Enantioselective synthesis of branched allylic esters via rhodium-catalyzed coupling of allenes with carboxylic acids

Article abstract of DOI:10.1021/ja210149g

We report on the first intermolecular asymmetric catalytic regio- and enantioselective addition of carboxylic acids to terminal allenes to form valuable branched allylic esters, employing a rhodium(I)/(R,R)-DIOP catalyst system.

Full text of DOI:10.1021/ja210149g

Communication
pubs.acs.org/JACS
Enantioselective Synthesis of Branched Allylic Esters via
Rhodium-Catalyzed Coupling of Allenes with Carboxylic Acids
Philipp Koschker, Alexandre Lumbroso, and Bernhard Breit*
Institut fur Organische Chemie und Biochemie, Freiburg Institute for Advanced Studies (FRIAS), Albert-Ludwigs-Universitat
̈
̈
Freiburg, Albertstrasse 21, 79104 Freiburg im Breisgau, Germany
S
* Supporting Information
transition-metal-catalyzed intra- and intermolecular addition
of C-, N-, O-, and S-nucleophiles to allenes are known,11−13
only two examples, reported by Yamamoto14 and Krische,15
describe the addition of carboxylic acids leading to allylic esters.
But because palladium is used as a catalyst for Yamamoto’s
report, and the scope is restricted to 1,1-dimethyl allene for
Krische’s report, only linear esters and reverse prenylated
esters, respectively, can be formed, which limits both methods
to the synthesis of achiral products thus far. Since allenes are an
easily accessible and remarkably stable substrate class,16 we
wondered if by starting directly from allenes, our rhodium
catalyzed methodology could be used to develop the first
general atom-economic and enantioselective synthesis of
branched allylic esters by intermolecular addition of carboxylic
acids to terminal allenes (Scheme 2).
ABSTRACT: We report on the first intermolecular asym-
metric catalytic regio- and enantioselective addition of carboxylic
acids to terminal allenes to form valuable branched allylic esters,
employing a rhodium(I)/(R,R)-DIOP catalyst system.
he selective synthesis of enantiopure allylic alcohols and their
derivatives as versatile intermediates for the construction of
T
complex molecules1 has been intensively studied, and many
different methods for their preparation are known.2 In the past
decade, access to these compounds via transition-metal-catalyzed
allylic substitution3−6 and allylic oxidation7,8 has drawn consid-
erable interest. Both approaches require a stoichiometric amount
of a leaving group and an oxidant, respectively, making them less
attractive in terms of atom economy,9 whereas methods for allylic
oxidation additionally suffer from limited scope and/or low ee.
A different and, in terms of utility, more advanced approach
for the synthesis of allylic esters has recently been developed in
our working group.10 It offers a truly atom-economic and redox-
neutral process by rhodium-catalyzed CH oxidation of terminal
alkynes with the alkyne serving as the formal oxidant for the
internal redox reaction. Although this method focuses on the
use of the achiral DPEphos ligand, giving racemic products,
initial experiments employing a rhodium(I)/(R,R)-DIOP
catalyst system led to the branched allylic esters with a
promising enantioselectivity of 70% ee (Scheme 1).
Scheme 2. General Reaction Scheme for Enantioselective
Coupling of Terminal Allenes with Carboxylic Acids
We started our investigations on looking at the addition of
benzoic acid to cyclohexyl allene and screening different
reaction conditions and chiral bidentate phosphine ligands
varying widely in terms of natural bite angle and electronic
properties (Table 1). Whereas most tested ligands led to
disappointingly low conversions, (R,R)-DIOP appeared to be
the best ligand with complete conversion and promising
enantiomeric excess of 86% ee at 60 °C. This can be explained
by the very similar bite angle and flexibility range of
(R,R)-DIOP and DPEphos,17 which had been found as the
optimal ligand for our racemic alkyne methodology. Since
starting from the highly reactive allene makes the initial
isomerization step, which is needed for our alkyne method-
ology, redundant, milder reaction conditions could be achieved.
Although a reaction temperature of −3 °C resulted in a very
high enantioselectivity of 95% ee, the drop in reactivity led to
incomplete conversion. We were pleased to find that the
addition of a catalytic amount of Cs2CO3 accelerated the
Scheme 1. Previous Results for Racemic and
Enantioselective Coupling of Terminal Alkynes with
Carboxylic Acids
We proposed that this transformation proceeds via an
intermediate allene formation, evidence for which was obtained
by starting directly from this substrate, leading to the same
product in comparable yields with perfect regioselectivity for
the branched allylic ester. Although several methods for
Received: October 28, 2011
Published: November 23, 2011
© 2011 American Chemical Society
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Journal of the American Chemical Society
Communication
Table 1. Screening of Chiral Phosphine Ligands and
Reaction Conditions
Table 2. Enantioselective Rhodium-Catalyzed Synthesis of
Branched Allylic Esters: Scope of Carboxylic Acids
a
a
b
c
#
ligand
T/°C
t/h
additive conversion/% ee/%
1
2
3
4
5
6
7
8
9
(S,S)-chiraphos
(R,R)-Me-DuPhos
josiphos-I
60
60
60
60
60
25
0
16
16
16
16
16
0
0
14
80 (S)
59 (S)
86 (R)
88 (R)
91 (R)
95 (R)
95 (R)
(R)-segphos
(R,R)-DIOP
(R,R)-DIOP
(R,R)-DIOP
(R,R)-DIOP
(R,R)-DIOP
26
100
100
90
d
16
48
48
−3
−3
63
e
48 Cs2CO3
100
a
A screw-cap flask was charged with 0.020 mmol of [Rh(COD)Cl]2,
0.040 mmol of the ligand, and 0.44 mmol of acid in 4.4 mL of 1,2-
dichloroethane and set to the according reaction temperature. Allene
(0.53 mmol) was added, and the reaction was stirred for the according
b
reaction time. Determined by integration of the aromatic signals in
c
the crude 1H NMR spectrum. Determined by chiral HPLC.
Complete conversion after 5 h. Cs2CO3 (0.040 mmol) was added.
a
d
e
A screw-cap flask was charged with 0.020 mmol [Rh(COD)Cl]2,
0.040 mmol (R,R)-DIOP, 0.040 mmol Cs2CO3, and 0.44 mmol of acid
in 4.4 mL of 1,2-dichloroethane and cooled to −3 °C. Allene (0.53
mmol) was added, and the reaction was stirred for 48 h. Isolated
reaction significantly, with complete conversion being observed
after 48 h (Table 1, entry 9).
b
c
d
yields. Determined by chiral HPLC. Reaction performed at 15 °C.
e
Utilizing the optimized conditions (entry 9, Table 1), we
investigated the scope of the process with respect to the
carboxylic acid substrates (Table 2). We were pleased to find that
the reaction worked efficiently for all acids tested, with the
desired products being obtained in good to almost quantitative
yields and very high enantioselectivities (>90% ee). In all cases,
the branched allylic ester was the only product observed. Besides
the unsubstituted benzoic acid (1), both electron-rich and
electron-poor aromatic carboxylic acids were suitable reaction
partners (2−5). Also, cinnamic acid as a vinylogous benzoic acid
presented a suitable substrate for the reaction (6). N- and O-
heteroaromatic carboxylic acids turned out to serve well as
substrates for our methodology, although the increased steric
hindrance of the N-methylated compound required a higher
reaction temperature (15 °C) in order to obtain complete
conversion (7 and 8). Furthermore, aliphatic carboxylic acids
(linear and branched) worked well, leading to the desired allylic
esters (9−11) in excellent yields and high enantioselectivities.
However, an elevated reaction temperature (25 °C) was
necessary for complete conversion. A terminal alkene function-
ality in the molecule is also tolerated, leading to an interesting
ester product bearing two terminal alkene functional groups,
offering the possibility to access enantiopure lactones via RCM.18
The successful enantioselective addition of α,β-unsaturated acids
opens up the possibility for a quick access to γ-butyrolactones as
an important structural motif in an array of natural products.19
This was demonstrated by performing a RCM on the cinnamic
Reaction performed at 25 °C.
Scheme 3. Enantioselective Two-Step Synthesis of the
γ-Butyrolactone 6b
ester product (6), which led to the corresponding γ-butyrolactone
6b in very good yield without loss of chirality (Scheme 3).
The product was isolated with an overall yield of 60% over two
steps and an enantiomeric purity of 91% ee.
Furthermore, the scope of the allene coupling partner was
investigated (Table 3). The terminal allenes used were either
commercially available or easily prepared by one or two steps
(see the Supporting Information).16 Besides cyclohexyl allene
with its branched saturated side chain, linear aliphatic
substituents on the allene functionality worked with very high
yields, albeit reduced enantioselectivity was noted (12).
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Journal of the American Chemical Society
Communication
Table 3. Enantioselective Rhodium-Catalyzed Synthesis of
Branched Allylic Esters: Scope of Allenes
Scheme 5. Isotopic Labeling Experiments with Deuterated
Benzoic Acid
a
Scheme 6. Proposed Mechanism for the Enantioselective
Rhodium-Catalyzed Coupling of Terminal Allenes with
Carboxylic Acids
a
A screw-cap flask was charged with 0.020 mmol [Rh(COD)Cl]2,
0.040 mmol (R,R)-DIOP, 0.040 mmol Cs2CO3, and 0.44 mmol of acid
in 4.4 mL of 1,2-dichloroethane and cooled to −3 °C. Allene (0.53
b
mmol) was added, and the reaction was stirred for 48 h. Isolated
c
yields. Determined by chiral HPLC.
species D followed by β-hydrogen elimination could explain the
incorporation of the deuterium at the terminal position. A
slower hydrometalation of the more substituted allene double
bond generates the Rh-π-allyl complex E (step II), which after
reductive elimination (or external carboxylate attack) would
furnish the allylic ester product F (step III). The observed
regioselectivity for the final step has previously been described
in the literature and is typical for Rh-π-allyl complexes.21
In summary, we have documented the first intermolecular
addition of carboxylic acids to terminal allenes to form highly
useful branched allylic esters with perfect regioselectivity and
excellent enantioselectivities employing a simple and commer-
cially available rhodium(I)/DIOP catalyst. The reaction is
completely atom economic and displays a broad scope. Even
1,1-disubstituted allenes could be employed, leading to the
formation of allylic esters with a quaternary chiral center.
Further studies will focus on mechanistic investigations as well
as on the extension toward other nucleophiles.
However, an allene equipped with a related phenethyl
substituent performed with significantly improved enantio-
selectivity (13).20 Comparable results were obtained with
heteroatom-containing allenes (14 and 15). Even an
unprotected alcohol at the α-position of the new chiral center
formed was very well tolerated (16), formally giving access to
1,2- and 1,3-dihydroxylated structures and showing the
potential of this methodology for the preparation of
heteroatom-containing target structures.
Scheme 4. Enantioselective Rh-Catalyzed Synthesis of a
Branched Allylic Ester with a Quaternary Center
ASSOCIATED CONTENT
■
Furthermore a 1,1-unsymmetrically disubstituted allene was
probed as a substrate (Scheme 4). We were pleased to see that
the corresponding tertiary alcohol derivative was obtained in
high yield and excellent enantioselectivity for the formation of a
quaternary stereocenter (17).
Taking into account the results of labeling experiments using
deuterated benzoic acid (Scheme 5), the following mechanistic
rationale can be proposed (see Scheme 6). The catalytic cycle
may start by oxidative addition of the carboxylic acid A, leading
to the Rh(III) complex C (step I). A fast hydrometalation of
the less substituted allene double bond furnishing σ-vinyl-Rh
S
* Supporting Information
Experimental procedures and analytic data for synthesized
allenes and new compounds, including 1H NMR and 13C NMR
spectra as well as scanned HPLC data sheets for chiral
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
bernhard.breit@chemie.uni-freiburg.de
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Journal of the American Chemical Society
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́ ́
2009, 131, 9178. (g) Mauleon, P.; Zeldin, R. M.; Gonzalez, A. Z.;
ACKNOWLEDGMENTS
■
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This work was supported by the DFG, the International
Research Training Group “Catalysts and Catalytic Reactions for
Organic Synthesis” (IRTG 1038), the Fonds der Chemischen
Industrie, the Krupp Foundation. We thank Umicore, BASF,
and Wacker for generous gifts of chemicals.
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