Preparation and crystal structures of two 3-anthracenyl isoxazolyl sulfonamides

Article abstract of DOI:10.1002/jhet.5570450132

(Chemical Equation Presented) Lateral metalation and oxidation of 3-(9′-anthryl)-isoxazoles (1), using Davis' oxaziridine (6), produced the desired hydroxylation (2), along with sulfonamide adduct (3), and in the case of the use of butyl lithium as base,

Full text of DOI:10.1002/jhet.5570450132

Jan-Feb 2008
259
Preparation and Crystal Structures of Two 3-Anthracenyl Isoxazolyl
Sulfonamides
Chun Li, Brendan Twamley and Nicholas R. Natale*
Department of Chemistry, University of Idaho, Moscow, ID 83844-2343
and Center for Structural and Functional Neuroscience, University of Montana, Missoula MT 59812
Nicholas.natale@umontana.edu
Received July 9, 2007
Cl
Cl
Cl
1. base/THF, -78 o
C
O
+
N
O
2. oxaziridine 6 or 7, -78 oC
O
O
R2
N
O
N
O
R2
R2
Ph
R1
R1
R1
HN
HO
SO2
Ph
1 R1=CH2Ph, R2=OCH2CH3
8 R1=H, R2=OCH2CH3
2 R1=CH2Ph, R2=OCH2CH3
4 R1=CH2Ph, R2=n-Bu
9 R1=H, R2=OCH2CH3
3a SR/RS- R1=CH2Ph, R2=OCH2CH3
3b SS/RR- R1=CH2Ph, R2=OCH2CH3
5a SR/RS- R1=CH2Ph, R2=nBu
10 R1=H, 2=OCH2CH3
Lateral metalation and oxidation of 3-(9'-anthryl)-isoxazoles (1), using Davis' oxaziridine (6), produced
the desired hydroxylation (2), along with sulfonamide adduct (3), and in the case of the use of butyl lithium
as base, butyl addition products (4) and (5). Structures of isoxazole sulfonamides (3a) and (5a), were
obtained as the SR/RS-diastereomer, however, studies indicate that this is a consequence of the
crystallization process. Metalation studies with isoxazole (8) demonstrate that hydroxylation (9), can be
carried out cleanly, minimizing formation of (10), using camphorsulfonyloxaziridine (7) as an electrophile.
J. Heterocyclic Chem., 45, 259 (2008).
DNA's sugar phosphate backbone should increase G-4
interaction specificity. Furthermore, ꢀ-hydroxylation of a
substituted isoxazole should help us better understand the
physiological behavior of this series of analogues. Based
upon the above studies and hypotheses, hydroxylations
using oxaziridines were carried out on the C-5 methyl or
methylene groups of our substrates. Our results are
discussed in this paper.
INTRODUCTION
We previously reported a new class of isoxazoles [1-3],
which were subsequently found to exhibit significant anti-
cancer activity in the National Cancer Institute's 60 cell
line screening protocol [4]. Our working hypothesis is
based on the fact that the single-stranded G-rich overhang
of the human telomere, or other similar oligonucleotide
sequences, can adopt a G-quadruplex (G-4) structure, and
stabilization of this G-4 by a small molecule ligand
inhibits tumor cell proliferation. Many such ligands have
been reported [5-7], among which notably is fluoroquino-
benzoxazine CX-3543, which is the first-in-class G-4
binding molecule to advance to clinical trials [8]. This
type of molecule bears some similar structural features to
our anthracenylisoxazoles. The binding modes of these
types of molecules to G-4 are thought to involve ꢀ-
stacking onto the terminal G-tetrad. We calculated the
coordination of G-4 with one of our lead compounds
(NSC D 694332), using SGI INSIGHT II [9]. The result
showed that the hydrogen on C-10 was proximal to the K+
in the G-4 cavity, the N of the isoxazole moiety
coordinated with the NH2 group in guanine, and the C-5
methyl on the isoxazole falls into the groove formed by a
TTA loop. Most of the reported G-4 ligands have planar
structures and are non-chiral. Introduction of a chiral
center (i.e., hydroxyl group) for hydrogen bonding to
RESULTS AND DISCUSSION
Oxaziridines have been widely investigated and used in
organic synthesis as both oxygen and nitrogen transferring
reagents for a wide variety of nucleophiles [10]. The
unusually high reactivity comes from the presence of an
inherently weak N-O bond in a strained three-membered
ring [10-13]. Although other nitrogen and oxygen transfer
reagents are known, oxaziridine-mediated processes are of
interest because they are more easily prepared, more
stable and have higher stereoselectivity [14]. In spite of
oxaziridines dual reactivity, the predominance of one
process over another can be affected by varying the
substitution pattern on nitrogen. In general, oxaziridines
with small groups on nitrogen (H, Me) act as aminating
agents [15], whereas those with bulky or electron-
withdrawing groups on nitrogen preferentially transfer the
oxygen atom. Electron deficient oxaziridines, such as

260
C. Li, B. Twamley, and N. Natale
Vol 45
to what was observed by Davis [14], for simple enolates and
indicated that the preference of oxygen transfer over sulfon-
imine addition from oxaziridine depends on the base used.
After recrystallization, sulfonamides (3a) and (5a) were
obtained as single racemic diastereomers, as determined by
single crystal X-ray analysis (Table 1 for the crystal-
lographic data and parameters). The relative configurations
shown in Figure 1 and Figure 2 represent the C21S, C29R
and C23S, C31R diastereomers of compounds (3a) and
N-sulfonyl oxaziridines, oxaziridinium salts, and
perfluorinated oxaziridines have found extensive use as
sources of electrophilic oxygen.
We conducted lateral metallation on the C-5 methylene
group of anthracenylisoxazole (1) and quenched with phenyl-
sulfonyloxaziridine (6) to introduce a ꢀ-hydroxyl group at the
isoxazole C-5 position (Scheme 1). It was not without
Scheme 1
Cl
Cl
Cl
Cl
Cl
1. base/THF, -78 o
C
+
+
+
O
O
O
O
O
2. 2-sulfonyloxaziridine (6),
-78 oC
N
N
N
N
N
O
O
O
O
O
O
O
O
*
Ph
Ph
Ph
Ph
Ph
Ph
HO
Ph
HO
*
HN SO2
Ph
HN SO2
Ph
1
2
3a=21S, 29R or 21R, 29S
3b=21S, 29S or 21R, 29R
4
5=21S, 29R or 21R, 29S
precedent, when using either n-BuLi or Lithium diiso-
propylamide (LDA) as base, that the hydroxylation was
complicated by a side reaction in which the vinylogous lithium
enolate added to the sulfonimine, the requisite product
resulting from oxaziridine oxygen transfer, even though the
reactions were carried out at –78 ºC. The same result was
obtained when the anion solution was added to a solution of
oxaziridine (reverse addition). When potassium hexamethyl-
disilazine (KHMDS) was used as base, the sulfonimine
addition proceeded in trace amount. These results are similar
(5a), respectively. Further experiments were conducted to
examine the diasteroselectivity of the reactions producing
the sulfonamines (Table 2). For compound (3), the ratio of
(S,R)/(R,S) to (S,S)/(R,R) was about 3 to 2. This can be
explained from Newman projections (Figure 3) where the
hydrogen bond observed in the crystal structure between
O2 of the carbonyl and N2 of the sulfonamine for (3a)
exhibit fewer unfavorable non-bonding interactions for the
SR/RS diastereomer after protonation and during
crystallization, whereas the precursor vinylogous lithio

Jan-Feb 2008
Preparation And Crystal Structures Of 3-Anthracenyl Isoxazolyl Sulfonamides
261
enolate must not be as rigidly organized under the reaction
conditions studied. However, this does suggest that useful
diasteroselectivites could possibly be obtained, under
optimally coordinating reaction conditions, and this issue
will be addressed in our ongoing studies.
Another observation from oxaziridine oxidation is that
KHMDS was not a good base for oxidation of the C-5
methyl group of (8), in terms of unwanted products that
were highly polar and immobile on silica gel. The smaller
methyl group on the C-5 position seemed to make the
isoxazole prone to putative ring opening in the presence
of highly reactive potassium ion. The use of n-BuLi or
LDA as base in this reaction for oxidizing the C-5 methyl
group of (8) with (6) resulted in poor yields with the
formation of an undesired sulfonamide adduct (10)
(Scheme 2). To eliminate the addition product,
(camphorylsulfonyl)oxaziridine (7) was used to oxidize
the C-5 methyl group. The desired primary alcohol (9)
was obtained in 70% isolated yield based on the recovery
of starting material, and no adduct was detected (Table 3).
This is again analogous to observations by Davis [13,16]
for simpler nucleophiles.
Table 1
Crystallographic Data and Structure Refinement Parameters.
3a
5a
CCDC reference
639428
639429
Formula
Mol wt
C41H33ClN2O5S
701.20
C43H37ClN2O4S
713.26
Cryst syst, Space grp
Cryst color and habit
Triclinic, P-1
Yellow needle
11.035(2)
11.130(2)
16.666(3)
72.11(3)
74.33(3)
70.28(2)
1801.8(7)
2
Monoclinic, P2(1)/c
Yellow fragment
15.089(3)
12.830(3)
18.722(4)
90
93.23(3)
90
3618.7(13)
4
a (Å)
b (Å)
c (Å)
ꢀ (°)
ꢁ (°)
ꢂ (°)
3
V (Å )
Z
ꢃ
(Mg/m3)
1.292
0.211
1.309
0.210
calcd
μ (mm-1)
F(000)
732
1496
Crystal size (mm3)
ꢄ range (°)
0.40 x 0.10 x 0.08 0.26 x 0.24 x 0.17
isox.
isox.
isox.
2.00 to 27.50
-14ꢀhꢀ14,
-14ꢀkꢀ14,
-21ꢀlꢀ21
1.93 to 27.50
-19ꢀhꢀ19,
-16ꢀkꢀ16,
-24ꢀlꢀ24
H
N
H
Ph
H
H
H
N
Ph
H
SO2Ph
PhO2S
Index ranges
H
No. refl. collected
23677
8253 [R(int) =
0.0346]
47185
8311 [R(int) =
0.0533]
Ph
Ph
HN
B
Ph
Ph
A
H
SO2Ph
No. indep. reflections
C
Max. and min.
transmission
Data/restraints/param.
GOF
0.9833 and 0.9202 0.9652 and 0.9475
8253 / 0 / 452
1.021
0.0483
8311 / 0 / 464
1.051
0.0576
isox.
isox.
isox.
H
N
H
*R1 [I>2ꢅ (I)]
Ph
H
Ph
N
SO2Ph
PhO2S
H
H
*wR2 [I>2ꢅ (I)]
0.1121
0.1319
H
H
Largest diff. peak, hole
(eÅ-3)
0.555, -0.494
0.763, -0.395
Ph
Ph
Ph
H
HN
B'
Ph
C'
* R1 = ꢆ||Fo| - |Fc||/ꢆ|Fo|; wR2 = {ꢆ[ w(Fo2 - Fc2)2]/ ꢆ [w(Fo )2]}1/2
2
SO2Ph
A'
Table 2
Figure 3. Newman projections of 3 in staggered conformations. Top
(A-C): S, R configuration. Bottom (A'-C'): S, S configuration.
Hydroxylation of isoxazole (1) using lateral metallation and quenching
with 2-sulfonyloxaziridine (6).
Isolated Yield, %
Entry
Base
2
3*
4
5
Using n-BuLi as the base for metalation of anthryl
isoxazole (8) has previously been reported to give slightly
higher yields than lithium diisopropylamide (LDA) in
lateral metallation, without attacking the ester group [9].
However, in this study, when n-BuLi was used as a base
for the metallation on the C-5 methylene group of (1)
(Scheme 2), addition of n-butyl lithium to the ester moiety
occurred. In the crystal structure of (8), a relatively strong
hydrogen bond between carbon-oxygen double bond and
the C-5 methyl hydrogen points the ethoxy group towards
the anthracene [3,17], as evidenced in solution by
anisotropy in the chemical shift. This orientation shields
the carbonyl with the dirigible like anthracenyl moiety,
and possibly enhances the reactivity of the C-5 methyl. In
contrast, in the presence of phenethyl moiety, the
1
2
3
n-BuLi
LDA
36
10(1.5:1)
18
4
52
81
11(1.5:1)
<3
KHMDS
* Ratios of diastereomers (SR/RS to SS/RR) before separation for
compounds 3 are in parentheses.
Table 3
Hydroxylation of C-5 methyl group of isoxazole (8).
Oxazir-
idine
Isolated Yield, %
Entry
Base
9
10
36
24
1
2
6
6
n-BuLi
LDA
43
40
3
4
6
7
KHMDS
n-BuLi
No desired products found
70 Not detected

262
C. Li, B. Twamley, and N. Natale
Vol 45
Scheme 2
Cl
Cl
Cl
1. base/THF, -78 o
C
+
O
O
O
2. sulfonyloxaziridine (6) or (7), -78 o
C
N
N
N
O
O
O
O
O
O
OH
O2
*
S
Ph
N
Ph
H
8
10
9
O
N
N
Ph
S
Ph
O
O
S
O
O
O
6. trans-2-(phenylsulfonyl)-3-phenyloxaziridine
7. (1R)-(-)-(10-camphorsulfonyl)oxaziridine
phenyloxaziridine (1.2 equiv.) dissolved in THF was added in
one portion. After stirring for 2 hours at -78 ºC, the mixture was
quenched with saturated aqueous NH4Cl solution, and warmed
up to room temperature. Workup included extraction of aqueous
layer with CH2Cl2, extraction of the combined organic layers
with brine solution, removal of solvent using rotary evaporation.
The crude mixture was purified by radial chromatography
(hexanes-ethyl acetate, 6:1) to give pure products.
Ethyl 3-(9'-anthracenyl-10'-chloro-)-5-hydroxymethyl-4-
isoxazole carboxylate (9). This compound was crystallized as
yellow solid from hexanes-ethyl acetate (3:1), mp 129-131 ºC;
1H nmr: ꢀ 0.24 (t, 3H, J=7.1Hz), 3.70 (q, 2H, J=7.1Hz), 4.33 (t,
1H, J=7.2Hz), 5.17 (d, 2H, J=7.2Hz), 7.53 (m, 2H), 7.65 (m, 4H)
and 8.61 ppm (d, 2H, J=8.4Hz); 13C nmr: ꢀ 12.55, 57.09, 61.05,
112.53, 121.72, 125.09, 125.67, 126.74, 128.30, 131.15, 131.31,
160.06, 162.42, 178.39; ms: m/z 383 (36, M+2+), 382 (23), 381
(100, M+), 322 (23), 277 (56), 237 (32), 176 (57). Anal. Calcd.
for C21H16NO4Cl: C, 66.06; H, 4.22; N, 3.67. Found: C, 65.76;
H, 4.47; N, 3.67.
carbonyl orientation in (1) is reversed in the solid state
[9]. Thus, in (1) the C-5 phenethyl may inhibit the
reactivity at that position, and now nucleophilic addition
at the carbonyl can compete more favorably.
We continue to be intrigued by the novel chemistry
observed in our studies of the lateral metalation and
electrophilic quenching of highly functionalized
isoxazoles, as well as being motivated by their potentially
useful biological activities, and will report on our progress
in due course.
EXPERIMENTAL
Mass spectra were obtained on a JEOL JMS-AX505 HA. The
NMR spectra (1H and 13C) were obtained on a Bruker Avance
300 Digital NMR (300 MHz) using SGI-IRIX 6.5. The spectra
were recorded in deuteriochloroform unless otherwise noted.
Elemental analyses were performed by Desert Analytics
Laboratory, PO Box 41838, Tucson, Arizona 85717. Single-
crystal X-ray analysis was obtained on Bruker (Siemens)
SMART APEX instrument. All reactions were performed under
Argon atmosphere. Tetrahydrofuran was distilled from sodium-
benzophenone immediately before use. Radial chromatography
was performed on silica gel (Merck 60 A, 230-400mesh). trans-
2-Phenylsulfonyl-3-phenyl-oxaziridine was prepared according
to previously reported procedure [18]. Ethyl 3-(9'-anthracenyl-
10'chloro)-5-methyl-4-isoxazole carboxylate and ethyl 3-(9'-
anthracenyl-10'-chloro-)-5-phenylethyl-4-isoxazole carboxylate
were synthesized via routes developed in our laboratory [3,9].
LDA solution was generated in situ by adding n-BuLi (1.2
equiv.) to a solution of freshly distilled diisopropylamine (1.4
equiv.) in THF (ca. 0.1 M) at 0 ºC and stirred for 10 minutes at 0
ºC before cooling to –78 ºC.
Ethyl 3-(9'-anthracenyl-10'-chloro-)-5-(2-phenyl)-2-
[(phenylsulfonyl)amino]ethyl-4-isoxazole carboxylate (10).
This compound was crystallized as white needles from hexanes-
ethyl acetate (3:1), mp 160.5-162.5 ºC (decomposed); 1H nmr: ꢀ
0.26 (t, 3H, J=7.2Hz), 3.69 (m, 3H), 3.90 (dd, 1H, J=14.1,
9.3Hz), 5.11 (ddd, 1H, J=14.1, 8.1, 5.4Hz), 5.83 (d, 1H,
J=8.1Hz), 7.20 (m, 5H), 7.38 (m, 2H), 7.50 (m, 4H), 7.64 (m,
3H), 7.72 (m, 2H), 8.60 ppm (d, 2H, J=8.7Hz); 13C nmr: ꢀ 12.65,
34.92, 56.87, 60.59, 113.27, 122.17, 124.85, 124.95, 125.88,
126.01, 126.19, 126.48, 126.61, 126.80, 126.82, 126.95, 128.12,
128.24, 128.27, 128.72, 128.78, 131.03, 131.09, 131.21, 132.38,
139.12, 140.58, 159.93, 161.89, 175.01 ppm; ms: m/z 612 (49.8,
M+2+), 611 (54), 610 (94, M+), 454 (41), 350 (25), 307(11), 246
(100), 154 (93), 131 (89). Anal. Calcd. for C34H27N2O5SCl: C,
66.82; H, 4.45; N, 4.58. Found: C, 66.74; H, 4.47; N, 4.36.
Ethyl 3-(9'-anthracenyl-10'-chloro-)-5-(1''-hydroxy-2-
phenylethyl)-4-isoxazole carboxylate (2). This compound was
crystallized as yellow flakes from hexanes-ethyl acetate (6:1),
General procedure for hydroxylation. To a stirred solution
of ethyl isoxazolecarboxylate in THF (ca. 0.1 M) at –78 ºC was
added base (1.2 equiv.) (n-BuLi or LDA or KHMDS) over 10
minutes. After the reaction mixture was stirred for 30 minutes at
-78 ºC, a pre-cooled (-78 ºC) solution of 2-(phenylsulfonyl)-3-
1
mp 123-124 ºC; H nmr: ꢀ 0.14 (t, 3H, J=14.0Hz), 3.44 (d, 2H,
J=6.5Hz), 3.58 (dq, 2H, J=14.0, 2.1Hz), 4.97 (d, 1H, J=8.5),
5.57 (dd, 1H, J=6.5, 8.5Hz), 7.32 (m, 3H), 7.38 (m, 2H), 7.50

Jan-Feb 2008
Preparation And Crystal Structures Of 3-Anthracenyl Isoxazolyl Sulfonamides
263
(ddd, 2H, J=10, 5.6, 1.4Hz), 7.57 (ddd, 2H, J=9, 1.25, 0.6), 7.62
(ddd, 2H, J=10, 5.6, 1.4Hz), 8.60ppm (ddd, 2H, J=8.9, 1.25,
0.6Hz); 13C nmr: ꢀ 12.52, 42.41, 61.11, 69.17, 112.05, 122.02,
125.13, 125.17, 125.76, 125.78, 126.73, 126.81, 126.85, 127.17,
128.34, 128.36, 128.62, 129.70, 129.71, 131.18, 131.22, 131.27,
135.98, 160.12, 162.45, 180.01ppm; ms: m/z 473 (55, M+2+),
472(86), 471 (100, M+), 380 (5.3, M+-PhCH2), 306 (26, M+-
PhCH2-COOC2H5), 278 (25.5), 176 (10), 91 (17.6). Anal. Calcd.
for C28H22NO4Cl: C, 71.26; H, 4.70; N, 2.97. Found: C, 71.33;
H, 4.52; N, 2.99.
acetate (6:1), mp 173ºC (decomp.); 1H nmr: ꢀ 0.24 (t, 3H,
J=7.1Hz), 0.37 (m, 2H), 0.76 (m, 2H), 1.28 (dt, 2H, J=7.1,
2.1Hz), 2.79 (dd, 1H, J=13.2, 4.5Hz), 3.27 (t, 1H, J=13.2Hz),
4.39 (m, 1H), 5.03 (t, 1H, J=9.0Hz), 6.28 (d, 1H, J=9.0Hz), 7.08
(dd, 2H, J=7.5, 1.5Hz), 7.27 (m, 11H), 7.39 (tt, 1H, 10.2, 1.5Hz),
7.45 (ddd, 1H, J=8.7, 6.6, 1.2Hz), 7.63 (m, 6H), 8.59 ppm (dd,
2H, J=8.9, 0.9Hz); 13C nmr: ꢀ 12.93, 21.43, 25.49, 36.35, 40.70,
46.85, 61.12, 121.18, 122.57, 125.06, 125.23, 125.41, 125,58,
126.51, 126.76, 126.87, 127.08, 127.26, 127.87, 128.11, 128.34,
128.36, 128.56, 128.69, 128.74, 131.12, 131.25, 131.92, 132.03,
138.10, 138.80, 141.01, 158.19, 176.68, 197.52 ppm; ms: m/z
714 (50, M+2+), 713 (49.7), 712 (100, M+), 467 (46), 246 (62),
141 (28). Anal. Calcd. for C43H37N2O4SCl: C, 72.41; H, 5.23; N,
3.93. Found: C, 72.34; H, 5.50; N, 3.95.
Ethyl 3-(9'-anthracenyl-10'-chloro-)-5-{1(S)-benzyl-2(R)-
phenyl-[(phenylsulfonyl)amino]ethyl}-4-isoxazole carboxyl-
ate (3a). This compound was crystallized as pale yellow needles
1
from hexanes-ethyl acetate (6:1), mp 168.5-169.5 ºC; H nmr: ꢀ
Procedure for X-ray analysis. Crystals of compound 3a or
5a were removed from the flask and covered with a layer of
hydrocarbon oil. A suitable crystal was selected, attached to a
glass fiber and placed in the low-temperature nitrogen stream
[19]. Data were collected at 83(2) K using a Bruker/Siemens
SMART APEX instrument (Mo Kꢁ radiation, ꢂ = 0.71073 Å)
equipped with a Cryocool NeverIce low temperature device.
Data were measured using omega scans of 0.3° per frame for 5
seconds for 3a and 10 seconds for 5a, and a full sphere of data
was collected. A total of 2132 frames were collected with a final
resolution of 0.77 Å for both 3a and 5a. The first 50 frames were
recollected at the end of data collection to monitor for decay.
Cell parameters were retrieved using SMART [20] software and
refined using SAINTPlus [21] on all observed reflections. Data
reduction and correction for Lp and decay were performed using
the SAINTPlus software. Absorption corrections were applied
using SADABS [22]. The structure was solved by direct
methods and refined by least squares method on F2 using the
SHELXTL program package [23]. The structure was solved in
the space group P-1 [P2(1)/c] by analysis of systematic
absences. All atoms were refined anisotropically. Both 3a and
5a crystallize in non-chiral space groups, which means they are
racemic. 3a is presented as C21, S and C29, R, and 5a as C23, S
and C31, R. No decomposition was observed during data
collection.
0.16 (t, 3H, J=7.1Hz), 2.94 (dd, 1H, J=13.5, 4.8Hz), 3.34 (dd,
1H, J=13.5, 10.8Hz), 3.48 (m, 2H), 4.60 (m, 1H), 5.05 (t, 1H,
J=9.1Hz), 5.91 (d, 1H, J=9.1Hz), 7.13 (m, 5H), 7.21 (m, 5H),
7.29 (m, 3H), 7.39 (m, 1H), 7.41 (t, 1H, J=7.3Hz), 7.48 (dd, 2H,
J=2.0, 2.6Hz), 7.60 (m, 2H), 7.66 (m, 2H), 8.56 (d, 1H,
J=8.8Hz), 8.57 (d, 1H, J=8.8Hz); 13C nmr: ꢀ 12.54, 36.54, 46.69,
60.28, 60.69, 114.47, 122.31, 124.79, 124.87, 125.76, 125.96,
126.32, 126.43, 126.53, 126.61, 126.74, 126.76, 126.86, 128.03,
128.17, 128.20, 128.40, 128.65, 128.69, 128.77, 130.90, 131.01,
131.06, 132.21, 137.81, 138.64, 140.77, 159.62, 161.40, 177.28;
ms: m/z 702 (24, M+2+), 701 (28), 700 (41, M+), 455 (10), 246
(100), 131 (53). Anal. Calcd. for C41H33N2O5SCl: C, 70.23; H,
4.74; N, 3.99. Found: C, 69.94; H, 4.85; N, 4.05.
Ethyl 3-(9'-anthracenyl-10'-chloro-)-5-{1(S)-benzyl-2-(S)-
phenyl-2-[(Phenylsulfonyl)amino]ethyl}-4-isoxazole carbox-
ylate (3b). This compound was crystallized as pale yellow
needles from hexanes-ethyl acetate (6:1), mp 207 ºC
1
(decomposed); H nmr: ꢀ 0.20 (t, 3H, J=7.1Hz), 3.33 (t, 1H,
J=12Hz), 3.41 (q, 2H, J=7.1Hz), 3.79 (dd, 1H, J=12, 4.8Hz),
4.64 (dt, 1H, J=10.5, 4.8Hz), 5.01 (t, 1H, J=9.7Hz), 5.92 (d, 1H,
J=9.3Hz), 6.59 (d, 1H, J=9.0Hz), 6.93 (d, 1H, J=9.0Hz), 7.08
(m, 4H), 7.22 (m, 5H), 7.33 (t, 3H, J=8.0Hz), 7.51 (m, 5H), 7.75
(dd, 2H, J=8.5, 1.2Hz), 8.47ppm (dd, 2H, J=8.8, 0.6Hz); 13C
nmr: ꢀ12.74, 37.33, 46.93, 60.03, 113.44, 122.09, 124.87,
124.88, 125.63, 125.74, 126.19, 126.31, 126.46, 126.53, 126.65,
127.20, 127.84, 128.13, 128.13, 128.16, 128.38, 128.43, 128.90,
129.00, 130.81, 130.84, 130.88, 132.60, 138.12, 138.45, 159.48,
160.21, 176.80ppm; ms: m/z 702 (35.3, M+2+), 701 (34.8), 700
(66, M+), 545 (1.6), 455 (27), 351 (7.1), 246 (77), 154 (2.0), 77
(100). Anal. Calcd. for C41H33N2O5SCl: C, 70.23; H, 4.74; N,
3.99. Found: C, 70.05; H, 4.81; N, 4.06.
3-(9'-Anthracenyl-10'-chloro-)-[5-(1''-hydroxy)-phenylisox-
azol-4-yl]pentan-1-one (4). This compound was crystallized as
pale yellow flakes from hexane-ethyl acetate (6:1), mp 105-106
ºC; 1H nmr: ꢀ 0.28 (t, 3H, J=7.5Hz), 0.53 (m, 2H), 0.99 (m, 2H),
1.53 (t, 2H, J=7.5Hz), 3.40 (t, 2H, J=6.9Hz), 5.21 (d, 1H,
J=9.0Hz), 5.46 (dt, 1H, J=9.0, 6.9Hz), 7.35 (m, 5H), 7.56 (m,
4H), 7.68 (m, 2H), 8.65ppm (dd, 2H, J=8.7, 3.0Hz); 13C nmr: ꢀ
12.87, 21.48, 25.20, 40.41, 41.54, 69.31, 119.93, 121.20, 125.20,
125.24, 125.41, 125.45, 127.05, 127.10, 127.16, 127.53, 127.63,
128.45, 128.47, 128.52, 129.56, 131.25, 131.32, 132.25, 136.14,
159.05, 180.15, 197.82; ms: m/z 485 (41, M+2+), 484 (37), 483
(100, M+), 392 (68, M+-PhCH2), 374 (11, M+-PhCH2-H2O), 228
(11), 176 (17). Anal. Calcd. for C30H26NO3Cl: C, 74.45; H, 5.41;
N, 2.89. Found: C, 74.37; H, 5.41; N, 3.05.
Acknowledgement. The authors thank NIH for grants
NS038444(NN), P20RR015583(NN), and P20RR16454(CL), as
well as the University of Idaho Research Council for financial
support. CL acknowledges the Malcolm and Carol Renfrew
Scholarship Endowment, and thanks Dr. Ronald Crawford for
help during manuscript preparation. The Bruker (Siemens)
SMART APEX diffraction facility was established at the
University of Idaho with the assistance of the NSF-EPSCoR
program and the M. J. Murdock Charitable Trust, Vancouver,
WA, USA.
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