a Bruker AC-300
spectrometer at 300 MHz (1H) or 75 MHz (13C). High-
resolution accurate mass determinations were per-
formed on a VG70-250S spectrometer using chemical
ionisation with isobutane. Melting points were mea-
sured on a Reichert hot stage microscope and are

1750
R. H. Furneaux et al. / Carbohydrate Research 339 (2004) 1747–1751
170.0, 169.5, 169.4 (COCH3), 74.1 (C-7), 67.6 (C-6), 66.7
(C-8), 64.4 (C-1), 60.7 (C-8a), 40.6 (C-5), 38.4 (C-2),
20.9, 20.7, 20.6, 20.6 (CH3). HRMS: Calcd for
C16H22NO9, m=z 372.1294; found, m=z 372.1279 (MH+).
Anal. Calcd for C16H21NO9: C, 51.75; H, 5.66; N, 3.77.
Found: C, 51.6; H, 5.71; N, 4.05.
(D2O): d 178.4 (C-3), 80.0, 70.9, 70.4, 67.3 (C-6, C-7,
C-8, C-8a), 45.9 (C-5), 43.5 (C-2). HRMS: Calcd for
C8H14NO5, m=z 204.0872; found, m=z 204.0896 (MHþ).
Anal. Calcd for C8H13NO5: C, 47.3; H, 6.45; N, 6.89.
Found: C, 47.2; H, 6.65; N, 7.03.
3.5. Crystal structure analysis of compound 13
3.3. (6S,7R)-6,7-Diacetoxy-6,7-dihydroindolizin-3(5H)-
one (12)
Crystals of the compound 13 (molecular formula
C8H13NO5) were grown from EtOAc–methanol, M
203.08, monoclinic space group P21 (No 4),14
DBU (2.2 mL, 14.5 mmol) was added to a solution of
tetraacetyllactam 11 (2.5 g, 6.7 mmol) in CH2Cl2. After
24 h the reaction mixture was washed with 1 M HCl and
aq satd NaHCO3, dried and concentrated under reduced
pressure. Column chromatography of the residue using
1:2 hexanes–EtOAc as eluant gave the title compound
(1.5 g, 6.0 mmol, 89%), mp 100–102 ꢁC. 1H NMR
(CDCl3): d 7.02 (d, 1H, J 5.8 Hz, H-2), 6.28 (d, 1H, J
5.8 Hz, H-1), 5.58 (d, 1H, J 5.2 Hz, H-8), 5.32 (m, 1H,
H-7), 5.23 (m, 1H, H-6), 4.07 (m, 1H, H-5), 3.61 (dd,
1H, J 2.9, 13.9 Hz, H-50), 2.09, 2.05 (2s, 6H, COCH3).
13C NMR (CDCl3): d 169.7, 169.6, 169.0 (COCH3, C-3),
141.5 (C-8a), 134.9 (C-1), 127.2 (C-2), 104.1 (C-8), 66.1
(C-6), 65.3 (C-7), 38.4 (C-5), 20.9 (COCH3). HRMS:
Calcd for C12H14NO5, m=z 252.0872; found, m=z
252.0853 (MHþ). Anal. Calcd for C12H13NO5: C, 57.4;
H, 5.22; N, 5.58. Found: C, 57.5; H, 5.04; N, 5.65.
ꢀ
a ¼ 6.673(2), b ¼ 8.859(3), c ¼ 8.459(3) A, b ¼ 111.94(3)ꢁ,
V ¼ 449.7(3) A , Z ¼ 2, Dc ¼ 1.501 g cmꢁ3, F ð000Þ ¼ 216,
3
ꢀ
lMo ¼ 0.126 mmꢁ1. Data were collected using x:2h scans
at 143(2) K with a Nicolet R3m diffractometer with
Mo Ka radiation (graphite monochromator,
k
ꢀ
0.71073 A). The crystals were colourless prisms,
0.40 · 0.25 · 0.25 mm; 1182 reflections were measured,
1096 unique (5:2 < 2h < 55:0ꢁ) of which 1020 ‘observed’
reflections had I > 2:5rðIÞ, Rint ¼ 0:028. Corrections
were applied for Lorentz and polarisation effects. No
absorption correction was applied. The structure was
solved by direct methods15 and refined on F 2 using ob-
served data.16 Final R1, wR2 values were 0.033, 0.076
(observed data) and 0.036, 0.078 (all data). All hydrogen
atoms were included but were not refined in calculated
16
ꢀ
positions (0.97–1.0 A as defined ) with constrained
thermal isotropic parameters (1.2 times parent C, O or
N equivalent values). Final max., min. residual electron
3.4. (1S,6S,7R,8R,8aR)-1,6,7,8-Tetrahydroxyhexahydro-
indolizin-3-one (13) and (6S,7R)-6,7-dihydroxy-6,7-dihydro-
indolizin-3(5H)-one (14)
ꢁ3
ꢀ
densities were 0.305 and )0.195 e A
.
4. Supplementary material
Tetraacetoxylactam 11 (0.52 g, 1.4 mmol) was stirred in
methanolic 0.2 M NaOMe (2 mL) until dissolved, and
the solution was neutralised with HOAc. The solvent
was removed under reduced pressure, and the syrupy
residue was passed through a column of cation-
exchange resin (Dowex 50 X-8, Hþ). Concentration
under reduced pressure, followed by column chroma-
tography (4:1 EtOAc–MeOH) gave dihydroxydiene 14
Crystallographic data (excluding structure factors) for
compound 13 have been deposited with the Cambridge
Crystallographic Centre as supplementary publications,
No CCDC 221352. These data can be obtained, free of
charge,
through
http://www.ccdc.cam.ac.uk/conts/
retrieving.html or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk.
1
(50 mg, 0.32 mmol, 23%): mp (MeOH) 194–195 ꢁC. H
NMR (D2O): d 7.16 (d, 1H, J 5.8 Hz, H-2), 6.22 (d, 1H,
J 5.8 Hz, H-1), 5.79 (d, 1H, J 4.7 Hz, H-8), 4.29 (t, 1H, J
4.6 Hz, H-7), 4.02 (m, 1H, H-6), 3.63 (m, 2H, H-5, -50).
13C NMR (D2O): d 174.3 (C-3), 141.2 (C-8a), 138.7 (C-
1), 128.3 (C-2), 115.6 (C-8), 70.0, 68.6 (C-6, C-7), 42.9
(C-5). HRMS: Calcd for C8H10NO3, m=z 168.0661;
found, m=z 168.0652 (MHþ). Anal. Calcd for C8H9NO3:
C, 57.48; H, 5.45; N, 8.38. Found: C, 57.6; H, 5.51; N,
8.33.
Acknowledgements
The work was funded by the New Zealand Foundation
for Research, Science and Technology. Dr. Herbert
Wong provided the NMR service and Professor Robin
Ferrier assisted with the preparation of the manuscript.
Further elution with the same solvent gave tetraol 13
(100 mg, 0.52 mmol, 37%): mp 188–194 ꢁC (EtOAc–
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