Synthesis of azasugars via lanthanide-promoted aza Diels-Alder reactions in aqueous solution

Article abstract of DOI:10.1021/jo962074s

Aqueous aza Diels-Alder reactions of chiral aldehydes, prepared from carbohydrates, with benzylamine hydrochloride and cyclopentadiene, were promoted by lanthanide triflates. The exo/endo selectivities and diastereoselectivities of the reactions were elucidated by NMR, CD spectroscopy, and X-ray crystallography. The nitrogen-containing heterocyclic products were further transformed to azasugars, which are potential inhibitors against glycoprocessing enzymes.

Full text of DOI:10.1021/jo962074s

J . Org. Chem. 1997, 62, 903-907
903
Syn th esis of Aza su ga r s via La n th a n id e-P r om oted Aza Diels-Ald er
Rea ction s in Aqu eou s Solu tion
Libing Yu, J un Li, J ohnny Ramirez, Depu Chen, and Peng George Wang*
Department of Chemistry, University of Miami, P.O. Box 249118, Coral Gables, Florida 33124
Received November 5, 1996X
Aqueous aza Diels-Alder reactions of chiral aldehydes, prepared from carbohydrates, with
benzylamine hydrochloride and cyclopentadiene, were promoted by lanthanide triflates. The exo/
endo selectivities and diastereoselectivities of the reactions were elucidated by NMR, CD
spectroscopy, and X-ray crystallography. The nitrogen-containing heterocyclic products were further
transformed to azasugars, which are potential inhibitors against glycoprocessing enzymes.
Sch em e 1
In tr od u ction
The aqueous aza Diels-Alder (DA) reaction combines
three components (an aldehyde, an amine salt, and a
diene) to produce heterocyclic products which are useful
synthetic intermediates.1 Although chiral amines such
as amino acids have been used as the amine part to
prepare optically pure heterocyclic compounds, the reac-
tions were largely limited to formaldehyde and activated
aldehydes such as glyoxylate.2 Recently, we found3 that
lanthanide triflates can promote the aqueous aza Diels-
Alder reaction (Scheme 1), and this has allowed us to
employ larger inactivated aldehydes to prepare hetero-
cyclic compounds efficiently. Since reactions in aqueous
media allow the use of unprotected carbohydrates or their
derivatives as one of the components, application of the
lanthanide-promoted aqueous aza DA reaction in carbo-
hydrate chemistry promises to provide a novel entry to
numerous carbohydrate-derived nitrogen-containing het-
erocycles (Scheme 1). Currently, we are especially
interested in utilizing this methodology to synthesize
azasugars and their analogs, which are potential inhibi-
tors against glycoprocessing enzymes.4 Here, we describe
lanthanide-promoted reactions of two chiral aldehydes,
prepared from D-mannitol and D-glucosamine, with ben-
zylamine hydrochloride and cyclopentadiene, and sub-
sequent transformations to azasugars from the adducts.
Sch em e 2
Resu lts a n d Discu ssion
We started with glyceraldehyde acetonide 2 prepared
from D-mannose derivative 1.5 The reaction of 2 with
benzylamine hydrochloride and cyclopentadiene was
carried out in water, in the presence of lanthanide
triflates (Scheme 2). Three products (3, 4, and 5) were
isolated. Table 1 lists the yields of the reaction with
different lanthanides. It was found that the lanthanides
of medium sizes gave better yields than smaller or larger
ones. Among the seven lanthanides tested, Nd(OTf)3
exhibited the best catalytic effect and gave 44% yield
when 10% equiv of lanthanide triflate, based on benzyl-
amine hydrochloride, was used. Different lanthanides
did not significantly change the product distributions,
and the ratios of 3/4/5 were around 1/8/3. When the
amount of Nd(OTf)3 was increased to 40% equiv, the
reaction yield was increased to 72%.
X Abstract published in Advance ACS Abstracts, February 1, 1997.
(1) (a) Larsen, S. D.; Grieco, P. A. J . Am. Chem. Soc. 1985, 107,
1768-1769. (b) Grieco, P. A.; Larsen, S. D. Org. Synth. 1990, 68, 206.
(c) Grieco, P. A.; Larsen, S. D.; Fobare, W. F. Tetrahedron Lett. 1986,
27, 1975. (d) Grieco, P. A.; Parker, D. T.; Fobare, W. F.; Ruckle, R. J .
Am. Chem. Soc. 1987, 109, 5859. (e) Grieco, P. A.; Bahsas, A. J . Org.
Chem. 1987, 52, 5746. (f) Grieco, P. A.; Clark, J . D. J . Org. Chem. 1990,
55, 2271. (g) Grieco, P. A.; Parker, D. T.; Fobare, W. F.; Ruckle, R. J .
Am. Chem. Soc. 1987, 109, 5859.
We prepared another chiral aldehyde 7 via the diazo-
tization of D-glucosamime hydrochloride 6, followed by a
ring contraction rearrangement.6 The resultant aqueous
solution of 7 was then combined with benzylamine
hydrochloride and cyclopentadiene, followed by the ad-
dition of Nd(OTf)3. The aza DA reaction produced only
one major product 8, which was acetylated to give 9 in a
combined yield of 35% for the three steps (Scheme 3).
(2) (a) Waldman, H. Angew. Chem., Int. Ed. Engl. 1988, 27, 274-
275. (b) Waldmann, H. Liebigs Ann. Chem. 1989, 231. (c) Walmann,
H. Braun, M. Liebigs Ann. Chem. 1991, 1045. (d) Pombo-Villar, E.;
Boelsterli, J .; Cid, M. M.; France, J .; Fuchs, B.; Walkinshaw, M.; Weber,
H.-P. Helv. Chim. Acta 1992, 76, 1203-1215. (f) Bailey, P. D.; Brown,
G. R.; Korber, F.; Reed, A.; Wilson, R. D. Tetrahedron: Asymmetry 1991,
2, 1263-1282. (g) Bailey, P. D.; Wilson, R. D.; Brown, G. R. J . Chem.
Soc., Perkin Trans. 1, 1991, 1337. (h) Stella, L.; Abraham, H.; Feneau-
Dupont, J .; Tinant, B.; Decercq, J . P. Tetrahedron Lett. 1990, 31, 2603.
(i) Abraham, H.; Stella, L. Tetrahedron 1992, 48, 9707.
(3) Yu, L.-B.; Chen, D.-P.; Wang, P. G. Tetrahedron Lett. 1996, 37,
4467.
(4) (a) Ganem, B. Acc. Chem. Res. 1996, 29, 340. (b) Hudlicky, T.;
Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J . Chem. Rev. 1996, 96, 1195.
(c) Look, G. C.; Fotsch, C. H.; Wong, C.-H. J . Am. Chem. Soc. 1993,
182.
(5) Schmid, C. R.; Bryant, J . D.; Dowlatzedah, M.; Phillips, J . L.;
Prather, D. E.; Renee, D. S.; Sear, N. L.; Vianco, C. S. J . Org. Chem.
1991, 56, 4056.
(6) Bera, B. C.; Foster, A. B. Stacey, M. J . Chem. Soc. 1956, 4531.
S0022-3263(96)02074-9 CCC: $14.00 © 1997 American Chemical Society

904 J . Org. Chem., Vol. 62, No. 4, 1997
Yu et al.
Ta ble 1. Rea ction a of 2 w ith Bn NH2‚HCl a n d C5H5
Sch em e 5
p r om oted by La n th a n id es Tr ifla tes
Ln(OTf)3
yield (%)b
Ln(OTf)3
yield (%)b
La
Pr
Nd
Gd
7
14
44
32
Dy
Er
Yb
10
15
8
a
The reaction was run with 1 mmol of BnNH2‚HCl, 1 mmol of
2, and 170 µL of cyclopentadiene in the presence of 0.1 mmol of
b
lanthanide triflate in 4 mL of water for 48 h. Isolated yields.
Sch em e 3
tions of the enantiomers.7 For our system, the benzyl
group was trans to the bulky substituent at the 3-posi-
tion. Thus, the benzyl group was downward in exo
compounds 3, 4, and 8 and upward in the endo compound
5 (Figure 1). On the basis of the direction of rotation
from the benzyl group to the double bond in these four
compounds, the negative Cotton effect of 3 and 8 indi-
cated their configurations shown in Scheme 2 and 3,
respectively, and the positive Cotton effect of 4 and 5
indicated their configurations shown in Scheme 2.
The assigned structures were further verified by X-ray
crystallography and NOE study of their derivatives.
Firstly, the double bond of product 3 was hydrogenated
in ethyl acetate in the presence of Pd/C catalyst to give
11,11 which was recrystallized in hexane to give single
crystals. The X-ray crystallography of 11 confirmed the
structure of 3 (Scheme 5).8 Secondly, we studied 2D
Sch em e 4
Ta ble 2. Selected Ch em ica l Sh ifts (δ) a n d Cou p lin g
Con sta n ts (J ) of 3-H in com p ou n d s 3, 4, 5, 8 a n d 10a
compd
δb
J c
1
NOESY of 9, since H NMR of 9 displayed well-resolved
10
3.18
1.52
1.80
1.89
2.03
2.76
8.8, 3.2
8.8, 1.6
8.0
7.6
6.0
and separated peaks. The 2D NOESY NMR exhibited a
cross peak between a-H and d-H, which supported the
exo structure (Figure 2). The cross peaks between b-H
and e-H, c-H and e-H suggested that the three hydrogens
were spatially close, which was compatible to the con-
figuration assigned to 8.
3
4
8
5
6.4, 3.2
All 1H NMR spectra were recorded in CDCl3. In ppm. c In
a
b
hertz.
The explanation of the stereoselectivity of the two aza
DA reactions is depicted in Scheme 6. We assume that
the lanthanide(III) coordinates the nitrogen of the Schiff
base and the adjacent oxygen to form a 5-membered ring
intermediate. The formation of the ring may require a
lanthanide(III) with a suitable atomic radius. This may
explain why the reaction of 2 with benzylamine hydro-
chloride and cyclopentadiene achieved the best yields
with medium-sized lanthanides. On the basis of this
5-membered ring intermediate, si attack for the forma-
tion of 3 would be unfavorable due to stereohindrance.
Between the two choices of re attacks, the pathway to
produce compound 4 should be more favorable. This
rationalization is consistent with our experimental re-
sults (e.g., 3/4/5 ) 1/8/3). Similarly, sterically favored si
attack to a 5-membered ring intermediate produces
compound 8.
To determine the structures of the above products, we
studied the NMR spectra of a simple model compound
10, which was prepared by an aza DA reaction of
formaldehyde, benzylamine hydrochloride and cyclopen-
tadiene (Scheme 4).1b The 1H NMR peaks were assigned
by 2D COSY NMR. Table 2 lists chemical shifts and
coupling constants of 3-H in compound 3, 4, 5, 8, and
10. For 10, the peak at 3.18 ppm with coupling constants
of 8.8 and 3.2 Hz was assigned to the 3-exo-H; the peak
at 1.52 ppm with coupling constants of 8.8 and 1.60 Hz
was assigned to the 3-endo-H. Thus, the exo and endo
hydrogens at the 3-position have quite different chemical
shifts, and this was used to characterize 3, 4, 5, and 8.
Since chemical shifts of 3-H in 3, 4, and 8 are 1.80, 1.89,
and 2.03 ppm, respectively, products 3, 4, and 8 were
assigned to exo isomers. In contrast, product 5 was
assigned to the endo isomer due to the chemical shift of
2.76 ppm and the coupling mode (dd, J ) 6.4, 3.2 Hz) for
its 3-H.
Finally, products 4 and 9 were converted into azasug-
ars. In order to work out general procedures, we started
with the model compoud 10. Dihydroxylation of 10 by
The absolute configurations of the azanorbornene
products were determined by CD spectroscopy. For the
2-aza-N-benzyl-bicyclo[2.2.1]-5-heptene system without
substitution at the 3-position, it was reported that the
double bond and the benzyl group served as two exitons
in CD measurement to deduce the absolute configura-
(7) Pombo-Villar, E.; Boelsterli, J .; Cid, M. M.; France, J .; Fuchs,
B.; Walkinshaw, M.; Weber, H.-P. Helv. Chim. Acta 1993, 76, 1203.
(8) X-ray data for 11: C18H23NO2; FW ) 287.41; monoclinic P21; a
) 9.7557(7) Å, b = 6.4260(6) Å, c ) 13.4426(9) Å; â ) 104.465(6)°, Σ )
0.710 73 Å, V ) 816.0(1) Å; R ) 0.0427, Rw ) 0.0423, S ) 1.76 based
on 2872 observed reflections.

Synthesis of Azasugars
J . Org. Chem., Vol. 62, No. 4, 1997 905
F igu r e 1. CD spectra of 3, 4, 5, and 8 measured in methanol at 25 °C.
Catalytic hydrogenation of 12 in methanol gave racemic
azasugar 13 (Scheme 7). Similarly, dihydroxylation of
4 by OsO4/Me3NO in acetone and water afforded diol 14,
which was converted to the polyhydroxy compound 15
by acid-catalyzed deketalization in acetic acid and water
(8/2). The azasugar 16 was synthesized through Pd-
catalyzed debenzylation of 15 in methanol (Scheme 8).
Further, compound 9 was dihydroxylated to afford com-
pound 17, which was deacetylated to afford compound
18 by NaOMe/MeOH. The aza disaccharide 19 was
prepared through debenzylation of 18 (Scheme 9).
In summary, lanthanide-catalyzed aza DA reactions
of two chiral aldehydes, prepared from carbohydrates,
F igu r e 2. Illustration of NOE interactions of 9.
OsO4/Me3NO/pyridine9 in 2-propanol gave 12, which was
characterized as the exo diol because no vicinal couplings
between 1-H and 6-H, 4-H and 5-H were observed.10
(9) (a) Larsen, S. D.; Monti, S. A. J . Am. Chem. Soc. 1977, 99, 8015.
(b) Ray, R.; Matteson, D. S. Tetrahedron Lett. 1980, 21, 449.
(10) J a¨ger, M.; Polborn, K.; Steglich, W. Tetrahedron Lett. 1995, 36,
861.
(11) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

906 J . Org. Chem., Vol. 62, No. 4, 1997
Yu et al.
Sch em e 6
mL) were added 2, 3-di-O-isopropylidene glyceraldehyde (130
mg, 1 mmol) and cyclopentadiene (0.17 mL, 2 mmol). The
reaction flask was sealed tightly, and the reaction mixture was
allowed to stir vigorously for 48 h. The resulting solution was
extracted with chloroform (10 mL × 3). The combined organic
phase was washed with 1 N NaOH solution and brine and then
dried over anhydrous sodium sulfate. The volatiles were
removed under reduced pressure, and the residue was chro-
matographed to give 3, 4, and 5 sequentially, eluting with a
mixture of ethyl acetate and hexane (1/9, 2/8, and 6/4). 3: 1H
NMR (CDCl3) δ 1.31 (d, J ) 8.40 Hz, 1 H), 1.36 (s, 3 H), 1.40
(s, 3 H), 1.73 (d, J ) 8.40 Hz, 1 H), 1.80 (d, J ) 8.0 Hz, 1 H),
3.02 (s, 1 H), 3.32 (d, J ) 13.2 Hz, 1 H), 3.48 (d, J ) 13.2 Hz,
1 H), 3.65 (m, 2 H), 3.93 (m, 2 H), 4.06 (dd, J ) 8.0, 6.0 Hz, 1
H), 6.16 (dd, J ) 5.60, 1.60 Hz, 1 H), 6.47 (m, 1 H), 7.25-7.31
(m, 5 H); 13C NMR (CDCl3) δ 25.9, 26.9, 45.0, 46.4, 59.0, 63.3,
65.7, 68.3, 80.0, 108.6, 127.0, 128.3, 128.3, 133.0, 137.1; ΜS
m/e 285 (M+); HRMS calcd for C18H23NO2 285.1729, found
285.1732. 4: 1H NMR (CDCl3) δ 1.30 (d, J ) 8.40 Hz, 1 H),
1.41 (s, 3 H), 1.45 (s, 3 H), 1.73 (d, J ) 8.40 Hz, 1 H), 1.89 (d,
J ) 7.6 Hz, 1 H), 2.57 (s, 1 H), 3.18 (d, J ) 13.8 Hz, 1 H), 3.70
(m, 2 H), 3.83 (m, 1 H), 4.11 (m, 2 H), 6.14 (d, J ) 5.60, 2.0
Hz, 1 H), 6.46 (m, 1 H), 7.30 (m, 5 H); 13C NMR (CDCl3) δ
25.9, 26.9, 45.6, 45.8, 58.8, 62.4, 66.3, 67.2, 80.5, 108.9, 126.7,
128.2, 129.1, 132.5, 136.8; MS m/e 285 (M+); HRMS calcd for
C18H23NO2 285.1729, found 285.1738. 5: 1H NMR (CDCl3) δ
1.32 (s, 3 H), 1.41 (s, 3 H), 1.47 (d, J ) 8.80 Hz, 1 H), 1.71 (d,
J ) 8.80 Hz, 1 H), 2.77 (dd, J ) 6.4, 3.6 Hz, 1 H), 2.87 (d, J )
3.6 Hz, 1 H), 3.60 (s, 1 H), 3.61 (d, J ) 13.4 Hz, 1 H), 3.66 (m,
1 H), 3.77 (m, 1 H), 3.99 (m, 1 H), 4.15 (d, J ) 13.4 Hz, 1 H),
6.04 (dd, J ) 5.6, 2.8 Hz, 1 H), 6.32 (dd, J ) 5.6, 3.0 Hz, 1 H),
7.32 (m, 5 H); MS m/e 285 (M+); HRMS calcd for C18H23NO2
285.1729, found 285.1734.
Sch em e 7
Sch em e 8
Sch em e 9
1-Deoxy-C-(1 f 3)-((1S,3S,4R)-2-a za -N-ben zylbicyclo-
[2.2.1]-3-h ep t-5-en yl)-r-D-a r a bin ofu r a n ose (8) a n d 2,3,5-
Tr i-O-acetyl-1-deoxy-C-(1 f 3)-((1S,3S,4R)-2-aza-N-ben zyl-
b icyclo[2.2.1]h ep t -5-en yl)-D-r-a r a b in ofu r a n ose (9).
A
solution of glucosamine hydrochloride (11 g, 50 mmol) in water
(80 mL) was stirred at room temperature for 6 h to reach
mutarotational equilibrium. After the solution was cooled to
0 °C with an ice-salt bath, sodium nitrite (3.5 g, 55 mmol)
was added. When acetic acid (9 mL, 150 mmol) in water (5
mL) was added dropwise, the reaction solution generated
bubbles. After 1 h of stirring at 0 °C, TLC (iPrOH/MeOH/H2O,
8/2/1) showed the disappearance of the starting material. The
cooling bath was removed, and then the reaction mixture was
allowed to warm to room temperature. To the solution were
added benzylamine hydrochloride (7.2 g, 50 mmol) and Nd-
(OTf)3 (20 mmol) followed by the addition of cyclopentadiene
(6.2 mL, 75 mmol). The reaction flask was sealed tightly, and
the reaction mixture was stirred vigorously for 60 h. The
reaction mixture was extracted with chloroform (50 mL × 3).
The combined organic phases were washed with 1 N NaOH
and brine and dried over anhydrous magnesium sulfate.
Removal of solvents in vacuo gave a residue, half of which was
chromatographed to afford 8 using chloroform and methanol
(7/3, v/v) as eluents. The other half was mixed with 100 mL
of a solution of dry pyridine and acetic anhydride (5/4). The
resulting solution was stirred overnight. After the evaporation
of solvents in vacuo, chloroform was added and the solution
was washed with water and brine. The organic layer was dried
over anhydrous sodium sulfate and concentrated in vacuo to
give an oil. Product 9 was obtained by silica gel flash
stereoselectively produced chiral heterocyclic compounds,
two of which were converted to the constrained azasug-
ars. Work is in progress to study the inhibition of these
coumpounds against a variety of glycoprocessing enzymes
and to apply this methodology for the synthesis of
bioactive carbohydrate analogs.
Exp er im en ta l Section
Gen er a l. 1H and 13C spectra were recorded on a 400 MHz
NMR spectrometer. Mass spectra were run on the mass
spectrometry facility at the University of California, Riverside.
Thin-layer chromatography was conducted on Baker Si250F
silica gel TLC plates with a fluorescent indicator. Column
chromatography was conducted with silica gel, grade 62, 60-
200 mesh, 150 Å.
(1S,4R)-2-Aza -N-b en zyl-3(S)-(1′(S), 2′-d i-O-isop r op yl-
id en eeth yl)bicyclo[2.2.1]-5-h ep ten e (3) a n d (1R,4S)-2-
Aza -N-b en zyl-3(R)-(1′(S),2′-d i-O-isop r op ylid en eet h yl)-
bicyclo[2.2.1]-5-h ep ten e (4), a n d (1S,4R)-2-Aza -N-ben zyl-
3(R)-(1′(S),2′-d i-O-isop r op ylid en eet h yl)b icyclo[2.2.1]-5-
h ep ten e (5). To a solution of benzylamine hydrochloride (144
mg, 1 mmol) and lanthanide triflate (0.1 mmol) in water (2

Synthesis of Azasugars
J . Org. Chem., Vol. 62, No. 4, 1997 907
chromatography eluting with a mixture of ethyl acetate and
hexane (3/7, 1/1, and 8/2 sequentially). 8: 1H NMR (CDCl3) δ
1.35 (d, J ) 8.2 Hz, 1 H), 1.81 (d, J ) 8.2 Hz, 1 H), 2.03 (d, J
) 6.0 Hz, 1 H), 2.96 (s, 1 H), 3.07 (d, J ) 12.4 Hz, 1 H), 3.59
(s, 1 H), 3.71 (dd, J ) 11.6, 1.7 Hz, 1 H), 3.78 (dd, J ) 11.6,
2.4 Hz, 1 H), 3.86 (d, J ) 8.4 Hz, 1 H), 3.98 (m, 1 H), 4.16-
4.21 (m, 3 H), 6.12 (m, 1 H), 6.53 (m, 1 H), 7.32 (m, 5 H); 13C
NMR (CDCl3) δ 45.9, 59.9, 62.5, 62.8, 66.0, 78.8, 79.6, 86.6,
88.2, 127.5, 128.5, 129.5, 132.5, 137.4, 138.7; MS m/e 318 (M
+ 1); HRMS calcd for C18H24NO4 318.1705, found 318.1699.
9: 1H NMR (CDCl3) δ 1.23 (d, J ) 8.20 Hz, 1 H), 1.67 (d, J )
8.20 Hz, 1 H), 1.90 (d, J ) 8.0 Hz, 1 H), 2.00 (s, 3 H), 2.01 (s,
3 H), 2.04 (s, 3 H), 2.73 (s, 1 H), 3.13 (d, J ) 12.8 Hz, 1 H),
3.59 (s, 1 H), 3.71 (d, J ) 12.8 Hz, 1 H), 3.98 (dd, J ) 8.0, 3.60
Hz, 1 H), 4.16 (m, 3 H), 5.06 (m, 1 H), 5.21 (m, 1 H), 6.11 (dd,
J ) 5.60, 2.0 Hz, 1 H), 6.41 (m, 1 H), 7.16-7.33 (m, 5 H); MS
m/e 444 (M + 1); HRMS calcd for C24H29NO7 444.2022, found
4434.2033.
(1S,4R)-2-Aza -N-b en zyl-3(S)-(1′(S),2′-d i-O-isop r op yl-
id en eeth yl)bicyclo[2.2.1]h ep ta n e (11). To a solution of 3
(300 mg) in ethyl acetate was added 5% Pd/C (30 mg). The
reaction mixture was hydrogenated under a hydrogen pressure
of 40 lb/cm2. The reaction was complete in 3 h. The reaction
mixture was filtered, and the filtrate was condensed, followed
by flash chromatography to give a solid 11 (272 mg) in 91%
yield. The compound 11 was recrystallized in hexane to
prepare single crystals for X-ray crystallography. 11: mp 62-
63 °C; 1H NMR (CDCl3) δ 1.18 (d, J ) 9.6 Hz, 1 H), 1.19-1.30
(m, 2 H), 1.33 (s, 3 H), 1.39 (s, 3 H), 1.65 (m, 1 H), 1.75 (d, J
) 9.6 Hz, 1 H), 2.01 (m, 1 H), 2.17 (d, J ) 7.2 Hz, 1 H), 2.40
(d, J ) 4.4 Hz, 1 H), 3.08 (s, 1 H), 3.65 (d, J ) 13.6 Hz, 1 H),
3.68 (t, J ) 8.0 Hz, 1 H), 3.75 (d, J ) 13.6 Hz, 1 H), 3.82 (m,
1 H), 3.93 (dd, J ) 8.0, 5.6 Hz, 1 H), 7.22-7.32 (m, 5 H); MS
m/e 287 (M+).
2-Aza -5,6-exo-d ih yd r oxy-N-b en zylb icyclo[2.2.1]h ep -
ta n e (12). To the solution of 10 (0.93 g, 5 mmol) in 50 mL of
2-propanol and water (3/1, v/v) were added trimethylamine
oxide (1.4 g, 12 mmol), pyridine (0.5 mL), and osmium
tetraoxide (75 mg, 0.3 mmol). The reaction mixture was
refluxed overnight. After the mixture was cooled to room
temperature, sodium sulfite was added. Water (50 mL) was
added, and the resulting solution was extracted with chloro-
form. The combined organic phases were washed with brine
and dried over anhydrous sodium sulfate. Evaporation of
solvents afforded the residue which was purified by chroma-
tography (ethyl acetate/hexane, 1:1) to give 12 in 85% yield.
12: 1H NMR (CDCl3) δ 1.55 (d, J ) 10.8 Hz, 1 H), 1.74 (d, J
) 10.8 Hz, 1 H), 2.31 (d, J )3.6 Hz, 1 H), 2.40 (d, J ) 10.0 Hz,
1 H), 2.51 (dd, J ) 10.0, 4.0 Hz, 1 H), 3.05 (s, 1 H), 3.30 (br,
OH), 3.69 (s, 2 H), 3.83 (d, J ) 6.0 Hz, 1 H), 4.01 (d, J ) 6.0
Hz, 1 H), 7.31 (m, 5 H); MS m/e 219 (M+); HRMS calcd for
C13H17NO2 219.1259, found 219.1268.
2-Aza -5,6-exo-d ih yd r oxybicyclo[2.2.1]h ep ta n e (13). To
a solution of 12 (660 mg, 3 mmol) in methanol (50 mL) was
added 10% Pd/C (100 mg). The resulting black suspension was
charged with hydrogen overnight, with a pressure of 40 lb/
in.2, through a Parr hydrogenation apparatus. The suspension
was filtered, and the filtrate was concentrated to give the
product 13 in quantitative yield: 1H NMR (CDCl3) δ 1.37 (d,
J ) 8.4 Hz, 1 H), 1.88 (d, J ) 8.4 Hz, 1 H), 2.33 (d, 1 H), 2.42
(d, J ) 8.0 Hz, 1 H), 2.78 (dd, J ) 10.0, 3.6 Hz, 1 H), 2.98 (br,
OH), 3.22 (s, 1 H), 3.71 (d, J ) 5.6 Hz, 1 H), 3.81 (d, J ) 5.6
Hz, 1 H); MS m/e 130 (M+); HRMS cacld for C6H12NO2
130.0868, found 130.0867.
(1R,4R)-2-Aza -N-b en zyl-3(R)-(1′(S),2′-h yd r oxyet h yl)-
5(R),6(S)-exo-d ih yd r oxybicyclo[2.2.1]h ep ta n e (15). A so-
lution of 14 (200 mg) in acetic acid and water (8/2,v/v) was
stirred in a bath of 55 °C for 10 h. The solvents were
evaporated in vacuo to give a residue, which was purified via
flash chromatography using chloroform and methanol (8/2, v/v)
1
as eluents to give 15 in 90% yield: H NMR (CD3OD) δ 1.58
(d, J ) 10.6 Hz, 1 H), 1.79 (d, J ) 10.6 Hz, 1 H), 2.26 (s, 1 H),
2.39 (d, J ) 6.40 Hz, 1 H), 2.97 (s, 1 H), 3.52 (m, 2 H), 3.64
(dd, J ) 13.2, 7.2 Hz, 1 H), 3.82 (d, J ) 13.2 Hz, 1 H), 3.85
(dd, J ) 4.80, 1.60 Hz, 1 H), 4.07 (d, J ) 13.2 Hz, 1 H), 4.38
(dd, J ) 4.80, 1.60 Hz, 1 H), 7.30-7.45 (m, 5 H); MS m/e 280
(M + 1); HRMS calcd for C15H21NO4 280.1549, found 280.1543.
(1R,4R)-2-Aza -3(R)-(1′(S),2′-h yd r oxyet h yl)-5(R),6(S)-
exo-d ih yd r oxybicyclo[2.2.1]h ep ta n e Hyd r och lor id e (16).
16 was prepared in 90% yield from 15 by Pd/C-catalyzed
hydrogenolysis in methanol: 1H NMR (CD3OD) δ 1.87 (d, J )
12.0 Hz, 1 H), 2.12 (d, J )12.0 Hz, 1 H), 2.50 (s, 1 H), 3.17 (d,
J ) 7.20 Hz, 1 H), 3.63 (m, 2 H), 3.68 (m, 2 H), 3.94 (d, J ) 5.4
Hz, 1 H), 4.02 (d, J ) 5.4 Hz, 1 H); MS m/e 190 (M + 1); HRMS
for C8H15NO4 190.1079, found 190.1077.
2,3,5-Tr i-O-a cetyl-1-d eoxy-C-(1 f 3)-((1S,3S,4S)-2-a za -
N-ben zyl-5(S),6(R)-exo-d ih yd r oxybicyclo[2.2.1]h ep tyl)-r-
D-a r a bin ofu r a n ose (17). Following the same procedure for
preparation of 12, 17 was prepared in 80% yield from 9: 1H
NMR (CDCl3) δ 1.59 (d, J ) 10.4 Hz, 1 H), 1.65 (d, J ) 10.4
Hz, 1 H), 2.04 (s, 3 H), 2.10 (s, 6 H), 2.23 (m, 2 H), 2.92 (s, 1
H), 3.63 (d, J ) 12.8 Hz, 1 H), 3.81 (d, J ) 5.60 Hz, 1 H), 3.95
(m, 2 H), 4.16 (m, 3 H), 4.27 (d, J ) 5.6 Hz, 1 H), 5.07 (dd, J
) 3.6, 2.8 Hz, 1 H), 5.18 (dd, J ) 3.6, 2.4 Hz, 1 H), 7.25-7.38
(m, 5 H); MS m/e 478 (M + 1); HRMS calcd for C24H32NO9
478.2077, found 478.2057.
1-Deoxy-1-C-(1 f 3)-((3S,1S,4S)-2-a za -N-ben zyl-5(S),6-
(R)-exo-d ih yd r oxyb icyclo[2.2.2]h ep t yl)-r-D-a r a b in ofu -
r a n ose (18). To a solution of 9 (200 mg, 0.42 mmol) in 5 mL
of anhydrous methanol was added sodium methoxide (20 mg).
After 2 h of stirring, Dowex resin (H+ form) was added to
neutralize the reaction solution until a pH of 7-7.5, and then
the resin was filtered. The filtrate was concentrated in vacuo
to give 18 (140 mg) in 97% yield: 1H NMR (CD3CD) δ 1.55 (d,
J ) 10.0 Hz, 1 H), 1.67 (d, J ) 10.0 Hz, 1 H), 2.23 (d, J ) 9.60
Hz, 1 H), 2.32 (s, 1 H), 2.82 (s, 1 H), 3.60 (m, 2 H), 3.67 (m, 2
H), 3.78 (m, 2 H), 3.86 (m, 1 H), 3.94 (m, 1 H), 4.07 (d, J )
12.4 Hz, 1 H), 4.35 (d, J ) 5.2 Hz, 1 H), 7.22-7.48 (m, 5 H);
MS m/e 352 (M + 1); HRMS calcd for C18H26NO6 352.1760,
found 352.1766.
1-Deoxy-C-(1 f 3)-((3S,1S,4S)-2-a za -5(S),6(R)-exo-d ih y-
d r oxybicyclo[2.2.1]h ep tyl)-r-D-a r a bin ofu r a n ose (19). 19
was prepared from 18 in 92% by Pd/C catalyzed hydrogenolysis
in methanol: 1H NMR (CD3OD) 1.78 (d, J ) 10.8 Hz, 1 H),
2.03 (d, J ) 10.8 Hz, 1 H), 2.55 (s, 1 H), 3.58 (m, 2 H), 3.64 (m,
1 H), 3.76 (m, 2 H), 3.82 (m, 1 H), 3.98 (m, 4 H); MS m/e 262
(M+); HRMS calcd for C11H20NO6 262.1291, found 262.1303.
Ack n ow led gm en t. We thank Dr. Simon G. Bott at
the University of North Texas for solving the X-ray
structure of compound 11. This work was supported
by American Cancer Society, Florida Division, Inc.
(F95UM-2), the Petroleum Research Fund (PRF# 30616-
G1), administered by the American Chemical Society,
and the NIH (GM54074). J un Li thanks the Matag
fellowship for the University of Miami and J ohnny
Ramirez
thanks
the
predoctoral
fellowship
(1R,4R)-2-Aza -N-b en zyl-3(R)-(1′(S),2′-d i-O-isop r op yli-
d e n e e t h y l)-5(R ),6(S )-exo-d i h y d r o x y b i c y c lo [2.2.1]-
h ep ta n e (14). Following the same procedure for preparation
of 12, 14 was prepared in 84% yield from 4: 1H NMR (CDCl3)
δ 1.33 (s, 3 H), 1.40 (s, 3 H), 1.53 (d, J ) 10.8 Hz, 1 H), 1.65
(d, J ) 10.8 Hz, 1 H), 2.05 (s, 1 H), 2.12 (s, J ) 6.80 Hz, 1 H),
2.93 (s, 1 H), 3.65 (m, 2 H), 3.83 (d, J ) 5.80 Hz, 1 H), 3.98 (m,
3 H), 4.28 (d, J ) 5.80 Hz, 1 H), 7.22-7.38 (m, 5 H); MS m/e
320 (M + 1); HRMS calcd for C18H26NO4 320.1862, found
320.1858.
(1F31CA70109) from the National Cancer Institute.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra in-
cluding 2D COSY and NOESY (25 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
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