Asymmetric Hydrogenation of 3-Amido-2-arylpyridinium Salts by Triply Chloride-Bridged Dinuclear Iridium Complexes Bearing Enantiopure Diphosphine Ligands: Synthesis of Neurokinin-1 Receptor Antagonist Derivatives

Article abstract of DOI:10.1002/adsc.201600203

We describe a most straightforward synthetic method for preparing neurokinin-1 (NK1) receptor antagonist derivatives by asymmetric hydrogenation of 3-amido-2-arylpyridinium salts using dinuclear iridium complexes with enantiopure diphosphine ligands, affo

Full text of DOI:10.1002/adsc.201600203

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DOI: 10.1002/adsc.201600203
Asymmetric Hydrogenation of 3-Amido-2-arylpyridinium Salts by
Triply Chloride-Bridged Dinuclear Iridium Complexes Bearing
Enantiopure Diphosphine Ligands: Synthesis of Neurokinin-1
Receptor Antagonist Derivatives
Atsuhiro Iimuro,a Kosuke Higashida,a Yusuke Kita,a and Kazushi Mashimaa,*
a
Department of Chemistry, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8531, Japan
Fax: (+81)-(0)6-6850-6249; e-mail: mashima@chem.es.osaka-u.ac.jp
Received: February 19, 2016; Revised: April 11, 2016; Published online: June 2, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600203.
Abstract: We describe a most straightforward syn-
thetic method for preparing neurokinin-1 (NK1) re-
ceptor antagonist derivatives by asymmetric hydro-
genation of 3-amido-2-arylpyridinium salts using di-
nuclear iridium complexes with enantiopure diphos-
phine ligands, affording the corresponding chiral pi-
peridines in high cis-diastereoselectivity (>95:5)
and moderately high enantioselectivity (up to
86%). Deprotection treatments afforded the NK-
1 receptor antagonist (+)-CP-99,994 (83% ee). In
addition, we observed unique additive effects of 10-
Figure 1. Antagonists of neurokinin-1 (NK1) substance P re-
ceptor.
camphorsulfonic acid in the asymmetric hydrogena-
tion of 3-amido-2-arylpyridinium salts.
Keywords: asymmetric catalysis; hydrogenation; iri-
dium; nitrogen heterocycles
method for preparing chiral 2-aryl-3-aminopiperi-
dines; however, the aromatic nature and strong coor-
dination ability of pyridine and piperidine derivatives
has prevented the practical development of such an
Optically active piperidines are highly important mo- asymmetric hydrogenation of pyridines.[5–8] In fact,
lecular skeletons abundant in natural alkaloids and a strategy of modifying pyridines, i.e., N-iminopyridi-
biologically active compounds, and are key intermedi- nium ylides[9] and N-benzylpyridinium salts,[10] is re-
ates for synthesizing drugs and fragrances. Among quired to actuate substrates for asymmetric hydroge-
them, 3-amino-2-phenylpiperidine and its derivatives nation. We recently developed a protocol for the
have attracted special interest due to their strong bio- asymmetric hydrogenation of the hydrogen halide
logical relevance as non-peptide antagonists of neuro- salts of multisubstituted pyridines using enantiopure
kinin-1 (NK-1) substance
P receptors, such as dinuclear iridium complexes 1 (Figure 2) to furnish
(+)-(2S,3S)-CP-99,994, (+)-(2S,3S)-GR-205,171, and the corresponding chiral piperidines with high diaste-
(+)-(2S,3S)-T-2,328, as shown in Figure 1.[1] From reoselectivity and enantioselectivity.[11] Soon after,
a synthetic point of view, chiral pool synthesis[1b,2] and Zhou et al. applied our synthetic method to the asym-
diastereoselective reactions[3] for constructing the ste- metric hydrogenation of the HCl salts of trisubstitut-
reochemistry of the C-2 and C-3 positions of chiral pi- ed pyridine.[12] In this communication, we report that
peridine derivatives have been investigated, but these the asymmetric hydrogenation of 3-amido-2-arylpyri-
synthetic methodologies require multistep synthesis dinium salts catalyzed by enantiopure dinuclear iridi-
after constructing the stereogenic centers.[4] Thus, um complexes 1 in the presence of additional organic
asymmetric hydrogenation of 2-aryl-3-aminopyridines acids afforded the corresponding 3-amido-2-arylpiper-
is considered the most simple and atom economical idines in high diastereoselectivity and very high enan-
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Table 1. Screening of Brønsted acids.[a,b]
[a]
[b]
Reaction conditions: mixture of 2a·HCl (0.15 mmol), (S)-
1d (7.5 mmol), Brønsted acid (0.15 mmol), and 1,4-diox-
ane (3 mL) under H2 (30 bar) for 18 h.
cis-(2R,3R)-3a was only observed in the H NMR spec-
trum, and thus diastereoselectivity was estimated to be
1
Figure 2. Chloride-bridged dinuclear iridium complexes
bearing enantiopure diphosphine ligands.
more than 95%.
Determined by H NMR analysis using phenanthrene as
an internal standard.
Determined by HPLC analysis of corresponding
trifluoroacetamide.
Reaction conditions: mixture of 2a (0.15 mmol), (S)-1d
(7.5 mmol), (À)-CSA (0.30 mmol), and 1,4-dioxane
(3 mL) under H2 (30 bar) was heated at 608C for 18 h.
Complex mixture was obtained. 1H NMR and HPLC
analysis were not applicable.
[c]
[d]
[e]
1
tioselectivity, providing a reliable access to the synthe-
sis of NK1 receptor antagonist derivatives.
We selected 3-(N-benzyl-2,2,2-trifluoroacetamido)-
2-phenylpyridin-1-ium chloride (2a·HCl) as a test sub-
strate, and began by its hydrogenation under the con-
ditions of [{Ir(H)[(S)-segphos]}2(m-Cl)3]Cl [(S)-1d] in
1,4-dioxane at 608C for 18 h under H2 (30 bar) to
obtain the corresponding piperidine derivative
(2R,3R)-3a in 60% yield with 82% ee after a basic
work-up (Table 1, entry 1). After hydrogenation, we
[f]
1
measured the H NMR spectrum of the crude mixture
to detect a trihyride dinuclear iridium complex (S)-4d
(Figure 3), which was already reported to be catalyti-
cally inactive, but reactivated by the addition of suita-
ble Brønsted acids.[13] Accordingly, we surveyed some
Brønsted acids (100 mol% to the substrate) for ad-
justing the asymmetric hydrogenation of 2a·HCl by
(S)-1d, and the results are summarized in Table 1. Ad-
dition of (À)-10-camphorsulfonic acid [(À)-CSA] sig-
nificantly increased the yield from 60% to 85% and
the enantioselectivity from 82% to 84% (entry 1 vs.
Figure 3. Structure of (S)-4d.
2). On the other hand, (+)-CSA had smaller additive tion catalyzed by palladium and iridium complexes.[14]
effects on the reactivity and enantioselectivity than Among the Brønsted acids examined, (À)-CSA was
(À)-CSA (entry 3). These match/mismatch effects of found to be superior to other additives, including
CSA suggested that CSA interacted with the catalyti- TsOH·H2O, acetic acid, adamantanecarboxylic acid
cally active species. CSA was reported to activate in- (AdCOOH), benzoic acid, and pentafluorobenzoic
doles and qunolines prior to asymmetric hydrogena- acid (entries 4–8). In contrast to pyridinium salts,
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Table 3. Ir-catalyzed asymmetric hydrogenation of 2·HCl.[a]
unionized pyridine 2a was not hydrogenated at all to
(2R,3R)-3a under the reaction conditions at 608C
using 200 mol% of (À)-CSA, indicating that hydrogen
chloride was crucially required for the reaction to
proceed (entry 9).
Further optimization was carried out using various
iridium complexes (S)-1a–(S)-1e using 100 mol% of
(À)-CSA (Figure 2 and Table 2). Hydrogenation using
(S)-1a [L=(S)-BINAP] and (S)-1c [L=(S)-DI-
FLUORPHOS] furnished (2R,3R)-3a in lower yield
and lower enantioselectivity than when using (S)-1d
(entries 1 and 3). (S)-1b [L=(S)-SYNPHOS] in-
creased the yield to 88%; however, enantioselectivity
was decreased to 72% (entry 2). Sterically-bulky (S)-
1e [L=(S)-DM-SEGPHOS] did not improve the
enantioselectivity (entry 5). Accordingly, we selected
(S)-1d [L=(S)-SEGPHOS] as the optimal catalyst. In
the 1.5 mmol scale reaction under the optimized con-
ditions, (2R,3R)-3a was isolated in 70% with 85% ee.
A series of 3-amido-2-arylpyridinium salts was sub-
jected to asymmetric hydrogenation under the opti-
mized reaction conditions (Table 3). 2b·HCl bearing
an electron-donating group on the aryl group was hy-
drogenated with high enantioselectivity, although
a higher temperature was required (entry 2). 2c·HCl
and 2d·HCl bearing electron-withdrawing groups
were also hydrogenated with moderate enantiomeric
excess (entries 3 and 4). Hydrogenation of 2e·HCl,
[a]
Reaction conditions: A mixture of 2·HCl (0.15 mmol),
(S)-1d (7.5 mmol), (À)-CSA (0.15 mmol), and 1,4-dioxane
(3 mL) under H2 (30 bar) was heated for 18 h.
[b]
Determined by 1H NMR analysis.
[c]
Isolated yield.
[d]
Determined by HPLC analysis of corresponding
Table 2. Optimization of the reaction conditions.[a,b]
trifluoroacetamide.
[e]
A 1H NMR analysis was not applicable.
[f]
An HPLC analysis was not applicable.
Determined by HPLC analysis.
[g]
whose aryl groups bear ortho substituents, led to
lower reactivity because of the steric hindrance of the
substituent in the ortho position (entry 5). A 2-thienyl
group was tolerated under the hydrogenation condi-
tions (entry 6). Salt 2g·HCl bearing a 2-naphthyl
group was also hydrogenated with moderate enantio-
meric excess (entry 7), and salt 2h·HCl without any
substituent on the 2-position was not hydrogenated
probably due to the tightly coordinating ability of
substrate lacking a 2-aryl substituent (entry 8). Other
protecting groups of the amino group were examined
(entries 9 and 10): A benzoyl group improved the
enantioselectivity (entry 9), while a 3,5-bis(trifluoro-
methyl)benzoyl group completely retarded the reac-
tion (entry 10).
[a]
Reaction conditions: A mixture of 2a·HCl (0.15 mmol),
(S)-1 (7.5 mmol), (À)-CSA (0.15 mmol), and 1,4-dioxane
(3 mL) under H2 (30 bar) was heated at 608C for 18 h.
[b]
1
cis-(2R,3R)-3a was only observed in the H NMR spec-
trum, and thus diastereoselectivity was estimated to be
We applied this asymmetric hydrogenation as a key
step in the synthesis of (+)-CP-99,994, a non-peptide
antagonist of the NK1 receptor,[1b,c] to demonstrate
the advantage of this synthetic protocol. The catalytic
hydrogenation of 2a·HCl using the combination of
more than 95%.
Determined by the H NMR analysis using phenanthrene
[c]
[d]
[e]
1
as an internal standard.
Determined by HPLC analysis of corresponding
trifluoroacetamide.
Isolated yield obtained in the 1.5 mmol scale reaction.
[{Ir(H)[(R)-segphos]}2(m-Cl)3]Cl
[(R)-1d]
and
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night. The reaction mixture was washed with 1M aqueous
solution of HCl and poured into a saturated aqueous solu-
tion of NaHCO3. After filtration through a short plug of
Na2SO4 and silica gel and eluted with EtOAc the filtrate
was concentrated under vacuum to provide a yellowish
brown oil, which was dissolved in HPLC-grade IPA and ana-
lyzed by HPLC.
Scheme 1. Synthetic application of Ir-catalyzed hydrogena-
tion. Reagents and conditions: a) (R)-1d (5.0 mol%),
(+)-CSA (100 mol%), 1,4-dioxane, 608C, H2 (30 bar), 18 h,
then basic work-up; b) K2CO3, MeOH/H2O (3/1), 658C,
12 h; c) Pd(OH)2/C, HCl (ether solution), MeOH, 508C, H2
(15 bar), 18 h; d) o-anisaldehyde, NaBH(OAc)3, i-PrOAc,
room temperature, 3 h.
Acknowledgements
This work was financially supported by a Grant-in-Aid for
Scientific Research (A) from the Japan Society for the Pro-
motion of Science (JSPS KAKENHI Grant Number
26248028). A.I. expresses his special thanks for the JSPS Re-
search Fellowships for Young Scientists for financial support.
(+)-CSA, followed by a basic work-up gave (2S,3S)-
3a in 79% yield with 83% ee, similar to the reaction
using (S)-1d (Table 1, entry 2). After deprotection of
the trifluoromethyl group and benzyl group, an o-me-
thoxybenzyl group was attached to the 3-amino group
without loss of enantiomeric purity, achieving the
asymmetric synthesis of (+)-CP-99,994 (Scheme 1).
In summary, 3-amido-2-arylpyridinium salts were
hydrogenated by chloride-bridged dinuclear iridium
complexes to the corresponding 2-aryl-3-amidopiperi-
dines in high diastereoselectivity and moderately high
enantioselectivity. Current efforts are directed toward
mechanistic studies on the effects of CSA on the
asymmetric hydrogenation of pyridinium salts.
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