Synthesis of all stereoisomers and some congeners of isocytoxazone

Article abstract of DOI:10.1055/s-2003-37353

cis-Isocytoxazone 2a and trans-isocytoxazone 2b, structural isomers of the antiasthmatic agent cytoxazone (-)-1, and their 5-substituted congeners 23-28 have been prepared. Aldol reaction of para-substituted benzaldehydes with 7-chloro-1-methyl-5-phenyl-1,4-benzodiazepin-2-one, followed by separation of diastereomeric racemates afforded 3-10. Acid-catalyzed 1,4-benzodiazepine ring opening, and transformation of the methyl esters of β-aryl-β-hydroxy-α-amino acids (11-16) via 4-methoxycarbonyl derivatives of 1,3-oxazolidin-2-one (17-22) and their reduction afforded the target oxazolidin-2-one derivatives 23-28. Racemic isocytoxazones 2a and 2b were prepared by an independent route starting from 4-methoxystyrene epoxide. Pure enantiomers of these diastereomeric racemates were separated by HPLC chromatography on chiral stationary phases. Their CD spectra, along with those of previously prepared enantiomers of cis-cytoxazone 1a and trans-cytoxazone 1b are discussed.

Full text of DOI:10.1055/s-2003-37353

PAPER
375
Synthesis of All Stereoisomers and Some Congeners of Isocytoxazone
S
ynthesis of Ste
d
reoisomer
s
a
e
nd
C
ongen
n
e
rs of Isocyt
k
a
Ru er Boškovi Institute, Bijeni ka c. 54, POB 180, 10002 Zagreb, Croatia
Fax +385(1)4680195; E-mail: sunjic@rudjer.irb.hr
b
PLIVA Research and Development Institute, Ul. Baruna Filipovi a 25, 10000 Zagreb, Croatia
Received 23 October 2002; revised 28 November 2002
The reaction pathway for the synthesis of the diastereo-
meric racemic forms 23–28 is summarized in Scheme 1.
Conventionally, all formula in this scheme represent only
one enantiomer of the racemic form actually obtained.
Abstract: cis-Isocytoxazone 2a and trans-isocytoxazone 2b, struc-
tural isomers of the antiasthmatic agent cytoxazone (–)-1, and their
5-substituted congeners 23–28 have been prepared. Aldol reaction
of para-substituted benzaldehydes with 7-chloro-1-methyl-5-phe-
nyl-1,4-benzodiazepin-2-one, followed by separation of diastereo-
meric racemates afforded 3–10. Acid-catalyzed 1,4-benzodiazepine
ring opening, and transformation of the methyl esters of β-aryl-β-
hydroxy-α-amino acids (11–16) via 4-methoxycarbonyl derivatives
of 1,3-oxazolidin-2-one (17–22) and their reduction afforded the
target oxazolidin-2-one derivatives 23–28. Racemic isocytoxazones
2a and 2b were prepared by an independent route starting from 4-
methoxystyrene epoxide. Pure enantiomers of these diastereomeric
racemates were separated by HPLC chromatography on chiral sta-
tionary phases. Their CD spectra, along with those of previously
prepared enantiomers of cis-cytoxazone 1a and trans-cytoxazone
1b are discussed.
In the first step, the aldol reaction between a 1,4-benzodi-
azepine derivative and a number of aliphatic and aromatic
aldehydes is completed according to our recently reported
protocol8 to give easily separable mixtures of cis and trans
diastereomeric racemic forms of 3/4, 5/6, 7/8, and 9/10.
Cis and trans racemic diastereomers of 3/4 and 9/10 were
separated by fractional crystallization from ethyl acetate,
and further purified by flash chromatography, whereas the
racemic diastereomers 5/6 and 7/8 were separated by
chromatography.
After hydrolytic opening of the 1,4-benzodiazepine ring
with concentrated aqueous hydrochloric acid in acetic
acid as solvent, the ammonium salts of α-amino-β-hy-
droxy acids were obtained in high yield from all interme-
diary aldol products but from 9/10, and were transformed
without isolation into the corresponding methyl esters 11–
16. Diastereomers 9/10 were found to be unstable under
all hydrolytic conditions attempted; a number of side
products resulted on the acid-catalyzed cleavage of the 4-
methoxybenzyl group via a stable carbenium ion. There-
fore, a detour was needed to complete preparation of the
stereoisomers 2a,b. The best approach is the reaction se-
quence recently reported by Nicolaou et al. in the course
of the total synthesis of vancomycine (Scheme 2).9
Key words: 1,4-benzodiazepines, ring opening, oxazolidin-2-ones,
chiral HPLC
Following the finding that Streptomyces sp. exerts into
fermentation broth a compound (4R,5R)-5-(hydroxymeth-
yl)-4-(4-methoxyphenyl)-1,3-oxazolidine 2-one [(–)-1,
generic name cytoxazone],1 which was shown to posses
high cytokine modulator activity by acting on the Th2
cells,2 we,3 and others,4–7 have reported the preparation of
(–)-1 and its three stereoisomers in the optically pure
form. Continuing this project, prompted by the first posi-
tive biological results, here we report the preparation of
cis- and trans-isocytoxazones 2a,b, structural isomers of
cytoxazone 1a and its trans epimer 1b, and some conge-
ners (Figure 1). Isomeric structures are characterized by
the inverted position of the oxygen and nitrogen atom in
the oxazolidin-2-one ring.
Acid-catalyzed ring opening of trans-epoxide 29 yielded
a 7:3 mixture of trans/cis diols, with trans-30 as the pre-
vailing diastereomer. Under carefully controlled condi-
tions [low temperature, slow addition of 4-nitrobenzene
sulfonyl chloride (NsCl)] only the hydroxy group at C(2)
of trans-diole 30 reacts selectively affording 31. Azidoly-
sis of trans-nosylate 31 furnished the cis-azide 32 in high
yield with inversion of configuration at C(2). Carbobenz-
oxylation, ring closure to cis-34, and final reduction of the
ester group afforded racemic cis-isocytoxazone 2a in ex-
cellent yield.
To obtain the trans diastereomeric racemic form 2b,
epimerization of the oxazolidinone derivative 34 was
completed under basic conditions and the trans diastere-
omer 35 was purified by column chromatography on sili-
cagel. The assignment of the cis and trans configuration
of oxazolidinones 34/2a and 35/2b, respectively, is based
on the 3J constants for C(4)-H/C(5)-H coupling in the 1H
Figure 1 Formula 1 and 2
Synthesis 2003, No. 3, Print: 28 02 03.
Art Id.1437-210X,E;2003,0,03,0375,0382,ftx,en;Z13602SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

376
Z. Hameršak et al.
PAPER
CH3
N
CH3
N
CH3
N
O
O
O
OH
OH
a
+
N
Cl
N
Cl
N
Cl
R
R
(±)-cis 3,5,7,9
(±)-trans 4,6,8,10
O
OH
from 3,5,7
COOMe
NH2
O
NH
c
COOMe
(±)-trans 17-19
R
(±)-cis 11-13
b
R
O
OH
O
NH
COOMe
NH2
c
COOMe
(±)-cis 20-22
from 4,6,8
R
R
(±)-trans 14-16
O
O
NH
CH2OH
(±)-trans 23-25
R
R
H
3, 4, 11, 14, 17, 20, 23, 26
5, 6, 12, 15, 18, 21, 24, 27
d
O
Cl
NO2 7, 8, 13, 16, 19, 22, 25, 28
MeO 9, 10
O
NH
CH2OH
(±)-cis 26-28
R
Scheme 1 Synthesis of congeners of epicytoxazone. Reagents and conditions: a) LDA/THF/Ar-CHO; b) i. concd HCl/AcOH, ii. aq NH4OH,
iii. TMSCl/MeOH; c) (CCl3)2CO/Et3N/THF; d) NaBH4/CaCl2/THF
NMR spectra; for all oxazolidinones in the cis series 3J is
ca 8 Hz, while for the trans series 3J is ca 5 Hz.
The racemic diastereomers 2a and 2b were separated by
HPLC on the chiral columns Chiralcel OB-H and Chiral-
pak AS, respectively. Their CD spectra in MeCN, and
those of the formerly prepared enantiomers of cytoxazone
1a and epicytoxazone 1b,3 are presented in Figures 2
and 3.
The absolute configuration (4R,5R) of (–)-cytoxazone
was elucidated by means of an X-ray structure analysis,2
and of its trans-(–)-1 epimer as (4R,5S) by chemical cor-
relation.6 Former structural and synthetic studies, and our
completed synthesis of all four stereoisomers, have re-
vealed for enantiomers of 1 that the sign of [α]D is dictated
by the absolute configuration at C(4); (+) for the (4S)
stereoisomers and (–) for the (4R) stereoisomers. We ex-
pected to obtain some information from the CD spectra of
Figure 2 CD spectra of (+)-1a (_____), (–)-1a (-.-.-.-), (+)-1b (- - - -)
and (–)-1b (.....), measured in MeCN
Synthesis 2003, No. 3, 375–382 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of All Stereoisomers and Some Congeners of Isocytoxazone
OH
377
O
COOMe
COOMe
a
b
OH
(±)-trans 30
MeO
MeO
(±)-trans 29
OH
OH
COOMe
ONs
(±)-trans 31
COOMe
d
c
N3
MeO
MeO
(±)-cis 32
O
COOPh
O
NH
O
e
N3
COOMe
COOMe
(±)-cis 34
(±)-cis 33
MeO
MeO
O
f
O
NH
CH2OH
(±)-cis 2a
MeO
g
O
O
f
O
NH
O
NH
COOMe
(±)-trans 35
CH2OH
(±)-trans 2b
MeO
MeO
Scheme 2 Synthesis of cis- and trans-epicytoxazones. Reagents and conditions: a) H+/aq 1,4-dioxane; b) NsCl, Et3N; c) NaN3/DMF; d)
PhOCOCl/CH2Cl2, –5 °C; e) PPh3/aq THF, 50 °C; f) NaBH4/CaCl2/EtOH, r.t.; g) i. KOH/EtOH, reflux, ii. MeI/Na2CO2/DMF, r.t.
compounds 2 that will allow the determination of the ab-
solute configuration in the iso series.
In the CD spectra of 1a and 1b, a group of week bands (∆ε
ca 0.5) is observed between λ = 250–290 nm, two stron-
ger bands (∆ε = 1.5–2) in the region λ = 210–240 nm, and
a third band (∆ε = 6.5 for 1a and 2.5 for 1b) in the region
λ = 195–200 nm. In the CD spectra of 2a and 2b the re-
gion of week bands (∆ε > 0.5) extends between λ = 240–
300 nm; stronger bands at λ ca 230 nm (∆ε = 1–2.5), and
between λ = 190–200 nm (∆ε = 4–4.5) are observed. In
the cytoxazine series the (+)-enantiomers of 1a and 1b ex-
hibit a negative sign of the short- and medium-wavelength
band at λ ca 200 nm and λ ca 220 nm, whereas in the iso
series the (+)-enantiomers of 2a and 2b exhibit a positive
Figure 3 CD spectra of (+)-2a (_____), (–)-2a (.....), (+)-2b (- - - -)
and (–)-2b (-.-.-.-), measured in MeCN
sign of the two bands.
This nearly enantiomorphic relation of the strong CD
bands of cytoxazone (1a) enantiomers and their isomers
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378
Z. Hameršak et al.
PAPER
HRMS: m/z [M + H+] calcd for C10H13NO3, 196.0968; found,
196.0987.
(2a) is remarkable. Both isomers in the epi-(trans) series
have the same sign of [α]D and the same sign of CD ex-
tremes. However, all these data do not allow the assign-
ment of the absolute configuration to the trans
enantiomers. Namely, there is no suitable and clearly
identifiable π–π* transition that can serve as the second
chromophore for excitation coupling with the aryl chro-
mophore, since the UV properties of the HN–C(=O)–O-
chromophore are not known. The application of a more
sophisticated, recently developed method, based on the
complexes with a porphyrin tweezer, is envisaged.10,11
Methyl ( R)-4-Chloro- -hydroxy-l-phenylalaninate [( )-12]
The pure product was crystallized from MeOH, yield: 41%.
Mp 102.5–103.0 °C.
IR (KBr): 3440, 3250, 1735, 1355, 1340, 1215, 1200, 1090, 990,
840, 800 cm–1.
1H NMR (CDCl3): δ = 3.53 (d, J = 4.4 Hz, 1 H), 3.65 (s, 3 H), 4.82
(d, J = 4.4 Hz, 1 H), 7.22–7.31 (m, 4 H).
13C NMR (CDCl3): δ = 52.1, 60.3, 73.2, 127.2, 128.3, 133.3, 139.2,
173.3.
HRMS: m/z [M + H+] calcd for C10H12ClNO3, 230.0578; found,
230.0557.
IR spectra were recorded on a Perkin Elmer 297 spectrometer with
KBr pallets. 1H and 13C NMR spectra were obtained with a Varian
Gemini XL 300 spectrometer, with δ in ppm relative to TMS as in-
ternal reference, and J in Hz. CD spectra were recorded on a JAS-
CO-810 spectropolarimeter (at 25 °C using 1 mm quartz cells in the
concentration range 1 × 10–4 to 5 × 10–4 moldm–3. HPLC chroma-
tography was performed on a HP 1050 chromatograph with a Nu-
cleosil C18 reversed phase column (250 × 4.6 mm); separation was
monitored by a HP 1050 UV detector set up at λ = 235 nm and con-
nected to a HP 3396A integrator. Melting points were determined
on a Electrothermal Apparatus and are uncorrected. HRMS was
performed on an Extrel-FTMS 2001 DD instrument; the HPLC pur-
ity of all analytical samples was >99.5%.
Methyl ( R)- -Hydroxy-4-nitro-l-phenylalaninate [( )-13]
The pure product was crystallized from MeOH, yield. 60%.
Mp 141.0–142.0 °C.
IR (KBr): 3330, 3280, 2900, 2830, 1725, 1615, 1510, 1345, 1215,
1010, 710 cm–1.
1H NMR (DMSO-d6): δ = 1.63 (br s, 2 H), 3.53 (d, J = 3.3 Hz, 1 H),
3.67 (s, 3 H), 4.98 (s, 1 H), 5.83 (d, J = 4.7 Hz, 1 H), 7.59 (d, J = 8.3
Hz, 2 H), 8.15 (d, J = 8.6 Hz, 2 H).
13C NMR (DMSO-d6): δ = 61.4, 70.1, 82.9, 132.5, 137.3, 156.1,
160.6, 183.6.
All commercial reagents were used as received; during usual work-
up all organic solutions were dried with Na2SO4 and evaporated in
vacuo. Intermediates 3–10,8 and epoxide 2912 have been prepared as
reported in the literature.
HRMS: m/z [M + H+] calcd for C10H12N2O5, 241.0819; found,
241.0832.
Methyl ( S)- -Hydroxy-l-phenylalaninate [( )-14]
The pure product was crystallized from EtOAc–n-hexane, yield:
59%.
Hydrolytic Cleavage of the cis- and trans-Aldol Products 3–10;
General Procedure
A solution of the racemic diastereomer (11.0 mmol) in a mixture of
concd aq HCl (40 mL) and CH3CO2H (60 mL) was refluxed for 16
h. The solvent mixture was evaporated in vacuo azeotropically with
i-PrOH (3 × 120 mL). The crude product was dissolved in H2O (15
mL), adjusted to neutral pH with aq NH4OH (5.0 mL) and the side
product, 2-amino-5-chloro-benzophenone, was extracted with
CH2Cl2 (4 × 10 mL). The aqueous layer was evaporated in vacuo
azeotropically with i-PrOH (2 × 50 mL). The crude ammonium salt
of the α-amino-β-hydroxy acid was dried at 0.1 mm Torr and used
without purification in the next step.
Mp 105.5–106.0 °C.
IR (KBr): 3080, 2860, 1725, 1580, 1435, 1285, 1210, 1170, 1040,
910, 770, 700 cm–1.
1H NMR (CDCl3): δ = 3.66 (s, 3 H), 3.76 (d, J = 5.5 Hz, 1 H), 4.91
(d, J = 5.5 Hz, 1 H), 7.24–7.34 (m, 5 H).
13C NMR (CDCl3): δ = 51.8, 59.8, 74.1, 126.1, 127.9, 128.1, 139.6,
173.3.
HRMS: m/z [M + H+] calcd for C10H13NO5, 196.0968; found,
196.0971.
To the suspension of the crude ammonium salt of the α-amino-β-
hydroxy acid (8.0 mmol) in absolute MeOH (10 mL) chlorotrime-
thylsilane (TMSCl, 4.3 g, 5.0 mL, 40 mmol) was added, the reaction
mixture (protected from moisture by P2O5) was stirred for 18 h at r.t.
and then heated at reflux for 3 h. The solvent and TMSCl were evap-
orated at reduced pressure. The crude product was dissolved in
EtOAc (15 mL), washed with a diluted aq solution of NaHCO3 (10
mL), and the aqueous layer extracted with EtOAc (3 × 10 mL). Af-
ter the usual workup the products were purified by chromatography
or by crystallization.
Methyl ( S)-4-Chloro- -hydroxy-l-phenylalaninate [( )-15]
The pure product was crystallized from MeOH, yield: 23%.
Mp 119.5–120.0 °C.
IR (KBr): 3100, 2840, 1715, 1575, 1435, 1280, 1200, 1170, 1030,
915, 820 cm–1.
1H NMR (CDCl3): δ = 3.69 (s, 3 H), 3.81 (br s, 1 H), 4.94 (br s, 1
H), 7.23–7.30 (m, 4 H).
13C NMR (CDCl3): δ = 52.0, 59.5, 73.3, 127.5, 128.4, 133.7, 138.1,
173.2.
HRMS: m/z [M + H+] calcd for C10H12ClNO3, 230.0578; found,
230.0605.
Methyl ( R)- -Hydroxy-l-phenylalaninate [( )-11]
The pure product was obtained as thick oil after chromatography on
silica gel (CH2Cl2–MeOH, 5.0:0.3), yield: 38%.
IR (film): 3280, 2940, 2215, 1735, 1435, 1345, 1200, 1010, 740,
700 cm–1.
1H NMR (acetone-d6): δ = 3.69 (s, 3 H), 3.76 (d, J = 7.7 Hz, 1 H),
4.80 (d, J = 7.7 Hz, 1 H), 7.25–7.40 (m, 5 H).
13C NMR (acetone-d6): δ = 52.5, 69.0, 83.0, 127.1, 128.5, 129.1,
141.7, 172.7.
Methyl ( S)- -Hydroxy-4-nitro-l-phenylalaninate [( )-16]
The pure product was crystallized from EtOAc, yield: 48%.
Mp 121.0–122.0 °C.
IR (KBr): 3350, 3100, 2840, 1700, 1500, 1350, 1215, 1015, 840
cm–1.
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PAPER
Synthesis of All Stereoisomers and Some Congeners of Isocytoxazone
379
1H NMR (CDCl3): δ = 3.67 (s, 3 H), 3.88 (d, J = 4.7 Hz, 1 H), 5.07
1H NMR (CDCl3): δ = 3.96 (s, 3 H), 4.62 (d, J = 5.1 Hz, 1 H), 6.00
(d, J = 4.8 Hz, 1 H), 7.47 (d, J = 8.5 Hz, 2 H), 8.19 (d, J = 8.3 Hz, 2
H).
(d, J = 4.7 Hz, 1 H), 7.61 (s, 1 H), 7.91 (d, J = 8.5 Hz, 2 H), 8.48 (d,
J = 8.7 Hz, 2 H).
13C NMR (CDCl3): δ = 51.5, 59.9, 78.0, 123.3, 127.1, 147.2, 147.5,
13C NMR (CDCl3): δ = 53.5, 60.8, 77.9, 124.2, 126.1, 144.7, 148.2,
172.7.
157.2, 169.3.
HRMS: m/z [M + H+] calcd for C10H12N2O5, 241.0819; found,
HRMS: m/z [M + H+] calcd for C11H10N2O6, 267.0612; found,
241.0797.
267.0604.
Cyclization of -Amino- -hydroxy Esters to 1,3-Oxazolidin-2-
ones; General Procedure
Methyl (4R,5R)-2-Oxo-5-phenyl-1,3-oxazolidin-4-carboxylate
[( )-20]
The reaction was performed under an atmosphere of dry argon. To
a cold (–10 °C to –15 °C) solution of cis-11–13 or trans-14–16 (1.5
mmol) and Et3N (425 mg, 4.2 mmol) in absolute THF (10 mL)
triphosgene (145 mg, 0.6 mmol) was added at once. The reaction
mixture was stirred 60 min at –10 °C and 90 min at r.t., then
Et3N·HCl was filtered off and washed with THF (10 mL). The fil-
trate was evaporated and the crude product was dissolved in EtOAc
(5 mL) and washed with a sat. aq solution of NaHCO3 (5 mL). The
aqueous layer was extracted with EtOAc (4 × 5 mL) and worked up
as usual. The crude products were purified by chromatography on
silica gel; the solvent mixtures used and the recrystallization solvent
are indicated for any single product.
Starting from trans-14, the reaction was completed in 1 h at r.t. The
product was purified by chromatography (15 g silica gel; TBME–
MeOH, 5.0:0.3), yield: 85%.
Mp 160.0–161.0 °C.
IR (KBr): 3060, 1720, 1590, 1425, 1200, 995 cm–1.
1H NMR (DMSO-d6): δ = 3.17 (s, 3 H), 4.76 (d, J = 9 Hz, 1 H), 5.93
(d, J = 8.7 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.48 (d, J = 8.4 Hz, 2
H), 8.32 (s, 1 H).
13C NMR (acetone-d6): δ = 52.2, 60.6, 78.7, 129.0, 129.3, 135.1,
158.9, 170.4.
HRMS: m/z [M+] calcd for C11H10ClNO4, 255.0293; found,
255.0306.
Methyl (4S,5R)-2-Oxo-5-phenyl-1,3-oxazolidin-4-carboxylate
[( )-17]
Methyl (4R,5R)-5-(4-Chlorophenyl)-2-oxo-1,3-oxazolidin-4-
carboxylate [( )-21]
Starting from trans-15, the reaction mixture was stirred for 1 h at
–10 °C, then 4 h at r.t. until completion. The crude product was pu-
rified by crystallization from EtOAc, yield: 83%.
Starting from cis-11, the reaction was completed after 120 min at 0–
5 °C. The crude product was purified by chromatography (12 g sil-
ica gel; TBME–EtOAc, 5.0:0.3) and recrystallized from TBME,
yield: 211 mg (60%).
Mp 75.0–76.0 °C.
Mp 151.0–152.0 °C.
IR (KBr): 3250, 1750, 1710, 1300, 1220, 1190, 1215, 980, 930, 760,
730 cm–1.
1H NMR (CDCl3): δ = 3.86 (s, 3 H), 4.33 (d, J = 4.9 Hz, 1 H), 5.65
(d, J = 5.0 Hz, 1 H), 6.88 (s, 1 H), 7.35–7.50 (m, 5 H).
13C NMR (CDCl3): δ = 53.1, 61.2, 79.3, 125.2, 128.8, 129.0, 137.9,
158.4, 170.1.
IR (KBr): 3260, 1750, 1355, 1240, 1225, 1210, 1330, 1320, 1015,
760, 700 cm–1.
1H NMR (CDCl3): δ = 3.21 (s, 3 H), 4.71 (d, J = 9.1 Hz, 1 H), 5.85
(d, J = 9.1 Hz, 1 H), 6.69 (s, 1 H), 7.30–7.37 (m, 5 H).
13C NMR (CDCl3): δ = 52.0, 59.9, 79.1, 126.0, 128.2, 129.1, 133.8,
159.1, 169.0.
HRMS: m/z [M+] calcd for C11H11NO4, 221.0682; found, 221.0658.
HRMS: m/z [M+] calcd for C11H11NO4, 221.0682; found, 221.0656.
Methyl (4S,5R)-5-(4-Chlorophenyl)-2-oxo-1,3-oxazolidin-4-car-
boxylate [( )-18]
The crude product was purified by chromatography (15 g silica gel;
CH2Cl2–MeOH, 5.0:0.3) and recrystallized from CCl4, yield: 77%.
Methyl (4R,5R)-5-(4-nitrophenyl)-2-oxo-1,3-oxazolidin-4-car-
boxylate [( )-22]
Starting from trans-16, the reaction was completed in 30 min at r.t.
After aqueous workup, the crude product was purified by crystalli-
zation from EtOAc, yield: 77%.
Mp 90.5–91.0 °C.
IR (KBr): 3240, 3140, 2950, 2400, 1790, 1755, 1495, 1440, 1385,
1310, 1250, 1225, 1190, 1040, 1000, 905, 820, 745 cm–1.
Mp 171.0–172.0 °C.
IR (KBr): 3330, 1765, 1725, 1510, 1340, 1215, 1130, 1095, 850,
740 cm–1.
1H NMR (acetone-d6): δ = 3.31 (s, 3 H), 4.77 (d, J = 8.8 Hz, 1 H),
5.58 (s, 1 H), 5.96 (d; J = 9.1 Hz, 1 H), 7.56 (d, J = 8.5 Hz, 2 H),
8.28 (d, J = 8.5 Hz, 2 H).
13C NMR (acetone-d6): δ = 52.3, 60.5, 78.3, 124.3, 128.5, 143.4,
149.2, 158.6, 170.3.
1H NMR (CDCl3): δ = 3.89 (s, 3 H), 4.26 (d, J = 4.9 Hz, 1 H), 5.66
(d, J = 5.0 Hz, 1 H), 6.07 (s, 1 H), 7.37–7.44 (m, 4 H).
13C NMR (CD3OD): δ = 53.6, 62.7, 80.2, 128.5, 130.3, 136.1,
138.9, 171.9.
HRMS: m/z [M + H+] calcd for C11H10ClNO4, 256.0371; found,
256.0368.
HRMS: m/z [M+] calcd for C11H10N2O6, 266.0533; found,
266.0512.
Methyl (4S,5R)-5-(4-nitrophenyl)-2-oxo-1,3-oxazolidin-4-car-
boxylate [( )-19]
Starting from cis-13, the reaction was completed in 2.5 h at r.t. After
the usual workup the crude product was crystallized from EtOAc,
yield: 86%.
Reduction of Oxazolidincarboxylic Acid Esters to Hydroxyme-
thyl Derivatives 23–28; General Procedure
In the solution of trans-17–19 or cis-20–22 (0.7 mmol) in absolute
EtOH (10 mL) CaCl2 (1.2 mmol) was slurried, then NaBH4 (1.3
mmol) was added at once. The reaction mixture was stirred at r.t. for
1 h under dry argon atmosphere, then quenched with a sat. aq NH4Cl
solution (10 mL). EtOH was evaporated and the residue triturated
with a sat. aq solution of NH4Cl (5 mL). After extraction with
Mp 125.0–126.0 °C.
IR (KBr): 3230, 3140, 1760, 1740, 1510, 1340, 1275, 1225, 1035,
840, 730 cm–1.
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380
Z. Hameršak et al.
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EtOAc (3 × 10 mL) and the usual workup, the crude product was
HRMS: m/z [M + H+] calcd for C10H11NO3, 194.0812; found,
purified by chromatography or by crystallization.
194.0800.
(4R,5R)-4-Hydroxymethyl-5-phenyl-1,3-oxazolidin-2-one [( )-
23]
(4S,5R)-5-(4-Chlorophenyl)-4-(hydroxymethyl)-1,3-oxazolidin-
2-one [( )-27]
The crude product was purified by chromatography (TBME–
MeOH, 5.0:0.5) and recrystallized from CH2Cl2–i-Pr2O, yield: 113
mg (83%).
The crude product was purified by chromatography (CH2Cl2–
MeOH, 5.0:0.5) and recrystallization from MeOH–TBME, yield:
150 mg (95%).
Mp 109.0–109.5 °C.
Mp 106.5–107.5 °C.
IR (KBr): 3460, 3240, 1715, 1390, 1275, 1240, 1200, 1040, 1010,
755 cm–1.
1H NMR (acetone-d6): δ = 3.70–3.81 (m, 3 H), 4.50 (br s, 1 H), 5.42
(d, J = 4.7 Hz, 1 H), 7.04 (s, 1 H), 7.34–7.45 (m, 5 H).
IR (KBr): 3280, 1715, 1370, 1290, 1040, 1015, 1000, 790 cm–1.
1H NMR (acetone-d6): δ = 3.09–3.22 (m, 2 H), 3.98 (s, 1 H), 4.15–
4.22 (m, 1 H), 5.79 (d, J = 8.3 Hz, 1 H) 6.88 (s, 1 H), 7.43 (s, 4 H).
13C NMR (acetone-d6): δ = 57.5, 61.8, 78.3, 128.2, 128.5, 133.6,
135.0, 158.0.
13C NMR (acetone-d6): δ = 62.7, 63.9, 80.0, 126.6, 129.3, 129.7,
141.2, 159.5.
HRMS: m/z [M + H+] calcd for C10H10ClNO3, 228.0422; found,
228.0409.
HRMS: m/z [M + H+] calcd for C10H11NO3, 194.0812; found,
194.0839.
(4S,5R)-5-(4-Nitrophenyl)-4-(hydroxymethyl)-1,3-oxazolidin-2-
one [( )-28]
The pure product was obtained by crystallization from MeOH,
yield: 158 mg (94%).
(4R,5R)-5-(4-Chlorophenyl)-4-(hydroxymethyl)-1,3-oxazolidin-
2-one [( )-24]
The crude product was purified by chromatography (CH2Cl2–
MeOH, 5.0:0.5) and recrystallized from MeOH–TBME, yield: 120
mg (75%).
Mp 159.0–160.0 °C.
IR (KBr): 3200, 3110, 1735, 1500, 1340, 1225, 1200, 1090, 1030,
980 cm–1.
Mp 105.5–106.5 °C.
IR (KBr): 3310, 1725, 1395, 1290, 1205, 1085, 1025, 1010, 815,
805 cm–1.
1H NMR (acetone-d6): δ = 3.67–3.77 (m, 3 H), 4.42 (br s, 1 H), 5.40
(d, J = 4.3 Hz, 1 H), 6.95 (s, 1 H), 7.44 (s, 4 H).
1H NMR (acetone-d6): δ = 2.91 (s, 1 H), 3.11–3.27 (m, 2 H), 4.25–
4.31 (m, 1 H), 5.96 (d, J = 8.3 Hz, 1 H), 6.95 (s, 1 H), 7.72 (d,
J = 8.3 Hz, 2 H), 8.28 (d, J = 8.3 Hz, 2 H).
13C NMR (acetone-d6): δ = 58.1, 62.1, 78.8, 124.1, 128.5, 144.3,
148.8, 158.9.
13C NMR (acetone-d6): δ = 61.8, 63.1, 78.6, 127.6, 128.9, 133.8,
139.3, 158.3.
HRMS: m/z [M + H+] calcd for C10H10N2O5, 239.0662; found,
239.0675.
HRMS: m/z [M + H+] calcd for C10H10ClNO3, 228.0422; found,
228.0416.
Methyl (2R,3R)-2,3-Dihydroxy-3-(4-methoxyphenyl)propan-
oate [( )-30]
(4R,5R)-5-(4-Nitrophenyl)-4-(hydroxymethyl)-1,3-oxazolidin-
2-one [( )-25]
The pure product was obtained by crystallization from MeOH–
TBME, yield: 160 mg (95%).
To the solution of trans-epoxide 29 (4.0 g, 19.0 mmol) in 1,4-diox-
ane–H2O (80:20 mL), concd H2SO4 (0.5 mL) was added at r.t. The
reaction mixture was stirred for 30 min, EtOAc (100 mL) was added
and the organic layer was washed with sat. aq NaHCO3 solution fol-
lowed by H2O. Upon usual workup, 3.7 g (85%) of a 7:3 mixture of
trans/cis-30 was obtained and used as such in the next step.
Mp 129.5–130.0 °C.
IR (KBr): 3350, 1740, 1500, 1340, 1035, 735 cm–1.
1H NMR (CDCl3): δ = 3.92 (s, 2 H), 4.29 (d, J = 5.2 Hz, 1 H), 5.80
(d, J = 5.2 Hz, 1 H), 6.39 (s, 1 H), 7.67 (d, J = 8.2 Hz, 2 H), 8.31 (d,
J = 8.8 Hz, 2 H).
13C NMR (acetone-d6): δ = 62.4, 64.0, 78.9, 124.8, 127.6, 148.5,
148.7, 159.5.
HRMS: m/z [M + H+] calcd for C10H10N2O5, 239.0662; found,
239.0655.
Methyl (2R,3R)-2-Nosyl-3-hydroxy-3-(4-methoxyphenyl)pro-
panoate [( )-31]
The crude mixture of cis/trans-30 (3.0 g, 13.2 mmol) was dissolved
in CH2Cl2 (40 mL). The solution was cooled to –10 °C, Et3N (2.0
mL, 15 mmol) was added, followed by NsCl (2.5 g, 10 mmol),
which was added in portions during 2 h. The reaction mixture was
stirred for another 2 h at 10 °C, than was diluted with CH2Cl2 (50
mL) and washed with 0.5 M aq HCl, H2O and aq bicarbonate solu-
tion. The crude product (4.1 g) was crystallized from EtOAc–n-hex-
ane (25:75) to afford 1.4 g (28%) of stereochemically pure trans-
nosylate 31 (96% pure by HPLC).
(4S,5R)-4-Hydroxymethyl-5-phenyl-1,3-oxazolidin-2-one [( )-
26]
The crude product was purified by chromatography (TBME–
MeOH, 5.0:1.0) and recrystallized from MeOH–TBME, yield: 118
mg (87%).
Mp 121.0–122.0 °C (dec.).
IR (KBr): 3510, 3100, 2960, 1730, 1610, 1350, 1175, 1000, 900
cm–1.
Mp 97.5–98.0 °C.
IR (KBr): 3380, 1800, 1710, 1415, 1240, 1220, 1040, 1015, 930,
690 cm–1.
1H NMR (acetone-d6): δ = 3.18–3.30 (m, 2 H), 3.94 (br s, 1 H),
4.28–4.35 (m, 1 H), 5.90 (d, J = 8.3 Hz, 1 H), 6.93 (s, 1 H), 7.46–
7.56 (m, 5 H).
1H NMR (CDCl3): δ = 3.76 (s, 6 H), 4.99 (d, J = 3.5 Hz, 1 H), 5.20
(d, J = 3.5 Hz, 1 H), 6.71 (d, J = 8.7 Hz, 2 H), 7.13 (d, J = 8.7 Hz, 2
H), 7.81 (d, J = 8.3 Hz, 2 H), 8.21 (d, J = 8.3 Hz, 2 H).
13C NMR (CDCl3): δ = 53.0, 55.1, 70.5, 73.0, 80.6, 82.3, 113.7,
123.9, 127.1, 127.9, 129.0, 141.3, 150.3, 159.7, 166.8.
13C NMR (acetone-d6): δ = 58.4, 62.9, 79.5, 127.0, 129.1, 136.7,
159.4.
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Synthesis of All Stereoisomers and Some Congeners of Isocytoxazone
381
Methyl (2S,3R)-2-Azido-3-hydroxy-3-(4-methoxyphenyl)pro-
panoate [( )-32]
Methyl (4S,5R)-5-(4-methoxyphenyl)-2-oxo-1,3-oxazolidine-4-
carboxylate [( )-35]
To a solution of trans-31 (1.05 g, 2.3 mmol) in DMF (20 mL) NaN3
(260 mg, 3.1 mmol) was added. The reaction mixture was heated to
45 °C for 15 h, then EtOAc (60 mL) was added. The solution was
washed with H2O and 5% aq NaHCO3 solution. Upon usual workup
the crude product was purified on a silica gel column (EtOAc–n-
hexane, 3.0:7.0). Pure fractions yielded 455 mg (78%) of cis-32.
Epimerization of cis-34 (250 mg, 1.0 mmol) in EtOH (5.0 mL) was
completed after heating for 1 h under reflux in the presence of KOH
(70 mg, 1.2 mmol). Upon cooling, the pH was adjusted to acid me-
dium by 10% aq HCl and the crude product was extracted with
EtOAc. The combined extracts were worked up as usual, the crude
product was dissolved in DMF (5 mL), K2CO3 (150 mg, 1.1 mmol)
and MeI (200 mg, 1.40 mmol) were added. The reaction mixture
was stirred overnight at r.t., H2O (15 mL) and EtOAc (20 mL) were
added and the organic layer was successively washed with H2O.
The crude product was purified by column chromatography on sili-
ca gel (TBME–n-hexane, 4.0:1.0). Pure fractions yielded 98 mg
(40%) of trans-35 as pale-yellow oil.
Mp 114.0–115.0 °C.
IR (KBr): 3420, 2900, 2110, 1720, 1605, 1220, 1020,780 cm–1.
1H NMR (CDCl3): δ = 3.79 (s, 3 H), 3.81 (s, 3 H), 4.10 (d, J = 7 Hz,
1 H), 4.96 (d, J = 7 Hz, 1 H), 6.85 (d, J = 8.5 Hz, 2 H), 7.31 (d,
J = 8.5 Hz, 2 H).
IR (neat): 3300, 2930, 1745, 1600, 1500, 1250, 1115, 820 cm–1.
13C NMR (CDCl3): δ = 52.7, 55.1, 66.7, 73.6, 113.9, 127.7, 130.8,
1H NMR (CDCl3): δ = 3.82 (s, 3 H), 3.84 (s, 3 H), 4.32 (d, J = 5.5
Hz, 1 H), 5.58 (d, J = 5.5 Hz, 1 H), 6.81 (br s, 1 H), 6.92 (d, J = 8.5
Hz, 2 H), 7.34 (d, J = 8.5 Hz, 2 H).
159.7, 169.3.
HRMS: m/z [M+] calcd for C11H14N3O4, 252.0979; found,
252.1002.
13C NMR (CDCl3): δ = 53.0, 55.2, 61.2, 79.3, 114.2, 126.9, 129.7,
158.3, 160.0, 170.1.
HRMS: m/z [M+] calcd for C12H14NO5, 252.0866; found, 252.0878.
Methyl (4R,5R)-5-(4-Methoxyphenyl)-2-oxo-1,3-oxazolidine-4-
carboxylate [( )-34]
To the solution of cis-32 (60 mg, 0.25 mmol) in CH2Cl2 (2.0 mL)
containing (50 µL, 1.0 mmol) of pyridine, phenylchloroformate
(100 µL, 0.7 mmol) was added at –10 °C. After stirring overnight at
r.t., the reaction mixture was poured on H2O (20 mL) and extracted
with EtOAc (3 × 30mL). The extracts were washed with H2O, aq bi-
carbonate solution, and worked up as usual. Crude cis-33 (160 mg)
was dissolved in THF (2.0 mL), then triphenylphosphane (330 mg,
1.2 mmol) and H2O (80 µL) were added. The reaction mixture was
stirred at 50 °C for 1 h, the solvent was evaporated and the solid res-
idue dissolved in EtOAc (50 mL), washed with 5% aq NaCl solu-
tion and dried. Crystallization of the crude product from i-Pr2O
yielded 50 mg (80%) of cis-34 (98% pure by HPLC).
(4R,5R)-4-Hydroxymethyl-5-(4-methoxyphenyl)-1,3-oxazoli-
din-2-one [( )-2b]
trans-Isocytoxazone 2b was prepared in 62% yield as described for
2a; the crude product was recrystallized from TBME–EtOAc
(9.0:1.0),
Mp 131.5–133.0 °C.
IR (KBr): 3500, 2950, 1750, 1505, 1230, 1010, 815 cm–1.
1H NMR (CD3OD): δ = 3.65–3.97 (m, 3 H), 3.89 (s, 3 H), 5.41 (d,
J = 5.7 Hz, 1 H), 7.05 (d, J = 8.5 Hz, 2 H), 7.42 (d, J = 8.5 Hz, 2 H).
13C NMR (CD3OD): δ = 52.9, 60.5, 60.8, 78.5, 112.4, 125.6, 129.6,
Mp 136.0–137.0 °C.
IR (KBr): 3420, 2930, 1730, 1600, 1500, 1240, 1090, 980 cm–1.
1H NMR (CD3OD): δ = 3.33 (s, 3 H), 3.88 (s, 3 H), 4.79 (d, J = 9
Hz, 1 H), 5.96 (d, J = 9 Hz, 1 H), 7.01 (d, J = 9 Hz, 2 H), 7.33 (d,
J = 9 Hz, 2 H).
158.7.
HRMS: m/z [M+] calcd for C11H13NO4, 223.0839; found, 223.0829.
Enantiomers of 2b were separated on the preparative scale on
Chiralpak AS column (1.0 × 25 cm; 2-PrOH–n-hexane, 50:50).
25
First eluted enantiomer: ee >99.5%, [α]D +70 (c = 0.4, MeOH);
13C NMR (CD3OD): δ = 52.8, 56.0, 61.7, 80.8, 115.0, 128.0, 129.1,
162.0, 171.5.
second eluted enantiomer: ee 98.2%, [α]D25 –67.5 (c = 0.4, MeOH).
HRMS: m/z [M+] calcd for C12H14NO5, 252.0866; found, 252.0857.
Acknowledgment
(4S,5R)-4-Hydroxymethyl-5-(4-methoxyphenyl)-1,3-oxazoli-
din-2-one [( )-2a]
Isocytoxazone 2a was prepared by reduction of cis-34 as described
in the general procedure for the reduction of 17–22; compound 2a
was obtained in 97% yield.
The authors are indebted to Prof. N. Berova, Columbia University,
New York, for critical reading of the manuscript, and to Mr. . Ma-
rini, Ru er Bokovic Institute, for the NMR spectra. This work was
completed within a collaboration project with PLIVA d.d, Zagreb.
Mp 136.0–137.0 °C.
IR (KBr): 3460, 3220, 2910, 1730, 1310, 1230, 1015 cm–1.
References
1H NMR (CD3OD): δ = 3.17–3.21 (m, 2 H), 3.89 (s, 3 H), 4.15–4.25
(m, 1 H), 5.80 (d, J = 8.5 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 2 H), 7.35
(d, J = 8.5 Hz, 2 H).
13C NMR (CD3OD): δ = 50.1, 56.0, 59.5, 63.3, 81.1, 115.1, 128.4,
128.7, 161.6, 162.0.
HRMS: m/z [M + H+] calcd for C11H13NO4, 224.0917; found,
224.0936.
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Synthesis 2003, No. 3, 375–382 ISSN 0039-7881 © Thieme Stuttgart · New York