Construction of Arene-Fused-Piperidine Motifs by Asymmetric Addition of 2-Trityloxymethylaryllithiums to Nitroalkenes: The Asymmetric Synthesis of a Dopamine D1 Full Agonist, A-86929

Article abstract of DOI:10.1021/ja031760n

The straightforward methodology for the construction of chiral arene-fused-piperidine motifs using a highly enantioselective addition of 2-trityloxymethylaryllithiums to cyclic and acyclic nitroalkenes has been developed. The versatility of the process wa

Full text of DOI:10.1021/ja031760n

Published on Web 01/30/2004
Construction of Arene-Fused-Piperidine Motifs by Asymmetric Addition of
2-Trityloxymethylaryllithiums to Nitroalkenes: The Asymmetric Synthesis of a
Dopamine D1 Full Agonist, A-86929
Mitsuaki Yamashita, Ken-ichi Yamada, and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received December 16, 2003; E-mail: tomioka@pharm.kyoto-u.ac.jp
Chiral arene-fused-piperidine 1 is one of the representative
structural motifs often observed in biologically active compounds
such as naturally occurring phenanthridine and isoquinoline alka-
loids1,2 as well as artificial pharmaceuticals.3 A straightforward
synthetic way toward 1 is the conjugate addition of 2-hydroxym-
ethylaryllithiums 2 to nitroalkenes 3 and subsequent reduction of
the nitro group to an amino group and cyclization to construct
piperidine motifs 1 (Figure 1).4 The first asymmetric alkyllithium
addition to nitroalkenes was developed by the mediation of a chiral
ligand, giving the â-alkyl nitroalkanes in moderate enantioselec-
tivity.5 The catalytic asymmetric additions of dialkylzinc6 and
arylboronic acid7 were impressive recent successes. However, there
have been only few that achieve asymmetric addition of 2-hy-
droxymethylaryl or its equivalent nucleophiles to nitroalkenes. A
spectacular exception was the sparteine-mediated conjugate addition
of the lithiated N-Boc allylic and benzylic amines to nitroalkenes,
which provided an efficient way to the synthesis of simple
piperidines in high enantioselectivities.8 We describe the straight-
forward construction of chiral arene-fused-piperidines 1 by a highly
enantioselective addition of 2-trityloxymethylaryllithiums 2 (R )
CPh3) to cyclic and acyclic nitroalkenes 3.9,10 The versatility of
the process was proven by the first asymmetric synthesis of a
dopamine D1 full agonist, A-86929 (20).3a,b
Figure 1. A straightforward construction of chiral arene-fused-piperidine
motif 1 by the asymmetric addition of 2-hydroxymethylaryllithium 2 to
nitroalkene 3.
Table 1. Asymmetric Addition of Aryllithiums 2 to Nitroalkene 3a
by the Mediation of Chiral Ligands 5-8
We began our studies with the reaction of a cyclic nitroalkene
3a with 2-hydroxymethylphenyllithiums 2, generated from the
corresponding aryl bromides by treatment with butyllithium in the
presence of chiral ligands 5-8 in toluene at -78 °C for 0.5 h, to
find an efficient chiral mediator from our stocks.10 Although the
reaction of 3a with nonprotected dianion 2a did not give 4a (R )
H) in satisfactory chemical yield and enantioselectivity (at most
26% yield and 5% ee), the reaction of protected aryllithiums 2
seemed promising. Thus, the reaction of TBDMS-protected monoan-
ion 2b was mediated by the ligands 5-7, giving 4b (R ) TBDMS)
in 52-84% yields. However, the enantioselectivity was at most
21% ee by using 5 (Table 1, entries 1-3). Improvement in
enantioselectivity was realized when the trityl group-protected
aryllithium 2c was used as a carbonucleophile, giving 4c (R )
CPh3) in higher 42% ee (entry 4). More improvement was realized
by using chiral aminodiether ligand 710c at -95 °C to give 4c in
81% ee (entry 6). Satisfactorily high 98% yield and 95% ee were
realized by using chiral aminodiether 810f as a ligand at -95 °C
(entry 7).11 A trans/cis-mixture of 4c was readily isomerized to the
thermodynamically stable trans-4c quantitatively. It is also impor-
tant to note that 8 was recovered nearly quantitatively and reused.
Under the mediation of 8, 2c was an excellent nucleophile,
reacting with cyclic 9 gave 12c in 99% yield with cis-12c of 90%
ee as a major isomer (Table 2, entry 1). The reaction with linear
10 and 11 gave 13c and 14c in 93% and 66% yields with 85% and
91% ee, respectively (entries 4 and 5).12
entry
ArLi
5−8
4
yield (%)
trans:cisa
eeb
1
2
3
4
2b
2b
2b
2c
2c
2c
2c
5
6
7
5
6
7
8
ent-4b
ent-4b
4b
ent-4c
ent-4c
4c
52
87
84
40
74
94
98
75:25
98:2
21
7
12
42
5
83:17
56:44
59:41
77:23
69:31
5
6c
7c,d
81
95
4c
a Determined by 1H NMR of the crude product. b Determined after
conversion to trans-4a (R ) H) (4b, TBAF, THF; 4c, NaHCO3, EtOH,
reflux; concentrated HCl-MeOH). c At -95 °C. d 2c (1.5 equiv) and 8 (2.1
equiv).
2d and 2e satisfactorily reacted with 9 to give 12d and 12e in 94%
and 99% yields with the cis-isomer of 94% and 91% ee as a major
diastereomer, respectively (entries 2 and 3). It was also exciting to
find that 2d reacted with 3a to produce 15, a key synthetic
intermediate for A-86929 (20),3a,b in 92% yield with 97% ee (entry
6). These cis-major mixtures were quantitatively isomerized to trans-
products (>96:4) by treatment with sodium bicarbonate in refluxing
ethanol.
The trityl group in 2c-e plays critical roles in protection and
efficiency control13 and was not replaceable by a triphenylsilyl or
diphenylmethylsilyl group. The reactions of the corresponding silyl-
Thienyl- and furanyllithium bearing trityloxymethyl substituents
9
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J. AM. CHEM. SOC. 2004, 126, 1954-1955
10.1021/ja031760n CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Addition of Aryllithiums 2 to Nitroalkenes 3a,
9-11
In conclusion, we have developed the efficient and straightfor-
ward synthesis of arene-fused-piperidine motifs through the highly
enantioselective addition of 2-trityloxymethylaryllithiums to ni-
troalkenes using the chiral aminodiether ligand.
Acknowledgment. This research was partially supported by the
21st Century Center of Excellence Program “Knowledge Informa-
tion Infrastructure for Genome Science” and a Grant-in-Aid for
Scientific Research on Priority Areas (A) “Exploitation of Multi-
Element Cyclic Molecules” from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
entry
nitroalkene
ArLi
product
yield (%)
trans:cisa
ee
Supporting Information Available: Additional entries with other
aryllithiums, the experimental procedure, characterization data, NMR
spectra, and HPLC traces (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
1
2
3
4
9
9
9
10
11
3a
2c
2d
2e
2c
2c
2d
12c
12d
12e
13c
14c
15d
99
94
99
93
66
92
12:88
6:94
11:89
89/90b
95/94b
91/91b
85
5
91
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6c
37:63
97e
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Scheme 1. Construction of Chiral Arene-Fused-Piperidines and
Asymmetric Synthesis of Dopamine D1 Full Agonist A-86929 (20)a
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(11) The procedure for Table 1, entry 7: a hexane solution of BuLi (0.75 mmol)
was added to a solution of aryl bromide (0.75 mmol) and a chiral ligand
8 (1.1 mmol) in toluene (5 mL) at -78 °C. The solution was stirred for
0.5 h at -78 °C. A solution of 3a (0.5 mmol) in toluene (2.5 mL) was
dropwise added to the solution at -95 °C. The whole mixture was stirred
at -95 °C for 0.5 h and then quenched with MeOH and then saturated
NH4Cl.
Stereospecific construction of piperidine motifs 1 was readily
achievable from the addition products (Scheme 1). Both cis- and
trans-12c, which were easily separated by column chromatography,
were converted to cis- and trans-phenanthridine 16 in 68% and
70% overall yields, respectively, through removal of the trityl group,
reduction of the nitro group, conversion to amino-chlorides, and
cyclization without any loss of stereochemical integrity. By the same
procedure, 13c and 14c were converted to isoquinoline motifs 17
and 18 in 73% and 72% overall yields, respectively.
A-86929 (20) is a dopamine D1 full agonist developed by Abbott
Laboratories, and its diacetate is under clinical trial for cocaine
addiction.3a,b The first asymmetric synthesis of 20 was achieved
starting from trans-15. Reduction of the nitro group with zinc
followed by detritylation gave the corresponding amino alcohol.
Cyclization via the alkoxyphosphonium salt14 and enantioenrich-
ment by recrystallization from MeOH-AcOEt gave optically pure
19. Demethylation of the two methoxy groups furnished 20 in 58%
overall yield in seven steps from 3a.
(12) The shown absolute configurations of 4a-c, 14c, and 15 were determined
by conversion to known compounds. See Supporting Information.
(13) The reactions of other aryllithiums having a bulky substituent at the ortho
position also gave products in good selectivities. See Supporting Informa-
tion.
(14) Shishido, Y.; Kibayashi, C. J. Org. Chem. 1992, 57, 2876-2883.
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J. AM. CHEM. SOC. VOL. 126, NO. 7, 2004 1955