Enantioselective synthesis of (-)-cytoxazone and (+)-epi-cytoxazone, novel cytokine modulators via Sharpless asymmetric epoxidation and l-proline catalyzed Mannich reaction

Article abstract of DOI:10.1016/j.tet.2006.03.079

A short and efficient enantioselective synthesis of (-)-cytoxazone and its stereoisomer (+)-epi-cytoxazone, novel cytokine modulators, has been described with good yield and enantioselectivity. Ti-catalyzed Sharpless asymmetric epoxidation of allyl alcoho

Full text of DOI:10.1016/j.tet.2006.03.079

Tetrahedron 62 (2006) 5756–5762
Enantioselective synthesis of (L)-cytoxazone and (+)-epi-
cytoxazone, novel cytokine modulators via Sharpless asymmetric
epoxidation and L-proline catalyzed Mannich reaction
*
Abhimanyu S. Paraskar and Arumugam Sudalai
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road,
Pune 411008, Maharashtra, India
Received 10 December 2005; revised 2 March 2006; accepted 23 March 2006
Available online 12 April 2006
Abstract—A short and efficient enantioselective synthesis of (ꢀ)-cytoxazone and its stereoisomer (+)-epi-cytoxazone, novel cytokine
modulators, has been described with good yield and enantioselectivity. Ti-catalyzed Sharpless asymmetric epoxidation of allyl alcohol
and L-proline catalyzed three-component Mannich reaction constitute the key steps in introducing stereogenicity into the molecule.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Cytoxazone 1, containing a novel 4,5-disubstituted-2-oxazo-
lidinone moiety was isolated1 from Streptomyces sp., and its
absolute configuration was unambiguously established by
asymmetric synthesis.2 (ꢀ)-Cytoxazone [(ꢀ)-1] exhibits
cytokine-modulating activity by inhibiting the signaling
pathway of Th2 cells. Inhibitors of Th2-dependent cytokine
production would be potent chemotherapeutic agents in the
field of immunotherapy. Since Th2 cells play a role in medi-
ating the immune response to allergens, cytoxazone 1 could
be a useful lead compound for the development of therapeu-
tic agents for atopic dermatitis and asthma.
Retrosynthetic analysis of cytoxazone (1) reveals that amino
alcohol 3 could be visualized as a key intermediate (Fig. 1).
The key intermediate (Z)-olefinic ether (8) was obtained
in three steps: (i) Sonogashira coupling (cat. Pd(PPh3)4
(0.5 mol %), cat. CuI (10 mol %), Et2NH, 25 ꢁC, 96%) of
4-iodoanisole with propargyl alcohol to give aryl propargyl
alcohol 6 in 96% yield; (ii) acetylenic alcohol 6 was pro-
tected with TBS chloride to give TBS ether 7, which was
O
O
Due to its potential bioactivity and the simple structure, sev-
eral methods of synthesizing (ꢀ)-cytoxazone (1) have been
accomplished.3 The stereoisomer of (ꢀ)-cytoxazone (1),
(+)-epi-cytoxazone (2) has also been synthesized.4 In this
paper, we wish to report a short enantioselective synthesis
of (ꢀ)-cytoxazone and its stereoisomer (+)-epi-cytoxazone
in good yields by employing Ti-catalyzed Sharpless asym-
metric epoxidation of allyl alcohol and L-proline catalyzed
Mannich reaction, respectively, as the key steps in introduc-
ing stereogenic centers into the molecule.
HN
HN
O
O
OH
OH
MeO
MeO
(+)-Epi-cytoxazone 2
(-)-Cytoxazone 1
NH2
OH
NH2
OH
OH
OH
MeO
MeO
MeO
MeO
4
3
O
CHO
OH
Keywords: Asymmetric synthesis; Aminohydroxylation; Epoxidation;
Mannich reaction; Oxidation; Ozonolysis.
5
* Corresponding author. Tel.: +91 20 25902174; fax: +91 20 25893359;
e-mail: a.sudalai@ncl.res.in
Figure 1. Retrosynthesis of (ꢀ)-cytoxazone (1) and (+)-epi-cytoxazone (2).
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.079

A. S. Paraskar, A. Sudalai / Tetrahedron 62 (2006) 5756–5762
5757
OR
O
stereospecifically reduced with Lindlar catalyst to obtain
OH
ii
I
(Z)-olefinic ether 8 in 99% yield. However, several attempts
to functionalize (Z)-olefinic ether 8 with Os-catalyzed asym-
metric aminohydroxylation (AA) failed despite employing
various reaction conditions (Scheme 1).5
i
iv
79%
81%
78%
AcO
AcO
14
15
AcO
16 R = H
87% iii
R = Ac
17
O
O
O
OR
N3
OR
OAc
O
HN
OTBS
O
O
HN
HN
ii
iii
vi
87%
vii
MeO
98%i
99%
OTBS
OAc
OH
MeO
6
7
R = H
R = TBS
8
9
AcO
93% v
MeO
AcO
RO
18
R = H
20
Scheme 1. Reagents and conditions: (i) TBSCl, Et3N, CH2Cl2, 0–25 ꢁC,
98%; (ii) Lindlar catalyst (5% Pd on CaCO3 with Pb poisoned), dry hexane,
H2 (1 atm), 25 ꢁC, 99 %; (iii) cat. K2OsO6, (DHQD)2PHAL, Urethane, tert-
BuOCl or 1,3-dichoro-5,5-dimethyl hydantoin, aq 10% NaOH, n-PrOH,
25 ꢁC, 24 h.
21 R = H
R = Me
(-)-cytoxazone
19 R = CO2Ph
69% viii
1
Scheme 3. Reagents and conditions: (i) allyl alcohol (3 equiv), AgOAc
(1 equiv), cat. Pd(OAc)2 (5 mol %), cat. PPh3 (10 mol %), DMF, 70 ꢁC,
16 h, 81%; (ii) anhyd 5.4 M TBHP in CH2Cl2, 4 A Molecular sieves, cat.
˚
After failing to functionalize aminohydroxylate (Z)-olefinic
ether 8, we then turned our attention to functionalize (E)-
allyl alcohol 11.
Ti(OiPr)4 (10 mol %), cat. (+)-DIPT (12 mol %), CH2Cl2, ꢀ20 ꢁC, 20 h,
78%; (iii) AcCl, Et3N, cat. DMAP (10 mol %), CH2Cl2, 25 ꢁC, 87%;
(iv) NaN3, cat. NH4Cl (30 mol %), THF/H2O (2:1), 50 ꢁC, 3 h, 79%; (v)
PhOCOCl, pyridine, CH2Cl2, ꢀ5 to 25 ꢁC, 1 h, 93%; (vi) PPh3 (4 equiv),
THF/H2O (10:1), 50 ꢁC, 2 h, 87%; (vii) aq NaHCO3, MeOH, reflux, 1 h;
(viii) NaH, MeI, THF, 0–25 ꢁC, 3 h, 69%, 83% ee.
Accordingly, we subjected (E)-allyl alcohol 11 to Ti-cata-
lyzed asymmetric epoxidation (AE) under standard reaction
conditions;6 here again, all our attempts to obtain chiral ep-
oxide 12 failed. The reason may be due to the positive induc-
tive effect of methoxy group present on an aromatic ring,
which facilitates the opening of epoxide ring, thus deactivat-
ing the Ti-catalyst by forming metal chelate 13 (Scheme 2).
methylation with methyl iodide in the presence of NaH to
afford (ꢀ)-cytoxazone (1) in 65% yield and 83% ee [deter-
mined by HPLC using ChirasphereÒ column and optical
rotation].
In order to eliminate this positive inductive effect due to
OMe group, we changed our strategy by replacing elec-
tron-rich OMe group on the aromatic ring with electron-
deficient OAc group. This protecting group can be further
deprotected easily during the course of the synthesis
(Scheme 3).
Based on the retrosynthetic analysis of (+)-epi-cytoxazone 2
(Fig. 1), amino alcohol 4 is the key intermediate, which can
be obtained from L-proline catalyzed asymmetric Mannich
reaction (Scheme 4).9 Thus, 4-methoxybenzaldehyde was
condensed with hydroxyacetone and p-anisidine in the pres-
ence of 30 mol % L-proline, to obtain chiral amino alcohol
22 in 76% yield with syn/anti ratio 2:1. Efforts to improve
the diastereomeric ratios were not successful despite replac-
ing OMe group with electron withdrawing groups such as
OAc or OMs on the aromatic nucleus. However, the required
diastereomer was separated by simple column chromato-
graphic purification. Amino alcohol 22 was then protected
with triphosgene to give oxazolidinone 23 in 82% yield. At-
tempts to convert methyl ketone in 23 to the corresponding
carboxylic acid via haloform reaction were not fruitful. Al-
ternately, we tried to prepare kinetically controlled silyl enol
ether 7 from oxazolidinone 23 so that enol ether 24 could be
further easily converted to epi-cytoxazone (2) by ozonolysis
with reductive work up. However, all attempts to isolate enol
ether 24 in pure form resulted in the isolation of the starting
ketone 23. Then we subjected in situ generated silyl enol
ether for ozonolysis without purification. Reductive work
up of ozonide and PMP deprotection with CAN gave (+)-
epi-cytoxazone 2 in 59% yield and 81% ee.
4-Iodophenol was protected as its acetyl derivative 14 (Et3N,
CH2Cl2, 25 ꢁC). The Pd-catalyzed arylation of allyl alcohol
with 14 gave the trans-allylic alcohol 15 in 81% yield.7 The
allylic alcohol 15 was subjected to Sharpless asymmetric ep-
oxidation [(+)-DIPT, Ti(OiPr)4, anhyd TBHP, 25 ꢁC] to give
the chiral epoxide 16 in 78% yield and 92.5% ee (determined
by chiral HPLC using Chiralcel OD-HÒ column). The alco-
hol 16 was acetylated (CH3COCl, Et3N, DMAP (cat.),
CH2Cl2, 25 ꢁC) to give epoxy acetate 17 in 86% yield. The
nucleophilic opening of the epoxide at the benzylic position
with N3 was achieved (NaN3, NH4Cl (cat.), THF, 25 ꢁC) to
give azido alcohol 18 in 88% yield. We then followed re-
ported procedure8 for the conversion of azido alcohol 18 to
the corresponding oxazolidinone 21 in two steps by alcohol
protection followed by reductive cyclization with triphenyl-
phosphine. Basic hydrolysis of both acetate groups in
MeOH gave the phenol 21 which was directly subjected to
_
OH
O
O
i
ii
OH
OH
Ti-catalyst
OH
Ar
90%
Ar
Ar
10
11
12
MeO
+
Ar = 4-MeOC6H4
13
Scheme 2. Reagents and conditions: (i) LAH, THF, 0 ꢁC, 3 h, 90%. (ii) Ti(OiPr)4 (10 mol %), (+)-DIPT (12 mol %), anhydrous TBHP, CH2Cl2, ꢀ20 ꢁC, 24 h.

5758
A. S. Paraskar, A. Sudalai / Tetrahedron 62 (2006) 5756–5762
Yield: 96%; mp: 74–75 ꢁC; IR (CHCl3, cmꢀ1): 669, 757,
H
NH2
CHO
OMe
N
PMP
O
O
833, 1033, 1172, 1215, 1249, 1292, 1463, 1510, 1606,
2856, 2927, 3018, 3421; 1H NMR (200 MHz, CDCl3):
d 2.61 (br s, 1H), 3.78 (s, 3H), 4.48 (s, 2H), 6.79 (d,
J¼9.0 Hz, 2H), 7.34 (d, J¼9.0 Hz, 2H); 13C NMR
(50 MHz, CDCl3): d 51.42, 55.13, 85.38, 85.90, 113.83,
114.57, 133.06, 159.59; LRMS m/z (% rel intensity): 162
(M+, 100), 145 (33), 131 (40), 108 (30), 102 (33), 91 (57),
77 (30), 63 (43); Analysis: C10H10O2 requires C, 74.06; H,
6.21; found C, 74.17; H, 6.14 %.
i
ii
Me
+
+
76%
82%
OH
22
OH
MeO
O
OMe
O
O
N
O
PMP
N
O
PMP
MeO
HN
O
iv
59%
iii
Me
OTMS
O
OH
MeO
23
2
MeO
24
4.3. Preparation of (3-(4-methoxyphenyl)prop-2-ynyl-
oxy)(tert-butyl)dimethylsilane (7)
Scheme 4. Reagents and conditions: (i) p-anisidine (1.1 equiv), hydroxy-
acetone (10 equiv), cat. L-proline (20 mol %), DMSO, 25 ꢁC, 24 h, 76%;
(ii) triphosgene, Et3N, CH2Cl2, ꢀ10 to 25 ꢁC, 82%; (iii) Li-HMDS, TMSCl,
THF, ꢀ78 ꢁC; (iv) (a) O3, PPh3, CH2Cl2, ꢀ78 ꢁC; (b) NaBH4, MeOH,
25 ꢁC; (c) CAN, CH3CN, 5 h, (59% in three steps), 81% ee.
To a stirred solution of alcohol 6 (2.46 g, 15.2 mmol) in dry
CH2Cl2 (25 ml), Et3N (2.29 g, 22.7 mmol) and tert-butyldi-
methylsilyl chloride (2.75 g, 18.2 mmol) were added portion
wise at 0 ꢁC. This mixture was then brought to room temper-
ature and stirred for 12 h and then quenched with MeOH. It
was poured into water and extracted with EtOAc. The or-
ganic phase was washed with aq NaHCO3 solution, water,
and brine, dried over MgSO4 and purified over column chro-
matography using pet. ether as eluent to afford pure 7
(4.11 g, 98%) as yellow colored oil.
3. Conclusion
In conclusion, we have achieved a simple and efficient asym-
metric synthesis of (ꢀ)-cytoxazone (1) using asymmetric
epoxidation of allylic alcohol (AE) in the presence of
Ti(OiPr)4 as a catalyst and (+)-DIPT as ligand with a overall
yield of 23%, and optical purity of 83% ee (by HPLC) in
nine steps starting from readily available 4-iodophenol.
We have also achieved asymmetric synthesis of (+)-epi-
cytoxazone (1) using L-proline catalyzed Mannich reaction
with overall yield of 37%, and optical purity of 81% in six
steps starting from readily available p-anisaldehyde.
Yield: 98%; IR (CHCl3, cmꢀ1): 776, 845, 1125, 1230, 1522,
1605; 1H NMR (200 MHz, CDCl3): d 0.02 (s, 6H), 0.78 (s,
9H), 3.61 (s, 3H), 4.34 (s, 2H), 6.61 (d, J¼8.9 Hz, 2H),
7.15 (d, J¼8.9 Hz, 2H); 13C NMR (50 MHz, CDCl3): d
ꢀ5.23, 18.03, 25.62, 51.94, 54.64, 84.62, 86.26, 113.62,
114.90, 132.70, 159.37; LRMS m/z (% rel intensity): 276
(M+, 5), 261 (3), 231 (3), 219 (65), 205 (5), 189 (80), 174
(5), 159 (5), 145 (100), 130 (15), 115 (10), 102 (20), 94
(20), 75 (15), 57 (10), 41 (12); Analysis: C16H24O2Si re-
quires C, 69.51; H, 8.75; found C, 69.47; H, 8.70%.
4. Experimental
4.1. General information
Solvents were purified and dried by standard procedures
before use; petroleum ether of boiling range 60–80 ꢁC was
used. Melting points were uncorrected. HPLC analyses
were performed on a chiral column (Chiralcel OD-HÒ and
ChirasphereÒ). Optical rotations were measured using so-
dium D line on a JASCO-181 digital polarimeter. Infrared
spectra were recorded on a Shimadzu FTIR-8400 spectro-
4.4. Preparation of (Z)-(4-methoxycinnamyloxy)(tert-
butyl)dimethylsilane (8)
To a 50 ml two-necked RB flask equipped with a condenser
and a balloon filled with H2 at 1 atm was added Lindlar cat-
alyst (5% Pd on CaCO3 poisoned with lead, 1.4 g), silyl ether
7 (2.76 g, 10 mmol), quinoline (2.6 g, 21 mmol), and 45 ml
of dry n-hexane. The resulting mixture was stirred at room
temperature under H2 (1 atm) for 1 h. When starting material
was consumed (monitored by TLC), the reaction mixture
was filtered through sintered funnel. After distilling off
hexane, we obtained 2.75 g (99%) of pure (Z)-olefin 8 as
yellow colored oil.
1
meter. H NMR and 13C NMR were recorded on Bruker
AC-200 and MSL-300 NMR spectrometers, respectively.
Mass spectra were obtained with a Finnigan MAT-1020B-
70 eV mass spectrometer. Elemental analysis was carried
out on a Carlo Erba EA 110B CHNS-O analyzer.
4.2. Preparation of 3-(4-methoxyphenyl)prop-2-yn-1-ol
(6)
Yield: 99%; IR (CHCl3, cmꢀ1): 534, 617, 650, 668, 814,
837, 909, 938, 960, 983, 1006, 1035, 1085, 1175, 1216,
1253, 1302, 1361, 1405, 1442, 1464, 1471, 1511, 1575,
1607, 1681, 2401, 2857, 2897, 2931, 2956, 3019, 3443; 1H
NMR (200 MHz, CDCl3): d 0.01 (s, 6H), 0.84 (s, 9H),
3.76 (s, 3H), 4.37 (d, J¼5.9 Hz, 2H), 5.61 (q, J¼5.9 Hz,
1H), 6.34 (d, J¼12.0 Hz, 1H), 6.79 (d, J¼8.8 Hz, 2H),
7.06 (d, J¼8.8 Hz, 2H); 13C NMR (50 MHz, CDCl3): d
ꢀ5.18, 18.25, 25.87, 55.08, 60.36, 113.51, 129.04, 129.49,
130.00, 130.76, 158.55; LRMS m/z (% rel intensity): 278
(M+, 5), 222 (15), 221 (50), 205 (5), 189 (5), 175 (10), 166
(5), 147 (100), 131 (45), 115 (75), 103 (65), 91 (90), 75
A two-necked 100 ml RB flask was charged with p-iodoani-
sole (4.68 g, 20 mmol), propargyl alcohol (1.68 g, 30 mmol),
CuI (0.40 g, 2 mmol), Pd(PPh3)4 (0.12 g, 0.10 mmol), and di-
ethylamine (50 ml). The resulting mixture was stirred at
25 ꢁCfor 6 h. Then the reaction was diluted with ethyl acetate
(80 ml), washed with 10% HCl (10 ml), water and brine,
dried over anhydrous sodium sulfate, and concentrated under
reduced pressure to give black colored thick oil. This crude
product was purified on column chromatography using
20% ethyl acetate in pet. ether as eluent to afford pure 6
(3.10 g, 96%) as pale yellow colored solid.

A. S. Paraskar, A. Sudalai / Tetrahedron 62 (2006) 5756–5762
5759
(90), 57 (80), 41 (90); Analysis: C16H26O2Si requires C,
69.01; H, 9.41; found C, 69.00; H, 9.35%.
(0.53 ml, 0.585 g, 2.5 mmol) was added sequentially and
the mixture was stirred for 10 min before the addition of allyl
alcohol 15 (3.84 g, 20 mmol). Finally, a 5.4 M anhydrous
TBHP solution in CH2Cl2 (7.6 ml, 41 mmol) was added
and the resulting mixture was stirred at ꢀ20 ꢁC for 20 h. Af-
ter completion of reaction (monitored by TLC), 10% aq tar-
taric acid (20 ml) was added and the aqueous layer solidifies.
After 1 h the reaction was brought to room temperature and
stirring was continued until the aqueous layer becomes clear.
The organic layer was washed with brine, dried over an-
hydrous sodium sulfate, and evaporated under reduced
pressure. The crude product was purified by column chroma-
tography using pet. ether/EtOAc (3:1) as eluent to furnish
epoxide 16 as white solid (3.23 g).
4.5. Preparation of (E)-3-(4-methoxyphenyl)prop-2-en-
1-ol (11)
LAH (0.29 g, 7.8 mmol) was taken in THF (23 ml) and the
slurry was cooled to 0 ꢁC in an ice bath under nitrogen atmo-
sphere. To this mixture, alcohol 6 (1.60 g, 9.88 mmol) was
added dropwise and the reaction mixture was stirred at
0 ꢁC for 30 min. After completion of reaction (monitored
by TLC), ice-cold water (20 ml) was added and extracted
with ether (3ꢂ30 ml). The ethereal layer was washed with
10% HCl, saturated sodium bicarbonate solution, and with
brine successively. The ether extract was dried over anhy-
drous sodium sulfate and evaporated under reduced pressure.
The crude product was purified by column chromatography
using pet. ether/EtOAc (3:1) as eluent to furnish 11 as color-
less solid (1.18 g).
Yield: 78%; mp: 96 ꢁC (crystallized from EtOH); [a]2D5
+23.59 (c 1.3, CHCl3); HPLC: 92.5% ee, Chiralcel OD-
HÒ, l¼254 nm, 5% 2-propanol/hexane, 1 ml/min, retention
time: (R,R) 10.81 min, (S,S) 15.716 min; IR (CHCl3, cmꢀ1):
527, 605, 703, 736, 784, 872, 971, 1045, 1152, 1175, 1200,
1232, 1369, 1417, 1504, 1605, 1740, 2939, 3029, 3060,
Yield: 73%; IR (CHCl3, cmꢀ1): 761, 890, 1098, 1375, 1452,
1504, 2989, 3010, 3409, 3610; 1H NMR (200 MHz, CDCl3):
d 1.60 (br s, 1H), 3.81 (s, 3H), 4.28 (d, J¼6.0 Hz, 2H), 6.17–
6.30 (m, 1H), 6.52–6.60 (d, J¼16.0 Hz, 1H), 6.84 (d,
J¼8.0 Hz, 2H), 7.31 (d, J¼8.0 Hz, 2H); 13C NMR
(50 MHz, CDCl3): d 55.13, 63.58, 113.90, 126.29, 127.54,
129.42, 130.67, 159.15; Analysis: C10H12O2 requires C,
73.15; H, 7.37; found C, 73.12; H, 7.80%.
1
3499; H NMR (200 MHz, CDCl3): d 2.04 (br s, 1H), 2.39
(s, 3H), 3.78–4.08 (m, 4H), 7.25–7.37 (m, 4H); 13C NMR
(50 MHz, CDCl3): d 20.75, 54.67, 60.89, 62.63, 122.11,
127.22, 136.13, 148.81, 149.23, 170.11; Analysis: C11H12O4
requires C, 63.45; H, 5.81; found C, 63.38; H, 5.78%.
4.8. Preparation of 4-((2S,3S)-3-(acetoxymethyl)oxiran-
2-yl)phenyl acetate (17)
4.6. Preparation of 4-((E)-3-hydroxyprop-1-enyl)phenyl
acetate (15)
The mixture of epoxy alcohol 16 (2.08 g, 10 mmol), acetyl
chloride (0.858 g, 11 mmol), Et3N (1.52 g, 15 mmol), and
DMAP (0.122 g, 10 mol %) in dry CH2Cl2 (10 ml) was
stirred at room temperature. After the reaction was complete
(TLC, 2 h), the solvent was removed under reduced pressure
to give the crude product. The residue was diluted with water
(10 ml) and was extracted with ethyl acetate (2ꢂ25 ml). The
organic layer was washed with saturated NaHCO3
(2ꢂ15 ml) and brine (15 ml) and dried over anhydrous
Na2SO4. Evaporation of solvent gave the crude product,
which was purified by column chromatography to afford
2.17 g (87%) of epoxy ester 17 as colorless gum.
A mixture of 4-iodophenyl acetate (7.89 g, 30 mmol) and
allyl alcohol (3.48 g, 60 mmol) was stirred for 16 h in the
presence of the AgOAc (5.01 g, 30 mmol), PPh3 (0.78 g,
3 mmol), and Pd(OAc)2 (0.33 g, 1.5 mmol) at 70 ꢁC in
50 ml DMF. The reaction mixture was filtered through
sintered funnel and washed with aq HCl (15 ml), water
(15 ml), aq NaHCO3 (15 ml), and brine (15 ml) sequentially.
The crude allyl alcohol was purified by column chromato-
graphy using pet. ether/EtOAc (3:1) as eluent to furnish
4.65 g of 15 as colorless solid.
Yield: 81%; mp: 81–83 ꢁC (crystallized from EtOH); IR
(CHCl3, cmꢀ1): 504, 524, 692, 755, 872, 970, 1016, 1087,
1151, 1196, 1332, 1414, 1503, 1600, 1677, 1714, 2869,
Yield: 87%; IR (CHCl3, cmꢀ1): 526, 604, 702, 735, 783,
871, 970, 1016, 1044, 1109, 1152, 1175, 1200, 1232,
1369, 1418, 1504, 1605, 1740, 1913, 2939, 3029, 3062,
3499; 1H NMR (200 MHz, CDCl3): d 2.12 (s, 3H), 2.40 (s,
3H), 3.20–3.25 (m, 1H), 3.84 (d, J¼2.0 Hz, 1H), 4.07–
4.16 (m, 1H), 4.44–4.51 (m, 1H), 7.22 (d, J¼9.1 Hz, 2H),
7.30 (d, J¼7.2 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d 20.55, 20.76, 55.45, 59.29, 63.67, 122.09, 127.15,
129.71, 135.57, 148.93, 170.51; Analysis: C13H14O5 re-
quires C, 50.34; H, 4.93; found C, 50.28; H, 4.89%.
1
2939, 3029, 3366; H NMR (200 MHz, CDCl3): d 1.67 (br
s, 1H), 2.38 (s, 3H), 4.32 (d, J¼4.9 Hz, 2H), 6.27–6.40 (m,
1H), 6.57 (d, J¼15.9 Hz, 1H), 7.20 (d, J¼8.7 Hz, 2H),
7.39 (d, J¼8.7 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d 20.74, 61.84, 121.52, 127.15, 128.01, 129.76, 135.84,
147.80, 169.28; LRMS m/z (% rel intensity): 192 (M+, 5),
174 (3), 150 (50), 131 (10), 121 (10), 107 (100), 94 (60),
76 (30), 65 (15), 50 (20); Analysis: C11H12O3 requires C,
68.74; H, 6.29; found C, 68.61; H, 6.18%.
4.9. Preparation of (2R,3R)-3-azido-2-hydroxy-3-(4-
acetoxyphenyl)propyl acetate (18)
4.7. Preparation of 4-((2S,3S)-3-(hydroxymethyl)oxiran-
2-yl)phenyl acetate (16) using Sharpless asymmetric
epoxidation
To a solution of NaN3 (0.29 g, 5.2 mmol) and NH4Cl
(0.054 g, 1 mmol) in water (5 ml), a solution of epoxy ester
17 (0.775 g, 3.1 mmol) in THF (10 ml) was added. The reac-
tion mixture was stirred at 50 ꢁC for 3 h. Cooled to room
temperature and the solution was extracted with EtOAc
and washed with water (50 ml), dried over anhydrous
˚
A 100 ml two-necked RB flask was charged with 4 A mole-
cular sieves (1 g), 20 ml CH2Cl2, and cooled at ꢀ25 ꢁC.
Then Ti(OiPr)4 (0.59 ml, 0.568 g, 2 mmol) and L-(+)-DIPT

5760
A. S. Paraskar, A. Sudalai / Tetrahedron 62 (2006) 5756–5762
Na2SO4. Upon evaporation of the solvent, the crude product
was purified by column chromatography over silica gel
(EtOAc/pet. ether, 2:8) yielding 0.717 g (79%) of azido alco-
hol 18 as yellow colored solid.
159.92, 170.10, 171.15; Analysis: C14H15NO6 requires
C, 57.34; H, 5.16; N, 4.78; found C, 57.28; H, 5.12; N,
4.69%.
4.12. Preparation of (4R, 5R)-5-hydroxymethyl-4-(4-
methoxyphenyl)-oxazolidin-2-one: (L)-cytoxazone (1)
Yield: 79%; mp: 61 ꢁC; [a]D25 ꢀ9.16 (c 0.8, CHCl3); IR
(CHCl3, cmꢀ1): 527, 604, 668, 757, 873, 908, 970, 1018,
1044, 1108, 1151, 1176, 1217, 1332, 1371, 1417, 1503,
1603, 1735, 2108, 2401, 2939, 3022, 3472; 1H NMR
(200 MHz, CDCl3): d 2.09 (s, 3H), 2.38 (s, 3H), 2.66 (br s,
1H), 3.98–4.09 (m, 1H), 4.15 (d, J¼2.5 Hz, 1H), 4.17 (d,
J¼1.4 Hz, 1H), 4.63 (d, J¼6.3 Hz, 1H), 7.31 (d, J¼8.7 Hz,
2H), 7.43 (d, J¼8.7 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d 20.62, 20.76, 64.79, 66.09, 72.03, 122.27, 129.40,
135.17, 148.96, 169.12, 171.21; Analysis: C13H15N3O5 re-
quires C, 53.24; H, 5.16; N, 14.33; found C, 53.15; H,
5.10; N, 14.30%.
A mixture of oxazolidinone 20 (0.237 g, 0.81 mmol), and
10% aq NaHCO3 (2 ml) in methanol (5 ml) was heated un-
der reflux for 1 h. After the reaction was complete (TLC),
solvent was removed under reduced pressure to give the
crude product. The residue was diluted with water (5 ml)
and was extracted with ethyl acetate (2ꢂ5 ml). The organic
layer was dried over anhydrous Na2SO4. Evaporation of sol-
vent gave crude product 21, which without purification, was
then added to THF (5 ml) containing NaH (60% suspension
in paraffin) (0.034 g, 0.85 mmol) at 0 ꢁC and stirred for 1 h.
To this mixture was further added MeI (0.12 g, 0.85 mmol)
at 0 ꢁC and then stirred at room temperature for 3 h. After
the reaction was complete, the reaction mixture was diluted
with water (3 ml) and extracted with diethyl ether (2ꢂ5 ml).
The organic layer was dried over anhydrous Na2SO4. Evapo-
ration of solvent gave crude product, which was purified by
column chromatography and recrystallized from MeOH to
afford the required (ꢀ)-cytoxazone 1 in 69% (0.124 g) yield
as colorless solid.
4.10. Preparation of (1R,2R)-3-acetoxy-1-azido-1-(4-
acetoxyphenyl)propan-2-yl phenyl carbonate (19)
To a solution of azido alcohol 18 (0.469 g, 1.6 mmol) and
pyridine (0.14 ml, 1.7 mmol) in CH2Cl2 (20 ml), a solution
of phenylchloroformate (0.22 ml, 0.28 g, 1.7 mmol) in
CH2Cl2 (1 ml) was added at ꢀ5 ꢁC over10 min. After stir-
ring at ꢀ5 ꢁC for 1 h, the reaction mixture was poured into
water. The organic layer was washed with 1% H3PO4, then
with 3% NaHCO3, and dried over anhydrous Na2SO4.
Upon evaporation of the solvent, 0.614 g of gummy azido
ester 19 was obtained as brown colored gum.
Yield: 69%; mp: 117–120 ꢁC (crystallized from MeOH),
(lit.1118–121 ꢁC); [a]D25 ꢀ60.16 (c 0.3, MeOH), (lit.1 [a]D25
ꢀ71 (c 0.1, MeOH)); HPLC: 83% ee, ChirasphereÒ,
l¼254 nm, 5% 2-propanol/hexane, 1 ml/min, retention
time: (S,S) 16.776 min, (R,R) 21.001 min; IR (KBr, cmꢀ1):
450, 766, 965, 997, 1026, 1041, 1050, 1177, 1215, 1236,
1254, 1398, 1514, 1615, 1712, 1720, 2948, 3228, 3255,
Yield: 93%; IR (KBr, cmꢀ1): 602, 670, 761, 873, 1045, 1109,
1150, 1175, 1245, 1510, 1610, 1760, 2100, 2955; 1H NMR
(200 MHz, CDCl3): d 2.10 (s, 3H), 2.37 (s, 3H), 4.16–4.20
(m, 2H), 4.45–4.56 (m, 1H), 4.63 (d, J¼6.3 Hz, 1H), 7.12–
7.48 (m, 9H); 13C NMR (50 MHz, CDCl3): d 20.64, 20.75,
64.81, 66.11, 72.05, 122.32, 124.95, 129.44, 135.22,
148.98, 152.24, 159.73, 166.65, 171.37; Analysis:
C20H19N3O7 requires C, 58.11; H, 4.63; N, 10.16; found
C, 58.05; H, 4.60; N, 10.10%.
1
3352, 3476; H NMR (200 MHz, DMSO-d6): d 2.95–2.97
(m, 2H), 3.75 (s, 3H), 4.62–4.73 (m, 1H), 4.82 (t,
J¼5.0 Hz, 1H), 4.90 (d, J¼4.9 Hz, 1H), 6.91 (d, J¼8.8 Hz,
2H), 7.15 (d, J¼8.8 Hz, 2H), 7.92 (br s, 1H); 13C NMR
(50 MHz, DMSO-d6): d 55.17, 56.82, 61.93, 80.48,
113.79, 128.17, 129.45, 158.81, 160.09; Analysis:
C11H13NO4 requires C, 59.19; H, 5.87; N, 6.27; found C,
59.17; H, 5.80; N, 6.19%.
4.11. Preparation of ((4R,5R)-4-(4-acetoxyphenyl)-2-
oxooxazolidin-5-yl)methyl acetate (20)
4.13. Preparation of (3S,4R)-4-(4-methoxyphenylami-
no)-3-hydroxy-4-(4-methoxyphenyl)butan-2-one (22)
Azido ester 19 (0.454 g, 1.1 mmol) and PPh3 (1.18 g,
4.5 mmol) were dissolved in THF (20 ml) and water
(2 ml). The reaction mixture was heated at 50 ꢁC for 2 h.
Evolution of N2 was observed during the first 1 h of the re-
action. Solvent was evaporated; the solid residue was dis-
solved in EtOAc (20 ml), washed with brine (10 ml), and
dried over anhydrous Na2SO4. Crude product was purified
by column chromatography and recrystallized from CHCl3
to obtain 0.280 g (87%) of oxazolidinone 20 as gray colored
solid.
A mixture of L-proline (0.23 g, 2 mmol), p-anisidine (1.35 g,
11 mmol), p-anisaldehyde (1.36 g, 10 mmol), and hydroxy-
acetone (2 ml) in DMSO (10 ml), was stirred at 25 ꢁC for
24 h. After completion of reaction, aq saturated NH4Cl
(10 ml) was added and the mixture was extracted with ethyl
acetate. Upon evaporation of the solvent, crude product was
purified by column chromatography on silica gel (EtOAc/
pet. ether, 3:4) yielding required Mannich product (22)
2.39 g (76%) as yellow oil.
Yield: 87%; mp: 103 ꢁC (crystallized from CHCl3); [a]2D5
ꢀ54.82 (c 0.8, CHCl3); IR (KBr, cmꢀ1): 971, 1025, 1043,
1051, 1173, 1233, 1367, 1514, 1605, 1712, 1720, 1740,
2938, 3228, 3255, 3475; 1H NMR (200 MHz, CDCl3):
d 2.09 (s, 3H), 2.34 (s, 3H), 3.14–3.16 (m, 2H), 4.66–4.78
(m, 1H), 4.92 (d, J¼8.2 Hz, 1H), 7.13–7.25 (m, 4H), 8.11
(br s, 1H); 13C NMR (50 MHz, CDCl3): d 20.64, 20.75,
56.86, 67.49, 80.55, 121.51, 128.59, 132.73, 148.66,
Yield: 76%; [a]D25 ꢀ1.28 (c 1.3, CHCl3); IR (CHCl3, cmꢀ1):
1092, 1237, 1346, 1513, 1709, 2360, 2916, 3269; 1H NMR
(200 MHz, CDCl3): d 2.36 (s, 3H), 3.75 (s, 3H), 3.83 (s,
3H), 4.42 (d, J¼2.20 Hz, 1H), 4.91 (d, J¼2.0 Hz, 1H), 6.54–
6.63 (m, 2H), 6.72–6.81 (m, 2H), 6.96–7.05 (m, 2H), 7.35–
7.44 (m, 2H); 13C NMR (50 MHz, CDCl3): d 25.79, 55.62,
56.12, 60.14, 81.32, 114.15, 115.24, 115.76, 128.60, 131.58,

A. S. Paraskar, A. Sudalai / Tetrahedron 62 (2006) 5756–5762
5761
140.00, 152.77, 159.44, 207.98; Analysis: C18H21NO4 re-
quires C, 68.55; H, 6.71; N, 4.44; found C, 68.50; H, 6.80;
N, 4.39%.
trated to furnish after column chromatography pure (+)-
epi-cytoxazone (2) as colorless solid in (0.105 g) 59% yield
and 81% ee.
4.14. Preparation of (4R,5S)-5-acetyl-3,4-bis(4-meth-
oxyphenyl)oxazolidin-2-one (23)
Yield: 59%; mp: 159–160 ꢁC (crystallized from MeOH),
(lit.4b 158–160 ꢁC); [a]D25 +22.89 (c 0.4, MeOH), (lit.4b
[a]2D5 +28.6 (c 1, MeOH)); HPLC: 81% ee, Chiracel OD-
HÒ, l¼280 nm, 15% 2-propanol/hexane, 0.8 ml/min, reten-
tion time: (R,S) 14.32 min, (S,R) 15.28 min; IR (KBr, cmꢀ1):
830, 1025, 1240, 1510, 1720, 2920, 3290; 1H NMR
(200 MHz, DMSO-d6): d 3.62–3.66 (m, 1H), 3.75 (s, 3H),
3.80–3.84 (m, 1H), 4.43–4.47 (m, 1H), 4.78 (d, J¼5.9 Hz,
1H), 6.93 (d, J¼8.7 Hz, 2H), 7.2 (d, J¼8.5 Hz, 2H); 13C
NMR (50 MHz, DMSO-d6): d 55.41, 57.12, 62.23, 85.58,
114.81, 128.73, 131.52, 159.77, 161.00; Analysis:
C11H13NO4 requires C, 59.19; H, 5.87; N, 6.27; found C,
59.14; H, 5.72; N, 6.22%.
The Mannich product 22 (0.315 g, 1 mmol), in dry CH2Cl2
(20 ml) was cooled to ꢀ20 ꢁC and to this Et3N (506 mg,
5 mmol) and triphosgene (297 mg, 1 mmol) was added.
The mixture was warmed to room temperature, stirred for
3 h, and quenched with aq NH4Cl (10 ml). After extraction
with CH2Cl2 (20 ml), the organic layer was dried over
Na2SO4 and concentrated to furnish crude trans-oxazolidi-
none 23, which was further purified by column chromato-
graphy (EtOAc/pet. ether, 5:3) yielding 0.28 g (82%) of
white solid.
Yield: 82%; mp: 106–108 ꢁC (crystallized from EtOH);
[a]D25 ꢀ18.14 (c 0.5, CHCl3); IR (CHCl3, cmꢀ1): 740, 807,
927, 1035, 1099, 1179, 1248, 1367, 1452, 1513, 1612,
1726, 2860, 2934, 3228, 3300; 1H NMR (200 MHz,
CDCl3): d 2.37 (s, 3H), 3.66 (s, 3H), 3.74 (s, 3H), 4.58 (d,
J¼4.8 Hz, 1H), 5.41 (d, J¼4.8 Hz, 1H), 6.55–6.59 (m,
2H), 6.71–6.82 (m, 2H), 6.95–7.06 (m, 2H), 7.37–7.46 (m,
2H); 13C NMR (50 MHz, CDCl3): d 26.72, 55.24, 55.97,
62.43, 83.12, 114.16, 115.24, 115.76, 128.87, 129.19,
129.34, 137.77, 157.00, 204.55; Analysis: C19H19NO5 re-
quires C, 66.85; H, 5.61; N, 4.10; found C, 66.77; H, 5.56;
N, 4.04%.
References and notes
1. Kakeya, H.; Morishita, M.; Kobinata, K.; Osono, M.; Ishizuka,
M.; Osada, H. J. Antibiot. 1998, 51, 1126.
2. (a) Sakamoto, Y.; Shiraishi, A.; Seonhee, J.; Nakata, T. Tetra-
hedron Lett. 1999, 40, 4203; (b) Kakeya, H.; Morishita, M.;
Koshino, H.; Morita, T.; Kobayashi, K.; Osada, H. J. Org.
Chem. 1999, 64, 1052.
3. (a) Kim, J. D.; Kim, I. S.; Jin, C. H.; Zee, O. P.; Jung, Y. H. Org.
Lett. 2005, 7, 4025; (b) Lin, X.; Bentley, P. A.; Xie, H. Tetrahe-
dron Lett. 2005, 46, 7849; (c) Miyata, O.; Hashimoto, J.; Iba, R.;
Naito, T. Tetrahedron Lett. 2005, 46, 4015; (d) Tokic-Vujosevic,
Z.; Petrovic, G.; Rakic, B.; Matovic, R.; Saicic, R. N. Synth.
Commun. 2005, 35, 435; (e) Asano, M.; Nagasawa, C.; Suzuki,
M.; Nishiyama, S.; Sugai, T. Biosci. Biotechnol. Biochem. 2005,
69, 145; (f) Swamy, N. R.; Krishnaiah, P.; Reddy, N. S.; Venka-
teswarlu, Y. J. Carbohydr. Chem. 2004, 23, 217; (g) Boruwa, J.;
Borah, J. C.; Kalita, B.; Barua, N. C. Tetrahedron Lett. 2004, 45,
7355; (h) Miyata, O.; Koizumi, T.; Asai, H.; Iba, R.; Naito, T.
Tetrahedron 2004, 60, 3893; (i) Sugiyama, S.; Arai, S.; Ishii,
K. Tetrahedron: Asymmetry 2004, 15, 3149; (j) Milicevic, S.;
Matovic, R.; Saicic, R. N. Tetrahedron Lett. 2004, 45, 955; (k)
Ravi, K. A.; Bhaskar, G.; Madhan, A.; Venkateswara, R. B.
Synth. Commun. 2003, 33, 2907; (l) Carda, M.; Gonzalez, F.;
Sanchez, R.; Marco, J. A. Tetrahedron: Asymmetry 2002, 13,
1005; (m) Madhan, A.; Kumar, A. R.; Rao, B. V. Tetrahedron:
Asymmetry 2001, 12, 2009; (n) Miyata, O.; Asai, H.; Naito, T.
Synlett 1999, 1915.
4. (a) Matsunaga, S.; Yoshida, T.; Morimoto, H.; Kumagai, N.; Shi-
basaki, M. J. Am. Chem. Soc. 2004, 126, 8777; (b) Davies, S. G.;
Hughes, D. G.; Nicholson, R. L.; Smith, A. D.; Wright, A. J.
Org. Biomol. Chem. 2004, 2, 1549; (c) Carter, P. H.; LaPorte,
J. R.; Scherle, P. A.; Decicco, C. P. Bioorg. Med. Chem. Lett.
2003, 13, 1237; (d) Park, J. N.; Ko, S. Y.; Koh, H. Y. Tetrahedron
Lett. 2000, 41, 5553.
5. (a) Barta, N. S.; Sidler, D. R.; Somerville, K. B.; Weissman,
S. A.; Larsen, R. D.; Reider, P. J. Org. Lett. 2000, 2, 2821; (b)
Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999,
1, 783; (c) Pringle, W.; Sharpless, K. B. Tetrahedron Lett.
1999, 40, 5151; (d) Goossen, L. J.; Liu, H.; Dress, R.; Sharpless,
K. B. Angew. Chem., Int. Ed. 1999, 38, 1080; (e) Reiser, O.
Angew. Chem., Int. Ed. 1996, 35, 1308; (f) Kolb, H. C.; Sharpless,
4.15. Preparation of (4R,5S)-5-(hydroxymethyl)-4-(4-
methoxyphenyl)oxazolidin-2-one: (+)-epi-cytoxazone (2)
To a 1 M solution of lithium hexamethyldisilylamide
(1.6 ml, 1.6 mmol) at ꢀ78 ꢁC under an argon atmosphere
was added chlorotrimethylsilane (0.64 ml, 4.88 mmol) drop-
wise. A cold (ꢀ78 ꢁC) solution of oxazolidinone 23
(0.275 g, 0.8 mmol) in THF (2 ml) was then added dropwise.
After being stirred for 25 min at ꢀ78 ꢁC, the reaction mix-
ture was warmed to 0 ꢁC and stirred for 30 min and then con-
centrated in vacuum. After drying (MgSO4) and removal of
the solvent in vacuum, the crude silyl enol ether 24 was used
directly in the next step without further purification because
it partly rearranged to ketone 23 during attempted purifica-
tion. A solution of this crude silyl enol ether 24 in MeOH
(15 ml) and CH2Cl2 (10 ml) was cooled to ꢀ78 ꢁC, and
ozone was bubbled through this solution for 45 min. Triphe-
nylphosphine (0.223 g, 0.885 mmol) was added, and the re-
action mixture was warmed to room temperature and stirred
for 1 h. The reaction mixture was concentrated in vacuum,
and the residue was dissolved in absolute EtOH (4 ml),
CaCl2 (0.15 g, 1.35 mmol) and NaBH4 (0.16 g, 4 mmol)
was added, and the reaction mixture was stirred for
20 min at 25 ꢁC. The excess of reducing agent was de-
stroyed by the addition of satd NH4Cl (0.5 ml) and then
EtOH was evaporated; the residue was then dissolved in
CH3CN (5 ml) at 0 ꢁC which was then treated with cerium
ammonium nitrate (2.2 g, 4 mmol) in water (3 ml). The
mixture was stirred for 5 min, treated with 10 ml of satd
aq NaHCO3, warmed to 25 ꢁC, and treated with solid
Na2SO3 (0.126 g, 1 mmol). The reaction mixture was ex-
tracted with ethyl acetate (3ꢂ6 ml), dried, and concen-

5762
A. S. Paraskar, A. Sudalai / Tetrahedron 62 (2006) 5756–5762
K. B. In Transition Metals for Organic Synthesis; Beller, M.,
7. Jeffery, T. Tetrahedron Lett. 1991, 32, 2121.
8. (a) Hamerak, Z.; Ljubovic, E.; Mercep, M.; Mesic, M.; Sunjic,
V. Synthesis 2001, 1989; (b) Seki, M.; Mori, K. Eur. J. Org.
Chem. 1999, 2965.
Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 2, p 243.
6. (a) Li, G.; Chang, H. T.; Sharpless, K. B. Angew. Chem., Int. Ed.
1996, 35, 451; (b) Katsuki, T.; Sharpless, K. B. J. Am. Chem.
Soc. 1980, 102, 5974.
9. List, B. J. Am. Chem. Soc. 2000, 122, 9336.