Bicyclic diazasugars. Part 3: β-D-Mannose and 6-deoxy-β-L-gulose analogues

Article abstract of DOI:10.1016/S0040-4020(01)01011-0

A bicyclic analogue of β-D-mannopyranose with nitrogen atoms replacing the ring and glycosidic oxygen atoms has been prepared in a single step from 5-O-mesyl-D-mannofuranose by a process that likely involves double displacement and an epoxide intermediate. A similar but protected bicyclic analogue of 6-deoxy-β-L-gulopyranose has been prepared by an electrophilic cyclization reaction.

Full text of DOI:10.1016/S0040-4020(01)01011-0

TETRAHEDRON
Pergamon
Tetrahedron 57 22001) 9915±9924
Bicyclic diazasugars. Part 3: b-d-Mannose
and 6-deoxy-b-l-gulose analogues
David A. Berges,p Jianmei Fan, Nannan Liu and N. Kent Dalley
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA
Received 8 August 2001; accepted 11 October 2001
AbstractÐA bicyclic analogue of b-d-mannopyranose with nitrogen atoms replacing the ring and glycosidic oxygen atoms has been
prepared in a single step from 5-O-mesyl-d-mannofuranose by a process that likely involves double displacement and an epoxide inter-
mediate. A similar but protected bicyclic analogue of 6-deoxy-b-l-gulopyranose has been prepared by an electrophilic cyclization reaction.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
`Azasugar' is a name that has been given to a class of sugar
analogues that contain a nitrogen atom in place of the
ring oxygen atom of sugars 2both pyranose and furanose
forms). These compounds have been of considerable
interest because many of them inhibit glycosidases,
enzymes that catalyze the hydrolysis of glycosidic bonds
in polysaccharides and glycoproteins. Some azasugars
have been shown to have therapeutic utility in the treatment
of diabetes and cancer, and other medical applications of
azasugars have been and are being investigated.1±3 The
azasugar research reported by this laboratory4±7 has
focused on the incorporation of a singly bonded glycosidic
heteroatom into analogues 21; XˆO, N, or S; nˆ0 or 1), a
feature found in only a few naturally occurring azasugars.
The previous synthetic azasugar analogues 1 reported by
this laboratory have all lacked the hydroxymethyl group
common to the hexopyranoses. Because a hydroxymethyl
grouphas been shown to be an important azasugar sub-
stituent for the inhibition of some glycosidases,12 incorpo-
ration of this groupinto azasugars with a glycosidic
heteroatom has been the object of the research reported
herein. These initial efforts have focused on d-mannose
analogues which might inhibit mannosidases and have
utility in cancer chemotherapy as does the a-mannosidase
inhibitor swainsonine. Attention has been directed toward
diazasugar analogue 4 since previous analogues with
oxygen or sulfur as the glycosidic heteroatom had poorer
inhibitory activity than their nitrogen atom counterparts.7
Based on observations with analogues reported earlier, it
was recognized that a diazasugar analogue may exist pre-
dominantly as the b-anomer which probably will make it
unsuitable as an a-mannosidase pseudosubstrate. Conse-
quently, a parallel effort at controlling the anomeric
preferences of azasugars is ongoing in this laboratory.
Examples include polyhydroxylated piperidines 2 such as
nojirimycin,8 mannonojirimycin,9 and galactostatin,10
which have a glycosidic hydroxyl groupand exist as
mixtures of anomers. Kifunensine 23) is a bicyclic azasugar
with a glycosidic nitrogen atom in the form of an amide.11
Azasugars with a glycosidic heteroatom have the potential
of acting as pseudosubstrates for glycosidases and be
converted by these enzymes into transition states and inter-
mediates resembling those of the normal reaction pathway
with sugar substrates. Consequently, these analogues may
be potent and selective glycosidase inhibitors.
Keywords: carbohydrate mimetics; aza compounds; enzyme inhibitors;
X-ray crystal structure.
p
Corresponding author. Tel.: 11-801-378-8933; fax: 11-801-378-5474;
e-mail: david_berges@byu.edu
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020201)01011-0

9916
D. A. Berges et al. / Tetrahedron 57 *2001) 9915±9924
Scheme 1.
Figure 1. X-Ray structure of 26R,7R,8S,9R,9aS)-octahydro-7-hydroxy-6-methyl-8,9-[21-methylethylidine)bis2oxy)]-2H-pyrido[1,2-a]pyrimidine 210).
Table 1. Crystal data and summary of X-ray experimental conditions
2. Results and discussion
Compound
10
The approaches that were considered for the synthesis of
diazamannose analogues are 2A) electrophilic addition to a
vinyl sugar aminal derivative and 2B) nucleophilic displace-
ment of a leaving groupfrom the 5-position of a sugar
aminal derivative 2Scheme 1). The ®rst approach had the
possible advantage of avoiding the use of protecting groups
and the potential drawback of leading to the wrong epimer
or a mixture of epimers at the 5-position. The second would
be expected to give stereoisomeric control at the 5-position
but undoubtedly would require selective activation through
use of protecting groups; without hydroxyl group protec-
tion, internal displacement might also occur to form
epoxides, which could be precursors to other unwanted
products. The route involving electrophilic addition was
chosen for initial exploration because it appeared to be
more direct.
Formula
Formula weight
F 2000)
C12H22N2O3
242.32
264
Crystal size 2mm3)
0.35£0.25£0.08
m 2mm21
)
0.090
Monoclinic
P21
Crystal system
Space group
Ê
a 2A)
7.179 23)
7.043 22)
13.104 25)
103.45 23)
644.4
Ê
b 2A)
Ê
c 2A)
b 28)
V 2A )
Ê 3
Z
2
1.249
D 2g/cm3)
2u range 28)
2.92±25.06
1236 2Rintˆ0.0415)
1236/0/154
R1ˆ0.0580, wR2ˆ0.1138
1.052
Independent data
Data/restraints/parameters
Final R indices [I.2s2I)]
Goodness of ®t on F2
Largest peak
0.219
20.192
Ê 23
The synthesis began with conversion of 2,3-O-isopropyl-
idene-a-d-mannofuranose 25)13 to dimesyl a-d-manno-
furanosyl chloride derivative 6 265%). Treatment of 6
with sodium iodide in re¯uxing 1,2-dimethoxyethane
effected elimination of both mesylate groups and aqueous
workupgave known vinyl sugar derivative 7 296%).14
Electrophilic cyclization was ®rst tried using this protected
Hole in difference map2eA
)
Tables containing the structure determination summary, atomic positional
and thermal parameters, bond lengths, and bond angles for these
compounds have been deposited in the Cambridge Crystallographic
Data Center. These data can be obtained from the Director, Cambridge
Crystallographic Center, University Chemical Laboratory, Lens®eld
Road, Cambridge, CB2 IEW, UK.

D. A. Berges et al. / Tetrahedron 57 *2001) 9915±9924
9917
compound. Treatment of 7 with 1,3-propanediamine gave
aminal 8 which, without puri®cation, was treated with
mercuric acetate to bring about cyclization to a single
mercury derivative 288%) that was determined to have the
structural skeleton shown for 9 based on the appearance in
its 13C NMR spectrum of a methylene signal at 28.8 ppm
2CH2Hg) and a methine signal at 59.3 ppm 2CHN) in place
of the vinyl carbons of 8. The stereochemistry of 9 could not
be determined at this point. However, reduction of the
organomercurial with sodium borohydride gave the corre-
sponding methyl derivative 10 278%) which was obtained in
crystalline form and subjected to X-ray crystallography
which showed the stereochemistry to be l-gulo as depicted
in structure 10 2Fig. 1 and Table 1). Since the reduction is a
free radical process,15 it is expected that 9 has the same
stereochemistry as 10. An attempt to remove the acetonide
protecting group from 10 using dilute hydrochloric acid in
tetrahydrofuran gave a material with no 13C NMR signals
characteristic of an azasugar; one or more pyridinium
compounds probably resulted by analogy with a similar
dehydration process that occurred when nojirimycin was
treated with acid.8 Compound 9 was converted into the
corresponding hydroxymethyl compound 11 260%) by free
radical trapping of dioxygen and reduction of the resulting
hydroperoxide.16 However, compound 11 was of limited
interest since the stereochemistry was anticipated to
also be l-gulo and deprotection of it was expected to be
problematic.
In order to avoid having to remove an acetonide protecting
groupand to hopefully obtain the desired d-manno stereo-
chemistry, the electrophilic cyclization method was applied
to unprotected vinyl sugar 12 that was obtained 298%) from
7 by treatment with a mixture of tri¯uoroacetic acid 2TFA)
and water. Compound 12 was converted to crystalline
aminal 13 247%) by treatment with 1,3-propanediamine.
Treatment of 13 with mercuric acetate unexpectedly gave
14, a mercury-containing amidino sugar instead of a diaza-
sugar. The stereochemistry of the CH2HgOAc groupwas
not de®nitively determined although 14 is thought to also
possess the l-gulo con®guration; the coupling between
protons at positions 6 and 7 is only 5.0 Hz and not near
9 Hz as expected for a compound with the d-manno con-
®guration whose favored conformation places these two
coupled protons in pseudoaxial orientations. Apparently,
the mercuric acetate effected a dehydrogenation of the
aminal functional group. Followup to this observation
has led to the preparation of a number of amidino sugars
from diazasugars, and these results will be reported
separately.

9918
D. A. Berges et al. / Tetrahedron 57 *2001) 9915±9924
In view of the unsuccessful attempts to obtain the
d-mannose diazasugar analogue using electrophilic
addition, the approach utilizing nucleophilic displacement
was investigated. A direct route to 4 beginning with readily
available 2,3-O-isopropylidene-l-gulono-1,4-lactone 215)17
was chosen. Tritylation of the primary hydroxyl group
followed by mesylation of the secondary alcohol gave
lactone 16 266%) which was then reduced with diisobutyl-
aluminum hydride to produce gulofuranose derivative 17
262%). Complete deprotection of 17 was effected by
cautious treatment with a TFA/water mixture to give
5-O-mesyl-l-gulose 18 278%). Treatment of 18 in aqueous
solution with 1 equiv. of 1,3-propanediamine added all at
once gave a mixture of two products which were dif®cult to
separate. Quantitative 13C NMR was used to distinguish the
peaks belonging to each product. Comparison of these 13C
chemical shift data with those for the analogue of 4 lacking
the hydroxymethyl group7 led to the conclusion that the
mixture contained target compound 4 along with an
unknown azasugar. It was considered likely that the other
azasugar arose via an epoxide intermediate formed by
base-catalyzed internal displacement of the mesylate by a
vicinal hydroxyl group.
Since the 6-hydroxy groupseemed more likely to have been
involved in epoxide formation, it was protected prior to the
cyclization reaction. l-Gulono-1,4-lactone derivative 1917
was reduced to the protected gulofuranose 2018 261%)
which was then converted to the methyl glycoside and
partially deprotected to give 21 258%).19,20 Selective
6-O-benzylation was effected 288%) by ®rst formation of
the dibutylstannylene derivative and then reaction of this
intermediate with benzyl bromide promoted by cesium
¯uoride. The product 2221 was converted to mesylate 23
240%) which was then deprotected to 6-O-benzyl-5-O-
mesyl-l-gulose 24 277%) with a TFA/water mixture. Treat-
ment of 24 with 1 equiv. of 1,3-propanediamine added all at
once gave a mixture of products. However, when only half
an equivalent of 1,3-propanediamine was added at ®rst
followed by a second half equivalent 30 min later, primarily
the desired benzyl derivative 25 271%) was obtained.
1
Vicinal H±1H coupling constants 2Table 2) corresponded

D. A. Berges et al. / Tetrahedron 57 *2001) 9915±9924
9919
4
with those of d-mannose in the C1 conformation. The
vicinal couplings in Table 2) established that in aqueous
solution the product was, within the limits of detection,
only the b-anomer 4b in the conformation depicted; it
follows, therefore, that 25 was also the b-anomer. It is likely
that the intermediate epoxide involved in the formation of
4b is compound 30 which should form more readily than the
more sterically encumbered 4,5-epoxide. When formation
of only the 4,5-epoxide was possible 2reaction of 24 with
the diamine), a more complex mixture of products was
formed suggesting that cyclization to a pyrrolidine type of
product was competitive with formation of 4b. With
epoxide 30, cyclization to a seven-membered ring product
would not be expected to be very competitive with
formation of 4b.
anomeric stereochemistry was not de®nitively deduced at
this point since J9,9a was 1.5 Hz which conceivably could
have ®t either anomer. Hydrogenolytic removal of the
benzyl groupgave 4 contaminated with by-products that
were dif®cult to remove.
The dif®culty of purifying 4 obtained from the ®rst two
displacement processes prompted the investigation of a
third route. Inasmuch as it was felt that formation of epoxide
intermediates was leading to mixtures of cyclization
products, it was decided to try to exploit epoxide formation
and use it in a double-displacement process to get the
d-manno con®guration from a d-manno precursor. If a
mannose derivative could be converted to an epoxide with
inversion at the 5-position, then attack at this position of the
epoxide would give back the d-manno con®guration. To this
end, methyl 2,3-O-isopropylidene-a-d-mannofuranoside
226)22 was selectively tritylated at the 6-position to give
2721 283%) which was then converted to mesylate 28
285%). Cautious deprotection of 28 gave 5-O-mesyl-d-
mannofuranose 229, 86%). One equivalent of 1,3-propane-
diamine added all at once to an aqueous solution of 29
In conclusion, a bicyclic diazasugar analogue of d-mannose
has been prepared, structurally characterized, and found to
be the b-anomer, 4b. It was formed both by direct displace-
ment using an l-gulose derivative and by way of an epoxide
intermediate from a d-mannose derivative. Diazasugar
analogues of l-gulose were formed by an electrophilic
addition process. A side reaction in a variation of the latter
process formed an amidinosugar, and this observation has
led to additional work on this class of compounds, which is
being reported separately. Inasmuch as the mannose ana-
logue prepared exists almost exclusively as the b-anomer
rather than the desired a-anomer, means to remotely control
anomeric preference are also being explored with hopes of
®nding a way to get predominantly an a-anomer.
1
produced 4 as the major product 232% puri®ed yield). H
NMR spectral data 2difference nOe data in Fig. 2 and 1H±1H
Table 2. Selected 1H±1H NMR coupling constants of compounds 4b and 25
in D2O
Compound
J 2Hz)
J6,7
J6,10a
J6,10b
J10a,10b
J7,8
J8,9
J9,9a
3. Experimental
3.1. General
4b
25
2.4
2.0
2.9
3.4
12.7
11.2
9.8
9.8
9.8
9.8
3.4
3.4
1.5
1.5
General methods and procedures are described in previous
publications from this laboratory.4±7 Unless indicated other-
wise, the following were used as NMR reference signals in
1
the solvents indicated: CDCl3, for H NMR either TMS or
residual CHCl3 2d 7.26) and for 13C NMR the center peak
of CDCl3 2d 77.23); CD3OD, for 1H NMR the center peak of
CHD2OD 2d 3.31) and for 13C NMR the center peak of
1
CD3OD 2d 49.15); CD3SOCD3, for H NMR the center
peak of CD3SOCHD2 2d 2.51). In instances where noted,
a small amount of NH4OH was added to an NMR sample to
effect a change in chemical shift allowing the multiplicity
and coupling of signals to be ascertained.
Figure 2. Difference nOe data used in determining the con®guration and
conformation of compound 4b: H4ax to H9a 23.8%); H6 to H4ax 23.6%), H6 to
H8 26.2%); H6 to H9a 26.2%).

9920
D. A. Berges et al. / Tetrahedron 57 *2001) 9915±9924
3.1.1.
[6R-.6a,7b,8a,9a,9ab)]Octahydro-6-hydroxy-
NH4OH, reference CH3CN d 1.39, HETCOR) d 75.6
2C-9a), 74.4 2C-8), 71.4 2C-9), 67.9 2C-7), 66.8 2C-6),
57.9 2C-10), 50.3 2C-4), 43.6 2C-2), 26.0 2C-3); HRMS
2CI): calcd for C9H18N2O4: 219.1345 2M11), found
219.1343.
methylpyrido[1,2-a]pyrimidine-7,8,9-triol .4b). From
18. A solution of 18 274 mg, 0.29 mmol) and 1,3-propane-
diamine 227.2 mL, 0.33 mmol) in H2O was stirred for 0.5 h
and then treated with Amberlite CG-400 anion exchange
resin 2hydroxide form). The solvent was evaporated to
give a gum 283 mg) whose 13C NMR spectrum showed
two compounds. 4: 13C NMR 2D2O, reference CH3CH2OH
d 17.31) d 75.6, 74.3, 71.4, 67.8, 66.9, 57.8, 50.3, 43.6,
25.9. Unknown: 13C NMR 2D2O, reference CH3CH2OH d
17.31) d 80.7, 73.4, 72.7, 70.9, 69.5, 64.1, 52.8, 44.4, 25.3;
HRMS 2CI): calcd for C9H18N2O4: 219.1345 2M11), found
219.1341.
3.1.2. 2,3-O-Isopropylidene-5,6-O-dimethanesulfonyl-a-
d-mannofuranosyl chloride .6). To a solution of 2,3-O-
isopropylidene-a-d-mannofuranose 25)13 22.7 g, 12 mmol)
in 100 mL of anhydrous pyridine in an ice bath was added
slowly methanesulfonyl chloride 24.8 mL, 61 mmol). The
solution was stirred for 4 h and then was concentrated.
Water was added followed by extraction with CHCl3 and
evaporation of the extract to give a gum 23.0 g, 65%).
Crystallization from EtOAc/hexane gave needles: mp
From 25. A solution of 25 2120 mg, 0.390 mmol) in 95%
EtOH containing Pd/C 2380 mg, 10 wt% Pd) was stirred for
12 h under an H2 atmosphere 260 psi). The catalyst was
removed by ®ltration, and the solvent was evaporated to
give a gum 280 mg) whose 13C NMR spectrum showed a
mixture including a component matching 4 from the
previous method of preparation; HRMS 2CI): calcd for
C9H18N2O4: 219.1345 2M11), found 219.1351.
1
123.5±124.58C; H NMR 2CDCl3, COSY) d 6.07 2s, 1H,
H-1), 5.13 2ddd, J4,5ˆ7.6 Hz, J5,6aˆ2.2 Hz, J5,6bˆ4.6 Hz,
1H, H-5), 4.99 2dd, J2,3ˆ5.9 Hz, 1H, H-2), 4.91 2dd, J3,4ˆ
3.7 Hz, 1H, H-3), 4.70 2dd, J6a,6bˆ12.0 Hz, 1H, H-6a), 4.52
2dd, 1H, H-4), 4.42 2dd, 1H, H-6b), 3.15, 3.09 22s, each 3H,
both OSO2CH3), 1.50, 1.34 22s, each 3H, acetonide CH3);
13C NMR 2CDCl3, DEPT, HETCOR) d 113.7 2acetonide C),
96.5 2C-1), 88.9 2C-2), 78.8 2C-4), 77.8 2C-3), 75.0 2C-5),
68.4 2C-6), 38.7, 37.5 2both OSO2CH3), 25.8, 24.7 2both
CH3); HRMS 2CI) calcd for C11H19O9ClS2 2M11)
395.0237, 397.0208, found 395.0248, 397.0202.
From 29. A solution of 28 21.3 g, 2.3 mmol) in TFA 29 mL)
and H2O 23.9 mL) was stirred for 12 h. Water 220 mL) was
added, and a white precipitate formed at once. The solid was
removed by ®ltration, and solution was evaporated under
vacuum. Then another 20 mL of H2O was added to the
residue and evaporated. The same procedure was repeated
two more times. The residue was dissolved in H2O
and treated with Amberlite CG-400 anion exchange resin
2hydroxide form) until the solution reached neutral pH.
Removal of the H2O under vacuum gave 5-O-methane-
sulfonyl-d-mannofuranose 229) as a gum which was a
mixture of anomers 2520 mg, 86.0%): major anomer 13C
NMR 2D2O, reference MeOH d 49.15) d 101.2, 80.4,
77.5, 76.8, 71.0, 60.7, 38.3; HRMS 2CI): calcd for
C7H14O8S: 163.0607 2M2CH3SO3), found 163.0610. A
solution of 29 2330 mg, 1.28 mmol) and 1,3-propane-
diamine 2107 mL) in H2O 22 mL) was stirred for 0.5 h and
then treated with Amberlite CG-400 anion exchange resin
2hydroxide form) to remove methanesulfonic acid. After
evaporation under vacuum, Et2O was added to an EtOH
solution of the residue, and a white solid precipitated that
was separated from the solvent by centrifugation. The solid
was dissolved in EtOH, and Et2O was added to produce a
solid again. The same procedure was repeated one more
time, and then the resulting solid was dissolved in H2O
3.1.3. 5,6-Dideoxy-2,3-O-isopropylidene-a-d-lyxo-hex-5-
enofuranose .7). A solution of 6 22.0 g, 5.3 mmol) and
NaI 26.0 g, 40 mmol) in 200 mL anhydrous 1,2-dimethoxy-
ethane was heated at re¯ux for 24 h. The solvent was evapo-
rated, and the residue was partitioned between CHCl3 and a
10% aqueous Na2S2O3 solution. The CHCl3 extract was
washed with water, dried, and evaporated to give the
product as a gum 20.95 g, 96%). Crystals were obtained
from ether/hexane: mp60 8C 2lit. 618C);14 1H NMR
2CDCl3) d 5.99 2ddd, J4,5ˆ7.3 Hz, J5,6aˆ17.7 Hz, J5,6b
ˆ
10.3 Hz, 1H, H-5), 5.41 2ddd, J4,6aˆ1.5 Hz, J6a,6bˆ1.5 Hz,
1H, H-6a), 5.41 2s, 1H, H-1), 5.34 2m, J4,6bˆ1.0 Hz, 1H, H-
6b), 4.73 2dd, J2,3ˆ5.9 Hz, J3,4ˆ3.4 Hz, 1H, H-3), 4.63 2d,
1H, H-2), 4.61 2m, 1H, H-4), 1.47, 1.32 22s, each 3H, CH3);
13C NMR 2CDCl3) d 132.4, 119.5, 112.9, 101.2, 85.9, 81.7,
81.6, 26.1, 24.9 21H NMR assignments were in accord with
those in the literature).
3.1.4. .6R,7R,8S,9R,9aS)-6-.Acetoxymercuriomethyl)-
octahydro-7-hydroxy-8,9-[.1-methylethylidene)bis.oxy)]-
2H-pyrido[1,2-a]pyrimidine .9). A solution of 7 20.64 g,
3.5 mmol) in 5 mL of 1,3-propanediamine was stirred under
nitrogen overnight. Excess diamine was removed under
high vacuum to give hexahydro-2-[[d-lyxo-3-hydroxy-1,2-
[21-methylethylidene)bis2oxy)]-4-pentenyl]]pyrimidine 28)
as a gum 20.84 g, 100%) which was used without puri®-
1
and lyophilized to give 4b 290 mg, 32%); H NMR 2D2O,
NH4OH, reference CH3CN d 1.94, COSY) d 3.84 2dd,
Jˆ2.4, 12.7 Hz, 1H, H-10a), 3.69 2dd, Jˆ2.9, 12.7 Hz,
1H, H-10b), 3.65 2dd, Jˆ1.5, 3.4 Hz, 1H, H-9), 3.52 2t,
Jˆ9.8 Hz, 1H, H-7), 3.47 2dd, Jˆ3.4, 9.8 Hz, 1H, H-8),
3.24 2bd, Jˆ11.7 Hz, 1H, H-4eq), 2.93 2d, Jˆ1.5 Hz, 1H,
H-9a), 2.91 2bd, Jˆ13.7 Hz, 1H, H-2eq), 2.46 2ddd, Jˆ6.3,
9.3, 13.7 Hz, 1H, H-2ax), 2.03 2ddd, Jˆ6.4, 9.0, 11.7 Hz,
1H, H-4ax), 1.82 2ddd, Jˆ2.4, 2.9 9.8 Hz, 1H, H-6), 1.51
2m, 2H, H-3); difference nOe: H6!H10a 22.2%), H6!H10b
22.1%), H6!H8 26.2%), H6!H9a 26.2%), H6!H4a 23.6%),
H4a!H4e 219.5%), H4a!H9a 23.8%), H4a!H2a 22.9%),
H4a!H6 24.9%), H4a!H3a 22.1%), H2a!H2e19a 230.3%),
H2a!H4a 21.5%), H2a!H3a 21.7%), H4e!H10a110b 25.8%),
H4e!H4a 220.6%), H4e!H3e 24.7%); 13C NMR 2D2O,
cation; 1H NMR 2CDCl3) d 6.06 2ddd, J3 ,4 ˆ4.9 Hz,
0
0
0
0
0
0
0
J4 ,5a ˆ17.1 Hz, J4 ,5b ˆ10.3 Hz, 1H, H-4 ), 5.40 2ddd,
0
0
0
0
0
J3 ,5a ˆ2.0 Hz, J5a ,5b ˆ2.0 Hz, 1H, H-5a ), 5.20 2ddd,
0
0
0
J3 ,5b ˆ2.0 Hz, 1H, H-5b ), 4.36 2m, 1H, H-4), 4.27 2dd,
0
0
0
0
0
J1 ,2 ˆ7.8 Hz, J2 ,3 ˆ1.5 Hz, 1H, H-2 ), 4.12 2dd, 1H,
H-10), 3.82 2d, J1 ,2ˆ2.9 Hz, 1H, H-2), 3.22 2m, 2H, H-4a),
0
2.78 2m, 2H, H-4b), 1.6±1.8 2m, 2H, H-5a and H-5b);
13C NMR 2CDCl3) d 139.1, 115.1, 108.6, 80.1, 80.0,
70.0, 69.5, 45.6, 44.6, 27.0, 26.4, 24.1; HRMS 2CI) calcd
for C12H22N2O3 2M11) 243.1709, found 243.1711. A

D. A. Berges et al. / Tetrahedron 57 *2001) 9915±9924
9921
suspension of 8 20.48 g, 1.9 mmol) and Hg2OAc)2 20.72 g,
2.3 mmol) in 50 mL of anhydrous CH3CN was stirred under
N2 overnight. A gray precipitate formed. The solution was
®ltered, and the ®ltrate was evaporated to give a yellow
3.1.7. 5,6-Dideoxy-d-lyxo-hex-5-enofuranose .12). After a
solution of 7 20.13 g, 0.70 mmol) in 5 mL of 6:4 CF3CO2H/
H2O was stirred for 1.5 h, it was diluted with water and
evaporated partially. This process of dilution and partial
evaporation was repeated several times to eventually give
a gum consisting of two anomers 20.10 g, 98%); 13C NMR
2D2O) d major: 133.2, 120.3, 101.2, 82.0, 78.1, 73.4; minor:
134.1, 119.9, 96.0, 82.2, 72.3, 72.0; HRMS 2CI) calcd for
C6H10O4 2M11) 147.0658, found 147.0666.
1
solid 20.87 g, 88%); H NMR 2CD3OD, COSY) d 4.41
2dd, J8,9ˆ5.4 Hz, J9,9aˆ6.8 Hz, 1H, H-9), 4.34 2dd, J7,8ˆ
2.4 Hz, 1H, H-8), 4.10 2d, 1H, H-9a), 3.83 2dd, J6,7ˆ
1.5 Hz, 1H, H-7), 3.56 2m, 1H, H-4a), 3.54 2m, 1H, H-2a),
3.24 2m, 1H, H-2b), 2.97 2dd, J6,10aˆ5.4 Hz, J6,10b,1 Hz,
1H, H-6), 2.23 2m, 1H, H-4b), 2.15 2dd, J10a,10bˆ12.5 Hz,
1H, H-10a), 2.15 2m, 1H, H-3a), 2.03 2m, 1H, H-3b), 1.93 2s,
3H, acetate CH3), 1.71 2br d, 1H, H-10b), 1.54, 1.39 22s,
each 3H, CH3); 13C NMR 2CD3OD, DEPT, HETCOR) d
178.3 2CvO), 112.0 2acetonide C), 82.9 2C-9a), 77.3
2C-8), 75.8 2C-9), 69.5 2C-7), 59.3 2C-6), 50.9 2C-4), 49.0
2C-2), 28.8 2C-10), 28.2 2C-3), 27.3, 26.6 2both acetonide
CH3), 23.1 2acetate CH3); HRMS 2FAB) calcd for dialkyl-
mercury form C24H42200HgN4O6 2M21) 681.2709, found
681.2717.
3.1.8. Hexahydro-2-.d-lyxo-1,2,3-trihydroxy-4-pentenyl)-
pyrimidine .13). A solution of 12 20.10 g, 0.71 mmol) in
3 mL of 1,3-propanediamine was stirred under N2 over-
night. Excess diamine was removed under high vacuum to
give the product as a gum. Crystallization from Et21O/
CH2Cl2 gave needles 20.066 g, 47%): mp108±109 8C; H
0
0
0
0
0
0
NMR 2DMSO-d6) d 5.91 2ddd, J3 ,4 ˆ5.4 Hz, J4 ,5a
ˆ
ˆ
ˆ
ˆ
0
0
0
0
16.1 Hz, J4 ,5b ˆ10.7 Hz, 1H, H-4 ), 5.17 2ddd, J3 ,5a
0
0
0
0
2.0 Hz, J5a ,5b ˆ2.0 Hz, 1H, H-5a ), 5.21 2ddd, J3 ,5b
2.0 Hz, 1H, H-5b0), 4.10 2m, 1H, H-30), 3.50 2d, J1 ,2
0
0
0
0
0
3.1.5. .6R,7R,8S,9R,9aS)-Octahydro-7-hydroxy-6-methyl-
8,9-[.1-methyl-ethylidine)bis.oxy)]-2H-pyrido[1,2-a]-
pyrimidine .10). To 9 278 mg, 0.16 mmol) in 10 mL of
THF was added 1 mL of a 0.5 M NaBH4 solution in 3.0 M
NaOH. The mixture was stirred for 15 min and centrifuged
to separate the two layers. After saturation with NaCl, the
aqueous layer was extracted with THF. The THF extract
was dried and evaporated to give a gum 230 mg, 78%).
Crystallization from ether gave needles: mp140±141 8C;
1H NMR 2CDCl3, COSY) d 4.27 2dd, J7,8ˆ2.9 Hz, 1H,
H-8), 3.75 2dd, J8,9ˆ5.4 Hz, 1H, H-9), 3.71 2dd, J6,7ˆ
1.5 Hz, 1H, H-7), 3.12 2m, J3ax,4eqˆ3.0 Hz, J3eq,4eqˆ3.0 Hz,
J4ax,4eqˆ11.2 Hz, 1H, H-4eq), 3.06 2m, J2ax,2eqˆ12.7 Hz,
J2eq,3axˆ2.0 Hz, J2eq,3eqˆ2.0 Hz, 1H, H-2eq), 2.93 2d,
J9,9aˆ7.8 Hz, 1H, H-9a), 2.61 2m, J6,10ˆ6.8 Hz, 1H, H-6),
2.60 2m, J2ax,3axˆ12.7 Hz, J2ax,3eqˆ3.9 Hz, 1H, H-2ax), 2.03
2m, J3ax,4axˆ11.2 Hz, J3eq,4axˆ4.4 Hz, 1H, H-4ax), 1.63 2m,
2H, H-3a and H-3b), 1.53, 1.36, 22s, each 3H, CH3), 1.17 2d,
3H, H-10); 13C NMR 2CDCl3) d 109.7, 79.8, 77.3, 76.4,
70.0, 55.3, 49.8, 44.6, 27.9, 27.1, 26.2, 15.4; HRMS
2FAB) calcd for C12H22N2O3 2M11) 243.1708, found
243.1701. X-ray crystallography con®rmed the structure.
3.9 Hz, 1H, H-2), 3.38 2dd, J1 ,2 ˆ7.8 Hz, J2 ,3 ˆ2.0 Hz,
1H, H-20), 3.36 2dd, 1H, H-10), 3.02 2m, J4ax,4eqˆ12.7 Hz,
J4eq,5axˆ2.0 Hz, J4eq,5eqˆ2.0 Hz, 2H, H-4eq and H-6eq),
2.65 2m, J4ax,5axˆ12.7 Hz, J4ax,5eqˆ3.4 Hz, 2H, H-4ax and
H-6ax), 1.38 2m, J5ax,5eqˆ12.2 Hz, 1H, H-5ax), 1.29 2m, 1H,
H-5eq); 13C NMR 2DMF-d7, reference center peak at d
163.15) d 141.5, 114.4, 76.1, 74.3, 72.9, 72.6, 45.9, 45.8,
27.7; HRMS 2CI) calcd for C9H18N2O3 2M11) 203.1396,
found 203.1403.
3.1.9. .6R,7R,8S,9R)-6-.Acetoxymercuriomethyl)-3,4,6,
7,8,9-hexahydro-7,8,9-trihydroxy-2H-pyrido[1,2-a]-
pyrimidine .14). A suspension of 13 242 mg, 0.21 mmol)
and Hg2OAc)2 266 mg, 0.21 mmol) in 20 mL of anhydrous
DMF was stirred under N2 overnight. The solution was
1
®ltered and evaporated to give a gum; H NMR 2D2O,
COSY) d 4.87 2d, J8,9ˆ3.2 Hz, 1H, H-9), 4.30 2dd,
J7,8ˆ5.0 Hz, 1H, H-8), 4.24 2dd, J6,7ˆ4.1 Hz, 1H, H-7),
4.19 2ddd, J6,10aˆ8.7 Hz, J6,10bˆ3.7 Hz, 1H, H-6), 3.78 2m,
J3ax,4axˆ9.2 Hz, J3eq,4axˆ4.1 Hz, J4ax,4eqˆ13.3 Hz, 1H, H-
4ax), 3.60 2m, J2ax,2eqˆ13.3 Hz, J2eq,3axˆ5.0 Hz, J2eq,3eq
5.0 Hz, 1H, H-2eq), 3.51 2m, J3eq,4axˆ4.6 Hz, J3eq,4eq
4.6 Hz, 1H, H-4eq), 2.15 2m, J2ax,3axˆ8.7 Hz, J2ax,3eq
ˆ
ˆ
ˆ
3.1.6. .6R,7R,8S,9R,9aS)-Octahydro-7-hydroxy-6-hydroxy-
methyl-8,9-[.1-methylethylidene)bis.oxy)]-2H-pyrido-
[1,2-a]pyrimidine .11). Through a solution of NaBH4
276 mg, 0.20 mmol) in 4 mL of DMF in a 25 mL 2-neck
round-bottom ¯ask capped with a rubber stopper containing
a small syringe needle as a vent and a 25 mL additional
funnel was bubbled oxygen gas for 20 min. A solution of
9 261 mg, 0.13 mmol) in 4 mL of DMF was also saturated
with oxygen and then was added dropwise via the addition
funnel over a 2 h period to the NaBH4 solution. After
complete addition, a vigorous ¯ow of oxygen was main-
tained for 2 h. A gray precipitate formed. The solution
was ®ltered, and the ®ltrate was concentrated to a gum
which was chromatographed on silica gel using a step
gradient of 10±50% CH3OH in CH2Cl2 containing 1%
NH4OH to give the product as a gum 220 mg, 60%) that
still contained minor impurities; 13C NMR 2CD3OD) d
111.1, 86.3, 78.0, 75.6, 70.3, 70.2, 63.9, 59.0, 43.7, 28.3,
26.5, 21.8; HRMS 2FAB) calcd for C12H22N2O4 2M11)
259.1658, found 259.1662.
4.6 Hz, 1H, H-2ax), 2.28 2dd, J10a,10bˆ12.4 Hz, 1H,
H-10a), 2.22 2m, 1H, H-3e), 2.19 2m, 1H, H-10b), 2.09
2m, 1H, H-3a), 2.09 2s, 3H, acetate CH3); 13C NMR 2D2O,
reference DMF d 163.17, DEPT, HETCOR) d 178.0, 159.3,
67.8, 66.5, 62.5, 57.8, 42.6, 36.4, 20.7, 19.1, 16.5.
3.1.10. 2,3-O-Isopropylidene-5-O-methanesulfonyl-6-O-
triphenylmethyl-l-gulono-1,4-lactone .16). A solution of
2,3-O-isopropylidene-l-gulono-1,4-lactone 215)17 23.80 g,
17.4 mmol) and triphenylmethyl chloride 27.3 g, 26 mmol)
in pyridine 240 mL) was stirred for 12 h. A 13C NMR spec-
trum con®rmed the presence of 2,3-O-isopropylidene-6-O-
triphenylmethyl-l-gulono-1,4-lactone, and no starting
material was left. The product was used directly without
puri®cation. 13C NMR 2CDCl3) d 173.9, 143.7, 128.7,
128.1, 127.4, 114.2, 86.9, 80.1, 76.4, 76.2, 70.2, 63.7,
26.7, 25.7. To the solution of 2,3-O-isopropylidene-6-O-
triphenylmethyl-l-gulono-1,4-lactone in pyridine was
added methanesulfonyl chloride 25.40 mL, 115 mmol).
The reaction was followed by TLC 2CH2Cl2). After stirring

9922
D. A. Berges et al. / Tetrahedron 57 *2001) 9915±9924
4 h at 608C, the pyridine was removed under vacuum, and
the residue was puri®ed by chromatography on silica gel.
Elution with CH2Cl2 gave 16 which was crystallized from
CH2Cl2 and MeOH 26.2 g, 66%, yield based on two steps):
mp125±126 8C; 1H NMR 2CDCl3, COSY) d 7.47 2d,
Jˆ7.3 Hz, 6H, H-20 and 60, phenyl ring), 7.33 2t, Jˆ
7.3 Hz, 6H, H-30 and 50), 7.26 2t, Jˆ7.3 Hz, 3H, H-40),
4.98 2dd, Jˆ3.2, 8.8 Hz, 1H, H-4), 4.88 2dt, Jˆ2.4,
8.8 Hz, 1H, H-5), 4.77 2d, Jˆ4.9 Hz, 1H, H-2), 4.35 2dd,
Jˆ3.2, 4.9 Hz, 1H, H-3), 3.84 2dd, Jˆ2.4, 11.2 Hz, 1H,
H-6a), 3.29 2dd, Jˆ2.4, 11.2 Hz, 1H, H-6b), 3.15 2s, 3H,
CH3SO2), 1.35 2s, 3H, CH3), 1.12 2s, 3H, CH3); 13C NMR
2CDCl3, HETCOR) d 172.9 2C-1), 143.1 2C-10), 128.6 2C-30
or C-20), 128.3 2C-20 or C-30), 127.6 2C-40), 114.6
[C2CH3)2], 87.1 2CPh3), 81.1 2C-5), 77.7 2C-4), 76.2 2C-2),
75.3 2C-3) 63.4 2C-6), 39.0 2CH3SO2), 26.9 2CH3), 25.8
2CH3). Anal. calcd for C29H30O8S: C, 64.67; H 5.61.
Found: C, 64.56; H, 5.70.
To a solution of 2,3:5,6-di-O-isopropylidene-l-gulono-
lactone 219)17 25.00 g, 19.4 mmol) in CH2Cl2 210 mL) at
2788C was added dropwise DIBAH 21.0 M in THF,
50 mL). The reaction was followed by TLC 2CH2Cl2).
After stirring at 2788C for 4 h, the reaction was allowed
to warm to room temperature, and H2O was added. After
stirring overnight, the solvent was evaporated under
vacuum, and a white precipitate formed. The solid was
extracted with CH2Cl2 23£50 mL), and the solvent was
evaporated to give 20 as a single anomer 23.08 g, 61.0%);
13C NMR 2CDCl3) d 113.0, 109.9, 101.5, 85.8, 82.3, 80.0,
75.7, 66.1, 26.8, 26.1, 25.6, 24.8 2matched literature
values).18
3.1.14. Methyl 2,3-O-isopropylidene-b-l-gulofuranoside
.21). A mixture of acetone 258 mL), MeOH 258 mL), 2,2-
dimethoxypropane 263 mL), concentrated HCl 20.86 mL),
and 20 23.08 g, 11.8 mmol) was heated at 708C for 3 h.
Water 2120 mL) was added, the solution was concentrated
to 100 mL, and then MeOH 285 mL) and concentrated HCl
22 mL) were added. After stirring for another 6 h, the reac-
tion was stopped by adding saturated NaHCO3 solution until
the pH was 7±8. The solution was concentrated to 10 mL
and extracted with CH2Cl2 23£30 mL). After drying
2MgSO4), the CH2Cl2 solution was evaporated to give
2119,20 as a slightly yellow oil 21.6 g, 58%); 13C NMR
2CDCl3) d 112.6, 106.8, 85.2, 79.8, 79.7, 71.1, 63.2, 54.5,
25.8, 24.4; HRMS 2CI): calcd for C10H18O6: 234.1103 2M),
found 234.1094.
3.1.11. 2,3-O-Isopropylidene-5-O-methanesulfonyl-6-O-
triphenylmethyl-l-gulofuranose .17). To a solution of 16
2760 mg, 1.41 mmol) in CH2Cl2 210 mL) at 2788C was
added diisobutylaluminum hydride 21.0 M in THF,
1.92 mL). The reaction was followed by TLC 2CH2Cl2).
After stirring at 2788C for 1 h, the reaction was allowed
to warm to room temperature, and H2O was added. After
stirring overnight, the solvent was removed under vacuum.
The residue was extracted with CH2Cl2 23£30 mL).
Evaporation of the solvent gave 17 which crystallized
from CH2Cl2 and MeOH 2470 mg, 62%): mp152.5±
1
153.58C; H NMR 2CDCl3, COSY) d 7.47 2d, Jˆ7.8 Hz,
3.1.15. Methyl 6-O-benzyl-2,3-O-isopropylidene-b-l-
gulofuranoside .22). A solution of 21 21.60 g, 6.84 mmol)
and dibutyltin oxide 21.70 g, 6.82 mmol) in anhydrous
benzene 2250 mL) was heated at re¯ux for 15 h in a soxhlet
6H, H-20 and 60, phenyl ring), 7.31 2t, Jˆ7.8 Hz, 6H, H-30
and 50), 7.24 2t, Jˆ7.8 Hz, 3H, H-40), 5.39 2d, Jˆ2.4 Hz, 1H,
H-1), 4.93 2ddd, Jˆ2.4, 3.4, 8.8 Hz, 1H, H-5), 4.58 2dd,
Jˆ3.4, 8.8 Hz, 1H, H-4), 4.54 2d, Jˆ5.9 Hz, 1H, H-2),
4.40 2dd, Jˆ3.4, 5.9 Hz, 1H, H-3), 3.71 2dd, Jˆ2.4,
10.7 Hz, 1H, H-6a), 3.30 2dd, Jˆ3.4, 10.7 Hz, 1H, H-6b),
3.07 2s, 3H, CH3SO2), 2.72 2d, Jˆ2.4 Hz, 1H, OH), 1.35 2s,
3H, CH3), 1.12 2s, 3H, CH3); 13C NMR 2CDCl3, HETCOR)
d 143.5 2C-10), 128.8 2C-30 or C-20), 128.2 2C-20 or C-30),
127.4 2C-40), 112.8 [C2CH3)2], 101.4 2C-1), 87.1 2CPh3),
85.9 2C-2), 82.0 2C-5), 79.5 2C-4), 79.1 2C-3) 63.5 2C-6),
38.8 2CH3SO2), 26.2 2CH3), 24.6 2CH3). Anal. calcd for
C29H32O8S: C, 64.43; H, 5.97. Found: C, 64.50; H, 5.98.
Ê
apparatus containing 4 A molecular sieves. The solvent was
evaporated under vacuum leaving a white solid 23.1 g). A
solution of the solid 22.60 g, 5.59 mmol), benzyl bromide
21.30 mL, 10.9 mmol), and CsF 23.0 g, 20 mmol) in DMF
260 mL) was stirred at 1208C for 12 h. The reaction was
followed by TLC 23% MeOH in CH2Cl2). The DMF was
evaporated under vacuum, and the residue was puri®ed by
chromatography on silica gel. Elution with a gradient of 1:1
hexanes and CH2Cl2 to only CH2Cl2 followed by 3% MeOH
in CH2Cl2 gave 22 as a yellow oil 21.6 g, 88% for 2 steps);
13C NMR 2CDCl3) d 138.3, 128.6, 128.0, 128.0, 112.9,
107.0, 85.6, 80.6, 79.2, 73.7, 71.0, 69.9, 54.8, 26.2, 24.7
2matched literature values);21 HRMS 2CI): calcd for
C17H24O6: 324.1573 2M), found 324.1581.
3.1.12. 5-O-Methanesulfonyl-l-gulofuranose .18).
A
solution of 17 21.2 g, 2.2 mmol) in TFA 29 mL) and H2O
23.9 mL) was stirred for 3 h. Water 220 mL) was added, and
a white precipitate formed at once. The solid was removed
by ®ltration, and solution was evaporated under vacuum.
Water 220 mL) was added and evaporated. The same pro-
cedure was repeated two more times. The residue was
dissolved in H2O and treated with Amberlite CG-400
anion exchange resin 2hydroxide form) until the solution
reached neutral pH. Removal of the H2O under vacuum
gave 18 as a gum 2450 mg, 78%) which consisted primarily
of one anomer and was used without puri®cation in a reac-
tion with 1,3-propanediamine; 13C NMR 2D2O, reference
CH3COOH d 21.03) d 101.1, 84.6, 78.3, 78.0, 71.6, 61.0,
38.7; HRMS 2CI): calcd for C7H14O8S: 163.0603
2M2CH3SO3), found 163.0611.
3.1.16. Methyl 6-O-benzyl-2,3-O-isopropylidene-5-O-
methanesulfonyl-b-l-gulofuranoside .23). A solution of
22 21.60 g, 4.94 mmol) and methanesulfonyl chloride
21.50 mL, 19.3 mmol) in pyridine was stirred at 508C for
4 h. The reaction was followed by TLC 2CH2Cl2). The pyri-
dine was evaporated under vacuum, and the residue was
puri®ed by chromatography on silica gel. Elution with
20% EtOAc in hexanes ®rst and then CH2Cl2 gave 23 as
1
an oil 2803 mg, 40.0%); H NMR 2CDCl3, COSY) d 7.34
2m, 5H, Ph), 4.96 2ddd, Jˆ2.2, 3.7, 9.0 Hz, 1H, H-5), 4.91
2s, 1H, H-1), 4.73 2d, Jˆ11.8 Hz, 1H, OCH2Ph), 4.61 2dd,
Jˆ3.4, 5.7 Hz, 1H, H-3), 4.55 2d, Jˆ5.7 Hz, 1H, H-2), 4.52
2d, Jˆ11.8 Hz, 1H, OCH2Ph), 4.27 2dd, Jˆ3.4, 9.0 Hz, 1H,
H-4), 3.93 2dd, Jˆ3.7, 11.8 Hz, 1H, H-6a), 3.85 2dd, Jˆ2.2,
3.1.13. 2,3:5,6-Di-O-isopropylidene-l-gulofuranose .20).

D. A. Berges et al. / Tetrahedron 57 *2001) 9915±9924
9923
11.8 Hz, 1H, H-6b), 3.30 2s, 3H, OCH3), 3.11 2s, 3H,
CH3SO2), 1.43 2s, 3H, CH3), 1.24 2s, 3H, CH3); 13C NMR
2CDCl3, HETCOR) d 137.7 2Ph), 128.6 2Ph), 128.1 2Ph),
113.0 [C2CH3)2], 107.2 2C-1), 85.4 2C-2), 82.0 2C-5), 79.4
2C-3), 78.5 2C-4), 73.8 2OCH2Ph), 69.7 2C-6), 54.8 2CH3),
38.6 2CH3SO2), 26.3 2CH3), 24.9 2CH3); HRMS 2CI): calcd
for C18H26O8S: 402.1349 2M), found 402.1339.
9.8 Hz, 1H, H-6a), 3.32 2dd, Jˆ4.8, 9.8 Hz, 1H, H-6b), 3.26
2s, OCH3), 2.97 2d, Jˆ6.8 Hz, 1H, OH), 1.46 2s, CH3), 1.32
2CH3); 13C NMR 2CDCl3, HETCOR) d 144.1 2Ph), 128.9
2Ph), 128.0 2Ph), 127.3 2Ph), 112.7 2C2CH3)2), 107.3 2C-1),
86.8 2CPh3), 85.1 2C-2), 80.6 2C-3), 79.1 2C-4), 69.5 2C-5),
65.3 2C-6), 54.7 2CH3), 26.1 2CH3), 24.8 2CH3); HRMS 2CI):
calcd for C29H32O6: 476.2198 2M), found 476.2206.
3.1.17.
octahydropyrido[1,2-a]pyrimidine-7,8,9-triol .25).
[6R-.6a,7b,8a,9a,9ab)]-6-.Benzyloxymethyl)-
A
3.1.19. Methyl 2,3-O-isopropylidene-5-O-methanesul-
fonyl-6-O-triphenylmethyl-a-d-mannofuranoside .28).
A solution of 27 27.8 g, 16 mmol) and methanesulfonyl
chloride 23.6 mL, 47 mmol) in pyridine 260 mL) was stirred
at 608C for 1.5 h and at rt overnight. The reaction was
followed by TLC 2CH2Cl2). The pyridine was evaporated
solution of 23 2100 mg, 0.249 mmol) in TFA 22 mL) and
H2O 20.5 mL) was stirred for 5 h. Water 22 mL) was added,
and the solvent was removed under vacuum. Then another
2 mL of H2O was added and evaporated. The same pro-
cedure was repeated two more times. Removal of the H2O
under vacuum gave 6-O-benzyl-5-O-methanesulfonyl-l-
gulofuranose 224) as a gum 267 mg, 77%) which was a
mixture of anomers: major anomer 13C NMR 2D2O,
reference CH3CN d 1.39) d 136.4, 128.3, 128.2, 128.0,
100.1, 81.7, 77.1, 77.0, 72.7, 70.5, 67.6, 37.7. A solution
of 24 267 mg, 0.19 mmol) and 1,3-propanediamine 28.0 mL,
0.096 mmol) in H2O 22 mL) was stirred for 0.5 h, and then
additional 1,3-propanediamine 28.0 mL, 0.096 mmol) in
MeOH 210 mL) was added. After stirring overnight, the
solution was treated with Amberlite CG-400 anion
exchange resin 2hydroxide form) to remove methanesul-
fonic acid. The solvent was evaporated to give a gum,
which was dissolved in EtOH. Ether was added to the
EtOH solution, and a slightly yellow syrup precipitated.
The syrupwas separated from the solvent by centrifugation.
The syrupwas dissolved in EtOH, and ether was added to
form the syrup again. The same procedure was repeated one
more time to give 25 242 mg, 71%); 1H NMR 2D2O,
NH4OH, reference CH3CN d 1.94, COSY) d 7.31 2m, 5H,
Ph), 4.45 2d, Jˆ11.7 Hz, 1H, CH2Ph), 4.38 2d, Jˆ11.7 Hz,
1H, CH2Ph), 3.75 2dd, Jˆ2.0, 11.2 Hz, 1H, H-10a), 3.64
2dd, Jˆ1.5, 3.4 Hz, 1H, H-9), 3.58 2dd, Jˆ3.4 11.2 Hz,
1H, H-10b), 3.47 2t, Jˆ9.8 Hz, 1H, H-7), 3.35 2dd, Jˆ3.4,
9.8 Hz, 1H, H-8), 3.10 2bd, Jˆ11.7 Hz, 1H, H-4eq), 2.89
2bd, Jˆ13.7 Hz, 1H, H-2eq), 2.88 2d, Jˆ1.5 Hz, 1H, H-9a),
2.44 2ddd, Jˆ6.8, 9.3, 13.7 Hz, 1H, H-2ax), 1.98 2ddd,
Jˆ6.4, 9.2, 11.7 Hz, 1H, H-4ax), 1.92 2ddd, Jˆ2.0, 3.4,
9.8 Hz, 1H, H-6), 1.46 2m, 2H, H-3); 13C NMR 2D2O,
NH4OH, reference CH3CN d 1.39, HETCOR) d 137.9
2Ph), 129.2 2Ph), 128.8 2Ph), 75.5 2C-9a), 74.4 2C-8), 73.3
2OCH2Ph), 71.4 2C-9), 68.2 2C-7), 67.2 2C-10), 65.7 2C-6),
50.5 2C-4), 43.5 2C-2), 26.0 2C-3); HRMS 2CI): calcd for
C16H24N2O4: 309.1814 2M11), found 309.1819.
under vacuum, and the residue was taken upin CH Cl2
2
2150 mL) and H2O 260 mL). The H2O layer was extracted
three times with CH2Cl2, and the combined organic phase
was washed with H2O and dried 2MgSO4). After ®ltration, a
dark solution was obtained. It was decolorized by treatment
with activated carbon to a light yellow solution, which was
evaporated to give a light yellow syrup. Crystallization of
the syrupfrom 30% EtOAc in hexane gave colorless crystals
of 28 27.7 g, 85%): mp115±116 8C; 1H NMR 2CDCl3,
COSY) d 7.48 2d, Jˆ8.3 Hz, 2H, Ph), 7.30 2t, Jˆ7.8,
8.3 Hz, 2H, Ph), 7.23 2t, Jˆ7.8 Hz, 1H, Ph), 4.97 2brd,
Jˆ8.3 Hz, 1H, H-5), 4.80 2s, 1H, H-1), 4.79 2dd, Jˆ3.4,
5.9 Hz, 1H, H-3), 4.58 2d, Jˆ5.9 Hz, 1H, H-2), 4.48 2dd,
Jˆ3.4, 8.3 Hz, 1H, H-4), 3.73 2d, Jˆ11.0 Hz, 1H, H-6a),
3.33 2dd, Jˆ3.4, 11.0 Hz, 1H, H-6b), 3.21 2s, OCH3), 3.05
2s, CH3SO3), 1.34 2s, CH3), 1.29 2CH3); 13C NMR 2CDCl3,
HETCOR) d 143.8 2Ph), 128.9 2Ph), 128.1 2Ph), 127.3 2Ph),
113.0 2C2CH3)2), 107.2 2C-1), 86.7 2CPh3), 85.1 2C-2), 79.3
2C-5), 79.3 2C-3), 76.9 2C-4), 63.4 2C-6), 54.9 2CH3O), 38.8
2CH3SO3), 26.2 2CH3), 25.1 2CH3). Anal. calcd for
C30H34O8S: C, 64.96; H, 6.18. Found: C, 65.12; H, 6.30.
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