Asymmetric synthesis of (+)-epi-cytoxazone

Article abstract of DOI:10.1080/00397910600619499

The asymmetric synthesis of (+)-epi-cytoxazone, a stereoisomer of potent cytokine modulator cytoxazone, starting from anisaldehyde in six steps, is described. The required configuration was established via Sharpless kinetic resolution followed by the Mits

Full text of DOI:10.1080/00397910600619499

Synthetic Communicationsw, 36: 1795–1800, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600619499
Asymmetric Synthesis of (1)-epi-
Cytoxazone
G. Smitha and C. Sanjeeva Reddy
Department of Chemistry, Kakatiya University, Warangal, India
Abstract: The asymmetric synthesis of (þ)-epi-cytoxazone, a stereoisomer of potent
cytokine modulator cytoxazone, starting from anisaldehyde in six steps, is described.
The required configuration was established via Sharpless kinetic resolution followed
by the Mitsunobu reaction.
Keywords: Asymmetric synthesis, cytoxazone, Mitsunobu reaction, Sharpless kinetic
resolution
Cytoxazone 1 is a microbial metabolite isolated from Streptomyces sp., which
has been identified as a potent cytokine modulator.[1] Because of its potent
biological activity, the development of efficient routes to cytoxazone and its
stereoisomers has been a new subject of interest. A variety of synthetic
routes to cytoxazone have been reported, including chemoenzymatic resol-
ution,[2] Sharpless asymmetric dihydroxylation,[3] asymmetric amino
hydroxylation,[4] imino-Wittig rearrangement,[5] asymmetric aldol
reaction,[6] addition of Grignard reagents to protected imine,[7] and others.[8]
The stereo isomer of 1,-epi-cytoxazone 2, has also been synthesized using
different routes.[9] Herein we report the asymmetric synthesis of (þ)-epi-
cytoxazone starting from a commercially available anisaldehyde (Scheme 1).
Received in India December 12, 2005
Address correspondence to C. Sanjeeva Reddy, Department of Chemistry, Kakatiya
University, Warangal 506 009, India. E-mail: chsrkuc@yahoo.co.in
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G. Smitha and C. S. Reddy
Anisaldehyde 3 was treated with vinyl magnesium bromide to give the
allyl alcohol 4. The enantioselective epoxidation of the racemic allyl
alcohol 4 gave, in the presence of L-diisopropyl tartarate, the epoxy alcohol
5 in 46% yield.[10] The epoxy alcohol 5 was subjected to a Mitsunobu
reaction, in which hydrazoic acid served as an azide nucleophile and gave
the epoxy azide 6 in 91% yield.[10] Next, opening of the epoxide ring by
treatment with aqueous sodium hydroxide in tert-butanol furnished the
azido diol 7. Reduction of azide 7 to amine and subsequent protection of
amine as tert-butyl carbonate 8 was achieved in a one-pot reaction using
PMHS-Pd/C conditions in the presence of di-tert-butyl dicarbonate.[11]
Intramolecular cyclization of compound 8 in the presence of NaH in THF
gave (þ)-5-epi-cytoxazone 2, whose spectral data was in agreement with
the literature data.[2]
In conclusion, the asymmetric synthesis of (þ)-5-epi-cytoxazone was
achieved from anisaldehyde in six steps and in 32% overall yield.
EXPERIMENTAL
General
All the reagents were purchased from Aldrich or SD Fine Chemicals and were
used without further purification. Crude products were purified by column
1
chromatography on 60–120 mesh silica gel. H NMR and 13C NMR spectra
were obtained in CDCl3, chemical shifts are given in parts per million
(ppm) with respect to internal TMS, and J values are quoted in Hertz. IR
Scheme 1. Reagents and conditions: (a) 1M vinyl magnesium bromide in THF, dry
ether, 08C,4 h, 96%; (b) diisopropyl L-tartarate, Ti(iPrO)4, tert-butyl hydroperoxide,
CH2Cl2, 2208C, 14 h, 46%; (c) PPh3, diisopropyl azadicarboxylate, HN3, benzene,
08C, 1 h, 91%; (d) 0.5 M aq. NaOH, t-BuOH, 758C, 5 h, 92%; (e) PMHS, 10% Pd/C,
di-tert-butyl dicarbonate, EtOH, rt, 4 h, 90%; (f) NaH, dry THF, rt, 2.5 h, 95%.

Asymmetric Synthesis of (1)-epi-Cytoxazone
1797
spectra were obtained neat, and only the most significant absorptions in cm21
are indicated. The molecular ions and/or base peaks in MS are given.
1-(4-Methoxyphenyl)prop-2-en-1-ol (4)[12]
Vinyl magnesium bromide (55 mL of 1 M solution in THF, 55.1 mmol) was
added to a solution of anisaldehyde (5 g, 36.7 mmol) in dry THF (150 mL)
at 08C under nitrogen atmosphere, and the mixture was stirred for 4 h. After
the Grignard complex was decomposed with ice water (50 mL), the mixture
was extracted with ethyl acetate (150 mL) and the organic layer was washed
with brine (50 mL) and dried over Na2SO4. After evaporation of volatiles,
the crude product was purified by silica-gel column chromatography to give
1
the allyl alcohol 4 in 96% yield (5.8 g). H NMR (CDCl3, 400 MHz): d 7.29
(d, J ¼ 8.4 Hz, 2H), 6.88 (d, J ¼ 8.4 Hz, 2H), 6.09–6.0 (m, 1H), 5.34
(d, J ¼ 17.2 Hz, 1H), 5.18 (d, J ¼ 10 Hz, 2H), 3.8 (s, 3H); 13C NMR
(CDCl3, 100 MHz): d 159.23, 140.43, 134.93, 127.68 (2C), 114.71, 113.97
(2C), 74.85, 55.29; HRMS (ESI): calcd. for C10H12O2 187.0734 (M þ Na)þ,
found 187.0739.
(S)-(4-Methoxyphenyl)[(2R)-oxiran-2-yl]methanol (5)
The racemic alcohol 4 (5 g, 30.48 mmol) was dissolved in dry CH2Cl2
(100 mL), and then diisopropyl L-tartarate (4.28 g, 18.3 mmol) was added.
The mixture was cooled under N2 to 2208C. Titanium tetraisopropoxide
(4.33 g, 15.2 mmol) was added, and the mixture was stirred for 15 min at
2208C. Then anhydrous tert-butyl hydroperoxide (5.5 mL, 60.97 mmol) was
added. The mixture was left at 2208C overnight. The reaction mixture was
then diluted with Et2O (250 mL) and poured into an ice-cooled solution of
ferrous sulfate (15 g) in 10% aqueous tartaric acid (50 mL). The mixture
was then stirred for 1 h, and then the organic phase was decanted, dried
(Na2SO4), and concentrated. Column chromatography of the residue gave
1
the epoxide 5 (2.52 g, 46%). [a]2D5 ¼ þ74.51 (c 1.65, CHCl3); H NMR
(CDCl3, 400 MHz): d 7.32 (d, J ¼ 8.4 Hz, 2H), 6.91 (d, J ¼ 8.4 Hz, 2H), 4.9
(s, 1H), 3.81 (s, 3H), 3.2 (bs, 1H), 2.97 (bs, 1H), 2.78 (t, J ¼ 4.4 Hz, 1H);
13C NMR (CDCl3, 100 MHz): d 159.61, 131.68, 127.8 (2C), 114.02 (2C),
70.59, 55.29, 55.07, 43.69; HRMS (ESI): calcd. for C10H12O3 203.0683
(M þ Na)þ, found 203.0676.
(2S)-2-[(R)-azido(4-Methoxyphenyl)methyl]oxirane (6)
The epoxide 5 (2.2 g, 12.22 mmol) and PPh3 (6.4 g, 24.44 mmol) were
dissolved in benzene (30 mL). The solution was cooled in an ice bath, and

1798
G. Smitha and C. S. Reddy
then diisopropyl azodicarboxylate (4.94 g, 24.44 mmol) and anhydrous
hydrazoic acid (0.68 g, 15.8 mmol) were successively added, with stirring.
The mixture was stirred for 1 h at room temperature, and then it was diluted
with hexane (100 mL) and washed with 80% aqueous MeOH (2ꢀ5 mL).
Concentration of the benzene/hexane solution and column chromatography
of the residue gave pure 6 (2.28 g, 91%). [a]2D5 ¼ 226.41 (c 1.4, CHCl3);
1H NMR (CDCl3, 400 MHz): d 7.31 (d, J ¼ 8.4 Hz, 2H), 6.93 (d, J ¼ 8.4 Hz,
2H), 4.23 (d, J ¼ 5.6 Hz, 1H), 3.82 (s, 3H), 3.25 (bs, 1H), 2.84–2.79
(m, 2H); 13C NMR (CDCl3, 100 MHz): d 160.0, 128.66 (2C), 114.34 (2C),
66.34, 55.26, 54.71, 44.76; IR (neat): 3370, 2107, 1611, 1513, 1247,
1042 cm21; HRMS (ESI): calcd. for C10H11N3O2 206.0930 (M þ H)þ,
found 206.0938.
(2S,3R)-3-azido-3-(4-Methoxyphenyl)propane-1,2-diol (7)
Compound 6 (1.6 g, 7.8 mmol) was dissolved in 50 mL of t-BuOH. To this
solution were added 5 mL 0.5 M NaOH and 15 mL of distilled water. The
clear reaction mixture was stirred at 758C for 8 h and then extracted by
EtOAc (2 ꢀ 60 mL). The organic layer was evaporated at reduced pressure
to give 1.6 g (92%) of 7. [a]2D5 ¼ 2190.58 (c 1.39, CHCl3); 1H NMR
(CDCl3, 400 MHz): d 7.26 (d, J ¼ 7.6 Hz, 2H), 6.92 (d, J ¼ 7.6 Hz, 2H),
4.58 (d, J ¼ 8.4 Hz, 1H), 3.82 (s, 4H), 3.55–3.52 (m, 1H), 3.36–3.34
(m, 1H), 2.72 (bs, 1H); 13C NMR (CDCl3, 100 MHz): d 159.98, 128.91
(2C), 128.02, 114.43 (2C), 75.0, 67.98, 62.85, 55.31; IR (neat): 3370, 2918,
2099, 1612, 1513, 1189, 1031 cm21; HRMS (ESI): calcd. for C10H13N3O3
246.0854 (M þ Na)þ, found 246.0848.
(2S,3R)-3-tert-Butoxycarbonylamino-3-(4-Methoxyphenyl)propane-
1,2-diol (8)[8b]
To a solution of azide 7 (0.6 mg, 3.58 mmol) in ethyl alcohol (25 mL) was added
10% Pd-C (ꢀ15 mg), polymethylhydrosiloxane (0.64 mg, 10.76 mmol), and
di-t-butyl dicarbonate (0.86 g, 3.94 mmol). After stirring for 4 h, the reaction
mixture was filtered, and the filtrate was evaporated in vacuo. The residue
was chromatographed on silica gel to the corresponding NHBoc diol 8 in
90% yield (0.95 g). [a]D25 ¼ 226.84 (c 1.33, CHCl3); 1H NMR (CDCl3,
500 MHz): d 7.22 (d, J ¼ 8.5 Hz, 2H), 6.87 (d, J ¼ 8.5 Hz, 2H), 5.36 (br s,
1H), 4.74 (br s, 1H), 3.88 (br s, 1H), 3.79 (s, 3H), 3.55–3.49 (m, 2H), 3.13
(br s, 1H), 3.02 (br s, 1H) 1.42 (s, 9H); 13C NMR (CDCl3, 125 MHz): d
158.83, 156.64, 132.8, 127.83 (2C), 114.15 (2C), 80.4, 75.3, 63.91, 55.52
(2C), 28.66 (3C); IR (neat): 3384, 2975, 1686, 1613, 1513, 1168, 1034 cm21
HRMS (ESI): calcd. for C15H23NO5 320.1473 (M þ Na)þ, found 320.1468.
;

Asymmetric Synthesis of (1)-epi-Cytoxazone
1799
(4R, 5S)-5-Hydroxymethyl-4-(4-Methoxyphenyl)oxazolidin-2-one
(2)[2]
To a solution of diol 8 (0.6 g, 2.02 mmol) in dry THF (20 mL) was added
sodium hydride (0.1 g, 60% w/w, 4.04 mmol) at room temperature, and the
mixture was stirred under nitrogen atmosphere for 2.5 h. The reaction
mixture was concentrated, ethyl acetate (20 mL) was added, and washed
with saturated aq. NH4Cl (10 mL) and brine solution (10 mL). The organic
layer was separated, dried over Na2SO4, and concentrated. The crude
product was purified by column chromatography to give 2 as a white solid
(0.43 g, 95% yield). [a]2D5 ¼ þ28.62 (c 1.22, MeOH); H NMR (acetone-d6,
1
500 MHz): d 7.35 (d, J ¼ 8.5 Hz, 2H), 6.98 (d, J ¼ 8.5 Hz, 2H), 4.8
(d, J ¼ 6.5 Hz, 1H), 4.35 (t, J ¼ 6 Hz, 1H), 4.28–4.26(m, 1H), 3.86-3.83
(m, 1H), 3.82 (s, 3H), 3.75–3.7 (m, 1H); 13C NMR (acetone-d6, 125 MHz):
d 159.5, 157.89, 132.88, 127.42 (2C), 114.11 (2C), 84.8, 61.74, 56.99,
54.93; IR (neat): 3386, 2965, 1742, 1514, 1248, 1030 cm21; HRMS (ESI):
calcd. for C11H13NO4 224.0924 (M þ H)þ, found 224.0909.
ACKNOWLEDGMENTS
Authors are thankful to S. Chandrasekhar, Indian Institute of Chemical
Technology (IICT), India, for helpful discussions.
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