Practical synthesis of a key intermediate for lactacystin from (R)-4-hydroxymethyl-2-phenyl-4,5-dihydrooxazol-4-ylmethyl acetate

Article abstract of DOI:10.1248/cpb.56.738

A practical synthesis of a key intermediate for the proteasome inhibitor lactacystin from (R)-4-hydroxymethyl-2-phenyl-4,5-dihydrooxazol-4-ylmethyl acetate was established. (R)-4-Hydroxymethyl-2-phenyl-4,5-dihydrooxazol-4- ylmethyl acetate is a useful chiral building block for the synthesis of biologically active compounds containing α-substituted α-amino acid moieties.

Full text of DOI:10.1248/cpb.56.738

738
Notes
Chem. Pharm. Bull. 56(5) 738—741 (2008)
Vol. 56, No. 5
Practical Synthesis of a Key Intermediate for Lactacystin from (R)-4-
Hydroxymethyl-2-phenyl-4,5-dihydrooxazol-4-ylmethyl Acetate
Hiroaki MIYAOKA,* Makoto YAMANISHI, Ayako HOSHINO, Hidemichi MITOME,1) and
Etsuko KAWASHIMA
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences; 1432–1 Horinouchi, Hachioji, Tokyo 192–0392,
Japan. Received January 23, 2008; accepted February 19, 2008; published online February 19, 2008
A practical synthesis of a key intermediate for the proteasome inhibitor lactacystin from (R)-4-hydroxy-
methyl-2-phenyl-4,5-dihydrooxazol-4-ylmethyl acetate was established. (R)-4-Hydroxymethyl-2-phenyl-4,5-dihy-
drooxazol-4-ylmethyl acetate is a useful chiral building block for the synthesis of biologically active compounds
containing a-substituted a-amino acid moieties.
Key words lactacystin; formal synthesis; a-substituted a-amino acid; chiral building block; proteasome inhibitor
Natural products containing highly functionalized a-sub- ester 3 was confirmed to be ꢁ99% ee, as determined by
stituted a-amino acid moieties have recently been isolated HPLC analysis using the chiral column CHIRALPAK AS®
and shown to display interesting biological activity.2—5) Lac- (hexane : 2-propanolꢂ93 : 7). The primary hydroxy group in
tacystin, isolated from the culture broth of Streptomyces sp. 3 was protected as a tert-butyldimethylsilyl (TBS) ether fol-
¯
OM-6519 by Omura et al. in 1991, is an a-substituted a- lowed by diisobutylaluminium hydride (DIBAL-H) reduction
41)
amino acid derivative which first attracted interest given its in the presence of BF3·OEt2 to afford allylic alcohol 4.
ability to inhibit cell proliferation and induce nerve out-
growth in mouse neuroblastoma cells.6,7) Given that the cellu-
lar target of lactacystin is the 20S proteasome, lactacystin has
been used as a tool in the study of proteasome function.8—16)
Numerous attempts have been made to achieve the total syn-
thesis of lactacystin given its structural features and potential
biological significance. Since the first total synthesis of lacta-
cystin was reported by Corey and Reichard in 1992,17) a lot
of total and formal syntheses of lactacystin have been re-
ported.17—38)
The authors recently reported on the development of a use-
ful new chiral building block 1, (R)-4-hydroxymethyl-2-
phenyl-4,5-dihydrooxazol-4-ylmethyl acetate, employed in
Chart 1. Synthetic Strategy for Lactacystin
the synthesis of a-substituted a-amino acid derivatives using
lipase-catalyzed asymmetrization of prochiral diol. Chiral
building block 1 was efficiently converted to (R)-2-(hydroxy-
methyl)glutamic acid and a synthetic intermediate of (ꢀ)-
deoxydysibetaine.39) In this paper, the authors report on the
efficient formal synthesis of lactacystin using chiral building
block 1.
Results and Discussion
Our strategy outlining the synthesis of lactacystin is pre-
sented in Chart 1. Kang and coworkers reported on the syn-
thesis of lactacystin by introduction of an isopropyl unit to
lactam ester 2.25) Therefore, the authors synthesize lactam
ester 2, Kang’s synthetic intermediate, from chiral building
block 1. Lactam ester 2 is likely to be converted from dihy-
drooxazole A through hydrolysis of the dihydrooxazole moi-
ety and formation of a lactam ring. Dihydrooxazole A is syn-
thesized by diastereoselective introduction of a propionyl
unit to chiral building block 1 at the C-6 position.40)
Reagents and conditions: (a) (i) TBSCl, imidazole, DMF, rt, 98%, (ii) DIBAL-H,
Introduction of a propionyl unit at the C-6 position in 1
was achieved using a,b-unsaturated ester 3 (Chart 2). Chiral
building block 1 (ꢁ99% ee) was converted to (E)-a,b-unsat-
urated ester 3 by Swern oxidation, followed by a Horner–
Wadsworth–Emmons reaction and subsequent ethanolysis of
the acetate.39) The enantiomeric excess of a,b-unsaturated
BF3·OEt2, CH2Cl2, ꢀ78 °C to rt, 74%; (b) TBHP, D-(ꢀ)-DET, Ti(OiPr)4, MS, CH2Cl2,
ꢀ20 °C, 93%; (c) Me2CuLi, Et2O, ꢀ20 °C, 99%; (d) (i) TEMPO, NaClO, KBr,
NaHCO3, acetone, 0 °C, (ii) NaClO2, 2-methylbut-2-ene, NaH2PO4, tBuOH–H2O, 0 °C,
(iii) 1 M HCl, EtOH, 80 °C, 58% (three steps); (e) (i) TEMPO, BAIB, H2O–CH2Cl2, rt,
(ii) CH2N2, THF, 0 °C, 67% (two steps); (f) (i) K2CO3, MeOH, rt, (ii) TsOH, acetone,
rt, 60% (two steps).
Chart 2
∗ To whom correspondence should be addressed. e-mail: miyaokah@ps.toyaku.ac.jp
© 2008 Pharmaceutical Society of Japan

May 2008
739
C21H32NO4Si: MꢃꢃH, 390.2101); Anal. Calcd for C21H31NO4Si: C, 64.75;
H, 8.02; N, 3.60. Found: C, 64.76; H, 7.98; N, 3.70.
DIBAL-H reduction of a,b-unsaturated ester 3 in the ab-
sence of BF3·OEt2 resulted in a mixture comprising allylic
alcohol 4 and the reduced alcohol derived from reduction of
the carbon–carbon double bond in 4. Asymmetric epoxida-
tion of allylic alcohol 4 according to Sharpless’ procedure42)
gave epoxyalcohol 5. The diastereomer of epoxyalcohol 5
was not obtained. Epoxyalcohol 5 was treated with Me2CuLi
in Et2O to give 1,3-diol 6 as the sole product. The high re-
gioselectivity of epoxide-opening methylation was facilitated
To a cold (ꢀ78 °C) solution of the above TBS ether (331 mg, 849 mmol)
in CH2Cl2 (4.25 ml) was added BF3·OEt2 (139 ml, 1.10 mmol) and the mix-
ture was stirred for 30 min at the same temperature. DIBAL-H (2.19 ml,
2.12 mmol, 0.97 M in hexane) was added at ꢀ78 °C and the reaction mixture
was warmed to rt over 2 h. MeOH was added, the mixture was diluted with
Et2O and then an excess of Na2SO4·10H2O was added. After stirring at rt
for 8 h, the organic layer was dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by silica gel column chro-
matography (hexane : AcOEtꢂ2 : 1) to give allylic alcohol 4 (217 mg, 74%
by steric hindrance due to the dihydrooxazole ring. Given the yield) as a colorless oil: [a]D25 ꢀ36.4° (cꢂ1.30, CHCl3); IR (neat) cmꢀ1
:
1
3304, 2953, 2929, 2856, 1646, 1580, 1496; H-NMR (400 MHz, CDCl3) d:
7.95 (2H, m), 7.47 (1H, m), 7.40 (2H, m), 5.95 (2H, m), 4.58 (1H, d,
Jꢂ8.1 Hz), 4.18 (2H, m), 4.17 (1H, d, Jꢂ8.1 Hz), 3.70 (2H, t, Jꢂ10.3 Hz),
1.52 (1H, br t, Jꢂ5.9 Hz), 0.82 (9H, s), 0.05 (3H, s), ꢀ0.01 (3H, s); 13C-
NMR (100 MHz, CDCl3) d: 164.1, 132.5, 131.3, 130.2, 128.3, 128.2, 127.8,
75.5, 74.4, 68.0, 63.3, 25.7, 18.1, ꢀ5.3, ꢀ5.4; ESI-MS m/z: 348 (MꢃꢃH,
100); HR-ESI-MS m/z: 348.1969 (Calcd for C19H30NO3Si: MꢃꢃH,
348.1995); Anal. Calcd for C19H29NO3Si: C, 65.67; H, 8.41; N, 4.03. Found:
C, 65.64; H, 8.42; N, 4.01.
successful introduction of a C3 unit at the C-6 position, for-
mation of the lactam was then considered.
Selective oxidation of the primary hydroxy group in 1,3-
diol 6 was achieved by treatment with 2,2,6,6-tetramethyl-1-
piperodinyloxyl (TEMPO) and NaClO to give the alde-
hyde.43) The aldehyde was then oxidized with NaClO2 to give
the carboxylic acid, and subsequent hydrolysis of the dihy-
drooxazole ring by treatment with 1 M HCl afforded lactam 7.
The primary hydroxy group in lactam 7 was oxidized by
TEMPO and bis(acetoxy)iodobenzene (BAIB) to give the
carboxylic acid,44) and subsequent esterification of the car-
boxylic acid by treatment with CH2N2 afforded methyl ester
8. Methanolysis of the benzoate in 8 with K2CO3 in MeOH
gave the diol, which was then subjected to acetonization
using TsOH in acetone to give lactam ester 2, [a]D25 ꢃ10.2°
(cꢂ0.38, CHCl3) [lit.32) [a]D25 ꢃ9.1° (cꢂ1.08, CHCl3)],
which is Kang’s intermediate25,32) for the synthesis of lacta-
cystin.
{(2R,3R)-3-[(4R)-4-(tert-Butyldimethylsilanyloxymethyl)-2-phenyl-4,5-
dihydrooxazol-4-yl]oxiranyl}methanol (5) To a cold (ꢀ20 °C) suspen-
sion of 4A molecular sieves (3.60 g) in CH2Cl2 (64.1 ml) was added D-(ꢀ)-
DET (450 ml, 2.63 mmol), Ti(OiPr)4 (560 ml, 1.88 mmol) and TBHP
(4.98 ml, 56.4 mmol, 11.34 M in CH2Cl2). After stirring for 10 min at the
same temperature, a solution of allylic alcohol 4 (6.54 g, 18.8 mmol) in
CH2Cl2 (30.0 ml) was added over 30 min. Following stirring at ꢀ20 °C for
5 h, NaOH (3.01 ml, 30% in saturated aqueous NaCl) was added. The mix-
ture was diluted with Et2O, warmed to rt and stirred for 10 min. MgSO4
(2.68 g) and Celite (334 mg) were then added and after stirring for 15 min
the mixture was filtered through a Celite pad and the filtrate was concen-
trated under reduced pressure. The residue was purified by silica gel column
chromatography (hexane : AcOEtꢂ2 : 1) to give epoxyalcohol 5 (6.33 g, 93%
The formal synthesis of lactacystin from chiral building yield) as a colorless oil: [a]D25 ꢃ18.4° (cꢂ1.05, CHCl3); IR (neat) cmꢀ1
:
1
3366, 2953, 2929, 2857, 1646, 1580, 1496; H-NMR (400 MHz, CDCl3) d:
7.90 (2H, m), 7.47 (1H, m), 7.38 (2H, m), 4.45 (1H, d, Jꢂ8.7 Hz), 4.30 (1H,
d, Jꢂ8.7 Hz), 3.95 (1H, ddd, Jꢂ2.4, 5.3, 12.7 Hz), 3.85 (1H, d, Jꢂ10.1 Hz),
3.74 (1H, d, Jꢂ10.1 Hz), 3.67 (1H, ddd, Jꢂ4.1, 7.5, 12.7 Hz), 3.45 (1H, m),
3.32 (1H, d, Jꢂ2.1 Hz), 1.91, (1H, m), 0.86 (9H, s), 0.08 (3H, s), 0.04 (3H,
s); 13C-NMR (100 MHz, CDCl3) d: 165.2, 131.5, 128.4, 128.2, 127.5, 74.1,
71.6, 66.8, 61.2, 57.3, 55.2, 25.7, 18.2, ꢀ5.4, ꢀ5.5; ESI-MS m/z: 364
(MꢃꢃH, 100); HR-ESI-MS m/z: 364.1959 (Calcd for C19H30NO4Si: MꢃꢃH,
364.1944); Anal. Calcd for C19H29NO4Si: C, 62.78; H, 8.04; N, 3.85. Found:
C, 62.72; H, 8.04; N, 3.94.
block 1, (R)-4-hydroxymethyl-2-phenyl-4,5-dihydrooxazol-4-
ylmethyl acetate, was successfully achieved. Chiral building
block 1 can potentially be used in a broad range of applica-
tions directed towards the synthesis of biologically active
chiral compounds containing a-substituted a-amino acid
moieties.
Experimental
General Melting points (mp) were measured using a Yazawa melting
point apparatus BY-2 and are uncorrected. Optical rotations were measured
using a Jasco P-1030 polarimeter or a Jasco DIP-360 polarimeter. IR spectra
were recorded using a Jasco FT-IR/620 spectrometer. UV spectra were
(1S,2S)-1-[(4R)-4-(tert-Butyldimethylsilanyloxymethyl)-2-phenyl-4,5-
dihydrooxazol-4-yl]-2-methylpropane-1,3-diol (6) To a cold (ꢀ20 °C)
suspension of CuI (5.51 g, 28.9 mmol) in Et2O (200 ml) was added dropwise
methyllithium (50.7 ml, 57.9 mmol, 1.14 M in Et2O). After stirring at ꢀ20 °C
for 30 min, a solution of epoxyalcohol 5 (4.03 g, 11.1 mmol) in Et2O
(22.0 ml) was added. Following stirring at ꢀ20 °C for 1 h, a mixture of satu-
rated aqueous NH4Cl and 28% aqueous NH3 (9 : 1) was added. The reaction
mixture was diluted with Et2O and then washed with saturated aqueous
NH4Cl, water and finally saturated aqueous NaCl. The organic layer was
dried over MgSO4, filtered and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (hexane : AcOEtꢂ
2 : 1) to give diol 6 (4.16 g, 99% yield) as colorless crystals: mp: 70—72 °C;
[a]D25 ꢃ8.7° (cꢂ1.15, CHCl3); IR (KBr) cmꢀ1: 3388, 2954, 2929, 2856,
1
recorded using a Jasco V-550 spectrophotometer. H- and 13C-NMR spectra
were recorded on a Bruker DRX-400 spectrometer. Chemical shifts are
given on the d (ppm) scale using tetramethylsilane (TMS) as the internal
standard (s, singlet; d, doublet; t, triplet; m, multiplet; br, broad). ESI-MS
and high resolution ESI-MS (HR-ESI-MS) spectra were obtained using a
Micromass LCT spectrometer. Elemental analysis data were obtained using
an Elemental Vavio EL. Flash column chromatography was performed using
Kanto Chemical Silica Gel 60N (spherical, neutral) 40—50 mm.
(R,E)-3-[4-(tert-Butyldimethylsilanyloxymethyl)-2-phenyl-4,5-dihy-
drooxazol-4-yl]prop-2-en-1-ol (4) To a solution of alcohol 339) (214 mg,
777 mmol) and imidazole (68.8 mg, 1.01 mmol) in DMF (780 ml) was added
TBSCl (129 mg, 855 mmol) and the mixture was stirred for 30 min at rt. The
reaction mixture was diluted with Et2O and then washed with saturated
aqueous NaHCO3, water and finally saturated aqueous NaCl. The organic
layer was dried over MgSO4, filtered and concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatography
(hexane : AcOEtꢂ3 : 1) to give the TBS ether (296 mg, 98% yield) as a col-
orless oil: [a]D25 ꢀ45.9° (cꢂ1.05, CHCl3); IR (neat) cmꢀ1: 2954, 2930,
1
1652, 1582, 1497; H-NMR (400 MHz, CDCl3) d: 7.91 (2H, m), 7.51 (1H,
m), 7.41 (2H, m), 6.00 (1H, br s), 4.57 (2H, s), 3.92 (1H, d, Jꢂ10.1 Hz),
3.74 (1H, d, Jꢂ10.1 Hz), 3.71 (1H, m), 3.64 (1H, dd, Jꢂ9.3, 12.3 Hz), 3.46
(1H, br d, Jꢂ12.3 Hz), 2.18 (1H, m), 1.94 (1H, d, Jꢂ9.8 Hz), 1.00 (3H, d,
Jꢂ7.1 Hz), 0.84 (9H, s), 0.06 (3H, s), 0.02 (3H, s); 13C-NMR (100 MHz,
CDCl3) d: 166.3, 132.1, 128.6, 128.5, 126.6, 77.7, 76.8, 74.1, 66.0, 62.3,
36.7, 25.6, 18.0, 16.9, ꢀ5.5 (ꢄ2); ESI-MS m/z: 380 (MꢃꢃH, 100); HR-
ESI-MS m/z: 380.2264 (Calcd for C20H34NO4Si: MꢃꢃH, 380.2257); Anal.
Calcd for C20H33NO4Si: C, 63.29; H, 8.76; N, 3.69. Found: C, 63.24; H,
8.79; N, 3.50.
1
2857, 1721, 1648, 1580, 1496; UV lmax (EtOH) nm (e): 241 (14830); H-
NMR (400 MHz, CDCl3) d: 7.96 (2H, m), 7.49 (1H, m), 7.41 (2H, m), 7.16
(1H, d, Jꢂ15.8 Hz), 6.11 (1H, d, Jꢂ15.8 Hz), 4.61 (1H, d, Jꢂ8.4 Hz), 4.20
(2H, q, Jꢂ7.1 Hz), 4.19 (1H, d, Jꢂ8.4 Hz), 3.77 (1H, d, Jꢂ9.9 Hz), 3.71
(1H, d, Jꢂ9.9 Hz), 1.28 (3H, t, Jꢂ7.1 Hz) 0.84 (9H, s), 0.06 (3H, s), 0.01
(3H, s); 13C-NMR (100 MHz, CDCl3) d: 166.4, 164.7, 148.1, 131.6, 128.4,
128.3, 127.5, 121.9, 75.9, 74.0, 67.6, 60.4, 25.7, 18.2, 14.2, ꢀ5.4, ꢀ5.5;
ESI-MS m/z: 390 (MꢃꢃH, 100); HR-ESI-MS m/z: 390.2078 (Calcd for
(2S,3S,4R)-3-Hydroxy-2-hydroxymethyl-4-methyl-5-oxopyrrolidin-2-
ylmethyl Benzoate (7) To a cold (0 °C) solution of diol 6 (691 mg,
1.79 mmol) in acetone (13.1 ml) was added NaHCO3 (4.82 ml, 2.87 mmol,
5% aqueous solution), KBr (21.3 mg, 179 mmol), TEMPO (28.0 mg,
179 mmol) and NaClO (4.14 ml, 3.23 mmol, 0.78 M aqueous solution). After
stirring at 0 °C for 30 min, NaHCO3 (6.00 ml, 5% aqueous solution) was

740
Vol. 56, No. 5
(MꢃꢃH, 100); HR-ESI-MS m/z: 244.1188 (Calcd for C11H18NO5: MꢃꢃH,
244.1185); Anal. Calcd for C11H17NO5: C, 54.31; H, 7.04; N, 5.76. Found:
C, 54.62; H, 7.10; N, 5.77.
added. The mixture was diluted with AcOEt and then washed with water and
saturated aqueous NaCl. The organic layer was dried over MgSO4, filtered
and concentrated under reduced pressure to give the crude aldehyde, which
was used for the next reaction without further purification.
t
To a cold (0 °C) solution of the above crude aldehyde in BuOH–H2O
Acknowledgements This work was supported in part by a Grant-in-Aid
for Scientific Research from The Ministry of Education, Culture, Sports,
Science and Technology (MEXT) and “High-Tech Research Center” Project
for Private Universities: matching fund subsidy from MEXT, 2006-2008.
(2 : 1, 27.0 ml) was added NaH2PO4·2H2O (924 mg, 5.92 mmol), 2-methyl-
but-2-ene (950 ml, 8.97 mmol) and NaClO2 (406 mg, 4.49 mmol). After stir-
ring at 0 °C for 30 min, Na2SO3 was added. The mixture was diluted with
AcOEt and then washed with 1 M HCl, water and saturated aqueous NaCl.
The organic layer was dried over MgSO4, filtered and concentrated under re-
duced pressure to give the crude carboxylic acid, which was used for the
next reaction without further purification.
To a solution of the above crude carboxylic acid in EtOH (17.9 ml) was
added 1 M HCl (5.98 ml). After stirring at 80 °C for 1.5 h, the reaction mix-
ture was filtered through filter paper. The filtrate was diluted with AcOEt
and then washed with saturated aqueous NaHCO3, water and saturated aque-
ous NaCl. The organic layer was dried over MgSO4, filtered and concen-
trated under reduced pressure. The residue was purified by silica gel column
chromatography (hexane : acetoneꢂ1 : 2) to give lactam 7 (288 mg, 58%
yield, three steps) as a colorless oil: [a]D25 ꢀ23.0° (cꢂ1.31, CHCl3); IR
(neat) cmꢀ1: 3346, 2938, 1691, 1602, 1451; 1H-NMR (400 MHz, CDCl3) d:
8.01 (2H, m), 7.57 (1H, m), 7.42 (2H, m), 6.75 (1H, br s), 4.75 (1H, d,
Jꢂ11.7 Hz), 4.50 (1H, d, Jꢂ11.7 Hz), 4.38 (1H, t, Jꢂ6.4 Hz), 3.61 (2H, s),
3.60 (1H, m), 3.06 (1H, m), 2.80 (1H, m), 1.17 (3H, d, Jꢂ7.4 Hz); 13C-NMR
(100 MHz, CDCl3) d: 179.1, 167.2, 133.6, 129.8, 129.2, 128.6, 72.2, 65.2,
64.0, 63.5, 41.1, 8.3; ESI-MS m/z: 280 (MꢃꢃH, 100); HR-ESI-MS m/z:
280.1209 (Calcd for C14H18NO5: MꢃꢃH, 280.1185); Anal. Calcd for
C14H17NO5ꢃ1/2H2O: C, 58.33; H, 6.29; N, 4.86. Found: C, 58.60; H, 6.49;
N, 4.89.
Methyl (2S,3S,4R)-2-Benzoyloxymethyl-3-hydroxy-4-methyl-5-oxopyr-
rolidine-2-carboxylate (8) To a solution of alcohol 7 (33.4 mg, 120 mmol)
in H2O–CH2Cl2 (2 : 1, 600 ml) was added TEMPO (5.6 mg, 36.0 mmol) and
BAIB (116 mg, 360 mmol). After stirring at rt for 10 h the reaction mixture
was diluted with AcOEt and then washed with saturated aqueous Na2S2O3,
water and saturated aqueous NaCl. The organic layer was dried over
Na2SO4, filtered and concentrated under reduced pressure to give the crude
carboxylic acid, which was used for the next reaction without further purifi-
cation.
To a cold (0 °C) solution of the above crude carboxylic acid in THF
(1.20 ml) was added a solution of CH2N2 in Et2O until the color of the mix-
ture turned yellow. After stirring at 0 °C for 5 min, the reaction mixture was
warmed to rt, stirred for 50 min and then concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatography
(hexane : AcOEtꢂ1 : 3) to give methyl ester 8 (24.6 mg, 67% yield, two
steps) as colorless crystals: mp: 191—193 °C; [a]D25 ꢀ17.4° (cꢂ1.04,
MeOH); IR (KBr) cmꢀ1: 3383, 3318, 2961, 1737, 1701, 1452; 1H-NMR
(400 MHz, CDCl3) d: 7.94 (2H, m), 7.58 (1H, m), 7.42 (2H, m), 6.33 (1H,
br s), 4.93 (1H, d, Jꢂ11.5 Hz), 4.70 (1H, m), 4.62 (1H, d, Jꢂ11.5 Hz), 3.77
(3H, s), 2.73 (1H, d, Jꢂ6.9 Hz), 2.62 (1H, dq, Jꢂ6.0, 7.4 Hz), 1.55 (3H, s),
1.23 (3H, d, Jꢂ7.4 Hz); 13C-NMR (100 MHz, CDCl3) d: 177.3, 171.3,
166.2, 133.6, 129.7, 129.0, 128.6, 74.0, 68.6, 66.4, 53.2, 41.0, 8.0; ESI-MS
m/z: 308 (MꢃꢃH, 52), 317 (100); HR-ESI-MS m/z: 308.1130 (Calcd for
C15H18NO6: MꢃꢃH, 308.1134); Anal. Calcd for C15H17NO6: C, 58.63; H,
5.58; N, 4.56. Found: C, 58.42; H, 5.66; N, 4.58.
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1
2921, 2852, 1740, 1718, 1678, 1434; H-NMR (400 MHz, CDCl3) d: 6.13
(1H, br s), 4.62 (1H, dd, Jꢂ1.0, 5.1 Hz), 4.26 (1H, d, Jꢂ12.4 Hz), 3.78 (3H,
s), 3.75 (1H, d, Jꢂ12.4 Hz), 2.63 (1H, dq, Jꢂ5.1, 7.2 Hz), 1.49 (3H, s), 1.37
(3H, s), 1.14 (3H, d, Jꢂ7.2 Hz); 13C-NMR (100 MHz, CDCl3) d: 178.4,
171.5, 98.9, 71.4, 63.2, 61.8, 53.1, 40.3, 26.8, 20.5, 7.3; ESI-MS m/z: 244
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741
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