The synthesis of 6-azido and 6-amino analogues of 1-deoxynojirimycin and their conversion to bicyclic derivatives

Article abstract of DOI:10.1016/S0040-4020(00)00020-X

1-Amino-1-deoxy-D-glucitol (14) was converted to the N-Boc-2,3;5,6-di-O- isopropylidene derivative 16 which was transformed further into the selectively protected 2,3-O-isopropylidene 6-azido piperidine 3. The synthesis proceeded via a double inversion at C-5 involving internal attack of 4-OH to form the 4,5-epoxide 28, and ring opening of this epoxide by 1- NH₂ to generate the piperidine 3. This served as a valuable precursor of various target compounds, i.e. 6-azido- and 6-amino-1,6-dideoxynojirimycin 4 and 5, and the mono- and bicyclic derivatives 6-12. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00020-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1005–1012
The Synthesis of 6-Azido and 6-Amino Analogues of
1-Deoxynojirimycin and their Conversion to Bicyclic Derivatives
†
*
Amuri Kilonda, Frans Compernolle, Koen Peeters, Gert J. Joly, Suzanne Toppet and
Georges J. Hoornaert
Laboratorium voor Organische Synthese, Departement Scheikunde, K.U. Leuven Celestijnenlaan 200 F, B-3001 Heverlee, Belgium
Received 21 October 1999; revised 9 December 1999; accepted 23 December 1999
Abstract—1-Amino-1-deoxy-d-glucitol (14) was converted to the N-Boc-2,3;5,6-di-O-isopropylidene derivative 16 which was transformed
further into the selectively protected 2,3-O-isopropylidene 6-azido piperidine 3. The synthesis proceeded via a double inversion at C-5
involving internal attack of 4-OH to form the 4,5-epoxide 28, and ring opening of this epoxide by 1-NH2 to generate the piperidine 3. This
served as a valuable precursor of various target compounds, i.e. 6-azido- and 6-amino-1,6-dideoxynojirimycin 4 and 5, and the mono- and
bicyclic derivatives 6–12. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
anti-HIV, activities. These properties have stimulated
synthetic efforts directed at structural modification of 1
and 2 such as the introduction of lipophilic (fluoro,3,4
alkyl,5 and acyl6), 2- 3- or 6-amino,7 and glucosyl8 groups
at specific positions of the piperidine and indolizidine ring
systems. The synthesis of bicyclic diazasugars has also been
reported.9
In recent years there has been considerable interest in the
polyhydroxylated alkaloids 1-deoxynojirmycin1 (1) and
castanospermine2 (2) (Fig. 1). As piperidine analogues of
glucopyranose, these compounds inhibit several gluco-
sidases and display antidiabetic and antiviral, including
Figure 1.
Keywords: acetals; amines; azides; carbohydrates.
* Corresponding author. Tel.: ϩ32-16-327407; fax: ϩ32-16-327990; e-mail: frans.compernolle@chem.kuleuven.ac.be
†
´
´
´
Permanent address: Laboratoire de Chimie des Substances Naturelles, Departement de Chimie, Universite de Kinshasa, B.P. 190, Kinshasa XI, Republique
´
Democratique du Congo.
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00020-X

1006
A. Kilonda et al. / Tetrahedron 56 (2000) 1005–1012
In connection with our ongoing program about the
conversion of 1-amino-1-deoxy-d-glucitol to various poly-
hydroxylated piperidines,10 we now report the synthesis of
the azide synthon 3 and its transformation to target
compounds 4–12. The monocyclic 2,3,4-trihydroxy
compounds 4–8 are analogues of 1-deoxynojirimycin in
which the 6-OH group is replaced with an amino or azido
group. Since apolar substituents located at the 6-O-position
of 1 were shown to have a beneficial influence on the activity
as inhibitors of a-glucosidase,11 similar N-substituents such
as the p-fluorobenzoyl group were introduced also at the
6-amino position. The bicyclic target molecules 9–12
show analogy to the alkaloids castanospermine and
kifunensine 13. The latter compound, isolated from
Kitasatosporia kifunense, is a mannosidase I inhibitor
exhibiting anti-influenza activity.12 Part of this work has
appeared in a preliminary form.13
21, whereas the diacetonides isolated from the hexanes
were again subjected to the acid hydrolysis to give a second
5,6-diol fraction. Upon complete evaporation of the
dichloromethane solutions, the 5,6-diol 21 readily under-
went migration of the 4-O-acetyl group to form the less
polar 6-O-acetylated compound. To avoid this conversion,
the solutions were evaporated to only half their original
volumes, and without further delay a reagent mixture
consisting of MsCl, DMAP and Et3N was added. The result-
ing 5,6-O-dimesylated products were combined and
subjected to column chromatography. NMR analysis indi-
cated that the dimesylate fraction consisted of a 19:1
mixture of the two regioisomers 23 and 24 (53% overall
yield from the mixture of 16 and 17). Selective substitution
of the primary mesylate group was achieved by heating this
mixture with sodium azide in DMF which led to chromato-
graphic isolation of the 6-azido compound 25 as a single
regioisomer in 73% yield.
To transform 25 into the acetal protected deoxynojirimycin
analogue 3, we envisaged a double inversion at C-5. In
sequential order this would involve (a) internal attack of
4-OH to form the 4,5-epoxide, and (b) ring opening of
this epoxide by 1-NH2 to generate the piperidine. Two
different ways were used to implement this double inversion
strategy (Scheme 2). As expected, base promoted deprotec-
tion of the 4-O-acetate group using NaOMe in methanol
led to further conversion of the intermediate alcohol to the
N-protected epoxide 26. However, subsequent deprotection
of the amino group using trimethylsilyl iodide afforded a
complex reaction mixture, probably due to reaction of the
epoxide group with the Me3SiI reagent.14 In the alternative
approach, the foregoing sequence of reactions was reversed:
the amino function was deprotected first (Me3SiI in
dichloromethane) to give the amino mesylate 27, and next
the epoxide 28 was generated by treatment with NaOMe in
methanol. The polar primary amine 28 was not isolated but
was converted directly into the less polar piperidine 3 in
boiling methanol (56% yield from 25). Apparently, the
regioselective opening of the 4,5-epoxide at the C-5 position
is governed by the trans-fused character of the bicyclic
system generated, which allows for intramolecular attack
of the amine to form the six-membered but not the five-
membered ring.
Results and Discussion
Our synthesis started with the protection of 1-amino-1-
deoxy-d-glucitol (14) as the N-Boc-2,3;5,6-di-O-isopropyli-
dene derivative 16 (Scheme 1). Regioselective acetal
formation was accomplished by subjecting the N-Boc
compound 15 to a brief treatment with acetone, 2,2-
dimethoxypropane and p-toluenesulfonic acid. After
10 min, NMR analysis revealed a 9:1 ratio of the regiomeric
2,3;5,6- and 3,4;5,6-di-O-isopropylidene compounds 16 and
17. An increased relative amount of diacetonide 17, and
partial conversion to the triacetonide 18 were observed on
prolonged reaction. Hence, following chromatographic
isolation, the 9:1 mixture of 16 and 17 was used as such
for further transformation, starting with acetylation of the
free OH-group. Without further purification, the mixture of
acetates 19 and 20 was subjected to acidic hydrolysis
(pyridinium p-toluenesulfonate in MeOH/H2O at 60Њ),
which effected a selective deprotection of the 5,6-diol
moiety. To minimise complete removal of the acetal groups,
the hydrolysis was interrupted when polar tetraol products
firstly were detected on TLC. At this stage the 5,6-diols
were separated from the starting diacetonides by successive
extraction of the acidic solution with hexanes and dichloro-
methane. The latter extract contained the desired 5,6-diol
Scheme 1. Reagents: (a) Me2CO/Me2C(OMe)2 (4:1), p-MeC6H4SO3H (0.5 equiv.), room temperature, 10 min; (b) Ac2O–pyridine, DMAP; (c) PPTS, MeOH–
H2O (9:1), 60ЊC; (d) CH2Cl2, MsCl, DMAP, Et3N; (e) NaN3 (1.1 equiv.), DMF, 80ЊC.

A. Kilonda et al. / Tetrahedron 56 (2000) 1005–1012
1007
Scheme 2.
The synthetic potential of synthon 3 was confirmed by its
conversion to various target compounds. The 6-azido-6-
deoxy analogue of deoxynojirimycin (4) was prepared by
treatment of 3 with HCl in MeOH, followed by chromato-
graphic purification (silica gel; NH4OH/H2O/MeOH/CHCl3,
1:1:28:70) and crystallisation in Et2O/MeOH. Reduction of
the azido function of 3 with triphenyl phosphine and water
was carried out according to the method of Knouzi et al.15
The resulting water-soluble 2,3-O-isopropylidene protected
diamine 29 was purified by partitioning the reaction mixture
between water and toluene. Final deprotection using HCl in
MeOH yielded the 6-amino analogue of deoxynojirimycin
primary amine or, conversely, by keeping it in the protected
form as the 6-azide. Treatment of diamine 29 with 1 or
2 equiv. of p-fluorobenzoyl chloride and an excess of Et3N
in methanol gave the mono- and disubstituted amides 30 and
31, respectively (Scheme 3). Subsequent acidic deprotection
furnished the corresponding N-p-fluorobenzoyl compounds
6 and 7 in crystalline form.
In contrast to the ready N-acylation observed for both amino
groups of diamine 29, benzoylation of the ring amino group
failed for the 6-azido compound 3. In a similar way the
octadecanoyl group could be introduced only under forcing
conditions using stearic acid, EDCI and DMAP in dichloro-
methane. However, the resulting product proved to be the
4-O-esterified derivative 32, as shown by an IR absorption
at 1740 cmϪ1 and the low-field chemical shift value
(dˆ5.08) for proton H-4. Upon reduction of the azide func-
1
(5). The H NMR spectra of 4 and 5 uniformly displayed
3
coupling constant values Jˆ9 Hz for the axial hydrogen
atoms H-2 to H-5, confirming their all-trans stereochemical
4
relationship and the C1 conformation of the piperidine
iminosugar.
tion (characterised by a strong IR absorption at 2105 cmϪ1
)
Our next goal was to functionalise the two amino groups in a
differential way by exploiting the greater reactivity of the
of 32 to the primary amine with Ph3P/H2O, the 4-O-acyl
diamine generated by hydrolysis of the intermediate
Scheme 3. Reagents: (a) p-F-BzCl (1 equiv.), Et3N, MeOH; (b) p-F-BzCl (2 equiv.), Et3N, MeOH; (c) HCl–MeOH; (d) n-C17H35CO2H, EDCI, DMAP;
CH2Cl2; (e) PPh3, H2O, THF.

1008
A. Kilonda et al. / Tetrahedron 56 (2000) 1005–1012
Scheme 4.
iminophosphorane 33 underwent rearrangement to form the
6-N-octadecanoyl amide 34. This was characterised as the
triol amide 8 following acidic removal of the acetal group.
The lack of reactivity observed for ring N-acylation of
azide 3 may be ascribed to the repulsion developed between
the equatorial azidomethyl side chain and the N-acyl
substituent, which are coplanar in the chair conformation
of the N-acyl product. This effect may be alleviated when
going from the N-monoacyl intermediate 30 to the N,N0-
diacyl product 31, possibly due to intramolecular hydrogen
bridge formation between the two amide groups or to the
generation of alternative conformations, e.g. the twist-boat
form.16
piperazine derivatives 11 and 12. In the spectra of the
latter compounds, five trans-1,2-diaxial interactions on six
consecutive axial protons H-1ax to H-6ax (numbering
according to that of the starting compound 1-amino-1-
deoxy-d-glucitol) were revealed by characteristic coupling
3
constant values in the range Jˆ9.3–11 Hz.
Conclusion
The azide synthon 3, easily prepared from aminoglucitol
14 in seven steps, offers excellent opportunities for the
synthesis of various iminosugars, as demonstrated here by
its conversion to the mono- and bicyclic products 4–12,
which are analogues of the known glycosidase-inhibitors
deoxynojirimycin, castanospermine and kifunensine. In
these and other diamine target structures, the relative loca-
tion of the amino nitrogens is similar to that in numerous
alkaloids and piperazine or piperidine drugs. Therefore,
structural features pertaining to both glucopyranose and
the 1,2-diamino compounds can be accommodated via
specific modification at either amino function.
The deprotected diamine 5 and its azido precursor 3 provide
access to the fused bicyclic systems 9–12 (Scheme 4),
which encompass an additional five- or six-membered
ring similar to that found in castanospermine (2) and
kifunensine (13). Treatment of 5 with phenylchloroformate
and potassium carbonate in methanol/water yielded the urea
derivative 9, which was purified by column chromatography
and subsequent crystallisation. The analogous diamide
10 was obtained by treating 5 with dimethyl oxalate in
methanol. As opposed to the N-acylation of the azide 3,
N-alkylation with methyl bromoacetate proceeded readily
to give the azido ester 35. This was not isolated but directly
reduced to form the bicyclic lactam 36 in almost quanti-
tative yield. Acidic removal of the isopropylidene group
afforded the corresponding trihydroxy lactam 11. Alter-
natively, the bicyclic diamine 37 was prepared via reduction
of the protected lactam 36 with LiAlH4 and subjected to
acidic deprotection to give the corresponding diamine salt
12.
Experimental
General procedures
Melting points were uncorrected. The optical rotations were
measured on a Propol polarimeter fitted with a 7 cm cell. IR
spectra were recorded as thin films between NaCl plates on a
1
Perkin–Elmer 297 grating IR spectrophotometer. H and
13C NMR were recorded on Bruker AMX 400 and WM
1
250 instruments operating at 400 and 250 MHz for H and
1
100 and 62.9 MHz for 13C. H and 13C chemical shifts are
The structures of the bicyclic target compounds 9–12 were
1
confirmed by their spectral data. Whereas the H NMR
reported in ppm relative to tetramethylsilane as an internal
reference. J values are reported in Hz. Mass spectra were
run on Kratos MS50 and Hewlett-Packard instruments; the
spectra of 9 and 10 displayed a number of unresolved multi-
plets, clear cut coupling patterns were observed for the

A. Kilonda et al. / Tetrahedron 56 (2000) 1005–1012
1009
ion source temperature was 150–250ЊC as required. Exact
mass measurements were performed at a resolution of
10 000. Analytical and preparative thin layer chromato-
graphy was performed using Merck silica gel 60 PF-224.
Column chromatography was carried out using 70–
230 mesh silica gel 60 (E. M. Merck). Dry solvents
were freshly distilled. Solutions were dried over MgSO4.
1-Amino-1-deoxy-d-glucitol was supplied by Cerestar.
followed by extraction as described above. To avoid the
migration of the 4-O-acetyl group of diol 21 to the 6-O-
position, the first CH2Cl2 extracts were dried immediately
and then were concentrated to half their volume, and the
mixture of diols 21 and 22 (TLC hexanes–EtOAc, 2:3, Rf
0.12) was sulfonylated by addition of MsCl (1.59 mL,
20.17 mmol), DMAP (0.50 g, 0.40 mmol), and Et3N
(7 mL) to this solution at 0ЊC. The sulfonylation was
complete in less than 10 min at rt. The CH2Cl2 extracts of
the second hydrolysis reaction were sulfonylated as
described, using 6 mmol of MsCl, 3 mmol of DMAP and
2 mL of Et3N. The CH2Cl2 solutions containing the products
from the two sulfonylation reactions were combined and
washed with an aqueous solution of K2CO3. The organic
phase was dried and evaporated, and the residue was
purified by column chromatography on silica gel
(hexanes–EtOAc, 3:2) to afford 2.65 g of a 19:1 mixture
of dimesylates 23 and 24 as an oily residue in 53% overall
yield from the 9:1 mixture of diacetonides 16 and 17. 23: IR:
nmax 1750, 1706 1362 cmϪ1; 1H NMR (400 MHz, CDCl3), d
1.40 (m, 15 H, Me2C, Me3C), 2.15 (s, 3 H, MeCO), 3.10 (s, 3
H, MeSO2), 3.18 (s, 3 H, MeSO2), 3.34 (dt, Jˆ15, 5 Hz, 1 H,
H-1a), 3.41 (ddd, Jˆ15, 7, 5 Hz, 1 H, H-1b), 3.75 (m, 1 H,
H-2), 3.98 (br d, Jˆ8.5 Hz, 1 H, H-3), 4.40 (dd, Jˆ12, 6 Hz,
1 H, H-6a), 4.69 (dd, Jˆ12, 2 Hz, 1 H, H-6b), 5.15 (td, Jˆ6,
12 Hz, 1 H, H-5), 5.24 (br s, 1 H, NH), 5.4 (br d, Jˆ6 Hz, 1
H, H-4); 13C NMR (100 MHz, CDCl3) d 20.3 (MeCO), 26.2,
26.8 (Me2C), 28.1 (Me3C), 37.4, 38.4 (2 MeSO2), 40.3 (C-1),
66.7 (C-6), 67.8 (C-4), 75.5 (2 C, C-2, C-3), 77.8 (C-5), 79.4
(OCMe3), 109.4 (Me2CO2), 156.1 (N–COO), 169.6 (COO);
HRMS: calcd for C13H22N1O12S2 (MϩϪCH3, Ϫisobutene)
448.05834, found 448.05949 (10%).
1-[(Tert-butoxycarbonyl)amino]-1-deoxy-d-glucitol (15).17
To a solution of 1-amino-1-deoxy-d-glucitol 14 (6.67 g,
35 mmol) in aqueous methanol (50%, 160 mL) was added
di-tert-butyl dicarbonate (10.80 g, 48 mmol). The mixture
was stirred at rt for 4 h. After evaporation of the solvent, the
residue was dissolved in a small volume of MeOH, 2-propa-
nol was added and the precipitate was collected by filtration.
The filtrate was evaporated and the residue was treated
twice as above. The precipitate was dried over P2O5 to
give compound 15 (9.43 g, 96% yield) as a white solid:
mp 72–73ЊC (literature 86–88ЊC).
1-[(Tert-butoxycarbonyl)amino]-1-deoxy-2,3:4,5-di-O-
isopropylidene-d-glucitol (16). Compound 15 (3.89 g,
13.84 mmol) was suspended in a 4:1 mixture (120 mL) of
acetone and 2,2-dimethoxypropane. To the suspension was
added p-TsOH·H2O (1.32 g, 6.92 mmol). The mixture was
stirred at rt for 10 min and the solution was made alkaline
with aqueous Na2CO3. The solution was extracted with
EtOAc. The organic phase was dried, evaporated and the
residue was subjected to column chromatography using
silica gel (hexanes–EtOAc, 7:3). This gave 3.76 g (75%
yield) of an inseparable 9:1 mixture of regioisomers 16
and 17 as an oil, and triacetonide 18 (12% yield). 16: IR:
nmax 2985, 1701 cmϪ1; 1H NMR (400 MHz, CDCl3), d 1.34
(s, 3 H), 1.40 (s, 6 H), 1.42 (s, 3 H), 1.45 (s, 9 H), 2.50 (d, 1
H, 4-OH), 3.30 (m, 1 H, H-1a), 3.43 (m, 1 H, H-1b), 3.47 (m,
1 H, H-4), 3.91 (dd, 1 H, H-3), 4.02 (m, 2 H, H-6), 4.09 (m, 1
H, H-2), 4.13 (m, 1 H, H-5), 4.98 (br s, 1 H, NH); 13C NMR
(100 MHz, CDCl3), d 25.2 (CH3), 26.7 (CH3), 26.8 (CH3),
27.3 (CH3), 28.3 (CH3), 41.7 (C-1), 66.9 (C-6), 70.4 (C-4),
76.2, 76.3 (C-2, C-5), 77.8 (C-3), 79.4 (OCMe3) 109.4
(Me2CO2), 155.8 (OCO–NH); HRMS calcd for
C16H28NO7 (MϩϪCH3) 346.1866, found 346.1863 (15%).
4-O-Acetyl-1-[(tert-butoxycarbonyl)amino]-6-azido-1,6-
dideoxy-2,3-O-isopropylidene-5-O-methanesulfonyl-d-
glucitol (25). Compound 23 prepared according to the
preceding procedure (1.96 g, 3.88 mmol) was dissolved in
10 mL of DMF. Sodium azide (0.29 g, 4.5 mmol) was added
and the solution was heated at 80ЊC for 2 h. The reaction
mixture was allowed to cool to rt, diluted with CH2Cl2, and
the organic solution was washed with water (3×). After
evaporation of the organic solvent, the residue was
subjected to column chromatography (hexanes–EtOAc,
3:2) to give compound 25 (2.77 g, 73% yield) as an oil:
4-O-Acetyl-1-[(tert-butoxycarbonyl)amino]-1-deoxy-2,3-
O-isopropylidene-5,6-di-O-methanesulfonyl-d-glucitol
(23). The 9:1 mixture of 16 and 17 (3.46 g, 9.59 mmol) was
dissolved at in a cooled (0ЊC) 1:1 (v/v) mixture of pyridine
and Ac2O. DMAP (0.25 g) was added to the solution and the
mixture was stirred at rt for 1 h. Water was added and the
aqueous solution was extracted (3×) with an equal volume
of toluene. The toluene solution was dried, and the solvent
was removed by evaporation to give 4.63 g of an insepar-
able mixture of acetates 19 and 20 as an an oily residue
(TLC hexanes–EtOAc, 7:3, Rf 0.33). Without further puri-
fication, the residue was dissolved in 90% aqueous methanol
(50 mL) and PPTS (4.41 g, 9.59 mmol) was added. The
solution was heated at 60ЊC for 6 h. The solution was diluted
with water and extracted successively with hexanes (3×)
and CH2Cl2 (2×). Evaporation of the hexanes extracts
provided 1.17 g of a mixture of unreacted 19 and 20,
which was subjected again to the hydrolysis with PPTS
(0.73 g, 2.90 mmol) in aqueous MeOH at 60ЊC for 3 h,
IR: nmax 2180, 1755, 1708 cmϪ1 1H NMR (400 MHz,
;
CDCl3), d 1.40 (m,15 H, Me2C, Me3C), 2.16 (s, 3 H,
MeSO3), 3.16 (s, 3 H, CH3CO2), 3.33 (ddd, Jˆ15, 7, 4 Hz,
1 H, H-1a), 3.36 (ddd, Jˆ15, 6, 4 Hz, 1 H, H-1b), 3.53 (dd,
Jˆ7, 14 Hz, 1 H, H-6a), 3.74 (m, 1 H, H-2), 3.84 (br m, 1 H,
H-4), 3.96 (dd, Jˆ8, 2 Hz, 1 H, H-3), 4.84 (broad, 1 H, NH),
4.92 (m, 1 H, H-5), 5.35 (br m, 1 H, H-6b); 13C NMR
(100 MHz, CDCl3),
d 20.5 (MeCO2), 26.52, 27.17
(Me2C), 28.4 (Me3C), 38.6 (MeSO3), 40.7 (C-1), 51.1
(C-6), 69.5 (C-4), 76.0 (2 C, C-2, C-3), 79.0 (C-5) 79.6
(Me3C), 109.4 (Me2C), 156.1 (NHCOO), 169.3 (COO);
HRMS calcd for C12H19N4SO9 (MϩϪCH3, Ϫisobutene)
395.0873, found 395.0878 (14%).
6-Azido-1,5-imino-2,3-O-isopropylidene-1,5,6-trideoxy-
d-glucitol (3). To a solution of azide 25 (0.66 g, 1.42 mmol)
in CH2Cl2 (20 mL) was added Me3SiI (0.42 mL,
2.85 mmol). The reaction mixture was stirred for 10 min,
followed by the addition of MeOH (3 mL) and Et3N (1 mL).

1010
A. Kilonda et al. / Tetrahedron 56 (2000) 1005–1012
The solvents and reagents were evaporated and the residue
of crude primary amine 27 (TLC MeOH–EtOAc, 3:47, Rf
0.12) was treated with MeONa (0.38 g, 7.13 mmol) in
MeOH (10 mL) for 1 h to form the epoxide 28 (TLC
MeOH–EtOAc, 3:47, Rf 0.15). Water was added and the
epoxide was extracted with EtOAc. The organic phase
was dried and evaporated and the residue was heated in
MeOH under reflux for 2 h. The solution was evaporated
and the residue was subjected to column chromatography
(EtOAc) to afford the piperidine 3 (0.184 g) as a white solid
in 56% overall yield from mesylate 25: mp 108–109.5ЊC;
[a]2D0 ϩ46.8 (c 0.45, CHCl3); IR: nmax 3426, 2105 cmϪ1; 1H
NMR (400 MHz, CDCl3), d 1.45 (6 H, s, Me2C), 2.58 (1 H,
m, H-5), 2.73 (1 H, m, H-1ax), 3.3-3.4 (3 H, m, H-1eq, H-2
and H-3 or H-4), 3.62 (1 H, t, Jˆ9 Hz, H-3 or H-4), 3.66
(1 H, dd, Jˆ5, 13 Hz, H-6a), 3.72 (1 H, dd, Jˆ3.5, 13 Hz,
H-6b); 13C NMR (100 MHz, CDCl3), d 26.6, 26.7 (Me2C),
46.6 (C-1), 51.9 (C-6), 59.4 (C-5), 71.0 (C-4), 75.7, 84.2
(C-2, C-3), 110.6 (Me2CO2); HRMS calcd for C8H13N4O3
(MϩϪCH3) 213.0988, found 213.0987 (3%), calcd for
C8H14NO3 (MϩϪCH2N3) 172.0974, found 172.0974
(100%).
methanolic HCl (3 mL) for 30 min. Following evaporation
of the solution and twofold co-evaporation of the reagents
with MeOH, the residue was treated with a solution of
ammonia in methanol. Upon evaporation and crystallisation
of the residue from Et2O–MeOH compound 5 was isolated
(45 mg, 94% yield) as white crystals (changing to brown on
standing at rt): mp 188ЊC; [a]2D0 ϩ11.5 (c 0.12, H2O); IR:
nmax 3425 cmϪ1; 1H NMR (400 MHz, D2O), d 2.57 (1 H, dd,
Jˆ11, 13 Hz, H-1ax), 2.91 (1 H, m, H-5), 3.08 (1 H, dd,
Jˆ7.5, 13 Hz, H-6), 3.22 (1 H, dd, Jˆ5, 13 Hz, H-1eq), 3.32
(1 H, t, Jˆ9 Hz, H-3), 3.38 (1 H, t, Jˆ9 Hz, H-4), 3.40 (1 H,
dd, Jˆ6.5, 13 Hz, H-60), 3.56 (1 H, ddd, Jˆ5, 9, 11 Hz,
H-2); 13C NMR (D2O, 100 MHz), d 41.0 (C-6), 48.1
(C-1), 56.4 (C-5), 69.9 (C-2), 73.3 (C-4), 77.4 (C-3);
HRMS calcd for C6H15N2O3 (MϩϩH) 163.1083, found
163.1095 (0.2%), calcd for C5H10NO3 (MϩϪCH2NH2)
132.0661, found 132.0683 (100%).
6-p-Fluorobenzamido-2,3-O-isopropylidene-1,5-imino-
1,5,6-trideoxy-d-glucitol (30). Compound 29 prepared
from 103 mg of azide 3 (0.45 mmol) was dissolved in
MeOH (5 mL). Et3N (0.14 mL, 1 mmol) and p-fluoro-
benzoyl chloride (0.06 mL, 0.49 mmol) were added. After
completion of the reaction (30 min, TLC AcOEt–MeOH,
47:3, Rf 0.2), the reaction mixture was evaporated, water
(5 mL) was added, and the mixture was extracted succes-
sively with toluene and AcOEt. Upon evaporation of the
AcOEt solution, 103 mg of compound 30 was isolated as
a white solid (71% overall yield from 3): mp 170–172ЊC;
[a]2D0 ϩ5.1 (c 0.2, CHCl3); IR: nmKBaxr 3340, 3280, 1645, 1600,
6-Azido-1,5-imino-1,5,6-trideoxy-d-glucitol (4). Compound
3 (60 mg, 0.26 mmol) was treated with saturated methanolic
HCl for 30 min. Evaporation of the solvent and column
chromatography of the residue (NH4OH–H2O–MeOH–
CHCl3, 1:1:28:70, Rf 0.3) afforded, following crystallisation
in Et2O–MeOH, 45.6 mg of azide 4 (92% yield) as a white
solid: mp 165–167ЊC; [a]2D0 ϩ26.0 (c 0.054, H2O); IR: nmax
1
1
3430, 2110 cmϪ1; H NMR (400 MHz, D2O), d 2.85 (1 H,
1550 cmϪ1; H NMR (400 MHz, CD3OD), d 1.5 (s, 6 H,
dd, Jˆ11, 13 Hz, H-1ax.), 3.16 (1 H, ddd, Jˆ3, 5, 9 Hz,
H-5), 3.41 (1 H, dd, Jˆ5, 13 Hz, H-1eq), 3.46 (1 H, t,
Jˆ9 Hz, H-3), 3.51 (1 H, t, Jˆ9 Hz, H-4), 3.73 (1 H, ddd,
Jˆ5, 9, 11 Hz, H-2), 3.79 (1 H, dd, Jˆ5, 14 Hz, H-6), 3.88
(1 H, dd, Jˆ3, 14 Hz, H-60); 13C NMR (D2O, 100 MHz), d
46.5 (C-1), 49.2 (C-6), 57.9 (C-5), 67.6 (C-2), 69.0 (C-4),
76.3 (C-3); HRMS calcd. for C5H10NO3 (MϩϪCH2N3)
132.0661, found 132.0660 (100%).
Me2C), 2.54–2.67 (m, 2 H, H-1ax, H-5), 3.21 (dd, Jˆ12,
4 Hz, 1 H, H-1eq), 3.31–3.47 (m, 3 H, H-2, H-3, H-4), 3.57
(dd, Jˆ14, 8 Hz, 1 H, H-6a), 3.75 (dd, Jˆ14, 8 Hz, 1 H,
H-6b), 7.16 (t, Jˆ9 Hz, 2 H, H-30, H-50 arom.), 7.90 (m, 2 H,
H-20, H-60 arom.); 13C NMR: (100 MHz, CD3OD), d 26.9,
27.1 (Me2C), 42.2 (C-6), 47.6 (C-1), 62.3 (C-5), 73.4 (C-4),
77.0, 84.9 (C-2, C-3), 111.4 (Me2CO2), 116.2, 116.4 (C0-3,
C0-5 arom.), 131.0, 131.1 (C0-2, C0-6 arom.), 131.8 (C0-1
arom.), 166.2 (C0-4 arom.), 169.7 (N–CO–); HRMS calcd
for C16H19N2O3F (MϩϪH2O) 306.1380, found 306.1386
(6%), calcd for C8H14NO3 (MϩϪCH2NHCOC6H4F)
172.0974, found 172.0975 (31), calcd for C7H4FO
(FC6H4COϩ) 123.0246, found 123.0244 (100%).
6-Amino-1,5-imino-2,3-O-isopropylidene-1,5,6-trideoxy-
d-glucitol (29). To a solution of azide 3 (103 mg,
0.51 mmol) in THF (3 mL) was added PPh3 (135 mg,
0.51 mmol) and water (0.2 mL). The mixture was allowed
to stand at rt for 7 h. Following evaporation of the solution,
the residue was partitioned between water (5 mL) and
toluene (5 mL). The aqueous phase was extracted further
with toluene (2×5 mL). Upon evaporation of the aqueous
solution, compound 29 (oil) was isolated (85 mg, 93%
yield): Rf 0.36 (CHCl3–MeOH–NH4OH–H2O, 50:45:1:5):
6-p-Fluorobenzamido-1,5-imino-1,5,6-trideoxy-d-glucitol
(6). Compound 30 (80 mg, 0.25 mmol) was treated with
saturated methanolic HCl (3 mL) for 30 min. The mixture
was evaporated and the residue was co-evaporated twice
with MeOH, followed by treatment with methanolic ammo-
nia and evaporation. Crystallisation of the residue from
Et2O–MeOH provided compound 6 (65 mg, 93% yield) as
[a]D20 Ϫ21.0 (c 0.072, MeOH); IR: nmax 3432, 2987 cmϪ1
;
1H NMR (400 MHz, CD3OD), d 1.40 (2 s, 6 H, Me2C), 2.37
(ddd, Jˆ9, 7, 4 Hz, 1 H, H-5), 2.60 (m, Jˆ12, 10 Hz, 1 H,
H-1ax), 2.74 (dd, Jˆ13, 7 Hz, 1 H, H-6a), 3.08 (dd, Jˆ13,
4 Hz, H-6b), 3.21 (m, Jˆ12, 4 Hz, 1 H, H-1eq), 3.32–3.43
(m, 3 H, H-2, H-3, H-4); 13C NMR (100 MHz, CD3OD), d
26.8, 27.1 (Me2C), 43.2 (C-6), 47.6 (C-1), 63.0 (C-5), 73.5
(C-4), 77.1, 85.2 (C-2, C-3), 111.2 (Me2CO2); HRMS calcd
for C9H15O3N (MϩϪNH3) 185.1052, found 185.1043
(15%).
a white solid: mp 176–178ЊC; [a]2D0 ϩ13.6 (c 0.14, H2O);
KBr
max
IR: n
3400, 3390, 3340, 1650, 1610, 1580, 1510 cmϪ1
;
1H NMR (400 MHz, CD3OD), d 2.49 (dd, Jˆ12, 10.5 Hz, 1
H, H-1ax), 2.78 (ddd, Jˆ10, 8, 3 Hz, 1 H, H-5), 3.14 (dd,
Jˆ12, 5 Hz, 1 H, H-1eq), 3.24 (t, Jˆ10, 9 Hz, 1 H, H-4),
3.37 (t, Jˆ9 Hz, 1 H, H-3), 3.52 (m, 1 H, H-6a), 3.53 (m, 1
H, H-2), 3.76 (dd, Jˆ15, 3 Hz, H-6b), 7.25 (t, Jˆ9 Hz, 2 H,
H-30, H-50 arom.), 7.93 (m, 2 H, H-20, H-60 arom.); 13C
NMR (100 MHz, H2O), d 41.0 (C-6), 48.5 (C-1), 59.2
(C-5), 70.3 (C-2), 72.6, 77.8 (C-3, C-4), 115.4, 115.6
(C-30, C-50 arom.), 129.5, 129.6 (C-20, C-60 arom.), 129.6
6-Amino-1,5-imino-1,5,6-trideoxy-d-glucitol (5). Compound
29 (60 mg, 0.297 mmol) was treated with saturated

A. Kilonda et al. / Tetrahedron 56 (2000) 1005–1012
1011
(C-10 arom.), 164.6 (C-40 arom.), 170.2 (CO–NH); HRMS
calcd for C13H15N2FO3 (MϩϪH2O) 266.1067, found
266.1069 (13%), calcd for C8H7NFO ([CH2NHCOC6H4F]ϩ)
152.0512, found 152.0508 (8%), calcd for C5H10NO3
(MϩϪCH2NHCOC6H4F) 132.0661, found 132.0663 (100%).
0.21 mmol) in THF (5 mL), were added PPh3 (61 mg,
0.23 mmol) and water (0.1 mL). The mixture were stirred
overnight and evaporated. Column chromatography
(MeOH–CHCl3, 3:22) afforded 88.3 mg (90% yield) of
compound 34 as a white solid. This compound (20 mg,
0.04 mmol) was treated with methanolic HCl (3 mL) for
30 min. The solution was evaporated and the residue was
crystallised from Et2O–MeOH to give 18 mg (91% yield) of
8·HCl (white solid): mp 189.0–190.1ЊC; [a]2D0 ϩ33.5 (c
6-p-Fluorobenzamido-1,5-[(p-fluorobenzoyl)imino]-1,5,
6-trideoxy-d-glucitol (7). Compound 29 prepared from
103 mg of azide 3 (0.45 mmol) was dissolved in MeOH
(5 mL). Et3N (0.28 mL, 2 mmol) and p-fluorobenzoyl
chloride (0.12 mL, 0.98 mmol) was added. After comple-
tion of the reaction (30 min), the mixture was evaporated,
water (5 mL) was added, and the aqueous solution was
extracted (3×) with an equal volume of toluene. The organic
phase was evaporated and the residue, consisting of the
protected diamide 31 (TLC EtOAc–MeOH, 47:3, Rf 0.56),
was treated with methanolic HCl (5 mL) for 1 h. The
mixture was evaporated and the residue was distributed
between water (5 mL) and toluene (5 mL). The aqueous
solution was extracted with toluene (2×) and EtOAc (5×).
The EtOAc solution was dried and evaporated, and the resi-
due was crystallised from Et2O–MeOH to give compound 7
(173 mg) as a white crystalline solid in 94% overall yield
from azide 3: mp 113–114ЊC; [a]2D0 ϩ4.9 (c 0.2, H2O); IR:
1
0.86, MeOH); IR: nmax 3426, 2951, 1710, 1656 cmϪ1; H
NMR (400 MHz, CD3OD), d 0.88 (t, Jˆ6.7 Hz, 3 H, CH3),
1.12 (m, 2 H, CH2–CH3), 1.28 (m, 26 H, CH2), 1.62 (m, 2 H,
CH2CH2CO), 2.27 (t, Jˆ7.4 Hz, 2 H, CH2CO), 2.83 (dd,
Jˆ12.5, 11 Hz, 1 H, H-1ax), 3.11 (m, 1 H, H-5), 3.37 (m,
3 H, H-1eq, H-3, H-4), 3.50 (dd, Jˆ15, 7 Hz, 1 H, H-6a),
3.64 (m, 2 H, H-2, H-6b); 13C NMR (100 MHz, CD3OD), d
14.2 (CH3), 23.6, 26.5, 30.5, 32.9, 36.9 (CH2), 39.9 (C-6),
48.0 (C-1), 61.8 (C-5), 68.6 (C-2), 70.7 (C-4), 78.0 (C-3);
HRMS: calcd for C24H46O3N2 [MϩϪH2O], 410.3508, found
410.3505 (19%).
(6S,7R,8R,8aR)Hexahydro-6,7,8-trihydroxyimidazo[1,5a]-
pyridin-3(2H)-one (9). To a solution of diamine 5
(59.7 mg, 0.37 mmol) in 50% aqueous MeOH (5 mL),
were added K2CO3 (276 mg, 2 mmol) and PhOCOCl
(0.05 mL, 0.39 mmol). The mixture was stirred for 1 h
and evaporated. The residue was dissolved in MeOH and
the insoluble material was filtered off. The methanolic
solution was evaporated and the residue was purified by
chromatography on a silica gel column (NH4OH–H2O–
MeOH–CHCl3, 1:1:48:50) to afford, after crystallisation
from Et2O–MeOH, 63.4 mg (91% yield) of compound 9
as a white solid: mp Ͼ400ЊC; [a]2D0 ϩ0.96 (c 0.15, H2O);
KBr
max
1
n
3380, 1710, 1640, 1600 cmϪ1; H NMR (400 MHz,
CD3OD), d 3.35 (dd, Jˆ16, 4 Hz, 1 H), 3.40–4.00 (m, 5
H), 4.20–4.70 (m, 2 H), 6.70–7.50 (m, 6 H), 7.70–7.90 (m,
2 H); 13C NMR (100 MHz, CDO3D), d 40.0 (C-6), 46.3
(C-1), 57.7 (C-5), 70.2, 70.8, 71.5 (C-2, C-3, C-4), 116.0,
116.3, 116.5 (C0-3, C0-5 arom.), 130.9, 131.0 (C0-2, C0-6
arom.), 133.3 (C0-1 arom.), 164.1, 166.6 (C0-4 arom.),
174.5 (N–CO–); HRMS calcd for C20H20N2F2O5 (Mϩ)
406.1340, found 406.1356 (0.3%), calcd for C20H18N2F2O4
(MϩϪH2O) 388.1235, found 388.1251 (2%), calcd for
C12H13NFO4 (MϩϪCH2NHCOC6H4F) 254.0829, found
254.0860 (16%).
1
IR: nmax 3426, 1655 cmϪ1; H NMR (400 MHz, D2O), d
2.64 (dd, Jˆ12, 10 Hz, 1 H), 3.38 (m, 1 H), 3.31 (m, 3
H), 3.51 (m, 2 H), 3.78 (dd, Jˆ12, 5 Hz, 1 H); 13C NMR
(100 MHz, D2O), d 43.6 (C-1), 45.9 (C-5), 60.3 (C-8a), 71.2
(C-6), 74.6 (C-8), 79.5 (C-7), 165.1 (C-3); HRMS: calcd for
C7H12O4N2 [Mϩ], 188.0797, found 188.0801 (12%).
6-Azido-1,5-imino-2,3-O-isopropylidene-4-O-octadecanoyl-
1,5,6-trideoxy-d-glucitol (32). To a solution of azide 3
(102 mg, 0.44 mmol) in CH2Cl2 (5 mL), were added stearic
acid (157 mg, 0.54 mmol), EDCI (172 mg, 0.90 mmol) and
DMAP (24.4 mg, 0.20 mmol). The mixture was stirred for
18 h at rt, and then was washed with water. The organic
phase was dried and evaporated. The residue was purified
by column chromatography (hexanes–EtOAc, 7:3) to give
ester 32 (147 mg, 68% yield) as a white solid: mp 73.6–
74.5ЊC; [a]2D0 ϩ4.7 (c 0.12, CHCl3); IR: nmax 3426, 2105,
1740 cmϪ1; 1H NMR (400 MHz, C6D6), d 0.95 (t, 3H, CH3),
1.20–1.50 (m, 34 H, 14 CH2, 2 CH3), 1.52 (m, 2 H,
CH2CH2CO), 2.15 (td, Jˆ8, 1.5 Hz, 2 H, CH2CO), 2.39
(dd, Jˆ10, 11.5 Hz, 1 H, H-1ax), 2.43 (m, Jˆ9, 7, 3 Hz, 1
H, H-5), 2.91 (dd, Jˆ11.5, 4.5 Hz, 1 H, H-1eq), 2.99 (dd,
Jˆ12.5, 7 Hz, 1 H, H-6a), 3.18 (m, 2 H, H-2, H-6b), 3.42 (t,
Jˆ9.5, 9 Hz, 1 Hz, H-3), 5.08 (t, Jˆ9.5, 9 Hz, 1 H, H-4); 13C
NMR (100 MHz, CDCl3), d 14.1 (CH3), 22.7, 25.0 (CH2),
26.7, 26.8 (Me2C), 29.1, 29.3, 29.4, 29.5, 29.6,29.7, 32.0,
34.4 (CH2), 46.6 (C-1), 52.1 (C-6), 58.2 (C-5), 71.8 (C-4),
76.2 (C-3), 81.5 (C-2), 110.8 (Me2CO2), 172.9 (O–CO);
HRMS: calcd for C26H47O4N4 [MϩϪCH3] 479.3597,
found 479.3592 (3%).
(7S,8R,9R,9aR)Hexahydro-7,8,9-trihydroxy-2H-pyrido-
[1,2a]pyrazine-3,4(4H)-dione (10). Diamine 5 (69.4 mg,
0.43 mmol) was dissolved in MeOH (5 mL). (MeOCO)2
(144 mg, 1.3 mmol) was added and the mixture was heated
under reflux for 96 h. The mixture was evaporated and the
residue was subjected to column chromatography
(NH4OH–H2O–MeOH–CHCl3, 1:1:48:50) to provide,
after crystallisation from Et2O–MeOH, 45 mg (48%
yield) of compound 10 as a white solid: mp 367.2–
368.4ЊC; [a]2D0 ϩ0.89 (c 1.6, H2O); IR: nmax 3421,
;
1658 cmϪ1 1H NMR (400 MHz, D2O), d 2.95 (dd,
Jˆ12.5, 11 Hz, 1 H), 3.45–3.70 (m, 6 H), 4.80 (dd,
Jˆ12.5, 5 Hz, 1 H); 13C NMR (100 MHz, D2O), d(37.6
(C-1), 46.9 (C-6), 56.7 (C-9a), 68.1 (C-7), 70.4 (C-9),
77.2 (C-8); HRMS: calcd for C8H12O5N2 [Mϩ], 216.0746,
found 216.0747 (26%).
(7S,8R,9R,9aR)Hexahydro-7,8-O-isopropylidene-7,8,9-
trihydroxy-2H-pyrido[1,2a]pyrazin-3(4H)-one (36). To a
solution of azide 3 (219.6 mg, 0.96 mmol) in acetone
(5 mL) were added BrCH2CO2Me (0.26 mL, 2.89 mmol)
and K2CO3 (414 mg, 3 mmol). The mixture was heated
under reflux and the progress of the reaction was followed
1,5-Imino-6-octadecanamido-1,5,6-trideoxy-d-glucitol
hydrochloride (8). To a solution of amide 32 (100 mg,

1012
A. Kilonda et al. / Tetrahedron 56 (2000) 1005–1012
by TLC (hexanes–EtOAc, 7:3). After 24 h the solution was
evaporated, and the residue was distributed between water
and CH2Cl2. After further extraction with CH2Cl2, the
organic phases were combined, dried, and evaporated. The
residue consisting of crude compound 35 was treated over-
night with PPh3 (263 mg, 1 mmol) and water (0.2 mL) in
THF (5 mL). Following evaporation and column chromato-
graphy (CHCl3–MeOH, 17:3, Rf 0.35), compound 36
(245 mg) was isolated as a white solid in 66% overall
yield from azide 3: mp Ͼ400ЊC; [a]2D0 ϩ78.3 (c 0.10,
Acknowledgements
The authors are indebted to F.K.F.O. and the ‘Ministerie
voor Wetenschapsbeleid, I.U.A.P.’ for financial support
and to the K.U. Leuven (A.K.) for a fellowship. They
¨
wish to thank Dr H. Roper (Cerestar, Vilvoorde, Belgium)
for generous supplies of 1-amino-1-deoxy-d-glucitol, and
Mr R. De Boer for technical assistance.
1
H2O); IR: nmax 3408, 1712 cmϪ1; H NMR (250 MHz,
References
CD3OD–CDCl3), d 2.30 (m, 2 H), 3.07 (d, Jˆ17 Hz, 1
H), 3.20 (m, 2 H), 3.35–3.60 (m, 4 H), 3.64 (dd, Jˆ12,
4 Hz, 1 Hz, 1 H); 13C NMR (62.9 MHz, CD3OD–CDCl3),
d 26.9 (CH3), 27.1 (CH3), 45.6 (CH2), 56.2 (CH2), 57.5
(CH2), 62.1 (CH), 72.5 (CH), 74.5 (CH), 84.1 (CH), 112.1
(C), 170.5 (CO); HRMS calcd for C11H18O4N2 [Mϩ],
242.1266, found 242.1268 (32%).
1. Hughes, A. B.; Rudge, A. J. Nat. Prod. Rep. 1994, 11, 135.
2. Burgess, K.; Henderson, I. Tetrahedron 1992, 48, 4045.
3. Furneaux, R. H.; Mason, J. M.; Tyler, P. C. Tetrahedron Lett.
1994, 19, 3143; Lee, C.-K.; Sim, K. Y.; Zhu, J. Tetrahedron 1992,
48, 8541.
4. Lee, C.-K.; Jiang, H.; Linden, A.; Scofield, A. Carbohydr. Lett.
1996, 1, 417; Arnone, A.; Bravo, P.; Donadelli, A.; Resnati, G.
Tetrahedron 1996, 52, 131; Di, J.; Rajanikanth, B.; Szarek, W. A.
J. Chem. Soc., Perkin Trans. 1 1992, 2152.
5. Stoltefuss, J. Ger. Offen. DE 2,380,469, 1980 (Chem. Abstr.
1980, 93, 47104x); Kurihara, H.; Ishida, S.; Tsuruoka, T.;
Yamamoto, H.; Fukuyasu, H. Jpn. Kokai Tokkyo Koho JP
02,306,962 [90,306,963], 1990 (Chem. Abstr. 1991, 114,
185939b).
6. Delinck, D. L.; Margolin, A. L. Tetrahedron Lett. 1990, 31, 3093.
7. Kiso, M.; Kitagawa, M.; Ishida, H.; Hasegawa, A. J. Carbo-
hydr. Chem. 1991, 10, 25; Khanna, I. K.; Mueller, R. A.; Weier,
R. M.; Stealy, M. A. U.S. US5,216,168, 1993 (Chem. Abstr. 1993,
(7S,8R,9R,9aR)Hexahydro-7,8,9-trihydroxy-2H-pyrido-
[1,2a]pyrazin-3(4H)-one (11). Compound 36 (45 mg,
0.18 mmol) was treated with methanolic HCl (3 mL) for
1 h. After evaporation, the residue was purified by chroma-
tography on a column of silica gel (NH4OH–H2O–MeOH–
CHCl3, 1:1:48:50, Rf 0.41) to give 36 mg of compound 11
(94% yield) as a white solid: mp 296ЊC; [a]2D0 ϩ52.9 (c 0.17,
H2O); IR: nmax 3414, 1712 cmϪ1
;
1H NMR (400 MHz,
D2O), d 2.21 (t, Jˆ11 Hz, 1 H, H-6ax), 2.53 (td, Jˆ9.5,
5 Hz, 1 H, H-9a), 3.07 (dd, Jˆ11, 5 Hz, 1 H, H-6eq), 3.07
(d, Jˆ17 Hz, 1 H, H-4ax), 3.18 (dd, Jˆ13, 10 Hz, 1 H,
H-1ax), 3.24 (t, Jˆ9.3 Hz, 1 H, H-9), 3.39 (t, Jˆ9.3 Hz, 1
H, H-8), 3.47 (d, Jˆ17 Hz, 1 H, H-4eq), 3.60 (ddd, Jˆ11,
9.3, 5 Hz, 1 H, H-7), 3.66 (dd, Jˆ13, 4 Hz, 1 H, H-1eq); 13C
NMR (100 MHz, D2O), d 44.1 (C-1), 54.7 (C-4), 57.2 (C-6),
58.5 (C-9a), 68.2 (C-7), 73.0 (C-9), 76.8 (C-8), 170.1 (C-3);
HRMS: calcd for C8H14O4N2 [Mϩ], 202.0954, found
202.0959 (100%).
´
119, 250376k); Fitremann, J.; Dureault, A.; Depezay, J.-C.
Tetrahedron Lett. 1994, 35, 1201; Synlett 1995, 235.
8. Johns, B. A.; Pan, Y. T.; Elbei, A. D.; Johnson, C. R. J. Am.
Chem. Soc. 1997, 119, 4856; Asano, N.; Oseki, K.; Kaneko, E.;
Matsui, K. Carbohydr. Res. 1994, 258, 255.
9. Berges, D. A.; Ridges, M. D.; Dalley, N. K. J. Org. Chem. 1998,
63, 391; Berges, D. A.; Hong, L.; Dalley, N. K. Tetrahedron 1998,
54, 5097.
(7S,8R,9R,9aR)Octahydro-7,8,9-trihydroxy-2H-pyrido-
[1,2a]pyrazine dihydrochloride (12). LiAlH4 (71 mg,
1.85 mmol) was added to a solution of compound 36
(90 mg, 0.37 mmol) in THF (10 mL). The mixture was
heated under reflux for 2 h and evaporated. The residue
was applied on a column of silica gel using the solvent
system NH4OH–H2O–MeOH–CHCl3, 1:1:48:50, (Rf 0.27)
to give impure compound 37 (62 mg). Without further puri-
fication, the latter material was treated directly with
MeOH–HCl (3 mL) for 1 h. The solution was evaporated
and the residue was crystallised from Et2O–MeOH to afford
57.9 mg of pyrazine 12 (60% overall yield from 36): mp
10. Compernolle, F.; Gert. J.; Peeters, K.; Toppet, S.; Hoornaert,
G.; Kilonda, A.; Babady-Bila Tetrahedron 1997, 53, 12 739;
Kilonda, A.; Compernolle, F.; Toppet, S.; Hoornaert, G. Tetrahedron
Lett. 1994, 35, 9047; Kilonda, A.; Compernolle, F.; Hoornaert, G.
J. Org. Chem. 1995, 60, 5826; Kilonda, A.; Dequeker, E.;
Compernolle, F.; Delbeke, P.; Badady-Bila; Hoornaert, G. Tetrahedron
1995, 51, 849.
11. van den Broeck, L. A. G. M.; Vermaas, D. J.; van Kemenade,
F. J.; Tan, M. C. C. A.; Rotteveld, F. T. M.; Zandberg, P.; Butters,
T. D.; Mienda, F.; Ploegh, H. L.; van Boeckel, C. A. A. Recl. Chim.
Trav. Pays-Bas 1994, 113, 507.
12. Hudlicky, T.; Rouden, J.; Luna, H.; Allen, S. J. Am. Chem.
Soc. 1994, 116, 5099.
Ͼ400ЊC; [a]2D0 ϩ18.8 (c 0.19, H2O); IR: nmax 3410 cmϪ1
;
1H NMR (400 MHz, D2O), d 2.99 (t, Jˆ11 Hz, 1 H, H-6ax),
3.23 (dd, Jˆ14, 12 Hz, 1 H, H-4ax), 3.29 (m, 1 H, H-1ax),
3.35 (m, 1 H, H-9a), 3.40 (td, Jˆ14, 2 Hz, 1 H, H-3ax), 3.53
(m, 2 H, H-8, H-9), 3.55 (dd, Jˆ11, 5 Hz, 1 H, H-6eq), 3.76
(m, 2 H, H-1eq, H-3eq), 3.81 (m, 1 H, H-7), 3.98 (dbrt,
Jˆ14 Hz, v1/2ˆ2 Hz, 1 H, H-4eq); 13C NMR (100 MHz,
D2O), d(40.9 (C-3), 43.3 (C-4), 49.6 (C-1), 55.8 (C-6),
60.2 (C-9a), 66.2 (C-7), 69.5 (C-9), 75.7 (C-8); HRMS:
calcd for C8H16O3N2 [Mϩ], 188.1161, found 188.1157
(6%).
13. Kilonda, A.; Compernolle, F.; Hoornaert, G. J. Chem. Soc.,
Chem. Commun. 1994, 2147.
14. Lott, R.; Chauhan, V.; Stammer, C. J. Chem. Soc., Chem.
Commun. 1979, 495.
´
15. Knouzi, N.; Vaultier, M.; Carrie, R. Bull. Soc. Chim. Fr. 1985,
815.
16. See Ref. 10: Kilonda, A.; Compernolle, F.; Hoornaert, G.
J. Org. Chem. 1995, 60, 5826.
17. Kinast, G.; Schedel, M.; Koebernick, W. Eur. Pat. Appl. 1982,
EP 49 858; Chem. Abstr. 1982, 97, 182801v.