Enantioselective desymmetrizing palladium catalyzed carbonylation reactions: The catalytic asymmetric synthesis of quaternary carbon center containing 1,3-dienes

Article abstract of DOI:10.1039/b923186b

A desymmetrization protocol has been used to develop a palladium catalyzed enantioselective carbonylation process. Achiral cyclic bis-alkenyltriflates are converted to their corresponding monoester derivatives with selectivities of up to 96% ee. The Royal

Full text of DOI:10.1039/b923186b

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COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective desymmetrizing palladium catalyzed carbonylation reactions:
the catalytic asymmetric synthesis of quaternary carbon center containing
1,3-dienes†
Simon J. Byrne,b Anthony J. Fletcher,a Paul Hebeisenc and Michael C. Willis*a
Received 5th November 2009, Accepted 3rd December 2009
First published as an Advance Article on the web 21st December 2009
DOI: 10.1039/b923186b
A desymmetrization protocol has been used to develop a
palladium catalyzed enantioselective carbonylation process.
Achiral cyclic bis-alkenyltriflates are converted to their cor-
responding monoester derivatives with selectivities of up to
96% ee.
The catalytic asymmetric synthesis of all carbon quaternary
centers remains a challenge to synthetic chemists.1 Despite some
notable successes,2 a general, single strategy that allows access
to a varied range of functional groups has not been described.
Scheme 1 Palladium catalyzed enantioselective desymmetrization as a
One approach to developing such a strategy is to target a
route to enantioenriched compounds.
key class of catalytic intermediates that are capable of being
transformed into a number of distinct functionalities; if these
coupling.7 For example, the coupling of an achiral ditriflate 6
with 3-acetyl benzene boronic acid, employing a catalyst featuring
the chiral phosphine ligand MeO-MOP (7), delivered the Suzuki
product 8 with 86% ee (Scheme 2). In this Communication
we demonstrate how the same class of ditriflate precursors
can be employed successfully in a second palladium catalyzed
enantioselective transformation; enantioselective carbonylation (6
→ 9, Scheme 2).
intermediates can be accessed in an enantioselective fashion,
then the asymmetric synthesis of a diverse range of products
should be possible. Palladium(0) complexes are known to catalyze
a host of synthetically useful transformations, including cross-
couplings, Heck-type processes, carbonylations, reductions, and
many more.3 Importantly, the majority of these transformations
involve a notional common intermediate; the oxidative addition
product of the palladium(0) catalyst to an aryl- or vinyl halide
(or pseudohalide). It follows that if the subsequently formed
aryl- or vinyl palladium species could be obtained with high
enantioselectivities, then asymmetric versions of these important
catalytic processes should be possible.4 Scheme 1 presents a version
of this concept based on enantioselective desymmetrization.5,6
Achiral substrate 1 contains two enantiotopic groups X, each
capable of undergoing oxidative addition with a Pd(0) catalyst.
Selective oxidative addition to 1 would generate key vinyl palla-
dium intermediate 2 in an enantiomerically enriched form. The
chiral vinyl palladium intermediate 2 could then be advanced
through a number of different processes, for example, Suzuki
coupling (2 → 3), carbonylation (2 → 4) or amination (2 → 5).
To adapt this process to the enantioselective synthesis of an all
carbon quaternary center would simply require that the substrate
1 contains a suitable achiral quaternary center.
Scheme 2 Enantioselective desymmetrization based Suzuki coupling and
carbonylation reaction.
Palladium catalyzed carbonylation reactions of aryl and vinyl
halides (and pseudohalides) are well established,8 and a number of
enantioselective reactions have been developed,9 including exam-
ples based on enantioselective desymmetrization.10 However, as far
as we are aware no examples of processes distinguishing between
two enantiotopic vinyl halides (or pseudohalides) leading to an
asymmetric quaternary center have been reported. To validate our
proposed reaction we elected to study the carbonylation chemistry
of 6-membered ditriflate 10 (Table 1).11 Our initial reaction
conditions were based on those successfully employed by Schmalz
in the palladium catalyzed desymmetrization of dihaloaryl tricar-
bonylchromium complexes.10b Treatment of ditriflate 10 with a
We have previously reported a version of the process described in
Scheme 1 in the context of developing an enantioselective Suzuki
aDepartment of Chemistry, Chemistry Research Laboratory, University
of Oxford, Mansfield Road, Oxford, UK, OX1 3TA. E-mail: michael.
willis@chem.ox.ac.uk; Fax: +44 1865 285002; Tel: +44 1865 285126
bDepartment of Chemistry, University of Bath, Bath, UK, BA2 7AY
cDiscovery Chemistry, F. Hoffmann-La Roche Ltd, Pharmaceutical Research
Basel, CH-4070, Basel, Switzerland
† Electronic supplementary information (ESI) available: Experimen-
tal procedures and analytical data for new compounds. See DOI:
10.1039/b923186b
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Table 1 The development of reaction conditions for the desymmetriza-
tion of ditriflate 10a
entry
ligand
temp./◦C time/h yield 11 b(ee)c yield 12b
1d
2
3
4
5
6
7
8
9
PtBu3·HBF4
60
60
60
60
45
45
45
45
20
45
2
2
2
2
2
1
2
4
17
2
34% (—)
<5% (—)
46%
0%
0%
13%
9%
45%
55%
57%
8%
13
14
7
21% (21%)
41% (65%)
34% (74%)
38% (89%)
40% (95%)
34% (95%)
33% (78%)
27% (96%)
7
15
15
15
15
16
Fig. 1 The enantioselective carbonylation of ditriflate 10 to generate
monoester 11 and diester 12 using a Pd(OAc)2/ligand 15 catalyst.
Conversions determined by 1H NMR spectroscopy and ees determined
by chiral HPLC.
10
57%
a Reaction conditions; ditriflate 10 in 2 : 1 MeOH : NEt3 (0.1 M), Pd(OAc)2
(10 mol%), ligand (10 mol%). b Isolated yields. c Determined by chiral
HPLC. d PdCl2 used.
values shown in Fig. 1 do not match exactly with those in Table 1,13
the same trends, i.e., an increase in the ee of the monoester as the
amount of the diester increases, are apparent.
With conditions established to deliver monoester 11 with high
ee, albeit with only moderate yield, we next explored the scope
of the enantioselective carbonylation process (Table 2). Using
the methyl/benzyl-substituted substrate (10) we established that
both ethyl and isopropyl esters could be efficiently and selectively
generated, however, the use of tert-butanol as a nucleophile was
unsuccessful (Entries 1–3). We next explored a variety of sub-
stituents on the benzyl group of the quaternary center; entries 4–7
demonstrate that substitution of the 4-position is well tolerated,
with the required monoesters being generated in excellent ee. The
use of a 2-Me-substituent was less successful, resulting in reduced
selectivity (Entry 8). The 2-naphthyl example, shown in Entry 9,
underwent highly selective carbonylation. Exchange of the aryl
portion of the benzyl substituent for a cyclohexenyl group also
resulted in reduced reactivity and selectivity (Entry 10). The final
two Entries examine substrates featuring methyl/n-propyl and
methyl/ethyl quaternary centers; the methyl/n-propyl example is
desymmetrized to deliver the monoester with an impressive 87% ee
(Entry 11). Although the methyl/ethyl example is not as selective,
the monoester is still obtained in 61% ee.
In summary, the catalytic enantioselective desymmetrization of
cyclic bis-alkenyltriflates has been achieved by palladium catalyzed
carbonylation. This provided the monoester products featuring
all-carbon quaternary centers in excellent ee (up to 96%), and
reasonable yield (approx. 40%). The reaction was also applicable to
a range of alcohol coupling partners, showing little or no detriment
to either yield or enantioselectivity. The high enantioselectivities
seen in this reaction were partly due to the presence of a kinetic
resolution, which preferentially removed the minor enantiomer of
the monoester via a second coupling reaction to form an achiral
diester. Variation of the substrate structure was also performed
at the quaternary carbon center, with enantiotopic groups of
different size and electronic nature explored.
balloon pressure of CO in a 2 : 1 MeOH : NEt3 solvent mix, using
a simple achiral catalyst, delivered a mixture of the mono- and
diesters 11 and 12 in reasonable yield (Entry 1). Disappointingly,
exchanging the achiral ligand for BINAP (13) resulted in a poorly
active catalyst (Entry 2). The P–N chelating phosphine oxazoline
14 fared slightly better, delivering 21% of the monoester with
21% ee (Entry 3). A significant increase in reactivity and selectivity
was achieved when MeO-MOP (7) was employed as ligand; a
◦
2 h reaction at 60 C delivered 41% of the monoester in 65% ee,
along with 13% of the diester (Entry 4). Lowering the reaction
temperature to 45 ◦C allowed the monoester to be obtained in
34% yield with an ee of 74% (Entry 5). Further improvements
were achieved with the modified MOP-ligand 15, which features a
bulky, electron-rich PCy2 substituent;12 optimum conditions with
this ligand system involved a reaction of 2 h at 45 ◦C, to deliver the
monoester in 40% yield with an ee of 95% (Entries 6–9). The final
entry in the Table shows that the diisopropylphosphine-variant of
MOP (16) is also an effective ligand (Entry 10). It is interesting
to note that the optimal ligands for the palladium catalyzed
desymmetrizing-carbonylation of ditriflate 10 feature the same
general structure as the optimum ligand for the corresponding
desymmetrizing Suzuki couplings. In particular, the requirement
for a P–O ligand seems important to achieve good levels of
reactivity and selectivity in both reactions.
Inspection of the relationship between monoester 11 yield and
ee, and the yield of diester 12, for the reactions given in Table 1,
suggested that the excellent ees obtained in these reactions were the
result of an in situ kinetic resolution. To confirm this we recorded
the conversion to monoester 11 and diester 12, as well as the ee of
monoester 11, as a function of time (Fig. 1). Although the absolute
In establishing this second enantioselective palladium catalyzed
transformation using the same substrate class, we have begun
to establish palladium catalyzed desymmetrization as a platform
to develop a range of enantioselective coupling processes. The
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Table 2 Scope of the enantioselective carbonylation of cyclic 1,3-
increasing range of functional groups and generating products
useful in organic synthesis.
ditriflatesa
Acknowledgements
This work was supported by the EPSRC and F. Hoffmann-La
Roche Ltd.
entry
product
monoester yield b(ee)c
diester yieldb
Notes and references
1 Reviews: (a) O. Riant and J. Hannedouche, Org. Biomol. Chem., 2007,
5, 873; (b) A. Steven and L. E. Overman, Angew. Chem., Int. Ed., 2007,
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2 Selected recent examples of the catalytic enantioselective synthesis of
quaternary all carbon centers, see: (a) T. Hashimoto, K. Sakata and K.
Maruoka, Angew. Chem., Int. Ed., 2009, 48, 5014; (b) S. R. Levine, M.
R. Krout and B. M. Stoltz, Org. Lett., 2009, 11, 289; (c) T. L. May, M.
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3701; (e) S. Mukherjee and B. List, J. Am. Chem. Soc., 2007, 129, 11336.
3 (a) J. Tsuji, Palladium Reagents and Catalysts: New Perspectives for the
21st Century, Wiley, Chichester, 2004; (b) Handbook of Organopalla-
dium Chemistry for Organic Synthesis, (Eds, E. Negishi, A. de Meijere),
Wiley, New York, 2002.
1
2
3
R1 = Et
34% (94%)
48% (90%)
14% (—)
47%
18%
<5%
i
R1 = Pr
t
R1 = Bu
4
5
6
7
8
R = OMe
R = CN
R = CF3
R = F
34% (94%)
44% (89%)
40% (85%)
35% (95%)
36% (80%)
47%
32%
15%
36%
28%
4 For an excellent review on enantioselective palladium-catalyzed trans-
formations, see: L. F. Tietze, H. Ila and H. P. Bell, Chem. Rev., 2004,
104, 3453.
5 For reviews on enantioselective desymmetrization, see: (a) M. C. Willis,
J. Chem. Soc., Perkin Trans. 1, 1999, 1765; (b) T. Rovis, in Recent
Advances in Catalytic Asymmetric Desymmetrization Reactions, in
New Frontiers in Asymmetric Catalysis, (Eds, K. Mikami, M. Lautens),
Wiley, New York, 2007, pp. 275–312.
6 For alternative examples of palladium catalyzed enantioselective
desymmetrizations, see: (a) E. P. Ku¨ndig, P. D. Chaudhuri, D. House
and G. Bernardinelli, Angew. Chem., Int. Ed., 2006, 45, 1092; (b) A.
B. Machotta, B. F. Straub and M. Oestreich, J. Am. Chem. Soc., 2007,
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1999, 5, 3279; (f) M. Shibasaki and E. M. Vogl, J. Organomet. Chem.,
1999, 576, 1–15; (g) T. Hayashi, S. Niizuma, T. Kamikawa, N. Suzuki
and Y. Uozumi, J. Am. Chem. Soc., 1995, 117, 9101.
9
44% (93%)
41% (74%)
33%
20%
10
7 M. C. Willis, L. H. W. Powell, C. K. Claverie and S. J. Watson, Angew.
Chem., Int. Ed., 2004, 43, 1249.
8 A. Brennfu¨hrer, H. Neumann and M. Beller, Angew. Chem., Int. Ed.,
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and K. Inomata, Chem. Lett., 2007, 36, 1328; (d) T. Kusakabe, K. Kato,
S. Takaishi, S. Yamamura, T. Mochida, H. Akita, T. A. Peganova, N.
V. Vologdin and O. V. Gusev, Tetrahedron, 2008, 64, 319.
10 (a) T. Suzuki, Y. Uozumi and M. Shibasaki, J. Chem. Soc., Chem.
Commun., 1991, 1593; (b) B. Gotov and H.-G. Schmalz, Org. Lett.,
2001, 3, 1753.
11 The 5-membered ditriflates were unstable under the described carbony-
lation conditions and delivered dienone byproducts. The majority of
the 6-membered ditriflates were prepared according to: M. C. Willis
and C. K. Claverie, Tetrahedron Lett., 2001, 42, 5105.
11
12
R = Pr
R = Et
32% (87%)
31% (61%)
38%
38%
a Reaction conditions; ditriflate in 2 : 1 MeOH : NEt3 (0.1 M), Pd(OAc)2 (10
mol%), ligand 15 (10 mol%). The absolute configurations of the products
have not been established, and are arbitrarily shown above. b Isolated yields.
c Determined by chiral HPLC.
12 Y. Uozumi and T. Hayashi, J. Am. Chem. Soc., 1991, 113, 9887.
13 The yield of monoester 11 recorded in Fig. 1 is less than the values
shown in Table 1. This is attributed to sampling of the reaction needed
for aliquot removal.
ability to selectively access a common vinyl palladium intermediate
should allow further reactions to be developed, thus delivering an
760 | Org. Biomol. Chem., 2010, 8, 758–760
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©