N-alkoxy analogues of 3,4,5-trihydroxypiperidine

Article abstract of DOI:10.1021/jo971535m

Two practical procedures are described for the synthesis of the N- alkoxy analogues of 3,4,5-trihydroxypiperidine. The key feature of these methods is the intramolecular N-cyclization of hydroxylamine derivatives which are readily obtained from the reduction of the corresponding oximes. One method is to reductively hydroxyaminate an aldehyde group in the presence of a primary tosylated alcohol which is subsequently cyclized in situ upon neutralization. The intramolecular Mitsunobu coupling of a hydroxylamine with a primary alcohol proved useful for the preparation of compounds which contained the trans diol structure.

Full text of DOI:10.1021/jo971535m

6472
J . Org. Chem. 1998, 63, 6472-6475
N-Alk oxy An a logu es of 3,4,5-Tr ih yd r oxyp ip er id in e
Lihong Sun,† Pan Li, Nduka Amankulor, Weiping Tang, Donald W. Landry,‡ and Kang Zhao*
Department of Chemistry, New York University, New York, New York 10003, and Department of
Medicine, Columbia University, College of Physicians & Surgeons, New York, 10032
Received August 15, 1997
Two practical procedures are described for the synthesis of the N-alkoxy analogues of 3,4,5-
trihydroxypiperidine. The key feature of these methods is the intramolecular N-cyclization of
hydroxylamine derivatives which are readily obtained from the reduction of the corresponding
oximes. One method is to reductively hydroxyaminate an aldehyde group in the presence of a
primary tosylated alcohol which is subsequently cyclized in situ upon neutralization. The
intramolecular Mitsunobu coupling of a hydroxylamine with a primary alcohol proved useful for
the preparation of compounds which contained the trans diol structure.
In tr od u ction
Naturally occurring polyhydroxylated piperidine alka-
loids have attracted much attention due to their ability
to act as glycosidase inhibitors.1 The inhibitory proper-
ties of these alkaloides hold great therapeutic potential
for the treatment of infectious diseases,2 and recent
progress in this area has prompted considerable interest
in the structure-function relationship for polyhydroxy-
lated piperidines. A plethora of synthetic analogues,
including 1-deoxynojirimycin (1) and n-butylnojirimycin
(2) (Figure 1), have been prepared and evaluated for
glycosidase inhibition and for anticancer, antidiabetic,
and antiviral (anti-HIV) activities.3 The majority of the
synthetic analogues, which are designed to mimic the
transition states of glycoprotein processing, maintain the
replacement of the glycoside ring oxygen with a basic
piperidinyl nitrogen atom. We reasoned that the direct
attachment of an electron-withdrawing alkoxy group to
the nitrogen in iminoglycosides can potentially bridge two
units of saccharides for a unique class of multisubstrate
glycosidase inhibitors.
F igu r e 1.
vidual hydroxyl groups on inhibitory potency and the
contribution of each hydroxyl group in the glycosides to
the free energy of binding with enzyme.4 It was also of
interest to prepare diastereoisomers of N-alkoxytrihy-
droxypiperidines in order to develop potential inhibitors
for variant glycosidases. The specific inhibition of a
variety of glycosidases appears to require structural
similarity between inhibitor and natural substrate. For
example, deoxynojrimycin has been shown to be a supe-
rior inhibitor of glucosidase-I compared to the mannose
analogue, deoxymannojirimycin.5
We also report a detailed procedure for the preparation
of disaccharide analogues (e.g., 7) as a demonstration of
the efficiency of the hydroxylamine cyclization methods
for the construction of structurally diverse piperidine
derivatives. The N-O moiety of 7, in addition to serving
as the pivotal center of a transition-state analog-based
inhibitor, also served as a handle for coupling the
iminosugar to a saccharide unit. These compounds and
related polysaccharide analogues are postulated to re-
semble the structural feature of both donor and acceptor
moieties of enzymatic substrates.6
We wish to report an efficient route to the N-alkoxy-
3,4,5-trihydroxypiperidines (3-6) based on tandem re-
ductive cyclization (Figure 1). The four possible isomers
for this structure were prepared to study the influence
of the absolute stereochemical configurations of indi-
† Present address: Biogen Inc., 14 Cambridge Center, Cambridge,
MA 02143.
‡ Columbia University.
(1) For a selected review, see: Hughes, A. B.; Rudge, A. J . Nat. Prod.
Rep. 1994, 135.
(2) (a) Liu, P. S.; Kang, M. S.; Sunkara, P. S. Tetrahedron Lett. 1991,
32, 719. (b) Liu, P. S.; Rhinehart, B. L.; Daniel, J . K. U.S. Pat. US
5,017,563, 1991; Chem. Abstr. 1991, 115, 136471e. (c) Horii, S.; Fukase,
H.; Matsuo, T.; Kameda, Y.; Asano, N.; Matsui, K. J . Med. Chem. 1986,
29, 1038.
(3) (a) Fleet, G. W. J .; Karpas, A.; Dwek, R. A.; Fellows L. E.; Tyms,
A. S.; Petursson, S.; Namgoong, S. K.; Ramsden, N. G.; Smith, P. W.;
Son, J . C.; Wilson, F.; Witty, D. R.; J acob, G. S.; Rademacher, T. W.
FEBS Lett. 1988, 237, 128. (b) Karpas, A.; Fleet, G. W. J .; Dwek, R.
A.; Petursson, S.; Namgoong, S. K.; Ramsden, N. G.; J acob, G. S.;
Rademacher, T. W. Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 9229. (c)
van den Broek, L. A. G. M.; Vermaas, D. J .; Heskamp, B. M.; van
Boeckel, C. A. A.; Tan, M. C. A. A.; Bolscher, J . G. M.; Ploegh, H. L.;
van Kemenade, F. J .; de Goede, R. E. Y.; Miedema, F. Recl. Trav. Chim.
Pays-Bas 1993, 112, 82. (d) Papandreou, G.; Tong, M. K.; Ganem, B.
J . Am. Chem. Soc. 1993, 115, 11682. (e) Wong, C.-H.; Provencher, L.;
Porco, J . A., J r.; J ung, S.-H.; Wang, Y.-F.; Chen, L.; Wang, R.;
Steensma, D. H. J . Org. Chem. 1995, 60, 1492.
(4) Bernotas, R. C.; Papandreou, G.; Urbach, J .; Ganem, B. Tetra-
hedron Lett. 1990, 31, 3393.
(5) Schweden, J .; Borgmann, C.; Legler, G.; Bause, E. Arch. Biochem.
Biophys. 1986, 248, 335.
(6) Sun, L.; Li, P.; Landry, D. W.; Zhao, K. Tetrahedron Lett. 1996,
37, 1547.
S0022-3263(97)01535-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/21/1998

N-Alkoxy Analogues of 3,4,5-Trihydroxypiperidine
J . Org. Chem., Vol. 63, No. 19, 1998 6473
Sch em e 1
Sch em e 2
Resu lts a n d Discu ssion
Structural analysis of compounds 3-7 revealed that
the polyhydroxylated carbons of the piperidine rings
corresponded to those of the pentose derivatives 8
(Scheme 1). A practical approach to the desired com-
pounds 3-7 would be the connection of both terminal
carbons of 8 to hydroxylamine derivatives 9. One con-
nection could be achieved via the reductive amination of
8 and 9, and another by an intramolecular SN cyclization
of the resulting hydroxylamine. This approach raised
some interesting issues including the relative reactivities
of the tosylate and aldehyde toward 9. Another issue was
the protection and deprotection of polyhydroxyl groups,
an essential element if the nucleophilicity of hydroxyl
moieties was comparable with that of the N-alkoxy-
substituted nitrogen.
Sch em e 3
Ribose derivative 10 was used for the initial studies
since it could be readily prepared from ribose by a
literature procedure7 and the primary hydroxyl group
could be selectively tosylated to give 11. The cyclic acetal
in 11 was desired to protect the nucleophilic hydroxyl
groups, thereby preventing their intramolecular displace-
ment of the tosyl group. The treatment of 11 with
propylhydroxylamine produced the corresponding oxime
12 in high yield,8 and the tosyl group survived in the
presence of O-propylhydroxylamine. The resulting oxime
12 was reduced by NaBH3CN under acidic conditions,
and the subsequent neutralization by ethylenediamine
afforded piperidine 13 which was easily converted to the
final product 3.6 This efficient and practical method
permitted the preparation of trihydroxypiperidine 3 from
the readily available 10 in four synthetic operations with
64% overall yield, and the preparation of analogues 4 and
5 from 3-isopropylidenelyxoses 14 and 15,9 in 50% and
56% overall yields, respectively.
The difficulty of cyclic acetal formation posed by the
trans diol in 16 required an acyclic alcohol-protecting
group, and allyl ethers were tested (Scheme 3). D-Py-
ranoside 16 was alkylated under aqueous conditions10 to
give the corresponding triallylpyranoside which was hy-
drolyzed into corresponding triallyl xylose 17. Acetal 17
was allowed to react with O-n-butylhydroxylamine to
produce alcohol 18 which was then tosylated in pyridine
to give 19 in 92% yield. When compound 19 was sub-
jected to the same conditions of NaBH3CN reduction and
ethylenediamine neutralization as described in Scheme
2, only about 40% of the desired product 20 was obtained.
We also isolated the corresponding tetrahydrofuran
product 21 in 30% yield, which showed only two allyl
groups and two nitrogen-connected protons. It is neces-
sary to indicate that ethylenediamine neutralization of
acetic acid is an exothermic reaction, raising the reaction
temperature to 70 °C. This reaction temperature is
needed for the conversion of 19 to compound 20, but the
intramolecular displacement of tosylate 19 by the allyl-
protected oxygen at the three position also occurred to
produce tetrahydrofuran 21.
The Mitsunobu reaction was subsequently investigated
for the intramolecular cyclization of primary alcohol and
N-alkoxypiperidine (Scheme 4). Alcohol 22, readily
available from the reduction of oxime 18 in 95% yield,
possesses a nucleophilic nitrogen center which may result
in the desired Mitsunobu coupling.11,12 The treatment
(7) Tronchet, J . M. J .; Zosimo-Landolfo, G.; Villedon-Denaide, F.;
Balkadjian, M.; Cabrini, D.; Barbalat-Rey, F. J . Carbohydr. Chem.
1990, 9, 823.
(8) Primary tosylates and mesylates have been used successfully to
react with hydroxylamine in triethylamine at reflux, see: Goti, A.;
Cicchi, S.; Fedi, V.; Nannelli, L.; Brandi, A. J . Org. Chem. 1997, 62,
3119.
(9) Barbat, J .; Gelas, J .; Horton, D. Carbohydr. Res. 1991, 219, 115.
(10) Wang, H.; Sun, L.; Glazebnik, S.; Zhao, K. Tetrahedron Lett.
1995, 36, 2953.
(11) For selected reviews, see: (a) Mitsunobu, O. Synthesis 1981,
1. (b) Hughes, D. L. Org. React. 1992, 42, 335. (c) Hughes, D. L. Org.
Prep. Proc. Int. 1996, 28, 127. (d) Simon, C.; Hosztati, S.; Makleit, S.
J . Heterocycl. Chem. 1997, 34, 349.
(12) The coupling of alcohol and amine derivatives by the intramo-
lecular Mitsunobu reactions has been reported. (a) Bernotas, R. C.;
Cube, R. V. Tetrahedron Lett. 1991, 32, 161. (b) Chen, Y.; Vogel, P. J .
Org. Chem. 1994, 59, 2487. (c) Grandel, R.; Kazmaier, U. Tetrahedron
Lett. 1997, 38, 8009.

6474 J . Org. Chem., Vol. 63, No. 19, 1998
Sun et al.
Sch em e 4
resulting molecules structurally resemble glycoside sub-
strates and retain the electronic property of the pivotal
piperidine nitrogen for mimicking the transition state of
glycosyl hydrolysis. This work also demonstrates the
usefulness of the Mitsunobu coupling of hydroxylamine
and alcohol, a reaction with potential for the general
synthesis of N-alkylhydroxylamines and through reduc-
tion for the corresponding amines.
Exp er im en ta l Section
General details are as previously described.15
N-n -P r op oxy-[3(e),4(a ),5(e)]-3,4,5-t r ih yd r oxyp ip er i-
d in e (3). A cold (0 °C) magnetically stirred solution of 2,3-
O-cyclopentylideneribofuranose 108 (2.85 g, 12.0 mmol) in
anhydrous pyridine (10 mL) was treated with p-TsCl (3 g, 15.7
mmol), warmed to room temperature, and stirred for 5 h. After
workup (ice water, Et2O) and column chromatography puri-
fication (silica gel), intermediate 11 was isolated. A solution
of O-n-propylhydroxylamine hydrochloride (270 mg, 2.42
mmol) in MeOH (10 mL) was treated with NaOH (90 mg, 2.25
mmol), stirred for 15 min, and transferred into the solution of
11 (690 mg, 1.86 mmol) in MeOH (10 mL) at room tempera-
ture. The reaction mixture was stirred overnight and then
concentrated. Column chromatography purification (silica gel)
gave oxime 12 (E/Z ) 3/2) (615 mg, 1.44 mmol) in 75% overall
Sch em e 5
1
yield: Rf ) 0.27 (20% EtOAc/petroleum ether); H NMR (200
MHz, CDCl3) δ 7.81 (2H, d, J ) 8.3 Hz), 7.37 (0.6H, d, J ) 6.5
Hz, E-isomer), 7.33 (2H, d, J ) 8.3 Hz), 6.78 (0.4H, d, J ) 5.5
Hz, Z-isomer), 5.14 (0.4H, dd, J ) 5.4, 5.6 Hz, Z-isomer), 4.67
(0.6H, dd, J ) 6.0, 7.1 Hz, E-isomer), 4.05 (6H, m), 2.64 (1H,
br), 2.45 (3H, s), 1.70 (10H, m), 0.91 (3H, t, J ) 7.3 Hz); 13C
NMR (50 MHz, CDCl3) δ 149.6, 146.9, 145.4, 145.2, 133.1,
130.2, 128.4, 120.3, 120.1, 78.4, 77.1, 76.3, 75.3, 72.3, 71.9, 69.4,
68.3, 37.5, 37.0, 24.3, 23.8, 22.8, 22.2, 10.8. Anal. Calcd for
of 22 with triphenylphosphine and diethyl azodicarboxy-
late (DEAD), indeed, gave the N-cyclization product 20
as the only product in 75% yield. To our knowledge, this
is the first example of the Mitsunobu-promoted cycliza-
tion of alcohols and N-alkylhydroxylamine derivatives.12
It is also interesting to observe that the nitrogen of the
hydroxylamine moiety of 22 becomes an improved nu-
cleophile under Mitsunobu conditions. The final step to
the desired product was to deprotect the O-alkyl groups
of 20, and we investigated Corey’s method.13 Treatment
of 20 with rhodium chloride-triphenylphosphine complex
promoted allyl migration to give the corresponding enol
ether, and hydrolysis released the hydroxyl groups. The
N-alkoxyamine group of 20 survived under these condi-
tions, and the desired piperidine 6 was isolated via
acetate 23 which was used as an intermediate for
purification by silica gel chromatography.
We have also prepared pseudodisaccharides 7a and 7b
by tandem reductive cyclization. The pseudodisaccharide
7a was prepared from 11 and O-aminogalactose deriva-
tive 25,14 while 7b was obtained from 11 and O-amino-
glucose derivative 2614 as shown in Scheme 5. Addition-
ally, the cyclization step could be accomplished by the
Mitsunobu method (not shown here).
C
20H29NO7S: C, 56.18; H, 6.84; N, 3.28; S, 7.48. Found: C,
56.27; H, 6.89; N, 3.26; S, 7.42.
A solution of oxime 12 (560 mg, 1.31 mmol) in AcOH (5 mL)
was treated with NaBH3CN (250 mg, 3.95 mmol) at room
temperature and stirred until the reaction mixture became a
homogeneous solution (ca. 1 h). To the above solution was
added ethylenediamine (2 mL), and the resulting mixture was
then stirred for 30 min. After workup (saturated NaHCO3,
EtOAc) and column chromatography purification (silica gel),
piperidine 13 (265 mg, 1.03 mmol, 79%) was isolated: Rf )
0.50 (40% EtOAc/petroleum ether); 1H NMR (200 MHz, CDCl3)
δ 4.22 (1H, m), 4.09 (1H, t, J ) 4.0 Hz), 4.00 (1H, m), 3.55
(2H, t, J ) 6.7 Hz), 3.16 (2H, m), 2.63 (3H, m), 1.74 (8H, m),
1.50 (2H, m), 0.86 (3H, t, J ) 7.3 Hz); 13C NMR (50 MHz,
CDCl3) δ 120.0, 75.1, 74.1, 72.6, 65.9, 57.1, 56.2, 38.4, 38.1,
24.3, 24.0, 22.4, 11.1.
A solution of piperidine 13 (105 mg, 0.41 mmol) in water
(10 mL) was treated with Dowex [50WX8 (H+), 200 mg] at
room temperature and stirred for 12 h prior to the addition of
Et3N (0.2 mL). The mixture was stirred for 5 h and then
filtered through Celite. The filtrate was concentrated and
azeotropically dried with benzene to give 3 (73 mg, 0.41 mmol,
100%): 1H NMR (200 MHz, CD3OD) δ 3.85 (3H, br), 3.62 (2H,
t, J ) 6.5 Hz), 3.04 (2H, br), 2.82 (2H, br), 1.56 (2H, m), 0.93
(3H, t, J ) 7.4 Hz); 13C NMR (50 MHz, CD3OD) δ 74.8, 72.4,
67.8, 56.0, 23.4, 11.4. Anal. Calcd for C8H17NO4‚0.4H2O: C,
48.42; H, 9.04; N, 7.06. Found: C, 48.90; H, 8.63; N, 6.99.
N-n -P r op oxy-[3R(a ),4(e),5R(e)]-3,4,5-tr ih yd r oxyp ip er i-
The present work succeeds in the efficient preparation
of several N-alkoxylpiperidine analogues via two comple-
mentary approaches, which are based on the property of
alkoxylamine. The stability of and unique reactivity of
N-alkoxylamines allows for their selective coupling with
appropriately protected saccharides to form the corre-
sponding oximes, and after reduction, intramolecular SN2
cyclizations can occur to give oxy-imine saccharides. The
d in e (4). 41% overall yield; [R]25 ) -6.0 (c ) 10, CH3OH);
D
1H NMR (200 MHz, CD3OD) δ 4.07 (1H, m), 3.92 (1H, m), 3.73
(2H, t, J ) 6.6 Hz), 3.55 (1H, br), 2.20-3.40 (4H, br), 1.56 (2H,
m), 0.91 (3H, t, J ) 7.4 Hz); 13C NMR (50 MHz, CD3OD) δ
76.7, 70.4, 70.1, 61.9, 24.4, 12.9. Anal. Calcd for C8H17NO4:
C, 50.25; H, 8.96; N, 7.32. Found: C, 50.15; H, 8.95; N, 7.17.
(13) Corey, E. J .; Suggs, W. J . J . Org. Chem. 1973, 38, 3224.
(14) Compounds 25 and 26 were prepared from the corresponding
carbohydrates bearing the unprotected 6-hydroxyl group. The Mit-
sunobu reaction of those derivatives with N-hydroxyphthalimide
followed by the treatment with hydrazine in methanol produced the
desired hydroxylamine products 25 and 26. Grochowski, E.; J urczak,
J . Carbohydr. Res. 1976, 50, C15.
(15) (a) Wang, T.; Chen, J .; Zhao, K. J . Org. Chem. 1995, 60, 2668.
(b) Gi, H. J .; Xiang, Y.; Schinazi, R. F.; Zhao, K. J . Org. Chem. 1997,
62, 88-92.

N-Alkoxy Analogues of 3,4,5-Trihydroxypiperidine
N-n -P r op oxy-[3S(e),4(e),5S(a )]-3,4,5-tr ih yd r oxyp ip er i-
J . Org. Chem., Vol. 63, No. 19, 1998 6475
to the generalized reductive cyclization procedure to give
piperidine 20 (220 mg, 0.67 mmol, 42%): Rf ) 0.40 (10%
EtOAc/petroleum ether); 1H NMR (200 MHz, CDCl3) δ 5.91
(3H, m), 5.20 (6H, m), 4.10-4,35 (6H, m) 3.64 (2H, t, J ) 6.2
Hz,), 3.41-3.52 (4H, m), 3.20 (1H, t, J ) 11.5 Hz), 2.38 (2H, t,
J ) 11.6 Hz), 1.43 (4H, m), 0.90 (3H, t, J ) 7.2 Hz); 13C NMR
(50 MHz, CDCl3) δ 136.0, 135.5, 117.1, 116.6, 86.1, 76.6, 74.5,
72.7, 72.3, 58.2, 31.4, 19.9, 14.5. Anal. Calcd for C18H31NO4:
C, 66.43; H, 9.60; N, 4.30. Found: C, 66.22; H, 9.51; N, 4.35.
O-n -Bu t yl N-[(2R,3S,4R)-2,3,4-t r ia llyloxy-5-h yd r oxy-
p en tyl]h yd r oxyla m in e 22. To a solution of the oxime 18
(685 mg, 2.01 mmol) and NaBH3CN (380 mg, 6.03 mmol) in
MeOH (30 mL) was added concentrated HCl (2 mL) at room
temperature. The reaction mixture was stirred for 1 h and
then concentrated in vacuo. The residue was purified by
column chromatography (silica gel) to provide hydroxylamine
22 (668 mg, 1.94 mmol, 97%): Rf ) 0.25 (33% EtOAc/petroleum
d in e (5). 37% overall yield; [R]25 ) +6.0 (c ) 10, CH3OH);
D
1H NMR (200 MHz, CD3OD) δ 3.97 (1H, m), 3.83 (1H, m), 3.65
(2H, t, J ) 6.5 Hz), 3.47 (1H, br), 2.20-3.40 (4H, br), 1.56 (2H,
m), 0.92 (3H, t, J ) 7.4 Hz); 13C NMR (50 MHz, CDCl3) δ 76.7,
70.4, 70.1, 61.9, 24.4, 12.9. Anal. Calcd for C8H17NO4: C,
50.25; H, 8.96; N, 7.32. Found: C, 50.20; H, 9.03; N, 7.28.
6-O-{1-[3(e),4(a ),5(e)]-3,4,5-Tr ih yd r oxyp ip er id in yl}-D-
ga la ctose (7a ). 53% overall yield; [R]25D ) +34.0 (c ) 1, H2O);
1H NMR (200 MHz, D2O) δ 5.25 (1H, d, J ) 3.3 Hz), 4.57 (1H,
d, J ) 7.7 Hz), 3.40-4.25 (9H, m), 2.80-3.20 (4H, br); 13C NMR
(50 MHz, D2O) δ 99.4, 95.3, 75.8, 75.4, 74.8, 74.6, 74.1, 73.0,
72.9, 72.6, 72.2, 72.0, 71.3, 70.9, 68.6, 56.6. Anal. Calcd for
C
11H21NO9‚0.5H2O: C, 41.25; H, 6.92; N, 4.37. Found: C,
41.79; H, 6.80; N, 4.41.
6-O-{1-[3(e),4(a ),5(e)]-3,4,5-Tr ih yd r oxyp ip er id in yl}-D-
glu cose (7b). 37% overall yield; [R]25 ) +55.0 (c ) 1, H2O);
D
1H NMR (200 MHz, D2O) δ 5.19 (1H, d, J ) 3.7 Hz), 4.61 (1H,
d, J ) 11.8 Hz), 3.31-4.10 (9H, m), 3.20 (2H, br), 2.80 (2H,
br); 13C NMR (50 MHz, D2O) δ 98.9, 95.0, 78.8, 77.1, 76.8, 75.8,
ether); H NMR (200 MHz, CDCl3) δ 5.91 (3H, m), 5.20 (6H,
1
m), 3.58-4.21 (15H, m), 3.21 (1H, dd, J ) 11.5, 5.0 Hz), 2.97
(1H, dd, J ) 11.5, 7.3 Hz), 1.45 (4H, m), 0.92 (3H, t, J ) 7.3
Hz). Anal. Calcd for C18H33NO5: C, 62.95; H, 9.68; N, 4.08.
Found: C, 62.83; H, 9.64; N, 4.07.
74.4, 73.7, 73.6, 73.0, 72.5, 68.6, 56.5. Anal. Calcd for C11H21
-
NO9‚H2O: C, 40.12; H, 7.03; N, 4.25. Found: C, 39.96; H, 6.86;
N, 3.97.
P r oced u r e for th e Mitsu n obu Cycliza tion . N-Bu tyl-
oxy-[3(e),4(e),5(e)]-3,4,5-tr ia llyloxyp ip er id in e (20). To a
solution of 22 (665 mg, 1.93 mmol) in anhydrous THF (100
mL) were added Ph3P (1.02 g, 3.86 mmol) and DEAD (0.67
mL, 4.25 mmol) at room temperature. The reaction mixture
was stirred overnight at room temperature and then concen-
trated in vacuo. The residue was purified by silica gel column
chromatography to afford 20 (470 mg, 1.45 mmol, 75%): Rf )
0.60 (20% EtOAc/petroleum ether).
(2R,3S,4R)-2,3,4-Tr is(a llyloxy)-5-tosyloxyp en ta n a l O-n -
Bu tyloxim e (19). A solution of methyl â-D-xylopyranoside
(10 g, 61.0 mmol) in DMSO (150 mL) was treated with 50%
aqueous NaOH (25 mL, 311 mmol) and stirred until it became
homogeneous. Allyl bromide (23.8 mL, 274 mmol) was then
added. The reaction mixture was stirred until no starting
material was detected by TLC and extracted with Et2O (2 ×
250 mL). The combined organic layers were washed with
water (2 × 100 mL), dried over magnesium sulfate, and
concentrated in vacuo. The resulting crude product was
dissolved in a solution of AcOH (100 mL) and 2 N sulfuric acid
(100 mL), and the mixture was refluxed until no starting
material was detected by TLC. After workup (saturated
NaHCO3, 250 mL; EtOAc, 2 × 250 mL) and column chroma-
tography (silica gel) purification, triallylxylose 17 (13.0 g, 48.2
mmol) was isolated in 79% yield. Rf ) 0.50 (40% EtOAc/
petroleum ether).
Gen er a lized Dea llyla t ion P r oced u r e. N-Bu t yloxy-
[3(e),4(e),5(e)]-3,4,5-tr ih yd r oxyp ip er id in e (6). A mixture
of 20 (600 mg, 1.85 mmol), Rh(PPh3)3Cl (120 mg, 0.13 mmol),
DABCO (41 mg, 0.37 mmol), EtOH (18 mL), and water (2 mL)
was refluxed for 1 h. The resultant solution was treated with
2 N HCl (20 mL) and refluxed for another hour. The reaction
mixture was cooled to room temperature and washed with CH2-
Cl2 (40 mL). The aqueous layer was collected and concentrated
in vacuo. The anhydrous residue was treated with a mixture
of Ac2O (1.3 mL, 13.45 mmol) and Et3N (5 mL) in CH2Cl2 (25
mL) and was stirred overnight. After workup (water, CH2-
Cl2) and column chromatography purification, triacetate 23
(507 mg, 1.53 mmol) was isolated in 83% yield. Compound
23 was subjected to basic Amberlite (1 g) in MeOH (10 mL) at
room temperature overnight. The resin was filtered off, and
the filtrates were concentrated and dried to give 6 (314 mg,
1.53 mmol, 100%) as a white solid. 23: 1H NMR (200 MHz,
CDCl3) δ 5.14 (2H, br), 4.99 (1H, t, J ) 9.1 Hz), 3.55 (2H, t, J
) 6.5 Hz), 3.42 (2H, dd, J ) 12.0, 4.6 Hz), 2.50 (2H, t, J )
11.5 Hz), 1.93 (6H, s), 1.92 (3H, s), 1.38 (4H, m), 0.82 (3H, t,
J ) 7.1 Hz); 13C NMR (50 MHz, CDCl3) δ 170.5, 170.1, 74.2,
72.7, 68.5, 56.1, 31.1, 21.3, 19.8, 14.4. 6: 1H NMR (200 MHz,
CDCl3) δ 5.15 (3H, br), 3.50 (7H, m), 2.46 (2H, br), 1.40 (4H,
m), 0.90 (3H, t, J ) 7.2 Hz); 13C NMR (50 MHz, CDCl3) δ 79.7,
72.4, 68.8, 59.7, 31.3, 19.9, 14.5. Anal. Calcd for C9H19NO4:
C, 52.65; H, 9.33; N, 6.83. Found: C, 52.50; H, 9.24; N, 6.66.
A solution of O-n-butylhydroxylamine hydrochloride (315
mg, 2.51 mmol) in MeOH (10 mL) was treated with NaOH
(100 mg, 2.51 mmol) and stirred for 15 min prior to the
addition of a solution of 17 (565 mg, 2.09 mmol) in MeOH (10
mL) at room temperature. The mixture was stirred overnight,
concentrated in vacuo, and purified by column chromatography
(silica gel) to provide oxime 18 (710 mg, 2.08 mmol, 99%) as a
mixture of two isomers (E/Z ) 3/1): Rf ) 0.6 (33% EtOAc/
1
petroleum ether); H NMR (200 MHz, CDCl3) δ 7.36 (0.75H,
d, J ) 7.9 Hz, E isomer), 6.82 (0.25H, d, J ) 6.0 Hz, Z isomer),
5.85 (3H, m), 5.20 (6H, m), 3.60-4.20 (13H, m), 2.41 (1H, br),
1.63 (2H, m), 1.38 (2H, m), 0.92 (3H, t, J ) 7.1 Hz); 13C NMR
(50 MHz, CDCl3) δ 151.5, 148.2, 135.3, 134.4, 117.9, 117.3,
80.8, 79.5, 76.8, 74.2, 72.5, 70.5, 62.0, 31.6, 19.5, 14.4. Anal.
Calcd for C18H31NO5: C, 63.32; H, 9.15; N, 4.10. Found: C,
63.34; H, 9.17; N, 4.05.
To the solution of oxime 18 (600 mg, 1.76 mmol), pyridine
(3 mL), and several crystals of DMAP was added tosyl chloride
(503 mg, 2.64 mmol). The reaction mixture was stirred for 1
h at room temperature. After workup (ice water, 100 mL;
Et2O, 2 × 100 mL) and column chromatography (silica gel)
purification, oxime tosylate 19 (798 mg, 1.61 mmol) was
isolated in 92% yield: Rf ) 0.60 (20% EtOAc/petroleum ether);
1H NMR (200 MHz, CDCl3) δ 7.80 (2H, d, J ) 7.3 Hz), 7.33
(1H, d, J ) 6.9 Hz), 7.23 (2H, d, J ) 7.3 Hz), 5.78 (3H, m),
5.20 (6H, m), 4.33 (1H, dd, J ) 4.5, 11.0 Hz), 4.12 (1H, t, J )
6.9 Hz), 4.03 (2H, t, J ) 6.2 Hz), 4.02-4.10 (6H, m), 3.80 (2H,
m), 3.52 (1H, t, J ) 4.5 Hz), 2.42 (3H, s), 1.62 (4H, m), 0.90
(3H, t, J ) 7.2 Hz); 13C NMR (50 MHz, CDCl3) δ 14.4, 19.5,
22.1, 31.6, 70.5, 70.6, 72.8, 73.8, 74.2, 76.2, 76.7, 79.3, 117.8,
118.1, 128.4, 130.2, 133.3, 134.3, 134.8, 145.2, 147.9.
Ack n ow led gm en t. We thank the American Cancer
Society, the NSF Faculty Early Career Development
Program, and the donors of the Petroleum Research
Fund, administered by the American Chemical Society,
for support of this work. P.L. acknowledges the New
York University Dean’s Dissertation Fellowship.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of the final products and intermediates (51 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
N -Bu t yloxy-[3(e ),4(e ),5(e )]-3,4,5-t r ia llyloxyp ip e r i-
d in e (20). The oxime 19 (790 mg, 1.60 mmol) was subjected
J O971535M