A strategy for the solution-phase parallel synthesis of N- (pyrrolidinylmethyl)hydroxamic acids

Article abstract of DOI:10.1021/jo000186k

Both five- and six-membered iminocyclitols have proven to be useful transition-state analogue inhibitors of glycosidases. They also mimic the transition-state sugar moiety of the nucleoside phosphate sugar in glycosyltransferase-catalyzed reactions. Described here is the development of a general strategy toward the parallel synthesis of a five-membered iminocyclitol linked to a hydroxamic acid group designed to mimic the transition state of GDP-fucose complexed with Mn(II) in fucosyltransferase reactions. The iminocyclitol 8 containing a protected hydroxylamine unit was prepared from D-mannitol. The hydroxamic acid moiety was introduced via the reaction of 8 with various acid chlorides. The strategy is generally applicable to the construction of libraries for identification of glycosyltransferase inhibitors.

Full text of DOI:10.1021/jo000186k

J . Org. Chem. 2000, 65, 3811-3815
3811
A Str a tegy for th e Solu tion -P h a se P a r a llel Syn th esis of
N-(P yr r olid in ylm eth yl)h yd r oxa m ic Acid s
Masaru Takayanagi, Timo Flessner, and Chi-Huey Wong*
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La J olla, California 92037
Received February 10, 2000
Both five- and six-membered iminocyclitols have proven to be useful transition-state analogue
inhibitors of glycosidases. They also mimic the transition-state sugar moiety of the nucleoside
phosphate sugar in glycosyltransferase-catalyzed reactions. Described here is the development of
a general strategy toward the parallel synthesis of a five-membered iminocyclitol linked to a
hydroxamic acid group designed to mimic the transition state of GDP-fucose complexed with
Mn(II) in fucosyltransferase reactions. The iminocyclitol 8 containing a protected hydroxylamine
unit was prepared from D-mannitol. The hydroxamic acid moiety was introduced via the reaction
of 8 with various acid chlorides. The strategy is generally applicable to the construction of libraries
for identification of glycosyltransferase inhibitors.
Five- and six-membered iminocyclitols have been shown
to be potent inhibitors of glycosidases as they mimic the
transition state of the enzymatic reaction.1 These het-
erocycles also mimic the transition state of the sugar
moiety of the nucleoside phosphate derivative in glyco-
syltransferase-catalyzed reactions and thus have been
used as core structures for development of inhibitors of
glycosyltransferases.2 Most glycosyltransferases require
Mn(II) or Mg(II), which presumably form a complex with
the pyrophosphate group of the nucleoside phosphate
sugar substrate.3 Incorporation of a metal chelating
functionality to the iminocyclitol at the corresponding
pyrophosphate position is thus considered to be a useful
strategy for development of glycosyltransferase inhibi-
tors. Here we report a new method suitable for the
parallel synthesis of N-(pyrrolidinylmethyl)hydroxamic
acids as a representative example designed to target
fucosyltransferases (Figure 1), which are often associated
with inflammatory diseases and cancer metastasis. We
chose hydroxamic acid as it has been used successfully
in the development of metalloprotease inhibitors.4
To begin our parallel synthesis, the fuco-type iminocy-
clitol, N-(pyrrolidinylmethyl)hydroxylamine (8), was first
prepared for the introduction of a substituted hydroxamic
acid moiety. Thus, 1-trityl-3,4-isopropylidene-D-mannitol
1 was prepared from D-mannitol as reported previously.5
Selective tosylation of the primary hydroxy group fol-
lowed by reduction with lithium aluminum hydride gave
diol 2 in 84% yield (Scheme 1). Selective monomesylation
on the less hindered 5-hydroxy group was conducted to
give monomesylate 3 in 46% yield, which was treated
with sodium azide in HMPA to afford the azide derivative
4. Further improvement could be achieved by directly
converting diol 2 into the azido alcohol 4 via a selective
Mitsunobu reaction using hydrazoic acid as the azide
source (Scheme 2). Compound 4 was oxidized with NMO
in the presence of catalytic amounts of TPAP6 and
deprotected under acidic conditions to obtain ketotriol 5
in high yield. After selective protection on the primary
hydroxy group with TBS,7 reduction of the azide group
followed by intramolecular reductive amination was
performed with 5% rhodium on alumina under an
atmospheric pressure (15 psi). For this reaction, rhodium
on alumina is a superior catalyst8 for the preparation of
6, which was obtained in > 4% facial selectivity. Indeed,
using 10% Pd-C gave only 80% facial selectivity even
under a high hydrogen pressure (50 psi). The nitrogen
group on the pyrrolidine ring was protected by the Cbz
group and the two hydroxy groups were protected as
benzyl ether. The TBS group on the primary hydroxy
group was then removed by TBAF to give alcohol 7 in
81% yield in three steps. Subsequent oxidation of alcohol
7 with TPAP-NMO gave an aldehyde, which was reduc-
tively coupled with O-benzylhydroxylamine to afford
(1) (a) Ganem, B. Acc. Chem. Res. 1996, 29, 340. (b) Hughes, A. B.;
Rudge, A. J . Nat. Prod. Rep. 1994, 135. (c) Legler, G. Adv. Carbohydr.
Chem. Biochem. 1990, 48, 319. (d) Look, G. C.; Fotsch, C. H.; Wong,
C.-H. Acc. Chem. Res. 1993, 26, 182. (e) Winchester, B.; Fleet, G. W.
J . Glycobiology 1992, 2, 199. (f) Bols, M. Acc. Chem. Res. 1998, 31, 1.
(g) Sears, P.; Wong, C.-H. Angew. Chem. Int. Ed. Engl. 1999, 38, 2300.
(h) Ichikawa, Y.; Igarashi, Y.; Ichikawa, M.; Suhara, Y. J . Am. Chem.
Soc. 1998, 120, 3007.
(2) (a) Wong, C.-H.; Dumas, D. P.; Ichikawa, Y.; Koseki, K.;
Danishefsky, D. J .; Weston, B. W.; Lown, J . B. J . Am. Chem. Soc. 1992,
114, 7321. (b) Qiao, L.; Murray, B. W.; Shimazaki, M.; Schultz, J .;
Wong, C.-H. J . Am. Chem. Soc. 1996, 118, 7653. (c) Kim, Y. J .;
Ichikawa, M.; Ichikawa, Y. J . Am. Chem. Soc. 1999, 121, 5829.
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90, 47. (c) Breuer, W.; Bause, E. Eur. J . Biochem. 1995, 228, 689. (d)
Ram, B. P.; Munjal, D. D. CRC Crit. ReV. Biochem. 1987, 17, 257. (e)
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262, 5784.
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Almstead, N. G.; Bradley, R. S.; Pikul, S.; De, B.; Natchus, M. G.;
Taiwo, Y. O.; Gu, F.; Williams, L. E.; Hynd, B. A.; J anusz, M. J .;
Dunaway, C. M.; Mieling, G. E. J . Med. Chem. 1999, 42, 4547. (c)
Groneberg, R. D.; Burns, C. J .; Morrissette, M. M.; Darnbrough, S.;
Djuric, S. W.; Condon, S. M.; McGeehan, G. M.; Labaudiniere, R.;
Neuenschwander, K.; Scotese, A. C.; Kline, J . A. J . Med. Chem. 1999,
42, 541. (d) Levy, D. E.; Lapierre, F.; Liang, W.; Ye, W.; Lange, C. W.;
Li, X.; Grobelny, D.; Casabonne, M.; Tyrrell, D.; Holme, K.; Nadzan,
A.; Galardy, R. E. J . Med. Chem. 1998, 41, 199.
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10.1021/jo000186k CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/18/2000

3812 J . Org. Chem., Vol. 65, No. 12, 2000
Takayanagi et al.
F igu r e 1.
Sch em e 1a
a
Conditions: (a) ref 5; (b) TsCl, py, 12 h; (c) LAH, THF, reflux, 10 h; (d) MsCl, Et3N, CH2Cl2, 0 °C, 10 h; (e) NaN3, HMPA, 80 °C, 8 h;
(f) TPAP (cat.), NMO, 4A-MS, CH2Cl2, 1 h; (g) 80% TFA, 20 min; (h) TBSCl, TEA, DMAP, CH2Cl2, 12 h; (i) H2, Rh-Al2O3, EtOH, 8 h; (j)
CbzCl, K2CO3, THF-H2O (4:1), 0 °C, 30 min; (k) BnBr, NaH, DMF, 10 h; (l) TBAF, THF, 0 °C, 1 h; (m) TPAP (cat.), NMO, 4Å-MS,
CH2Cl2, 1 h; (n) H2NOBn‚HCl, py, 2 h; (o) NaBH3CN, AcOH, 2 h.
Sch em e 2a
(pyrrolidinylmethyl)hydroxylamine 8 was treated with
1.5 equiv of acid chloride in dichloromethane in the
presence of polymer-supported base 11. After the reaction
was complete (1 h) as monitored by TLC, scavenger resins
were added and the reaction mixtures were stirred for
additional 4 h. During this period, the excess acid
chloride was trapped on the polyamine-type resin (12)
by amide formation, and trace amounts of the unreacted
starting material 8 were trapped by the isocyanate-type
resin (13) through the formation of urea. Filtration to
remove the resins followed by evaporation yielded suf-
ficiently pure products without aqueous workup or
further purification. Deprotection of the Cbz and benzyl
groups by hydrogenation with 10% Pd-C in acetic acid
gave the desired N-(pyrolidinylmethyl)hydroxamic acids
a
Conditions: (a) DEAD, PPh3, HN3 in toluene (1.3 M), THF,
3 h.
protected N-(pyrrolidinylmethyl)hydroxylamine 8 in 79%
yield. The stereochemistry of 6 was determined by NMR
on the basis of NOE between H-2 and H-5.
A substituted hydroxamic acid was then introduced to
8 in a format suitable for library construction. The
solution-phase parallel synthesis of N-(pyrrolidinylmeth-
yl)hydroxamic acids was performed with polymer-sup-
ported base (11), polyamine-type scavenger resins (12),
and isocyanate-type scavenger resin (13).9 Thus, N-
(9) (a) Creswell, M. W.; Bolton, G. L.; Hodges, J . C.; Meppen, M.
Tetrahedron 1998, 54, 3983. (b) Kaldor, S. W.; Siegel, M. G.; Fritz, J .
E.; Dressman, B. A.; Hahn, P. J . Tetrahedron Lett. 1996, 37, 7193. (c)
Kaldor, S. W.; Fritz, J . E.; Tang, J .; Mckinney, E. R. Bioorg. Med. Chem.
Lett. 1996, 6, 3041.

Synthesis of N-(Pyrrolidinylmethyl)hydroxamic Acids
J . Org. Chem., Vol. 65, No. 12, 2000 3813
Sch em e 3
Ta ble 1. Solu tion -P h a se P a r a llel Syn th esis of
N-(P yr r olid ylm eth yl)h yd r oxa m ic Acid s,
N-(P yr r olid ylm eth yl)-N-h yd r oxyca r ba m a tes, a n d
N-(P yr r olid ylm eth yl)-N-h yd r oxyu r ea s
distilled before use. Solvent evaporation was performed under
reduced pressure below 30 °C using a rotary evaporator,
followed by evacuation (<0.1 mmHg) to constant sample
weight. High-resolution mass spectra (HRMS) were recorded.
1H NMR spectra were obtained at 400, 500, or 600 MHz and
13C NMR at 125 or 150 MHz. Silica gel 60 (230-240 mesh)
was used in chromatography.
6-Deoxy-3,4-O-isopr opyliden e-1-O-tr ityl-D-m an n itol (2).
To a solution of 3,4-O-isopropylidene-1-O-trityl-D-mannitol (1)
(35.1 g, 75.6 mmol) in dry pyridine (200 mL) was added
p-tolenesulfonyl chloride (17.3 g, 90.7 mmol) at room temper-
ature under argon. The reaction mixture was stirred for 12 h
at room temperature and quenched by addition of saturated
aqueous NaHCO3 solution. The aqueous layer was then ex-
tracted with EtOAc three times. The combined organic extracts
were washed with saturated aqueous CuSO4 solution (to
remove pyridine), saturated aqueous NaHCO3 solution, water,
and brine successively and dried over Na2SO4. Removal of
solvent gave 3,4-O-isopropylidene-6-O-p-tolenesunfonyl-1-O-
trityl-D-mannitol as a crude compound. To a solution of crude
3,4-O-isopropylidene-6-O-p-toluenesulfonyl-1-O-trityl-D-man-
nitol in dry THF (500 mL) was added LAH (11.5 g, 302.4 mmol)
at 0 °C under argon. The reaction mixture was refluxed for
10 h and quenched by addition of 10% aqueous KHSO4 solu-
tion. Then the aqueous layer was extracted with ethyl acetate
three times. The combined organic extracts were washed with
10% aqueous KHSO4 solution, saturated aqueous NH4Cl
solution, water, and brine successively and dried over Na2SO4.
Removal of the solvent followed by silica gel column chroma-
tography (EtOAC/toluene ) 1:5) gave 2 (28.5 g, 84% in two
steps): 1H NMR (500 MHz, acetone-d6) δ 1.21 (d, 3 H, J )
5.9 Hz), 1.25 (s, 3 H), 1.28 (s, 3 H), 3.22 (dd, 1 H, J ) 5.9, 9.5
Hz), 3.35 (dd, 1 H, J ) 2.6, 9.5 Hz), 3.68 (t, 1 H, J ) 7.2
Hz), 3.73 (m, 1 H), 3.84 (m, 1 H), 3.89 (dd, 1 H, J ) 7.2, 8.3
Hz), 4.53 (d, 1 H, J ) 3.3 Hz), 4.97 (d, 1 H, J ) 3.7 Hz), 7.22-
7.26 (m, 3 H), 7.29-7.33 (m, 6 H), 7.51-7.54 (m, 6 H); 13C
NMR (125 MHz, acetone-d6) δ 20.73, 27.24, 27.30, 66.90, 69.53,
73.32, 81.13, 85.42, 87.25, 109.27, 127.74 (3 C), 128.49 (6 C),
molecular
formula
obsd yieldb purityc
entry electrophile product
MSa
(%)
(%)
1
2
3
4
5
14
15
16
17
18
10a
10b
10c
10d
10e
C8H16N2O4 205.1
14H28N2O4 289.2
C9H18N2O5 235.1
82
83
90
88
85
84
93
77
93
83
C
C
C
11H22N2O5 263.1
15H31N3O4 318.2
Confirmed by mass spectra (ESI, MH+). Yields are based on
a
b
weight of crude sample. c Purity was determined by HPLC analysis
of crude product.
10a ,b in good yield and purity. This method was also
applied successfully using chloroformates and isocyanates
as electrophiles to obtain N-hydroxycarbamates 10c,d
and N-hydroxyurea 10e in good yields and purity (Scheme
3, Table 1). In the isocyanate case, it was not necessary
to use the polymer-supported resin 11.
In summary, we have described a new parallel method
for the synthesis of N-(pyrrolidinylmethyl)hydroxamic
acids. We have also described a novel method for the
solution-phase parallel synthesis of hydroxamic acids
using polymer-supported reagents and scavenger resins.
This method is useful for the rapid construction of
iminocyclitol libraries containing hydroxamic acid, N-
hydroxycarbamate, or N-hydroxyurea side chains, which
may have potential applications in development of gly-
cosyltransferase inhibitors.
129.65 (6 C), 145.27 (3 C); [R]20 8.1 (c 1.27, EtOAc); HRMS
D
(MALDI-FTMS) calcd for C28H32O5 + Na+ 471.2147, found
471.2149.
Exp er im en ta l Section
6-Deoxy-3,4-O-isop r op ylid en e-5-O-m eth a n esu lfon yl-1-
O-tr ityl-D-m a n n itol (3). To a mixture of 2 (14.4 g, 32.0 mmol)
and triethylamine (8.9 mL, 64.0 mmol) in dry CH2Cl2 (320 mL)
Gen er a l Meth od s. The reagents and solvents used were
reagent grade and used as supplied except for THF, which was

3814 J . Org. Chem., Vol. 65, No. 12, 2000
Takayanagi et al.
was added methanesulfonyl chloride (3.0 mL, 38.4 mmol) at 0
°C under argon. The reaction mixture was stirred for 10 h at
0 °C and quenched by addition of saturated aqueous NaHCO3
solution. The aqueous layer was then extracted with EtOAc
three times. The combined organic extracts were washed with
saturated aqueous NaHCO3 solution, water, and brine suc-
cessively and dried over Na2SO4. Removal of the solvent
followed by silica gel column chromatography (EtOAC/toluene
) 1:5) gave 3 (7.75 g, 46%): 1H NMR (600 MHz, CDCl3) δ 1.29
(s, 3 H), 1.36 (s, 3 H), 1.44 (d, 3 H, J ) 6.6 Hz), 2.60 (d, 1 H,
J ) 4.4 Hz), 2.96 (s, 3 H), 3.27 (dd, 1 H, J ) 6.6, 9.7 Hz), 3.43
(dd, 1 H, J ) 3.5, 9.7 Hz), 3.73 (m, 1 H), 3.79 (t, 1 H, J ) 7.0
Hz), 4.19 (dd, 1 H, J ) 3.5, 7.0 Hz), 4.95 (dq, 1 H, J ) 3.5, 6.6
Hz), 7.22-7.47 (m, 15 H); 13C NMR (150 MHz, CDCl3) δ 15.96,
26.98, 27.11, 38.45, 65.08, 72.48, 77.35, 78.33, 81.53, 87.02,
110.33, 127.12 (3 C), 127.86 (6 C), 128.52 (6 C), 143.59 (3 C);
for 12 h at room temperature and quenched by addition of
saturated aqueous NaHCO3 solution. Then the aqueous layer
was extracted with EtOAc three times. The combined organic
extracts were washed with saturated aqueous NaHCO3 solu-
tion, water, and brine successively and dried over Na2SO4.
Removal of solvent gave 5-azido-1-O-(tert-butyldimethylsilyl)-
5,6-deoxy-L-xylo-hex-2-ulose as a crude compound. A mixture
of crude 5-azide-1-O-(tert-butyldimethylsilyl)-5,6-deoxy-L-xylo-
hex-2-ulose and 5% rhodium-alumina (100 mg) in ethanol (50
mL) was hydrogenated under an atmospheric pressure of
hydrogen using a balloon with vigorous stirring for 3 h. The
mixture was filtered through Celite, and the solvent was
evaporated. Purification by silica gel column chromatography
(MeOH/CH2Cl2 ) 5:95) gave 6 (1.08 g, 78% in two steps): 1H
NMR (500 MHz, MeOH-d4) δ 0.11 (s, 6 H), 0.93 (s, 9 H), 1.20
(d, 3 H, J ) 6.6 Hz), 2.99 (q, 1 H, J ) 4.6 Hz), 3.31 (dq, 1 H,
J ) 6.6, 4.1 Hz), 3.77 (dd, 1 H, J ) 4.6, 10.3 Hz), 3.79 (dd, 1
H, J ) 2.0, 4.6 Hz), 3.82 (dd, 1 H, J ) 4.6, 10.3 Hz), 3.84 (dd,
1 H, J ) 2.0, 4.1 Hz); 13C NMR (125 MHz, MeOH-d4) δ -5.39,
-5.33, 13.27, 19.19, 26.37 (3 C), 58.20, 63.80, 68.80, 80.13,
80.51; [R]20D 20.9 (c 0.54, MeOH); HRMS (MALDI-FTMS) calcd
for C12H27NO3Si + H+ 262.1833, found 262.1834.
[R]20 9.4 (c 1.57, EtOAc); HRMS (MALDI-FTMS) calcd for
D
C29H34O7S + Na+ 549.1917, found 549.1929.
6-Deoxy-3,4-O-isopr opyliden e-5-azido-1-O-tr ityl-D-m an -
n itol (4). (A) To a solution of 3 (7.75 g, 14.7 mmol) in dry
HMPA (150 mL) was added sodium azide (9.57 g, 147 mmol)
at room temperature under argon. The reaction mixture was
stirred for 8 h at 80 °C and quenched by addition of saturated
aqueous NH4Cl solution. The aqueous layer was then extracted
with EtOAc three times. The combined organic extracts were
washed with saturated aqueous NH4Cl solution, saturated
aqueous NaHCO3 solution, water, and brine successively and
dried over Na2SO4. Removal of solvent gave 5-azide-5,6-
dideoxy-3,4-O-isopropylidene-1-O-trityl-L-gulitol as a crude
compound. The yield was determined when compound 5 was
purified.
5-N-Ben zyloxycar bon yl-3,4-di-O-ben zyl-2,5-im in o-2,5,6-
tr id eoxy-L-id itol (7). To a mixture of 5 (439 mg, 1.68 mmol)
and K2CO3 (423 mg, 5.04 mmol) in a 2:1 mixture of THF and
water (8 mL) was added benzyl chloroformate (360 µL, 2.52
mmol) at 0 °C. The reaction mixture was stirred for 30 min at
0 °C and quenched by addition of saturated aqueous NaHCO3
solution. Then the aqueous layer was extracted with EtOAc
three times. The combined organic extracts were washed with
saturated aqueous NaHCO3 solution, water, and brine suc-
cessively and dried over Na2SO4. Removal of solvent gave 5-N-
benzyloxycarbonyl-1-O-(tert-butyldimethylsilyl)-2,5-imino-2,5,6-
trideoxy-L-iditol as a crude compound. To a mixture of crude
5-N-benzyloxycarbonyl-1-O-(tert-butyldimethylsilyl)-2,5-imino-
2,5,6-trideoxy-L-iditol and benzylbromide (799 µL g, 6.72 mmol)
in dry DMF (17 mL) was added 95% sodium hydride (170 mg,
6.72 mmol) at room temperature under argon. The reaction
mixture was stirred for 10 h at room temperature and
quenched by addition of saturated aqueous NH4Cl solution.
Then the aqueous layer was extracted with ether three times.
The combined organic extracts were washed with saturated
aqueous NH4Cl solution, water, and brine successively and
dried over Na2SO4. Removal of solvent gave 3,4-di-O-benzyl-
5-N-benzyloxycarbonyl-1-O-(tert-butyldimethylsilyl)-2,5-imino-
2,5,6-trideoxy-L-iditol as a crude compound. To a solution of
crude 3,4-di-O-benzyl-5-N-benzyloxycarbonyl-1-O-(tert-butyldi-
methylsilyl)-2,5-imino-2,5,6-trideoxy-L-iditol in THF (17 mL)
was added 1.0 M THF solution of tetrabutylammonium
fluoride (20.2 mL, 2.02 mmol) at 0 °C. The reaction mixture
was stirred for 1 h at 0 °C and quenched by addition of
saturated aqueous NH4Cl solution. Then the aqueous layer
was extracted with EtOAc three times. The combined organic
extracts were washed with saturated aqueous NH4Cl solution,
water, and brine successively and dried over Na2SO4. Removal
of the solvent followed by silica gel column chromatography
(EtOAc/hexane ) 1:2) gave 7 (628 mg, 81% in three steps):
1H NMR (500 MHz, C6D6, 340 K) δ 1.21 (d, 3 H, J ) 6.6 Hz),
3.72 (t, 2 H, J ) 6.3 Hz), 3.88 (m, 1 H), 3.95 (t, 1 H, J ) 5.5
Hz), 4.00 (m, 1 H), 4.17 (m, 1 H), 4.19 (d, 1 H, J ) 12.5 Hz),
4.21 (d, 1 H, J ) 12.5 Hz), 4.46 (d, 1 H, J ) 12.1 Hz), 4.50 (d,
(B) To an ice-cold solution of 2 (2.0 g, 4.46 mmol) and
triphenylphoshine (1.64 g, 6.24 mmol) in 20 mL of THF were
added diethylazodicarboxylate (983 µL, 6.24 mmol) and a 1.3
M solution of hydrazoic acid in toluene (11 mL). After 3 h at
room temperature, water and Et2O were added. The aqueous
layer was extracted with Et2O, and the combined organic
layers were washed with brine and dried over Na2SO4. After
removal of the solvent the crude material was purified on silica
gel (EtOAc/hexanes 1/15, then 1/10) to give 4 (1.79 g, 85%):
1H NMR (400 MHz, CDCl3) δ 1.32 (s, 3 H), 1.37 (d, 3 H, J )
7.0 Hz), 1.45 (s, 3 H), 3.32 (m, 2 H), 3.38 (dq, 1 H, J ) 2.4, 6.8
Hz), 3.74 (m, 1 H), 3.93 (dd, 1 H, J ) 7.3, 2.4 Hz), 4.04 (dd, 1
H, J ) 7.3, 7.3 Hz), 7.22-7.44 (m, 15 H); 13C NMR (150 MHz,
CDCl3) δ 16.22, 26.79, 27.24, 56.49, 64.71, 72.05, 77.15, 82.56,
87.01, 109.81, 127.18 (3 C), 127.92 (6 C), 128.57 (6 C), 143.55
(3 C); HRMS (MALDI-FTMS) calcd for C28H31N3O4 + Na+
496.2212, found 496.2202.
5-Azid e-5,6-d id eoxy-L-xylo-h exo-2-u lose (5). To a sus-
pension of cude 5-azide-5,6-dideoxy-3,4-O-isopropylidene-1-O-
trityl-L-gulitol and predried 4 Å molecular sieves (2.5 g) in dry
CH2Cl2 (150 mL) was added N-methylmorpholine N-oxide (2.58
g, 22.1 mmol) at room temperature under argon. The reaction
mixture was stirred for 10 min at room temperature, before
TPAP (258 mg, 0.74 mmol) was added. The reaction mixture
was stirred for 1 h at room temperature and filtered through
a pad of silica gel, eluting with CH2Cl2. Evaporation of the
filtrate gave 5-azide-5,6-deoxy-3,4-O-isopropylidene-1-O-trityl-
L-xylo-hexo-2-ulose as a crude compound. The solution of crude
5-azide-5,6-deoxy-3,4-O-isopropylidene-1-O-trityl-L-xylo-hexo-
2-ulose in 80% TFA (50 mL) was stirred for 1 h at 0 °C.
Removal of the solvent followed by silica gel column chroma-
tography (MeOH/CH2Cl2 ) 5:95) gave 5 (2.03 g, 73%): 1H NMR
(600 MHz, MeOH-d4) δ 1.23 (d, 3 H, J ) 7.0 Hz), 3.66 (dq, 1
H, J ) 7.0, 7.0 Hz), 3.76 (dd, 1 H, J ) 2.6, 7.0 Hz), 4.29 (d, 1
H, J ) 2.6 Hz), 4.46 (d, 1 H, J ) 19.3 Hz), 4.54 (d, 1 H, J )
19.3 Hz); 13C NMR (150 MHz, MeOH-d4) δ 16.29, 60.89, 67.68,
77.06 (3 C), 212.99; [R]20D -20.5 (c 0.79, MeOH); HRMS (FAB)
calcd for C6H11N3O4 + Na+ 212.0647, found 212.0639.
1-O-(ter t-Bu tyld im eth ylsilyl)-2,5-im in o-2,5,6-tr id eoxy-
L-id itol (6). To a mixture of 5 (1.00 g, 5.31 mmol), triethyl-
amine (1.48 mL, 10.6 mmol), and 4-(N,N-dimethylamino)-
pyridine (6.5 mg, 0.05 mmol) in dry CH2Cl2 (50 mL) was added
tert-butyldimethylsilyl chloride (1.20 g, 7.97 mmol) at room
temperature under argon. The reaction mixture was stirred
1 H, J ) 12.1 Hz), 5.08 (s, 2 H), 6.98-7.24 (m, 15 H); [R]20
D
12.5 (c 1.03, EtOAc); HRMS (MALDI-FTMS) calcd for C28H31
-
NO5 + Na+ 484.2100, found 484.2081.
1-Am in o-1-N-ben zyloxy-5-N-ben zyloxyca r bon yl-3,4-d i-
O-ben zyl-2,5-im in o-1,2,5,6-tetr a d eoxy-L-id itol (8). To a
suspension of 7 (558 mg, 1.21 mmol) and predried 4 Å
molecular sieves (210 mg) in dry CH2Cl2 (12 mL) was added
N-methylmorpholine N-oxide (213 mg, 1.82 mmol) at room
temperature under argon. The reaction mixture was stirred
for 10 min at room temperature, and TPAP (21.3 mg, 0.061
mmol) was then added. The reaction mixture was stirred for
1 h at room temperature and filtered through a pad of silica
gel, eluting with a 1:1 mixture of EtOAc and CH2Cl2. Evapora-
tion of the filtrate gave 3,4-di-O-benzyl-5-N-benzyloxycarbonyl-

Synthesis of N-(Pyrrolidinylmethyl)hydroxamic Acids
J . Org. Chem., Vol. 65, No. 12, 2000 3815
2,5-imino-2,5,6-trideoxy-L-idose as a crude compound. The
mixture of crude 3,4-di-O-benzyl-5-N-benzyloxycarbonyl-2,5-
imino-2,5,6-trideoxy-L-idose and O-benzylhydroxylamine hy-
drochloride (251 mg, 1.57 mmol) in dry pyridine (12 mL) was
stirred for 2 h at room temperature. Removal of solvent gave
oxime as a crude compound. To a solution of oxime in glacial
AcOH (12 mL) was added sodium cyanoborohydride (129 mg,
2.06 mmol) at room temperature under argon. The reaction
mixture was stirred for 2 h at room temperature and quenched
by addition of water. Then the aqueous layer was extracted
with EtOAc three times. The combined organic extracts were
washed with saturated aqueous NaHCO3 solution, water ,and
brine successively and dried over Na2SO4. Removal of the
solvent followed by silica gel column chromatography (EtOAc/
hexane ) 1:4) gave 8 (542 mg, 79% in three steps): 1H NMR
(500 MHz, C6D6, 340 K) δ 1.32 (d, 3 H, J ) 6.6 Hz), 3.28 (dd,
1H, J ) 7.1, 13.0 Hz), 3.39 (dd, 1 H, J ) 4.6, 13.0 Hz), 3.75
(dd, 1 H, J ) 4.4, 6.6 Hz), 4.12 (t, 1 H, J ) 4.4 Hz), 4.20 (d, 1
H, J ) 11.7 Hz), 4.25 (d, 1 H, J ) 11.7 Hz), 4.27 (m, 2 H), 4.48
(d, 1 H, J ) 12.5 Hz), 4.51 (d, 1 H, J ) 12.5 Hz), 4.61 (d, 1 H,
J ) 12.2 Hz), 4.64 (d, 1 H, J ) 12.2 Hz), 5.11 (s, 2 H), 5.69 (br
s, 1 H), 7.00-7.35 (m, 20 H); 13C NMR (125 MHz, C6D6, 340
K) δ 15.96, 55.18, 56.31, 61.88, 67.49, 72.29, 72.89, 76.51,
83.71, 84.16, 128.10, 128.25, 128.68, 128.85, 128.93, 128.98,
Hz), 4.02 (dd, 1 H, J ) 6.6, 12.5 Hz), 4.06 (br s, 1 H); HRMS
(MALDI-FTMS) calcd for C8H16N2O4 + H+ 205.1183, found
205.1178.
1-Am in o-1-N-h yd r oxy-2,5-im in o-1-N-sep t ylca r b on yl-
1,2,5,6-tetr a d eoxy-L-id itol (10b): 1H NMR (500 MHz, MeOH-
d4, 330 K) δ 0.89 (t, 3 H, J ) 7.0 Hz), 1.26 (d, 3 H, J ) 7.0 Hz),
1.28-1.36 (m, 8 H), 1.61 (m, 2 H), 2.48 (dt, 2 H, J ) 4.9, 7.6
Hz), 3.38 (ddd, 1 H, J ) 3.3, 4.8, 8.1 Hz), 3.46 (dq, 1 H, J )
3.7, 7.0 Hz), 3.84 (dd, 1 H, J ) 1.8, 3.7 Hz), 3.85 (dd, 1 H, J )
4.8, 14.7 Hz), 3.93 (dd, 1 H, J ) 1.8, 3.3 Hz), 3.97 (dd, 1 H, J
) 8.1, 14.7 Hz); HRMS (MALDI-FTMS) calcd for C14H28N2O4
+ H+ 289.2122, found 289.2120.
1-Am in o-1-N-et h oxyca r b on yl-1-N-h yd r oxy-2,5-im in o-
1,2,5,6-tetr a d eoxy-L-id itol (10c): 1H NMR (500 MHz, MeOH-
d4, 330 K), δ 1.24 (t, 3 H, J ) 7.2 Hz), 1.27 (d, 3 H, J ) 7.0
Hz), 3.82 (m, 2 H), 3.86 (br s, 1 H), 3.94 (br s, 1 H), 4.13 (q, 2
H, J ) 7.2 Hz), 4.17 (d, 1 H, J ) 7.0 Hz), 4.20 (d, 1 H, J ) 7.0
Hz); HRMS (MALDI-FTMS) calcd for C9H18N2O5 + H+
235.1288, found 235.1288.
1-Am in o-1-N-h ydr oxy-2,5-im in o-1-N-isobu toxycar bon yl-
1,2,5,6-tetr a d eoxy-L-id itol (10d ): 1H NMR (500 MHz, MeOH-
d4, 330 K), δ 0.93 (d, 6 H, J ) 7.0 Hz), 1.24 (d, 3 H, J ) 6.6
Hz), 1.28 (m, 1 H), 3.44 (t, 1 H, J ) 4.4 Hz), 3.62 (t, 1 H, J )
4.4 Hz), 3.72-3.78 (m, 2 H), 3.84-3.92 (m, 4 H); HRMS
(MALDI-FTMS) calcd for C11H22N2O5 + H+ 263.1601, found
263.1608.
1-Am in o-1-N-h yd r oxy-2,5-im in o-1-N-octyla m in oca r bo-
n yl-1,2,5,6-t et r a d eoxy-L-id it ol (10e): 1H NMR (500 MHz,
MeOH-d4, 330 K), δ 0.88 (t, 3 H, J ) 7.0 Hz), 1.25 (d, 3 H, J
) 6.6 Hz), 1.28-1.33 (m, 12 H), 3.00 (t, 2 H, J ) 6.8 Hz), 3.20-
3.36 (m, 3 H), 3.55 (dq, 1 H, J ) 4.0, 6.6 Hz), 3.81 (dd, 1 H, J
) 2.5, 4.0 Hz), 3.86 (dd, 1 H, J ) 2.5, 4.0 Hz).
129.03, 138.07, 138.99, 139.41, 139.48, 154.14; [R]20 10.2 (c
D
1.23, EtOAc); HRMS (MALDI-FTMS) calcd for C35H38N2O5 +
H+ 567.2853, found 567.2851.
Gen er a l P r oced u r e for Solu tion -P h a se P a r a llel Syn -
th esis. To a suspension of morpholinomethyl polystyrene resin
(0.3 mmol) in dry CH2Cl2 (1 mL) was added 8 (0.1 mmol) and
the electrophile (0.3 mmol) at room temperature under argon.
The reaction mixture was stirred for 1 h at room temperature,
and then methylisocyanate polystyrene resin (0.1 mmol) and
Tris-(2-aminoethyl)amine polystyrene resin (0.6 mmol) were
added. The reaction mixture was stirred for additional 4 h at
room temperature and filtered. Evaporation of the filtrate gave
9. A mixture of 9 and 10% Pd-C (10 mg) in AcOH (1 mL) was
hydrogenated under 1 atm pressure of hydrogen using a
balloon with vigorous stirring for 3 h. The mixture was filtered
through Celite, and the solvent was evaporated to afford 10.
1-N-Acetyl-1-a m in o-1-N-h yd r oxy-2,5-im in o-1,2,5,6-tet-
r a d eoxy-L-id itol (10a ): 1H NMR (600 MHz, MeOH-d4) δ 1.39
(d, 3 H, J ) 6.5 Hz), 2.14 (s, 3 H), 3.63 (m, 1 H), 3.75 (dt, 1 H,
J ) 3.1, 6.6 Hz), 3.91 (br s, 1 H), 3.98 (dd, 1 H, J ) 6.6, 12.5
Ack n ow led gm en t. This research was supported by
the NIH (GM 44154) and the Deutsche Forschungsge-
meinschaft DFG (fellowship for T.F.).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
the compounds 2-8 and 10 and 13C NMR spectra for the
compounds 2-6 and 8. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O000186K