Highly enantioselective hydrogenation of 2-substituted-2-alkenols catalysed by a ChenPhos-Rh complex

Article abstract of DOI:10.1039/c3cc47727d

Highly enantioselective hydrogenation of a variety of 2-substituted-2- alkenols has been achieved using a ChenPhos-Rh complex as catalyst, giving ≥99% ee for most substrates. Optically active antifungal agent amorolfine was first synthesised using hydrogenation as the key step. This journal is

Full text of DOI:10.1039/c3cc47727d

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Highly enantioselective hydrogenation
of 2-substituted-2-alkenols catalysed
by a ChenPhos–Rh complex†
Cite this: Chem. Commun., 2014,
50, 978
Received 8th October 2013,
Quanjun Wang, Xueying Liu, Xian Liu, Bin Li, Huifang Nie, Shengyong Zhang* and
Weiping Chen*
Accepted 13th November 2013
DOI: 10.1039/c3cc47727d
www.rsc.org/chemcomm
Highly enantioselective hydrogenation of a variety of 2-substituted-2-
alkenols has been achieved using a ChenPhos–Rh complex as catalyst,
giving Z99% ee for most substrates. Optically active antifungal agent
amorolfine was first synthesised using hydrogenation as the key step.
Chiral 2-substituted alkanol derivatives are key building blocks in
the syntheses of many important pharmaceuticals, bioactive com-
pounds, natural products and polymers.1,2 However, generally, the
Rh- and Ru-complexes of known phosphine ligands are not effective
for the asymmetric hydrogenation of 2-substituted-2-alkenols3 since
these catalysts usually require a coordinating functional group (CFG)
(most common CFG: ester, carboxylic acid and amide) at the suitable
position to anchor the substrate to the metal in order to achieve high
enantioselectivity,4 and the hydroxyl group in 2-substituted-2-
alkenols does not serve as a typical CFG.2 A breakthrough has been
made by Pfaltz who has demonstrated that Ir–PHOX complexes can
Scheme 1 Asymmetric hydrogenation of 2-substituted-2-alkenols catalysed
using a ChenPhos–Rh complex.
We initially chose the most studied 2-methyl-3-phenyl-2-propenol
catalyse the hydrogenation of various unfunctionalized olefins with 1a as a model substrate. To our delight, the ChenPhos–Rh
very high enantioselectivities,5 subsequently followed by others.6 complex exhibited excellent enantioselectivity for the asymmetric
Although the asymmetric hydrogenation of 2-methyl-3-phenyl-2- hydrogenation of 1a. Thus, hydrogenation of 1a in the presence of
propenol catalysed by a variety of chiral Ir-complexes based on the ChenPhos–Rh complex, generated in situ from [Rh(NBD)2]BF4
P,N- or C,N-ligands has been well studied,7 the enantioselective (1.0 mol%; NBD = 2,5-norbornadiene) and ChenPhos (1.05 equiva-
hydrogenation of other 2-substituted-2-alkenols is rare.
lent with respect to Rh), in dichloromethane (DCM) under 25 atm
Previously, we reported TriFer and ChenPhos as well as their of hydrogen pressure at room temperature, gave (S)-2a with
high enantioselectivities in the Rh-catalysed asymmetric hydro- unprecedented enantioselectivities of up to >99% ee (Table 1,
genation of a-substituted cinnamic acids.8 The key to our success entry 1). The choice of solvent plays a critical role in this
for TriFer and ChenPhos is probably owing to a secondary hydrogenation. An almost racemic product was obtained using
electrostatic interaction between the dimethylamino group polar protic solvents MeOH, EtOH and i-PrOH (entries 2–4). Polar
of the ligand and the carboxylate unit of the substrate. We aprotic solvents THF and EtOAc improved the enantioselectivities,
envisioned that a hydrogen-bonding interaction between the but the results were unsatisfactory (Table 1, entries 5 and 6). Non-
substrate and the catalyst might form in the asymmetric hydro- polar solvent toluene gave 90% ee, but the activity was very low
genation of 2-substituted-2-alkenols catalysed by a ChenPhos–Rh (entry 7). High activity was achieved using polar chlorinated
complex (Scheme 1), leading to highly enantioselective and solvents but the enantioselectivity was still somewhat low utilising
efficient hydrogenation.
CHCl3 (entry 8). Dichloromethane (DCM) or dichloroethane (DCE)
gave perfect results (entries 1 and 9), and is the solvent of
choice for the catalyst system. Importantly, for reactions at
higher substrate concentrations, substrate-to-catalyst (S/C)
ratios, hydrogen pressure and temperature seem to have no
significant effect on ee values (Table 1, entries 10–14).
School of Pharmacy, Fourth Military Medical University, 169 Changle West Road,
Xi’an, 710032, P.R. China. E-mail: wpchen@fmmu.edu.cn
† Electronic supplementary information (ESI) available: Detailed procedure,
NMR spectra and ee determination. See DOI: 10.1039/c3cc47727d
978 | Chem. Commun., 2014, 50, 978--980
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Table 1 Asymmetric hydrogenation of 2-methyl-3-phenylpropenol catalysed
using a ChenPhos–Rh complexa
Table 2 Asymmetric hydrogenation of 2-substituted-2-alkenola
Conv.b (%)
eec (%)
Entry
R2, R1 (1)
Product
ee (%)
Entry
Solvent
H2 (atm)
Temp. (1C)
1
2
3
4
5
6
7
8
Ph, Me (1a)
2a
2b
2c
2d
2e
2f
2g
2h
2i
>99 (S)
99 (S)
>99 (À)
>99 (S)
>99 (À)
95 (S)
99 (À)
98 (À)
99 (S)
1
2
3
4
5
6
7
8
DCM
MeOH
EtOH
i-PrOH
THF
EtOAc
Toluene
CHCl3
DCE
DCM
DCM
DCM
DCM
DCM
25
25
25
25
25
25
25
25
25
5
50
60
80
25
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
100
80
50
10
10
86
23
100
100
9
100
100
100
100
>99
0
5
2-MeOC6H4, Me (1b)
3-MeOC6H4, Me (1c)
4-MeOC6H4, Me (1d)
4-MeC6H4, Me (1e)
4-(t-Bu)C6H4, Me (1f)
4-(t-Pentyl)C6H4, Me (1g)
4-FC6H4, Me (1h)
4-ClC6H4, Me (1i)
4-BrC6H4, Me (1j)
4-CF3C6H4, Me (1k)
6
40
71
90
85
97
>99
>99
>99
>99
98
9
10
11
9
2j
2k
99 (À)
10
11
12
13
14
93 (À)
12
2l
97 (À)
a
Reaction conditions: 0.2 mmol scale, [substrate] = 0.1 mol LÀ1
,
13
14
15
16
17
18
4-MeOC6H4, Et (1m)
C6H5, nPentyl (1n)
Ph, Ph (1o)
2-Thiophenyl, Me (1p)
2-Furanyl, Me (1q)
2-Furanyl, iPr (1r)
2m
2n
2o
2p
2q
2r
97 (+)
99 (À)
>99 (R)
>99 (S)
>99 (S)
>99 (S)
solvent = 2 mL, 1.0 mol% of catalyst. Determined by 1H NMR analysis.
b
c
Determined by chiral HPLC analysis.
Some well-known diphosphine ligands were tested in the
hydrogenation as well (see ESI†). The appropriately oriented
dimethylamino group in the ligand seems to be crucial for
achieving high enantioselectivity. Most of the ligands tested
showed low activity and enantioselectivity except for TriFer that
contains an almost identical dimethylamino group to ChenPhos.
Under the optimized conditions of 25 atm of hydrogen pressure,
1.0 mol% of ChenPhos–Rh complex, dichloromethane as solvent,
room temperature and 20 h of reaction time, a series of
2-substituted-2-alkenols were hydrogenated successfully. As shown
in Table 2, the hydrogenation appears to be insensitive to the
position and the steric properties of the substituent on the aromatic
ring as well as the substituent at the 2-position, giving almost perfect
enantioselectivities of Z99% ee for most substrates (Table 2,
entries 1–10 and 12–15), but the electron-withdrawing group seems
19
2b
2t
92 (S)
20b
>99 (S)
21b
ent-2t
92 (R)
22c
Ph, Me (1a)
2a
>99 (S)
a
The reaction conditions and analysis were the same as those in
b
to reduce the enantioselectivity somewhat (entry 11). Importantly, Table 1, entry 1. Full conversions were obtained in all cases. Only
c
C2QC3 double bond was hydrogenated. S/C = 1000.
heteroaromatic ring substituted substrates afforded extremely high
enantioselectivities (entries 16–18). More importantly, the (E)- and
(Z)-alkenols afforded products with the same configuration albeit the the enantioselectivities of o95% ee, and some impressive results
enantioselectivity of the (Z)-isomer was somewhat lower (entry 2 vs. have been achieved using o-Tol-PHOX (98% ee),5 SimplePHOX
entry 19). In addition to 2-substituted-2-alkenols, 3-substituted-2- (97% ee),7a phoshine thiazole ligands (up to 99% ee),7b,c,f Cab-
alkenols geraniol and its cis-isomer nerol were also tested in this PHOX (up to 96% ee)7e and QUINAP (95% ee).7d Thus, the
catalyst system. Interestingly, geraniol provided optically pure ChenPhos–Rh complex is the most enantioselective catalyst
(S)-citronellol while nerol gave (R)-citronellol in 92.0% ee (entries system for the asymmetric hydrogenation of a broad range of
20 and 21).9 Notably, the ChenPhos–Rh complex is highly active for 2-substituted-2-alkenols reported so far.
the hydrogenation as well, giving full conversion in >99% ee with
Although we are unable to clarify the exact mechanism for
0.1 mol% of catalyst loading in the hydrogenation of 2-methyl-3- the outstanding catalytic performance of the ChenPhos–Rh
phenyl-2-propenol 1a (Table 2, entry 22). It is worth noting that complex in the hydrogenation presently, the experimental facts
the ChenPhos–Rh complex is inactive for the hydrogenation of seem to be in support of our hypothesis: a hydrogen-bonding
some similar substrates without a hydrogen-bonding donor, such interaction between a substrate and a catalyst might form,
as 2-methyl-1-phenyl-1-butene, (E)-ethyl 2-methyl-3-phenylacrylate leading to highly enantioselective and efficient hydrogenation.
and (E)-2-methyl-3-phenylallyl acetate.
Firstly, the distinct solvent effects on the catalytic outcome
In the chiral Ir-complex catalysed asymmetric hydrogena- observed in Table 1 provide circumstantial evidence for the
tion of 2-methyl-3-phenyl-2-propenol, most catalysts showed involvement of H-bonding interactions in the hydrogenation.
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receptor such as DCM and DCE but in the protic solvents such
as MeOH, EtOH and i-PrOH or the solvents with a H-bonding
receptor such as THF and EtOAc, this kind of hydrogen bonding
could be destroyed by the solvents and consequently decrease the
enantioselectivity and activity. Secondly, in accord with the postulate
of a hydrogen-bonding secondary interaction, the ChenPhos–Rh
complex is inactive for the hydrogenation of the similar substrates
without a hydrogen-bonding donor, and, among the tested eight
diphosphine ligands, only the ligands containing appropriately
oriented dimethylamino groups (H-bonding receptors) show high
enantioselectivity in the hydrogenation of 2-methyl-3-phenyl-2-
propenol 1a. Hydrogen-bonding interactions have been utilised to
account for some metal-catalysed asymmetric transformations,10 but
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demonstrated in the first asymmetric synthesis of antifungal
agent (À)-amorolfine (see ESI†).
In summary, a highly enantioselective hydrogenation of a variety
of 2-substituted-2-alkenols catalysed by a ChenPhos–Rh complex has
been developed. To the best of our knowledge, the ChenPhos–Rh
complex is the most enantioselective catalyst system for the
asymmetric hydrogenation of a broad range of 2-substituted-2-
alkenols reported so far, probably due to a hydrogen-bonding
secondary interaction of the dimethylamino unit of the ligand
with the hydroxyl group of the substrate. Optically active
antifungal agent amorolfine was first synthesised using the
enantioselective hydrogenation as the key step. Further studies
to explore the application of this methodology in the synthesis
of bioactive compounds are underway in our lab.
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980 | Chem. Commun., 2014, 50, 978--980
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