Synthesis of enantiomerically pure analogues of the meta-substituted aniline antibiotics

Article abstract of DOI:10.1016/j.tetasy.2007.03.003

A practical route is described for the preparation of enantiomerically pure analogues of the meta-substituted aniline antibiotics. Starting with enantiomerically pure anilinide, photooxygenation, reduction and diastereoselective Weitz-Scheffer epoxidation

Full text of DOI:10.1016/j.tetasy.2007.03.003

Tetrahedron: Asymmetry 18 (2007) 791–796
Synthesis of enantiomerically pure analogues of the
meta-substituted aniline antibiotics
Kani Zilbeyaz, Ertan Sahin and Hamdullah Kilic*
Department of Chemistry, Ataturk University, 25240 Erzurum, Turkey
Received 26 February 2007; accepted 5 March 2007
Abstract—A practical route is described for the preparation of enantiomerically pure analogues of the meta-substituted aniline antibi-
otics. Starting with enantiomerically pure anilinide, photooxygenation, reduction and diastereoselective Weitz-Scheffer epoxidation pro-
tocols provide enantiomerically pure analogues of the meta-substituted aniline antibiotics in three steps.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
meta-substituted aniline (m-C7N) antibiotic analogues,
which may display biological activity. We have recently
reported a convenient diastereoselective synthesis of the
racemic cis-aminoepoxyquinol 5, in which we employed
an effective sequence of photooxygenation, reduction and
Weitz-Scheffer epoxidation.13 Herein, we report the suc-
cessful implementation of this strategy, resulting in the syn-
thesis of enantiomerically pure analogues 10a and 10b of
meta-substituted aniline antibiotics.
There are many natural products with antibiotic and anti-
tumor activity whose common feature is an aminoepoxy-
cyclohexenone (m-C7N) unit with polyunsaturated side
chains linked to C-4 and to the amine substituent, respec-
tively.1 Manumycin A 1, isolated as the main metabolite
of Streptomyces parvulus, is the most representative mem-
ber of the meta-substituted aniline (m-C7N) antibiotics.2
The meta-substituted aniline unit is thought to originate
from 3-amino-4-hydroxybenzoic acid through a biosyn-
thetic pathway.3
2. Result and discussion
A consequence of this synthetic pathway is the syn-orienta-
tion of the epoxide (relative to the hydroxyl group), a fea-
ture that is common to the meta-substituted aniline (m-
C7N) antibiotics. Manumycin A 1, and related natural
products such as asukamycin,4 U62162,5 U56407,6 nisamy-
cin,7 alisamycin,8 and colabomycin,9 are known to exhibit
antibiotic, antifungal, cytotoxic and elestase inhibitory
activities. A significant discovery is that they act as selective
inhibitors of Ras farnesyltransferase and might be of use in
cancer chemotherapy. Their activity depends on meta-
substituted aniline unit (m-C7N); complex side chains are
not essential, since a series of smaller meta-substituted ani-
line (m-C7N) analogues without complex side chains such
as MM 14201 2,10 LL10037a 3,11 and MT 35214 412 also
act as antitumor antibiotics (Fig. 1). The latter observation
indicates that it should be worthwhile to prepare simplified
Tetraphenylporphine (TPP)-sensitized photooxygenation
of 7, obtained from the reaction of acetanilide 6 with enan-
tiomerically pure (S)-1-chloro-1-oxopropan-2-yl acetate,14
at 20 ꢁC in the presence of tetrabutylammonium fluoride
gave a mixture of diasteromeric hydroperoxides 8a and
8b in a ratio of 1:1 (Scheme 1). These products were sepa-
rated by fractional crystallization and silica column chro-
matography at room temperature. The structural
assignments of hydroperoxides 8a and 8b are made on
the basis of their spectral data. Elemental analysis con-
firmed the empirical formula C12H15NO6, while the cyclo-
hexadienyl hydroperoxide structures were established by
their 400 MHz 1H NMR, 100 MHz 13C NMR and IR spec-
tra. The IR spectra exhibited the characteristic hydroper-
oxide band and a strong, highly conjugated carbonyl
absorption. In the 1H NMR spectrum, the olefinic protons
displayed an AB pattern, as required by the a,b-unsatu-
rated enone functionality, of which the olefinic proton
proximate to the methyl group is further split into a
*
Corresponding author. Tel.: +90 442 231 4426; fax: +90 442 236 0948;
e-mail: hkilic@atauni.edu.tr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.03.003

792
K. Zilbeyaz et al. / Tetrahedron: Asymmetry 18 (2007) 791–796
O
O
O
O
O
H
N
R1
NH2
NHAc
NHAc
NHAc
O
O
O
O
O
O
HO R2
HO CH3
OH
OH
OH
1
2
3
4
5
Manumycin A
MM 14201
LL-10037α
MT 35214
Bu
R1=
R2=
HO
O
N
H
O
Figure 1. Some members of the manumycin family of antibiotics.
O
OH
OH
OAc
O
OAc
CH3
O
OAc
CH3
H
N
H
N
H
N
NH2
Cl
ν
O2, TPP, h
CHCl3
OAc
+
O
O
O
CH2Cl2/Acetone
Imidazole
H3C
H3C
OOH
OOH
CH3
6
CH3
7
8a
8b
Scheme 1. Synthesis and photooxygenation of acetanilide 7.
doublet by the vinylic proton next to the acetamide group
through W coupling. The 13C NMR spectra possess the
three expected carbonyl resonances, which confirm the
presence of the conjugated enone, amide, and acetate func-
tionalities in 8a and 8b. Having confirmed the structures of
the hydroperoxides, the exact structure of 8a was deter-
mined by X-ray analysis. Unfortunately, an acceptable
crystal of 8b for the X-ray analysis could not be obtained.
The absolute configuration of 8a was determined by X-ray
analysis as (3R,8S). The absolute configuration of the new
stereogenic center linked to the hydroperoxide functional-
ity, C3, was determined relatively by taking account of
the C8 center as the reference point (Fig. 2).
and catalytic amounts of DBU as base afforded the enantio-
merically pure cis-epoxides 10a and 10b as a single diaste-
reomer (relative to the hydroxy group) in 80% yield
(Scheme 2). We knew from our previous work with rac-5
that epoxidation occurs regioselectively and diastereoselec-
tively at the more electrophilic, unfunctionalized enone
C=C double bond and not at the N-substituted double
bond. The hydroxy-directing effect operates efficiently in
the Weitz-Scheffer epoxidation to afford the cis-configured
epoxide exclusively. A hydrogen bond between the quinol
hydroxy group and the tert-butyl hydroperoxide anion di-
rects the delivery of the oxygen atom to the dienone face
towards which the hydroxy group points. The structural
assignment of cis-epoxides 10a and 10b was based on their
1H, 13C NMR spectra and X-ray analysis. The olefinic pro-
ton occurs as a doublet, the epoxide protons display an AB
pattern, in which the low-field portion is further coupled to
the olefinic proton proximate to the acetamide group. The
13C NMR spectrum consists of five sp2 and six sp3 carbon
signals, in support of the assigned structures for the epox-
ides 10a and 10b. Having confirmed the structures of the
hydroperoxides, the exact structure of 10b was determined
by X-ray analysis. Unfortunately, we could not obtain an
The reduction of hydroperoxides 8a and 8b was achieved
by using titanium tetraisopropoxide in the presence of
dimethyl sulfide as a reductant,15 which gave the desired
quinols 9a and 9b (Scheme 2) in high yield. The proposed
structures for quinols 9a and 9b are based on spectral
and analytic data. Thus, in an efficient two-step sequence,
the hydroxyl and enone functionalities were conveniently
introduced in acetanilide 7. The Weitz-Scheffer epoxidation
of quinols 9a and 9b with t-butyl hydroperoxide (TBHP)
Figure 2. X-ray crystal structures of hydroperoxide 8a (left) and epoxide 10b (right).

K. Zilbeyaz et al. / Tetrahedron: Asymmetry 18 (2007) 791–796
793
O
OAc
CH3
O
OAc
CH3
O
OAc
CH3
H
N
H
N
H
N
a
b
O
O
O
O
H3C
H3C
H3C OH
OOH
OH
8a
9a
10a
O
OAc
CH3
O
OAc
CH3
O
OAc
CH3
H
N
H
N
H
N
a
b
O
O
O
O
H3C
H3C OH
H3C
OH
OOH
8b
9b
10b
˚
Scheme 2. Reagents and conditions: (a) Me2S, (3.0 equiv), Ti(O-i-Pr)4 (60 mol %), CH2Cl2, 1 h, 4 A molecular sieves; (b) TBHP (3.0 equiv), DBU,
CH2Cl2, 4 h.
acceptable crystal of 10a for X-ray analysis. The stereo-
chemistry of 10b was fully determined by X-ray crystallo-
graphic analysis, and the absolute configuration of the
new stereogenic centers were established unequivocally to
be (1S,2R,6R) (Fig. 2 displacement ellipsoids are plotted
at the 50% probability level and chloroform has been omit-
ted from structure 10b for clarity). Hydroperoxide 10b
crystallizes in the trigonal space group R3 with Z = 3.
There are three chloroform molecules in the unit cell. Each
one is trapped with the three neighbouring epoxide
O-molecule, causing intermolecular H-bonding [Cchlf ꢀ ꢀ ꢀ
merically pure analogues of the meta-substituted aniline
antibiotics.
4. Experimental
4.1. General
(S)-1-Chloro-1-oxopropan-2-yl acetate was synthesized
from L-lactic acid according to the literature.14 Reagents
and solvents were purchased from standard chemical sup-
pliers and purified to match the reported physical and
spectral data. Melting points were determined with a Buchi
apparatus. Solvents were concentrated at reduced pressure
(ca. 20 ꢁC, 20 Torr). IR spectra were obtained on KBr
O1i,ii,iii = 3.193(7) A; symmetry codes: (i) 2/3 + x, 1/3 + y,
˚
ꢁ2/3 + z, (ii) 2/3 ꢁ y, 1/3 + x ꢁ y, ꢁ2/3 + z, (iii) 2/3 ꢁ
x + y, 1/3 ꢁ x, ꢁ 2/3 + z)]. The epoxide ring is approxi-
mately an equilateral triangle. Its bond angles are about
1
pellets with a Perkin–Elmer apparatus. H and 13C NMR
˚
60ꢁ, but O1–C1 bond length [1.425(4) A] is slightly shorter
˚
spectra were recorded on a Varian 400 spectrometer in
CDCl3. Enantiomeric excesses were determined by HPLC
analysis using a chiral column (Chiralcel OD) with eluent
n-hexane–i-PrOH, 90:10, flow rate of 0.6 mL/min, detec-
tion performed at 254 nm. Optical rotations were mea-
sured with a Bellingham + Stanley, ADP220, 589 nm
spectropolarimeter in a 1dm tube; Concentrations are
given in g/mL. A polarimetric Chiralyser detector was used
to assess the sign of configuration of the enantiomer
formed. All column chromatography was performed on
silica gel.
than O1–C2 [1.440 (4) A]. The angle between hydroxyl O3
and methyl C7 atom is 106.7ꢁ. This result led us to the con-
clusion that diastereomer 10a should have a (1R,2S,6S)-
configuration, and the hydroperoxide 8b should have a
(3S,8S)-configuration. Hydroperoxide 8a crystallizes in
the non-centrocymmetric monoclinic space group C2 with
Z = 4 (Fig. 2). It possess (3R,8S) stereogenic centers, so
hydroperoxide 8b should have the (3S,8S)-configuration.
The cyclohexa-1,4-diene ring is almost planar, maximum
˚
deviations from mean plane (C1/C2/C4/C5) are 0.042 A
˚
and 0.039 A for C6 and C3 atoms, respectively. The angle
between hydroperoxide (O2) and methyl (C9) atoms is
102.3ꢁ. Moreover, the crystal structure is effectively stabi-
4.1.1. (S)-1-(2-Hydroxy-5-methylphenylamino)-1-oxopro-
pan-2-yl acetate 7. To a stirred solution of 6 (2.0 g,
16 mmol) in 100 mL of CH2Cl2/acetone (80:20) was added
imidazole (1.2 g, 17 mmol) and cooled to 10 ꢁC in an ice-
water bath. Then 10 mL of (S)-acetic acid 1-chlorocar-
bonyl-ethyl ester (2.6 g, 17 mmol) in CH2Cl2 was added
within 1 h. The resulting mixture was stirred for 2 h at
room temperature. After evaporation of the solvent at
ꢂ20 ꢁC and 15 Torr, the mixture was chromatographed
on silica gel (120 g) with hexane–EtOAc (3:2) as eluent to
afford 3.6 g (97%) of acetanilide 7 as colourless solids:
mp 138–139 ꢁC from CH2Cl2–hexane; 1H NMR
(400 MHz, CDCl3) d 8.22 (br s, 1H), 7.99 (br s, 1H), 7.07
(s, 1H,), 6.86–6.92 (AB system, 2H), 5.38 (q, J = 6.4 Hz,
1H), 2.25 (s, 3H), 2.21 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 170.1, 169.6, 145.9,
130.4, 127.9, 124.5, 122.7, 119.0, 70.7, 21.3, 20.6, 18.2; IR
lized by hydrogen bonding networks [O3–H ꢀ ꢀ ꢀ O1i =
ii
˚
˚
2.763(2) A (angle 156ꢁ); C11–H ꢀ ꢀ ꢀ O6 = 3.130(7) A
(angle 160ꢁ); symmetry codes: (i) 1 ꢁ x, y, ꢁz, (ii) 1/2 ꢁ x,
1/2 + y, z].
3. Conclusion
The present methodology employing photooxygenation,
reduction and diastereoselective Weitz-Scheffer epoxida-
tion would be applicable to the synthesis of enantiomeri-
cally pure analogues of the meta-substituted aniline
antibiotics. We are currently applying the methodology de-
scribed herein to prepare other enantiomers of 10a and 10b
starting from D-lactic acid and carrying out a programme
to assess the biological activity of the synthesised enantio-

794
K. Zilbeyaz et al. / Tetrahedron: Asymmetry 18 (2007) 791–796
(KBr, cmꢁ1) 3397, 3160, 3012, 2935, 2871, 1741, 1664,
1600, 1554, 1510, 1457, 1380, 1355, 1234, 1151, 925. Anal.
ene chloride (30 mL) at room temperature. After 1 h of
stirring, the reaction was stopped by the addition of
water (25 lL), and the solids were removed by filtration.
The solvent was evaporated (ꢂ25 ꢁC, 15 Torr), the
residue was loaded onto a short silica gel column
(30 g), and eluted with a 4:1 mixture of hexane–EtOAc
to afford the title compounds (0.21 g, 83%) as white
solids.
Calcd for C12H15NO4: C, 60.75; H, 6.37; N, 5.90. Found:
19
C, 60.72; H, 6.24; N, 6.03; ½aꢃD ¼ ꢁ50 (c 0.05, CHCl3);
retention time: 7.1 min, Chiralcel OD, n-hexane–i-PrOH,
60:40, flow rate of 0.6 mL/min, 254 nm.
4.1.2. Photooxygenation of acetanilide 7: preparation of 8a
and 8b. A sample of acetanilide 7 (0.5 g, 2.0 mmol), meso-
tetraphenylporphine (TPP, 10 mg) and tetrabutylammo-
nium fluoride (0.2 g,) in chloroform (70 mL) was irradiated
for 2 d at room temperature with a 250 W tungsten lamp,
while a gentle stream of dry oxygen gas was allowed to pass
through the solution. After removal of the solvent (ꢂ10 ꢁC,
15 Torr), the mixture was chromatographed on silica gel
(120 g) with hexane–EtOAc (1:1) as eluent to remove
TPP as the first fraction. Further elution gave a mixture
of hydroperoxides 8a and 8b (0.4 g, 70%) as white
solids. Hydroperoxide 8a was obtained after fractional
crystallization from hexane–diethyl ether as colourless
plates. The rest of the mixture was chromatographed on sil-
ica gel (100 g) with hexane–EtOAc (3:1) as eluent to give
8b.
4.1.3.1. (S)-1-((R)-3-Hydroxy-3-methyl-6-oxocyclohexa-
1,4-dienylamino)-1-oxopropan-2-yl acetate 9a. Crystalliza-
tion from a mixture of EtOAc–hexane gave colourless nee-
dles, mp 92–93 ꢁC; 1H NMR (400 MHz, CDCl3) d 8.61 (br
s, 1H), 7.68 (d, J = 3.0 Hz, 1H), 6.98 (dd, A part AB sys-
tem, J = 10.0, 3.0 Hz, 1H), 6.14 (d, B part of AB system,
J = 10.0 Hz, 1H), 5.18 (q, J = 7.0 Hz, 1H), 3.52 (br s,
1H), 2.17 (s, 3H), 1.49 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 180.0, 169.9, 169.7,
155.5, 132.7, 129.3, 124.4, 70.7, 67.9, 27.7, 21.1, 17.9; IR
(KBr, cmꢁ1) 3373, 2984, 2937, 1748, 1709, 1668, 1530,
1451, 1371, 1228, 1124, 1093, 1054. Anal. Calcd for
C12H15NO5: C, 56.91; H, 5.97; N, 5.53. Found: C, 56.44;
19
H, C.6.30; N, 5.08; ½aꢃD ¼ ꢁ29 (c 0.05, CHCl3); retention
time: 11.9 min, Chiralcel OD, n-hexane–i-PrOH, 80:20,
4.1.2.1. (S)-1-((R)-3-Hydroperoxy-3-methyl-6-oxocyclo-
hexa-1,4-dienylamino)-1-oxopropan-2-yl acetate 8a. Mp
150–151 ꢁC (dec) from CHCl3–hexane; 1H NMR
(400 MHZ, CDCl3) d 9.52 (br s, 1H), 8.74 (br s, 1H),
7.73 (d, J = 3.0 Hz, 1H), 7.05 (dd, A part AB system,
J = 10.0, 3.0 Hz, 1H), 6.36 (d, B part of AB system,
J = 10.0 Hz, 1H), 5.20 (q, J = 7.0 Hz, 1H), 2.19 (s, 3H),
1.48 (s, 3H), 1.47 (d, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 179.9, 170.3, 169.7, 153.1, 131.9,
flow rate of 0.6 mL/min, 254 nm.
4.1.3.2. (S)-1-((S)-3-Hydroxy-3-methyl-6-oxocyclohexa-
1,4-dienylamino)-1-oxopropan-2-yl acetate 9b. Colourless
1
oil; H NMR (400 MHz, CDCl3) d 8.61 (br s, 1H), 7.71
(d, J = 3.0 Hz, 1H), 6.98 (dd, A part AB system,
J = 10.0, 3.0 Hz, 1H), 6.16 (d, B part of AB system,
J = 10.0 Hz, 1H), 5.21 (q, J = 7.0 Hz, 1H), 3.21 (br s,
1H), 2.17 (s, 3H), 1.50 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 180.1, 169.8, 169.8 155.2,
132.5, 129.4, 124.5, 70.7, 68.1, 27.8, 21.1, 17.9; IR (KBr,
cmꢁ1) 3373, 2981, 2931, 2873, 2856, 1745, 1704, 1666,
1619, 1529, 1452, 1400, 1375, 1226, 1128, 1099. Anal. Calcd
129.6, 127.6, 79.5, 70.6, 23.4, 21.1, 17.9; IR (KBr, cmꢁ1
)
3275, 3084, 2984, 2818, 1729, 1693, 1670, 1618, 1546,
1427, 1398, 1303, 1251, 1143, 1070, 983. Anal. Calcd for
C12H15NO6: C, 53.53; H, 5.62; N, 5.20. Found: C, 53.26;
19
H, 5.61; N, 5.27; ½aꢃD ¼ ꢁ12 (c 0.05, CHCl3); retention
for C12H15NO5: C, 56.91; H, 5.97; N, 5.53. Found: C,
time: 12.7 min, Chiralcel OD, n-hexane–i-PrOH, 80:20,
19
56.62; H, C.6.45; N, 5.02; ½aꢃD ¼ ꢁ40 (c 0.05, CHCl3);
flow rate of 0.6 mL/min, 254 nm.
retention time: 10.9 min, Chiralcel OD, n-hexane–i-PrOH,
80:20, flow rate of 0.6 mL/min, 254 nm.
4.1.2.2. (S)-1-((S)-3-Hydroperoxy-3-methyl-6-oxocyclo-
hexa-1,4-dienylamino)-1-oxopropan-2-yl acetate 8b. Col-
ourless oil; 1H NMR (400 MHz, CDCl3) d 9.00 (br s,
1H), 8.73 (br s, 1H), 7.69 (d, J = 3.0 Hz, 1H), 7.04 (dd, A
part AB system, J = 10.0, 3.0 Hz, 1H), 6.37 (d, B part of
AB system, J = 10.0 Hz, 1H), 5.25 (q, J = 7.0 Hz, 1H),
2.21 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H), 1.48 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 179.9, 170.1, 169.7, 152.9,
132.1, 129.4, 127.7, 79.5, 70.7, 23.4, 21.1, 17.9; IR (KBr,
cmꢁ1) 3327, 2991, 2852, 1742, 1663, 1616, 1539, 1451,
1395, 1375, 1354, 1140, 1101, 1038. Anal. Calcd for
4.1.4. General procedure for the preparation of 10a and
10b. Anhydrous tert-butylhydroperoxide (TBHP) (0.27 g,
3.0 mmol) and one drop of DBU were added to a magnet-
ically stirred solution of the quinol (0.25 g, 1.0 mmol) in
CH2Cl2 (25 mL) at room temperature (ꢂ20 ꢁC). The result-
ing mixture was stirred (ꢂ20 ꢁC) for 4 h, the solvent was
removed (10 ꢁC, 10 Torr), and the mixture was
chromatographed on silica gel (30 g), by eluting with a
4:1 mixture of EtOAc–hexane. The first fraction consisted
of unreacted TBHP; further elution gave the epoxide
(0.21 g, 80%) as a white solid.
C12H15NO6: C, 53.53; H, 5.62; N, 5.20. Found: C, 53.28;
19
H, 5.54; N, 5.21; ½aꢃD ¼ ꢁ38 (c 0.05, CHCl3); retention
time: 12.1 min, Chiralcel OD, n-hexane–i-PrOH, 80:20,
flow rate of 0.6 mL/min, 254 nm.
4.1.4.1. (S)-1-((1S,5S,6R)-5-Hydroxy-5-methyl-2-oxo-7-
oxabicyclo[4.1.0]hept-3-en-3-ylamino)-1-oxopropan-2-yl ace-
tate 10a. Crystallization from a mixture of CHCl3–
hexane gave colourless needles, mp 115–116 ꢁC; H NMR
(400 MHz, CDCl3) d 8.24 (br s, 1H), 7.44 (d, J = 2.5 Hz,
1H), 5.18 (q, J = 7.0 Hz, 1H), 3.66 (dd, dd, A part AB sys-
tem, J = 3.6, 2.5 Hz, 1H), 3.61 (d, B part of AB system,
4.1.3. General procedure for the preparation of 9a and
9b. Dimethyl sulfide (0.19 g, 3.0 mmol) and titanium
tetraisopropoxide (18.0 mg, 0.6 mmol) were added to a
magnetically stirred solution of the hydroperoxide
1
˚
(0.27 g, 1 mmol) and 4 A molecular sieves (1 g) in methyl-

K. Zilbeyaz et al. / Tetrahedron: Asymmetry 18 (2007) 791–796
795
J = 3.6 Hz, 1H), 2.85 (br s, 1H), 2.18 (s, 3H), 1.53 (s, 3H),
1.48 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
188.6, 169.7, 169.6, 130.6, 126.9, 70.7, 68.5, 58.8, 53.3,
26.7, 21.1, 17.8. IR (KBr, cmꢁ1) 3454, 3427, 3367, 2981,
2948, 1754, 1683, 1631, 1523, 1375, 1234, 1112, 1074,
1054, 1027. Anal. Calcd for C12H15NO6: C, 53.53; H,
[I > 2r(I)]: R1 = 0.065, wR2 = 0.146; R indices (all data):
R1 = 0.080, wR2 = 0.153; extinction coefficient: 0.00; larg-
ꢁ3
˚
est diff. peak and hole: 0.148 and ꢁ0.183e A
.
4.2.2. Crystal data for compound 10b. C12H15NO6ÆCHCl3,
crystal system, space group: trigonal, R3; (No. 146); unit
5.62; N, 5.20. Found: C, 53.26; H, 5.64; N, 5.27;
˚
˚
cell
dimensions:
a = 15.939(5) A,
b = 15.939(5) A,
19
½aꢃD ¼ ꢁ122 (c 0.05, CHCl3); retention time: 18.1 min, Chi-
3
˚
˚
c = 14.570(5) A, c = 120ꢁ; volume: 3205.62(12) A ; Z = 3;
ralcel OD, n-hexane–i-PrOH, 80:20, flow rate of 0.6 mL/
calculated density: 1.44 mg/m3; absorption coefficient:
min, 254 nm.
0.293 mmꢁ1
; F(000): 1452; crystal size: 0.023 mm ·
0.017 mm · 0.012 mm; h range for data collection 2.6–
30.5ꢁ; completeness to h: 30.5ꢁ, 99.7%; refinement method:
full-matrix least-squares on F2; data/restraints/parameters:
3217/0/192; goodness-of-fit on F2: 1.105; final R indices
[I > 2r(I)]: R1 = 0.082, wR2 = 0.229; R indices (all data):
R1 = 0.099, wR2 = 0.244; extinction coefficient: 0.0046;
4.1.4.2. (S)-1-((1R,5R,6S)-5-Hydroxy-5-methyl-2-oxo-7-
oxabicyclo[4.1.0]hept-3-en-3-ylamino)-1-oxopropan-2-yl ace-
tate 10b. Crystallization from a mixture of CHCl3–
hexane gave colourless needles, mp 118–119 ꢁC; H NMR
(400 MHz, CDCl3) d 8.24 (br s, 1H), 7.42 (d, J = 2.5 Hz,
1H), 5.22 (q, J = 7.0 Hz, 1H), 3.66 (dd, A part AB system,
J = 3.8, 2.5 Hz, 1H), 3.61 (d, B part of AB system,
J = 3.8 Hz, 1H), 2.85 (br s, 1H), 2.18 (s, 3H), 1.52 (s,
3H), 1.47 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 188.6, 169.7, 169.6, 130.5, 126.9, 70.8, 68.6,
58.8, 53.3, 26.7, 21.1, 17.9. IR (KBr, cmꢁ1) 3462, 3429,
3371, 2994, 2941, 1749, 1675, 1643, 1517, 1380, 1222,
1126, 1089, 1076, 1024. Anal. Calcd for C12H15NO6: C,
1
ꢁ3
˚
largest diff. peak and hole: 0.512 and ꢁ0.578e A
.
Crystallographic data (excluding structure factors) for the
structures of hydroperoxide 8a and epoxide 10b in this
paper have been deposited with the Cambridge Crystallo-
graphic Data Center as Supplementary Publication
Numbers CCDC 636629 and 636628, respectively. Copies
of the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
53.53; H, 5.62; N, 5.20. Found: C, 53.28; H, 5.54 N, 5.21;
19
½aꢃD ¼ þ115 (c, 0.05, CHCl3); retention time: 15.1 min,
Chiralcel OD, n-hexane–i-PrOH, 80:20, flow rate of
0.6 mL/min, 254 nm.
Acknowledgements
4.2. X-ray structure analysis
The authors are indebted to Ataturk University and The
State Planning Organization of Turkey (DPT) for the
financial support of this work.
For the crystal structure determination, a single crystal of
the compounds C12H15NO6 hydroperoxide 8a and
C12H15NO6 epoxide 10b was used for data collection on
a four-circle Rigaku R-AXIS RAPID-S diffractometer
equipped with a two-dimensional area IP detector. The
graphite-monochromatized Mo Ka radiation (k =
References
˚
0.71073 A) and oscillation scans technique with Dx = 5ꢁ
for one image were used for data collection. Images for
hydroperoxide 8a and epoxide 10b were successfully taken
by varying x with three sets of different v and / values. For
each compound, the 108 images for six different runs cov-
ering about 99.7% of the Ewald spheres were performed.
The lattice parameters were determined by least-squares
methods on the basis of all reflections with F2 > 2r(F2).
Integration of the intensities, correction for Lorentz and
polarization effects and cell refinement was performed
using CrystalClear software.16 The structures were solved
by direct methods (SHELXS-97) and non-H atoms were
refined by a full-matrix least-squares method with aniso-
tropic temperature factors (SHELXL-97).17
1. (a) Taylor, R. J. K.; Alcaraz, L.; Eyer-Kapfer, I.; Macdonald,
G.; Wei, X.; Lewis, N. Synthesis 1998, 775–790; (b) Mag-
dziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104,
1383–1429; (c) Marco-Contelles, J.; Molina, M. T.; Anjum, S.
Chem. Rev. 2004, 104, 2857–2899; (d) Miyashita, K.; Iman-
ishi, T. Chem. Rev. 2005, 105, 4515–4536.
2. Alcaraz, L.; Macdonald, G.; Ragot, J.; Lewis, N. J.; Taylor,
R. J. K. Tetrahedron 1999, 55, 3707–3716.
3. Hu, Y.; Melville, C. R.; Gould, S. J.; Floss, H. G. J. Am.
Chem. Soc. 1997, 119, 4301–4302.
4. (a) Kakinuma, K.; Ikekawa, N.; Nakagawa, N.; Omura, S. J.
Am. Chem. Soc. 1979, 101, 3402–3404; (b) Cho, H.; Sattler, I.;
Beale, J. M.; Zeeck, A.; Floss, H. G. J. Org. Chem. 1993, 58,
7925–7928.
5. Alcaraz, L.; Taylor, R. J. K. Chem. Commun. 1998, 1157–
1158.
6. Brodasky, T. F.; Stroman, D. W.; Dietz, A.; Mizsak, S. J.
Antibiot. 1983, 36, 950–956.
7. Wipf, P.; Coish, P. D. G. J. Org. Chem. 1999, 64, 5053–
5061.
8. Alcaraz, L.; Macdonald, G.; Kapfer, I.; Lewis, N. J.; Taylor,
R. J. K. Tetrahedron Lett. 1996, 37, 6619–6622.
9. Wei, X.; Cronje, J. J.; Taylor, R. J. K. J. Chem. Soc., Perkin
Trans. 1 1999, 1143–1145.
4.2.1. Crystal data for compound 8a. C12H15NO6, crystal
system, space group: monoclinic, C2; (No. 5); unit cell
dimensions: a = 20.7316(9) A, b = 6.2512(3) A, c =
˚
˚
3
˚
˚
14.4451(9) A, b = 132.853(12)ꢁ; volume: 1372.40(35) A ;
Z = 4; calculated density: 1.30 mg/m3; absorption coeffi-
cient: 0.105 mmꢁ1; F(000): 568; crystal size: 0.027 mm ·
0.023 mm · 0.012 mm; h range for data collection 2.7–
30.6ꢁ; completeness to h: 30.6ꢁ, 99.7%; refinement method:
full-matrix least-squares on F2; data/restraints/parameters:
3396/0/177; goodness-of-fit on F2: 1.141; final R indices
10. Box, S. J.; Gilpin, M. L.; Gwynn, M.; Hanscomb, G.; Spear,
S. R.; Brown, A. G. J. Antibiot. 1983, 36, 1631–1637.

796
K. Zilbeyaz et al. / Tetrahedron: Asymmetry 18 (2007) 791–796
11. Kapfer, I.; Lewis, N. J.; Macdonald, G.; Taylor, R. J. K.
Tetrahedron Lett. 1996, 37, 2101–2104.
15. Adam, W.; Balci, M.; Kilic, H. J. Org. Chem. 2000, 65, 5926–
5931.
12. Macdonald, G.; Alcaraz, L.; Lewis, N. J.; Taylor, R. J. K.
Tetrahedron Lett. 1998, 39, 5433–5436.
13. Adam, W.; Kilic, H.; Saha-Mo¨ller, C. R. Synlett 2002, 510–
512.
16. Rigaku, CrystalClear, Version 1.3.6. Rigaku American Cor-
poration, 9009 New Trails Drive, The Woodlands, TX 77381-
5209, USA, 2005.
17. Sheldrick, G. M. SHELXS97 and SHELXL97; University of
Go¨ttingen: Germany, 1997.
14. Bergman, J.; Brynolf, A. Tetrahedron 1990, 46, 1295–1310.