Enantioselective hydrogenation of allylphthalimides: An efficient method for the synthesis of β-methyl chiral amines

Article abstract of DOI:10.1002/anie.200501332

(Chemical Equation Presented) High yields and up to 98% ee have been achieved by asymmetric hydrogenation of allylphthalimides followed by hydrolysis to give β-methyl chiral amines by using a Ru-C₃-tunephos catalyst (see scheme). The synthetic utility of this procedure has been demonstrated through the synthesis of the key intermediate of the LTs receptor antagonist (Zeneca ZD 3532).

Full text of DOI:10.1002/anie.200501332

Angewandte
Chemie
Asymmetric Catalysis
mides, which act as precursors to the b-methyl chiral amines
[Eq. (1)].
DOI: 10.1002/anie.200501332
Enantioselective Hydrogenation of
Allylphthalimides: An Efficient Method for the
Synthesis of b-Methyl Chiral Amines**
Chun-Jiang Wang, Xianfeng Sun, and Xumu Zhang*
We initiated our studies on the asymmetric hydrogenation
ofan N-2-ethylallylphthalimide (6a) by screening several
known catalysts. Since the asymmetric hydrogenation of
functionalized olefins using chiral phosphine/Rh complexes is
well known,[6] a diverse array ofbisphosphine/Rh complexes
could be applied as catalyst precursors in this hydrogenation
reaction. Some representative results are shown in Table 1.
Chiral amines bearing a b-methyl group on the chiral center,
and their derivatives, are key structural elements in natural
products and pharmaceuticals.[1–3] For example, compound A
is a key intermediate in the synthesis ofthe leukotrienes (LTs)
receptor antagonist (Zeneca ZD3532, a phase II drug candi-
date; Scheme 1). This compound is particularly useful for the
Table 1: Asymmetric hydrogenation of 6a.
Entry
Catalyst
T [8C]
P(H2) [atm]
Conv. [%]
ee [%][a]
1
2
3
4
1
2
3c
3c
RT
RT
RT
80
5
5
5
100
100
0
21
15
NA
96
100
100
[a] Determined by chiral-phase GC (see the Supporting Information).
[Rh(cod){(1S,1S’,2R,2R’)-tangphos}]BF4 (1)
[Rh(cod)(R,R)-(Et-duphos)]BF4 (2)
[RuCl2{(S)-Cn-tunephos}](dmf)m (3a–f)
n=1, 3a; n=2, 3b; n=3, 3c
n=4, 3d; n=5, 3e; n=6, 3 f
(S)-Cn-tunephos, n=1–6
Scheme 1. Examples of b-methyl chiral amine hydrochlorides and
Zeneca ZD3525.
[2]
treatment ofasthma. Compound B (NPS 1392) is a potent
Although the complexes [Rh(cod){(1S,1S’,2R,2R’)-tang-
phos}]BF4 (1)[7] (cod = cycloocta-1,5-diene, tangphos = 1,1’-
di-tert-butyl-[2,2’]-diphosphanyl) and [Rh(cod){(R,R)-Et-
duphos}]BF4 (2)[8] (duphos = 1,2-bis(phospholanyl)benzene)
were successful for the highly enantioselective hydrogenation
ofvarious substituted oleifns, only low enantioselectivities
were obtained at room temperature under low hydrogen
pressure (Table 1, entries 1 and 2). However, Ru–diphosphine
complexes have also been applied to asymmetric hydro-
genation reactions. Catalyst 3c[9] exhibited no reactivity under
similar conditions (Table 1, entry 3). However, up to 96% ee
and 100% conversion was observed when high hydrogen
pressure (100 atm) and high temperature (808C) were
employed (Table 1, entry 4)
Encouraged by the results described above, we inves-
tigated the effects of solvents and catalyst precursors to
enable the reaction conditions to be optimized (Table 2). A
dramatic solvent effect was observed. Complex 3c performs
well in a number ofalcohols to give 7a with moderate to high
enantioselectivities (Table 2, entries 1–4); an excellent level
ofenantioselectivity was observed when the reaction was
carried out in methanol. Reaction in other solvents such as
stereoselective antagonist ofthe NMDA receptor, which can
be used for the control of ischemic strokes.[3] To our knowl-
edge, there has been no successful catalytic method to make
such important functional groups. Although some stoichio-
metric asymmetric synthesis or resolution routes have been
reported for constructing this class of chiral amines,[2–4] the
development of efficient and catalytic synthetic methods
remains a significant challenge. Herein we report the first
highly enantioselective catalytic asymmetric hydrogenation
ofdisubstituted allylphthalimides
[5]
to form chiral phthali-
[*] Dr. C.-J. Wang, X. Sun, Prof. X. Zhang
Department of Chemistry
The Pennsylvania State University
University Park, PA, 16802 (USA)
Fax: (+1)814-863-8403
E-mail: xumu@chem.psu.edu
[**] This work was supported by the National Institutes of Health. We
acknowledge the generous gift of Ru complexes from Heraeus Inc.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 4933 –4935
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Communications
Table 2: Effects of solvents and catalyst precursors on the asymmetric
hydrogenantion of 6a.
the substituent on this hydrogenation system. The enantiose-
lectivities decreased gradually along with increased steric
hindrance ofthe substituents in the substrates (Table 3,
entries 2 and 4–6). However, hydrogenation ofcyclohexyl-
and cyclopentyl-substituted substrates (6g and 6h) still
afforded products in 98 and 96% ee, respectively (Table 3,
entries 7 and 8). The hydrogenation ofthe aromatic substrate
6i proceeded smoothly with moderate enantioselectivity
(Table 3, entry 9). To our surprise, 2-chloroallylphthalimide
(6j) can also be hydrogenated and 7j was obtained with up to
93% ee (Table 3, entry 10).
Entry
Catalyst
Solv.
Conv. [%]
ee [%][a]
1
2
3
4
5
6
7
8
9
3c
3c
3c
3c
3c
3c
3c
3a
3b
3d
3e
3 f
MeOH
EtOH
100
100
100
100
0
100
100
100
100
100
100
100
96
76
37
23
NA
19
12
88
91
94
92
92
TFE[b]
iPrOH
CH2Cl2
EtOAc
THF
MeOH
MeOH
MeOH
MeOH
MeOH
To determine the configuration of the hydrogenation
product 7a obtained with (S)-C3-tunephos as a chiral ligand,
phthalimide 7a was hydrolyzed in refluxing ethanol in the
presence ofNH NH2·H2O followed by treatment with con-
2
centrated HCl according to a literature procedure to form the
known compound 8 in 65% yield [Eq. (2)].[2b,10] The absolute
10
11
12
[a] Determined by chiral-phase GC. [b] TFE=trifluoroethanol. NA=not
available.
CH2Cl2, EtOAc, or THF led to lower enantioselectivities and
reactivities (Table 2, entries 5–7). To test the effect of the
dihedral angle ofthe chiral biaryl ligands on the enantiose-
[9]
lectivity ofthe reaction, a set oftunephos
ligands with
stereochemistry of 7a was assigned as S by comparing the sign
ofthe optical rotation ofthe obtained compound 8 with the
reported data[4] (see the Supporting Information).
This asymmetric hydrogenation method can be applied to
the preparation ofthe key intermediate A for the synthesis of
the LTs receptor antagonist (Zeneca ZD3532;[2] Scheme 1).
To the best ofour knowledge, asymmetric hydrogenation
provides the simplest method for the synthesis of this
compound [Eq. (3)].
different dihedral angles were employed (Table 2, entries 1
and 8–12). The best result was observed when (S)-C3-
tunephos was used as the ligand (Table 1, entry 1).
The asymmetric hydrogenation reaction was carried out
on a variety ofsubstrates under the optimal reaction
conditions (Table 3). Substrates with a primary n-alkyl sub-
stituent such as ethyl, n-butyl, or benzyl group at the 2-
position of the allylphthalimides afforded products with high
ee values (Table 3, entries 1–3). Several substrates with bulky
substituents were also employed to probe the steric effects of
Table 3: Asymmetric hydrogenantion of N-2-substituted allylphthal-
imides.
Entry
Substrate
R
Product
Yield [%][a]
ee [%]
1[b]
2
3
4
5
6a
6b
6c
6d
6e
6 f
6g
6h
6i
Et
nBu
Bn
iPu
iPr
tBu
cyclohexyl
cyclopentyl
Ph
7a
7b
7c
7d
7e
7 f
7g
7h
7i
98.5
98.0
97.0
94.0
93.0
96.0
95.0
96.0
97.0
97.0
96[c]
96[c]
92[d]
91[c]
84[c]
67[c]
98[c]
96[c]
55[d]
93[c]
In conclusion, we have developed the first highly enan-
tioselective method for the synthesis of chiral phthalimides
with a b-methyl group on the chiral center based on
asymmetric hydrogenation, and up to 98% ee has been
achieved with a Ru–C3-tunephos catalyst. The synthetic
utility has been demonstrated through the synthesis ofthe
key intermediate A ofthe LTs receptor antagonist (Zeneca
ZD3532). Since these hydrogenation substrates are easily
obtainable, this methodology is potentially practical for the
synthesis ofsuch chiral amines, which are important pharma-
ceutical intermediates.
6
7
8
9[b]
10
6j
Cl
7j
[a] Yield of isolated product. [b] The reaction was performed at 508C in
16 h. [c] Determined by chiral-phase GC. [d] Determined by chiral-phase
HPLC.
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Angewandte
Chemie
Experimental Section
General hydrogenation procedure: [RuCl2(cymene)]2 (6.2 mg,
0.01 mmol) and (S)-C3-tunephos (12.5 mg, 0.021 mmol) were dis-
solved in degassed DMF (3 mL) in a Schlenk tube under N2. The
solution was heated at 1008C for 3.5 h. After the mixture had cooled
to 508C, the solvent was removed under vacuum to give the catalyst as
an orange-red solid. The catalyst was dissolved in degassed methanol
(16 mL) in a glovebox and divided equally between eight vials.
Substrate (0.25 mmol) was then added to the catalyst solution and the
resulting mixture transferred to an autoclave and charged with H2
(100 atm). The autoclave was stirred at 50 or 808C for 16–48 h, before
cooling it to room temperature and carefully releasing the H2. The
solvent was then evaporated and the residue was purified by column
chromatography to give the corresponding hydrogenation product,
which was then analyzed directly by chiral-phase GC (gamma
dex 225) or HPLC (Chiralpak AD) to determine the enantiomeric
excess.
Received: April 17, 2005
Published online: June 27, 2005
Keywords: amines · asymmetric catalysis · enantioselectivity ·
.
hydrogenation · ruthenium
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Angew. Chem. Int. Ed. 2005, 44, 4933 –4935
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4935