Highly enantioselective hydrogenation of 1-alkylvinyl benzoates: A simple, nonenzymatic access to chiral 2-alkanols

Article abstract of DOI:10.1002/chem.201303500

Going chiral! Highly enantioselective catalytic hydrogenations of enol esters 1 by using a Rh catalyst bearing a P?￡?OP ligand are described (see scheme; NBD=norbornadiene). The catalytic system has a broad scope and allows the preparation of a wide range of chiral esters 2 bearing diverse alkyls or a benzyl group with high enantioselectivities. These esters can easily be converted in highly enantioenriched 2-alkanols. Copyright

Full text of DOI:10.1002/chem.201303500

COMMUNICATION
DOI: 10.1002/chem.201303500
Highly Enantioselective Hydrogenation of 1-Alkylvinyl Benzoates:
A Simple, Nonenzymatic Access to Chiral 2-Alkanols
Patryk Kleman,[a] Pedro J. Gonzꢀlez-Liste,[b] Sergio E. Garcꢁa-Garrido,[b]
Victorio Cadierno,*[b] and Antonio Pizzano*[a]
Enantiopure 2-alkanols (A, Figure 1) constitute a primary
class of building blocks for organic synthesis, used in the
preparation of a plethora of chiral compounds.[1] Currently,
a broad range of alcohols A are efficiently obtained in high
enantiomeric purity by diverse enzymatic procedures.[2] In
contrast, the synthesis of these alcohols by chemocatalytic
reactions has not reached such a high performance in terms
of enantioselectivity and product scope.[3–5]
lective reduction of enol esters C[6] followed by a hydroxyl
deprotection of the resulting chiral esters D. The hydrogena-
tion of several classes of prochiral enol esters has been de-
scribed in the literature,[7] but little information about the
reduction of 1-alkylvinyl derivatives C is available. This is
mainly limited to reactions catalyzed by Rh complexes bear-
ing monodentate phosphorus ligands, under relatively high
hydrogen pressures (40–60 bar).[8,9] Thus, the groups of
Reetz and Goossen have reported enantioselectivities of up
to 94% ee in the hydrogenation of a 1-n-butylvinyl ester by
using a carbohydrate-based phosphite.[8a] The latter group
has also shown that this catalytic system provides high enan-
tioselectivities (up to 98% ee) in the hydrogenation of struc-
turally related 1,2-dimethylvinyl esters, whereas enantiose-
lectivity decreases to values near 80% ee for substrates bear-
ing longer alkyl chains at position 1.[8b] On the other hand,
the group of Ding has described the application of catalysts
based on phosphoramidites in the hydrogenation of 1-n-al-
kylvinyl substrates, giving enantioselectivities between 87
and 90% ee.[8c] Inspired by these precedents, and following
our interest in asymmetric hydrogenation,[10] we describe
herein a study on the hydrogenation of 1-alkylvinyl esters
with Rh catalysts based on chelating phosphane–phosphite
Figure 1. Structures of A–D-type compounds.
A very convenient synthesis of alcohols A can be provid-
ed by hydrogenation or transfer hydrogenation reactions of
methyl alkyl ketones B. However, high enantioselectivities
are limited to substrates bearing relatively bulky R1 substitu-
ents (e.g. iPr, Cy, tert-alkyl), whereas lower enantioselectivi-
ties are obtained in the case of ketones with linear alkyl R1
groups.[3] In this regard, promising results have been ach-
ieved by the use of a Rh surfactant[3g] type or a Ru–cyclo-
dextrin catalysts,[3d] providing high enantioselectivities (up to
94% ee; ee=enantiomeric excess) for substrates bearing
long R1 chains, such as n-decyl methyl ketone, although the
enantioselectivity decreases with the length shortening of
this substituent (e.g. 74–76% ee for n-butyl methyl ketone).
An alternative route to the synthesis of alcohols A, using
catalytic hydrogenation reactions, is based on the enantiose-
À
chiral ligands (P OP, Figure 2), which provides an efficient
route for the preparation of chiral esters D.
[a] P. Kleman, Dr. A. Pizzano
À
Instituto de Investigaciones Quꢀmicas, CSIC and
Universidad de Sevilla, Avda Amꢁrico Vespucio 49
41092 Sevilla (Spain)
Figure 2. Structure of phosphane–phosphite (P OP) ligands.
E-mail: pizzano@iiq.csic.es
Initially, a family of enol esters 1 (Scheme 1) was pre-
pared in high yield by a Ru-catalyzed condensation between
carboxylic acids and terminal alkynes in water, which produ-
ces the desired Markovnikov isomer in high yield.[6b] Cata-
lytic hydrogenations were then performed with a set of Rh
À
[b] P. J. Gonzꢂlez-Liste, Dr. S. E. Garcꢀa-Garrido, Dr. V. Cadierno
Laboratorio de Compuestos Organometꢂlicos y Catꢂlisis
(Unidad Asociada al CSIC), Departamento de Quꢀmica Orgꢂnica
e Inorgꢂnica
Instituto de Quꢀmica Organometꢂlica “Enrique Moles”
Universidad de Oviedo, 33006 Oviedo (Spain)
E-mail: vcm@uniovi.es
catalyst precursors of formula [RhACHTUNGRTENNUG(NBD)ACHTUNGTRENN(UGN P OP)]BF4
À
(NBD=norbornadiene; P OP=(S)-3a (4a), (R)-3a (4a’),
(S)-3b (4b), (S)-3c (4c), (S)-3d (4d)).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303500.
Chem. Eur. J. 2013, 19, 16209 – 16212
ꢃ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 2. Hydrogenation of 1b–n with catalyst precursors 4.[a]
Entry
Cat.
Substrate
S/C
ee [%] (conf)
1
2
3
4
5
6
4c
4c
4c
4c
4c
4c
4d
4c
4a
4a
4a’
4c
4a
4c
4d
4d
4c
4c
4c
4c
1b
1c
1d
1e
1 f
1g
1g
1h
1h
1h
1h
1i
1j
1j
1j
1j
1k
1l
1m
1n
500
96 (R)
95 (R)
97 (R)
98 (R)
98 (R)
86 (S)
85 (S)
78 (S)
97 (S)
97 (S)
96 (R)
99 (R)
98 (R)
98 (R)
98 (R)
99 (R)
95 (R)
95 (R)
96 (R)
96 (R)
500
1000
500
500
500
500
500
500
1000
500
500
200
200
200
500
500
500
500
500
7[b]
8
9
Scheme 1. Hydrogenation of enol esters 1.
10
11
12
13
14
15
16
17
18
19
20
As a starting point, some hydrogenations of 1a, chosen as
a representative substrate, were performed at room temper-
ature and 20 bar of hydrogen. Under these conditions cata-
lyst precursors 4a and 4c completed the reaction with rela-
tively high enantioselectivities (88–89% ee, entries 1–2,
Table 1). We next noticed that these catalysts also displayed
[a] Reactions in CH2Cl2 at 408C and an initial pressure of 4 bar of hydro-
gen, [Rh]=2ꢄ10À4 m, [1]=0.04–0.2m. Reaction time: 24 h. Reactions
showed full conversion unless otherwise stated. Conversion determined
by 1H NMR spectroscopy and enantiomeric excess by chiral GC or
HPLC analysis. See the Supporting Information for determination of
configuration. [b] 95% conversion.
Table 1. Hydrogenation of 1a performed with catalyst precursors 4.[a]
Entry
Cat.
H2 [bar]
S/C
Conv. [%]
ee [%] (conf.)
1
2
3
4a
4c
4a
4b
4c
4d
4c
20
20
4
4
4
100
100
200
200
200
200
500
100
100
100
74
100
100
100
89 (R)
88 (R)
94 (R)
83 (R)
96 (R)
93 (R)
96 (R)
4[b]
5
6
4
4
lectivity at a S/C ratio of 1000 (97% ee, entry 3). In addition,
substrates 1e and 1 f, bearing cycloalkyl chains, provided ex-
ceedingly high values of 98% ee (entries 4 and 5).
7[c]
[a] Hydrogenations in CH2Cl2, [Rh]=2ꢄ10À4 m, [1a]=0.02–0.1m, at an
initial pressure and substrate to catalyst ratio (S/C) indicated. Reactions
performed at room temperature for 24 h unless otherwise stated. Conver-
sion was determined by 1H NMR spectroscopy and enantiomeric excess
by chiral HPLC analysis. Configuration was determined by comparison
of the optical rotation sign with literature data. [b] Reaction time 37.5 h.
[c] Reaction performed at 408C.
Along the series, cyclohexyl-substituted substrate 1g con-
stituted the most difficult case. Indeed, using 4a under the
standard conditions only a low conversion (34%) could be
reached. In turn, 4c exhibited full conversion and provided
a good enantioselectivity (86% ee, entry 6, Table 2), but un-
expectedly, with an opposite S configuration. Moreover, 4d
did not improve this value (entry 7). In contrast with the
above results, the catalyst precursor 4c provided a remarka-
bly lower enantioselectivity for the tert-butyl-substituted
enol ester 1h (78% ee, entry 8), whereas complex 4a provid-
ed the best catalyst for this substrate and afforded the S
product with a 97% ee (entry 9). Despite the presence of
a bulky R substituent in 1h, it showed a good reactivity that
allowed us to complete a reaction with a S/C of 1000
(entry 10).
An added value of the present system is that it allows
a ready preparation of both product enantiomers. For in-
stance hydrogenation of 1h with precatalyst 4a’ provided
(R)-2h with a 96% ee (entry 11, Table 2).
On the other hand, the benzyl derivative 1i was very effi-
ciently hydrogenated with 4c to give (R)-2i with a 99% ee
(entry 12, Table 2). This is a remarkable result since the
product is useful for the preparation of 2-phenylpropyla-
mines of pharmaceutical interest.[12] In addition, for compa-
rative purposes, Ph derivative 1j was also examined. This
substrate is less sensitive to the structure of the catalyst and
complexes 4a, 4c, and 4d provided (R)-2j with very high
enantioselectivities, between 98 and 99% ee (entries 13–16).
good activity at lower pressure (4 bar), enough to complete
the reactions at S/C values of 200. Most remarkably, the de-
crease in hydrogen pressure produced an important en-
hancement on enantioselectivity.[11] Thus, 4a gave 94% ee
(entry 3), whereas 4c improved this value up to 96% ee
(entry 5). By comparison, a lower enantioselectivity was ob-
served with the isopropyl-substituted catalyst 4b (entry 4),
whereas p-tolyl derivative 4d also provided a good enantio-
selectivity, but it did not improve the result of 4c (entry 6).
Finally, it should be remarked that a slight increase in reac-
tion temperature allowed completion of the reaction with
a S/C of 500 in 24 h without a decrease in enantioselectivity
(entry 7).
Following the finding of a highly effective system for the
hydrogenation of 1a, we have next explored the scope of
4c, by examining the reaction with substrates 1b–n. Re-
markably, this catalyst precursor showed high enantioselec-
tivities in the hydrogenation of substrates bearing a linear
alkyl substituent R. Thus, 1b and 1c were hydrogenated
with 96 and 95% ee, respectively (entries 1 and 2, Table 2).
Likewise, the propanoate 1d also provided high enantiose-
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Chem. Eur. J. 2013, 19, 16209 – 16212

Highly Enantioselective Hydrogenation of 1-Alkylvinyl Benzoates
COMMUNICATION
It is interesting to note that the enantioreversal observed
in the hydrogenation of 1h, relative to 1j, parallels that ob-
served before in the hydrogenation of tert-butyl and aryl en-
amides.[13] This phenomenon has been studied in detail in
the literature and assigned to an opposite regioselectivity of
the olefin insertion step depending on the nature of the
olefin substituent, favoring a b-alkyl in the case of the tBu
enamide.[13b–c] Similar to the hydrogenation of 1h, the S
enantiomer is also favored in the case of the cyclohexyl sub-
strate 1g, although the enantioselectivity is lower. Apparent-
ly, the size of the Cy substituent is not high enough to com-
pletely disfavor an a-alkyl pathway; therefore, competition
with the b-alkyl pathway may operate, with a concomitant
erosion on enantioselectivity.
A particularly appealing application of the present hydro-
genation is the preparation of chiral benzoates substituted
at the benzene ring. These derivatives have interest, for in-
stance, in the preparation of liquid crystals.[14] Accordingly,
a set of Br and MeO-substituted benzoates (1k–n) were also
examined. Worth noting is that the substitution did not sig-
nificantly affect the reaction and compounds 2k–n were ob-
tained with full conversion and enantioselectivities between
95 and 96% ee (entries 17–20, Table 2), which are similar to
that shown by unfunctionalized benzoate 1c.
Prompted by these considerations, we performed the hydro-
genation of 1a with precatalyst 4c at a S/C ratio of 500 in
the neat substrate. Worth noting is that the catalyst is not in-
hibited at high substrate concentration and full conversion
was obtained after 24 h, leading to 2c with a 96% ee
(entry 1, Table 3). Likewise, reactions performed in neat 1h,
Table 3. Hydrogenations performed with precatalysts 4 at high substrate
concentration.[a]
[b]
Entry
1
Cat.
1/CH2Cl2
ee [%] (conf)
1
2
3
4
1a
1h
1i
1j
1n
1p
4c
4a
4c
4c
4c
4c
n
n
1:1
n
n
1:1
96 (R)
95 (S)
99 (R)
99 (R)
96 (R)
5
6[c]
>99 (R,R)
[a] Reactions at 408C and an initial pressure of 4 bar of hydrogen, S/C=
500. Reaction time: 24 h. [b] Substrate: solvent weight ratio, n denotes
a reaction performed in the neat substrate. [c] 2% of meso compound ob-
served.
1j, and 1n provided high conversions and enantioselectivi-
ties (entries 2, 4 and 5, respectively). This procedure is not
suitable for benzyl substrate 1i, which is solid. In turn, a re-
action in a 1i/CH2Cl2 1:1 (w/w) mixture was performed. As
in the previous examples, an excellent enantioselectivity was
obtained and (R)-2j was obtained with a 99% ee (entry 3).
Likewise, 1p was hydrogenated more satisfactorily by using
a substrate/CH2Cl2 1:1 mixture. Noticeably, this reaction
gave only 2% of the meso product (entry 6).
An alternative application of the present reaction is the
hydrogenation of bis-enol benzoates suitable for the prepa-
ration of synthetically useful diols.[7a,15] To this aim, the
novel dibenzoate 1o was prepared and examined
(Scheme 2). By using 4c and a S/C ratio of 200 (i.e. 400
Despite the fact that the corresponding debenzoylation is
a simple, well-known reaction in the literature,[18] due to the
interest of products 2 in the preparation of alcohols, we
wanted to fully validate the concept including some exam-
ples of deprotection of benzoates 2 (Scheme 3). Thus, treat-
Scheme 2. Hydrogenation of dibenzoates.
olefin bonds per Rh atom), the reaction was completed
under our standard conditions and only 2% of the meso
compound was observed. The remaining product corre-
sponds to the R,R enantiomer, as the S,S enantiomer was
not observed. For the dibenzoate 1p, similar results were
observed. Thus, 3% of the meso and an enantioselectivity
higher than 99% ee was observed. Remarkably, this proce-
dure gives comparable results to the dynamic kinetic resolu-
tion process of analogous 1,4- and 1,5-diacetates described
by Bꢅckvall and co-workers.[15a]
Considering the synthetic application and scale-up of the
hydrogenations of enol esters 1, an important point to con-
sider is the catalyst performance at a high substrate concen-
tration or even in the neat substrate. Thus, a minimization
of solvent added has a high environmental interest and,[16] in
addition, the reduction of the volume reaction for a certain
amount of product is an aspect of industrial value.[17]
Scheme 3. Deprotection of benzoates 2.
ment of 2c with an excess of K2CO3 in methanol provided
(R)-2-octanol (5c) in high yield without a decrease on enan-
tioselectivity (95% ee). A similar reaction was performed
with 2h, which also proceeded without loss on enantioselec-
tivity (98% ee). Finally, particularly interesting debenzoyla-
tion of 2i provided synthetically useful[12] (R)-1-phenyl-2-
propanol 5i with 93% yield and 99% ee.
In summary, a highly enantioselective hydrogenation of
enol esters 1 by using Rh catalysts bearing chiral phos-
phane–phosphite ligands has been described.[19] The reaction
has a broad scope and provides a wide range of esters 2
with high enantiomeric purity, which are suitable precursors
Chem. Eur. J. 2013, 19, 16209 – 16212
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V. Cadierno, A. Pizzano et al.
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activity under high substrate concentration and even in the
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Keywords: alcohols
enantioselectivity · esters · rhodium
·
asymmetric
hydrogenation
·
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For some examples see, for instance: a) T. Ohkuma, M. Koizumi, H.
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wa, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1998, 120, 13529–
[19] In parallel to the present work, Leitner, Franciò, and co-workers
have just reported that chiral phosphane–phosphoramidites also
provide highly enantioselective Rh catalysts for these hydrogena-
tions, see: T. M. Konrad, P. Schmitz, W. Leitner, G. Franciò, Chem.
Eur. J. 2013, 19, 13299–13303.
Received: September 5, 2013
Published online: November 4, 2013
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