Stereoselective synthesis of (+)-polyoxamic acid based on the synthesis of chiral oxazine

Article abstract of DOI:10.1039/b717961h

A concise, stereocontrolled synthesis of (+)-polyoxamic acid was achieved. Starting from trans-oxazoline as a chiral building block, the key step involves diastereoselective oxazine formation catalyzed by palladium(0). The Royal Society of Chemistry.

Full text of DOI:10.1039/b717961h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereoselective synthesis of (+)-polyoxamic acid based on the synthesis of
chiral oxazine†
Jae-Eun Joo,a Van-Thoai Pham,a Yong-Shou Tian,a Yun-Sung Chung,a Chang-Young Oh,b Kee-Young Leeb and
Won-Hun Ham*a
Received 20th November 2007, Accepted 28th January 2008
First published as an Advance Article on the web 6th March 2008
DOI: 10.1039/b717961h
A concise, stereocontrolled synthesis of (+)-polyoxamic acid was achieved. Starting from
trans-oxazoline as a chiral building block, the key step involves diastereoselective oxazine formation
catalyzed by palladium(0).
Introduction
Polyoxamic acid (1) is the key component amino acid of the
polyoxins,1 which have exhibited high inhibitory potencies against
chitin synthetase of Candida albicans, a human fungal pathogen,
and of various phytopathogenic fungi (Fig. 1).2 Inhibition of
the chitin synthetase enzyme leads to the disruption of the
biosynthesis of chitin, an essential component of the fungal cell
wall. A number of its synthetic approaches have been reported due
Scheme 1
to its three contiguous stereocenters and its interesting biological
isomers can be stereoselectively prepared by changing only the
activities.3,4 Many synthetic studies are based on carbohydrate
chemistry, the use of chiral auxiliaries or asymmetric synthesis in
the presence of a chiral ligand. Despite their potential practicality,
there remains the need for a more general, efficient and a
stereoselective approach to polyoxamic acid.
◦
reaction temperature; syn-3a–d under kinetic control (0 C) and
anti-3a–d under thermodynamic control (40 ◦C).
As part of this program, we developed a novel strategy for the
synthesis of (+)-polyoxamic acid that utilizes oxazine as a chiral
building block.
Results and discussion
We envisioned that the intramolecular palladium(0)-catalyzed
oxazine formation of benzamide 5 would generate the oxazine
4 bearing a pendant vinyl group that could be elaborated to the
alcohol as shown in Scheme 2. It was also anticipated that the
primary alcohol of 4 could be converted to carboxylic acid via
oxidation.
Fig. 1 (+)-Polyoxamic acid.
On the basis of our previous research, we anticipated that the
palladium(0)-catalyzed oxazine formation of a c-allyl benzamide
having a benzoyl substituent as an N-protection group in the
presence of Pd(PPh3)4, NaH and n-Bu4NI might proceed with
high stereoselectivity. Unlike other palladium catalyzed reactions,
the diastereoselectivity of oxazine ring formation is predominantly
controlled by the temperature.5
Our study into intramolecular oxazine formation from 2a–d
has shown that the stereoselectivity of these cyclizations can be
critically dependent upon whether the reaction temperature results
in kinetic or thermodynamic control of the products (Scheme 1).
Starting from allyl chlorides 2a–d, both syn-3a–d and anti-3a–d
Scheme 2 Retrosynthetic analysis.
We have recently developed an efficient preparation of trans-
oxazoline 6 in enantiopure form from D-N-benzoylserinol by
employing the palladium(0)-catalyzed intramolecular cyclization
reaction.6
The synthesis of 1 began with ozonolysis of 66c,6f to give the
desired allyl chloride 9 following the sequence of our previous
papers (Scheme 3).5,6c,6f
However, the preparation of allyl chloride 9 via 6 from D-N-
benzoylserinol was plagued by protecting group manipulations
and functional group interconversions, leading to synthetic in-
efficiency. Consequently, a new method for synthesizing 9 was
aCollege of Pharmacy, SungKyunKwan University, Suwon, 440-746, Korea.
E-mail: whham@skku.edu; Fax: 82 31 292 8800; Tel: 82 31 290 7706
bYonsung Fine Chemicals Co., Ltd., 129-9 Suchon-ri, Jangan-myeon,
Hwaseong-si, 445-944, Korea. E-mail: cyoh@yonsungchem.co.kr; Fax: 82
31 351 6621; Tel: 82 31 351 6624
† Electronic supplementary information (ESI) available: Synthetic and
characterization data for compounds 7–9, 11, 13–14 and 5. See DOI:
10.1039/b717961h
1498 | Org. Biomol. Chem., 2008, 6, 1498–1501
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Table 1 Oxazine formation catalyzed by Pd(0)
Entry
Substrate
Temp./◦C
Yielda (%)
Ratiob (syn–anti)
1
2
3
4
5
5
0
rt
50
0
84
75
68
65
69
9.5 : 1
3 : 1
1 : 9
1 : 1
10 : 1
5
5
15
16
Scheme 3
0
conceived (Scheme 4). The ester 10 was readily converted into
Weinreb amide 11 by treatment with N,O-dimethylhydroxylamine
in the presence of trimethylaluminium in 91% yield. Reaction◦of
Weinreb amide 11 with vinyltin 12 and MeLi in THF at −78 C
gave a,b-unsaturated ketone 13 in 86% yield. To investigate the
anti-selective reduction, amino ketone 13 was treated with various
reducing agents and we found that reaction with lithium tri-tert-
butoxyaluminohydride in ethanol at −78 ◦C gave the desired
alcohol 14 as the major compound in good yield (87%) with
excellent stereoselectivity (anti–syn = 10 : 1).7 A p-nitrobenzoic
acid-catalyzed Mitsunobu-type reaction of anti-amino alcohol 14
gave the trans-oxazoline 9 in good yield (89%). The spectroscopic
data of the resulting cyclization precursor 9 were completely
identical to those of the compound formed from oxazoline 6.
a Yields refer to the isolated and mixture products. b Ratio was determined
by 1H NMR.
9.5 : 1 mixture of the syn–anti isomer (1H NMR) in a good yield
(Table 1, entry 1). The reaction at rt showed lower selectivity,
where the syn–anti ratio was 3 : 1 (entry 2). But when the reaction
temperature was increased to 50 ◦C, the reaction showed a different
diastereoselectivity. The anti-4ꢀ was obtained as the major isomer
(1 : 9, entry 3). In the case of the less bulky PMB group, the
selectivity was not good (entry 4). The change of the protection
group of the primary alcohol did not affect the selectivity
(entry 5).
It is interesting that the palladium-catalyzed reaction was so
dependent on temperature. The stereochemistry of the major
diastereomer 4 was assumed to be syn in the light of our previous
results5,8 and was finally confirmed by its conversion into (+)-
polyoxamic acid.
Completion of the synthesis of (+)-polyoxamic acid is shown
in Scheme 5. The terminal olefin of the syn,syn oxazine 4
was converted into the primary alcohol 19 via ozonolysis and
Scheme 4
The subsequent acid-catalyzed hydrolysis of the oxazoline,
followed by the addition of sodium bicarbonate to increase the pH
of the reaction mixture to 9.0 furnished the syn-amino alcohol.
The protection of the resulting alcohols by TBSCl afforded the
cyclization precursor 5 in 89% yield.
Under the conditions of Pd(PPh3)4, NaH, and n-Bu4NI in
THF at 0 ◦C, the stereoselective intramolecular cyclization of
the allyl chloride 5 afforded the oxazine syn-4 and anti-4ꢀ as a
Scheme 5
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subsequent sodium borohydride reduction in 86% yield. The
oxazine ring was cleaved by treatment with Pd/C under a hydrogen
atmosphere in the presence of (Boc)2O and the diol was protected
as an acetonide to afford 20. Regioselective desilylation of the
primary alcohol to give alcohol 21 occurred by addition of a
HF–pyridine complex to a mixture of pyridine and the acetonide
20. The hydroxyl group was then oxidized to 22 with ruthenium
trichloride–sodium periodate in 91% yield. Finally, the acetonide,
TBS and Boc protecting groups were removed by treatment
with 6 N HCl in methanol, which was purified by ion-exchange
chromatography through a Dowex 50 W X8(H+) to give the (+)-
polyoxamic acid 1 as a white solid. The spectroscopic data for
synthetic 1 showed good agreement with those reported. The
optical rotation of 1, [a]2D5 +2.3◦ (c 1.0, H2O), compared to the
reported value,4 [a]D25 +2.1◦ (c 1.0, H2O), confirms the identity of
the absolute configuration.
4.71 (dd, J = 6, 1.5 Hz, 1H), 5.35 (d, J = 10 Hz, 1H), 5.48–5.52 (d,
J = 18 Hz, 1H), 6.00–6.07 (ddd, J = 18, 10, 6 Hz, 1H), 7.28–7.42
(m, 3H), 7.93–7.95 (m, 2H); 13C NMR (125 MHz, CDCl3) d
−4.90, −4.88, −4.01, −3.57, 18.28, 18.44, 18.52, 18.56, 25.95,
26.16, 26.26, 26.27, 60.22, 63.47, 64.84, 79.93, 118.05, 127.46,
128.17, 130.41, 133.90, 135.53, 155.56; HRMS(M+) m/z calcd for
C25H43NO3Si2 461.2781 found 461.2779.
((4R,5S,6R)-5-(tert-Butyldimethylsilyloxy)-4-((tert-butyldime-
thylsilyloxy)-methyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazin-6-yl)-
methanol (19). A solution of the oxazine 4 (520 mg, 1.13 mmol)
in methanol (40 mL) was cooled to −78 ◦C. Ozone was passed
through the solution until the starting material had been consumed
(TLC analysis). The resulting blue solution was purged with
oxygen for 10 min, and sodium borohydride (51 mg, 1.35 mmol)
was then added. After the mixture had been stirred at rt for
30 min, saturated aqueous NH4Cl was added. The reaction
mixture was extracted with EtOAc, and washed with brine, dried
over anhydrous MgSO4, and then concentrated under reduced
pressure, followed by purification by silica gel chromatography
affording alcohol 19 (451 mg, 86%) as a white solid; M.p. 157 ◦C;
[a]2D5 +3.57 (c 1.0, CHCl3); IR (neat) mmax: 2939, 2858, 1651, 1464,
Conclusions
In summary, we report a new asymmetric synthetic method for
(+)-polyoxamic acid utilizing oxazine 4. The key feature in this
strategy is the stereoselective intramolecular oxazine formation by
palladium(0).
1
1155, 839 cm−1; H NMR (500 MHz, CDCl3) d 0.10–0.18 (m,
12H), 0.84 (s, 9H), 0.96 (s, 9H), 3.52–3.55 (m, 1H), 3.70–3.74 (t, J
= 10.0 Hz, 1H), 3.79–3.82 (br, 1H), 3.87–3.91 (dd, J = 10.0, 5.0 Hz,
1H), 3.95–3.99 (dd, J = 11.0, 7.5 Hz, 1H), 4.29 (dd, J = 2.0, 1.0 Hz,
1H), 4.31–4.33 (ddd, J = 7.0, 6.0, 1.0 Hz, 1H), 7.35–7.43 (m, 3H),
7.88–7.90 (m, 2H); 13C NMR (125 MHz, CDCl3) d −4.88, −4.28,
−4.02, 18.53, 18.57, 25.97, 26.05, 26.21, 26.23, 26.26, 26.27, 60.11,
61.87, 63.09, 63.16, 79.69, 127.44, 128.21, 130.53, 133.84, 155.46;
HRMS (FAB+) (M+ + H) m/z calcd for C24H44NO4Si2 466.2809
found 466.2805.
Experimental
General methods
Optical rotations were measured on a JASCO DIP 1020 digital
polarimeter. 1H NMR spectra were recorded at Varian inova FT-
NMR 500 MHz in CDCl3. 13C NMR spectra were recorded at
125 MHz in CDCl3. Chemical shifts are reported as d values
in ppm relative to CHCl3 (7.26) in CDCl3. IR spectra were
measured on a Bruker FT-IR spectrometer. The high resolution
mass spectra (FAB-MS) were taken on a JMS-700 Mstation. Flash
chromatography was executed with Merck Kiesegel 60 (230–400
mesh) using mixtures of ethyl acetate and hexane as eluants.
Ethyl acetate and hexane were dried and purified by distillation
prior to use. Tetrahydrofuran (THF) and diethylether (Et2O) were
distilled over sodium and benzophenone (indicator). Methylene
chloride (CH2Cl2) was shaken with concentrated sulfuric acid,
dried over potassium carbonate, and distilled. Commercially
available compounds were used without further purification.
tert-Butyl (5S,6R)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2,
3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-ylcarba-
mate (20). A solution of compound 19 (300 mg, 0.64 mmol) in a
3 : 2 mixture of hexane and methanol (10 mL) was stirred at room
temperature for 12 h under an atmosphere of hydrogen in the
presence of a catalytic quantity of 20% palladium hydroxide on
charcoal (60 mg) and Boc2O (562 mg, 2.58 mmol). The catalyst
was then removed by filtration through Celite, and the solvents
were evaporated under reduced pressure. The resulting residue
was purified by silica gel chromatography (ethyl acetate–hexane
= 1 : 8) to afford a diol (235 mg, 77%) as a white solid.
(4R,5S,6S)-5-(tert-Butyldimethylsilyloxy)-4-((tert-butyldime-
thylsilyloxy)-methyl)-2-phenyl-6-vinyl-5,6-dihydro-4H-1,3-oxazine
(4). NaH (60% in mineral oil, 64 mg, 1.61 mmol) and n-Bu4NI
(263 mg, 0.80 mmol) were added to a stirred solution of allyl
chloride 5 (400 mg, 0.80 mmol) in dry THF (30 mL) at 0 ◦C. After
being stirred for 5 min, Pd(PPh3)4 (186 mg, 0.16 mmol) was added
to the mixture and stirring was allowed to continue for 12 h at
the same temperature. The reaction mixture was filtered through
a pad of silica and then evaporated under reduced pressure to
give the crude product. Purification of this material by silica gel
chromatography (ethyl acetate–hexane = 1 : 30) gave 4 (320 mg,
2,2-Dimethoxypropane (0.48 mL, 3.91 mmol) and pyridinium
p-toluenesulfonate (12 mg, 0.049 mmol) were added to a stirred
solution of the diol (235 mg, 0.49 mmol) in dry acetone (5 mL) at
rt. After being stirred for 1 h, the reaction mixture was evaporated
in vacuo, diluted with H2O (10 ml), extracted with ethyl acetate,
dried with MgSO4, and evaporated in vacuo. Purification of this
material by silica gel chromatography (ethyl acetate–hexane = 1 :
15) gave acetonide 20 (218 mg, 86%) as a colorless oil; [a]2D5 +1.55
(c 1.0, CHCl3); IR (neat) mmax: 3452, 2930, 2858, 1719, 1493, 1254,
836 cm−1; 1H NMR (CDCl3, 500 MHz) d 0.06 (s, 3H), 0.07 (s, 3H),
0.11 (s, 3H), 0.15 (s, 3H), 0.88–0.92 (m, 18H), 1.35 (s, 3H), 1.40 (s,
3H), 1.45 (s, 9H), 3.42–3.48 (m, 2H), 3.51–3.55 (m, 2H), 3.94–3.96
(m, 1H), 4.04–4.08 (m, 2H), 4.78 (d, J = 8.5 Hz, 1H-NH); 13C
NMR (125 MHz, CDCl3) d −5.16, −5.09, −4.85, −3.71, 18.26,
18.68, 25.88, 26.01, 26.34, 26.76, 28.59, 53.42, 61.64, 66.59, 72.27,
84%) as a colorless oil; [a]2¦ 5 +14.0 (c 1.0, CHCl3); IR (neat)
D
2954, 2929, 2885, 2857, 1660, 1472, 1282, 1255, 1115, 836, 776,
1
696 cm−1; H NMR (500 MHz, CDCl3) d 0.07–0.14 (m, 12H),
0.83–0.97 (m, 18H), 3.59 (m, 1H), 3.71–3.75 (t, J = 10 Hz, 1H),
3.87–3.90 (dd, J = 10, 5 Hz, 1H), 4.20 (dd, J = 2, 1.5 Hz, 1H),
1500 | Org. Biomol. Chem., 2008, 6, 1498–1501
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78.21, 79.61, 109.37, 155.64; HRMS (FAB+) (M+ + H) m/z calcd
for C25H54NO6Si2 520.3490 found 520.3491.
58.09, 62.52, 68.21, 73.25, 172.97; MS m/z calcd for C5H12NO5
(M+ + H) 165.07 found 165.1.
tert-Butyl (1S,2R)-1-(tert-butyldimethylsilyloxy)-1-((S)-2,2-di-
methyl-1,3-dioxolan-4-yl)-3-hydroxypropan-2-ylcarbamate (21).
To a solution of◦compound 20 (218 mg, 0.42 mmol) in THF
(5 mL) held at 0 C under argon was added pyridine (0.31 mL)
and HF–pyridine complex (0.31 mL). After 30 min of stirring
at 0 ◦C, the reaction mixture was gradually allowed to come to
room temperature over 3 h. It was then diluted with ethyl acetate
(10 mL) and washed with water (10 mL × 2). The organic phase
was dried over MgSO4 and evaporated to dryness. The resulting
oily residue was purified by flash chromatography on silica gel
(ethyl acetate–hexane = 8 : 1) to afford alcohol 21 (159 mg,
94%) as an oil. [a]2D5 +6.5 (c 1.0, CHCl3); IR (neat) 3447, 2981,
2954, 2931, 2887, 2858, 1716, 1697, 1497, 1368, 1253, 1170,
1059, 835, 778 cm−1; 1H NMR (300 MHz, CDCl3) d 0.17 (s, 6H),
0.95 (s, 9H), 1.40 (s, 3H), 1.46 (s, 3H), 1.49 (s, 9H), 3.53 (dd,
J = 11.0, 6.0 Hz, 1H), 3.65 (m, 1H), 3.79 (t, J = 7.8 Hz, 1H),
3.95–3.85 (m, 2H), 4.08 (t, J = 7.0 Hz, 1H), 4.21 (dd, J = 11.0,
7.0 Hz, 1H), 5.22 (d, J = 8.1 Hz, 1H); 13C NMR (125 MHz,
CDCl3) d −4.36, −4.19, 18.44, 26.03, 26.07, 26.15, 26.49,
28.62, 53.84, 60.76, 66.45, 71.21, 75.72, 79.91, 109.94, 156.06;
HRMS (M+ + H) m/z calcd for C19H40NO6Si 406.2625 found
406.2624.
Acknowledgements
This work was financially supported by Yonsung Fine Chemicals
Co., Ltd., and Seoul R & BD Program (10541).
Notes and references
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(2S,3S)-2-(tert-Butoxycarbonylamino)-3-(tert-butyldimethyl-
silyloxy)-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)propanoic
acid
(22). To a solution of alcohol 21 (879 mg, 2.17 mmol) in carbon
tetrachloride (15 mL), acetonitrile (15 mL) and water (23 mL)
was added sodium periodate (2.78 mg, 13 mmol) and the mixture
was stirred. After 5 min, RuCl3 (67 mg, 0.32 mmol) was added
and the stirring was continued at room temperature for 6 h. The
mixture was filtered and the residue was washed with ethyl acetate
(50 mL), washed with brine, dried and evaporated. The resulting
residue was purified by flash chromatography on silica gel (ethyl
acetate–hexane = 1 : 1) to afford the pure acid 22 (823 mg, 91%);
[a]2D5 +8.6 (c 1.0, CHCl3); IR (neat) 3450, 2931, 2857, 1718, 1503,
4 A. K. Saksena, R. G. Lovey, V. M. Girijavallabhan and A. K. Ganguly,
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1369, 1254, 1161, 1115, 1069, 834 cm−1; H NMR (300 MHz,
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62, 333; (d) Y.-S. Lee, Y.-H. Shin, Y.-H. Kim, K.-Y. Lee, C.-Y. Oh, S.-J.
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CDCl3) d 0.15–0.21 (m, 6H), 0.93 (s, 9H), 1.39 (s, 3H), 1.47 (s,
3H), 1.51 (s, 9H), 3.75 (m, 1H), 4.18–4.07 (m, 2H), 4.28 (m, 2H),
5.30 (d, J = 8.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) d −5.03,
−3.96, 18.42, 25.69, 26.04, 26.71, 28.52, 31.21, 55.94, 66.18, 74.71,
80.76, 109.93, 156.04, 175.41; HRMS(FAB) (M+ + H) m/z calcd
for C19H38NO7Si 420.2418 found 420.2417.
(2S,3S,4S)-2-Amino-3,4,5-trihydroxypentanoic acid ((+)-poly-
oxamic acid, 1). To the acid 22 (134 mg, 0.32 mmol) in MeOH
(3 mL) was added 6 N HCl and the mixture was kept at room
temperature for 5 h. After concentration under reduced pressure,
the residue was dissolved in aqueous ammonium hydroxide (0.6 M;
2 mL) and chromatographed through a column of Dowex 50 W
X8 (H+) to give polyoxamic acid 1 (49 mg, 92%): [a]2D5 +2.3◦ (c
1.0, H2O), mp 161–165 ◦C (dec); (lit.4 [a]D25 +2.1◦ (c 1.0, H2O), mp
162–168 ◦C (dec); 1H NMR (300 MHz, D2O) d 3.76–3.72 (m, 2H),
3.98–3.95 (m, 2H), 4.29 (m, 1H); 13C NMR (125 MHz, D2O) d
7 (a) V.-T. Pham, J.-E. Joo, Y. S. Tian, C.-Y. Oh and W.-H. Ham, Arch.
Pharm. Res., 2007, 30, 22; (b) R. V. Hoffman, N. Maslouh and F. C. Lee,
J. Org. Chem., 2002, 67, 1045.
8 Compound 4 has almost similar TLC and 1H NMR patterns to a
previously reported benzyl oxazine compound. Protons of the terminal
olefin and H5 have peaks at 6.0 and 4.2 ppm. In addition, the coupling
constant of the newly generated chiral center (H5–H6) of compound 4
has the same value, 1.5 Hz, as all syn-oxazine compounds previously
reported.
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The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 1498–1501 | 1501
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