.
Angewandte
Communications
Table 2: Asymmetric hydrogenation of a-alkylidene succinimides.[a]
screened using (aS)-Ir/iPr-BiphPHOX and catalysis in CH2Cl2
provided the most promising result (entries 6–8). In addition
to CH2Cl2, other haloalkane solvents such as DCE and CHCl3
are compatible solvents for catalysis, thus giving the desired
product with excellent enantioselectivity (> 98% ee; entries 7
and 8). Furthermore, optimization of the hydrogen pressure
and catalyst loading were investigated using CH2Cl2 as the
solvent (entries 9–14). To our delight the hydrogenation was
also successful at lower pressures (entries 9 and 10). The
hydrogenation proceeded rapidly, with full conversion of
substrate in under 10 minutes at 5 bar of hydrogen (entry 9).
Even with a pressure of 1 bar of hydrogen, the reaction gave
a near-quantitative yield of the hydrogenated product in
96% ee with a prolonged reaction time (entry 10). A slight
decline in reaction enantioselectivity was observed when
decreasing or increasing the hydrogen pressure (entries 9–11).
In addition, reducing the catalyst loading to 0.05 mol% still
provided quantitative yield of product in 98% ee (entries 12–
14).
Entry
1
Conv. [%][b] ee [%][c]
1
2
3
4
1a: R1 =Bn
>99
>99
>99
99
96
98
95
1b: R1 =Ph
1c: R1 =nBu
1d: R1 =CH2CH2Ph >99
5
6
7
8
1e: R2 =4-MeC6H4
1 f: R2 =3-MeC6H4
>99
>99
99
98
99
97
84
99
98
98
82
95
95
1g: R2 =4-MeOC6H4 >99
1h: R2 =3-MeOC6H4 >99
1i: R2 =2-MeOC6H4 >99
9
10
11
12
13
14
15
1k: R2 =4-FC6H4
1l: R2 =4-ClC6H4
1m: R2 =3-ClC6H4
1n: R2 =2-ClC6H4
1o: R2 =4-BrC6H4
>99
>99
>99
>99
>99
1p: R2 =4-NO2C6H4 >99
The substrate scope of the catalytic system was explored
using the optimized reaction conditions (Table 2). The
catalysis of substituted a-alkylidene succinimides was con-
ducted at room temperature using (aS)-Ir/iPr-BiphPHOX
(1 mol%) in CH2Cl2 under 20 bar of hydrogen for 1 hour.
Substrates were converted in excellent yields and high
enantioselectivities (up to quantitative conversion and
99% ee). The N-protecting group, R1, has little effect on the
reaction yield and enantioselectivity of the substrates
(entries 1–4). Electron-donating and electron-withdrawing
substituents on the phenyl ring of the substrate also had
little influence on the enantioselectivity (entries 5–8, 10–12,
and 14–16). However, reduction in enantioselectivity was
noticed when steric bulk of the substituents increased
(entries 9, 13, 17, 22, and 23). Substrates with fused-ring aryl
substituents gave excellent yields of products and good to
excellent enantioselectivities (entries 17 and 18). Heteroaryl
or alkyl substituents could also be hydrogenated to give the
desired products with high yields and enantioselectivities
(entries 19–23). The a-alkylidene succinimides must be
E configured for the hydrogenation to be successful (see the
Supporting Information).
16
17
18
19
1j
>99
>99
>99
85
99
79
97
97
1q
1r
1s
20
21
22
23
1t: R2 =Et
1u: R2 =nPr
1v: R2 =iPr
1w: R2 =Cy
>99
>99
>99
>99
97
95
88
88
We next synthesized the biologically active compound 3
(Scheme 2). It can be used for synthesizing 4, a class of useful
compounds for modifying enzymes or proteins,[13] and 5,
derivatives for inhibition of human leukocyte elastase.[14] The
asymmetric hydrogenation of 1x was performed under
a hydrogen atmosphere at 20 bar in the presence of 1 mol%
of (aS)-Ir/iPr-BiphPHOX for 1 hour, thus giving the corre-
sponding succinimide derivative 2x in quantitative yield.
Deprotection using Pd/C under a hydrogen balloon gave 3 in
99% yield (over 2 steps) and 96% ee. This methodology
provides additional opportunities for preparing a series of
important intermediates with excellent yield and enantiose-
lectivity.
[a] Reactions were conducted on a 0.25 mmol scale in 2 mL of CH2Cl2 at
room temperature using 1 mol% (aS)-Ir/iPr-BiphPHOX under 20 bar of
hydrogen for 1 h. [b] The conversion was determined by 1H NMR
spectroscopy. [c] Enantioselectivity was determined by HPLC using
a chiral Daicel column. Cy=cyclohexyl.
readily converted into 3-benzyl pyrrolidine by reduction and
deprotection, and was isolated and characterized as the N-
benzoyl derivative 6 (in 73% yield over three steps). A series
of 3-benzyl pyrrolidines can therefore be obtained in high
yields and enantioselectivies through our methodology. The
pyrrolidine motif is important for activity in many biological
systems. Furthermore, 3-benzyl pyrrolidines, a particularly
interesting class of pyrrolidine pharmacophores, exhibit
portent activity as antagonists for the NK-3 receptor and[3h]
dopamine receptor,[3f] and also as protein kinase C inhibitor-
As a synthetic application of the present methodology,
hydrogenation of 1a, was carried out in the presence of
0.05 mol% (S/C = 2000) of (aS)-Ir/iPr-BiphPHOX on a gram
scale, thus giving the corresponding succinimide derivative 2a
as a single enantiomer (98% ee; Scheme 3). The product was
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 2203 –2206