A novel series of (S)-2,7-substituted-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acids: Peroxisome proliferator-activated receptor α/γ dual agonists with protein-tyrosine phosphatase 1B inhibitory activity

Article abstract of DOI:10.1248/cpb.59.1233

Novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and (S)-7-(2-{2-[(E)-2-cyclopentylvinyl]-5-methyloxazol-4-yl}ethoxy) -2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (14c) was identified as a peroxisome proliferator-activated receptor (PPAR) α/γ dual agonist. The transactivation activity of 14c was comparable to that of rosiglitazone in human PPARg (EC₅₀=0.14μM) and was much higher than in human PPARα (EC₅₀=0.20μM). In addition, 14c, but not rosiglitazone, showed human protein-tyrosine phosphatase 1B (PTP-1B) inhibitory activity (IC₅₀=1.85μM). 14c showed about 10-fold stronger hypoglycemic and hypotriglyceridemic effects than rosiglitazone by repeated application for 14 d in male KK-A^ymice. Furthermore, 14c, but not rosiglitazone, increased hepatic peroxisome acyl CoA oxidase activity at 30 mg/kg/d for 7 d in male Syrian hamsters, probably due to its PPARα agonist activity. 14c did not affect plasma volume at 100 mg/kg/d for 14 d in male ICR mice, while rosiglitazone significantly increased it. In conclusion, 14c is a promising candidate for an efficacious and safe anti-diabetic drug with triple actions as a PPARα/γ dual agonist with PTP-1B inhibitory activity.

Full text of DOI:10.1248/cpb.59.1233

October 2011
Regular Article
Chem. Pharm. Bull. 59(10) 1233—1242 (2011)
1233
A Novel Series of (S)-2,7-Substituted-1,2,3,4-tetrahydroisoquinoline-3-
a g
carboxylic Acids: Peroxisome Proliferator-Activated Receptor / Dual
Agonists with Protein-Tyrosine Phosphatase 1B Inhibitory Activity
Kazuya OTAKE, Satoru AZUKIZAWA, Masaki FUKUI, Michiko SHIBABAYASHI, Hikaru KAMEMOTO,
Tomohiro MIIKE, Kazuyoshi KUNISHIRO, Masayasu KASAI, and Hiroaki SHIRAHASE*
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.; 38, Nishinokyo Tsukinowa-cho, Nakagyo-ku, Kyoto
604–8444, Japan.
Received May 30, 2011; accepted July 22, 2011
Novel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and (S)-7-(2-{2-[(E)-2-
cyclopentylvinyl]-5-methyloxazol-4-yl}ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-car-
boxylic acid (14c) was identified as a peroxisome proliferator-activated receptor (PPAR) a/g dual agonist. The
transactivation activity of 14c was comparable to that of rosiglitazone in human PPARg (EC50ꢀ0.14 mM) and was
much higher than in human PPARa (EC50ꢀ0.20 mM). In addition, 14c, but not rosiglitazone, showed human pro-
tein-tyrosine phosphatase 1B (PTP-1B) inhibitory activity (IC50ꢀ1.85 mM). 14c showed about 10-fold stronger hy-
poglycemic and hypotriglyceridemic effects than rosiglitazone by repeated application for 14 d in male KK-Ay
mice. Furthermore, 14c, but not rosiglitazone, increased hepatic peroxisome acyl CoA oxidase activity at
30 mg/kg/d for 7 d in male Syrian hamsters, probably due to its PPARa agonist activity. 14c did not affect plasma
volume at 100 mg/kg/d for 14 d in male ICR mice, while rosiglitazone significantly increased it. In conclusion, 14c
is a promising candidate for an efficacious and safe anti-diabetic drug with triple actions as a PPARa/g dual ago-
nist with PTP-1B inhibitory activity.
Key words peroxisome proliferator-activated receptor; diabetes; hypoglycemic effect; tetrahydroisoquinoline derivative; pro-
tein-tyrosine phosphatase 1B; KK-Ay mouse
Thiazolidinedione (TZD) derivatives, such as rosiglita- heart failure, and cause hepatotoxicity.4—7) Thus, to find a
zone, have been used as anti-diabetic drugs and are known to new PPARg agonist without such adverse effects, many non-
enhance insulin sensitivity by activating peroxisome prolifer- TZD derivatives have been synthesized but none have been
ator-activated receptor g (PPARg) mainly expressed in developed successfully. Farglitazar, a tyrosine derivative, is a
adipocytes, resulting in the reduction of blood glucose levels potent PPARg agonist showing efficacious anti-diabetic ef-
in type 2 diabetic patients1—3); however, TZD derivatives fects, but its development was discontinued due to adverse
cause edema, increase the risk of weight gain and congestive effects such as edema8) (Fig. 1). We synthesized a novel se-
Fig. 1. Chemical Structures of PPAR Agonists
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: shirahase@kyoto-pharm.co.jp

1234
Vol. 59, No. 10
ries of tetrahydroisoquinoline derivatives, in which KY-021 with acetic anhydride and bases to give 5a—f, which were
has been identified as a PPARg agonist with high anti-dia- treated with phosphorous oxychloride to afford oxazole de-
betic efficacy and safety in experimental animals9); however, rivatives (6a—f).30) Amidation of 3g and h afforded 7g and
its clinical efficacy and safety remain to be determined (Fig. h, which were treated with methyl 4-bromo-3-oxopentanoate
1).
(8) to give oxazole derivatives (6g, h). Hydrogenation of 6c
In recent years, many efforts have been made to develop a afforded 6i. Reduction of 6a—i was performed with di-
PPARa/g dual agonist. PPARa is expressed in the liver and isobutyl aluminum hydride (DIBAH), and the products were
is related to fatty acid metabolism10); fibrates, including clofi- methanesulfonylated to afford 9a—i.
brate, bezafibrate and fenofibrate, have been used as anti-hy-
The general approach to the synthesis of 14a—i is out-
perlipidemic drugs and are known to exert their effects via lined in Chart 2. Alkylation of 10 with 9a—i in the presence
hepatic PPARa activation. PPARa agonists improved insulin of K2CO3 and tetrabutylammonium fluoride afforded 11a—i
resistance by reducing plasma lipids in experimental animals, in good yield. The Boc group of 11a—i was removed with
and showed hypoglycemic and insulin-resistance-improving HCl/HCO2H, affording 12a—i, which were treated with sor-
effects in patients.11—13) Their hypocholesterolemic effects bic acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
are expected to protect against cardiovascular diseases in dia- hydrochloride (EDC), or (2E,4E)-hexadienoyl chloride and
betic patients with hyperlipidemic complications. Further- triethylamine, to give 13a—i, which were treated with aque-
more, PPARa agonists have a body weight-reducing effect, ous LiOH to give carboxylic acid derivatives, and then 14a—
while PPARg agonists have a risk of body weight gain.14) i were isolated as tert-butylamine salts.28)
Thus, the combination of PPARa and PPARg agonistic ac-
tivities would result in synergenistic anti-diabetic efficacy Results and Discussion
and safety.15,16) A number of carboxylic acid derivatives have
In the previous study, we synthesized a series of tetrahy-
been reported as PPARa/g dual agonists;17—21) however, clin- droisoquinoline derivatives and found a novel PPARg ago-
ical development of most compounds has been discontinued: nist, KY-021, which has a more rigid structure, lower molec-
e.g., ragaglitazar due to carcinogenicity; muraglitazar due to ular weight and lipophilicity, and higher efficacy and safety
the risk of cardiovascular events; imiglitazar due to the po- than farglitazar.9) Then, we found a new tetrahydroisoquino-
tential risk of liver injury (Fig. 1). Excess activation of line derivative as a lead compound for a PPARa/g agonist
PPARa as well as PPARg may lead to carcinogenesis and to with weak PTP-1B inhibitory activity.28) In the present study,
adverse effects on the kidneys, heart and liver.16,22—26) Fur- another series of tetrahydroisoquinoline derivatives with vari-
thermore, many PPARa/g dual agonists have a relatively ous aliphatic ring moieties instead of phenyl moiety at the 2-
high molecular weight and 3—4 aromatic rings, and show position of oxazole were synthesized to find a novel
high lipophilicity; these structural and physicochemical prop- PPARa/g dual agonist with potent PTP-1B inhibitory activ-
erties may also be related to their adverse effects.27) On the ity. PPARg and PPARa agonist activity was determined as
other hand, we have found a new tetrahydroisoquinoline de- transactivation activity in COS-1 cells transfected with full-
rivative (compound 1, Fig. 1), which has a relatively low mo- length human PPARg1 plasmid or PPARa plasmid, and
lecular weight and smaller number of aromatic rings, as a human RXRa plasmid with reporter plasmid pGL3-
lead compound for a PPARa/g dual agonist (EC50: 0.38, PPREx4-tk-luc; EC50 and the maximal activation level rela-
0.16 mM, respectively) with weak protein-tyrosine phos- tive to the level activated by farglitazar, a PPARg agonist
phatase 1B (PTP-1B) inhibitory activity (9.4 mM).28) PTP-1B (10ꢀ7 M) or Wy-14643, a PPARa agonist (10ꢀ5 M) were deter-
is known to play a role as a negative regulator of insulin sig- mined. Glucose-lowering effects of derivatives were exam-
naling, and PTP-1B inhibition has been reported to enhance ined in KK-Ay mice, a type 2 diabetic model animal, and ex-
insulin sensitivity.29) Therefore, PTP-1B inhibitory activity is pressed as a % decrease in glucose in comparison with con-
expected to potentiate the insulin sensitivity-enhancing effect trol mice administered the vehicle. All animal experiments in
but not the adverse effects of PPARa/g dual agonist. In the the present study were conducted according to the guidelines
present study, to find a novel PPARa/g dual agonist with po- for animal experiments of our institute and the guidelines for
tent PTP-1B inhibitory activity, a new series of 2,7-substi- animal experimentation approved by the Japanese Associa-
tuted-tetrahydroisoquinoline derivatives were synthesized by tion of Laboratory Animal Science. PTP-1B inhibitory activ-
replacing of a phenyl group with a side chain having a non- ity was determined using human PTP-1B as an enzyme and
aromatic ring on the oxazole ring in compound 1.
p-nitrophenylphosphonic acid (pNPP) as a substrate, and
Chemistry (S)-7-Substituted-2-[(2E,4E)-hexadienoyl]- IC50 values were calculated.28)
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives
Compounds 14a—i showed moderate to potent PPARg
(14a—i) were synthesized by alkylation with 2-(2-substi- agonist activities (Table 1). In the compounds with cy-
tuted-5-methyloxazol-4-yl)ethyl methanesulfonate (9a—i) at cloalkylvinyl moieties (14a—d), activity increased depen-
the 7-position of methyl (S)-2-tert-butoxycarbonyl-7-hy- dent on the aliphatic ring size (cyclopropyl to cyclohexyl).
droxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
(10),9) Insertion of a methyl group at the 1-position of the cycloal-
followed by conversion of the tert-butoxycarbonyl (Boc) kyl group (14c vs. 14g, 14d vs. 14h) and at the 1-position of
group to hexadienoyl group at the 2-position, and hydrolysis the vinyl group (14c vs. 14f) decreased the activity. The cy-
of the methyl ester.
cloalkylidene structure (14e) and reduction of the vinyl
The general approach to the synthesis of 9a—i is outlined group (14i) markedly reduced the activity. All the com-
in Chart 1. Acylation of L-aspartic acid b-methyl ester (2) pounds showed almost full activation of PPARg (Max: 83—
with 3a—f afforded 4a—f. The carboxylic acid of 4a—f was 113%). The PPARg agonist activity of compound 14c and d
transformed to methylketone by the Dakin–West reaction was comparable to that of rosiglitazone and stronger than

October 2011
1235
Chart 1. Synthesis of 2-(2-Substituted-5-methyloxazol-4-yl)ethyl Methanesulfonates
Chart 2. Synthesis of 2,7-Substituted-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acids

1236
Vol. 59, No. 10
Table 1. Molecular Weight, Log D7.0, PPARg and PPARa Transactivation Effects, PTP-1B Inhibition, and Hypoglycemic Effects in KK-Ay Mice of 2,7-
Substituted-tetrahydroisoquinoline-3-carboxylic Acids
KK-Ay mice
PPARgb)
PPARab)
Maxd)
PTP-1Bb)
(10 mg/kg, 4 d)e)
Compound
R
M.W.a)
log D7.0
EC50
(mM)
Maxc)
(%)
EC50
(mM)
IC50
(mM)
Glucose
% decrease
(%)
14a
14b
14c
14d
14e
14f
462.54
476.56
490.59
504.62
490.59
504.62
504.62
518.64
2.42
3.15
3.54
4.01
3.38
3.95
3.81
4.22
1.08
0.27
0.14
0.10
0.43
0.25
0.24
0.41
113
110
84
1.01
0.23
0.20
0.13
0.15
0.18
—
81
8.20
4.90
1.85
1.80
3.40
1.38
1.28
6.35
50**
43*
45**
54**
5
81
76
47
35
53
—
98
84
85
13
14g
14h
94
27
90
—
—
—
—
21
14i
492.61
357.43
559.51
3.41
NT
0.23
0.14
NT
83
128
NT
1.28
ꢁ30
1.59
45**
48**
NT
Rosiglitazone
Ertiprotafib
(125% at 10 mM)
NT NT
NT
NT: not tested. a) Molecular weight as free form. b) nꢂ2. c) The activation level induced by farglitazar (10ꢀ7 M) was taken as 100%. d) The activation level induced by Wy-
14643 (10ꢀ5 M) was taken as 100%. e) nꢂ5, ∗ pꢃ0.05, ∗∗ pꢃ0.01, vs. control, Student’s t-test.
that of compound 1, indicating that a medium-sized cy- hibitory activities, which increased dependent on the ring
cloalkylvinyl structure is more preferable than a phenyl size. Insertion of a methyl group at the 1-position of cy-
structure for interaction with PPARg protein.
cloalkyl and vinyl groups in a cyclopentylvinyl derivative in-
On the other hand, compounds 14a—f showed moderate to creased activity (14f, g), while addition of a methyl group at
potent PPARa agonist activities, which increased dependent the 1-position of cycloalkyl in a cyclohexylvinyl derivative
on the aliphatic ring size; however, the maximal activation markedly decreased activity (14h). Reduction of the vinyl
level decreased dependent on the aliphatic ring size: the max- group increased activity (14i). The activity of compounds
imal response of 14d was lower than 50% at 10 mM. The cy- 14c, d, f, g and i was approximately 5-fold stronger than that
cloalkylidene structure (14e) and insertion of a methyl group of compound 1 and comparable to that of Ertiprotafib.
at the 1-position of vinyl group (14f) also markedly reduced
Among the compounds, 14a—d and i showed similar hy-
the maximal response. Insertion of a methyl group at the 1- poglycemic effects in KK-Ay mice, which are considered to
position of the cycloalkyl group (14g, h) and reduction of the be due to PPARg activation because the compounds failed to
vinyl group (14i) abolished PPARa agonist activity. From activate mouse PPARa (unpublished data); however, PPARg
these results, a relatively small cycloalkylvinyl structure is agonist activity was not related to hypoglycemic effects, sug-
preferable for interaction with PPARa protein; however, the gesting that the activity may inversely relate to oral bioavail-
structural requirement was different from the interaction with ability. Furthermore, the potent PTP-1B inhibitory activity of
PPARg. Among the compounds, 14b and c showed higher 14c, d and i may have contributed to their hypoglycemic ef-
activity than compound 1.
fects. From the results, 14c was chosen for further evaluation
All the compounds showed moderate to potent PTP-1B in- as a potent and well-balanced PPARa/g dual agonist with

October 2011
1237
Table 2. Effects of Repeated Administration of 14c and Rosiglitazone for Table 3. Effects of Repeated Administration of 14c and Rosiglitazone for
14 d on Plasma Glucose and Triglyceride Levels in Male KK-Ay Mice
7 d on Hepatic Acyl CoA Oxidase (ACO) Activity in Male Syrian Hamsters
Dose
(mg/kg/d)
Glucose
(mg/dl)
Triglyceride
(mg/dl)
Dose
(mg/kg/d)
ACO activity
(DOD502/min/mg)
Compound
Compound
Control
14c
—
1
3
—
10
30
623.2ꢄ49.8
790.2ꢄ123.6
832.2ꢄ71.8
464.7ꢄ42.4*
788.5ꢄ152.1
603.1ꢄ72.0
481.4ꢄ97.6
Control
14c
—
10
30
10
30
0.107ꢄ0.009
0.156ꢄ0.016
0.244ꢄ0.023**
0.152ꢄ0.021
0.160ꢄ0.017
450.2ꢄ48.1*
338.0ꢄ32.3**
676.9ꢄ53.5
430.1ꢄ49.0*
320.4ꢄ42.3**
Control
Rosiglitazone
Rosiglitazone
MeanꢄS.E. nꢂ4. ∗∗ pꢃ0.01, vs. control, Student’s t-test.
MeanꢄS.E. nꢂ4. ∗ pꢃ0.05, ∗∗ pꢃ0.01, vs. control, Student’s t-test.
Table 4. Effects of Repeated Administration of 14c and Rosiglitazone for 14 d in Male ICR Mice
14c (mg/kg/d)
Rosiglitazone (mg/kg/d)
Control
Control
30
100
30
100
Plasma (ml)
Heart (g)
Liver (g)
1.53ꢄ0.06
0.18ꢄ0.01
2.41ꢄ0.07
1.64ꢄ0.07
0.19ꢄ0.01
2.32ꢄ0.13
1.71ꢄ0.16
0.18ꢄ0.00
2.12ꢄ0.11
1.73ꢄ0.26
0.18ꢄ0.01
2.53ꢄ0.17
2.02ꢄ0.20
0.19ꢄ0.02
2.76ꢄ0.27
2.10ꢄ0.16*
0.19ꢄ0.01
2.78ꢄ0.20*
MeanꢄS.E. nꢂ5—6. ∗ pꢃ0.05, vs. control, Student’s t-test.
potent PTP-1B inhibitory activity.
as an anti-diabetic drug than rosiglitazone in mice, which
The effects of 14c were pharmacologically and toxicologi- may be due to, at least in part, its PTP-1B inhibitory activity.
cally evaluated in comparison with rosiglitazone. Compound In patients, its human PPARa agonist activity is also ex-
14c (1, 3 mg/kg/d) and rosiglitazone (10, 30 mg/kg/d) show- pected to potentiate PPARg-mediated anti-diabetic effects
ed similar hypoglycemic and hypotriglyceridemic effects in and reduce adverse effects.
KK-Ay mice, indicating that 14c was about 10-fold stronger
than rosiglitazone (Table 2); however, PPARg agonist activity
of 14c was comparable to that of rosiglitazone, and its in-
Experimental
General Melting points were measured on a melting point apparatus
(Yamato MP-21; Yamato Scientific Co., Ltd., Tokyo, Japan) and are uncor-
sulin-enhancing activity in adipocyte differentiation was
about 1/5-fold weaker than that of rosiglitazone (unpublished
data). In separate experiments, the Cmax of 14c (3 mg/kg) and
rosiglitazone (30 mg/kg) after oral administration in KK-Ay
mice was 1.7 and 34.6 mg/ml, respectively. It remains to be
determined why 14c had greater hypoglycemic and hy-
potriglyceridemic effects despite comparable PPARg agonist
activity and lower plasma concentrations than rosiglitazone.
It is likely that PTP-1B inhibitory activity is involved in the
hypoglycemic and hypotriglyceridemic effects since Cmax of
14c exceeded the IC50 value for PTP-1B inhibition. Involve-
ment of PPARa agonist activity can be eliminated in KK-Ay
mice since it failed to activate mouse PPARa. However, in
male Syrian hamsters, compound 14c, but not rosiglitazone,
at 30 mg/kg/d for 7 d significantly increased hepatic peroxi-
some acyl CoA oxidase (ACO) activity, probably due to its
rected. 1H-NMR spectra were obtained on a nuclear magnetic resonance
spectrometer at 90 MHz (R-1900; Hitachi High-Technologies Corporation,
Tokyo, Japan) or 400 MHz (JNM-AL-400; JEOL Ltd., Tokyo, Japan) using
tetramethylsilane (TMS) as an internal standard. IR spectra were recorded
with an infrared spectrometer (FT-IR8200PC; Shimadzu Corporation,
Kyoto, Japan). MS spectra were obtained on a QTRAP LC/MS/MS system
(API2000; Applied Biosystems, Foster, U.S.A.). Column chromatography
was performed on silica gel (Daisogel No.1001W; Daiso Co., Ltd., Osaka,
Japan). Reactions were monitored by TLC (TLC silica gel 60 F254, Merck,
Darmstadt, Germany).
Methyl {2-[(E)-2-Cyclopropylvinyl]-5-methyloxazol-4-yl}acetate (6a)
Triethylamine (52.0 ml, 373 mmol) was added dropwise to a suspension of 2
(22.7 g, 124 mmol) in CH2Cl2 (320 ml) and the suspension was stirred at
room temperature for 30 min. Separately, to a solution of 3a (9.40 g,
83.8 mmol) and triethylamine (13.0 ml, 93.3 mmol) in CH2Cl2 (130 ml) was
added isobutyl chloroformate (12.0 ml, 92.5 mmol) below 10 °C. After stir-
ring at the same temperature for 20 min, the mixture was added to the above
suspension below 10 °C, and stirred at the same temperature for 1 h. The re-
action mixture was washed with water, 1 M HCl and saturated brine, and
PPARa agonist activity (Table 3). It has been reported that dried over Na2SO4. The solvent was evaporated under reduced pressure to
give crude 4a (24.1 g) as an oil. Crude 4a (24.1 g), acetic anhydride (39.0 ml,
413 mmol), N-methylmorpholine (36.0 ml, 327 mmol) and 4-dimethyl-
aminopyridine (DMAP) (2.00 g, 16.3 mmol) were dissolved in toluene
(240 ml) and stirred at 60—70 °C for 1.5 h. After cooling to room tempera-
TZD18, a human but not mouse PPARa/g dual agonist, in-
creased hamster ACO activities.31) In male ICR mice, re-
peated administration of 14c at 30 and 100 mg/kg/d for 14 d
had little toxicity, while rosiglitazone at 100 mg/kg/d signifi-
cantly increased plasma volume and liver weight (Table 4).
From the results in KK-Ay mice and ICR mice, the safety
margin of 14c and rosiglitazone was estimated to be ꢁ100-
fold and 10-fold, respectively.
In conclusion, new tetrahydroisoquinoline derivatives were
identified as a PPARa/g dual agonist with PTP-1B inhibitory
activity stronger than compound 1. Cycloalkylvinyl moiety
was demonstrated to be more suitable than a phenyl group
for interaction with PPARg, PPARa and PTP-1B protein.
Compound 14c was proven to be more efficacious and safer
ture, the reaction mixture was neutralized with saturated aqueous NaHCO3
solution and separated into two layers. The organic layer was washed with
water and saturated brine, and dried over Na2SO4. The solvent was evapo-
rated under reduced pressure to give crude 5a (7.68 g) as a solid. To a solu-
tion of crude 5a (7.68 g) in toluene (150 ml) was added POCl3 (4.0 ml.
43 mmol), and the mixture was stirred at 100 °C for 45 min. After cooling,
the mixture was poured into cold water, neutralized with NaHCO3, and ex-
tracted with AcOEt. The organic layer was washed with water and saturated
brine, dried over Na2SO4, and then evaporated under reduced pressure. The
obtained residue was purified by silica gel column chromatography to give
1
6a (2.17 g, 12% yield) as an oil. H-NMR (CDCl3) d: 0.45—0.70 (2H, m),
0.75—1.05 (2H, m), 1.40—1.80 (1H, m), 2.25 (3H, s), 3.46 (2H, s), 3.70
(3H, s), 5.95—6.45 (2H, m). IR (neat) cmꢀ1: 1744, 1655, 1537.

1238
Compounds 6b—f were prepared according to the procedure for the syn-
Vol. 59, No. 10
12 mmol) at 0 °C, and the mixture was stirred for 20 min. The reaction mix-
ture was washed with 10% aqueous citric acid solution and saturated brine,
and dried over Na2SO4, The solvent was evaporated under reduced pressure.
thesis of 6a.
Methyl {2-[(E)-2-Cyclobutylvinyl]-5-methyloxazol-4-yl}acetate (6b)
1
Yield 32%. H-NMR (CDCl3) d: 1.80—2.01 (4H, m), 2.12—2.24 (2H, m), The obtained residue was purified by silica gel column chromatography to
1
2.27 (3H, s), 3.04—3.16 (1H, m), 3.47 (2H, s), 3.70 (3H, s), 6.13 (1H, dd, give 9a (1.67 g, 63% yield) as an oil. H-NMR (CDCl3) d: 0.50—0.70 (2H,
Jꢂ15.9, 1.5 Hz), 6.72 (1H, dd, Jꢂ15.9, 7.1 Hz). IR (neat) cmꢀ1: 1746, 1644, m), 0.75—1.10 (2H, m), 1.40—1.80 (1H, m), 2.25 (3H, s), 2.85 (2H, t,
1610, 1534.
Jꢂ6.6 Hz), 2.93 (3H, s), 4.44 (2H, t, Jꢂ6.6 Hz), 5.95—6.40 (2H, m). IR
Methyl {2-[(E)-2-Cyclopentylvinyl]-5-methyloxazol-4-yl}acetate (6c) (neat) cmꢀ1: 1655, 1538.
1
Yield 30%. H-NMR (CDCl3) d: 1.10—2.00 (8H, m), 2.27 (3H, s), 2.35—
2.78 (1H, m), 3.47 (2H, s), 3.70 (3H, s), 6.16 (1H, d, Jꢂ16.0 Hz), 6.62 (1H,
dd, Jꢂ16.0, 7.5 Hz). IR (neat) cmꢀ1: 2953, 2870, 1746, 1659, 1643, 1551,
1535.
Compounds 9b—i were prepared according to the procedure for the syn-
thesis of 9a.
2-{2-[(E)-2-Cyclobutylvinyl]-5-methyloxazol-4-yl}ethyl Methanesul-
1
fonate (9b) Yield 63%. H-NMR (CDCl3) d: 1.77—2.01 (4H, m), 2.12—
Methyl {2-[(E)-2-Cyclohexylvinyl]-5-methyloxazol-4-yl}acetate (6d) 2.23 (2H, m), 2.27 (3H, s), 2.86 (2H, t, Jꢂ6.6 Hz), 2.94 (3H, s), 3.04—3.16
1
Yield 38%. H-NMR (CDCl3) d: 0.80—2.40 (11H, m), 2.27 (3H, s), 3.47 (1H, m), 4.45 (2H, t, Jꢂ6.6 Hz), 6.10 (1H, dt, Jꢂ16.1, 1.4 Hz), 6.71 (1H, dt,
(2H, s), 3.70 (3H, s), 6.14 (1H, d, Jꢂ16.0 Hz), 6.60 (1H, dd, Jꢂ16.0, Jꢂ16.1, 7.1 Hz). IR (neat) cmꢀ1: 1645, 1533.
6.3 Hz). IR (neat) cmꢀ1: 1746, 1643, 1533.
2-{2-[(E)-2-Cyclopentylvinyl]-5-methyloxazol-4-yl}ethyl Methanesul-
Methyl (2-Cyclohexylidenemethyl-5-methyloxazol-4-yl)acetate (6e) fonate (9c) Yield 68%. 1H-NMR (CDCl3) d: 1.20—2.00 (8H, m), 2.26
1
Yield 23%. H-NMR (CDCl3) d: 1.40—1.90 (6H, m), 2.00—2.35 (2H, m), (3H, s), 2.36—2.78 (1H, m), 2.86 (2H, t, Jꢂ6.6 Hz), 2.94 (3H, s), 4.44 (2H,
2.60—3.00 (2H, m), 2.27 (3H, s), 3.49 (2H, s), 3.70 (3H, s), 5.95 (1H, s). IR t, Jꢂ6.6 Hz), 6.14 (1H, d, Jꢂ15.8 Hz), 6.62 (1H, dd, Jꢂ15.8, 7.5 Hz). IR
(neat) cmꢀ1: 2930, 2855, 1778, 1743, 1655, 1546, 1520.
(neat) cmꢀ1: 2955, 2870, 1736, 1645, 1533.
Methyl {2-[(Z)-2-Cyclopentyl-1-methylvinyl]-5-methyloxazol-4-yl}ace-
tate (6f) Yield 40%. H-NMR (CDCl3) d: 1.05—2.15 (8H, m), 2.05 (3H, fonate (9d) Yield 33%. H-NMR (CDCl3) d: 0.85—2.50 (11H, m), 2.26
s), 2.29 (3H, s), 3.16—3.60 (1H, m), 3.52 (2H, s), 3.71 (3H, s), 5.66 (1H, dd, (3H, s), 2.86 (2H, t, Jꢂ6.6 Hz), 2.94 (3H, s), 4.44 (2H, t, Jꢂ6.6 Hz), 6.11
2-{2-[(E)-2-Cyclohexylvinyl]-5-methyloxazol-4-yl}ethyl Methanesul-
1
1
Jꢂ9.5, 0.9 Hz). IR (neat) cmꢀ1: 2953, 2866, 1747, 1645, 1541, 1522.
(E)-3-(1-Methylcyclopentyl)acrylamide (7g) Thionyl chloride (18 ml,
0.25 mol) was added to (E)-3-(1-methylcyclopentyl)acrylic acid (12.5 g,
81.0 mmol) and the mixture was stirred at room temperature for 2 h. Thionyl
chloride was evaporated under reduced pressure, and the obtained residue
(1H, d, Jꢂ16.1 Hz), 6.46 (1H, dd, Jꢂ16.1, 6.6 Hz). IR (neat) cmꢀ1: 1643,
1533.
2-(2-Cyclohexylidenemethyl-5-methyloxazol-4-yl)ethyl Methanesul-
1
fonate (9e) Yield 69%. H-NMR (CDCl3) d: 1.40—1.90 (6H, m), 2.00—
2.35 (2H, m), 2.60—3.00 (2H, m), 2.26 (3H, s), 2.86 (2H, t, Jꢂ6.6 Hz), 2.93
was added dropwise to 28% aqueous NH3 (50 ml, 0.74 mol) below 0 °C and (3H, s), 4.46 (2H, t, Jꢂ6.6 Hz), 5.95 (1H, s). IR (neat) cmꢀ1: 1651, 1545.
the mixture was stirred at the same temperature for 1 h. AcOEt was added to
the reaction mixture and the organic layer was washed with saturated brine,
dried over Na2SO4, and then evaporated under reduced pressure. The ob-
tained residue was rinsed with n-hexane to give 7g (9.77 g, 79% yield) as a
2-{2-[(Z)-2-Cyclopentyl-1-methylvinyl]-5-methyloxazol-4-yl}ethyl
1
Methanesulfonate (9f) Yield 88%. H-NMR (CDCl3) d: 1.08—2.06 (8H,
m), 2.04, (3H, s), 2.29 (3H, s), 2.89 (2H, t, Jꢂ6.6 Hz), 2.94 (3H, s), 3.12—
3.61 (1H, m), 4.47 (2H, t, Jꢂ6.6 Hz), 5.67 (1H, dd, Jꢂ9.5, 1.2 Hz). IR (neat)
colorless solid. 1H-NMR (CDCl3) d: 1.12 (3H, s), 1.30—2.00 (8H, m), cmꢀ1: 3630, 3416, 3020, 2953, 2866, 1645, 1522.
5.20—6.40 (2H, br), 5.75 (1H, d, Jꢂ15.8 Hz), 6.92 (1H, d, Jꢂ15.8 Hz). IR
2-{5-Methyl-2-[(E)-2-(1-methylcyclopentyl)vinyl]oxazol-4-yl}ethyl
(Nujol) cmꢀ1: 3350, 3161, 1668, 1601.
Methanesulfonate (9g) Yield 96%. 1H-NMR (CDCl3) d: 1.06 (3H, s),
1.20—1.80 (8H, m), 2.28 (3H, s), 2.87 (2H, t, Jꢂ6.7 Hz), 2.95 (3H, s), 4.45
(2H, t, Jꢂ6.7 Hz), 6.12 (1H, d, Jꢂ16.5 Hz), 6.63 (1H, d, Jꢂ16.5 Hz). IR
(neat) cmꢀ1: 2928, 2852, 1645, 1531.
Compound 7h was prepared according to the procedure for the synthesis
of 7g.
(E)-3-(1-Methylcyclohexyl)acrylamide (7h) Yield 96%. 1H-NMR
(CDCl3) d: 1.03 (3H, s), 1.10—1.75 (10H, m), 5.20—6.20 (2H, br), 5.75
2-{5-Methyl-2-[(E)-2-(1-methylcyclohexyl)vinyl]oxazol-4-yl}ethyl
(1H, d, Jꢂ16.0 Hz), 6.84 (1H, d, Jꢂ16.0 Hz). IR (Nujol) cmꢀ1: 3339, 3186, Methanesulfonate (9h) Yield 81%. 1H-NMR (CDCl3) d: 1.15 (3H, s),
2928, 2853, 1672, 1638, 1609.
1.35—1.90 (10H, m), 2.27 (3H, s), 2.86 (2H, t, Jꢂ6.6 Hz), 2.94 (3H, s), 4.45
(2H, t, Jꢂ6.6 Hz), 6.13 (1H, d, Jꢂ16.3 Hz), 6.71 (1H, d, Jꢂ16.3 Hz). IR
(neat) cmꢀ1: 2957, 2871, 1645, 1551, 1533.
Methyl {5-Methyl-2-[(E)-2-(1-methylcyclopentyl)vinyl]oxazol-4-yl}ace-
tate (6g) Compound 8 (17.5 g, 83.7 mmol) was added to a suspension of
7g (9.75 g, 63.6 mmol) in toluene (50 ml) and the suspension was refluxed
for 14 h. AcOEt (100 ml) was added to the reaction mixture, and the mixture
was washed with water and saturated brine, and dried over Na2SO4. The sol- (4H, m), 1.68—1.83 (5H, m), 2.23 (3H, s), 2.67 (2H, t, Jꢂ7.8 Hz), 2.84 (2H,
vent was evaporated under reduced pressure. The obtained residue was puri-
2-[2-(2-Cyclopentylethyl)-5-methyloxazol-4-yl]ethyl Methanesulfonate
(9i) Yield 63%. 1H-NMR (CDCl3) d: 1.06—1.18 (2H, m), 1.46—1.65
t, Jꢂ6.8 Hz), 2.94 (3H, s), 4.42 (2H, t, Jꢂ6.8 Hz). IR (neat) cmꢀ1: 1738,
1653, 1578.
Methyl (S)-2-tert-Butoxycarbonyl-7-(2-{2-[(E)-2-cyclopropylvinyl]-5-
fied by silica gel column chromatography to give 6g (5.40 g, 32% yield) as a
1
white solid. H-NMR (CDCl3) d: 1.12 (3H, s), 1.30—2.00 (8H, m), 2.27
(3H, s), 3.48 (2H, s), 3.71 (3H, s), 6.15 (1H, d, Jꢂ16.5 Hz), 6.71 (1H, d, methyloxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
Jꢂ16.5 Hz). IR (neat) cmꢀ1: 2955, 2872, 1746, 1653, 1551.
Compound 6h was prepared according to the procedure for the synthesis
of 6g.
(11a) A mixture of 10 (1.25 g, 4.07 mmol), 9a (1.65 g, 6.08 mmol),
tetraethylammonium fluoride (250 mg) and K2CO3 (1.70 g, 12.3 mmol) in
toluene (40 ml) was stirred at 90 °C for 12 h. AcOEt was added to the reac-
Methyl {5-Methyl-2-[(E)-2-(1-methylcyclohexyl)vinyl]oxazol-4-yl}ace- tion mixture, which was washed with water and saturated brine, and dried
tate (6h) Yield 29%. 1H-NMR (CDCl3) d: 1.05 (3H, s), 1.20—1.80 (10H, over Na2SO4. The solvent was evaporated under reduced pressure. The ob-
m), 2.28 (3H, s), 3.48 (2H, s), 3.71 (3H, s), 6.15 (1H, d, Jꢂ16.5 Hz), 6.63
(1H, d, Jꢂ16.5 Hz). IR (neat) cmꢀ1: 2928, 2853, 1746, 1647.
tained residue was purified by silica gel column chromatography to give 11a
(1.95 g, 80% yield) as an oil. 1H-NMR (CDCl3) d: 0.50—0.70 (2H, m),
0.75—1.10 (2H, m), 1.40—1.80 (10H, m), 2.26 (3H, s), 2.86 (2H, t,
Jꢂ6.6 Hz), 2.95—3.25 (2H, m), 3.61 (3H, s), 4.16 (2H, t, Jꢂ6.6 Hz), 4.25—
5.20 (3H, m), 5.95—6.40 (2H, m), 6.55—6.80 (2H, m), 7.01 (1H, d,
Jꢂ8.6 Hz). IR (neat) cmꢀ1: 1742, 1699, 1655, 1614, 1587, 1535, 1506.
Compounds 11b—i were prepared according to the procedure for the syn-
thesis of 11a.
Methyl [2-(2-Cyclopentylethyl)-5-methyloxazol-4-yl]acetate (6i)
Compound 6c (2.00 g, 8.02 mmol) in MeOH (40 ml) was hydrogenated at
0.4 MPa in the presence of 10% Pd–C (300 mg) at room temperature for
15 h. After removal of the catalyst by filtration, the filtrate was evaporated
under reduced pressure to give crude 6i (1.86 g) as an oil. Crude 6i was used
for subsequent reaction without further purification.
2-{2-[(E)-2-Cyclopropylvinyl]-5-methyloxazol-4-yl}ethyl Methanesul-
fonate (9a) To a solution of 6a (2.15 g, 9.72 mmol) in toluene (30 ml) was
added 1.5 M diisobutylaluminum hydride in toluene (20.0 ml, 30.0 mmol) at
ꢀ40 °C, and the mixture was stirred at the same temperature for 1 h. The
mixture was poured into cold water (50 ml) and stirred at room temperature
for 30 min. The precipitate was removed by filtration, and the filtrate was
separated into two layers. The organic layer was washed with saturated
brine, dried over Na2SO4, and then evaporated under reduced pressure. To a
solution of the obtained residue (1.81 g) and triethylamine (1.76 ml,
12.6 mmol) in CH2Cl2 (20 ml) was added methanesulfonyl chloride (0.90 ml,
Methyl
(S)-2-tert-Butoxycarbonyl-7-(2-{2-[(E)-2-cyclobutylvinyl]-5-
methyloxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
(11b) Yield 87%. H-NMR (CDCl3) d: 1.45, 1.52 (total 9H, s, s), 1.77—
1
2.01 (4H, m), 2.12—2.23 (2H, m), 2.28 (3H, s), 2.87 (2H, t, Jꢂ6.6 Hz),
3.02—3.21 (3H, m), 3.60, 3.62 (total 3H, s, s), 4.14 (2H, t, Jꢂ6.6 Hz), 4.41,
4.64 (1H, AB-q, Jꢂ16.4 Hz), 4.46, 4.67 (1H, AB-q, Jꢂ16.4 Hz), 4.74 (0.5H,
t, Jꢂ5.6 Hz), 5.10 (0.5H, dd, Jꢂ5.6, 2.7 Hz), 6.11 (1H, d, Jꢂ16.1 Hz),
6.58—6.75 (3H, m), 7.01 (1H, d, Jꢂ8.3 Hz). IR (neat) cmꢀ1: 1743, 1699,
1615, 1533, 1506.
Methyl (S)-2-tert-Butoxycarbonyl-7-(2-{2-[(E)-2-cyclopentylvinyl]-5-

October 2011
1239
methyloxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
cmꢀ1: 1739, 1644, 1615, 1583, 1505.
Methyl (S)-7-(2-{2-[(E)-2-Cyclopentylvinyl]-5-methyloxazol-4-
(11c) Yield 80%. 1H-NMR (CDCl3) d: 1.20—2.00 (17H, m), 2.27 (3H, s),
2.34—2.74 (1H, m), 2.86 (2H, t, Jꢂ6.6 Hz), 2.99—3.20 (2H, m), 3.61 (3H, yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (12c) Yield
1
s), 4.12 (2H, t, Jꢂ6.6 Hz), 4.24—5.20 (3H, m), 6.15 (1H, d, Jꢂ16.1 Hz), 98%. H-NMR (CDCl3) d: 1.20—1.97 (8H, m), 1.99 (1H, s), 2.27 (3H, s),
6.61 (1H, dd, Jꢂ16.1, 7.5 Hz), 6.53—6.80 (2H, m), 7.01 (1H, d, Jꢂ8.3 Hz). 2.30—2.77 (1H, m), 2.86 (2H, t, Jꢂ6.7 Hz), 2.80—3.10 (2H, m), 3.60—
IR (neat) cmꢀ1: 2955, 2970, 1742, 1699, 1614, 1533, 1506.
3.83 (1H, m), 3.76 (3H, s), 3.95—4.34 (4H, m), 6.15 (1H, d, Jꢂ16.0 Hz),
6.41—6.80 (3H, m), 6.99 (1H, d, Jꢂ8.4 Hz). IR (neat) cmꢀ1: 3344, 2951,
2870, 2777, 2740, 1659, 1643, 1612, 1504.
Methyl (S)-2-tert-Butoxycarbonyl-7-(2-{2-[(E)-2-cyclohexylvinyl]-5-
methyloxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
1
(11d) Yield 91%. H-NMR (CDCl3) d: 0.70—2.50 (11H, m), 1.46, 1.51
Methyl (S)-7-(2-{2-[(E)-2-Cyclohexylvinyl]-5-methyloxazol-4-
(total 9H, s, s), 2.27 (3H, s), 2.86 (2H, t, Jꢂ6.7 Hz), 2.95—3.25 (2H, m),
yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (12d) Yield
1
3.61 (3H, s), 4.14 (2H, t, Jꢂ6.6 Hz), 4.25—5.20 (3H, m), 6.13 (1H, d, 92%. H-NMR (CDCl3) d: 0.80—2.45 (12H, m), 2.27 (3H, s), 2.70—3.20
Jꢂ16.0 Hz), 6.35—6.80 (3H, m), 7.01 (1H, d, Jꢂ8.3 Hz). IR (neat) cmꢀ1
:
(2H, m), 2.86 (2H, t, Jꢂ6.8 Hz), 3.55—3.85 (1H, m), 3.76 (3H, s), 4.04 (2H,
s), 4.14 (2H, t, Jꢂ6.8 Hz), 6.12 (1H, d, Jꢂ16.0 Hz), 6.40—6.80 (3H, m),
6.99 (1H, d, Jꢂ8.4 Hz). IR (neat) cmꢀ1: 1740, 1612, 1504.
1742, 1703, 1614, 1506.
Methyl (S)-2-tert-Butoxycarbonyl-7-[2-(2-cyclohexylidenemethyl-5-
methyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
Methyl (S)-7-[2-(2-Cyclohexylidenemethyl-5-methyloxazol-4-
1
(11e) Yield quant. H-NMR (CDCl3) d: 1.35—1.95 (15H, m), 2.00—2.35 yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (12e) Yield
(2H, m), 2.60—3.00 (2H, m), 2.27 (3H, s), 2.87 (2H, t, Jꢂ6.6 Hz), 3.00— 94%. 1H-NMR (CDCl3) d: 1.35—1.95 (6H, m), 2.00—2.35 (2H, m), 2.60—
3.25 (2H, m), 3.61 (3H, s), 4.15 (2H, t, Jꢂ6.6 Hz), 4.25—5.25 (3H, m), 5.94 3.00 (2H, m), 2.16 (1H, s), 2.27 (3H, s), 2.70—3.10 (4H, m), 3.50—3.70
(1H, s), 6.55—6.80 (2H, m), 7.01 (1H, d, Jꢂ8.4 Hz). IR (neat) cmꢀ1: 2977, (1H, m), 3.76 (3H, s), 4.05 (2H, s), 4.15 (2H, t, Jꢂ6.8 Hz), 5.94 (1H, s),
2930, 2855, 1741, 1701, 1654, 1643, 1613, 1546, 1507.
6.55 (1H, d, Jꢂ1.5 Hz), 6.70 (1H, dd, Jꢂ8.3, 1.5 Hz), 6.99 (1H, d,
Jꢂ8.3 Hz). IR (neat) cmꢀ1: 3344, 2929, 2854, 1740, 1653, 1645, 1612,
1545, 1505.
Methyl (S)-2-tert-Butoxycarbonyl-7-(2-{2-[(Z)-2-cyclopentyl-1-
methylvinyl]-5-methyloxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquino-
line-3-carboxylate (11f) Yield quant. 1H-NMR (CDCl3) d: 1.10—2.10
Methyl (S)-7-(2-{2-[(Z)-2-Cyclopentyl-1-methylvinyl]-5-methyloxazol-
(17H, m), 2.05 (3H, s), 2.30 (3H, s), 2.90 (2H, t, Jꢂ6.8 Hz), 3.00—3.20 4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (12f) Yield
1
(2H, m), 3.20—3.60 (1H, m), 3.62 (3H, s), 4.16 (2H, t, Jꢂ6.6 Hz), 4.28— quant. H-NMR (CDCl3) d: 1.09—2.09 (9H, m), 2.04 (3H, s), 2.29 (3H, s),
5.25 (3H, m), 5.65 (1H, d, Jꢂ9.6 Hz), 6.58—6.83 (2H, m), 7.02 (1H, d, 2.85—3.04 (4H, m), 3.16—3.60 (1H, m), 3.60—3.75 (1H, m), 3.76 (3H, s),
Jꢂ8.4 Hz). IR (neat) cmꢀ1: 3464, 2928, 2870, 1742, 1699, 1645, 1614, 4.05 (2H, s), 4.16 (2H, t, Jꢂ6.5 Hz), 5.64 (1H, d, Jꢂ9.5 Hz), 6.46—6.80
1587, 1506.
(2H, m), 7.00 (1H, d, Jꢂ8.2 Hz). IR (neat) cmꢀ1: 3346, 2951, 2868, 1740,
1643, 1612, 1504.
Methyl (S)-2-tert-Butoxycarbonyl-7-(2-{5-methyl-2-[(E)-2-(1-methyl-
cyclopentyl)vinyl]oxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-
carboxylate (11g) Yield 99%. H-NMR (CDCl3) d: 1.15 (3H, s), 1.25— 4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (12g) Yield
2.00 (17H, m), 2.28 (3H, s), 2.87 (2H, t, Jꢂ6.8 Hz), 3.00—3.25 (2H, m),
Methyl (S)-7-(2-{5-Methyl-2-[(E)-2-(1-methylcyclopentyl)vinyl]oxazol-
1
1
93%. H-NMR (CDCl3) d: 1.14 (3H, s), 1.30—1.94 (8H, m), 2.28 (3H, s),
3.61 (3H, s), 4.15 (2H, t, Jꢂ6.8 Hz), 4.45—5.30 (3H, m), 6.14 (1H, d, 2.31 (1H, s), 2.65—3.25 (4H, m), 3.60—3.80 (1H, m), 3.76 (3H, s), 4.08
Jꢂ16.3 Hz), 6.60—6.90 (3H, m), 7.01 (1H, d, Jꢂ8.6 Hz). IR (neat) cmꢀ1
:
(2H, s), 4.14 (2H, t, Jꢂ6.8 Hz), 6.14 (1H, d, Jꢂ16.3 Hz), 6.50—6.80 (3H,
m), 6.99 (1H, d, Jꢂ8.1 Hz). IR (neat) cmꢀ1: 3323, 2955, 2872, 1736, 1618,
1531, 1506.
2934, 2872, 1740, 1699, 1647, 1616, 1533, 1506.
Methyl (S)-2-tert-Butoxycarbonyl-7-(2-{5-methyl-2-[(E)-2-(1-methyl-
cyclohexyl)vinyl]oxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-
carboxylate (11h) Yield quant. H-NMR (CDCl3) d: 1.05 (3H, s), 1.10— 4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (12h) Yield
1.80 (19H, m), 2.28 (3H, s), 2.87 (2H, t, Jꢂ6.6 Hz), 2.95—3.20 (2H, m),
Methyl (S)-7-(2-{5-Methyl-2-[(E)-2-(1-methylcyclohexyl)vinyl]oxazol-
1
97%. 1H-NMR (CDCl3) d: 1.05 (3H, s), 1.20—1.80 (10H, m), 1.97 (1H, s),
3.61 (3H, s), 4.15 (2H, t, Jꢂ6.6 Hz), 4.25—5.25 (3H, m), 6.14 (1H, d, 2.28 (3H, s), 2.87 (2H, t, Jꢂ6.8 Hz), 2.90—3.05 (2H, m), 3.60—3.80 (1H,
Jꢂ16.5 Hz), 6.60—6.85 (3H, m), 7.01 (1H, d, Jꢂ8.6 Hz). IR (neat) cmꢀ1
:
m), 3.76 (3H, s), 4.04 (2H, s), 4.15 (2H, t, Jꢂ6.8 Hz), 6.14 (1H, d,
2928, 2853, 1742, 1701, 1616, 1506.
Jꢂ16.5 Hz), 6.55—6.85 (3H, m), 6.99 (1H, d, Jꢂ8.6 Hz). IR (neat) cmꢀ1
:
Methyl (S)-2-tert-Butoxycarbonyl-7-{2-[2-(2-cyclopentylethyl)-5-
3346, 2926, 2851, 1740, 1645, 1612, 1531, 1504.
methyloxazol-4-yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
Methyl (S)-7-{2-[2-(2-Cyclopentylethyl)-5-methyloxazol-4-yl]ethoxy}-
(11i) Yield quant. 1H-NMR (CDCl3) d: 1.06—1.16 (2H, m), 1.44, 1.52 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (12i) Yield 90%. H-NMR
(total 9H, s, s), 1.46—1.64 (4H, m), 1.70—1.83 (5H, m), 2.23 (3H, s), 2.67 (CDCl3) d: 1.03—1.19 (2H, m), 1.45—1.64 (4H, m), 1.68—1.83 (5H, m),
(2H, t, Jꢂ7.8 Hz), 2.84 (2H, t, Jꢂ6.8 Hz), 3.02—3.21 (2H, m), 3.60, 3.63 2.20—2.27 (4H, m), 2.67 (2H, t, Jꢂ7.8 Hz), 2.82—2.91 (3H, m), 3.01 (1H,
(total 3H, s, s), 4.07—4.17 (2H, m), 4.36—4.50 (1H, m), 4.58—4.77 (1.5H, dd, Jꢂ15.8, 4.6 Hz), 3.72 (1H, dd, Jꢂ10.2, 4.6 Hz), 3.77 (3H, s), 4.00—4.16
1
m), 5.07—5.14 (0.5H, m), 6.58—6.75 (2H, m), 7.01 (1H, d, Jꢂ8.3 Hz). IR
(4H, m), 6.55 (1H, d, Jꢂ2.2 Hz), 6.70 (1H, dd, Jꢂ8.3, 2.2 Hz), 6.99 (1H, d,
(neat) cmꢀ1: 1741, 1703, 1653, 1614, 1578, 1506.
Jꢂ8.3 Hz). IR (neat) cmꢀ1: 1742, 1653, 1612, 1578, 1504.
Methyl (S)-7-(2-{2-[(E)-2-Cyclopropylvinyl]-5-methyloxazol-4-
Methyl (S)-7-(2-{2-[(E)-2-Cyclopropylvinyl]-5-methyloxazol-4-
yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (12a) To a so- yl}ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-
lution of 11a (1.93 g, 4.00 mmol) in formic acid (10 ml) was added saturated
hydrogen chloride solution in 2-propanol (1.20 ml) under ice-cooling, which
was stirred at room temperature for 30 min. AcOEt (100 ml) was added to
the reaction mixture, and the mixture was neutralized with saturated aqueous
NaHCO3 solution and separated into two layers. The organic layer was
washed with brine and dried over Na2SO4. The solvent was evaporated under
carboxylate (13a) To a solution of 12a (1.39 g, 3.63 mmol) in CH2Cl2
(15 ml) was added triethylamine (0.76 ml, 5.5 mmol) and (2E,4E)-hexa-
dienoyl chloride (570 mg, 4.37 mmol) under ice-cooling, and the mixture
was stirred at the same temperature for 30 min. The reaction mixture was
washed with water and saturated brine, and dried over Na2SO4. The solvent
was evaporated under reduced pressure, and the obtained residue was puri-
reduced pressure to give 12a (1.41 g, 92% yield) as an oil. 1H-NMR (CDCl3) fied by silica gel column chromatography to give 13a (1.42 g, 82% yield) as
d: 0.50—0.70 (2H, m), 0.75—1.10 (2H, m), 1.40—1.80 (1H, m), 2.25 (3H, an oil. 1H-NMR (CDCl3) d: 0.50—0.70 (2H, m), 0.75—1.10 (2H, m),
s), 2.85 (2H, t, Jꢂ6.6 Hz), 2.90—3.10 (2H, m), 3.60—3.80 (1H, m), 3.76 1.40—1.80 (1H, m), 1.80—2.00 (3H, m), 2.26 (3H, s), 2.86 (2H, t,
(3H, s), 4.04 (2H, s), 4.16 (2H, t, Jꢂ6.6 Hz), 5.95—6.40 (2H, m), 6.54 (1H, Jꢂ6.6 Hz), 3.00—3.25 (2H, m), 3.60 (3H, s), 4.16 (2H, t, Jꢂ6.6 Hz), 4.40—
d, Jꢂ2.4 Hz), 6.69 (1H, dd, Jꢂ8.3, 2.4 Hz), 6.99 (1H, d, Jꢂ8.3 Hz). IR
5.20 (2H, m), 5.40—5.65 (1H, m), 5.80—6.50 (5H, m), 6.60—6.85 (2H, m),
7.03 (1H, d, Jꢂ8.4 Hz), 7.20—7.55 (1H, m). IR (neat) cmꢀ1: 1738, 1653,
1628, 1614, 1535, 1506.
Compounds 13b, 13f—h were prepared according to the procedure for
the synthesis of 13a.
(neat) cmꢀ1: 1738, 1651, 1614, 1583, 1537, 1504.
Compounds 12b—i were prepared according to the procedure for the syn-
thesis of 12a.
Methyl (S)-7-(2-{2-[(E)-2-Cyclobutylvinyl]-5-methyloxazol-4-
yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
(12b) Yield
Methyl (S)-7-(2-{2-[(E)-2-Cyclobutylvinyl]-5-methyloxazol-4-
1
94%. H-NMR (CDCl3) d: 1.76 (1H, br s), 1.77—2.01 (4H, m), 2.12—2.23 yl}ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-
1
(2H, m), 2.28 (3H, s), 2.86 (1H, dd, Jꢂ15.9, 10.2 Hz), 2.87 (2H, t, carboxylate (13b) Yield 88%. H-NMR (CDCl3) d: 1.79—1.99 (7H, m),
Jꢂ6.8 Hz), 3.01 (1H, dd, Jꢂ15.9, 4.4 Hz), 3.04—3.15 (1H, m), 3.71 (1H, 2.13—2.23 (2H, m), 2.28 (3H, s), 2.87 (2H, t, Jꢂ6.6 Hz), 3.04 (0.66H, dd,
dd, Jꢂ10.2, 4.4 Hz), 3.77 (3H, s), 4.02 (1H, d, Jꢂ16.1 Hz), 4.07 (1H, d, Jꢂ14.9, 5.8 Hz), 3.07—3.28 (1.68H, m), 3.15 (0.66H, dd, Jꢂ14.9, 3.4 Hz),
Jꢂ16.1 Hz), 4.14 (2H, t, Jꢂ6.8 Hz), 6.11 (1H, dd, Jꢂ16.1, 1.2 Hz), 6.54
3.60 (3H, s), 4.14 (2H, t, Jꢂ6.6 Hz), 4.52, 4.93 (0.68H, AB-q, Jꢂ17.6 Hz),
(1H, d, Jꢂ2.4 Hz), 6.64—6.76 (2H, m), 6.99 (1H, d, Jꢂ8.3 Hz). IR (neat) 4.70, 4.77 (1.32H, AB-q, Jꢂ15.4 Hz), 4.87—4.93 (0.34H, m), 5.53 (0.66H,

1240
Vol. 59, No. 10
extracted with AcOEt, and the organic layer was washed with water and sat-
urated brine, and then dried over Na2SO4. The solvent was evaporated under
reduced pressure and the obtained residue was dissolved in MeOH (2.0 ml).
After dropwise addition of tert-butylamine (0.60 ml, 5.7 mmol), diisopropyl
ether (100 ml) was added and the mixture was stirred under ice-cooling for
0.5 h. The precipitate was collected by filtration to give 14a (1.20 g, 76%
dd, Jꢂ5.8, 3.4 Hz), 6.06—6.36 (3H, m), 6.11 (1H, d, Jꢂ16.1 Hz), 6.63 (1H,
br s), 6.67—6.75 (2H, m), 7.03 (1H, d, Jꢂ8.3 Hz), 7.34 (1H, dd, Jꢂ14.7,
10.8 Hz). IR (neat) cmꢀ1: 1739, 1652, 1627, 1606, 1532, 1505.
Methyl (S)-7-(2-{2-[(Z)-2-Cyclopentyl-1-methylvinyl]-5-methyloxazol-
4-yl}ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-
1
carboxylate (13f) Yield 85%. H-NMR (CDCl3) d: 1.20—2.15 (11H, m),
1
yield) as a pale yellow solid, mp 169—171 °C. H-NMR (CDCl3) d: 0.50—
2.04 (3H, s), 2.29 (3H, s), 2.90 (2H, t, Jꢂ6.9 Hz), 3.00—3.22 (2H, m),
3.22—3.70 (1H, m), 3.60 (3H, s), 4.16 (2H, t, Jꢂ6.6 Hz), 4.33—5.65 (3H,
m), 5.65 (1H, d, Jꢂ9.6 Hz), 6.00—6.86 (5H, m), 7.04 (1H, d, Jꢂ8.3 Hz),
7.16—7.62 (1H, m). IR (neat) cmꢀ1: 3464, 2953, 2868, 1740, 1653, 1628,
1614, 1506.
0.70 (2H, m), 0.75—1.10 (2H, m), 0.98 (9H, s), 1.40—1.80 (1H, m), 1.80—
2.00 (3H, m), 2.25 (3H, s), 2.84 (2H, t, Jꢂ6.6 Hz), 2.90—3.40 (2H, m), 4.16
(2H, t, Jꢂ6.6 Hz), 4.25—5.45 (3H, m), 5.60—6.75 (8H, m), 6.60—6.85
(2H, m), 6.96 (1H, d, Jꢂ7.9 Hz), 7.05—7.35 (1H, m). IR (Nujol) cmꢀ1
:
1652, 1624, 1601, 1587, 1504. MS m/z: 463 [MꢅH]ꢅ. Anal. Calcd for
C27H30N2O5·C4H11N·0.6H2O: C, 68.13; H, 7.78; N, 7.69. Found: C, 67.88;
H, 7.54; N,7.62.
Methyl (S)-2-[(2E,4E)-Hexadienoyl]-7-(2-{5-methyl-2-[(E)-2-(1-
methylcyclopentyl)vinyl]oxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquino-
1
line-3-carboxylate (13g) Yield 87%. H-NMR (CDCl3) d: 1.14 (3H, s),
Compounds 14b—i were prepared according to the procedure for the syn-
thesis of 14a.
1.40—2.00 (11H, m), 2.28 (3H, s), 2.88 (2H, t, Jꢂ6.8 Hz), 3.00—3.30 (2H,
m), 3.60 (3H, s), 4.16 (2H, t, Jꢂ6.8 Hz), 4.50—5.20 (2H, m), 5.40—5.60
(1H, m), 6.00—6.50 (4H, m), 6.60—6.90 (3H, m), 6.99 (1H, d, Jꢂ8.1 Hz),
7.15—7.55 (1H, m). IR (neat) cmꢀ1: 1740, 1653, 1616, 1531, 1506.
(S)-7-(2-{2-[(E)-2-Cyclobutylvinyl]-5-methyloxazol-4-yl}ethoxy)-2-
[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid
tert-Butylamine Salt (14b) Yield 75%. A white solid, mp 167—169.5 °C.
1H-NMR (CDCl3) d: 1.01 (9H, s), 1.77—2.01 (4H, m), 1.79 (1.5H, d,
Jꢂ6.4 Hz), 1.85 (1.5H, d, Jꢂ6.8 Hz), 2.13—2.23 (2H, m), 2.27, 2.28 (total
3H, s, s), 2.85—3.21 (5H, m), 4.09 (1H, t, Jꢂ6.4 Hz), 4.10 (1H, t,
Jꢂ6.4 Hz), 4.45, 4.92 (1H, AB-q, Jꢂ17.6 Hz), 4.65, 4.70 (1H, AB-q,
Jꢂ16.4 Hz), 4.61—4.65 (0.5H, m), 5.00—5.05 (0.5H, m), 5.10—5.80 (3H,
br), 5.97—6.36 (4H, m), 6.56—6.74 (3H, m), 6.93 (0.5H, d, Jꢂ8.3 Hz), 6.97
(0.5H, d, Jꢂ8.3 Hz), 7.17 (0.5H, dd, Jꢂ14.4, 10.7 Hz), 7.20 (0.5H, dd,
Jꢂ14.4, 10.7 Hz). IR (Nujol) cmꢀ1: 1653, 1626, 1587, 1553, 1506. MS m/z:
477 [MꢅH]ꢅ. Anal. Calcd for C28H32N2O5·C4H11N·0.5H2O: C, 68.79; H,
7.94; N, 7.52. Found: C, 68.76; H, 7.79; N,7.45.
Methyl (S)-2-[(2E,4E)-Hexadienoyl]-7-(2-{5-methyl-2-[(E)-2-(1-
methylcyclohexyl)vinyl]oxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquino-
1
line-3-carboxylate (13h) Yield 99%. H-NMR (CDCl3) d: 1.05 (3H, s),
1.40—1.80 (10H, m), 1.86 (3H, d, Jꢂ4.9 Hz), 2.29 (3H, s), 2.88 (2H, t,
Jꢂ6.8 Hz), 3.00—3.25 (2H, m), 3.60 (3H, s), 4.16 (2H, t, Jꢂ6.8 Hz), 4.55—
5.20 (2H, m), 5.45—5.65 (1H, m), 6.00—6.50 (4H, m), 6.60—6.90 (3H, m),
7.04 (1H, d, Jꢂ8.6 Hz), 7.20—7.55 (1H, m). IR (neat) cmꢀ1: 2928, 2853,
1740, 1653, 1628, 1616, 1531, 1506.
Methyl (S)-7-(2-{2-[(E)-2-Cyclopentylvinyl]-5-methyloxazol-4-
yl}ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-
carboxylate (13c) To a solution of 12c (9.46 g, 23.0 mmol) in CH2Cl2
(100 ml) was added sorbic acid (2.70 g, 24.1 mmol) and EDC (5.20 g,
27.1 mmol) under ice-cooling, and the mixture was stirred at room tempera-
ture for 1.5 h. The reaction mixture was washed with water and saturated
brine, and dried over Na2SO4. The solvent was evaporated under reduced
pressure, and the obtained residue was purified by silica gel column chro-
(S)-7-(2-{2-[(E)-2-Cyclopentylvinyl]-5-methyloxazol-4-yl}ethoxy)-2-
[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid
tert-Butylamine Salt (14c) Yield 64%. A white solid. mp 115—118 °C
(dec.). 1H-NMR (CDCl3) d: 0.99 (9H, s), 1.20—2.05 (11H, m), 2.27 (3H, s),
2.38—2.73 (1H, m), 2.85 (2H, t, Jꢂ6.5 Hz), 2.90—3.40 (2H, m), 4.10 (2H,
t, Jꢂ6.5 Hz), 4.26—5.20 (3H, m), 5.86—7.38 (12H, m). IR (Nujol) cmꢀ1
:
1
matography to give 13c (7.54 g, 64% yield) as an oil. H-NMR (CDCl3) d:
3464, 2731, 2631, 2544, 1653, 1626, 1553, 1506. MS m/z: 491 [MꢅH]ꢅ.
Anal. Calcd for C29H34N2O5·C4H11N: C, 70.31; H, 8.05; N, 7.45. Found: C,
70.29; H, 7.92; N, 7.45.
1.20—1.97 (8H, m), 1.85 (3H, d, Jꢂ4.8 Hz), 2.27 (3H, s), 2.40—2.75 (1H,
m), 2.86 (2H, t, Jꢂ6.5 Hz), 3.00—3.22 (2H, m), 3.59 (3H, s), 4.14 (2H, t,
Jꢂ6.5 Hz), 4.36—5.00 (2H, m), 5.40—5.60 (1H, m), 6.07—6.80 (5H, m),
6.15 (1H, d, Jꢂ16.1 Hz), 6.61 (1H, dd, Jꢂ16.1, 7.2 Hz), 7.03 (1H, d,
Jꢂ8.4 Hz), 7.13—7.50 (1H, m). IR (neat) cmꢀ1: 3464, 2953, 2870, 1740,
1657, 1628, 1605, 1506.
(S)-7-(2-{2-[(E)-2-Cyclohexylvinyl]-5-methyloxazol-4-yl}ethoxy)-2-
[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid
tert-Butylamine Salt (14d) Yield 82%. A white solid, mp 170.5—173 °C.
1H-NMR (CDCl3) d: 0.98 (9H, s), 1.00—2.40 (14H, m), 2.27 (3H, s), 2.85
(2H, t, Jꢂ6.8 Hz), 2.90—3.30 (2H, m), 4.10 (2H, t, Jꢂ6.8 Hz), 4.20—5.20
(3H, m), 5.80—7.45 (12H, m). IR (Nujol) cmꢀ1: 2739, 2635, 2548, 1655,
1630, 1560, 1506. MS m/z: 505 [MꢅH]ꢅ. Anal. Calcd for
C30H36N2O5·C4H11N·0.6H2O: C, 69.38; H, 8.25; N, 7.14. Found: C, 69.19;
H, 8.10; N,7.18.
(S)-7-[2-(2-Cyclohexylidenemethyl-5-methyloxazol-4-yl)ethoxy]-2-
[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid
tert-Butylamine Salt (14e) Yield 72%. A pale yellow solid, mp 161.5—
163.5 °C. 1H-NMR (CDCl3) d: 1.01 (9H, s), 1.45—1.75 (6H, m), 1.75—
2.00 (3H, m), 2.00—2.40 (2H, m), 2.65—3.00 (2H, m), 2.27 (3H, s), 2.86
(2H, t, Jꢂ6.6 Hz), 2.90—3.30 (2H, m), 4.12 (2H, t, Jꢂ6.6 Hz), 4.25—5.20
(3H, m), 5.94 (1H, s), 5.95—7.40 (10H, m). IR (Nujol) cmꢀ1: 2631, 1542,
1652, 1624, 1549, 1506. MS m/z: 491 [MꢅH]ꢅ. Anal. Calcd for
C29H34N2O5·C4H11N·1.0H2O: C, 68.13; H, 8.14; N, 7.22. Found: C, 68.31;
H, 7.99; N,7.35.
(S)-7-(2-{2-[(Z)-2-Cyclopentyl-1-methylvinyl]-5-methyloxazol-4-
yl}ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-
carboxylic Acid tert-Butylamine Salt (14f) Yield 65%. A white solid, mp
131.5—133.5 °C. 1H-NMR (CDCl3) d: 0.98 (9H, s), 1.10—2.10 (11H, d,
Jꢂ6.6 Hz), 2.05 (3H, s), 2.29 (3H, s), 2.89 (2H, t, Jꢂ6.7 Hz), 2.90—3.20
(2H, m), 3.10—3.70 (1H, m), 4.12 (2H, t, Jꢂ6.7 Hz), 4.25—5.20 (3H, m),
5.64 (1H, d, Jꢂ9.5 Hz), 5.90—7.53 (10H, m). IR (Nujol) cmꢀ1: 3017, 2735,
2623, 2523, 1653, 1626, 1593, 1537. MS m/z: 505 [MꢅH]ꢅ. Anal. Calcd for
C30H36N2O5·C4H11N·0.5H2O: C, 69.60; H, 8.25; N, 7.16. Found: C, 68.69;
H, 8.26; N, 7.14.
Compounds 13d, e, i were prepared according to the procedure for the
synthesis of 13c.
Methyl (S)-7-(2-{2-[(E)-2-Cyclohexylvinyl]-5-methyloxazol-4-
yl}ethoxy)-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-
carboxylate (13d) Yield 77%. 1H-NMR (CDCl3) d: 0.85—2.45 (14H, m),
2.27 (3H, s), 2.87 (2H, t, Jꢂ6.8 Hz), 3.00—3.35 (2H, m), 3.59 (3H, s), 4.15
(2H, t, Jꢂ6.8 Hz), 4.30—5.65 (3H, m), 6.00—7.55 (8H, m), 7.03 (1H, d,
Jꢂ8.4 Hz). IR (neat) cmꢀ1: 1745, 1614, 1531, 1506.
Methyl (S)-7-[2-(2-Cyclohexylidenemethyl-5-methyloxazol-4-
yl)ethoxy]-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-car-
boxylate (13e) Yield 92%. 1H-NMR (CDCl3) d: 1.45—1.80 (6H, m),
1.80—2.00 (3H, m), 2.00—2.35 (2H, m), 2.60—3.00 (2H, m), 2.27 (3H, s),
2.87 (2H, t, Jꢂ6.8 Hz), 3.00—3.25 (2H, m), 3.59 (3H, s), 4.15 (2H, t,
Jꢂ6.8 Hz), 4.45—5.20 (2H, m), 5.40—5.70 (1H, m), 5.94 (1H, s), 5.95—
6.50 (3H, m), 6.60—6.90 (2H, m), 7.04 (1H, d, Jꢂ8.2 Hz), 7.15—7.55 (1H,
m). IR (neat) cmꢀ1: 2930, 2855, 1740, 1657, 1628, 1614, 1545, 1506.
Methyl (S)-7-{2-[2-(2-Cyclopentylethyl)-5-methyloxazol-4-yl]ethoxy}-
2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
(13i) Yield 87%. 1H-NMR (CDCl3) d: 1.04—1.17 (2H, m), 1.45—1.66
(4H, m), 1.69—1.82 (5H, m), 1.83—1.92 (3H, m), 2.24 (3H, s), 2.67 (2H, t,
Jꢂ7.8 Hz), 2.85 (2H, t, Jꢂ6.6 Hz), 3.01—3.29 (2H, m), 3.60 (3H, s), 4.14
(2H, t, Jꢂ6.6 Hz), 4.52 (0.2H, d, Jꢂ17.3 Hz), 4.70 (0.8H, d, Jꢂ15.4 Hz),
4.77 (0.8H, d, Jꢂ15.4 Hz), 4.88—4.93 (0.8H, m), 4.93 (0.2H, d,
Jꢂ17.3 Hz), 6.08—6.37 (3H, m), 6.63 (0.8H, s), 6.66—6.78 (1.2H, m), 7.03
(1H, d, Jꢂ8.5 Hz), 7.33 (1H, dd, Jꢂ14.6, 10.7 Hz). IR (neat) cmꢀ1: 1740,
1655, 1628, 1578, 1506.
(S)-2-[(2E,4E)-Hexadienoyl]-7-(2-{5-methyl-2-[(E)-2-(1-methylcy-
clopentyl)vinyl]oxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-
carboxylic Acid tert-Butylamine Salt (14g) Yield 81%. A white solid.
(S)-7-(2-{2-[(E)-2-Cyclopropylvinyl]-5-methyloxazol-4-yl}ethoxy)-2-
[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid
tert-Butylamine Salt (14a) To a solution of 13a (1.40 g, 2.03 mmol) in
tetrahydrofuran (THF)–MeOH (3 : 1, 20 ml) was added 1.0 M aqueous
lithium hydroxide solution (9.0 ml, 9.0 mmol), and the mixture was stirred at
room temperature for 1 h. The mixture was acidified with 6 M HCl and the
solvent was evaporated under reduced pressure. The obtained residue was
1
mp 145—147.5 °C. H-NMR (CDCl3) d: 0.99 (9H, s), 1.14 (3H, s), 1.30—
2.05 (11H, m), 2.28 (3H, s), 2.86 (2H, t, Jꢂ6.8 Hz), 2.90—3.40 (2H, m),
4.11 (2H, t, Jꢂ6.8 Hz), 4.25—5.30 (3H, m), 5.80—7.40 (12H, m). IR
(Nujol) cmꢀ1: 2632, 2543, 2212, 1634, 1549, 1504. MS m/z: 505 [MꢅH]ꢅ.

October 2011
1241
Anal. Calcd for C30H36N2O5·C4H11N·0.5H2O: C, 69.60; H, 8.25; N, 7.16. under deep anesthesia. After euthanasia, livers were isolated and weighed.
Found: C, 69.48; H, 8.07; N, 7.16.
Livers were homogenized and peroxisome fractions were isolated. Acyl CoA
(S)-2-[(2E,4E)-Hexadienoyl]-7-(2-{5-methyl-2-[(E)-2-(1-methylcyclo- oxidase activities were determined according to the methods previously re-
hexyl)vinyl]oxazol-4-yl}ethoxy)-1,2,3,4-tetrahydroisoquinoline-3-car-
ported.33) Enzyme activity was expressed as a change in absorbance at
502 nm (Dabsorbance/min).
boxylic Acid tert-Butylamine Salt (14h) Yield 62%. A white solid. mp
1
137.5—140 °C. H-NMR (CDCl3) d: 0.97 (9H, s), 1.05 (3H, s), 1.20—2.00
Effects of 14c and Rosiglitazone in Male ICR Mice Male ICR mice (7
(13H, m), 2.28 (3H, s), 2.86 (2H, t, Jꢂ6.6 Hz), 2.90—3.40 (2H, m), 4.11 weeks old, Japan SLC, Inc.) were allocated to control and treated groups
(2H, t, Jꢂ6.6 Hz), 4.25—5.20 (3H, m), 5.80—7.50 (12H, m). IR (Nujol)
(nꢂ5—6). 14c and rosiglitazone were suspended in 0.5% methylcellulose
cmꢀ1: 1651, 1622, 1599, 1585, 1547, 1508. MS m/z: 519 [MꢅH]ꢅ. Anal. solution and administered once a day for 14 d. Plasma volume was deter-
Calcd for C31H38N2O5·C4H11N·0.2H2O: C, 70.61; H, 8.36; N, 7.06. Found: mined by the dye dilution method using Evans blue.34) Briefly, mice were in-
C, 70.45; H, 8.17; N, 6.96.
jected intravenously with Evans blue solution (100 mg/animal) 24 h after the
(S)-7-{2-[2-(2-Cyclopentylethyl)-5-methyloxazol-4-yl]ethoxy}-2- last administration, and anesthetized with diethyl ether, and then blood sam-
[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid
tert-Butylamine Salt (14i) Yield 78%. A white solid, mp 151—153.5 °C.
ples were collected by orbital sinus puncture. Plasma concentrations of dye
were determined and plasma volume was calculated. The mice were bled to
1H-NMR (CDCl3) d: 0.99 (9H, s), 1.02—1.18 (2H, m), 1.42—1.66 (4H, m), death under deep anesthesia, after which the hearts and livers were isolated
1.68—1.88 (8H, m), 2.24 (3H, s), 2.66 (2H, t, Jꢂ6.3 Hz), 2.78—2.88 (2H, and weighed.
m), 2.90—3.30 (2H, m), 4.02—4.15 (2H, m), 4.43 (0.4H, d, Jꢂ17.6 Hz),
Plasma Concentration after Oral Administration of 14c and Rosigli-
4.57—4.74 (1.6H, m), 4.96—5.09 (1H, m), 5.95—6.34 (3H, m), 6.40—7.20 tazone in KK-Ay Mice Male KK-Ay mice (11 weeks old; Japan SLC,
(3H, br), 6.52—6.78 (2H, m), 6.89—7.01 (1H, m), 7.13—7.25 (1H, m). IR Inc.) were used. 14c (3 mg/kg) and rosiglitazone (30 mg/kg) suspended in
(Nujol) cmꢀ1: 1654, 1626, 1595, 1576, 1539, 1506. MS m/z: 493 [MꢅH]ꢅ. 0.5% methylcellulose solution were orally administered and then a blood
Anal. Calcd for C29H36N2O5·C4H11N·0.5H2O: C, 68.96; H, 8.42; N, 7.31. sample was taken by heart puncture under ether anesthesia at 1, 4, 12 or 24 h
Found: C, 69.12; H, 8.40; N,7.30.
Partition Coefficient at pH 7.0 Log D7.0 values (logarithm of n-oc- were determined using an HPLC system consisting of a pump (PU-980;
after administration in KK-Ay mice. Plasma concentrations of compounds
tanol–water partition coefficients at pH 7.0) were determined by HPLC
methods.32) Acetanilide, benzonitrile, benzene, bromobenzene, biphenyl and
hexachlorobenzene, the log D7.0 values of which are known, were used as
reference substances. Test compounds and reference substances were dis-
solved in acetonitrile containing 1% dimethylsulfoxide (DMSO) at
10 mg/ml, and then 10 ml of the solution was injected into the HPLC system.
The HPLC equipment consisted of a pump (PU-980; JASCO Corporation,
Tokyo, Japan), a UV detector (UV-970; JASCO Corporation), an autoinjec-
tor (AS-950; JASCO Corporation), and a Cosmosil 5C18-AR-II column
(5 mm, 4.6 mmꢆ150 mm; Nacalai Tesque, Inc., Kyoto, Japan). Phosphate
buffer (pH 7.0)–MeOH (8 : 2) was used as the eluent. The capacity factors of
test substances and reference substances were calculated from their retention
time. The log D7.0 values of test compounds were calculated using these ca-
pacity factors and the reported log D7.0 values of reference substances.
PPARg and PPARa Agonist Activity Full-length human PPARg1
plasmid (Open Biosystems, Huntsville, U.S.A.) or PPARa plasmid
(GeneCopoeia Inc., Rockville, U.S.A.), and human RXRa plasmid
(GeneCopoeia Inc.) with reporter plasmid pGL3-PPREx4-tk-luc were elec-
troporated into COS-1 cells (Dainippon Sumitomo Pharma Co., Ltd., Osaka,
Japan) using Nucleofator II (AAD-1001S, Lonza Group Ltd., Basel,
Switzerland). The cells were incubated for 24 h in the presence or absence of
the test compound in Dulbecco’s modified Eagle’s medium (DMEM; Nissui
Pharmaceutical Co., Ltd., Tokyo, Japan) containing 10% fetal bovine serum
(FBS) under 5% CO2 at 37 °C. The medium was removed and then lu-
JASCO), UV detector (UV-970; JASCO), autoinjector (AS-950; JASCO),
and STR-ODS-II column (5 mm, 4.6 mmꢆ150 mm; Shimadzu Techno Re-
search, Inc., Kyoto, Japan). The Cmax and AUC were calculated.
References
1) Bloomgarden Z. T., Diabetes Care, 28, 488—493 (2005).
2) Lebovitz H. E., Banerji M. A., Recent Prog. Horm. Res., 56, 265—294
(2001).
3) Tack C. J., Smits P., Neth. J. Med., 64, 166—174 (2006).
4) Staels B., Cell Metab., 2, 77—78 (2005).
5) Lehrke M., Lazar M. A., Cell, 123, 993—999 (2005).
6) Krische D., West. J. Med., 173, 54—57 (2000).
7) Hussein Z., Wentworth J. M., Nankervis A. J., Proietto J., Colman P.
G., Med. J. Aust., 181, 536—539 (2004).
8) Henke B. R., Blanchard S. G., Brackeen M. F., Brown K. K., Cobb J.
E., Collins J. L., Harrington W. W. Jr., Hashim M. A., Hull-Ryde E. A.,
Kaldor I., Kliewer S. A., Lake D. H., Leesnitzer L. M., Lehmann J. M.,
Lenhard J. M., Orband-Miller L. A., Miller J. F., Mook R. A. Jr., Noble
S. A., Oliver W. Jr., Parks D. J., Plunket K. D., Szewczyk J. R., Willson
T. M., J. Med. Chem., 41, 5020—5036 (1998).
9) Azukizawa S., Kasai M., Takahashi K., Miike T., Kunishiro K., Kanda
M., Mukai C., Shirahase H., Chem. Pharm. Bull., 56, 335—345
(2008).
10) Everett L., Galli A., Crabb D., Liver, 20, 191—199 (2000).
ciferase activities were determined using a commercial kit (PicaGene LT7.5, 11) Chou C. J., Haluzik M., Gregory C., Dietz K. R., Vinson C., Gavrilova
TOYO B-Net Co., Ltd., Tokyo, Japan) and a microplate luminescence reader
O., Reitman M. L., J. Biol. Chem., 277, 24484—24489 (2002).
(Dainippon Sumitomo Pharma Co., Ltd.). EC50 values and the maximal acti- 12) Kuwabara K., Murakami K., Todo M., Aoki T., Asaki T., Murai M.,
vation level relative to the level activated by farglitazar, a PPARg agonist
(10ꢀ7 M) or Wy-14643, a PPARa agonist (10ꢀ5 M) were determined.
PTP-1B Inhibitory Activity PTP-1B inhibitory activities were deter-
mined in the absence or presence of the test compound in 50 mM sodium ac-
etate buffer (pH 5.5) containing the enzyme, 3 mM pNPP, 1 mM dithiothreitol
and 1 mM ethylenediaminetetraacetic acid (EDTA). The reaction was started
by addition of pNPP and stopped by the addition of 50 ml of 1 M NaOH after
30 min of incubation at 37 °C, and the absorbance was determined at
405 nm.
Yano J., J. Pharmacol. Exp. Ther., 309, 970—977 (2004).
13) Koh K. K., Han S. H., Quon M. J., Yeal Ahn J., Shin E. K., Diabetes
Care, 28, 1419—1424 (2005).
14) Chaput E., Saladin R., Silvestre M., Edgar A. D., Biochem. Biophys.
Res. Commun., 271, 445—450 (2000).
15) Yajima K., Hirose H., Fujita H., Seto Y., Fujita H., Ukeda K.,
Miyashita K., Kawai T., Yamamoto Y., Ogawa T., Yamada T., Saruta
T., Am. J. Physiol. Endocrinol. Metab., 284, E966—E971 (2003).
16) Fiévet C., Fruchart J. C., Staels B., Curr. Opin. Pharmacol., 6, 606—
614 (2006).
17) Henke B. R., J. Med. Chem., 47, 4118—4127 (2004).
18) Ebdrup S., Pettersson I., Rasmussen H. B., Deussen H. J., Frost Jensen
A., Mortensen S. B., Fleckner J., Pridal L., Nygaard L., Sauerberg P., J.
Med. Chem., 46, 1306—1317 (2003).
19) Devasthale P. V., Chen S., Jeon Y., Qu F., Shao C., Wang W., Zhang H.,
Cap M., Farrelly D., Golla R., Grover G., Harrity T., Ma Z., Moore L.,
Ren J., Seethala R., Cheng L., Sleph P., Sun W., Tieman A., Wetterau J.
R., Doweyko A., Chandrasena G., Chang S. Y., Humphreys W. G.,
Sasseville V. G., Biller S. A., Ryono D. E., Selan F., Hariharan N.,
Cheng P. T., J. Med. Chem., 48, 2248—2250 (2005).
20) Cronet P., Petersen J. F., Folmer R., Blomberg N., Sjöblom K., Karls-
son U., Lindstedt E. L., Bamberg K., Structure, 9, 699—706 (2001).
21) Imoto H., Matsumoto M., Odaka H., Sakamoto J., Kimura H., Nonaka
M., Kiyota Y., Momose Y., Chem. Pharm. Bull., 52, 120—124 (2004).
Hypohyperglycemic and Hypotriglyceridemic Effects in Male KK-Ay
Mice Male KK-Ay mice (11 weeks old; Clea Japan, Inc., Tokyo, Japan)
were allocated to control and treated groups (nꢂ4). Test compounds were
suspended in 0.5% methylcellulose solution and orally administered once a
day for 4 or 14 d. Blood samples were taken from the tail vein of non-fasted
mice 24 h after the final administration. Plasma glucose and triglyceride lev-
els in mice administered the vehicle or test compounds were determined
using commercial kits (Wako Pure Chemical Industries, Ltd., Osaka, Japan).
Effects of 14c and Rosiglitazone in Male Syrian Hamsters Male Syr-
ian hamsters (10 weeks old; Japan SLC, Inc., Hamamatsu, Japan) were allo-
cated to control and treated groups (nꢂ4). 14c and rosiglitazone were sus-
pended in 0.5% methylcellulose solution and orally administered once a day
for 7 d. Animals were anesthetized with sodium pentobarbital (50 mg/kg, in-
traperitoneally (i.p.)) 24 h after the final administration and blood samples
were collected from the abdominal aorta. They were then bled to death

1242
Vol. 59, No. 10
22) Michalik L., Auwerx J., Berger J. P., Chatterjee V. K., Glass C. K.,
Gonzalez F. J., Grimaldi P. A., Kadowaki T., Lazar M. A., O’Rahilly
S., Palmer C. N. A., Plutzky J., Reddy J. K., Spiegelman B. M., Staels
B., Wahli W., Pharmacol. Rev., 58, 726—741 (2006).
23) Lai D. Y., J. Environ. Sci. Health C. Environ. Carcinog. Ecotoxicol.
Rev., 22, 37—55 (2004).
24) Cornwell P. D., De Souza A. T., Ulrich R. G., Mutat. Res., 549, 131—
145 (2004).
25) Zungu M., Felix R., Essop M. F., Mitochondrion, 6, 315—322 (2006).
26) Rubenstrunk A., Hanf R., Hum D. W., Fruchart J. C., Staels B.,
Biochim. Biophys. Acta, 1771, 1065—1081 (2007).
879 (2011).
29) Thareja S., Aggarwal S., Bhardwaj T. R., Kumar M., Med. Res. Rev.,
2010 Sep. 2 [Epub ahead of print].
30) Sohda T., Mizuno K., Momose Y., Ikeda H., Fujita T., Meguro K., J.
Med. Chem., 35, 2617—2626 (1992).
31) Guo Q., Sahoo S. P., Wang P. R., Milot D. P., Ippolito M. C., Wu M. S.,
Baffic J., Biswas C., Hernandez M., Lam M. H., Sharma N., Han W.,
Kelly L. J., MacNaul K. L., Zhou G., Desai R., Heck J. V., Doebber T.
W., Berger J. P., Moller D. E., Sparrow C. P., Chao Y. S., Wright S. D.,
Endocrinology, 145, 1640—1648 (2004).
32) Masumoto K., Takeyasu A., Oizumi K., Kobayashi T., Yakugaku
Zasshi, 115, 213—220 (1995).
33) Small G. M., Burdett K., Connock M. J., Biochem. J., 227, 205—210
(1985).
27) Ritchie T. J., Macdonald S. J., Drug Discov. Today, 14, 1011—1020
(2009).
28) Otake K., Azukizawa S., Takahashi K., Fukui M., Shibabayashi M.,
Kamemoto H., Kasai M., Shirahase H., Chem. Pharm. Bull., 59, 876— 34) Wilson R. J., Mills I. H., J. Clin. Pathol., 23, 286—290 (1970).