Asymmetric synthesis of (R)-(+)-6-(1,4-dimethoxy-3-methyl-2-naphthyl)-6-(4- hydroxyphenyl)hexanoic acid as a key intermediate for a neurodegenerative disease agent

Article abstract of DOI:10.1016/j.tetlet.2004.08.045

An asymmetric synthesis of (R)-(+)-6-(1,4-dimethoxy-3-methyl-2-naphthyl)-6- (4-hydroxyphenyl)hexanoic acid 2 as a key intermediate for a neurodegenerative disease agent 1 has been developed. A key reaction was an asymmetric hydrogenation of hindered acryl

Full text of DOI:10.1016/j.tetlet.2004.08.045

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7757–7760
Asymmetric synthesis of (R)-(+)-6-(1,4-dimethoxy-3-methyl-
2-naphthyl)-6-(4-hydroxyphenyl)hexanoic acid as
a key intermediate for a neurodegenerative disease agent
Tomomi Ikemoto, Toshiaki Nagata,* Mitsuhisa Yamano, Tatsuya Ito,
Yukio Mizuno and Kiminori Tomimatsu
Chemical Development Laboratories, Takeda Chemical Industries, Ltd., 2-17–85Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
Received 7 July 2004; revised 5 August 2004; accepted 6 August 2004
Abstract—An asymmetric synthesis of (R)-(+)-6-(1,4-dimethoxy-3-methyl-2-naphthyl)-6-(4-hydroxyphenyl)hexanoic acid 2 as a key
intermediate for a neurodegenerative disease agent 1 has been developed. A key reaction was an asymmetric hydrogenation of hin-
dered acrylic acid 13 catalyzed by the Rh-JOSIPHOS system in the presence of a base to afford a chiral acid up to 93% ee.
ꢀ 2004 Elsevier Ltd. All rights reserved.
In a search for new therapeutic drugs for neurodegener-
ative diseases, a naphthoquinone derivative 1 was found
to be a pharmaceutical agent useful for neurodegenetion
inhibition in the prevention and treatment of nerve dis-
ease (Fig. 1).1 Hence, the preparation of 1 on a large
scale was required to support toxicological evaluation.
For the synthesis of 1, the key intermediate was optically
active acid (R)-2. This was prepared by the enantioselec-
tive hydrolysis of the ester of rac-2 using lipase on a
large scale.2 We continued to research a more efficient
method, and found an asymmetric synthesis of (R)-2.
hydrogenation has been extensively developed to pro-
duce chiral pharmaceuticals,3 there were a few reports
on the access of 1,1-bisaryl ethane derivatives.4 In par-
ticular, the reduction of 1-naphthyl-1-aryl-ethene deriva-
tive as a hindered substrate has not been reported. In
this letter, we report an asymmetric preparation of
(R)-2 using a new type of asymmetric reduction of hin-
dered 1-naphthyl-1-aryl-ethene derivatives and the
determination of its absolute configuration, which was
not mentioned in the previous report.2
Initially, the model substrates were synthesized from
naphthalene derivative 82 in three steps, as shown in
Scheme 2. Aldehyde 8 was converted by Horner–Wads-
worth–Emmons reaction to E-a, b-unsaturated ester 9.
We planned the synthesis of (R)-2 using asymmetric
hydrogenation as shown in Scheme 1. While asymmetric
O
O
MeO
MeO
Me
H
Me
H
O
O
N
O
O
OH
MeO
MeO
Asymmetric
Reduction
Me
Me
R
1
(R)-2
(R)-2
CHO
O
OH
MeO
MeO
N
PhSO2H
8
Figure 1.
OMe
R = CO2Et
R = CO2H
R = Me
R = CH2OH
R = CH2OMe
3
6
7
4
Keywords: Asymmetric reduction; Rh-JOSIPHOS catalyst.
*
5
Corresponding author. Tel.: +81 6 300 6378; fax: +81 6 300 6251;
e-mail: nagata_toshiaki@takeda.co.jp
Scheme 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.045

7758
T. Ikemoto et al. / Tetrahedron Letters 45(2004) 7757–7760
to allylic alcohol 4 by DIBAL reduction in 98%. Fur-
thermore, ester 6 was hydrolyzed to acrylic acid 7 in
92% yields.
MeO
MeO
MeO
MeO
a
b
Me
Me
I
OR
CHO
CO2Et
MeO
9
8
For the initial experiments, allylic alcohol 4 was chosen
as a model substrate, since Lepoittevin and co-workers
have reported that the hydrogenation of 3,3-bisaryl ally-
lic alcohols in the presence of [Rh(nbd)(SS-bdpp)]ClO4
gave the enantioselective products in high selectivity
(80–94% ee).4 Therefore, the palladium, ruthenium and
rhodium catalysts were employed to hydrogenate of
allylic alcohol 4 in methanol at 70ꢁC under the pressure
of hydrogen (10MPa). However, no hydrogenations of 4
under these conditions were observed to provide
byproduct 3 and 5 in 5% and 34% yields, respectively.6
Stable allylic cations have been obtained by these reac-
tions.7 Furthermore, we thought that the olefins were
too rigid and perhaps sterically hindered because atrop-
isomerism7 was observed in these substrates.
R = Me
R = MOM
10
11
MeO
Me
Me
CO2H
R2
c
MeO
MeO
OR1
OR
R = Me
R1 = Me
R2 = Me
R2 = MOM
R2 = CO2Et
6
4
12
7
d
2
R = CH2OH
R = MOM
13
R2 = CO2Et
Scheme 2. Reagents and conditions; (a) (EtO)2P(O)CH2CO2Et, t-
BuONa, THF, 0–50ꢁC, 1h, 94%, (b) Pd(OAc)2 (10mol%), NaHCO3
(4equiv), n-Bu4 NBr (1equiv), DMF, 100ꢁC, 50h, 56% (6) or 57% (12),
(c) 6N NaOH, EtOH, 60ꢁC, 4h, 92% (7) or 95% (13), (d) DIBAL,
THF, ꢀ40ꢁC to rt, 98%.
Next, we applied acrylic acid 7, which were atropiso-
mers, as model substrates to an asymmetric hydrogena-
tion catalyzed by 5 mol% [Rh(nbd)(SS-bdpp)]ClO4.
Subsequently, we were pleased to find the reduction
product 14, which was not atropisomer, with good enan-
tioselectivities in the case of the presence of various
bases8 as shown in Table 1. We considered that, the rho-
Then, the Heck reaction of 9 with iodide 10 regioselec-
tively afforded Z-6 in 56% yield.5 Ester 6 was converted
Table 1. Asymmetric catalytic hydrogenation of compound 7
MeO
MeO
H2 (10 MPa)
Catalyst
Me
CO2H
Me
CO2H
H
(5 mol%)
MeO
MeO
Base (1.0 eq)
MeOH
14
7
70 oC, 24 h
OMe
OMe
14/7e
90/10
Entrya
Rh-catalystb
Base
% eee
Et3Ng
Et3N
85 (R)
86 (R)
86 (R)
86 (R)
86 (R)
87 (R)
87 (R)
6 (R)
f
1
[Rh(nbd)(SS-bdpp)]ClO4
[Rh(nbd)(SS-bdpp)]ClO4
[Rh(nbd)(SS-bdpp)]ClO4
[Rh(nbd)(SS-bdpp)]ClO4
[Rh(nbd)(SS-bdpp)]ClO4
[Rh(nbd)(SS-bdpp)]ClO4
Ac,d (SS)-BDPPd
f
f
f
f
f
2
93/7
96/4
3
KOH
(S)-MBAh
(R)-MBAh
Brucine
Et3N
4
90/10
89/11
73/27
97/3
5
6
7
8
Bc,d (R)-BINAPd
Et3N
Et3N
18/41
15/68
100/0
85/15
100/0
94/6
9
Ac,d (SS)-CHIRAPHOSd
Ac,d (SS)-BCPMd
27 (R)
48 (R)
45 (R)
3 (S)
10
11
12
13
14
15
16
17
Et3N
Et3N
Ac,d (SS)-BPPMd
Ac,d (RS)-BPPFAd
Et3N
Et3N
Ac,d (RS)-BPPFOHd
Ac,d CARBOPHOSd
Cc,d (RR)-Me-DuPHOSd
Cc,d (RR)-Et-DuPHOSd
Ac,d (SR)-JOSIPHOSd
2 (R)
60( R)
1 (S)
Et3N
Et3N
12/88
31/69
53/47
95/5
Et3N
Et3N
16 (R)
94 (R)
a Standard conditions: 0.37mmol of substance/catalysts 100/5.
b Abbreviations were used: nbd: norbordiene; cod: 1,5-cyclooctadiene.
c Rh catalyst; A: [Rh(nbd)2]ClO4, B: [Rh(cod)2]ClO4, C: [Rh(nbd)2]OTf.
d These catalysts were prepared in situ by mixing [Rh(dienes)2](anions) (0.019mmol) and chiral phosphines (0.019mmol).
e Optical purity and conversion of 14 was confirmed by HPLC analyses.
f [Rh(nbd)(SS-bdpp)]ClO4 catalyst was synthesized with [Rh(nbd)2]ClO4 and (SS)-BDPP in MeOH for 30min and concentrated in vacuo.
g Et3N (0.15equiv) was used (entry 1).
h Optically active a-methylbenzylamine (MBA) was used as the base.

T. Ikemoto et al. / Tetrahedron Letters 45(2004) 7757–7760
7759
dium catalyst could strongly interact with the carboxyl
group of substrate 7, that the coordination was
enhanced by these bases (entries 1–3), without undesira-
ble elimination of the coordination group such as steri-
cally hindered alcohol 4, respectively. In particular,
triethylamine played three important roles in this reduc-
tion. First, the solubility of 7 to methanol was extremely
increased. Second, the chelating effect was enhanced
against sterically hindered substrate. Third, the addition
of triethylamine (1.0equiv) slightly increased selectivity
and conversion. Although, in addition, we would expect
asymmetric kinetic resolution in the hydrogenation of 79
with chiral bases, no inductions were observed (Table 1,
entries 4–6).
Initially, a synthesized [Rh(nbd)(SS-bdpp)]ClO4 catalyst
was used (Table 1, entries 1–6). After researching, this
process was more simplified to the use of an ꢀin-situꢁ cat-
alyst system comprised of a 1:1 molar mixture of
Rh(dienes)2ClO4 or Rh(nbd)2 OTf and chiral phos-
phines (Table 1, entries 7–17). Though, the problems
of catalyst oxygen stability were avoided by substituting
two components of long-term stability.
Therefore, we explored a variety of chiral phosphines10
more easily (Fig. 3; Table 1, entries 8–17) . The hydro-
genation of 7 with Rh-CHIRAPHOS, Rh-DuPHOS or
Rh-BINAP11 catalysts showed lower enantioselectivities.
In these events, unsaturated acid 7 could be asymmetri-
cally hydrogenated with the Rh-JOSIPHOS12 catalyst
to afford (R)-1413 of 94% ee in a high yield (entry 17).
Next, we tried an asymmetric hydrogenation of 13
(Scheme 3). Required 13 was prepared in the same man-
ner as shown in Scheme 2. Then, acrylic acid 13 was
hydrogenated with a catalyst, formed in situ from
(SR)-JOSIPHOS and [Rh(nbd)2]ClO4, to afford 1514 of
93% ee15 in a high yield as an oil. Therefore, chiral acid
15 was resolved to give (R)-isomer over 99% ee using its
Figure 2. ORTEP view of 16.
MeO
Me
CO2H
H
a
b
13
MeO
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
15
oil (93% ee)
OMOM
N
H
H
(R)-BINAP
(SS)-CHIRAPHOS
(SS)-BDPP
MeO
MeO
c
d, e
H
15
15
N
O
H
O
R1
P
R
H
oil
R1
P
R
(> 99% ee)
PPh2
brucinium salt 16
crystal (> 99% de)
N
R
P
R2
R1 = Cy, R2 = H
R
(SS)-BCPM
(SS)-BPPM
MeO
Me
H
R1 = Ph, R2 = Boc
f-h
R = Me (RR)-Me-DuPHOS
(R)-2
CHO
R
=
EtR(R)-Et-DuPHOS
crystal
(> 99% ee)
MeO
17
Me
H
R
PPh
Me
PPh2
2PCy2
OMOM
BzO
O
Ph2P
Fe
O
H
O
Scheme 3. Reagents and conditions; (a) H2 (10MPa), [Rh(nbd)2]ClO4
(5mol%), (SR)-JOSIPHOS (5mol%), Et3N, MeOH, 70ꢁC, 63h,
conversion 94%, 93% ee, (b) brucine, acetone, rt, 86% (two steps),
99% de, (c) 1N HCl, EtOAc, 95%, (d) (1) ClCO2Et, Et3N, (2)
MeONHMeÆHCl, DBU, MeCN, 88%, (e) Red-Alꢂ, THF, 90%, (f)
Ph3P(Cl)CH2CH2CO2H, LiN(TMS)2, THF/DMSO (4/1), 56%, (g) H2,
5% Pd–C, EtOH, 98%, (h) 6N HCl, acetone, 75%.
Fe
Ph2P
PPh2
BzO
OMe
R = NMe2 (RS)-BPPFA
(SR)-JOSIPHOS R = OH (RS)-BPPFOH
CARBOPHOS
Figure 3. Chiral phosphines.

7760
T. Ikemoto et al. / Tetrahedron Letters 45(2004) 7757–7760
10.8min). Therefore, the difference was not so affective
to the enantiomeric excess as expected.
10. Chiral phosphines are shown in Figure 3.
11. (a) McGuire, M. A.; Shilcrat, S. C.; Sorenson, E.
Tetrahedron Lett. 1999, 40, 3293–3296; (b) Romero, D.
L.; Manninen, P. R.; Han, F.; Romero, A. G. J. Org.
Chem. 1999, 64, 4980; (c) Marchetti, M.; Alberico, E.;
Bertucci, C.; Botteghi, C.; Ponte, D. D. J. Mol. Catal.
1997, 125, 109.
brucinium salt 16, which was easily purified by single
crystallization in acetone, in 86% yield (two steps).
Therefore, the absolute stereochemistry was determined
by X-ray crystallography of 16 as shown in Figure 2.16
Salt 16 was acidified and extracted with EtOAc to give
15 in 99% ee. Condensation of 15 with N,O-dime-
thylhydroxylamine gave Weinreb amide, which was con-
verted to aldehyde 17 by Red-Alꢂ in 79% (two steps).
The Wittig reaction17 of aldehyde 17 followed by hydro-
genation gave MOM ether of (R)-2 in 43% yield (two
steps). Finally, the MOM group was deprotected with
6N HCl to give (R)-(+)-22 in 75% yield with >99% opti-
cal purity by a single recrystallization.
12. Blaser, H. U.; Schmidt, E. Asymmetric Catalysis on
Industrial Scale; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, Germany, 2004; p 286.
1
13. 14. H NMR (300 MHz, CDCl3). d 2.30(br s, 3H), 3.06
(dd, J = 16.23, 6.39Hz, 1H), 3.37–3.45 (dd, J = 16.27,
8.37Hz, 1H), 3.42 (s, 3H), 3.64 (s, 3H), 3.76 (s, 3H), 5.15
(br m, 1H), 6.72 (dd, J = 8.41, 1.95Hz, 2H), 7.03 (d,
J = 8.40Hz, 2H), 7.34–7.42 (m, 2H), 7.89–7.99 (m, 2H);
13C NMR (75MHz, CDCl3) d 13.7, 38.3, 55.6, 61.7, 62.4,
114.1, 122.7, 123.1, 125.8, 126.3, 127.0, 128.3, 128.6, 133.4,
In conclusion, we have achieved the asymmetric synthe-
sis of (R )-2 by asymmetric reductions of 13 with the
Rh-JOSIPHOS catalyst system in both high yield and
enantioselectivity. Therefore, we could determine the
absolute chemistry of (R)-2 using brucinium salt 16.
135.4, 150.9, 151.1, 158.2, 178.6; IR (KBr) 1706cmꢀ1
;
20
D
½aŠ þ 81:53 (c 0.536, MeOH); LRMS (EI, M+) 380.
Purity of 14 was confirmed by HPLC analysis (column:
YMC-ODS A302 column, 4.6 i.d. · 150mm, YMC; elu-
ent: 0.05M KH2PO4 aqueous solution/MeCN 55:45; flow
rate: 1.0mL/min; temperature: 25 ꢁC; detector: 243 or
237nm). Peaks of 7 and 14 were detected at tR 20.5 and
21.4min. Optical purity of 14 was confirmed by HPLC
analysis using a chiral column (column: Chiralcel OJR
column, 4.6 i.d. · 250mm, Daicel Chemical Ind., Ltd;
eluent: 0.5M NaClO4/0.5M HClO4/MeCN 100:1:101;
flow rate: 0.5mL/min; temperature: 25ꢁC; detector:
254nm). Peaks of atropisomer 7 (two peaks), (R)-14 and
(S)-14 were detected at tR 10.3, 10.8, 12.0 and 16.8min.
14. 15. 1H NMR (300MHz, CDCl3) d 2.35 (br s, 3H), 3.13
(dd, J = 15.30, 6.34Hz, 1H), 3.44 (s, 3H), 3.47 (dd, J =
15.30, 6.13Hz, 1H), 3.51 (br s, 1H), 3.83 (s, 3H), 5.12 (s,
2H), 5.22 (br m, 1H), 6.92 (d, J = 8.50Hz, 2H), 7.11 (d,
J = 8.50Hz, 2H), 7.43–7.49 (m, 2H), 7.97 (dd, J = 6.40,
Acknowledgements
We thank Mr. Akio Kamimura for his help in the high-
pressure laboratory. X-ray crystallographic analyses
were performed by Ms. Keiko Higashikawa at the
Medicinal Chemistry Research Laboratories. We also
thank Mr. Tadao Kawarasaki, Mr. Syunsuke Shima
and Mr. Tadashi Urai for their technical assistance.
References and notes
1. (a) Yamano, T.; Kato, K.; Kawata, M.; Ito, T.; Ikemoto
T. Japan Patent H 11-222458, 1999; (b) Kawata, M.;
Yamano, T.; Kikumoto, A.; Kato, K. Japan Patent H 11-
56388, 1999; (c) Kato, K.; Terauchi, J.; Takahashi, H.;
Naruo K. Japan Patent H 11-199570, 1999.
2. Ito, T.; Ikemoto, T.; Yamano, T.; Mizuno, Y.; Tomim-
atsu, K. Tetrahedron Asymmetry 2003, 14, 3525–3531.
3. For review articles see: (a) Valentine, D.; Scott, J. W.
Synthesis 1978, 329; (b) Caplar, V.; Comisso, G.; Sunjic,
V. Synthesis 1981, 85; (c) Noyori, R. Chem. Rev. 1989, 18,
187; (d) Brown, J. M. Chem. Soc. Rev. 1993, 22, 25.
4. (a) Bissel, P.; Sablong, R.; Lepoittevin, J.-P. Tetrahedron
Asymmetry 1995, 6, 835–838; (b) Bissel, P.; Nazih, A.;
Sablong, R.; Lepoittevin, J.-P. Org. Lett. 1999, 1, 1283–
1285.
2.96Hz, 1H), 8.05 (dd, J = 6.40, 2.05Hz, 1H); IR (KBr)
20
D
1706cmꢀ1; ½aŠ þ 64:9 (c 1.254, EtOAc). Purity of 15 was
confirmed by HPLC analysis [column: YMC-ODS A302
column, 4.6 i.d. · 150mm, YMC; eluent: 0.05M KH2PO4
aqueous solution/MeCN 55:45; flow rate: 1.0mL/min;
temperature: 25ꢁC; detector: 243 or 237nm] and peaks of
13 and 15 were detected at tR 20.6 and tR 21.2min.
15. Optical purity of 15 was determined by hydrolyzing the
MOM ether to the phenol with 6N HCl and analyzing the
phenol by HPLC using a Chiralcel OJR column [eluent:
0.5M NaClO4/0.5M HClO4/MeCN 100:1:101; flow rate:
0.5mL/min; temperature: 25ꢁC; detector: 254nm]. Peaks
of acrylic acids (two peaks) and reduction products (two
peaks) were detected at tR 5.2, 5.6, 7.2 [(R)-isomer]
and 10.3 [(S)-isomer] min.
5. Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989,
In this coupling reaction, substrate 9 was recovered in ca.
15%.
6. Rigby, J. H.; Kotnis, A.; Kramer, J. J. Org. Chem. 1990,
55, 5078.
7. March, J.; Smith, M. B. In Marchꢁs Advanced Organic
Chemistry: Reaction, Mechanisms, and Structure, 5th
ed.; Wiley-Interscience: New York, 2001; 131–132, and
p 221.
8. (a) Achiwa, K. J. Am. Chem. Soc. 1976, 98, 8265; (b)
Jorgenson, M. J.; Friend, A. W. J. Am. Chem. Soc. 1965,
87, 1815.
16. While the IR, 1H and 13C NMR spectral data were in
agreement with the proposed structure for brucinium salt
16, confirmation of 15 was sorted by X-ray crystallogra-
phy. CCDC 242134 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retriev-
ing.html (or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; tel:
+44-0-1223-336408; fax: +44-0-1223-336033; or e-mail:
linstead@ccdc.cam.ac.uk).
17. (a) Hann, M. M.; Sammes, P. G.; Kennewell, P. D.;
Taylor, J. B. J. Chem. Soc., Perkin Trans. 1 1982, 307; (b)
Baker, S. R.; Clissold, D. W.; McKillop, A. Tetrahedron
Lett. 1988, 29, 991.
9. It was observed that the conversion rate of atropisomer 7
(tR 10.3min) was slightly faster than that of 7 (tR