The first asymmetric synthesis of a dopamine D1 agonist, dihydrexidine, employing asymmetric conjugate addition technology

Article abstract of DOI:10.1016/S0040-4039(01)01823-8

The first asymmetric synthesis of benzophenanthridine dopamine D1 full agonist, dihydrexidine, was accomplished employing three key processes, external chiral ligand-controlled conjugate addition of phenyllithium, Curtius conversion of a carboxylic group

Full text of DOI:10.1016/S0040-4039(01)01823-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8493–8495
The first asymmetric synthesis of a dopamine D1 agonist,
dihydrexidine, employing asymmetric conjugate addition
technology
Yasutomi Asano, Mitsuaki Yamashita, Kazushige Nagai, Masami Kuriyama, Ken-ichi Yamada and
Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 5 September 2001; revised 25 September 2001; accepted 28 September 2001
Abstract—The first asymmetric synthesis of benzophenanthridine dopamine D1 full agonist, dihydrexidine, was accomplished
employing three key processes, external chiral ligand-controlled conjugate addition of phenyllithium, Curtius conversion of a
carboxylic group to an amino group, and finally Pictet–Spengler type cyclization completing skeleton construction. © 2001
Elsevier Science Ltd. All rights reserved.
Parkinson’s disease is characterized by the degeneration
of dopamine-secreting neurons in the nigrostriatal path-
way.1 Dopamine agonist replacement therapy with L-
Dopa, which is endogenously converted to dopamine
and thereby stimulates both the D1 and D2 families of
receptors, remains the cornerstone of Parkinson’s ther-
apy.2 A benzophenanthridine class compound, dihy-
drexidine 1, has been designed and developed by
Nichols as the first high affinity bioavailable full
dopamine D1 agonist.3 Dihydrexidine was shown to be
effective in a primate model of Parkinson’s disease and
is reported to be in clinical development. A benzoth-
ienoquinoline, A-86929 2, has been developed by
Abbott Laboratories as a potent and selective full
agonist at the D1 receptor that is efficacious in rodent
and primate models of Parkinson’s disease after both
acute and long-term administration.4 Its diacetate,
working as a prodrug of 2, is in clinical development.
These compounds were found to exhibit a high level of
enantiospecificity in their interaction with the D1 recep-
tor. The method by optical resolution has been the only
procedure reported so far to reach these optically active
compounds.5 We describe the first asymmetric synthesis
of 1 employing an asymmetric conjugate addition tech-
HO
HO
HO
NH
HO
NH
S
1: (+)-dihydrexidine
2: A-86929
MeO
MeO
MeO
MeO
Cyclization
Curtius
rearrangement
Arylation
CO2BHA
R
5
1
Li
3: R = NH2
Ph
4: R = CO2H
Figure 1. Asymmetric synthetic strategy for dopamine D1 agonist, dihydrexidine 1.
* Corresponding author. Tel.: +81-75-753-4553; fax: +81-75-753-4604; e-mail: tomioka@pharm.kyoto-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01823-8

8494
Y. Asano et al. / Tetrahedron Letters 42 (2001) 8493–8495
nology.6 The technology demonstrated here may be
applicable into the asymmetric synthesis of 2 as well as
their potent congeners (Fig. 1).
mixture of trans- and cis-carboxylic acids 4 in 90%
yield. The enantiomeric excess of trans-acid was then
determined to be 74% by a chiral stationary phase
HPLC analysis14 of the alcohol obtained by lithium
aluminum hydride reduction of 4. Other reputable chi-
ral external ligands were examined to improve efficiency
of the asymmetric conjugate addition reaction. How-
ever, such ligands as sparteine 9 (94%, ent-42% ee),
i-Pr-Box 1015 (96%, 61% ee), and phenyl-Box 1115
(53%, 74% ee) turned out not to be beneficial in giving
7. Fortunately, enantioenrichment was possible by sin-
gle recrystallization of dicyclohexylamine salt of 4 (74%
ee) from ethanol and gave enantiomerically and
diastereomerically pure trans-4 in 48% overall yield
from 7.
The synthetic pathway to 1 relies on three key pro-
cesses, an external chiral ligand-controlled asymmetric
conjugate addition reaction of phenyllithium with an
a,b-unsaturated ester 5,7 Curtius rearrangement-type
conversion of a carboxylic acid 4 into an amine 3, and
finally Pictet–Spengler-type cyclization of 3 completing
skeleton construction. An asymmetric conjugate addi-
tion reaction of organometallic reagents with a,b-unsat-
urated carbonyl compounds and their equivalents is a
powerful and fundamental method in forming a car-
bonꢀcarbon bond8 and has been one of targets of our
research.9
A conversion of enantiomerically pure 4 into an amine
3 was carried out by successive reactions with ethyl
chloroformate-triethylamine in acetone to a mixed
anhydride, sodium azide in acetone to acyl azide, heat-
ing in refluxing toluene to isocyanate, and finally
hydrochloric acid under reflux.16 The amine 3 was then
protected with tosyl chloride and triethylamine in meth-
ylene chloride giving a tosylamide 12 in 71% overall
yield from a carboxylic acid 4.
A reaction of a BHA (2,6-di-t-butyl-4-methoxyphenyl)
ester 510 with phenyllithium was conducted in the pres-
ence of a chiral diether (S,S)-611 in toluene at −78°C for
3 h predominantly giving an addition product cis-7 in
93% yield (Fig. 2). Isomerization of cis-7 was possible
with sodium methoxide in refluxing THF for 42 h to
give a thermodynamically stable trans-ester in 70%
yield. Attempted removal of a BHA group in cis- and
trans-7 by CAN treatment was unsuccessful giving a
mixture of oxidized products.12 Isomerization and con-
comitant hydrolysis of a BHA ester 7 were carried out
in a one-pot procedure13 by successive manipulation of
7 with sodium methoxide in refluxing toluene–NMP
(N-methylpyrrolidone) for 2.5 h to give methyl ester 8
and then with water at reflux for 1 h giving a 13:1
Direct cyclization of the amine 3 and its tosylamide 12
with formaldehyde or its equivalent in the presence of
some acid catalysts was unsuccessful due to poor reac-
tivity of a phenyl moiety recovering the starting mate-
rial.17 A two-step procedure overcame this problem.
H
O
O
Ph
Ph
N
H
N
N
N
MeO
OMe
R
R
6
9
10: R = i-Pr
11: R = Ph
MeO
MeO
MeO
b,c,d,e
a
CO2BHA
MeO
R
5
7: 93%
8: R = CO2Me
4: R = CO2H, 90%
3: R = NH2, 73%
12: R = NHTs, 97%
MeO
MeO
g,h
f
i
MeO
NTs
MeO
NR
14: R = Ts, 94%
15: R = H, 90%
13: 90%
OMe
1•HCl: 73%
Figure 2. Asymmetric synthesis of dopamine D1 agonist, dihydrexidine 1. (a) PhLi (2.0 equiv.)–6 (2.8 equiv.)/toluene, −78°C, 3
h, 7 (93%); (b) i. NaOMe/toluene–NMP, reflux, 2.5 h, ii. H2O, reflux, 1 h, 4 (90%); (c) i. HN(c-Hex)2/EtOH, ii. recrystallization
from EtOH, optically pure 4 (48%); (d) i. ClCO2Et, Et3N/acetone, −5ꢀ0°C, 20 min, ii. NaN3/acetone, −5ꢀ0°C, 1 h, iii. toluene,
reflux, 2 h, iv. aq. HCl, reflux, 2 h, 3 (73%); (e) TsCl, Et3N/CH2Cl2, rt, 2 h, 12 (97%); (f) CH2(OMe)2, BF3·OEt2, rt, 12 h, 13 (90%);
(g) TMSOTf/CH2Cl2, −40 to −5°C, 3 h, 14 (94%); (h) Na, naphthalene/DME, −78°C, 0.5 h, 15 (90%); (i) i. BBr3/CH2Cl2, rt, 12
h, ii. HCl/EtOH, 1·HCl (73%).

Y. Asano et al. / Tetrahedron Letters 42 (2001) 8493–8495
8495
Reaction of 12 with dimethoxymethane in the presence
of boron trifluoride diethyl etherate at rt for 12 h gave
a methoxymethylated tosylamide 13 in 90% yield.
Treatment of 13 with trimethylsilyl triflate in methylene
chloride at −40 to −5°C during 3 h afforded a cyclized
tosylamide 14 in 94% conversion yield. A tosyl group in
14 was easily removed by sodium naphthalenide
reduction18 and gave an amine 15 in 90% yield.19 The
final conversion was demethylation of two methoxy
groups of 15 using boron tribromide in methylene
chloride at rt for 12 h and following hydrochloride
formation with hydrochloric acid in ethanol afforded
1·HCl in 73% yield. Spectroscopic data, melting point,
and specific rotation were identical with those reported
for the clinically potent compound.5a
5. (a) Knoerzer, T. A.; Nichols, D. E.; Brewster, W. K.;
Watts, V. J.; Mottola, D. M.; Mailman, R. B. J. Med.
Chem. 1994, 37, 2453–2460; (b) Michaelides, M. R.;
Hong, Y.; DiDomenico, Jr., S.; Bayburt, E. K.; Asin, K.
E.; Britton, D. R.; Lin, C. W.; Shiosaki, K. J. Med.
Chem. 1997, 40, 1585–1599.
6. For reviews, see: (a) Tomioka, K.; Nagaoka, Y. In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer, 1999; Vol. III,
Chapter 31; (b) Tomioka, K. In Modern Carbonyl Chem-
istry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; Chap-
ter 12.
7. (a) Tomioka, K. Synthesis 1990, 541–549; (b) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; John Wiley
and Sons: New York, 1994; (c) Lagasse, F.; Kagan, H. B.
Chem. Pharm. Bull. 2000, 48, 315–324.
In conclusion, an external chiral ligand-controlled
asymmetric conjugate addition technology has been
proved to be applicable to an asymmetric synthesis of a
benzophenanthridine class of dopamine D1 full agonist,
dihydrexidine 1. The overall yield was as high as 16%
from 5 and this level of performance is tolerable in
process chemistry. Further studies on this field includ-
ing improved strategies and an asymmetric synthesis of
2 are currently under investigation in this laboratory.
8. Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033–
8061.
9. For recent examples of asymmetric conjugate addition-
type arylation, see: (a) Asano, Y.; Iida, A.; Tomioka, K.
Tetrahedron Lett. 1997, 38, 8973–8976; (b) Xu, F.;
Tillyer, R. D.; Tschaen, D. M.; Grabowski, E. J. J.;
Reider, P. J. Tetrahedron: Asymmetry 1998, 9, 1651–1654;
(c) Asano, Y.; Iida, A.; Tomioka, K. Chem. Pharm. Bull.
1998, 46, 184–186; (d) Kuriyama, M.; Tomioka, K. Tet-
rahedron Lett. 2001, 42, 921–923.
10. Prepared by treatment of the corresponding carboxylic
acid with 2,6-t-butyl-4-methoxyphenol in the presence of
trifluoroacetic anhydride. (a) Finkbeiner, H. L.; Cooper,
G. D. J. Org. Chem. 1962, 27, 3395–3400; (b) Tsuda, Y.;
Ohara, T.; Hosoi, S.; Kaneuchi, S.; Kiuchi, F.; Toda, J.;
Sano, T. Chem. Pharm. Bull. 1996, 44, 500–508; (c)
Holmes, H. L.; Trevoy, L. W. Org. Synth. Coll. Vol. 3,
300–302; (d) Parish, R. C.; Stock, L. M. J. Org. Chem.
1965, 30, 927–929.
Acknowledgements
We gratefully acknowledge financial support from a
Grant-in-Aid for Scientific Research on Priority Areas
(A) ‘Exploitation of Multi-Element Cyclic Molecules’
from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan.
11. Shindo, M.; Koga, K.; Tomioka, K. J. Org. Chem. 1998,
63, 9351–9357.
12. Shindo, M.; Koga, K.; Asano, Y.; Tomioka, K. Tetra-
hedron 1999, 55, 4955–4968.
13. Hattori, T.; Hayashizaka, N.; Miyano, S. Synthesis 1995,
41–43.
14. DAICEL CHIRALPAK AS, hexane/i-PrOH=5/1.
15. Kambara, T.; Tomioka, K. Chem. Pharm. Bull. 2000, 48,
1577–1580.
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