Catalytic enantioselective synthesis of A-86929, a dopamine D1 agonist

Article abstract of DOI:10.1039/c1cc10263j

A-86929, a dopamine D1 agonist was synthesized with 95% ee in five steps with overall yield of 56% via catalytic enantioselective one-pot aziridination followed by Friedel-Crafts cyclization and a mild Pictet-Spengler cyclization protocol. The Royal Socie

Full text of DOI:10.1039/c1cc10263j

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COMMUNICATION
Catalytic enantioselective synthesis of A-86929, a dopamine D1 agonistw
Saumen Hajra* and Sukanta Bar
Received 14th January 2011, Accepted 25th January 2011
DOI: 10.1039/c1cc10263j
A-86929, a dopamine D1 agonist was synthesized with 95% ee in
five steps with overall yield of 56% via catalytic enantioselective
one-pot aziridination followed by Friedel–Crafts cyclization and
a mild Pictet–Spengler cyclization protocol.
Chiral arene-fused-hexahydrobenzoquinoline 1 is one the
important structural motifs found in many biologically
active compounds1 such as (–)-(5aR,11bS)-4,5,5a,6,7,11b-hexa-
hydro-2-propyl-3-thia-5-azacyclopenta[c]phenanthrene-9,10-diol].
A-86929 1a and its diacetyl prodrug derivative, ABT-431 1b are
known and developed as high affinity bio-available full dopamine
D1 agonists for Parkinson’s and other CNS disorders.2 More
Scheme 1 Retrosynthesis of A-86929.
importantly, this compound is found to exhibit a high level of
enantiospecificity in its interaction with the D1 receptor. So, the
alcohol and thiophene, respectively, by following the literature
development of efficient concise methods for the asymmetric
procedures.
synthesis of compound 1a is highly desirable. There are only
It was found that copper(II) triflate was an efficient dual
catalyst for the aziridination6 of alkenes as well as for the
two reports on asymmetric synthesis of 1a.
Ehrlich et al. from Abbott Laboratories synthesized
Friedel–Crafts cyclization of tethered and in situ generated
compound 1a based on double Friedel–Crafts reactions starting
aziridine7 and [N-(p-nitrobenzenesulfonyl)imino]phenyliodinane,
from costly N-(trifluoroacetyl)-D-aspartic acid anhydride.2b
PhINSO2(4-NO2C6H4) [PhINNs] was a successful nitrinoid
source for this purpose.8 Evans aziridation method, i.e. use of
Tomioka and co-workers developed an elegant and impressive
method for the asymmetric synthesis of 1a via 1,4-conjugate
chiral Box ligand, in particular the ligand derived from phenyl
addition of aryl lithium to dihydronitronaphthalene at À90 1C
glycinol, along with Cu(OTf)2 was also proved to be very
using more than stoichiometric amount of chiral ligand, followed
effective.9,10 So to commence the synthesis of A-86929, styrene
by reduction of the nitro group and cyclization.3 It is found that
4 (5.0 equiv.) was reacted with PhINNs (1.0 equiv.) in the
trans-2-amino-1-aryltetralins 2 is an advanced intermediate for
presence of Cu(OTf)2 (0.1 equiv.) and (R)-Box ligand 8
the synthesis of A-86929 1a and there is no catalytic and
(0.12 equiv.), derived from D-phenyl glycinol at rt
enantioselective method for the synthesis of trans-2-amino-1-
(Scheme 3). Within 2 h, it smoothly underwent one-pot
aryltetralin 2. A convenient strategy for this synthesis is the
aziridination and Friedel–Crafts cyclization and directly
intramolecular Friedel–Crafts (F–C) type cyclization of the
tethered chiral aziridine 3 (Scheme 1).
Herein, we report a concise asymmetric synthesis of
A-86929 1a via catalytic enantioselective aziridination and
subsequent one-pot Friedel–Crafts type cyclization with high
diastereo- and enantioselectivity.
To begin the synthesis, styrene 4 was prepared by Suzuki
coupling4 of in situ generated vinylborane 6, obtained by
Scheme 2 Synthesis of styrene 4.
heating alkyne 5 with catecholborane and 2-propyl-4-bromo-
thiophene (Scheme 2). Alkyne 55 and bormothiophene 72b
were synthesized from the corresponding dihydrocinnamyl
Department of Chemistry, Indian Institute of Technology Kharagpur,
Kharagpur 721302, India. E-mail: shajra@chem.iitkgp.ernet.in;
Fax: +91 3222 255303; Tel: +91 3222 283340
w Electronic supplementary information (ESI) available: See DOI:
10.1039/c1cc10263j
Scheme 3 Synthesis of compound 2.
c
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provided compound 2 in 81% yield with excellent diastereo-
selectivity (dr >99 : 1) and good enantioselectivity (87% ee).
Interestingly, this reaction showed a temperature effect.
Reactions at 0 and À25 1C showed improved ee values of 91
and 95%, respectively, with the same yield of 82%, but
required longer times (6 and 10 h, respectively) for completion.
Further lowering the temperature to À50 1C, led to very slow
reaction (18% yield after 18 h) and also reduced ee (85%).11
Deprotection and Pictet–Spengler cyclization would realize
the synthesis of A-86929. However, heating with formaldehyde
(paraformaldehyde) in presence of acid leads to contamination
by the fully aromatized (oxidized) byproduct.2b,12
We thank DST, New Delhi for providing financial support.
S. B. thanks CSIR, New Delhi, for his fellowship.
Notes and references
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To avoid this problem, we introduced milder conditions.
Thus the sodium salt of compound 2, generated by the
reaction with NaH (2.0 equiv.), was reacted with MOMCl
(2.0 equiv.) at 0 1C and within 1 h, provided compound 9 in
96% yield (Scheme 4). Now the Pictet–Spengler type cyclization
of compound 9 using TMSOTf (1 equiv.) at À60 1C in DCM led
to the formation of the target N-nosyl hexahydrobenphenan-
thridine compound 10 in 89% yield after 12 min. This reaction
requires quenching at À60 1C using an excess of Et3N
(10 equiv.), followed by dilution with EtOAc, and then washing
with saturated NaHCO3 solution. Deprotection of N-nosyl of the
compound 10 was carried out by use of p-methoxythiophenol
(3.0 equiv.) and K2CO3 (3.0 equiv.) in CH3CN–DMSO (49 : 1)
at rt. Within
3 h, hexahydro-3-thia-5-aza-cyclopenta[c]-
phenanthrene 11 was obtained in 94% yield. The optical rotation
of compound 11 {[a]2D3 À311 (c 0.43, MeOH)} was comparable
with the literature3 data {[a]2D5 À348 (c 0.43, MeOH)}. Finally
demethylation of compound 11 by BBr3 at À78 1C accomplished
the synthesis of A-86929 as its hydrobromide salt 1aÁHBr
in 86% of yield. Optical rotation of compound 1aÁHBr
{[a]2D3 À161 (c 0.75, MeOH)} well matched with the literature3
data {[a]2D5 À171 (c 0.76, MeOH)}.
3 M. Yamashita, K. Yamada and K. Tomioka, J. Am. Chem. Soc.,
2004, 126, 1954.
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Scheme 4 Synthesis of A-86929 1a.
9 D. A. Evans, M. M. Fad and M. T. Bilodeau, J. Am. Chem. Soc.,
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2010, 352, 3112.
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12 Y. Asano, M. Yamashita, K. Nagai, M. Kuriyama, K. Yamada
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In summary, we have accomplished a concise asymmetric
synthesis of (–)-(5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-
3-thia-5-azacyclopenta[c]phenanthrene-9,10-diol], A-86929 1a
via one-pot catalytic enantioselective aziridination and
subsequent one-pot Friedel–Crafts cyclization with tethered
and in situ generated aziridine with high diastereo- and
enantioselectivity. The above synthesis of A-86929 has been
achieved in 56% overall yield in five steps from styrene 4.
c
3982 Chem. Commun., 2011, 47, 3981–3982
This journal is The Royal Society of Chemistry 2011