Enantioselective synthesis of the PPARα agonist (R)-K-13675 via (S)-2-hydroxybutyrolactone

Article abstract of DOI:10.1055/s-2008-1032123

Enantioselective synthesis of enantiomerically pure PPARα agonist (R)-K-13675 can be achieved starting from (S)-2-hydroxybutyrolactone. An important intermediate, 2-(aryloxy)butyrolactone, was prepared by reaction of the phenol with (S)-2-hydroxybutyrolactone in excellent yield without loss of enantiomeric purity using the Mitsunobu reaction, followed by conversion into the 2-(aryloxy)butanoic acid via the 2-(aryloxy)-4-iodobutanoate by cleavage of the lactone on exposure to iodotrimethylsilane, followed by hydrogenolysis and hydrolysis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032123

PAPER
1017
Enantioselective Synthesis of the PPARa Agonist (R)-K-13675 via
(S)-2-Hydroxybutyrolactone
Enantioselective
S
u
ynthesis of
(
R
)-K-13675 iyoshi Yamazaki,* Takaaki Araki, Minoru Koura, Kimiyuki Shibuya
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co. Ltd., 2-17-43, Noguchicho, Higashimurayama,
Tokyo 189-0022, Japan
Fax +81(42)3950312; E-mail: y-yamazk@kowa.co.jp
Received 2 November 2007; revised 19 December 2007
Abstract: Enantioselective synthesis of enantiomerically pure
N
O
PPARa agonist (R)-K-13675 can be achieved starting from (S)-2-
hydroxybutyrolactone. An important intermediate, 2-(aryloxy)bu-
tyrolactone, was prepared by reaction of the phenol with (S)-2-hy-
droxybutyrolactone in excellent yield without loss of enantiomeric
purity using the Mitsunobu reaction, followed by conversion into
the 2-(aryloxy)butanoic acid via the 2-(aryloxy)-4-iodobutanoate
by cleavage of the lactone on exposure to iodotrimethylsilane, fol-
lowed by hydrogenolysis and hydrolysis.
O
O
O
N
OH
O
(R)-K-13675 (1)
Figure 1 Structure of (R)-K-13675
Key words: Mitsunobu reaction, ethers, ring opening, enantiose-
lective synthesis, PPARa agonist
N
O
O
O
O
N
OH
O
Peroxisome proliferator-activated receptor a (PPARa) is
a member of the PPAR nuclear receptor superfamily, ac-
tivation of which leads to a decrease in triglyceride level
and increase in HDL-cholesterol level in humans.1 During
the course of our drug discovery program, we identified
(R)-2-[3-({benzoxazol-2-yl[3-(4-methoxyphenoxy)pro-
pyl]amino}methyl)phenoxy]butanoic acid [(R)-K-13675,
1] as a highly potent and selective PPARa agonist2
(Figure 1). In a previous study, we obtained enantiomeri-
cally pure (R)-K-13675 by resolution of the racemate us-
ing column chromatography, however, this is very
inefficient and wasteful for large-scale production. There-
fore, it is necessary to develop a practical synthetic route
for (R)-K-13675. Although the chiral part corresponding
to (S)-2-hydroxybutanoate unit 3 is commercially avail-
able, it is too expensive to be used in large-scale produc-
tion. We noted the synthetic equivalent (S)-2-
hydroxybutyrolactone (4), which can be obtained easily
starting from L-malic acid (7),3 can be used to replace (S)-
2-hydroxybutanoate 3, as shown in Scheme 1. Our strate-
gy involves halogenative cleavage of the lactone moiety
on exposure to a Lewis acid (BBr3 or TMSI) followed by
hydrogenolysis, as shown in Scheme 2.
1
N
OH
O
O
N
O
2
O
HO
OR
(S)-2-hydroxybutanoate (3)
O
O
HO
O
HO
O
O
5
(S)-2-hydroxybutyrolactone (4)
O
O
(S)-2-Hydroxybutyrolactone (4) was prepared efficiently
from L-malic acid (7) by our modified method. It was
reported3 that the crude product 5 obtained from 6 can be
cyclized in the presence of trifluoroacetic acid or 4-tolue-
nesulfonic acid to provide 4 in 55–72% yield. In this step,
the formation of byproducts can be monitored by TLC and
HO
HO
OH
O
O
O
O
OH
6
L-malic acid (7)
Scheme 1
the removal of trifluoroacetic acid is the major technical
burden in large-scale production.
SYNTHESIS 2008, No. 7, pp 1017–1022
Advanced online publication: 06.03.2008
DOI: 10.1055/s-2008-1032123; Art ID: F20007SS
x
x
.
x
x
.2
0
0
8
We used Amberlyst 15 in place of trifluoroacetic acid or
4-toluenesulfonic acid to reduce the amounts of byprod-
© Georg Thieme Verlag Stuttgart · New York

1018
Y. Yamazaki et al.
PAPER
OH
HN
O
O
O
a
b
c
O
CN
O
NH2
O
OH
O
10
11
8
9
O
N
N
O
OH
O
f
d
e
O
O
O
O
N
N
O
+
RO
O
O
O
R = H (4)
2
13
= Ms (12a)
= Ts (12b)
N
O
N
O
O
O
g
O
O
O
N
OEt
N
OEt
O
O
I
O
14
15
N
O
O
h
O
N
OH
O
O
1
Scheme 2 Synthesis of (R)-K-13675. Reagents and conditions: (a) Triton B, acrylonitrile; (b) BH3–THF, THF; (c) 3-hydroxybenzaldehyde,
NaBH4, MeOH; (d) 2-chlorobenzoxazole, Et3N, MeCN; (e) see Table 1; (f) TMSI, EtOH, CHCl3; (g) H2, 10% Pd/C, Et3N, EtOH; (h) aq 4 M
NaOH, EtOH.
ucts produced in the formation of 4; this method provided racemization of sulfonates could not be avoided because
4 in 89% yield without loss of enantiomeric purity (>99% the proton at the a-position of the 2-(sulfonyloxy)butyro-
ee) and it was convenient to filter off the resin on comple- lactone can be easily abstracted. This may be explained by
tion of the reaction.4
the increased acidity of H2, the proton between the lac-
tone carbonyl and the sulfonate.5
The phenol 2 was prepared as shown in Scheme 2. 4-
Methoxyphenol (8) was alkylated with acrylonitrile to To overcome the problem of racemization, we applied the
give the nitrile 9 in 76% yield, followed by reduction with Mitsunobu reaction6 for coupling between 2 and 4 under
borane–tetrahydrofuran to provide the amine 10 (90% mild conditions (Table 1). Interestingly, we found that the
yield). Reductive alkylation of 10 with 3-hydroxybenzal- polarity of solvent influenced the reactivity. In polar sol-
dehyde and sodium borohydride gave the secondary vents, the yields were less than 50% (entries 5–10). On the
amine 11 in 86% yield, then reaction with 2-chloro- other hand, nonpolar solvents, such as toluene, gave mod-
benzoxazole afforded 2 (72% yield).
erate yield, while maintaining enantiomeric purity (63%
yield, 97% ee; entry 11). The enantiomeric purity tended
to decrease at higher temperatures (100 °C), while the
yield increased (73%, 94% ee; entry 12). Next, we exam-
ined various azodicarboxylates (entries 13–16). Di-tert-
butyl azodicarboxylate (DBAD) gave the most satisfacto-
ry results for both yield and enantiomeric purity (92%
yield, 98% ee; entry 14). Diamide-type reagents resulted
in poor yield (<50% yield; entries 15 and 16). Using tert-
butyl (S)-2-hydroxybutanoate instead of 2-hydroxybuty-
rolactone gave lower yields under the Mitsunobu reaction
conditions.7 For the practical scaleup of production, we
selected diisopropyl azodicarboxylate (DIAD; entry 13)
because of the ease of separation of 13 from the resultant
hydrazine dicarboxylate.
First, we investigated the conditions for the coupling reac-
tion between the phenol 2 and the sulfonates of (S)-2-hy-
droxybutyrolactone 12a,b in the presence of a base
(Table 1). Reaction of 2 with the mesylate 12a and the to-
sylate 12b at room temperature in the presence of potassi-
um carbonate in acetonitrile resulted in unsatisfactory
yields and significant loss of enantiomeric purity (entries
1 and 2).
Changing the solvent from acetonitrile to N,N-dimethyl-
formamide and the base from potassium carbonate to ce-
sium carbonate resulted in a marked increase in the
chemical yield of 13, but not the enantiomeric purity (en-
tries 3 and 4). In this reaction system, we concluded that
Synthesis 2008, No. 7, 1017–1022 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of (R)-K-13675
1019
Table 1 Coupling Reaction between 2 and the Lactones 4, 12a, and
O
O
BBr3
12ba
O
O
BBr2
Ar
OR
+
O
Ar
O
δ
R = H (4)
= Ms (12a)
= Ts (12b)
O
R-OH
O
N
RO
Ar
O
O
Br
OH
Br
O
O
H
N
O
intermediate
Scheme 3 Ring-opening reaction of lactone with boron tribromide
2
O
N
Table 2 Ring-Opening Reaction of 13 with Iodotrimethylsilane and
Ethanola
O
O
N
O
O
O
N
TMSI
EtOH
13
O
Solvent
MeCN
MeCN
DMF
O
O
O
N
O
Entry
1
R
Reagent
K2CO3
K2CO3
K2CO3
Yieldb (%) ee (%)
O
solvent
Ms
Ts
Ts
Ts
H
44
35
74
97
34
26
trace
48
14
37
63
73
77
92
47
37
11c
59c
62c
54c
13
2
3
N
O
O
d
O
4
Cs2CO3
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
DEAD
DEADe
DIAD
DMF
N
OEt
O
5
THF
I
6
H
t-BuOMe
MeCN
EtCN
O
14
7
H
Entry
TMSI
(equiv)
EtOH
(equiv)
Solvent
Time (h) Yieldb (%)
8
H
1
2
3
4
5
6
7
8
9
1.5
–
EtOH
15
15
15
15
15
15
3
5
9
H
CH2Cl2
DMF
1.5
1.5
1.5
1.5
5
MeCN
THF
22
–
10
11
12
13
14
15
16
H
1.5
H
toluene
toluene
toluene
toluene
toluene
toluene
97c
94c
97c
98c
1.5
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
91
11
10
95
72
90
H
1.5
H
2.0
5
H
DBAD
TMADf
ADDPg
2.5
5
H
2.5
1.5
3
3
H
2.5
3
a Conditions: entries 1–4: 2 (100 mg), 12a or 12b (1.2 equiv), base
(1.2 equiv), r.t., 2 d; entries 5–15: 2 (100 mg), 4 (2.0 equiv), Ph3P (2.0
equiv), azodicarboxylates or TMAD (2.0 equiv), r.t., 1 d; entry 16: 2
(100 mg), 4 (2.0 equiv), Ph3P (3.0 equiv), ADDP (3.0 equiv), r.t., 1 d.
b Isolated yield.
a To a soln of 13 (100 mg) and EtOH in solvent (4 mL) was added
TMSI at 0 °C under argon. The mixture was stirred at r.t.
b Isolated yield.
c Determined by HPLC analysis.
d Stirred for 12 h.
14, following by hydrogenolysis using palladium-on-car-
bon under a hydrogen atmosphere.
e Reacted at 100 °C.
f TMAD = N,N,N¢,N¢-tetramethylazodicarboxamide.
g ADDP = 1,1¢-(azodicarbonyl)dipiperidine.
Following exposure of 13 to boron tribromide, the result-
ant intermediate was treated with ethanol according to the
conventional method8 (Scheme 3); this reaction resulted
Finally, it was necessary to address the issue of converting in a complex mixture. Next, we attempted to use iodotri-
the (aryloxy)butyrolactone 13 into the aryloxy ester 15 in methylsilane as the ring-opening agent (Table 2).9 A sig-
an efficient manner.
nificant improvement in the isolated yield of 14 was
achieved using 2.5 equivalents of iodotrimethylsilane and
5.0 equivalents of ethanol in chloroform at room temper-
ature (95% yield; entry 7). Interestingly, the ring-opening
reaction did not proceed in the absence of alcohol. Al-
Our tactic involved cleavage of the lactone ring by halo-
gen attack at the g-position of 13 leading to the halo ester
Synthesis 2008, No. 7, 1017–1022 © Thieme Stuttgart · New York

1020
Y. Yamazaki et al.
PAPER
graph using Chiralpak AS and AD (manufactured by Daicel), 5.0
cm × 0.46 cm.
H
OR
Me3Si
O
I
Me3SiO
O
OR
δ+
O
(S)-2-Hydroxybutyrolactone (4)
O
O
Ar
O
Ar
O
Ar
O
To a soln of 2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic
acid3 (6, 100 g, 0.574 mol) in THF (900 mL) was added BH3·SMe2
(65.3 mL, 0.689 mol) dropwise over 30 min at –10 °C under argon;
the mixture was stirred at r.t. for 20 h. MeOH (200 mL) was added
to the mixture over 10 min at –10 °C and it was stirred for 1 h then
concentrated in vacuo. The residue was dissolved in CHCl3 (500
mL) and Amberlyst 15 (8.03 g) was added at r.t. The mixture was
stirred at r.t. for 16 h and the resin was filtered off through a pad of
Celite. The filtrate was concentrated in vacuo and the residue was
purified by column chromatography (silica gel, CHCl3–MeOH,
20:1) to give 4 as a colorless oil (52.0 g, 89%).
I
II
R
O
Me3SiOH
O
+
O
Ar
OR
O
Ar
O
I–
I
III
IR (neat): 3413, 1767, 1219, 1175, 1121, 1013, 991 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.24–2.35 (m, 1 H), 2.58–2.66 (m,
1 H), 3.49 (br s, 1 H), 4.21–4.28 (m, 1 H), 4.42–4.55 (m, 2 H).
Scheme 4 Plausible mechanism of lactone ring-opening reaction by
iodotrimethylsilane
though cleavage of the lactone ring by iodotrimethylsilane
was reported in some studies, it required reflux conditions
in acetonitrile to form trimethylsilyl 4-iodobutanoate.10
We presumed that each reaction proceeded by a different
(S)-2-(4-Nitrobenzoyloxy)butyrolactone; Determination of the
Enantiomeric Purity of 4
To a soln of 4 (86.0 mg, 0.84 mmol) and pyridine (0.5 mL) in
mechanism; a plausible mechanism is described in CH2Cl2 (0.5 mL) was added 4-nitrobenzoyl chloride (156 mg, 0.84
mmol) at r.t. and it was then stirred at this temperature for 1 h. The
mixture was diluted with EtOAc and the organic layer was washed
with 4 M HCl, H2O, and brine, dried (Na2SO4), and concentrated in
vacuo. The residue was purified by column chromatography (silica
Scheme 4. Initially, iodotrimethylsilane coordinates the
carbonyl of the lactone to form the silyl oxonium I, which
successively adds alcohol and loses silanol. The oxonium
intermediate III thus formed was attacked by the iodide
ion to open the butyrolactone ring, finally leading to the 4-
iodobutanoate.
gel, n-hexane–EtOAc, 3:1) to give a colorless solid (130 mg, 62%);
>99% ee [HPLC (Chiralpak AS, 35 °C, n-hexane–EtOH, 60:40,
flow rate: 1 mL/min): tR = 8.00 min (S-isomer), 8.80 min (R-iso-
mer)].
Then, the obtained 2-(aryloxy)-4-iodobutanoate 14 was
converted into the final compound (Scheme 2). Hydro-
genolysis of 14 was carried out in the presence of triethyl-
amine and 10% palladium on carbon under a hydrogen
atmosphere (99% yield). In the absence of triethylamine,
this reaction did not proceed due to deactivation of the cat-
alyst by the generated hydrogen iodide. Finally, hydroly-
sis of the ester 15 furnished (R)-K-13675 without
racemization at the a-position of the carboxylic acid even
under alkaline conditions (90% yield).
1H NMR (400 MHz, CDCl3): d = 2.41–2.52 (m, 1 H), 2.82–2.87 (m,
1 H), 4.38 (dt, J = 9.9, 6.5 Hz, 1 H), 4.56 (dt, J = 9.3, 2.3 Hz, 1 H),
5.68 (dd, J = 9.8, 8.8 Hz, 1 H), 8.24 (dt, J = 9.0, 1.9 Hz, 2 H), 8.30
(dt, J = 9.0, 1.9 Hz, 2 H).
(R)-3-[3-({Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]ami-
no}methyl)phenoxy]dihydrofuran-2(3H)-one (13); Typical Pro-
cedure for Sulfonates
To a soln of 2 (263 mg, 0.65 mmol) and Cs2CO3 (319 mg, 0.98
mmol) in DMF (10 mL) was added (S)-(tosyloxy)butyrolactone
(12b; 250 mg, 0.98 mmol) and it was stirred for 12 h. The mixture
was diluted with EtOAc and the organic layer was washed with H2O
and brine, dried (Na2SO4), and concentrated in vacuo. The residue
was purified by column chromatography (silica gel, n-hexane–
EtOAc, 1:1) to give 13 as a colorless oil (307 mg, 97%).
In conclusion, we have established a method for the enan-
tioselective synthesis of (R)-K-13675 starting from (S)-2-
hydroxybutyrolactone. In addition, we optimized the Mit-
sunobu reaction conditions to achieve excellent yield and
enantiomeric purity for large-scale production. Further-
more, we developed an efficient method of butyrolactone
ring opening, yielding the 4-iodobutanoate using iodotri-
methylsilane in the presence of an alcohol under mild con-
ditions.
For the physicochemical data refer to the scaled-up synthesis.
Scale-up Synthesis of (R)-K-13675
3-(4-Methoxyphenoxy)propanenitrile (9)
To a soln of acrylonitrile (684 g, 12.9 mol), 4-methoxyphenol (800
g, 6.44 mol) and Triton B (56.0 mL) were added at r.t. and the mix-
ture was stirred at 80 °C under argon for 24 h. The mixture was di-
luted with EtOAc (3.2 L) and the organic layer was washed with 5%
aq NaOH, H2O, 1 M HCl, H2O, sat. NaHCO3, and brine, dried
(Na2SO4), and concentrated in vacuo. The residue was recrystal-
lized [EtOAc (0.8 L)–n-heptane (4.0 L)] to give 9 as pale yellow
prisms (870 g, 76%); mp 64–65 °C.
IR (solid sample): 2254, 1507, 1230, 1055, 1032, 833, 804 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.79 (t, J = 6.5 Hz, 2 H), 3.77 (s,
3 H), 4.15 (t, J = 6.5 Hz, 2 H), 6.85 (d, J = 6.9 Hz, 4 H).
Commercially available reagents and solvents were used without
further purification. TLC analyses were carried out on silica gel 60
F
254 plates (Merck). 1H NMR and 13C NMR spectra were recorded
on a Jeol JNM-LA 400 MHz. TMS was used as an internal standard.
Chemical shifts are reported to the nearest 0.1 Hz. IR spectra were
recorded on a Thermo Nicolet 370 FT-IR (ATR) spectrophotome-
ter. Mass spectra were obtained on a Jeol MS-BU20 mass spectro-
meter. Elemental analyses (C, H, N) were performed by Yanaco
MT-5. Melting points were determined in open glass capillaries on
a Buche B-545 melting point apparatus. The chiral HPLC analyses
were performed on a Shimadzu LC-2010A HT liquid chromato-
13C NMR (100 MHz, CDCl3): d = 18.72, 55.77, 63.61, 114.83,
116.09, 117.35, 151.82, 154.71.
MS (EI): m/z = 177 [M+].
Synthesis 2008, No. 7, 1017–1022 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of (R)-K-13675
MS (EI): m/z = 404 [M+].
1021
Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C,
67.71; H, 6.28; N, 7.82.
Anal. Calcd for C24H24N2O4: C, 71.27; H, 5.98; N, 6.93. Found: C,
71.20; H, 6.06; N, 6.87.
3-(4-Methoxyphenoxy)propylamine (10)
To a soln of 9 (600 g, 3.39 mol) in anhyd THF (2.4 L) was added
BH3·THF (1.0 mol/L, 3.56 L, 3.56 mol) dropwise at 65 °C under ar-
gon. The mixture was stirred at 65 °C for 5 h and then allowed to
cool to r.t. 4 M NaOH (4.2 L) was added slowly to the mixture at 5
°C and it was stirred at 65 °C for 16 h. The mixture was allowed to
cool to r.t. and diluted with toluene (12 L). The organic layer was
washed with H2O (3 ×) and brine, dried (Na2SO4) and, concentrated
to give 10 as a colorless solid (551 g, 90%); mp 36–37 °C.
(R)-3-[3-({Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]ami-
no}methyl)phenoxy]dihydrofuran-2(3H)-one (13); Formation
Using the Mitsunobu Reaction
To a soln of 2 (558 g, 1.38 mol), (S)-2-hydroxybutyrolactone (4,
213 g, 2.09 mol), and Ph3P (548 g, 2.09 mol) in toluene (5.0 L) was
added 40% DIAD in toluene (1.1 L, 2.09 mol) under argon at ca. 6
°C. The mixture was stirred at 28 °C for 21 h and then it was washed
with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, n-hex-
ane–EtOAc, 3:1) to give 13 as a colorless oil (411 g, 61%); 97% ee
[HPLC (Chiralpak AS, 35 °C, n-hexane–EtOH, 60:40, flow rate: 1
mL/min): tR = 9.37 min (R-isomer), 6.86 min (S-isomer)].
IR (solid sample): 3360, 3341, 1507, 1225, 1031, 1002, 819 cm–1.
1H NMR (400 MHz, CD3OD): d = 2.05 (quint, J = 7.1 Hz, 2 H),
3.07 (t, J = 7.3 Hz, 2 H), 3.71 (s, 3 H), 4.01 (t, J = 5.9 Hz, 2 H),
6.79–6.85 (m, 4 H).
13C NMR (100 MHz, CD3OD): d = 31.22, 39.23, 56.07, 67.28,
115.64, 116.45, 154.59, 155.44.
[a]D25 +26.1 (c 1.04, CHCl3).
IR (neat): 1786, 1637, 1578, 1508, 1459, 1230, 756 cm–1.
MS (EI): m/z = 181 [M+].
1H NMR (400 MHz, CDCl3): d = 2.14 (quint, J = 6.6 Hz, 2 H),
2.36–2.44 (m, 1 H), 2.60–2.67 (m, 1 H), 3.71 (t, J = 7.0 Hz, 2 H),
3.76 (s, 3 H), 3.96 (t, J = 5.9 Hz, 2 H), 4.25–4.31 (m, 1 H), 4.43–
4.49 (m, 1 H), 4.77 (s, 2 H), 4.89 (t, J = 7.9 Hz, 1 H), 6.81 (s, 4 H),
6.95–7.03 (m, 4 H), 7.17 (t, J = 7.6 Hz, 1 H), 7.22–7.28 (m, 2 H),
7.37 (d, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 27.54, 29.65, 45.12, 52.07, 55.65,
65.21, 65.47, 72.20, 108.74, 114.58, 114.75, 115.13, 115.35,
116.05, 120.40, 121.53, 123.92, 129.90, 138.80, 143.34, 148.83,
152.71, 153.82, 157.52, 162.60, 173.30.
3-({[3-(4-Methoxyphenoxy)propyl]amino}methyl)phenol (11)
To a soln of 10 (551 g, 3.04 mol) in MeOH (2.7 L) was added 3-
hydroxybenzaldehyde (371 g, 3.04 mol) at r.t. and the mixture was
stirred for 5 h. A soln of NaBH4 (115 g, 3.04 mol) in H2O (5.4 L)
was added slowly at 0 °C and the mixture was stirred at r.t. for 1 h,
then it was filtered and the thus-obtained solid was washed with
H2O. The solid was dried in vacuo to give 11 as pale yellow crystals
(750 g, 86%); mp 140–141 °C.
IR (solid sample): 3274, 2948, 1510, 1282, 1227, 1034, 831 cm–1.
MS (EI): m/z = 488 [M+].
HRMS (EI): m/z [M+] calcd for C28H28N2O6: 488.1947; found:
1H NMR (400 MHz, DMSO-d6): d = 1.82 (quint, J = 6.6 Hz, 2 H),
2.60 (t, J = 6.8 Hz, 2 H), 3.35 (br s, 1 H), 3.60 (s, 2 H), 3.68 (s, 3 H),
3.95 (t, J = 6.6 Hz, 2 H), 6.60 (d, J = 7.8 Hz, 1 H), 6.73 (t, J = 7.6
Hz, 1 H), 6.74 (s, 1 H), 6.83 (s, 4 H), 7.07 (t, J = 7.8 Hz, 1 H), 9.34
(s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 29.29, 45.48, 53.04, 55.30,
66.35, 113.40, 114.54, 114.74, 115.26, 118.46, 128.95, 142.42,
152.67, 153.20, 157.26.
488.1967.
Ethyl (R)-2-[3-({Benzoxazol-2-yl[3-(4-methoxyphenoxy)pro-
pyl]amino}methyl)phenoxy]-4-iodobutanoate (14)
To a soln of 13 (542 g, 1.11 mol) and EtOH (256 g, 5.55 mol) in
CHCl3 (5.4 L) was added TMSI (555 g, 2.78 mol) at ca. –2 °C under
argon and the mixture was stirred at 20 °C for 6 h. It was then
washed with 2% Na2S2O3, sat. NaHCO3, H2O, and brine, dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, n-hexane–EtOAc, 2:1) to give
14 as a colorless oil (586 g, 82%).
MS (EI): m/z = 287 [M+].
Anal. Calcd for C17H21NO3: C, 71.06; H, 7.37; N, 4.87. Found: C,
70.75; H, 7.40; N, 4.96.
[a]D25 +22.1 (c 0.37, CHCl3).
IR (neat): 1752, 1637, 1578, 1508, 1459, 1230, 755 cm–1.
3-({Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]ami-
no}methyl)phenol (2)
To a soln of 11 (740 g, 2.58 mol) in DMF (3.0 L) and Et3N (292 g,
2.88 mol) was added 2-chlorobenzoxazole (396 g, 2.58 mol) at 75
°C and it was stirred for 2 h. The mixture was concentrated in vacuo
and the thus-obtained residue was dissolved in EtOAc and washed
with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, n-hex-
ane–EtOAc, 1:1) to give a yellow oil. The yellow oil was dissolved
with t-BuOMe and allowed to stand at r.t. for overnight. The crys-
tals were filtered off and dried in vacuo to give 2 as colorless nee-
dles (753 g, 72%); mp 103–104 °C.
1H NMR (400 MHz, CDCl3): d = 1.78 (t, J = 7.2 Hz, 3 H), 2.14
(quint, J = 6.6 Hz, 2 H), 2.37–2.43 (m, 2 H), 3.33 (t, J = 7.1 Hz, 2
H), 3.70 (t, J = 7.1 Hz, 2 H), 3.76 (s, 3 H), 3.96 (t, J = 5.9 Hz, 2 H),
4.09–4.18 (m, 2 H), 4.70 (dd, J = 7.8, 4.9 Hz, 1 H), 4.76 (s, 2 H),
6.76–6.81 (m, 5 H), 6.89 (s, 1 H), 6.93 (d, J = 7.6 Hz, 1 H), 7.01 (t,
J = 7.6 Hz, 1 H), 7.16 (t, J = 7.6 Hz, 1 H), 7.22–7.26 (m, 2 H), 7.37
(d, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.36, 27.87, 36.70, 45.50, 52.38,
56.02, 61.88, 65.82, 76.68, 77.32, 109.06, 114.48, 115.00, 115.12,
115.71, 116.47, 120.71, 121.53, 124.26, 130.20, 139.13, 143.75,
149.20, 153.10, 154.19, 158.28, 162.92, 170.90.
IR (solid sample): 3065, 2998, 1638, 1582, 1508, 1460, 1225 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.01 (quint, J = 6.8 Hz, 2 H), 3.41
(t, J = 6.8 Hz, 2 H), 3.76 (s, 3 H), 3.88 (t, J = 6.8 Hz, 2 H), 4.63 (s,
2 H), 6.67–6.83 (m, 7 H), 6.91–6.97 (m, 2 H), 7.04 (dt, J = 7.2, 2.0
Hz, 1 H), 7.13 (t, J = 8.1 Hz, 2 H), 9.41 (s, 1 H).
MS (EI): m/z = 644 [M+].
HRMS (EI): m/z [M+] calcd for C30H33IN2O6: 644.1383; found:
644.1386.
13C NMR (100 MHz, CDCl3): d = 27.62, 45.11, 52.06, 55.73, 65.33,
108.93, 113.04, 114.64, 115.24, 115.30, 115.36, 118.84, 120.66,
123.99, 129.79, 137.65, 141.58, 148.20, 152.72, 153.87, 157.75,
162.27.
Ethyl (R)-2-[3-({Benzoxazol-2-yl[3-(4-methoxyphenoxy)pro-
pyl]amino}methyl)phenoxy]butanoate (15)
To a soln of 14 (758 g, 1.18 mol) and Et3N (239 g, 2.36 mol) in
EtOH (7.0 L) was added 10% Pd/C (75.8 g) at r.t. under argon. The
Synthesis 2008, No. 7, 1017–1022 © Thieme Stuttgart · New York

1022
Y. Yamazaki et al.
PAPER
mixture was stirred at r.t. under H2 for 8 h. The catalyst was re-
moved by filtration and washed with EtOH. The filtrate was con-
centrated in vacuo and the residue was purified by column
chromatography (silica gel, n-hexane–EtOAc, 1:1) to give 15 as a
colorless oil (606 g, 99%).
Anal. Calcd for C28H30N2O6: C, 68.56; H, 6.16; N, 5.71. Found: C,
68.56; H, 6.16; N, 5.71.
Acknowledgments
[a]D25 +26.9 (c 1.19, CHCl3).
IR (neat): 1750, 1733, 1637, 1578, 1508, 1459, 1231 cm–1.
We are grateful to Dr. K. Sawanobori, Director of Tokyo Research
Laboratories, Kowa Co. Ltd., for his encouragement and support.
1H NMR (400 MHz, CDCl3): d = 1.05 (t, J = 7.3 Hz, 3 H), 1.17 (t,
J = 7.1 Hz, 3 H), 1.96 (quint, J = 7.3 Hz, 2 H), 2.14 (quint, J = 6.6
Hz, 2 H), 3.70 (t, J = 7.1 Hz, 2 H), 3.76 (s, 3 H), 3.96 (t, J = 5.9 Hz,
2 H), 4.04–4.18 (m, 2 H), 4.51 (t, J = 6.2 Hz, 1 H), 4.75 (s, 2 H),
6.77–6.81 (m, 5 H), 6.86 (s, 1 H), 6.90 (d, J = 7.8 Hz, 1 H), 7.01 (d,
J = 7.7 Hz, 1 H), 7.16 (t, J = 7.7 Hz, 1 H), 7.21–7.26 (m, 2 H), 7.37
(d, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 9.59, 14.07, 26.07, 27.48, 45.09,
52.03, 55.66, 61.09, 65.47, 77.58, 108.70, 113.83, 114.56, 114.58,
115.36, 116.10, 120.33, 120.67, 123.90, 129.78, 138.62, 143.43,
148.86, 152.76, 153.83, 158.27, 162.59, 171.50.
References and Notes
(1) (a) Staels, B.; Auwerx, J. Curr. Pharm. Des. 1997, 3, 1.
(b) Staels, B.; Dallongeville, J.; Auwerx, J.; Schoonjans, K.;
Leitersdorf, E.; Fruchart, J. C. Circulation 1998, 89, 2008.
(c) Fruchart, J. C.; Duriez, P.; Staels, B. Curr. Opin. Lipidol.
1999, 10, 245.
(2) Yamazaki, Y.; Abe, K.; Toma, T.; Nishikawa, M.; Ozawa,
H.; Okuda, A.; Araki, T.; Oda, S.; Inoue, K.; Shibuya, K.;
Staels, B.; Fruchart, J. C. Bioorg. Med. Chem. Lett. 2007, 17,
4689.
(3) (a) Trybulski, E. J.; Kramss, R. H.; Mangano, R. M.;
Brabander, H. J. Bioorg. Med. Chem. Lett. 1992, 2, 827.
(b) Durand, J. O.; Larcheveque, M.; Petit, Y. Tetrahedron
Lett. 1998, 39, 5743. (c) White, J. D.; Hrnciar, C. J. Org.
Chem. 2000, 65, 9129.
(4) When we used 0.1 equiv Amberlyst 15 instead of 1.0 equiv
TFA or TsOH, we could reduce the scale of silica gel from
40-fold weight of 5 to 5-fold.
(5) (a) March, J. Advanced Organic Chemistry, 4th ed.; Wiley-
VCH: Weinheim, 1992, 269. (b) Wang, X.; Houk, K. N.
J. Am. Chem. Soc. 1988, 110, 1870. (c) Wiberg, K. B.;
Laidig, K. E. J. Am. Chem. Soc. 1988, 110, 1872. (d)Stang,
P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85.
(6) (a) Wada, M.; Mitsunobu, O. Tetrahedron Lett. 1972, 13,
1279. (b) Mitsunobu, O. Synthesis 1981, 1. (c) Tsunoda, T.;
Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34, 1639.
(d) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Ito, S. Chem.
Lett. 1994, 539. (e) Tsunoda, T.; Nagaku, M.; Nagino, C.;
Kawamura, Y.; Ozaki, F.; Hioki, H.; Ito, S. Tetrahedron
Lett. 1995, 36, 2531. (f) Tsunoda, T.; Ozaki, F.; Ito, S.
Tetrahedron Lett. 1994, 35, 5081. (g) Tsunoda, T.; Nagino,
C.; Oguri, M.; Ito, S. Tetrahedron Lett. 1996, 37, 2459.
(h) Sakamoto, I.; Kaku, H.; Tsunoda, T. Chem. Pharm. Bull.
2003, 51, 474.
MS (EI): m/z = 518 [M+].
HRMS (EI): m/z [M+] calcd for C30H34N2O6: 518.2417; found:
518.2412.
(R)-2-[3-({Benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]ami-
no}methyl)phenoxy]butanoic Acid [(R)-K-13675, 1]
To a soln of 15 (605 g, 1.17 mol) in EtOH (4.5 L) was added 4 M
NaOH (1.2 L) and the mixture was stirred at r.t. for 1.5 h. After
evaporation of EtOH, the mixture was diluted with H2O and washed
with i-Pr2O. The aqueous layer was acidified with concd HCl with
ice cooling, and the mixture was extracted with EtOAc. The organic
layer was washed with H2O and brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was recrystallized [EtOAc (4.5 L)–n-
heptane (9.0 L)] to give (R)-K-13675 as colorless needles (515 g,
90%); mp 98–99 °C; 99.5% ee [HPLC (Chiralpak AD, 35 °C, n-
hexane–i-PrOH–TFA, 100:30:0.1, flow rate: 2 mL/min): tR = 4.19
min (R-isomer), 3.68 min (S-isomer).
[a]D25 +21.4 (c 0.51, CHCl3).
IR (solid sample): 2940, 1713, 1636, 1583, 1510, 1463, 1236 cm–1.
1H NMR (400 MHz, CD3OD): d = 0.94 (t, J = 7.4 Hz, 3 H), 1.76–
1.88 (m, 2 H), 1.99 (quint, J = 6.1 Hz, 2 H), 3.60 (t, J = 6.8 Hz, 2
H), 3.61 (s, 3 H), 3.85 (t, J = 5.9 Hz, 2 H), 4.40 (t, J = 5.9 Hz, 1 H),
4.65 (s, 2 H), 6.69–6.80 (m, 7 H), 6.91 (dt, J = 7.2, 1.0 Hz, 1 H),
7.05 (dt, J = 7.2, 1.2 Hz, 1 H), 7.12–7.18 (m, 3 H).
13C NMR (100 MHz, CD3OD): d = 9.86, 27.04, 28.65, 46.64, 53.06,
56.08, 66.73, 78.45, 109.96, 115.34, 115.46, 115.64, 116.47,
116.51, 121.61, 121.98, 125.27, 130.67, 139.93, 143.77, 149.95,
154.30, 155.40, 159.85, 164.11, 175.11.
(7) In the case of tert-butyl (S)-2-hydroxybutanoate, DEAD
gave better results than DIAD or DBAD; the yield was 60%
and enantiomeric purity was 94.0% ee.
(8) Olah, G. A.; Karpeles, R.; Narang, S. C. Synthesis 1982, 963.
(9) Kricheldorf, H. R. Angew. Chem., Int. Ed. Engl. 1979, 18,
689.
(10) Olah, G. A.; Narang, S. C.; Guputa, B. G. B.; Malhotra, R.
J. Org. Chem. 1979, 44, 1247.
MS (EI): m/z = 490 [M+].
Synthesis 2008, No. 7, 1017–1022 © Thieme Stuttgart · New York