Enantioselective Synthesis of 5-LO Inhibitor Hydroxyureas. Tandem Nucleophilic Addition-Intramolecular Cyclization of Chiral Nitrones

Article abstract of DOI:10.1021/jo9621736

An enantioselective synthesis of chiral hydroxyurea based 5-lipoxygenase inhibitors is reported via a five-step sequence in about 30% overall yield. The synthesis is based on a novel tandem nucleophilic addition-intramolecular cyclization reaction in which a chiral nitrone functions as the electrophilic acceptor species. A mannose-based chiral auxiliary controls the diastereoselectivity of the reaction in an 8:1 ratio. After the auxiliary removal and appropriate functionalization, a single recrystallization afforded the target structures in >99% ee.

Full text of DOI:10.1021/jo9621736

J . Org. Chem. 1997, 62, 5385-5391
5385
En a n tioselective Syn th esis of 5-LO In h ibitor Hyd r oxyu r ea s.
Ta n d em Nu cleop h ilic Ad d ition -In tr a m olecu la r Cycliza tion of
Ch ir a l Nitr on es
Ivan Lantos,*,† J oseph Flisak,† Li Liu,† Richard Matsuoka,† Wilf Mendelson,†
David Stevenson,† Ken Tubman,† Lynn Tucker,† Wei-Yuan Zhang,† J erry Adams,‡
Margaret Sorenson,‡ Ravi Garigipati,‡ Karl Erhardt,‡ and Steve Ross‡
Department of Chemistry, SmithKline Beecham Pharmaceuticals, P.O. Box 1539,
King of Prussia, Pennsylvania 19406
Received November 20, 1996X
An enantioselective synthesis of chiral hydroxyurea based 5-lipoxygenase inhibitors is reported
via a five-step sequence in about 30% overall yield. The synthesis is based on a novel tandem
nucleophilic addition-intramolecular cyclization reaction in which a chiral nitrone functions as
the electrophilic acceptor species. A mannose-based chiral auxiliary controls the diastereoselectivity
of the reaction in an 8:1 ratio. After the auxiliary removal and appropriate functionalization, a
single recrystallization afforded the target structures in >99% ee.
Sch em e 1
In tr od u ction
The leukotrienes have been implicated as mediators
in a number of inflammatory and vascular diseases.
Inhibition of their biosynthesis therefore has been con-
sidered to hold promise in the therapeutic intervention
of such diseases as asthma, allergy, and a host of others
and has been in the intense focus of pharmaceutical
research.1 The enzyme 5-lipoxygenase (5-LO) plays a
central role in the biosynthesis of leukotrienes by cata-
lyzing first the transformation of arachidonic acid to
5-HPETE and then to leukotriene-A4.2a This central role
has prompted several companies to initiate research
programs toward the discovery of drugs that would act
as inhibitors of this highly pivotal enzyme, and as the
result of this intense effort several drugs are now in
development.
Zileuton of Abbott Pharmaceuticals is the first selective
5-LO inhibitor on the market having received approval
from the FDA. Structurally, the compound contains a
chiral hydroxylamine moiety, and clinically the compound
is marketed as a racemate. Its chemical synthesis,
biological activities, and clinical data have been exten-
sively described in the literature.2b
In this communication we wish to report on the
extensive chemical development effort that was expended
on the synthesis of 1a and 1b culminating in an efficient
enantioselective synthesis capable of affording the com-
pounds in five steps, in 30% overall yield and >99% ee.
SmithKline Beecham has also been developing agents
that have shown very high inhibitory potency toward the
5-LO enzyme.3ab These compounds, 1a and 1b (SB
202235 and 210661), also contain the hydroxyurea phar-
macophore but now attached to a dihydrobenzofuran
moiety. The molecules are chiral, and our decision to
develop only the active enantiomer posed a major syn-
thetic challenge. Clearly, finding a chemical process
based on either an efficient resolution or an enantiose-
lective synthesis was the fundamental objective of this
program.
I. Th e F ir st Gen er a tion Syn th esis
The initial racemic synthesis is shown in Scheme 1.
Benzofuranone 2 was prepared from resorcinol and
chloroacetonitrile by the method of Shriner4 in 72% yield.
Conversion of 2 to the benzyl-substituted oximes 3a and
3b was achieved via standard methods in 81% and 94%
yields, respectively. Reduction of the oximes to the
hydroxylamines was carried out by applying a procedure
originally devised by Kikugawa5 involving treatment of
a (1:1) CH2Cl2/MeOH solution of 3 with a 5-fold excess
of the borane-pyridine complex in the presence of HCl.
The reaction routinely delivered the desired racemic
hydroxylamines 4a and 4b in better than 80% yield.
Resolution of the racemic compound was first ac-
complished via derivatization and chromatography.3a
While this method was successful in generating sufficient
† Chemical Development.
‡ Department of Medicinal Chemistry.
X Abstract published in Advance ACS Abstracts, J une 1, 1997.
(1) Brooks, C. D.; Summers, J . B. J . Med. Chem. 1996, 39, 2629.
(2) (a) Samuelsson, B. Science 1983, 220, 568. (b) Brooks, D. W.;
Carter, G. W. In The Search for Antiinflammatory Drugs; Merluzzi,
V. J ., Adams, J ., Eds.; Burkhauser: Boston, 1995; Chapter 5.
(3) (a) Garigipati, R. S.; Sorenson, M. E.; Erhardt, K. F.; Adams, J .
L. Tetrahedron Lett. 1993, 35, 5537. (b) Adams, J . L.; Garigipati, R.
S.; Sorenson, M.; Schmidt, S. J .; Brian, W. R.; Newton, J . F.; Tyrrell,
K. A.; Garver, E.; Yodis, L. A.; Chabot-Fletcher, M.; Tzimas, M.; Webb,
E. F.; Breton, J . J .; Griswold, D. E. J . Med. Chem. 1996, 39, 5035.
(4) Shriner, R. L.; Grosser, F. J . Am. Chem. Soc. 1942, 64, 382.
(5) Kawase, M.; Kikugawa, Y. J . Chem. Soc., Perkins Trans. 1 1979,
643.
S0022-3263(96)02173-1 CCC: $14.00 © 1997 American Chemical Society

5386 J . Org. Chem., Vol. 62, No. 16, 1997
Lantos et al.
Sch em e 2
enantiomerically pure materials for biological differentia-
tion the low throughput of the process prevented its use
for clinical development. A more practical solution was
provided by the finding that careful salt formation with
mandelic acid could accomplish an efficient resolution of
racemic precursor 4a in about 30-35% yield and 96-
98% ee. Resolution of 4b, however, was somewhat more
difficult on account of the lack of reproducibility of the
enantiopurity of the mandelic acid salts which varied over
the range of 34-92% ee. Recrystallization of these salts
from EtOAc, however, always consistently brought the
enantiomeric excess to >95%. As far as we know this is
the first time that the feasibility of classical resolution
of hydroxylamines has been documented in the literature.
Conversion of the enantiomerically pure hydroxyl-
amines 5a and 5b to the final hydroxyureas was per-
formed via the addition of KOCN/HOAc in DMF solution.
The reaction provided almost analytically pure sub-
stances in excess of 90% yield that could be further
purified to >99.0% optical purity by recrystallization from
hot DMF/TBME. The resolution process together with
the overall simplicity of the synthesis finally afforded us
the means to prepare both compounds (1a and 1b ) in
multikilogram quantities, thus fulfilling our initial objec-
tive. Having reached this initial goal, we could now turn
our attention to the invention of a more economical
synthesis based on the enantioselective generation of the
chiral hydroxylamine moiety.
amine and with excellent enantioselectivity (99% ee).
Similarly, reductive conversion of the O-benzyl oxime 6a
was also successful with 89.2% ee and in 63% yield.
It is noteworthy that neither the reagent of Corey9 nor
several related reagents were able to carry out the
reductions under identical conditions. Unfortunately, our
success in finding these reductive conditions10 for the
enantioselective formation of substituted hydroxylamines
did not lead to an efficient solution to the problem of
chiral synthesis. Numerous attempts at the selective
removal of hydroxylamino substituents resulted in re-
moval of both benzyl substituents in the molecule.
Surprisingly, attempted rebenzylation at the phenolic
hydroxyl could also not be accomplished. These results
were found not only with the penultimate intermediates
8 but also with their corresponding hydroxylurea deriva-
tives. These results forced us to pursue our goal in a
different direction.
The addition of carbon-bearing nucleophiles to nitrones
having a chiral auxiliary to form chiral hydroxylamines
was first noted by Chang and Coates.12 These workers
explored the addition of organometallic reagents to inter
alia chiral â-methoxy-R-phenylethyl-substituted nitrones.
Impressive diasteroselectivities were observed. This
approach was further progressed by Hu and Schwartz13
in their enantioselective synthesis of chiral hydroxyl-
amines via the addition of Grignard reagents to nitrones
bearing gulofuranosyl moieties. The very high diaste-
reoselectivities obtained and the mild conditions required
for auxiliary removal (the highly oxygen rich character
of the aryl moiety in 5a and 5b makes these molecules
inherently acid labile) prompted us to initiate an inves-
tigation into applying Schwartz’s method (interestingly
it now appears from the literature14 that three research
groups independently came to this same conclusion as
witnessed by subsequent publications).
II. En a n tioselective Syn th esis
Our first attempts explored the feasibility of generating
chiral hydroxylamines via the enantioselective reduction
of oxime ethers. Although highly effective asymmetric
reductions of oxime ethers to optically active amines have
been reported in recent years,6 useful enantioselective
conversions of oxime ethers into O-substituted hydroxy-
lamines have been relatively neglected. As far as we
know no such successful transformations have been
described.7 A method reported by Burk et al.8 involving
a highly efficient and enantioselective reduction of ben-
zoyl hydrazones to hydrazines by analogy appeared to
have potential for the reduction of oximes to hydroxyl-
amines. The analogous benzoyl oxime was readily pre-
pared; however, the reduction was not successful. Even
though we were able to fully reproduce Burk’s reported
results on his hydrazone substrates, the oximes totally
inhibited the reaction.
After surveying several other chiral reducing agents
for the asymmetric reduction of variously substituted
6-(benzyloxy)-2,3-dihydrobenzofuran 3-oximes, we found
that reagent 7, first reported by Sakito7 and prepared
from norephedrine and borane, reduced the O-(o-ni-
trobenzyl) ether 6b in respectable yields (55%) to the
corresponding optically active O-(o-nitrobenzyl) hydroxyl-
The route we have envisaged is shown in Scheme 3.
Conceptually, it involves a tandem nucleophilic addition
of dimethylsulfoxonium ylide to the benzaldehyde-based
nitrones 11a and 11b and cyclization of the in situ
generated intermediates. Commercially, readily avail-
(6) (a) Itsuno, S.; Nakano, M.; Miyazaki, K.; Masuda, H.; Ito, K. J .
Chem. Soc., Perkin Trans. 1 1985, 2039. (b) Itsuno, S.; Sakurai, Y.;
Shimizu, K.; Ito, K. J . Chem. Soc., Perkin Trans. 1 1989, 1548. (c)
Itsuno, S.; Sakurai, Y.; Shimizu, K.; Ito, K. J . Chem. Soc., Perkin Trans.
1 1990, 1859. (d) Itsuno, S.; Nakano, M.; Ito, K. J . Chem. Soc., Perkin
Trans. 1 1985, 2615. (e) Itsuno, S.; Tanaka, K.; Ito, K. Chem. Lett.
1986, 1133-1136. (f) Gibbs, D. E.; Barnes, D. Tetrahedron Lett. 1990,
31, 5555.
(9) Corey, E. J .; Bakshi, R. K.; Shibata, S. J . Am. Chem. Soc. 1987,
109, 5551.
(10) Dougherty, J . T.; Flisak, J . R.; Liu, L.; Tucker, L.; Lantos, I.;
Hayes, J . Tetrahedron: Asymm. 1997, 8, 497.
(11) Flisak, J . R; Lantos, I.; Liu, Li.; Matsuoka, R. T.; Mendelson,
W. L.; Tucker, L. M.; Villani, A. J .; Zhang, W.-Y. Tetrahedron Lett.
1996, 37, 4639.
(12) Chang, Z.-Y.; Coates, R. M. J . Org. Chem. 1990, 55, 3464.
(13) Hu, X.; Schwartz, M. A. Book of Abstracts, 204th National
Meeting of the American Chemical Society, Washington, D.C., 1992;
ORGN 5.
(7) Suzukamo et al. in their description of the asymmetric reduction
of oxime ethers to amines allude (in the notes to Table 1) to the
possibility of obtaining methyl ethers of hydroxylamines which were
not characterized: Sakito, Y.; Yoneyoshi, Y.; Suzukamo, G. Tetrahe-
dron Lett. 1988, 223-224.
(14) (a) Rohloff, J . C.; Alfredson, T. V.; Schwartz, M. A. Tetrahedron
Lett. 1994, 35, 1011. (b) Basha, A.; Henry, R.; Maclaughlin, M. A.;
Ratajczyk, J . D.; Wittenberger, S. J . J . Org. Chem. 1994, 59, 6103.
(8) Burk, M.; Feaster, J . E. J . Am. Chem. Soc. 1992, 114, 6266

Enantioselective Synthesis of 5-LO Inhibitor Hydroxyureas
J . Org. Chem., Vol. 62, No. 16, 1997 5387
Sch em e 3
needed for the reaction to take place. If the N-glycosyl
nitrone is pretreated with 1 equiv of potassium tert-
butoxide before methylide addition, the subsequent con-
densation-cyclization reaction is shut down completely.
On the other hand, if one pretreats the N-glycosyl nitrone
with 1 equiv of potassium tert-butoxide and subsequently
with trimethylsulfoxonium iodide at temperatures above
40 °C, the condensation-cyclization reaction proceeds,
albeit with much lower levels of diastereoselectivity due
to the rather high reaction temperature required.
Only one major side-product is formed in these reac-
tions, sulfoxides 14a and 14b (Scheme 4),18 which could
be minimized to <3% by treating the nitrones with no
more than 1 equiv of dimethylsulfoxonium methylide at
relatively low temperatures (ca. -10 °C).
The diastereoselectivity seen in the initial condensation
step of the addition of dimethylsulfoxonium methylide
to the various N-glycosyl nitrones was rationalized via
the Vasella transition state model19 known as the “kinetic
anomeric effect”. Vasella has used this model to describe
both additions of phosphorus nucleophiles and 1,3-dipoles
to N-glycosyl nitrones and observed selectivities similar
to what we observed in the methylide condensation. The
argument is schematically represented in Scheme 5.
The sterically less congested “O-endo” conformer of the
nitrone reacts preferentially over the “O-exo” conformer.
The nucleophile adds from the “syn” face because the
liberated p-orbital electrons have a stabilizing anomeric
interaction with the C(1)-O bond in the glycosyl moiety.
We attempted to obtain the final hydroxy ureas 1a and
1b in a single-pot operation by removing the mannose
chiral auxiliary with dilute HCl and after the pH was
adjusted at 4.0 reacting the resulting hydroxylamines
with KOCN as shown in Scheme 6.
Surprisingly, this one-pot procedure afforded, in ad-
dition to 70-75% yields of the target compounds, a few
percent of the (benzyloxy)benzofuran and a small per-
centage of an isomer 15 resulting from carbamoylation
of the hydroxyl group. A much more efficient conversion
could be readily demonstrated, however, by treatment
of the 12a and 12b mixtures with NH2OH‚HCl in
refluxing ethanol. Simply cooling the reaction mixture
to 0 °C precipitated the enantioenriched hydroxylamines
in 75% yield from the corresponding nitrones. Further-
more, concentration of the mother liquors enabled us to
recover the chiral auxiliary suitable for reuse. Conver-
sion of the hydroxylamines to 1a (SB 202235) and 1b (SB
210661) was carried out using the original protocol of
treatment with KOCN in the presence of acetic acid
(Scheme 1). Using this protocol no isomer or benzofuran
was generated, and the crude products were obtained in
96% and 85% yields, respectively, and 77% ee. The
enantiomeric purity of the product was improved to 99%
by one recrystallization from 2-propanol.
able mannose bis-acetonide 9 was chosen as the chiral
auxiliary, and the success of the sulfur ylide addition was
anticipated based on the work of Pyne and Hajipour.15
We were also hoping that the inherently exceptional
leaving group ability of dimethyl sulfoxide would allow
the initial adduct to undergo spontaneous cyclization.
In the event, the crystalline mannose-bearing nitrones
11a and 11b were prepared by condensation of 9 (an
approximately 1:1 mixture of the oxime and the cyclic
hydroxylamine) with benzaldehyde 10a and 10b16 in 80%
yield. A slurry of nitrone 11a in toluene was treated with
a solution of dimethylsulfoxonium methylide17 in THF
at -10 °C, and after warming the resulting solution to
10 °C it afforded a mixture of diastereomeric N-glyco-
sides, 12a and 13a , in relative ratios of about 7.5-8.0 to
1 (isolated yields ca 65-75%; solution yields >90%).
Identical reaction was carried out for 11b in THF,
affording a similar ratio of diastereomers. With both
substrates, the diastereoselectivity of the reaction is
temperature and concentration dependent; the lower the
temperature and the less concentrated the reaction
mixture, the higher the diastereoselectivity. The con-
densation-cyclization reaction is extremely sluggish at
temperatures below 0 °C. We currently believe that
mechanistically, the reaction involves initial condensa-
tion of the methylide with the nitrone, tautomerization
of the proton from the phenol to the hydroxylamine
moiety, and five-membered ring cyclization with the
elimination of dimethyl sulfoxide (as shown in Scheme
3). The phenol moiety of N-glycosyl nitrones 11 is not
deprotonated by the methylide during the condensation-
cyclization reaction because only 1 equiv of methylide is
Con clu sion
In summary, an efficient six-step enantioselective
synthesis of two related hydroxyurea lipoxygenase in-
hibitors 1a and 1b has been devised using the readily
(18) The formation of 14a ,b was postulated as arising from a five-
step reaction sequence shown in Scheme 4. Following initial condensa-
tion, R,â-elimination of the chiral auxiliary occurs. This is followed by
a 1,4-addition of a second equivalent of methylide, cyclization, and
Stevens rearrangement to afford the sulfoxide side-product.
(19) Huber, R.; Vasella, A. Tetrahedron 1990, 46, 33 and references
cited therein.
(15) Pyne, S. G.; Hajipour, A. R. Tetrahedron Lett. 1992, 48, 9385
(16) Mendelson, W. Synth. Commun. 1996, 26, 593.
(17) (a) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1962, 84,
867. Corey, E. J ., Chaykovsky, M. J . Am. Chem. Soc. 1965, 87, 1353.
(b) For a recent review on dimethylsulfoxonium methylide, see Gol-
ogobov, Y. G.; Nesmeyano, A. N.; Lysenko, V. P.; Boldeskul, I. E.
Tetrahedron 1987, 43, 2609.
(20) Ng, J . S. Synth. Commun. 1990, 20, 1193 and references cited
therein.

5388 J . Org. Chem., Vol. 62, No. 16, 1997
Lantos et al.
Sch em e 4
Sch em e 5
water (12 L). The precipitated solids were collected by
filtration and dried in vacuo, obtaining 554 g of the desired
compound (100%). 1H NMR (DMSO-d6, 300 MHz) 7.52 (d, J
) 8.7 Hz, 1H), 7.41 (m, 5H), 6.90 (bs, 1H), 6.76 (d, J ) 8.1 Hz,
1H), 5.22 (s, 2H), 4.76 (s, 2H). IR (KBr) 3070, 3040, 1710,
1610, 1446, 1320 cm-1. Anal. Calcd for C15H12O3: C, 74.99;
H, 5.03. Found: C,73.86; H, 5.05.
available protected mannose oxime as chiral auxiliary.
The synthesis is based on a novel nucleophilic addition-
intramolecular cyclization reaction and proceeds in 30%
overall yield and >99% ee. An additional feature is the
almost complete recovery of the auxiliary.
6-(Ben zyloxy)-3-oxim id o-2,3-d ih yd r oben zofu r a n (3a ).
To a solution of the 6-benzyloxy compound from the above
experiment (24 g, 0.1 mol) and anhyd NaOAc (24.6 g 0.30 mol)
in 95% EtOH (216 mL) was added hydroxylamine hydrochlo-
ride (NH2OH‚HCl) (14.6 g, 0.21 mol). The mixture was heated
under reflux for 1 h. The solution was cooled to about 60 °C,
and an additional portion of NH2OH‚HCl (5.60 g, 0.080 mol)
was added. After refluxing the solution for an 1 h, it was
cooled to rt and poured into water (534 mL). The precipitated
solids were filtered and dried in vacuo at 50 °C, yielding 21 g
of 3a (83%). 1H NMR (DMSO-d6, 300 MHz) 11.0 (s, 1H), 7.45-
7.30 (m, 6H), 6.70 (s, 1H), 6.64 (dd, J ) 8.4, 2.1 Hz, 1H), 5.12
Exp er im en ta l Section
Gen er a l Rem a r k s. NMR spectra are listed in ppm and
were measured in relation to internal TMS standard in the
solvent indicated. Commercial starting materials were ob-
tained from Aldrich Chemical Co. Melting points were uncor-
rected.
6-(Ben zyloxy)-3-oxo-2,3-d ih yd r oben zofu r a n . To a solu-
tion of 24 (363 g, 2.42 mol) in DMF (4 L) were added anhyd
K2CO3 (668 g, 4.84 mol) and BnBr (582 g, 3.40 mol) with
stirring at rt over the period of 30 min. The reaction mixture
was stirred for an additional 3 h and was poured into cold

Enantioselective Synthesis of 5-LO Inhibitor Hydroxyureas
Sch em e 6
J . Org. Chem., Vol. 62, No. 16, 1997 5389
(s, 4H). IR (KBr) 3418, 2922, 1615, 1261 cm-1. Anal. Calcd
for C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.64;
H, 5.17; N, 5.50.
2800, 1620, 1600, 1289, 1184 cm-1. Anal. Calcd for C15H15
-
NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 69.45; H, 5.81; N,
5.38.
P r ep a r a tion of 6-[(2,6-Diflu or op h en yl)m eth oxy]-2,3-
d ih yd r oben zofu r a n -3-on e. A solution of 24 (200.0 g, 1.332
mol) was obtained in DMF (1 L) by heating to 33 °C. After
being cooled to rt, K2CO3 (248.5 g, 1.798 mol) was added. In
a separate flask 2,6-difluorobenzyl bromide (331 g, 1.598 mol)
was dissolved in DMF (200 mL). This solution was transferred
over a 20 min period to the stirring reaction mixture containing
the benzofuranone. The reaction mixture was stirred for 1.5
h at rt and was then added to water (5 L), causing crystal-
lization of the product. The slurry was stirred for 30 min, and
the pale yellow solid was filtered and rinsed with water (6 L)
followed by EtOH (1 L). The product was dried in vacuo,
isolating 356 g (96.7%), mp 134.0-138.0 °C. 1H NMR (CDCl3,
300 MHz) 7.57 (bd, J ) 7.1 Hz, 1H), 7.41-7.33 (m, 1H), 7.00-
Th e 2,6-d iflu or o com p ou n d 4b was prepared in a similar
fashion from 3b in 85% yield. 1H NMR (DMSO-d6) 7.53 (tt, J
) 8.3, 6.5 Hz, 1H), 7.43 (br s, 1H), 7.29 (d, J ) 9.0 Hz, 1H),
7.18 (t, J ) 8.0 Hz, 2H), 6.51 (br m, 2H), 5.03 (s, 2H), 4.55 (dd,
J ) 6.5, 4.4 Hz, 1H), 4.49 (m, 2H). 13C NMR (DMSO-d6) 161.9,
161.2 (2C), 159.8, 131.6, 126.3, 119.2, 112.2, 111.7 (2C), 106.5,
96.4, 75.7, 62.5, 57.8. IR (KBr) 3440, 3100-2800, 1626, 1598,
1288, 1235, 1187 cm-1
. Anal. Calcd for C15H13F2NO3: C,
61.43; H, 4.47; N, 4.78. Found: C, 61.45; H, 4.39; N, 4.83.
Resolu tion of Ra cem ic 4a a n d 4b. To 4a (50 g, 0.194
mol) in MeOH (1.4 L) was added a solution of (+)-S-mandelic
acid (29.57 g, 0.194 mol) in MeOH (45 mL), and the mixture
was heated for 30 min to obtain a clear-yellow solution. The
solution was allowed to slowly cool to rt over 2.5 h and then
stirred for an additional 4 h. The precipitated salts were
filtered, washed with EtOAc, and dried, affording 24.4 g (0.06
mol, 30%). The isolated salts (20 g, 0.049 mol) were covered
with H2O (208 mL) and EtOAc (520 mL), and concd NH3
solution was slowly added with constant stirring until a pH
of 9.5 was obtained. The layers were separated, the aqueous
layer was extracted with EtOAc (2 × 100 mL), and the
combined organic solution was concentrated under reduced
pressure until a white suspension was obtained. Hexane (415
mL) was added, and the suspension was stirred in an ice-bath
for 1 h to complete crystallization. The crystalline product was
6.91 (m, 2H), 6.78-6.71 (m, 2H), 5.17 (s, 2H), 4.62 (s, 2H). 13
C
NMR (CDCl3, 100 MHz) 197, 175, 166, 161, 132, 124, 114, 111,
111, 111, 97, 75, 58. IR (KBr) 3075, 1700, 1610, 1595, 1454,
cm-1. Anal. Calcd for C15H10F2O3: C, 64.98; H, 3.63. Found:
C, 64.57; H, 3.33.
P r ep a r a tion of 6-[(2,6-Diflu or op h en yl)m eth oxy]-2,3-
d ih yd r oben zofu r a n -3-on e Oxim e (3b). To a stirred solu-
tion of 6-[(2,6-difluorophenyl)methoxy]-2,3-dihydrobenzofuran-
3-one (340 g, 1.231 mol) and NH2OH‚HCl (118 g, 1.698 mol)
in EtOH (2.57 L) was added NaOAc (135.3 g, 1.65 mol). The
reaction mixture was refluxed for 3 h and allowed to cool to
rt. The cooled reaction mixture was poured into H2O (3.42
L), causing crystallization. The slurry was stirred for 30 min,
and the product was filtered. The product was rinsed with
hexane (3.67 L) and dried at 40 °C in vacuo. Isolated 338 g of
3b (94.3%), mp 166-172 °C; 1H NMR (CDCl3, 400 MHz) 11.1
(s, 1H), 7.48 (bd, J ) 7 Hz, 1H), 7.45-7.26 (m, 1H), 7.0-6.88
(m, 2H), 6.68-6.50 (m, 2H), 5.14 (s, 2H), 5.11 (s, 2H). 13C NMR
(CDCl3, 100 MHz) 166, 161, 161, 154, 131, 122, 113, 112, 111,
filtered, yielding after drying 12.2 g of 5a (97%). [R]25
)
D
+24.04 (c 1.0, DMSO). 1H NMR (DMSO-d6) 7.35-7.44 (m, 6H),
7.23 (d, J ) 8.9, 1H), 6.50 (bs, 1H), 6.45 (bd, 1H), 5.89 (bs,
1H), 5.05 (s, 2H), 4.52 (t, 1H), 4.47 (bs, 1H), 4.45 (bs, 1H). 13C
NMR (DMSO-d6) 161, 159, 137, 128 (2C), 127, 127 (2C), 126,
118, 106, 96, 75, 69, 62. IR (KBr) 3435, 3252, 3100, 3000-
2800, 1625, 1599, 1281, 1150 cm-1; MS m/ z 258 (M + H)+.
Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44.
Found: C, 69.83; H, 5.91; N, 5.51.
109, 97, 71, 58. IR (KBr) 3311, 2945, 1616, 1595, 1470 cm-1
.
Anal. Calcd for C15H11F2NO3: C, 61.85; H, 3.80; N, 4.81.
Found C, 61.74; H, 3.45; N, 4.60.
Com p ou n d 5b w a s P r ep a r ed Sim ila r ly. [R]25D ) +21.15
(c 1.0, DMSO); 1H NMR (DMSO-d6) 7.50 (m, J ) 6.6 Hz, 1H),
7.45 (s, 1H), 7.23 (d, J ) 8.9 Hz, 1H), 7.16 (t, J ) 8.3, 7.8 Hz,
2H), 6.49 (bs, 1H), 6.47 (bd, 1H), 5.92 (bs, 1H), 5.05 (s, 2H),
4.52 (t, 1H), 4.47 (bs, 1H) 4.45 (br s, J ) 5.0 Hz, 1H). 13C NMR
(DMSO-d6) 161, 161(2C), 159, 131, 126, 119, 112, 111(2C), 106,
96, 75, 62, 57. IR (KBr) 3440, 3250, 3140, 1627, 1597, 1284,
N-[3-[6-(Ben zyloxy)-2,3-d ih yd r oben zofu r a n yl]]h yd r ox-
yla m in e (4a ). To a solution of 3a (505 g, 1.98 mol) in MeOH:
CH2Cl2 (1:1, 10 L) was added BH3-pyridine (808 g, 8.69 mol).
The resulting mixture was dropwise treated with 6 N HCl (1.5
L) over 1.15 h, and the reduction proceeded for 18 h at rt. The
clear-yellow solution was concentrated at reduced pressure to
a thick oil, which was cooled to 0-5 °C, and 3 N HCl was
cautiously added. The precipitated HCl salts were filtered and
suspended in cold H2O. The pH of the suspension was
adjusted to 10.5 first by the addition of 50% NaOH solution
to pH 8 and then concd NH3. The solid hydroxylamine was
filtered and dried in vacuo, yielding 440 g of 4a (86%). 1H
NMR (DMSO-d6, 400 Hz) 7.54 (br s, 1H), 7.41 (m, 4H), 7.27
(d, J ) 8.0 Hz, 1H), 6.51 (dd, J ) 8.0, 2.3 Hz, 1H), 6.48 (d, J
) 2.3 Hz, 1H), 5.08 (s, 2H), 4.55 (dd, J ) 6.7, 4.0 Hz, 1H), 4.48
(br s, 2H). 13C NMR (DMSO-d6) 161, 159, 137, 128(2C), 127,
127(2C), 126, 118, 106, 96, 75, 69, 62. IR (KBr) 3423, 3100-
1234, 1155 cm-1
.
MS m/ z 294 (M + H)+. Anal. Calcd for
C15H13NO3F2: C, 61.43; H, 4.47; N, 4.78. Found: C, 61.28; H,
4.48; N, 4.79.
N-[3-[6-(Ben zyloxy)-2,3-d ih yd r ob en zofu r a n yl]]-N-h y-
d r oxyu r ea (1a ). To a stirred solution of 5a (152 g, 0.59 mol)
in DMF (767 mL) and AcOH (53.27 g, 0.89 mol) was added a
solution of KOCN (72.0 g, 0.89 mol) in H2O (133 mL) at 0 °C
in one portion. A white suspension of the product formed
almost immediately which became a viscous mixture within
15 min. TBME (3000 mL) was added and stirring continued
for an additional 1 h while the mixture was cooled to 0-5 °C.
The product was filtered and recrystallized from DMF:TBME

5390 J . Org. Chem., Vol. 62, No. 16, 1997
Lantos et al.
(1:3) mixture, yielding 154 g of 1a (87.3%), mp 174-5 °C.
[The disappearance of tBuOK was monitored by treating
solutions of iminostilbene in THF (10-20 mg of iminostilbene/
10 mL of THF) with samples of the reaction mixture; a color
change of the iminostilbene solution upon treatment implies
the presence of excess potassium tert-butoxide.] The reaction
mixture was cooled to rt and then filtered to remove KI and
excess trimethylsulfoxonium iodide. The molarity of the
dimethylsulfoxonium methylide filtrate solution was deter-
mined via titration against standard aqueous HCl solutions
to the phenolphthalein endpoint. The methylide was then
used without further purification. The ylide was also prepared
following the procedure of Corey.17a
[R]25 ) +97.22 (c 1.0, DMSO). 1H NMR (DMSO-d6) 9.12 (s,
D
1H), 7.42 (dd, J ) 8.5, 1.8 Hz, 2H), 7.37 (dd, J ) 7.0, 8.5 Hz,
2H), 7.31 (tt, J ) 6.9, 1.7 Hz, 1H), 7.06 (d, J ) 8.2 Hz, 1H),
6.50 (dd, J ) 8.3, 2.3 Hz, 1H), 6.48 (br s, 2H), 6.45 (d, J ) 2.1
Hz, 1H), 5.79 (dd, J ) 9.1, 4.2 Hz, 1H), 5.05 (s, 2H), 4.55 (dd,
J ) 9.5, 9.3 Hz, 1H), 4.46 (dd, J ) 9.7, 4.3 Hz, 1H); 13C NMR
(DMSO-d6) 162, 161, 160, 137, 128(2C), 127, 127(2C), 125, 117,
107, 96, 73, 69, 58. IR (KBr) 3462, 3323, 3263, 3175, 3100-
2800, 1643, 1626, 1295, 1169, 1135, cm-1. MS m/ z 301 (M +
H)+, 318 (M + NH4)+. Anal. Calcd for C16H16N2O4: C, 63.99;
H, 5.37; N, 9.33. Found: C, 63.88; H, 5.42; N, 9.33.
P r ep a r a t ion of N-(2,3:5,6-Di-O-isop r op ylid en e-r-D-
m a n n ofu r a n osyl)[2-h yd r oxy-4-(p h en ylm eth oxy)p h en yl]-
m eth a n im in e N-Oxid e (11a ). To a solution of 4-(benzyloxy)-
2-hydroxybenzaldehyde16 (91.4 g, 0.401 mol) and (2,3:5,6-di-
O-isopropylidene-R-D-mannofuranosyl)hydroxylamine (100.0 g,
0.364 mol) in toluene (640 mL) at rt was added tributylamine
(74.3 g, 0.401 mol). The reaction was heated at reflux for 6 h,
and the water was removed via a Dean-Stark trap. After the
reaction was cooled to rt, heptanes (250 mL) was added to
facilitate crystallization. The mixture was further cooled to
10 °C, and stirred for 1 h. The product was filtered, rinsed
with heptanes (2 × 250 mL), and dried at reduced pressure to
give the desired nitrone, as a pale yellow powder. Isolated
P r ep a r a tion of (S)-(+)-N-(2,3:5,6-Di-O-isop r op ylid in e-
r-D-m a n n ofu r a n osyl)[2,3-d ih yd r o-6-(p h en ylm eth oxy)-3-
ben zofu r a n yl]h yd r oxyla m in e (12a ). A solution of dimeth-
ylsulfoxonium methylide in THF (52.9 mL, 100 mmol, a 1.89
M solution in THF) was added to a stirred slurry of nitrone
N-(2,3:5,6-di-O-isopropylidine-R-D-mannofuranosyl)[2-hydroxy-
4-(phenylmethoxy)phenyl]methanimine N-oxide 11a (48.6 g,
100 mmol) in toluene (447 mL) at -10 °C. The rate of
methylide addition was such that the reaction temperature
never rose above -5 °C. After the addition was complete, the
reaction mixture was stirred at 0 °C for 2 h and then stirred
at +10 °C for 19 h at which point the reaction was 96%
complete. The reaction mixture was cooled to 0 °C and treated
with an additional quantity of the solution of dimethylsul-
foxonium methylide (2.1 mL, 4.0 mmol, a 1.89 M solution in
THF), and the reaction mixture was warmed to 10 °C and
stirred for 5 h. The reaction was then concentrated in vacuo.
The residual yellowish-gold colored solid was dissolved in ethyl
acetate (500 mL), washed with water (2 × 250 mL), dried over
magnesium sulfate, and filtered. The solution was then
filtered through a pad of silica gel to remove any sulfoxide side-
product and concentrated in vacuo. The crude product was
recrystallized from toluene (250 mL) and hexane (400 mL) to
afford 11a , 33.7 g (67.5%) as a 7.0 to 1 mixture of diastereo-
mers. HPLC (Zorbax SBC8, CH3OH/H2O/CH3CN/0.5 M am-
monium acetate 5.72:2.25:1:1, 1.5 mL/min) tR (major diaster-
omer) 17.8 min; tR (minor diastereomer 15.3 min.
165.0 g (corrected 92.2%), mp 144.5-145.5 °C; [R]25
)
+7.85
D
(c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz) 13.4 (s, 1H), 7.52
(s, 1H), 7.45-7.38 (m, 5H), 6.98-6.96 (d, J ) 8.5 Hz, 1H),
6.51-6.48 (m, 2H) , 5.47 (s, 1H), 5.32-5.31 (d, J ) 6.0 Hz,
1H), 5.06 (s, 2H), 5.01 (dd, J ) 6.0, 3.9 Hz, 1H), 4.66 (dd, J )
6.9, 3.9 1H), 4.44 (dd, J ) 6.9, 5.9 Hz, 1H), 4.15-4.12 (m, 2H),
1.56 (s, 3H), 1.49 (s, 3H), 1.42 (s, 3H), 1.41 (s, 3H). 13C NMR
(CDCl3, 100 MHz) 164, 162, 139, 136, 134, 128, 128, 127, 113,
109, 108, 108, 104, 101, 85, 84, 80, 73, 70, 66, 26, 26, 25, 24.
IR (KBr) 3018, 1617, 1384, 1215 cm-1. Anal. Calcd for C26H31
-
NO8: C, 64.45; H, 6.24; N, 2.89. Found: C, 64.07, H, 6.37; N,
2.76.
P r ep a r a tion of 2,6-Diflu or o-N-(2,3:5,6-d i-O-isop r op y-
lid en e-r-D-m a n n ofu r a n osyl)[2-h yd r oxy-4-(p h en ylm eth -
oxy)p h en yl]m eth a n im in e N-Oxid e (11b). A solution of 2,6-
difluorobenzyl bromide (100.0 g, 0.483 mol) and KI (2.4 g, 15
mmol) in acetonitrile (200 mL) was added to a stirred solution
of 2,4-dihydroxybenzaldehyde (68.1 g, 0.499 mol) and NaHCO3
(45.5 g, 0.542 mol) in acetonitrile (420 mL) which was heated
to 60 °C. The reaction mixture was then heated at reflux for
16 h and cooled to 25 °C, and water (250 mL) was added. The
solution was extracted into toluene (1600 mL). The organic
layer was washed with water (500 mL), and the acetonitrile
and water were distilled off until the internal temperature
reached 111-2 °C. The mixture was cooled to 25 °C, and (2,3:
5,6-di-O-isopropylidene-R-D-mannofuranosyl)hydroxylamine (9)
(149.1 g, 0.542 mol) and tributylamine (100.5 g, 0.542 mol)
were added. The reaction mixture was refluxed for 6 h with
azeotropic removal of water via a Dean-Stark trap. The
reaction mixture was cooled to 25 °C, and heptanes (250 mL)
was added to facilitate crystallization. The pale-yellow crystals
were filtered, rinsed with heptanes (2 × 250 mL), and dried
under vacuum. The overall yield of 11b starting from 2,6-
difluorobenzyl bromide was 174.6 g (69.4%), mp 157.5-159.0
°C. [R]25D ) +43.5 ° (c 1.0, THF). 1H NMR (CDCl3, 400 MHz)
13.4 (s, 1H), 7.54 (s, 1H), 7.37 (m, 1H), 7.01-6.95 (m, 3H), 6.59
(d, J ) 2.4 Hz, 1H), 6.50 (d, J ) 8.8 Hz, 1H), 5.51 (s, 1H), 5.36
(d, J ) 6.0 Hz, 1H), 5.15 (s, 2H), 5.01-4.99 (m, 1H), 4.68-
4.65 (m, 1H), 4.45-4.43 (m, 1H), 4.15-4.12 (m, 2H), 1.55-
1.38 (m, 12H). 13C NMR (CDCl3, 100 MHz) 164, 162, 161, 139,
134, 131, 113, 112, 111, 109, 109, 108, 103, 101, 85, 84, 80,
73, 66, 57, 26, 25, 25, 24. IR (neat) 3018, 1617, 1596, 1473,
1215 cm-1. Anal. Calcd for C26H29F2NO8: C, 59.88; H, 5.61;
N, 2.69. Found: C, 59.75; H, 5.66; N, 2.93.
For the major diasteromer: [R]25 ) +18.9° (c 1.0, CHCl3);
D
1H NMR (CDCl3, 400 MHz) 7.19-7.43 (m, 6H), 6.46-6.55 (m,
2H), 5.03 (s, 2H), 4.92-4.95 (m, 1H), 4.82-4.86 (m, 2H), 4.68-
4.74 (m, H), 4.55 (bs, 1H), 4.50 (s, 1H), 4.30-4.36 (m, 2H),
4.06-4.14 (m, 2H), 1.49 (s, 3H), 1.46 (s, 3H), 1.39 (s, 3H), 1.34
(s, 3H). 13C NMR (CDCl3, 100 MHz) 162, 161, 136, 128, 127,
127, 126, 117, 112, 109, 107, 98, 97, 84, 84, 80, 73, 73, 70, 66,
65, 26, 26, 25, 24. Anal. Calcd for C27H31F2NO8: C, 64.92; H,
6.66; N, 2.80. Found: C, 64.93; H, 6.76; N, 2.99.
P r ep a r a tion of (S)-(+)-N-(2,3:5,6-d i-O-isop r op ylid en e-
r-D-m a n n ofu r a n osyl)-2,3-d ih yd r o-6-[(2,6-d iflu or op h en -
yl)m eth oxy]-3-ben zofu r a n ylh yd r oxyla m in e (12b). A so-
lution of dimethylsulfoxonium methylide (545 mL, 200 mmol,
a 0.367 M solution in THF) was diluted with THF (455 mL)
at rt to afford a final methylide solution with an approximate
concentration of 0.2 M. The solution was cooled to -10 °C.
Solid nitrone 11b (104.3 g, 200 mmol) was added with stirring
at such a rate that the reaction temperature never rose above
-5 °C. After the addition was complete, the reaction mixture
was warmed to +7 °C over a period of 45 min and then stirred
for 15 h at +7 °C. After 15 h, the reaction was about 87%
complete. The reaction mixture was cooled to -10 °C and
treated with an additional quantity of the solution of dimeth-
ylsulfoxonium methylide (70.85 mL, 26 mmol, a 0.367 M
solution in THF) at such a rate that the reaction temperature
never rose above -5 °C. After the addition was complete, the
reaction mixture was warmed to +7 °C and stirred for 4 h.
The reaction was determined to be complete at this point based
upon complete consumption of starting material. The reaction
mixture was used in the next step without further purification.
The reaction afforded approximately 104 g (HPLC weight-
based solution assay, 97% yield) of 12b as a 8 to 1 ratio of
diastereomers with the desired diastereomer being the major
product. For the major diasteromer (12b): 1H NMR (C3D6O,
360 MHz) 7.61 (bs, 1H), 7.58-7.50 (m, 1H), 7.26-7.23 (m, 1H),
7.16-7.08 (m, 2H), 6.58-6.55 (m, 1H), 6.50 (bs, 1H), 5.17 (s,
2H), 5.02 (d, 1H, J ) 3.6 Hz), 4.89-4.84 (m, 3H), 4.79-4.76
P r ep a r a t ion of Dim et h ylsu lfoxon iu m Met h ylid e in
Tetr a h yd r ofu r a n . A solution of potassium tert-butoxide (312
mL, 0.500 mol, a 1.60 M solution in THF) was added to THF
(1.06 L) at rt with stirring, and the resulting solution was
heated to 40 °C. Trimethylsulfoxonium iodide (121 g, 0.550
mol) was added, and the resulting white slurry was stirred at
40 °C until all the tBuOK had been consumed, usually 20 min.

Enantioselective Synthesis of 5-LO Inhibitor Hydroxyureas
J . Org. Chem., Vol. 62, No. 16, 1997 5391
(m, 1H), 4.54-4.46 (m, 2H), 4.32 (dd, 1H, J ) 3.6, 3.6 Hz),
4.13-4.08 (m, 2H), 1.44 (s, 3H), 1.40 (s, 3H), 1.34 (s, 3H), 1.31
(s, 3H). 13C NMR (C3D6O, 90.6 MHz) 163, 163, 161 131, 127,
118, 113, 111, 111, 108, 107, 98, 96, 85, 84, 81, 74, 74, 66, 65,
58, 26, 25, 25, 24. Anal. Calcd for C27H31F2NO8: C, 60.56; H,
5.83; N, 2.62. Found: C, 59.57; H, 5.92; N, 2.57.
treatment with 6 N NaOH (0.5 mL, 3 mmol) and HOAc (0.24
mL, 4.2 mmol). A solution of KOCN (0.34 g, 4.2 mmol) in
water (2 mL) was added and stirring continued at about 5 °C
for 30 min. The reaction mixture was treated with water (16
mL), and the resulting slurry was stirred for 10 min at about
5 °C. The white precipitate was filtered, washed with water
(10 mL) and hexanes (20 mL), and dried at 40 °C in vacuo to
yield 0.88 g of 1a and its enantiomer as a white solid in 77.9%
yield and 90.4% ee. This crude 1a (0.46 g, 1.55 mmol, 90.4%
ee) was recrystallized from DMF (3.73 mL)/TBME (10.5 mL)
to yield purified 1a (0.42 g, 1.4 mmol, 99.7% ee, 94.6% yield).
P r ep a r a tion of 1b. To a solution of 5b (9.6 g, 32.9 mmol,
72% ee) in DMF (73 mL) was added HOAc (3.51 mL, 61.4
mmol). The resulting solution was cooled in an ice bath to
∼5 °C. A solution of KOCN (5.0 g, 61.4 mmol) in water (9
mL) was added at such a rate that the internal temperature
did not exceed 15 °C. After stirring at ∼5 °C for 30 min, water
(208 mL) was added and the resulting suspension was stirred
at 20-25 °C for 1 h. The precipitated solids were filtered,
washed with water (200 mL) and hexanes (200 mL), and then
dried at 40 °C in vacuo to yield 1b as a very light-yellow solid
(9.9 g 29.5 mmol, 74% ee, 90.9% yield).
P r ep a r a tion of (S)-N-[6-(Ben zyloxy)-2,3-d ih yd r oben -
zofu r a n -3-yl]h yd r oxyla m in e (5a ) (r em ova l of th e m a n -
n ose a u xilia r y fr om isola ted 12a w ith NH2OH‚HCl). To
a solution of NaHCO3 (2.90 g, 34.5 mmol) in 60 mL of water
was slowly added hydroxylamine hydrochloride (2.60 g, 37.4
mmol). The resulting solution was added to a suspension of
12a (4.7 g, 9.4 mmol) as a 8 to 1 mixture of diastereomers in
EtOH (60 mL). The mixture was refluxed for 80 min and then
cooled to rt in 1 h. The white suspension was filtered, washed
with water (50 mL) and hexanes (50 mL), and dried at 40 °C
in vacuo, yielding 2.32 g of 5a as a white solid in 96.0% yield
and 98.6% ee [R]25 ) +24.04 (c 1.0, DMSO). Anal. Calcd for
D
C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 69.83; H,
5.91; N, 5.51.
The mother liquor from the filtration was concentrated to
remove EtOH and then extracted with EtOAc (3 × 75 mL).
Combined EtOAc extract was washed with water (70 mL),
dried over MgSO4, filtered, and evaporated to a residue which
was crystallized from EtOAc (6 mL)/hexanes (55 mL) to give
9 as a white solid (2.30 g, 8.4 mmol, 89.4% yield).
Recr ysta lliza tion of 1b. To crude 1b (38.4 g, 74.2% ee)
was added 2-propanol (950 mL). The resulting suspension was
heated to a clear solution and refluxed for 5 min and then
slowly cooled to rt in 3 h with minimum stirring (the reaction
mixture was seeded with 1b at 65 °C). The product was
filtered, washed with hexanes (1100 mL), and dried at 40 °C
in vacuo to yield 1b as a white solid (26.5 g, 75.8% yield, no R
isomer was detected). [R]25D ) +87.53 (c 1.0, DMSO). 1H NMR
(DMSO-d6) 9.12 (s, 1H), 7.50 (m, J ) 6.6 Hz, 1H), 7.16 (t, J )
8.3, 8.0 Hz, 2H), 7.08 (d, J ) 8.5 Hz, 1H), 6.51 (dd, J ) 2.5 Hz,
2H), 6.48 (br s, 2H), 5.79 (dd, J ) 9.2, 4.2 Hz, 1H), 5.05 (s,
2H), 4.57 (t, J ) 9.2 Hz, 1H), 4.47 (dd, J ) 9.7, 4.2 Hz, 1H).
13C NMR (DMSO-d6) 162, 161, 161(2C), 159, 131, 125, 118,
112, 111(2C), 106, 96, 73, 58, 57. IR (KBr) 3465, 3323, 3262,
3176, 3100-2800, 1642, 1627, 1233, 1165, 1109 cm-1. MS m/ z
P r epar ation of (S)-N-[6-[(2,6-Diflu or oph en yl)m eth oxy]-
2,3-d ih yd r ob en zofu r a n -3-yl]h yd r oxyla m in e, 5b (fr om
cr u d e r ea ction m ixtu r e of 12b). The reaction mixture of
12b (20.2 g, 37.7 mmol) was concentrated under reduced
pressure to an oil of a 8 to 1 ratio of diastereomers. EtOH (65
mL) was added, and a solution of NaHCO3 (11.3 g, 134 mmol)
and NH2OH‚HCl (10.1 g, 146 mmol) in water (65 mL). The
resulting suspension was refluxed for 1.5 h, cooled to rt, and
stirred for 1.5 h. The resulting white suspension was treated
with water (110 mL) for 10 min and filtered. The solid product
was washed with water (220 mL) and hexanes (220 mL) and
dried at 40 °C in vacuo to yield a yellow solid containing 10.1
337 (M + H)+, 359 (M + Na)+. Anal. Calcd for C16H14
-
g of 5b and its enantiomer in 91.1% yield and 72% ee [R]25
+21.15 (c 1.0, DMSO).
)
D
N2O4F2: C, 57.15; H, 4.20; N, 8.33. Found: C, 57.10; H, 4.12;
N, 8.17.
Con ver sion of 12a Dir ectly to (S)-N-[6-(Ben zyloxy)-2,3-
d ih yd r oben zofu r a n -3-yl]-N-h yd r oxyu r ea (1a ) w ith ou t
Isola tin g 5a . A solution of the mannosylhydroxylamine 12a
(1.9 g, 3.8 mmol) in DMF (20 mL) and water (4 mL) was cooled
to about 25 °C. To this stirred solution was added 1 N HCl
(7.0 mL, 7 mmol) over 50 min, the water bath was removed,
and the mixture was stirred at rt for 2 h. The reaction was
cooled to about 5 °C, and the pH was adjusted to about 4.5 by
Ack n ow led gm en t. The authors are indebted to our
Analytical Science Section for the analytical data, to Ms.
Edith Reich for the elemental analysis, and to Mr. Lewis
Kilmer for the mass spectra.
J O9621736