The use of a new carboranylamidophosphite ligand in the asymmetric Rh-catalyzed hydrogenation of α- And β-dehydroamino acid derivatives

Article abstract of DOI:10.1016/j.poly.2011.02.003

New chiral carboranylamidophosphite ligand was synthesized and tested in the Rh-catalyzed asymmetric hydrogenation of α- and β-dehydroamino acid derivatives (up to 93% ee). The catalytic performance is affected greatly by temperature and the nature of sol

Full text of DOI:10.1016/j.poly.2011.02.003

Polyhedron 30 (2011) 1258–1261
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The use of a new carboranylamidophosphite ligand in the asymmetric
Rh-catalyzed hydrogenation of a- and b-dehydroamino acid derivatives
a
a
a
Sergey E. Lyubimov a, , Eugenie A. Rastorguev , Tatiana A. Verbitskaya , Pavel V. Petrovskii ,
⇑
Evamarie Hey-Hawkins b, Valery N. Kalinin a, Vadim A. Davankov a
a A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov Street 28, 119991 Moscow, Russia
b Institut für Anorganische Chemie, Johannisallee 29, 04103 Leipzig, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
New chiral carboranylamidophosphite ligand was synthesized and tested in the Rh-catalyzed asymmetric
Received 17 January 2011
Accepted 3 February 2011
Available online 4 March 2011
hydrogenation of
a- and b-dehydroamino acid derivatives (up to 93% ee). The catalytic performance is
affected greatly by temperature and the nature of solvents. Importantly, we have shown that in the
hydrogenation of the b-dehydroamino acid derivatives the use of acidic 1,1,1,3,3,3-hexafluoro-2-propa-
nol led to a significant increase in the enantioselectivity, compared to isopropyl alcohol.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Amidophosphites
Carboranes
Asymmetric hydrogenation
Rhodium
Amino acids
1. Introduction
catalytic reactions [19–22]. Encouraged by excellent activities
and enantioselectivities in the asymmetric hydrogenation pro-
Enantiomerically pure unnatural amino acids and their deriva-
tives are very important chiral building blocks for the synthesis
of biologically active compounds [1–5]. Moreover, the incorpora-
tion of unnatural amino acids into recombinant proteins is a valu-
able tool for understanding protein function and engineering
proteins with increased potency and enzymatic stability [6–8].
For these reasons the enantioselective synthesis of unnatural ami-
no acids has attracted considerable interest. Among the catalytic
methods for the preparation of unnatural amino acids, asymmetric
hydrogenation seems to be the most attractive one due to low cat-
alyst loading and using hydrogen as cheap reducing agent [9]. Until
recently, most efforts have concentrated on the employment of
chiral bidentate P-ligands [10,11]. By using ruthenium or rhodium
catalysts with chiral bidentate P-ligands in the asymmetric hydro-
cesses and motivated by our continuing efforts in the design of no-
vel chiral carboranylphosphite-type ligands, we have prepared a
novel sterically congested carborane-containing monodentate
amidophosphite ligand for the application in the Rh-catalyzed
hydrogenation of a- and b-dehydroamino acid derivatives.
2. Material and methods
2.1. General
31P, 11B and 1H NMR spectra were recorded with a Bruker AV
400 instrument (162.0 MHz for 31P, 128.4 MHz for 11B and
400.13 MHz for 1H. Chemical shifts (ppm) are given relative to
Me4Si (1H), 85% H3PO4
(
31P NMR) and BF3 ⁄ Et2O (11B). Elemental
genation of a- and b-dehydroamino acid derivatives, good to excel-
analyses were performed at the Laboratory of Microanalysis
(Institute of Organoelement Compounds, Moscow). (Sa)-2-Chloro-
dinaphtho[2,1-d:10,20-f][1,2,3]dioxaphosphepine (1) [23], 3-ortho-
aminocarborane (2) [24], substrates 4a–c [1,25,26], 6a–c [27] and
[Rh(COD)2]BF4 [28] were prepared as published.
lent enantioselectivities have been accomplished [12,13].
However, monodentate phosphites and phosphoramidites have
been shown to be excellent, and sometimes superior alternatives,
to bidentate ligands, in terms of simplicity of synthesis, ease of
structural variation and enantioselectivity in the asymmetric
hydrogenation [9,14–18]. Recently, we designed a novel class of
phosphite-type ligands containing sterically congested carborane
fragments and showed their high efficiency for metallocomplex
2.2. Preparation of (S)-2-(ortho-carborane-3-ylamino)-dinaphtho[2,1-
d:10,20-f][1–3]dioxaphosphepine
3-Ortho-aminocarborane 0.202 g (1.27 mmol) was added to a
vigorously stirred solution of the (Sa)-2-chloro-dinaphtho[2,1-
d:10,20-f][1,2,3]dioxaphosphepine 0.45 g (1.27 mmol) and NEt3
⇑
Corresponding author. Tel.: +7 499 1352548; fax: +7 499 1356471.
E-mail address: lssp452@mail.ru (S.E. Lyubimov).
0277-5387/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2011.02.003

S.E. Lyubimov et al. / Polyhedron 30 (2011) 1258–1261
1259
(0.212 mL, 1.90 mmol) in benzene (25 mL). The mixture was stir-
red for 10 min. The reaction mixture was then heated to reflux
for 5 min, cooled and filtered. Benzene was removed under re-
duced pressure (40 Torr), the product was washed with hexane/
chloroform mixture (1/1, 10 mL total volume) and dried in vacuo
(1 Torr) for 1 h. White solid, 0.361 g (60% yield), mp: 226 °C.
31P{H} NMR (CDCl3) = 153.89. 1H NMR (CDCl3) = 1.44–3.64 (m,
9H, B–Hcarborane), 2.28 (s, 1H, CHcarborane), 2.69 (s, 1H, CHcarborane),
3.12 (s, 1H, NH), 7.01–7.81 (m, 12H, Ar). 11B NMR (CDCl3) = ꢀ17.12
to ꢀ12.25 (m, 6B), ꢀ9.51 (s, 1B), ꢀ4.81 to ꢀ1.86 (m, 3B). Anal. Calc.
for C22H24B10O2PN: C, 55.80; H, 5.11; N, 2.96. Found: C, 55.87; H,
5.19; N, 2.84%.
Scheme 2. Synthesis of Rh-complex 4.
2.3. Synthesis of rhodium complex 4
A solution of [Rh(COD)2]BF4 0.015 g, (0.037 mmol) in CH2Cl2
(2 mL) was added to a vigorously stirred solution of the ligand 3
0.035 g, (0.074 mmol) in CH2Cl2 (8 mL). The mixture was stirred
for additional 10 min and concentrated at reduced pressure to a
volume of ca. 0.5 mL, and hexane (8 mL) was added. The precipi-
tated solid was separated by centrifugation and dried in vacuo
(1 mm Hg) for 0.5 h.
Scheme 3. Rh-catalyzed asymmetric hydrogenation of
derivatives.
a
-dehydroamino acids
with monodentate phosphite and phosphoramidite ligands [29–
32].
2.3.1. [Rh(COD)(3)2]BF4 (4)
Yellow solid, mp: 134–136 °C (dec), 31P{H} NMR (CDCl3) =
141.60 (br d, JP,Rh = 242 Hz). Anal. Calc. for C52H60B21F4N2O4P2Rh
(%): C, 50.17; H, 4.86; N, 2.25. Found: C, 50.26; H, 4.78; N, 2.16%.
Our initial studies have focused on the enantioselective hydro-
genation of
a-dehydroamino acids esters (Scheme 3): (Z)-methyl
2-acetamido-3-(4-chlorophenyl)acrylate (5a), (Z)-methyl 2-acet-
amido-3-(4-fluorophenyl)acrylate (5b) and (Z)-methyl 2-acetam-
ido-3-(2-naphthyl)acrylate (5c). The catalyst was formed in situ
by mixing [Rh(COD)2]BF4 with 2 equiv. of the amidophosphite 3
(see experimental section). The reduction of chloro-containing
enamide 5a at 20 °C proceeded quantitatively in 12 h and high
enantioselectivity was observed (Table 1, entry 1). To evaluate
the effect of temperature and trying to increase the reaction rate,
the temperature was raised from 20 to 50 °C. In this case not only
complete conversion was reached in 3 h but also better enantiose-
lectivity was observed, compared to that obtained at 20 °C (Table 1,
entry 2). The hydrogenation of enamides 5b–c showed the same
trend, better reaction rate and enantioselectivity were obtained
at 50 °C (Table 1, entries 3–6). It should be noted, however, that
hydrogenation of the substrate 5c bearing a sterically hindered
naphthyl group provided lower enantioselectivity, compared to
enamides 5a,b. The use of the isolated cationic complex 4 in the
Rh-catalyzed hydrogenation of enamides 5a–c at 50 °C showed
the same activity and enantioselectivity as the catalyst formed
in situ (Table 1, entries 2, 4, 6 and 7–9).
2.4. General procedure for the catalytic hydrogenation of
dehydroamino acid derivatives
a- and b-
The hydrogenation experiments were carried out in a 10 mL
stainless-steel high-pressure reactor. The reactor was charged with
[Rh(COD)2]BF4 (2.4 mg, 0.006 mmol), ligand (5.6 mg, 0.012 mmol)
and CH2Cl2 (0.3 mL). The solution was stirred for 5 min before
removing the solvent in vacuo. Substrate (0.6 mmol) and the corre-
sponding solvent (2 mL) were added to the in situ prepared catalyst
or the complex 4 (0.006 mmol), the reactor was pressurized with
hydrogen (40 atm) and the mixture stirred at the required temper-
ature. After stirring, the vessel was depressurized. The reaction
products were dissolved in CH2Cl2 (2 mL), the catalyst removed
via a short silica gel column. The filtrate was concentrated in vacuo
to afford the target products.
3. Results and discussion
Next we decided to study amidophosphite 3 in the hydrogena-
tion of (Z)-b-dehydroamino acid derivatives (Scheme 4). It should
The new amidophosphite ligand 3 was synthesized by a conve-
nient one-step phosphorylation of 3-ortho-aminocarborane (2,
Scheme 1). The ligand 3 was characterized by 31P, 11B, 1H NMR
spectroscopy and by elemental analysis (see Section 2). It is a white
solid and has moderate solubility in common protic solvents.
Reaction of the amidophosphite ligand 3 with [Rh(COD)2]BF4
afforded cationic rhodium complex 4 (Scheme 2). 31P NMR data
for complex 4 showed chemical shift and coupling constant JP,Rh
(see experimental part) similar to those for rhodium complexes
Table 1
Asymmetric hydrogenation of
a
-dehydroamino acids derivatives.a,b
Entry
Substrate
T (°C)
t (h)
ee, (%)c
1
2
3
4
5
6
7
8
9
5a
5a
5b
5b
5c
5c
5a
5b
5c
20
50
20
50
20
50
50
50
50
12
3
12
3
12
3
3
91
93
90
93
81
84
93
92
84
3
3
a
b
c
Substrate/[Rh(COD)2]BF4/ligand = 1.0/0.01/0.02, 40 atm H2, CH2Cl2.
Conversion was 100% in each case according to 1H NMR spectroscopy.
Determined by HPLC (Chiralcel OD–H, 250 ꢁ 4.6 mm column, 9/1 hexane/i-
PrOH, 1.0 mL/min, 219 nm).
Scheme 1. Synthesis of chiral carborane-containing amidophosphite ligand.

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S.E. Lyubimov et al. / Polyhedron 30 (2011) 1258–1261
(Table 2, entries 3, 4). During the hydrogenation of substrates
7b–c, the same trends were observed. In general, HFIP leads to
an important increase in the enantioselectivity compared to
i-PrOH, and the use of higher temperature results in decrease in
the enantioselectivity (Table 2, entries 5–12). Concerning the steric
effect of the substrates, the best enantioselectivity (85% ee) was
obtained with enamide 7a containing less sterically demanding
methyl substituent (R1).
4. Conclusions
Scheme 4. Rh-catalyzed asymmetric hydrogenation of b-dehydroamino acids
derivatives.
In conclusion, we have prepared a novel carborane-containing
amidophosphite ligand for the use in asymmetric catalysis. The li-
gand proved to be efficient in the Rh-catalyzed asymmetric hydro-
genation of a- and b-dehydroamino acid derivatives (up to 93% ee).
Importantly, we have shown that increase of the temperature from
be noted, that the geometrical isomers of the b-dehydroamino
acid derivatives show different selectivity in metal-catalyzed
hydrogenations. In general, an (E)-isomer hydrogenated with
higher enantioselectivity than the corresponding (Z)-isomer [9].
Nevertheless, the known synthetic protocols for the synthesis of
the b-dehydroamino acid derivatives similar to 7a–c result in the
formation of (Z)-isomer as a major product [27,33–35]. Therefore,
the development of a catalytic system exhibiting high enantiose-
lectivity for (Z)-b-dehydroamino acid derivatives is important.
Firstly, we have examined the hydrogenation of ethyl (Z)-3-ace-
toamido-2-butenoate (7a) in i-PrOH at 20 and 50 °C under
40 atm of H2 pressure. In the both cases nearly racemic product
8a was observed despite complete conversion (Table 2, entries 1,
2). In contrast to the reaction in i-PrOH, the hydrogenation in the
more acidic alcohol – 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)
proceeded completely with 85% ee at 20 °C (Table 2, entry 3). It
should be noted, that (Z)-b-(acylamino)acrylates have intramolec-
ular hydrogen bond between the N–H of acylamide group and the
carbonyl oxygen of the ester, which prevents the desired bidentate
coordination of the substrate to the metal and the use of strongly
acidic HFIP may help to break down the hydrogen bond and thus
allow the olefin to coordinate at the metal center for further selec-
tive hydrogenation step [27,33,36,37]. Taking into account that
HFIP can form stronger hydrogen bonds than other alcohols, the
intermolecular hydrogen bond between the substrate and HFIP
should be the preferred structure, compared to i-PrOH [38,39]. To
achieve a higher reactivity the temperature was raised from 20
to 50 °C. In this case, complete conversion of 7a was observed in
3 h but product 8a was obtained with lower enantioselectivity
20 to 50 °C results in better reaction rate and enantioselectivity in
the Rh-catalyzed asymmetric hydrogenation of
a-dehydroamino
acid derivatives. In the hydrogenation of the b-dehydroamino acid
derivatives the use of acidic HFIP and lower temperature led to an
important increase in the enantioselectivity.
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Table 2
Asymmetric hydrogenation of b-dehydroamino acids derivatives.a
Entry
Substrate
Solvent
T (°C)
t (h)
Conversion (%)b
ee (%)
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7b
7b
7b
7b
7c
7c
7c
7c
i-PrOH
i-PrOH
HFIP
20
50
20
50
20
50
20
50
20
50
20
50
12
3
12
3
12
3
12
3
12
3
12
3
100
100
100
100
100
100
100
100
84
5c
2c
85c
78c
34d
31d
69d
56d
9e
HFIP
i-PrOH
i-PrOH
HFIP
HFIP
9
i-PrOH
i-PrOH
HFIP
10
11
12
100
100
100
1e
46e
42e
HFIP
a
b
c
Substrate/[Rh(COD)2]BF4/ligand = 1.0/0.01/0.02, 40 atm H2.
Determined by 1H NMR spectroscopy.
Determined by HPLC (Chiralcel OJ–H, 250 ꢁ 4.6 mm column, 95/5 hexane/i-
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PrOH, 1.0 mL/min, 219 nm).
d
Determined by HPLC (Chiralpak AD, 250 ꢁ 4.6 mm column, 95/5 hexane/i-
PrOH, 0.8 mL/min, 219 nm).
e
Determined by HPLC (Chiralcel OD–H, 250 ꢁ 4.6 mm column, 9/1 hexane/i-
PrOH, 1.0 mL/min, 219 nm).

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