Highly Stereoselective Synthesis and Hydrogenation of (Z)-1-Alkyl-2-arylvinyl Acetates: A Wide Scope Procedure for the Preparation of Chiral Homobenzylic Esters

Article abstract of DOI:10.1021/acscatal.6b00282

A synthesis of (Z)-1-alkyl-2-arylvinyl acetates 3 with broad scope is reported by using two complementary methods. The first one uses a stereospecific gold-catalyzed addition of acetic acid to 1-iodo-alkynes, followed by a Suzuki coupling. By the second,

Full text of DOI:10.1021/acscatal.6b00282

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Letter
Highly Stereoselective Synthesis and Hydrogenation of
(Z)-1-Alkyl-2-arylvinyl Acetates: a Wide Scope Procedure
for the Preparation of Chiral Homobenzylic Esters
Pedro J. González-Liste, Félix Leon, Inmaculada Arribas, Miguel Rubio,
Sergio Emilio García-Garrido, Victorio Cadierno, and Antonio Pizzano
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00282 • Publication Date (Web): 04 Apr 2016
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ACS Catalysis
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Highly Stereoselective Synthesis and Hydrogenation of (Z)-1-Alkyl-
2-arylvinyl Acetates: a Wide Scope Procedure for the Preparation of
Chiral Homobenzylic Esters
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Pedro J. González-Liste,§ Félix León,¶ Inmaculada Arribas,¶ Miguel Rubio,¶,‡ Sergio E. García-
Garrido,§ Victorio Cadierno*§ and Antonio Pizzano*¶
§Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al CSIC), Centro de Innovación en
Química Avanzada (ORFEO-CINQA), Departamento de Química Orgánica e Inorgánica, Instituto Universitario de
Química Organometálica “Enrique Moles”, Universidad de Oviedo, 33006 Oviedo, Spain.
¶Instituto de Investigaciones Químicas and Centro de Innovación en Química Avanzada (ORFEO-CINQA), CSIC
and Universidad de Sevilla, 41092 Sevilla, Spain.
ABSTRACT: A synthesis of (Z)-1-alkyl-2-arylvinyl acetates 3 with broad scope is reported by using two complementary
methods. The first one uses a stereospecific gold-catalyzed addition of acetic acid to 1-iodo-alkynes, followed by a Suzuki
coupling. By the second, 1-methyl-2-arylvinyl substrates have selectively been obtained as the Z isomers by O-acylation of
enolates of methyl benzyl ketones. In addition, the asymmetric hydrogenation of enol esters 3 has been covered for the
first time. Using rhodium catalysts based on chiral phosphine-phosphite ligands (P-OP), highly enantioselective hydro-
genations (up to 99 % ee) have been achieved for a wide range of substrates. Thus, the synthesis and enantioselective
hydrogenation of 3 provides a convenient and versatile procedure for the synthesis of valuable chiral homobenzylic esters.
KEYWORDS: iodo-alkenes, enol esters, asymmetric hydrogenation, chiral esters, Rh catalysts
Enantiopure homobenzylic alcohols (A in Scheme 1) form
a pivotal class of building blocks in organic synthesis,
useful for the preparation of diverse types of compounds
like aryl-2-propylamines, chromenes or benzofurans
tion have been reported in the literature, which in addi-
tion, show low to moderate enantioselectivity (up to 85 %
ee).7 Nevertheless, the group of Xiao has reported a highly
enantioselective (98 % ee) transfer hydrogenation of 3-
trifluoromethylphenyl-propan-2-one, but no information
about a further scope of the corresponding catalytic sys-
tem was provided.8
among
pharmaceutical
others,1
which
notably
Accordingly
include
to
some
this
products.2
importance, the synthesis of compounds
A
has
thoroughly been investigated.3 At this regard, it is
particularly remarkable
a procedure based on an
enantioselective catalytic diboration of terminal alkenes,
followed by a cross-coupling step, described by the group
of Morken, which provide a broad range of alcohols with
high enantioselectivity.4 Moreover, because of efficiency
and practical advantages, the enzymatic reduction of
benzyl alkyl ketones B has also received great attention.5
By using this procedure, diverse alcohols A have been
obtained with exceedingly high enantioselectivity.
However, most of these alcohols are methyl carbinols,
while information about the reduction of ketones with Ak
substituents other than Me is rather scarce.6 This factor
can be of high importance, due to the influence of the Ak
substituent on the enantioselectivity observed in some of
these enzymatic reactions.6a
Scheme 1. Structures of compounds A-E.
An alternative route to alcohols A based on an asymmet-
ric hydrogenation, which could also benefits of the inher-
ent practical advantages of this kind of reactions,9 is
based on the reduction of the olefin bond of 1-alkyl-2-
arylvinyl esters C followed by a trivial deacylation.9g,9l,10a,11
In a previous contribution, we described the highly enan-
tioselective hydrogenation of 1-benzylvinyl benzoate (D),
but extension of this reaction would only be suitable for
the synthesis of methyl carbinol derivatives.10 Towards a
more general method, we envisioned that the hydrogena-
tion of C would be of substantially higher value. This
reaction has not been reported before and represents a
The success of the enzymatic reduction of B strongly
contrasts with the results obtained in catalytic asymmet-
ric hydrogenations. Thus, only rare examples of this reac-
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considerable challenge.12,13 The closer precedent is consti- P-OP = 5d-5e (6d-6e)] were used (Chart 1).10 It is worthy
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tuted by the Rh catalyzed hydrogenation of 1-alkyl-2-
methylvinyl esters reported by Gooßen and coworkers,
which provided up to 98 % ee for the 1-Me substrate,
while it decreased down to 82 and 78 % ee for the corre-
sponding 1-nPr and 1-nBu derivatives, respectively.14 In this
context, we now report a highly enantioselective catalytic
system for the hydrogenation of C which operates under
mild conditions, along with very convenient procedures
for the synthesis of these substrates, which are selectively
obtained as Z isomers.
of noting that the set contains two novel diastereomeric
catalyst precursors 6d-6e characterized by a highly basic
P-stereogenic phosphine fragment and differing in the
configuration of the phosphite one. These complexes
were obtained from the corresponding phosphine-
phosphites 5d-5e, which were prepared from (S)-tert-
butyl-methyl-2-hydroxyethyl phosphine borane27 (see
supplementary material for details).
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As a first stage we investigated a wide scope synthesis for
olefins C as reports on the preparation of these com-
pounds are practically limited to 1-arylpropen-2-yl esters.15
Among different methods for the synthesis of enol-
esters,16 the intermolecular catalytic addition of carboxylic
acids to alkynes is a highly versatile and efficient proce-
dure.17 However, application of this procedure to internal
unactivated18 aryl-alkynes towards the synthesis of C is
hampered by a difficult control of regioselectivity, as well
as a biased addition of the carboxylic acid to the aryl
bonded carbon giving opposed regioisomers.19,20 With the
aim to circumvent these problems an alternative proce-
dure based on the unprecedented addition of carboxylic
acids to 1-iodo-alkynes 1 has been developed.21 Thus, we
found that gold(I)-catalyzed addition of AcOH to 1 pro-
ceeds with exquisite regio- and stereoselectivity, leading
to the corresponding iodo-alkenes 2 as pure Z isomers in
good yields (76-90%; Scheme 2).22 Subsequent arylation of
compounds 2 allowed us to reach a wide range of enol
esters 3a-3n, differing in the nature of the R and Ar
groups (52-72 % overall yields from 1, Scheme 2). From a
practical viewpoint it is also worth to recall that these
substrates are prepared as configurationally pure Z iso-
mers, thus avoiding a tedious separation of olefin isomers
before hydrogenation. An extension of the present meth-
od to the synthesis of 1-methylvinyl esters would require a
cumbersome deprotonation of propyne and handling of
relatively volatile 1-iodopropyne (b. p. 110 °C). As these
enol esters have a great interest because they can provide
a convenient access to methyl carbinols useful in the
synthesis of biologically active compounds,23 we have
investigated a more practical synthesis starting from
commercially available benzyl methyl ketones (Scheme
3). First, reaction of p-methoxyphenyl acetone with iso-
propenyl acetate, in the presence of a catalytic amount of
p-toluenesulfonic acid, produced enol ester 3o as a Z/E
1.7:1 mixture. Due to difficult isomer separation,24 we
alternatively investigated the acylation of the correspond-
ing enolate.25 This route satisfyingly produced 3o in high
yield as a Z/E 97:3 mixture. Using this procedure, Z iso-
mers of compounds 3p-3s were also obtained with high
selectivity (96-99 %), and generally good yields (72-91 %)
with the exception of 3s for which a low yield was ob-
tained.26
Scheme 2. Synthesis of enol esters 3a-3n (isolated yields
for two steps in brackets).
Scheme 3. Synthesis of enol esters 3o-3s (isolated yields
in brackets).
Chart 1. Chiral ligands used in the present study.
Among the different enol-esters synthesized, 3d was cho-
sen as a representative one and a set of hydrogenations
(Scheme 4) were prepared with it under mild conditions
(40 °C, 4 bar H2, S/C = 100, CH2Cl2, Table 1). These reac-
tions evidenced a rather low reactivity of 3d. Thus, cata-
lyst precursors 6a, 6b and 6e showed low conversion
values (entries 1,2, 4). This is a remarkable difference with
the hydrogenation of D, as 6a and 6b typically provide
complete conversion at S/C = 500 under these reaction
conditions.10 In contrast, complex 6d offered a great im-
provement on catalyst activity, also providing a very high
For hydrogenation studies a set of catalyst precursors
bearing phosphine-phosphite ligands (P-OP) of general
formula [Rh(diolefin)(P-OP)]BF4 [diolefin
=
1,4-
norbornadiene, P-OP = 5a-5c (6a-6c); 1,5-cyclooctadiene,
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5 in Table 2). Under the standard conditions, cyclopropyl
enantioselectivity (98 % ee, entry 3). Worth noting, an
1
2
3
4
5
6
7
8
important influence of the solvent in performance of 6d
was observed (entries 5-8), which allowed us to complete
the reaction in 1,2-dichloroethane (DCE) with high enan-
tioselectivity (98 % ee). Considering that several (Z)-3-
aryl-2-acyloxyacrylates have been hydrogenated under
mild conditions with very high enantioselectivity (>95 %
ee, 3-5 bar H2, rt) using commercially available Me-
DuPHOS13a and DiPAMP9b,9k catalysts, it looks of interest
to test these catalysts in the hydrogenation of 3d under
the optimized conditions. Thus, [Rh(COD)(S,S)-Me-
DuPHOS]BF4 (7a) provided a moderate conversion albeit
with a high enantioselectivity (57 %, 93 % ee, entry 11). On
the other hand [Rh(COD)(R,R)-DiPAMP]BF4 (7b) provid-
ed only moderate conversion and enantioselectivity (en-
try 12). For comparison, catalyst prepared in situ from
[Rh(COD)2]BF4 and 2 equiv of phosphoramidite (S)-
PipPHOS (7c)9f,13b was also tested. It showed both low
conversion and enantioselectivity (entry 13). This compar-
ison indicates a particular suitability of 6d for the present
hydrogenation. Finally, lowering of the catalyst loading
still showed a satisfactory performance at S/C = 250 (entry
9), while conversion sharply decreased at S/C = 500 (entry
10).
substrate 3f provided full conversion and only 77 % ee
(entry 6). However, an important enhancement on enan-
tioselectivity up to 92 % ee (entry 7) was observed when
the reaction was performed at 30 °C.28 Disappointingly,
the cyclohexyl substrate 3g showed low reactivity either
using 6d or 6c under 4 bar H2, with conversion values of
18 and 7 %, respectively (entries 8 and 9). Use of 6d under
20 bar H2, increased the conversion up to 50 % in 48 h,
although enantioselectivity was only moderate (47 % ee,
entry 10). Apparently, the steric hindrance introduced by
the cyclohexyl substituent is detrimental for both catalyst
activity and enantioselectivity, constituting a limitation
for the present catalytic system.
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Table 2. Hydrogenation of 3a-3n performed with 6da
Entry
1
Substrate H2 (bar)
% conv.
>99
>99
>99
>99
>99
>99
>99
18
% ee (conf.)
94 (S)
98 (S)
98 (S)
98 (S)
97 (S)
77 (n d)
92 (n d)
n d
3a
3b
3c
3d
3e
3f
4
2
4
3
4
4
4
5
4
6
7b
4
3f
4
8
3g
3g
3g
3h
3i
4
9c
10d
11
4
7
n d
Scheme 4. Asymmetric hydrogenation of enol esters 3.
Table 1. Hydrogenation of 3d performed with 6-7a
20
4
50
47 (n d)
96 (S)
95 (S)
97 (S)
95 (S)
96 (S)
n d
>99
83
Entry Cat. S/C
Solvent
% conv.
%
ee
12
13
14
15
16
17
18e
19
20
4
(conf.)
3j
4
94
1
6a
6b
6d
6e
6d
6d
6d
6d
6d
6d
7a
100
100
100
100
100
100
100
100
250
500
100
100
100
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
13
n d
3k
3l
4
>99
>99
<5
2
<5
79
38
>99
<5
37
77
98
41
n d
4
3
98 (S)
94 (R)
98 (S)
n d
3m
3n
3i
4
4
5
4
>99
>99
>99
>99
96 (S)
95 (S)
93 (S)
95 (S)
4
6
7
Toluene
2-Me-THF
PriOH
DCE
3j
20
20
77 (S)
79 (S)
98 (S)
98 (S)
93 (R)
45 (R)
16 (S)
3m
8
9
10
11
12
13
aHydrogenations performed at 40 °C in DCE for 24 h at
S/C = 100; [Rh] = 2 × 10-4 M, [3] = 0.02 M, unless otherwise
DCE
1
stated. Conversion determined by H NMR and % ee by
DCE
57
61
chiral HPLC. See supplementary material for determination
c
of configuration. bReaction performed at 30 °C. Reaction
7b
7c
DCE
d
e
performed with 6c. 48 h reaction time. [Rh] = 4 × 10-4 M,
DCE
13
[3i] = 0.04 M.
aHydrogenations under 4 bar H2, [Rh] = 2 × 10-4 M, [3d] =
Substrates with diverse aryl substituents were next exam-
ined. Thus, for a set of enol esters bearing a 1-hexyl sub-
stituent (3h-3n), outstanding enantioselectivities were
generally observed under our standard conditions (95-97
% ee, entries 11-15, 17). In addition, conversion was largely
high, except in the case of 3,4-dimethoxy substrate 3m,
for which no reactivity was observed under 4 bar H2 (en-
try 16). In contrast, a complete reaction with a high enan-
tioselectivity could be obtained under 20 bar H2 (95 % ee,
0.02-010 M, at 40 °C, unless otherwise stated. Conversion
1
determined by H NMR and % ee by chiral HPLC. See sup-
plementary material for determination of configuration.
In a next stage, the scope of the best catalytic system, i.e.
that based on complex 6d in DCE, was then examined. As
observed in the hydrogenation of 3d, substrates bearing a
primary alkyl R substituent (3a-3c, 3e) provided full con-
version and high enantioselectivity (94-98 % ee, entries 1-
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entry 20). Moreover, hydrogenations of 3i and 3j could be
k2(O,O)-coordination of the 3,4-dimethoxyphenyl frag-
1
2
3
4
5
6
7
8
forced to completion, without a significant decrease on
enantioselectivity, by using a higher substrate concentra-
tion (entry 18) or higher pressure (entry 19), respectively.
ment to the Rh center. For substrate 3s, complex 6d pro-
vided full conversion and good enantioselectivity (93 %
ee, entry 10). Finally, it is worth to recall that some of the
highly enantioenriched esters 4 have a considerable syn-
thetic interest. For instance, 4n can be a convenient pre-
cursor for the synthesis of Berkelic acid,1e,3b while 4s has
been applied in the synthesis of benzodiazepines23c and
chromanes.23e
On the other hand, hydrogenation of 3o with complex 6d
produced a lower enantioselectivity than previous exam-
ples (91 % ee, entry 1, Table 3) and some other catalyst
precursors were tested (entries 2-4). Among them 6c
provided most satisfactory results with full conversion
and very high enantioselectivity (97 % ee, entry 4). For
comparison, the hydrogenation of a Z/E 1.7:1 mixture of 3o
was also examined with some of these catalysts. Thus, 6a,
6b and 6d gave enantioselectivities of 58, 80 and 44 % ee,
respectively. These values account for a decrease between
15 and 47 % ee, with respect to corresponding hydrogena-
tions of the pure Z isomer and demonstrate a high influ-
ence of the ratio of olefin isomers on enantioselectivity.
Most importantly, these data indicate that the synthetic
procedures provided herein for enol esters 3 perfectly
match the requirements for Rh-catalyzed asymmetric
hydrogenation. It is also pertinent to note that a critical
influence of olefin configuration on enantioselectivity has
been reported by the groups of Zhang12a and Zhou12b in the
hydrogenation of β-aryl enamides E.
9
In conclusion, a convenient and broad scope procedure
for the synthesis of valuable chiral homobenzylic esters
has been described. The reaction sequence is based on an
unprecedented stereospecific gold-catalyzed addition of
acetic acid to 1-iodo-alkynes as well as on a highly enanti-
oselective hydrogenation of (Z)-1-alkyl-2-arylvinyl ace-
tates 3, which is also covered for the first time. These
results point to the feasibility of the hydrogenation of
other trisubstituted enol esters and research to broaden
the scope of this protocol is currently under way.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
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ASSOCIATED CONTENT
Supporting Information. Full characterization of new
compounds (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
Table 3. Hydrogenation of 3o-3s performed with
complexes 6a
AUTHOR INFORMATION
Corresponding Author
Entry Substrate. Cat. Prec.
% conv.
>99
62
% ee (conf.)
91 (S)
*E-mail: vcm@uniovi.es (VC).
*E-mail: pizzano@iiq.csic.es (AP).
1
3o
3o
3o
3o
3p
3q
3r
6d
6a
6b
6c
6c
6c
6c
6c
6c
6d
2
80 (R)
95 (S)
97 (S)
93 (S)
Present Addresses
‡Present address: Repsol Technology Center, 28931 Móstoles,
3
84
Madrid, Spain.
4
5
>99
76
Notes
The authors declare no competing financial interest.
6
7
>99
>99
59
98 (S)
99 (S)
87 (S)
91 (S)
ACKNOWLEDGMENT
MINECO (projects CTQ2013-42501-P, CTQ2013-40591-P and
CTQ2014-51912-REDC) of Spain and the Government of the
Principality of Asturias (project GRUPIN14-006) are
acknowledged for financial support. Mass Spectrometry
Service of Universidad de Sevilla (CITIUS) is acknowledged
for technical assistance.
8
9b
10
3s
3p
3s
>99
>99
93 (S)
aReaction conditions and analysis as described in foot-
note a of Table 1. bReaction prepared under 10 bar H2.
REFERENCES
Catalyst precursor 6c was next applied in the hydrogena-
tion of substrates 3p-3s, differing in the nature of the aryl
substituent. In general, a good catalytic performance was
observed in these reactions, with good to quantitative
conversion and enantioselectivities ranging between 93
and 99 % ee (entries 5-7). However, for p-tolyl substrate
3p, an uncompleted reaction (76 %, entry 5) with 93 % ee
was observed. An increase in pressure up to 10 bar H2
afforded full conversion and a slight decrease on enanti-
oselectivity (91 % ee, entry 9). An exception to this behav-
ior is constituted by the 3,4-dimethoxyphenyl substrate 3s
which showed a lower enantioselectivity (87 % ee, entry
8) and displayed a moderate conversion (59 %) using
catalyst precursor 6c. This effect may be related with the
low reactivity shown by 3m and suggests a competitive
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