Catalytic asymmetric synthesis with Rh-diene complexes: 1,4-Addition of arylboronic acids to unsaturated esters

Article abstract of DOI:10.1021/ol051533l

(Chemical Equation Presented) A general route to enantioenriched tert-butyl 3,3-diarylpropanoates is presented. These useful building blocks are prepared via an asymmetric rhodium-catalyzed conjugate addition of arylboronic acids to unsaturated tert-butyl

Full text of DOI:10.1021/ol051533l

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3821-3824
Catalytic Asymmetric Synthesis with
Rh Diene Complexes: 1,4-Addition of
Arylboronic Acids to Unsaturated Esters
−
Jean-Franc¸ois Paquin, Corey R. J. Stephenson, Christian Defieber, and
Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Ho¨nggerberg, HCI H335,
8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received June 30, 2005
ABSTRACT
A general route to enantioenriched tert-butyl 3,3-diarylpropanoates is presented. These useful building blocks are prepared via an asymmetric
rhodium-catalyzed conjugate addition of arylboronic acids to unsaturated tert-butyl esters in the presence of chiral dienes as ligands. The
addition of both electron-poor and electron-rich boronic acids proceeds smoothly with various enoates in 63
−90% yield with high
enantioselectivites (89 94% ee).
−
The stereoselective preparation of compounds bearing dia-
rylmethine stereocenters is challenging, particularly when
only minor electronic or steric effects differentiate the two
aryl groups. This structural motif is present in a number of
notable pharmaceuticals (for example, tolterodine and ser-
traline)1 and natural products;2 however, methods for the
stereoselective synthesis of these stereocenters is limited.3
An attractive approach to these compounds involves the
Rh-catalyzed conjugate addition of aryl boronic acid
nucleophiles to electron-deficient acceptors, because these
processes are generally insensitive to the electronic properties
of the nucleophile.4 Chiral dienes have recently been applied
as ligands for late-transition metals (i.e., Ir, Rh) for asym-
metric reactions of preparative importance.5,6 In particular,
the combination of metal-diene complexes and arylboronic
acids has been successfully applied in a number of trans-
formations.7 We have recently reported the catalytic, asym-
metric conjugate addition of arylboronic acids to a wide range
of electron-acceptors including enals,8 enones, enamides, and
coumarins (Figure 1).9,10
(1) (a) Hills, C. J.; Winter, S. A.; Balfour, J. A. Drugs 1998, 55, 813.
(b) McRae, A. L.; Brady, K. T. Expert Opin. Pharmacother. 2001, 2, 883.
(2) (a) Kamal, A.; Gayatri, N. L. Tetrahedron Lett. 1996, 37, 3359. (b)
Silva, D. H. S.; Davino. S. C.; de Moraes Barros, S. B.; Yoshida M. J. Nat.
Prod. 1999, 62, 1475. (c) Schwikkard, S.; Zhou, B.-N.; Glass, T. E.; Sharp,
J. L.; Mattern, M. R.; Johnson, R. K.; Kingston, D. G. I. J. Nat. Prod.
2000, 63, 457. (d) Xiao, K.; Xuan, L.; Xu, Y.; Bai, D.; Zhong, D.; Wu, H.;
Wang, Z.; Zhang, N. Eur. J. Org. Chem. 2002, 564.
(3) (a) Lautens, M.; Rovis, T. J. Org. Chem. 1997, 62, 5246. (b) Duursma,
A.; Hoen, R.; Schuppan, J.; Hulst, R.; Minnaard, A. J.; Feringa, B. L. Org.
Lett. 2003, 5, 3111. (c) Mauleo´n, P.; Carretero, J. C. Org. Lett. 2004, 6,
3195. (d) Bolshan, Y.; Chen, C.-y.; Chilenski, J. R.; Gosselin, F.; Mathre,
D. J.; O’Shea, P. D.; Roy, A.; Tillyer, R. D. Org. Lett. 2004, 6, 111.
(4) (a) Fagnou, K.; Lautens, M. Chem. ReV. 2003, 103, 169. (b) Hayashi,
T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829. (c) Darses, S.; Geneˆt, J.-P.
Eur. J. Org. Chem. 2003, 4313. (d) Hayashi, T. Pure Appl. Chem. 2004,
76, 465.
(5) For a mini-review, see: Glorius, F. Angew. Chem., Int. Ed. 2004,
43, 3364; Angew. Chem. 2004, 116, 3444.
(6) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem.
Soc. 2004, 126, 1628.
(7) (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem.
Soc. 2003, 125, 11508. (b) Tokunaga, N.; Otomaru, Y.; Okamoto, K.;
Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.
(c) Shintani, R.; Okamoto, K.; Otomaru, Y.; Ueyama, K.; Hayashi, T. J.
Am. Chem. Soc. 2005, 127, 54.
10.1021/ol051533l CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/14/2005

panoate in 72% yield, albeit in only 19% ee (Table 1, entry
1). The enantioselectivity was improved to 65% ee using
the isobutyl substituted ligand ent-8 (entry 2). Increasing the
size of the ester (R ) Bn) provided a small increase in
enantioselectivity to 71% ee. The combination of benzyl-
substituted ligand 9 and benzyl ester 2 provided 5 in
substantially improved enantioselectivity (entry 4, 89% ee).
Under optimal conditions, tert-butyl cinnamate 312 was
converted to diarylpropanoate 6 in the presence of the Rh-
(I)‚9 complex (3 mol % Rh) in excellent yield and enanti-
oselectivity (entry 6, 85% yield, 93% ee).
While examining the scope of the Rh-catalyzed conjugate
addition reaction to tert-butyl cinnamate 3, we observed that
both electron-rich (Table 2, entry 1) and electron-poor
Figure 1.
The use of cinnamic acid esters11 as acceptors is advanta-
geous for a number of reasons: the wide variety of
unsaturated acids that are commercially available, and the
increased stability of the esters, which thus make them easily
handled starting materials. Of additional importance in
pursuing this study was the fact that conjugate additions of
arylboronic acids to cinnamate ester acceptors in the presence
of metal-diene complexes were lacking in precedence.
We examined the Rh-catalyzed reaction of ethyl cinnamate
with 4-methoxybenzeneboronic acid in the presence of diene
ligand 7 using the conditions developed for the conjugate
addition of arylboronic acids to enones.10 As expected, the
reactivity of the esters was considerably attenuated compared
to that of the corresponding enals (18 h vs 75 min reaction
time).8 We were able to isolate the desired 3,3-diarylpro-
Table 2. Conjugate Addition Reactions Catalyzed by Rh(I)‚9
Table 1. Ligand Screening and Reaction Optimization
a Isolated yield after chromatography. b Determined by chiral HPLC.
c Assigned on the basis of our previous work (ref 9). d This value was
estimated because the signals could not be completely resolved in the chiral
HPLC.
boronic acids (entries 2 and 3) afforded the desired adducts
in 69-85% yield and 92-93% ee. By switching the aryl
acceptor and donor, we could easily prepare both enantiomers
of a given product (cf. entries 1 and 4) using a single
enantiomer of ligand 9.13 In addition, a wide variety of
substituted cinnamate esters could be used as acceptors in
entry ester ligand
solvent
yield (%)a ee (%)b
1
2
3
4
5
6
1
1
2
3
3
3
7
dioxane/H2O (10:1)
72
99
85
72
89
85
19
-65
71
89
92
ent-8 dioxane/H2O (10:1)
8
8
9
9
dioxane/H2O (10:1)
dioxane/H2O (10:1)
dioxane/H2O (10:1)
MeOH/H2O (10:1)c
93
(8) Paquin, J.-F.; Defieber, C.; Stephenson, C. R. J.; Carreira, E. M. J.
Am. Chem. Soc. 2005, 127, In Press.
(9) Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E. M. Org. Lett. 2004,
6, 3873.
a Isolated yield after chromatography. b Determined by chiral HPLC (see
Supporting Information for details). c Reaction time ) 75 min.
3822
Org. Lett., Vol. 7, No. 17, 2005

rich and -poor boronic acids to give the desired adducts in
62-68% yield and 91-92% ee (entries 1-2). Both regioi-
someric thienyl-substituted acceptors afforded adducts in 65-
68% yield and 89-91% ee (entries 3 and 4). We were
pleased to observe that the pyridyl-substituted enoate was
smoothly converted to the 1,4-addition product in 70% yield
and 93% ee (entry 5). In our previous study, the correspond-
ing enal did not afford the 1,4-addition product. Finally, the
indolyl-substituted enoate provided the conjugate addition
product in excellent yield and enantioselectivity (entry 6,
90%, 94% ee).
Table 3. Conjugate Addition Reactions Catalyzed by Rh(I)‚9
to Heterocylic Acceptors
To extend the utility of this methodology, we decided to
take advantage of the functional groups present in the
conjugate addition products for subsequent synthetic elabora-
tion. In particular, the adduct of phenylboronic acid and
o-NO2-substituted cinnamate ester provided the opportunity
to prepare optically enriched dihydroquinolin-2-ones from
the 1,4-adducts.14 Thus, subjection of 10 (Table 2, entry 7)
to hydrogenation (H2, Pd/C in MeOH) cleanly afforded the
amino ester, which could be converted to the desired lactam
11 by treatment with AcOH in THF (Scheme 1). A one-
a Isolated yield after chromatography. b Determined by chiral HPLC.
c Assigned on the basis of our previous work (ref 9). d The solvent for these
reactions was 1,4-dioxane.
Scheme 1. Conversion to Dihydroquinolin-2-one
the conjugate addition reaction. Aromatics substituted with
electron-donating (entry 4) and electron-withdrawing groups
(entries 5-8) provided the 3,3-diarylpropanoates in 78-95%
yield and 92-94% ee. In particular, the nitro-substituted
cinnamate (entries 7 and 8) were good substrates for this
conjugate addition reaction, whereas the corresponding
aldehydes afforded mostly decomposition. It is noteworthy
that the enantioselectivity of these reactions is independent
of substitution on the donor or acceptor, providing the desired
products within a narrow window of enantioselectivities (91-
94% ee).
step protocol involving hydrogenation of 10 in the presence
of 1 equiv of AcOH afforded a mixture of aniline and lactam
and continued stirring under argon furnished 11 in 96%
yield.15
We also examined a number of heterocyclic acceptors to
broaden the scope of the conjugate addition reaction while
generating functionalized products. In all cases, the hetero-
cycle-substituted enoates reacted more slowly than the
cinnamate derivatives, often requiring reaction times of 12-
18 h (Table 3). In some cases, it was advantageous to carry
out the reactions in 1,4-dioxane in place of MeOH (entries
3-6). Furyl-substituted acceptors reacted with both electron-
In summary, we have successfully demonstrated the
functional utility of chiral Rh-diene complexes in the
preparation of 3,3-diarylpropanoates in 76-95% yield and
91-94% ee. The Rh-catalyzed addition of arylboronic acids
was also used to prepare 3-aryl-3-heteroaryl-propanoates in
62-90% yield and 89-94% ee. This process is attractive
because of the ready availability of the starting materials
(esters and boronic acids) and its success with a wide variety
of donors and acceptors. In addition, we have established
the applicability of this reaction as exemplified by the simple,
one-pot synthesis of optically enriched dihydroquinolin-2-
one 11.
(10) Subsequently, Hayashi and co-workers reported the Rh‚phosphine
complex catalyzed addition of arylboronic acids to coumarins. See: Chen,
G.; Tokunaga, N.; Hayashi, T. Org. Lett. 2005, 7, 2285.
(11) (a) Xu, F.; Tillyer, R. D.; Tschaen, D. M.; Grabowski, E. J. J.;
Reider, P. J. Tetrahedron: Asymmetry 1998, 9, 1651. (b) Takaya, Y.; Senda,
T.; Kurushima, H.; Ogasawara, M.; Hayashi, R. Tetrahedron: Asymmetry
1999, 10, 4047. (c) Song, Z. J.; Zhao, M.; Desmond, R.; Devine, P.; Tschaen,
D. M.; Tillyer, R.; Frey, L.; Heid, R.; Xu, F.; Foster, B.; Li, J.; Reamer,
R.; Volante, R.; Grabowski, E. J. J.; Dolling, U. H.; Reider, P. J.; Okada,
S.; Kato, Y.; Mano, E. J. Org. Chem. 1999, 64, 9658. (d) Sakuma, S.; Sakai,
M.; Itooka, R.; Miyaura, N. J. Org. Chem. 2000, 65, 5951. (e) Navarre, L.;
Pucheault, M.; Darses, S.; Geneˆt, J.-P. Tetrahedron Lett. 2005, 46, 4247.
(12) For the facile preparation of tert-butyl esters using Boc2O and
DMAP, see: Takeda, K.; Akiyama, A.; Nakamura, H.; Takizawa, S.-i.;
Mizuno, Y.; Takayanagi, H.; Harigaya, Y. Synthesis 1994, 1063.
(13) At the current level of development, o-heteroatom-substituted
arylboronic acids (such as o-nitrophenylboronic acid) cannot be employed
in the reaction. Thus, for adducts requiring such substitution, it is best to
have the o-substituted acceptor reaction partner as described herein.
Acknowledgment. This research is supported by a Swiss
National Science Foundation Grant and by the ETHZ. J.-
F.P. is grateful to the National Sciences and Engineering
(14) (a) Higuchi, R. I.; Edwards, J. P.; Caferro, R. R.; Ringgenberg, J.
D.; Kong, J. W.; Hamann, L. G.; Arienti, K. L.; Marschke, K. B.; Davis,
R. L.; Farmer, L. J.; Jones, T. K. Biorg. Med. Chem. Lett. 1999, 9, 1335.
(b) Angibaud, P. R.; Venet, M. G.; Filliers, W.; Broeckx, R.; Ligny, Y. A.;
Muller, P.; Poncelet, V. S.; End, D. W. Eur. J. Org. Chem. 2004, 479.
(15) The hydrogenation was accelerated in the presence of AcOH (ca. 2
h compared to 24 h).
Org. Lett., Vol. 7, No. 17, 2005
3823

Research Council of Canada (NSERC) for a postdoctoral
fellowship.
and isolation and spectroscopic information for the new
compounds prepared. This material is available free of charge
via the Internet at http://pubs.acs.org.
Supporting Information Available: General experimen-
tal procedures, specific details for representative reactions,
OL051533L
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Org. Lett., Vol. 7, No. 17, 2005