New synthetic strategy for high-enantiopurity N-protected α-amino ketones and their derivatives by asymmetric hydrogenation

Article abstract of DOI:10.1002/adsc.201000680

Asymmetric hydrogenation of α-dehydroamino ketones catalyzed by a rhodium-chiral phosphorus ligand complex (up to 99% ee, 1000 TON), represents an efficient approach to chiral α-amino ketones. The reduction of α-amino ketones catalyzed by palladium on carbon (Pd/C) leads to amphetamine precursors with quantitative yield and no significant enantioselectivity loss.

Full text of DOI:10.1002/adsc.201000680

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DOI: 10.1002/adsc.201000680
New Synthetic Strategy for High-Enantiopurity N-Protected
a-Amino Ketones and their Derivatives by Asymmetric
Hydrogenation
Tian Sun,a Guohua Hou,a Miaofeng Ma,a and Xumu Zhanga,*
a
Department of Chemistry and Chemical Biology & Department of Medicinal Chemistry, Rutgers, The State University of
New Jersey, Piscataway, New Jersey 08854, USA
Fax : (+1)-732-445-6312; e-mail: xumu@rci.rutgers.edu
Received: September 1, 2010; Published online: February 4, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000680.
Abstract: Asymmetric hydrogenation of a-dehy-
droamino ketones catalyzed by a rhodium-chiral
phosphorus ligand complex (up to 99% ee, 1000
TON), represents an efficient approach to chiral a-
amino ketones. The reduction of a-amino ketones
catalyzed by palladium on carbon (Pd/C) leads to
amphetamine precursors with quantitative yield and
no significant enantioselectivity loss.
As a consequence of their high efficiency, atom
economy, and operational simplicity, asymmetric hy-
drogenations have provided powerful routes to enan-
tiomerically enriched compounds.[8] Actually, the
asymmetric hydrogenation of dehydroamino acids for
the synthesis of l-DOPA accomplished by Knowles
(Nobel Prize, 2001) is the first industrial catalytic
asymmetric synthesis.[9] Despite the remarkable suc-
cess achieved in the hydrogenation of various dehy-
droamino acids,[10] the hydrogenation of a-dehydro-
Keywords: a-amino ketones; amphetamines; enan-
tioselectivity; hydrogenation; rhodium
ACHTUNGTRENaNGNU mino ketones remains unexplored. In this research,
we report the synthesis of a series of new substrates,
a-dehydroamino ketones 1. Then we successfully ob-
tained the chiral a-amino ketones 2 by hydrogenation
with absolute chemoselectivity (enamide over
Chiral a-amino ketones represent an important class ketone), excellent enantioselectivity (up to 99% ee)
of compounds characterized by biological activity.[1] and high reactivity (1000 TON). We also report the
In particular, aryl a-amino ketones are employed in reduction of a-amino ketones catalyzed by Pd/C pro-
the clinical treatment of depression.[2] For example, ducing amphetamine precursors 3 with quantitative
bupropion, a large spectrum therapeutic agent, is mar- yield and no significant enantioselectivity loss
keted as one of the most effective antidepressants.[3] (Scheme 1).
Moreover, peptidyl ketones derived from a-amino ke-
Initially, we chose [RhACTHNUGTRENNU(G COD)ACHTUNGTNER(NNUG Sc,Rp)-DuanPhos]BF4
tones are of significant value for the development of as the catalyst, which has been proven to be efficient
molecular therapeutics, and diagnostic tools in chemi- for asymmetric hydrogenation of enamides, and N-(1-
cal biology.[4]
benzoylethenyl)-acetamide 1a as the standard sub-
Extensive efforts have been made on the construc- strate. When the hydrogenation was performed in
tion of enantiopure a-amino ketones starting from EtOAc (1a=0.3 mmol, S/C=100, EtOAc=3 mL)
chiral amino acids derivatives.[5–7] These metal-cata- under 5 bar of H2 at room temperature, the substrate
lyzed coupling reactions now have achieved a sophis- 1a was fully converted to the hydrogenation product
ticated level in terms of mild reaction conditions, high 2a with 92% ee (Table 1, entry 1). Solvent screening
enantiopurity and broad substrate scope.[6,7] Yet, one revealed that THF led to the best selectivity (Table 1,
of the most significant challenges remains: stoichio- 95% ee, entry 6). We also tested other commercially
metric or excess chiral reagents are required and con- available ligands: TangPhos (L2), BINAP (L3), and
sumed. Herein, we address a new strategy to solve Binapine (L4) in THF. Either low enantioselectivity
this issue: asymmetric hydrogenation of readily acces- or low activity was observed with these ligands
sible and highly modular a-dehydroamino ketones as (Table 1, entries 7–9). An increase in the hydrogen
a direct entry to chiral a-amino ketones and their de- pressure to 20 bar (Table 1, entry 10) led to low enan-
rivatives.
tioselectivity (85%) and no side product (amino alco-
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253

Tian Sun et al.
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Scheme 1. Asymmetric hydrogenation of a-dehydroamino ketones 1 as an entry to a-amino ketones 2 and amphetamines 3.
Table 1. Rhodium-catalyzed asymmetric hydrogenation of
1a under various conditions.[a]
Table 2. Rhodium-catalyzed asymmetric hydrogenation of
1a–1m.[a]
Entry L[b] Solvent P(H2) [bar] Yield [%] ee[c,d] [%]
Entry Substrate R1
R2 Time Product ee[b]
[h]
[%]
1
2
3
4
5
6
7
8
L1 EtOAc
L1 MeOH
L1 toluene
L1 CH2Cl2
L1 acetone
L1 THF
L2 THF
L3 THF
L4 THF
L1 THF
5
5
5
5
5
5
5
5
5
20
1
100
100
100
100
100
100
100
100
N.R.
100
100
92
87
90
85
92
95
65
5
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
H
H
H
H
H
H
1
1
1
1
1
0.5
2a
2b
2c
2d
2e
2f
2g
2h
2i
95 (R)
90
97
95
92
94
95
98
97
p-Me-C6H4
p-MeO-C6H4
p-F-C6H4
p-Cl-C6H4
m-Cl-C6H4
Ph
Me 2
p-MeO-C6H4 Me 2
9
–
85
95
10
9
p-Cl-C6H4
Et
Ph
Me 2
Me 2
11[e]
L1 THF
10
1j
2a
2j
3a
99
95
11[c]
H
48
[a]
Reaction conditions: [substrate]=0.1M, S/C=100, room
temperature.
L1=(SC,RP)-DuanPhos, L2=(1S,1S’, 2R,2R’)-TangPhos,
L3=(S)-BINAP, L4=(S)-Binapine.
[a]
Reaction conditions: substrate/catalyst=100.
[b]
[b]
[c]
Determined by GC or HPLC.
[1a]=0.1M, Pd/C:1a=100, MeOH, 50 bar of H2, room
[c]
[d]
Determined by chiral HPLC.
temperature, 48 h.
The absolute configuration was determined by reducing
2a to 3a, then comparison with reported data.
S/C=1000, room temperature, 10 bar of H2, 24 h.
[e]
the products (Table 2, entries 2, 5 and 6), except for a
higher 97% ee provided by the p-MeO-substituted
substrate 1c (Table 2, entry 7). Interestingly, we found
hol) was detected (Table 1, entry 10). We also tested that trisubstituted enamide moieties 1g–1i showed
the hydrogenation of 1a under atmospheric pressure higher ee (95%–98%). We further expanded the sub-
monitored by TLC. The reaction was complete within strate scope to the aliphatic substrate 1j, 99% ee was
1 h with 95% ee to our great delight. The high effi- observed, showing that the catalyst Rh/DuanPhos is
ciency of the catalyst Rh/DuanPhos was further dem- effective with a wide scope of substrates.
onstrated in an experiment with a lower catalyst load-
We have demonstrated that hydrogenation of both
ing (S/C=1000, 10 bar of H2), giving identical ee, aryl- and alkyl-substituted a-dehydroamino ketones
albeit the reaction required a longer time of 24 h leads to good to excellent enantioselectivity. As a
(Table 1, entry 11).
result, this methodology has great potential for impor-
Using the optimized reaction conditions, we con- tant pharmaceutical molecules (Figure 1). Aryl a-
ducted the hydrogenation of a set of substrates 1b–1j amino ketones like bupropion,[3] cathionone,[11] and
under atmospheric pressure (Table 2). All the sub- brephedrone[12] are effective in treating psychological
strates were completely converted to the correspond- diseases. Keto-ACE,[13] an alkyl-substituted a-amino
ing N-protected a-amino ketones 2 with high enantio- ketone derivative, is a key medicine to treat hyperten-
selectivity. The presence of substituents on the phenyl sion that affects an estimated 26% of the worldꢁs
moieties in 2 resulted in a slight decrease in the ee of adult population. Another important family of a-
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Adv. Synth. Catal. 2011, 353, 253 – 256

New Synthetic Strategy for High-Enantiopurity N-Protected a-Amino Ketones and their Derivatives
phetamine medicines like adderall,[16] selegilline,[17]
and flomax[18] that have been proven effective to treat
ADHD, Parkinsonꢁs disease and enlarged prostate,
respectively.
In summary, we have demonstrated that chemose-
lective asymmetric hydrogenation of substrates 1 is a
powerful entry to b-ketoamphetamines in terms of ac-
tivity (1000 TON), chemoselectivity (100%), and
enantioselectivity (up to 99% ee). We have also dem-
onstrated that the combination of Rh/DuanPhos and
Pd/C is an elegant approach to amphetamines. Fur-
ther exploration on substrate scope and catalyst com-
binations is currently under progress.
Figure 1. Important medicines bearing a-amino ketone
units.
Experimental Section
amino ketones is peptidyl ketones which have been
intensively studied because of their biological activi- Substrate Preparation
ties.[14]
A catalytic amount of p-TsOH and acetamide (5 equiv.)
Furthermore, it is of key importance to explore the
combination of asymmetric hydrogenation with other
methodologies to develop efficient protocols for phar-
maceutical and industrial applications. Herein, we
propose a new protocol integrating Rh-catalyzed hy-
drogenation and Pd/C-catalyzed reduction to maxi-
mize the efficiency of chiral amphetamine synthesis.
Previously, Zhangꢁs group reported the synthesis of
enantiopure amphetamines by asymmetric hydrogena-
tion of b-arylenamides.[15] However, Z/E isomers of b-
arylenamides were generated simultaneously, result-
ing in an extra separation step. In this research, we
developed a simple route to obtain enantiopure a-
amino ketones, and amphetamine building blocks sub-
sequently (Scheme 1). For example, the hydrogena-
tion product 2a was directly reduced to generate pro-
tected amphetamine 3a catalyzed by Pd/C with no sig-
nificant loss of ee % (Scheme 2). The new protocol
may further contribute to the synthesis of diverse am-
were added to a stirred solution of 4 (1.0 equiv.) in toluene.
The mixture was heated under reflux using a Dean–Stark
apparatus. TLC was used to monitor the reaction process.
The precipitate acetamide was separated by filtration and
the filter residue was washed with EtOAc thoroughly. The
combined filtrate was washed with saturated NaHCO3 solu-
tion and water, dried over Na2SO4. After removing of the
solvent by rotary evaporation, the product mixture was puri-
fied by flash column chromatography using 25% ethyl ace-
tate/hexane.
Hydrogenation
A 10.0-mL Schlenk tube was loaded with substrate 1
(0.3 mmol) and [RhACTHNUTRGENN(UG COD)ACHUTNGTRNE(NUGN Sc,Rp)-duanphos]BF4 (3ꢂ
10À4 mmol, 2.04 mg). The mixture was dissolved in 3 mL
THF at room temperature in the glove-box. Then the
Schlenk tube was brought into a hood and connected to a
hydrogen balloon. The inert atmosphere was replaced by H2
and reaction mixture was stirred at room temperature and
monitored by TLC. After the reaction was complete (20 min
to 2 h), hydrogen was released and thecatalyst was removed
through a silica gel-loaded plug. The ee was directly deter-
mined by chiral GC or HPLC.
Acknowledgements
We gratefully thank the National Institutes of Health
AHCTUNGTREG(NNNU GM58832) and Merck & Co., Inc. for the financial support.
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