Efficient synthesis of antihyperglycemic (S)-alpha-aryloxy-beta-phenylpropionic acid using a bifunctional asymmetric catalyst.

Article abstract of DOI:10.1248/cpb.50.1118

Antihyperglycemic (S)-alpha-aryloxy-beta-phenylpropionic acid was prepared using catalytic asymmetric cyanosilylation as a key reaction to construct alpha-oxycarboxylic acid moiety.

Full text of DOI:10.1248/cpb.50.1118

1118
Notes
Chem. Pharm. Bull. 50(8) 1118—1121 (2002)
Vol. 50, No. 8
a
b
Efficient Synthesis of Antihyperglycemic (S)- -Aryloxy- -phenylpropionic
Acid Using a Bifunctional Asymmetric Catalyst
b
Makoto TAKAMURA,*,a Hiroaki YANAGISAWA,a Motomu KANAI,b and Masakatsu SHIBASAKI
a Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd.; Hiromachi, Shinagawa-ku, Tokyo 140–8710, Japan: and
b Graduate School of Pharmaceutical Science, The University of Tokyo; Hongo, Bunkyo-ku, Tokyo 113–0033, Japan.
Received March 1, 2002; accepted May 26, 2002
Antihyperglycemic (S)-a-aryloxy-b-phenylpropionic acid was prepared using catalytic asymmetric cyanosi-
lylation as a key reaction to construct a-oxycarboxylic acid moiety.
Key words asymmetric catalysis; antihyperglycemic agent; PPARg; bifunctional catalyst
Antihyperglycemic thiazolidine-2,4-diones, such as trogli- tried the cyanosilylation using TMSCN pre-mixed with 10
tazone,1) rosiglitazone2) and pioglitazone,3) are believed to be mol% of MeOH.16) Then, the reaction rate and the enantiose-
ligands for peroxisome proliferator-activated receptor g lectivity became satisfactory, and product 2 was obtained in
(PPARg) and improve insulin resistance in insulin target or- 85% yield with 96% ee on a 0.5 mmol scale of the substrate.
gans.4,5) Recently some research groups revealed that a-oxy- Therefore, the addition of proton source is essential for the
b-phenylpropionic acids, as well as 5-benzylthiazolidine-2,4- present reaction (Chart 2 ).
diones, possess potent PPARg agonistic activity and glucose
Based on the previous mechanistic studies, a proposed cat-
lowering activity.6,7) According to this knowledge we synthe- alytic cycle and possible role of the proton source are de-
sized novel oxime derivatives having a-oxy-b-phenylpropi- picted in Chart 3. After the intramolecular transfer of the
onic acid moiety, which indicates strong antihyperglycemic cyanide through dual activation of the aldehyde and TMSCN
activity.8) In this series, compound 1 (Chart 1) shows potent by the Lewis acid and the Lewis base (12), catalytically inac-
antihyperglycemic activity compared to rosiglitazone.9) It is tive species 13 should be generated. If the proton source is
known that enantiomers of a-oxy-b-phenylpropionic acids not present, the transfer of the silyl cation to the oxide of the
show different antihyperglycemic activities,10) however, we product cyanohydrin might be slow. So, before the silyl
are not aware of any practical methods for preparing opti- cation is trapped by the oxide, it could promote a racemic re-
cally active a-oxy-b-phenylpropionic acids.10—12) Mean- action, thus decreasing the ee of the product.17) On the other
while, some of the authors have developed a highly enantio- hand, if the proton source (HCN) is present, the oxide should
selective catalytic cyanosilylation of aldehydes with broad be immediately trapped by the proton and the silyl cation
substrate generality, using a Lewis acid–Lewis base bifunc- should be converted to TMSCN, thus regenerating the active
tional catalyst 4 (Chart 2).13,14) We now describe a practical catalyst 10. The resulting free cyanohydrin was proved to be
route to 1 using catalytic asymmetric cyanosilylation as a key silylated by TMSCN under the reaction conditions, thus the
step.
proton source should be regenerated. Therefore, the proton
source should catalytically facilitate the regeneration of the
active enantioselective catalyst.18,19)
Results and Discussion
Although excellent results were obtained from a wide
Our synthetic procedure is depicted in Chart 2. Refluxing
range of aldehydes by the catalytic enantioselective cyanosi- 2 with 12 N HCl in degassed ethanol gave the a-hydroxyester
lylation using 4, there have been no precedents of using an 5 and undesired hydrolyzed and/or debenzylated compounds.
easily enolizable and unstable aryl acetaldehyde such as 315) To recover these compounds, esterification and benzylation
as a substrate. Therefore, we were pleased when we found were performed and 5 was obtained from 2 in a yield of 81%
that application of the representative procedure (9 mol% of in all. The a-hydroxyester 5 was initially converted to the a-
catalyst 4, 36 mol% of Bu3P(O), 1.8 eq of TMSCN [slow ad- phenoxyester 6 under standard Mitsunobu reaction condi-
dition for 10 h], CH2Cl2 solvent at Ϫ40 °C for 60 h) gave the tions, i.e. a solution of diethyl azodicarboxylate in toluene
product cyanohydrin 2 in 89% yield with 97% ee on a 0.25 was added to the solution of 5 and 4-t-butylphenol in toluene
mmol scale of 3 (ca. 50 mg). However, on a 0.5 mmol scale, for 5 min at 0 °C. The chemical yield was 50% and by-prod-
the reaction became slow and the ee of the product was de- uct 1920) was obtained in 20% yield. A plausible reaction
creased to 74% (80% yield for 60 h). A similar problem in mechanism for generating 19 is depicted in Chart 4. We sup-
scale-up of this reaction was also reported in ref. 14 and posed that a-keto acid 17 is generated to some extent by de-
which was solved by adding MeOH as an additive. Thus, we protonation of the intermediate 14 instead of phenol 16, then
Chart 1
To whom correspondence should be addressed. e-mail: takamu@shina.sankyo.co.jp
© 2002 Pharmaceutical Society of Japan

August 2002
1119
Chart 2
Chart 3
deprotonation of 17 at the b-position gives 18 which reacted crude 6 was converted to easily crystallizable carboxylic acid
with 14 to afford 19. To avoid the side reaction, we pro- 7 via deprotection of the benzyl group by hydrogenation and
longed the addition time of diethyl azodicarboxylate to 10 h subsequent alkaline hydrolysis. After aqueous work up and
so that the yield of 6 was improved to 80% and by-product crystallization, 7 was obtained in 70% yield (3 steps from 5).
19 could not be detected. Next we further optimized the reac- Esterification gave the phenol 8, which was subjected to the
tion conditions to avoid chromatographic purification after modified Mitsunobu reaction with the oximealcohol 9 as
the Mitsunobu reaction. We adopted the modified Mitsunobu mentioned above and subsequent alkaline hydrolysis to afford
reaction developed by Pelletier and Kincaid21) in which triph- the desired (S)-a-aryloxy-b-phenylpropionic acid 1 without
enylphosphine resin and di-t-butyl azodicarboxlate (DBAD) purification by chromatographic technique in 70% yield (2
are employed (a solution of DBAD in toluene was added for steps).
10 h). After treatment of the reaction products with TFA in
In summary, an efficient synthesis of non-thiazolidine-2,4-
order to decompose excess DBAD and its hydrazine dicar- dione antihyperglycemic agent 1 has been achieved by the
boxylate, triphenylphosphine resin and its oxide were re- use of a bifunctional asymmetric catalyst. We also utilized
moved by filtration. Evaporation and aqueous work up gave Pelletier’s modified Mitsunobu reaction conditions in which
crude 6. To avoid chromatographic purification, the obtained triphenylphosphine resin and di-t-butyl azodicarboxylate is

1120
Vol. 50, No. 8
Chart 4
used for avoiding chromatographic purification. This report 128.05, 128.62, 130.84, 136.78, 158.48. IR (KBr) cmϪ1: 3393, 2262, 1513,
1250, 1070, 740. HR-MS m/z: 253.1104 (Calcd for C16H15NO2: 253.1103).
The enantiomeric excess was determined by HPLC analysis using Chiralpak
OD (2-propanol/hexane, 1/100) after conversion to the corresponding TBDMS
provides a synthetic method which could be applicable to an-
tihyperglycemic agents having chiral a-oxy-b-phenylpropi-
onic acid moiety. Further extention of this route to large scale
synthesis and evaluation of the pharmaceutical use of 1 are
currently under investigation.
ether. The absolute configuration of 2 was determined to be R by the com-
parison of the optical rotation with the reported value22) after the conversion
to 3-(4-hydroxyphenyl)lactic acid. [a]2D5 ϩ17.5° (cϭ1.04, H2O) (lit. [a]1D9
ϩ19.8° [cϭ1.45, H2O] for R enantiomer).
(R)-Ethyl-3-(4-benzyloxyphenyl)-2-hydroxyphenylpropionate (5) To
a solution of 2 (507 mg, 2.0 mmol) in degassed EtOH (8.0 ml) was added
12 N HCl (2.0 ml) and the mixture was gently refluxed for 48 h. The solvent
was removed and the residue was extracted with EtOAc (30 mlϫ2). The
combined organic layer was washed with water and brine. The solvent was
dried over Na2SO4 and removed to give the crude mixture of 5, ethyl (R)-3-
(4-hydroxyphenyl)lactate, (R)-3-(4-benzyloxyphenyl)lactic acid and (R)-3-
(4-hydroxyphenyl)lactic acid.
To this crude mixture was added EtOH (5.0 ml) and H2SO4 (0.2 ml), and
the reaction mixture was stirred for 16 h at room temperature. The solvent
was removed and the residue was extracted with EtOAc (30 mlϫ2). The
combined organic layer was washed with water and brine, dried over Na2SO4
and concentrated. The residue was purified by chromatography on silica gel
(EtOAc/hexane, 1/3) to give 5 (157 mg, 26%) and ethyl (R)-3-(4-hydroxy-
phenyl)lactate (247 mg, 59%) as a colorless oil.
To a solution of ethyl (R)-3-(4-hydroxyphenyl)lactate (247 mg, 1.17
mmol) in DMF (2.5 ml) were added BnBr (167 ml, 1.40 mmol) and K2CO3
(303 mg, 2.19 mmol), and the mixture was stirred at 60 °C for 4 h. To the re-
action mixture was added H2O and extracted with EtOAc (30 mlϫ2). The
combined organic layer was washed with H2O and brine, dried over Na2SO4
and concentrated. The residue was purified by chromatography on silica gel
(EtOAc/hexane, 3/7) to give 5 (279 mg, 93% from ethyl (R)-3-(4-hydroxy-
phenyl)lactate, 96% ee) as a colorless oil.
Experimental
Melting points (mp) were determined with a Yanaco melting point appara-
tus and are not corrected. Infrared (IR) spectra were measured with a Nic
5SXCFT-IR spectrophotometer. 1H- and 13C-NMR spectra were recorded on
a Varian Mercury 400 or 500 spectrometer. Chemical shifts were expressed
in d ppm from the internal standard tetramethylsilane (TMS). MS or high-
resolution mass spectra (HR-MS) were obtained on a JEOL JMS-D 300
mass spectrometer. Optical rotations ([a]D) were determined on a Jasco
DIP-360 polarimeter. HPLC was performed on a. Shimadzu HPLC system
consisting of the following: pump, LC-10Advp; detector, SPD-M10Avp,
measured at 254 nm. Column chromatography was performed with silica gel
Merck 60 (230—400 mesh ASTM). In general, reactions were carried out in
dry solvents under an argon atmosphere, unless noted otherwise.
Dichloromethane was distilled from calcium hydride.
(R)-3-(4-Benzyloxyphenyl)-2-hydroxypropionitrile (2) To a stirred so-
lution of well-dried Bu3P(O) (37 mg, 0.17 mmol) in CH2Cl2 (0.25 ml) was
added Et2AlCl (44 ml, 41 mmol, 0.93 M in hexane) at room temperature, fol-
lowed by the addition of the chiral ligand (31 mg, 44 mmol) in CH2Cl2 (1.0
ml). The resulting mixture was stirred for 1 h at room temperature and
cooled to Ϫ40 °C. After the addition of the aldehyde 3 (105 mg, 0.46 mmol),
TMSCN (0.12 ml, 0.84 mmol) and MeOH (1.67 ml) in CH2Cl2 (0.12 ml)
were slowly added over 20 h, and then the mixture was stirred for 44 h. To
the reaction mixture were added 1 N HCl (1.0 ml) and THF (5 ml) in order to
hydrolyze the trimethylsilyl ether moiety of the product. The mixture was
stirred for 30 min and the organic layer was separated and washed with
water. The aqueous layer was extracted with ethyl acetate (30 mlϫ2). The
combined organic layer was washed with brine and dried over Na2SO4. The
crude cyanohydrin was purified by chromatography on silica gel (EtOAc/
hexane, 3/7) to give 2 (100 mg, 85%, 96% ee) as colorless crystals.
1H-NMR (400 MHz, CDCl3) d: 1.28 (3H, t, Jϭ7.0 Hz), 2.71 (1H, d,
Jϭ6.0 Hz), 2.92 (1H, dd, Jϭ6.5, 14.0 Hz), 3.07 (1H, dd, Jϭ4.5, 14.0 Hz), 4.22
(2H, q, Jϭ7.0 Hz), 4.37—4.22 (1H, m), 5.04 (2H, s), 6.91 (2H, d, Jϭ8.5
Hz), 7.14 (2H, d, Jϭ8.5 Hz), 7.30—7.44 (5H, m). 13C-NMR (125 MHz,
CDCl3) d: 14.04, 39.51, 61.45, 69.80, 71.21, 114.59, 127.29, 127.74,
128.39, 128.55, 130.40, 136.93, 157.62, 174.15. IR (liquid film) cmϪ1: 3489,
1734, 1512, 1242, 1177, 1026. HR-MS m/z: 323.1257 (Calcd for C18H20O4Na
323.1260). The enantiomeric excess was determined by HPLC analysis
using Chiralpak AD-RH (CH3CN/pH 2.2 buffer solution of phosphoric acid
and Et3N, 7/3).
mp: 124—125 °C. 1H-NMR (400 MHz, CDCl3) d: 2.43 (1H, d, Jϭ7.0
Hz), 3.07 (2H, d, Jϭ6.0 Hz), 4.62 (1H, dd, Jϭ6.5, 13.0 Hz), 5.06 (2H, s),
6.97 (2H, d, Jϭ8.5 Hz), 7.22 (2H, d, 8.5 Hz), 7.30—7.44 (5H, m). 13C-NMR
(125 MHz, CDCl3) d: 40.48, 62.24, 70.06, 115.30, 119.33, 125.89, 127.48,

August 2002
1121
(R)-2-(4-t-Butylphenoxy)-3-(4-hydroxyphenyl)propioic Acid (7) To a
Calcd for C34H36N2O5: C, 73.89; H, 6.57; N, 5.07; Found: C, 74.02; H, 6.57;
solution of 5 (896 mg, 2.90 mmol) in toluene (9.0 ml) were added 4-t- N, 4.99. The enantiomeric exess was determined by HPLC analysis using
butylphenol (671 mg, 4.47 mmol) and triphenylphosphine-resin (3 mmol/g, Chiralpak OJ-R (CH3CN/pH 2.2 buffer solution of phosphoric acid and
1.99 g, 5.97 mmol), and the mixture was stirred magnetically. To the stirred Et3N, 7/3).
reaction mixture, a solution of DBAD (1.03 g, 4.47 mmol) in toluene (9.0
ml) was slowly added over 10 h at 0 °C, and the mixture was stirred for an-
Acknowledgements Financial support was provided by JSPS’s Research
other 16 h. After completion of the reaction, TFA (5 ml) was added. After for the Future Program.
1 h, the reaction mixture was filtered (Celite®) and the residue was washed
with EtOAc and H2O. The combined filtrate was separated and the organic References and Notes
layer was washed with H2O and brine, and dried over Na2SO4. The solvent
was removed and 1.5 g of the crude 6 was obtained as a colorless oil.
To a solution of crude 6 (1.50 g) in EtOH (10 ml), 5% Pd–C (0.1 g) was
added, and the mixture was stirred under H2 atmosphere at 50 °C for 2 h. The
solvent was removed, and the residue was solved in EtOH (30 ml). 1 N NaOH
(6 ml) was added to the solution at 0 °C and the reaction mixture was stirred
at room temperature for 16 h. The solvent was removed and the residue was
washed with EtOAc. After the addition of 1 N HCl to pH 4, the mixture was
extracted with EtOAc and washed with H2O and brine. The organic layer
was dried over Na2SO4, and the solvent was removed. The crystals were col-
lected by filtration using isopropyl ether to give the title compound 7
(659 mg, 70%) as colorless crystals.
1) Yoshioka T., Fujita T., Kanai T., Aizawa Y., Kurumada T., Hasegawa
K., Horikoshi H., J. Med. Chem., 32, 421—428 (1989).
2) Cantello B. C. C., Cawthorne M. A., Cottam G. P., Duff P. T., Haigh
D., Hindley R. M., Lister C. A., Smith S. A., Thurlby P. L., J. Med.
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5) Berger J., Bailey P., Biswas C., Cullinan C. A., Doebber T. W., Hayes
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mp: 170—171 °C. 1H-NMR (400 MHz, DMSO-d6) d: 1.22 (9H, s), 3.00—
3.08 (2H, m), 4.72—4.76 (1H, m), 6.66 (2H, d, Jϭ8.5 Hz), 6.74 (2H, d,
Jϭ8.5 Hz), 7.09 (2H, d, Jϭ8.5 Hz), 7.25 (2H, d, Jϭ8.5 Hz). 13C-NMR
(125 MHz, DMSO-d6) d: 31.19, 33.66, 37.30, 76.83, 114.18, 114.87, 125.95,
6) Bucle D. R., Cantello B. C. C., Cawthorne M. A., Coyle P. J., Dean D.
K., Faller A., Haigh D., Hindley R. M., Jefcott L. J., Lister C. A., Pinto
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6, 2121—2126 (1996).
126.81, 130.15, 143.09, 155.28, 155.91, 172.16. IR (KBr pellet) cmϪ1
: 3234,
2964, 1717, 1513, 1238, 1207, 1187. HR-MS m/z: 314.1503 (Calcd for
C19H22O4 314.1518). Anal. Calcd for C19H22O4·l/10H2O: C, 72.10; H, 7.05;
Found: C, 71.99; H, 7.04.
(R)-Ethyl-2-(4-t-butylphenoxy)-3-(4-hydroxyphenyl)propionate (8) To
a solution of 7 (1.89 g, 6.0 mmol) in EtOH (20 ml), was added H2SO4 (0.5
7) Ishii F., Kotake J., Sato S., Honda H., Konno F., Nagao Y., EP-903343
(1999), SS Pharma Co., Ltd.
8) Yanagisawa H., Takamura M., Fujita T., Fujiwara T., JP-9323967
(1997), Sankyo Co., Ltd.
9) Unpublished data.
ml) and the mixture was stirred at room temperature for 16 h. The solvent 10) Haigh D., Allen G., Birrell H. C., Bucle D. R., Cantello B. C. C.,
was removed, and the residue was extracted with EtOAc (30 mlϫ2). The
combined organic layer was washed with water and brine, and dried over
Na2SO4. The solvent was removed and the title compound 8 was obtained as
a colorless oil (2.05 g, quant.).
Eggleston D. S., Haltiwanger R. C., Holder J. C., Lister C. A., Pinto I.
L., Rami H. K., Sime J. T., Smith S. A., Sweeney J. D., Bioorg. Med.
Chem., 7, 821—830 (1999).
11) Haigh D., Birrell H. C., Cantello B. C. C., Hindley R. M., Ramaswamy
A., Rami H. K., Stevens N. C., Tetrahedron: Asymmetry, 10, 1335—
1351 (1999).
1H-NMR (400 MHz, CDCl3) d: 1.23 (3H, t, Jϭ7.0 Hz) 1.26 (9H, s),
3.14—3.17 (2H, m), 4.15—4.21 (2H, m), 4.68—4.71 (1H, m), 6.73—6.78
(4H, m), 7.16 (2H, d, Jϭ8.5 Hz), 7.24 (2H, d, Jϭ8.5 Hz). 13C-NMR 12) Birrell H. C., Cantello B. C. C., Eggleston D. S., Haigh D., Halti-
(125 MHz, CDCl3) d: 14.11, 31.46, 34.09, 38.29, 61.30, 78.28, 114.80,
wanger R. C., Hindley R. M., Ramaswamy A., Stevens N. C., Tetrahe-
dron: Asymmetry, 10, 1353—1367 (1999).
115.26, 126.29, 128.50, 130.68, 144.39, 154.57, 155.51, 171.59. IR (Liquid
film) cmϪ1: 3421, 2963, 1731, 1514, 1238, 1187. HR-MS: 365.1739 (Calcd 13) Hamashima Y., Sawada D., Kanai M., Shibasaki M. J., Am. Chem.
for C21H26O4Na 365.1729).
Soc., 121, 2641—2642 (1999).
(S)-2-(4-t-Butylphenoxy)-3-[4-[2-[1-(4-pyridine-2-ylphenyl)ethylidene-
aminooxy]ethoxy]phenyl]propionic Acid (1) To a solution of 8 (2.05 g,
14) Hamashima Y., Sawada D., Nogami H., Kanai M., Shibasaki M., Tetra-
hedron, 57, 805—814 (2001).
6.0 mmol) in toluene (40 ml), were added oximealcohol 9 (2.31 g, 9.0 mmol) 15) Takaoka E., Yoshikawa N., Yamada Y. M. A., Sasai H., Shibasaki M.,
and triphenylphosphine resin (3 mmol/g, 4.0 g, 12.0 mmol), and the mixture Heterocycles, 46, 157—163 (1997).
was stirred magnetically. To the stirred reaction mixture, a solution of 16) The added MeOH must be immediatery converted to MeOTMS and
DBAD (2.76 g, 12.0 mmol) in toluene (30 ml) was slowly added over 1 h at HCN: Mai K., Patil G., J. Org. Chem., 51, 3545—3548 (1986).
0 °C, and the mixture was stirred for another 16 h at room temperature. After 17) For a discussion of the racemic reaction pathway mediated by the silyl
completion of the reaction, TFA (12 ml) was added. After 1 h, the reaction
mixture was filtered (Celite®), and the residue was washed with EtOAc and
H2O. The combined filtrate was washed with saturated aqueous NaHCO3
and brine, and dried over Na2SO4. The solvent was removed and to the ob-
tained crude oil (4 g) were added EtOH (25 ml), THF (25 ml) and 1 N NaOH
(12 ml) at 0 °C. The reaction mixture was stirred at room temperature for
cation, see: Carreira E. M., “Comprehensive Asymmetric Catalyst,”
Vol. 3, ed. by Jacobsen E. N., Pfaltz A., Yamamoto H., Springer, Hei-
delberg, 1999, pp. 997—1066.
18) Discussion on the role of proton source in catalytic enantioselective
Strecker-type reaction, see: Takamura M., Hamashima Y., Usuda H.,
Kanai M., Shibasaki M., Angew. Chem. Int. Ed., 39, 1650—1652 (2000).
16 h. The organic solvent was removed and the residue was washed with 19) Takamura M., Hamashima Y., Usuda H., Kanai M., Shibasaki M.,
Et2O. After the addition of 1 N HCl to pH 4, the mixture was extracted with Chem. Pharm. Bull., 48, 1586—1592 (2000).
EtOAc (80 mlϫ3) and washed with H2O and brine. The obtained organic 20) 1H-NMR (400 MHz, CDCl3) d: 1.00 (3H, t, Jϭ7.0 Hz), 1.32 (3H, t,
layer was dried over Na2SO4, and the solvent was removed. The solids were
collected by filtration using isopropylether and hexane to give the title com-
pound 1 (2.4 g, 72%, 93% ee.) as a colorless solid.
Jϭ7.0 Hz), 3.21 (2H, d, Jϭ6.0 Hz), 3.97 (2H, dq, Jϭ2.5, 7.0 Hz), 4.25
(2H, dq, Jϭ1.5, 7.0 Hz), 5.03 (2H, s), 5.04 (1H, t, Jϭ6.0 Hz), 5.07
(2H, s), 6.86 (1H, s), 6.89 (2H, d, Jϭ8.5 Hz), 6.90 (2H, d, Jϭ8.5 Hz),
7.14 (2H, d, Jϭ8.5 Hz), 7.29—7.48 (10H, m), 7.70 (2H, d, Jϭ8.5 Hz).
13C-NMR (125 MHz, CDCl3) d: 13.86, 14.27, 38.20, 60.90, 61.15,
69.89, 69.98, 79.88, 114.49, 114.66, 123.94, 126.33, 127.42, 127.47,
127.90, 128.02, 128.25, 128.54, 128.59, 130.65, 132.46, 136.70,
mp: 148—150 °C. 1H-NMR (400 MHz, CDCl3) d: 1.30 (9H, s), 2.31 (3H,
s), 3.26 (2H, d, Jϭ6.0 Hz), 4.34 (2H, t, Jϭ5.0 Hz), 4.59 (2H, t, Jϭ5.0 Hz),
4.84 (1H, t, Jϭ6.0 Hz), 6.86 (2H, d, Jϭ9.0 Hz), 6.93 (2H, d, Jϭ8.5 Hz),
7.25—7.35 (5H, m), 7.74—7.88 (4H, m), 7.95 (2H, d, Jϭ8.5 Hz), 8.76 (1H,
d, Jϭ4.5 Hz). 13C-NMR (125 MHz, CDCl3) d: 12.79, 31.45, 34.05, 38.10,
66.60, 72.61, 77.99, 114.63, 114.76, 121.56, 122.63, 126.26, 126.51, 127.26,
128.98, 130.54, 137.23, 137.78, 138.92, 144.25, 148.91, 154.86, 155.49,
137.05, 141.11, 157.73, 159.22, 164.15, 170.62. IR (liquid film) cmϪ1
:
2981, 1744, 1709, 1603, 1510, 1248, 1176. HR-MS: 603.2353 (Calcd
for C36H36O7Na 603.2359).
156.63, 157.79, 174.74. IR (KBr pellet) cmϪ1: 2960, 1512, 1242, 1185, 21) Pelletier J. C., Kincaid S., Tetrahedron Lett., 41, 797—800 (2000).
1071, 783. HR-MS m/z: 553.2698 (Calcd for C34H36N2O5 553.2703). Anal. 22) Sasaki T., Otsuka I., J. Biol. Chem., 32, 533—538 (1917).