Chiral [2.2.2] dienes as ligands for Rh(I) in conjugate additions of boronic acids to a wide range of acceptors

Article abstract of DOI:10.1021/ol048240x

We document a series of investigations that led to new substituted [2.2.2]-diene ligands which display high selectivity in Rh(I)-catalyzed conjugate addition reactions to substrates not previously examined with diene ligands. Moreover, we disclose an unexpected, interesting effect that results from the introduction of a third C=C onto the ligand scaffold (cf. 1).

Full text of DOI:10.1021/ol048240x

ORGANIC
LETTERS
2004
Vol. 6, No. 21
3873-3876
Chiral [2.2.2] Dienes as Ligands for
Rh(I) in Conjugate Additions of Boronic
Acids to a Wide Range of Acceptors
Christian Defieber, Jean-Franc¸ois Paquin, Sonia Serna, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Ho¨nggerberg, HCI H335,
8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received September 1, 2004
ABSTRACT
We document a series of investigations that led to new substituted [2.2.2]-diene ligands which display high selectivity in Rh(I)-catalyzed
conjugate addition reactions to substrates not previously examined with diene ligands. Moreover, we disclose an unexpected, interesting
effect that results from the introduction of a third CdC onto the ligand scaffold (cf. 1).
The recent reports by Hayashi and ourselves on the use of
chiral dienes derived from [2.2.1]bicycloheptadiene and
[2.2.2]bicyclooctadiene, respectively, as ligands for transition
metals open new avenues for the development of asymmetric
processes.1-3 The initial experiments indicated an interesting
complementarity between the two diene ligands, namely, that
the [2.2.1] diene was superior in the Rh(I)-catalyzed conju-
gate addition reaction of boronic acids, while the [2.2.2]
ligands proved beneficial in Ir(I)-catalyzed allylic displace-
ment reactions. A key advantage of the latter ligands is their
ease of synthesis (four steps) from readily available (R)- or
(S)-carvone, permitting diversity-oriented synthesis of the
[2.2.2] scaffold. Herein, we document new substituted [2.2.2]
diene ligands which display high selectivity in Rh(I)-
catalyzed conjugate addition reactions of boronic acids to
the standard set of substrates as well as some not previously
examined with diene ligands.4,5 Moreover, we disclose an
unexpected, interesting enhancement of selectivity that results
from the introduction of a third CdC onto the ligand scaffold
(cf. 1, eq 1).
(1) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem.
Soc. 2003, 125, 11508.
(2) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem.
Soc. 2004, 126, 1628.
(3) For a mini review, see: Glorius, F. Angew. Chem., Int. Ed. 2004, 43,
3364; Angew. Chem. 2004, 116, 3444.
10.1021/ol048240x CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/17/2004

In the study by Hayashi of norbornadiene-derived ligand
6 (Figure 1), only cycloalkenones as well as an unsaturated
With access to a family of ligands, we screened these in
the test reaction of PhB(OH)2 and 2-cyclohexenone under
conditions previously reported (Table 1).1 In general, the C-2/
Table 1. Effect of Ligand Substitution on Selectivity (eq 2)
ligand
yielda (%)
eeb (%)
1
2
3
4
5
87
91
91
85
63
95 (S)
88 (S)
91 (S)
82 (S)
93 (S)
Figure 1.
ester and a methyl ketone, both substituted at C-â with i-Pr,
were examined. Notably absent from this study were
additional substrates of interest such as coumarins along with
unsaturated amides and lactones.6-9
In our initial study, the carvone-derived [2.2.2] ligand 7
(Ar ) 4-t-Bu-Ph, Figure 1) effected the addition of PhB-
(OH)2 to 2-cyclohexenone to afford product in only 52%
yield and 71% ee. We have become interested in investigat-
ing whether the diminished selectivity with this ligand results
from an inherent structural disadvantage of the [2.2.2]
scaffold and whether the use of other substituted systems,
such as 1-5, could lead to improvements.
The initially disclosed synthesis for 7 provided access to
only C-2-substituted dienes, incorporating disubstituted and
trisubstituted CdC donors. Therefore, to generate a larger
class of [2.2.2] ligands, the development of a different
synthesis was necessary. In this respect, the modified
sequence shown in Scheme 1 permitted ready variation of
a Isolated yields of pure material. b Determined by chiral HPLC.
C-5 disubstituted systems (1 and 2-5) afford adducts in
higher selectivity (up to 95% ee) when compared to the
original ligand 7 (71% ee). For [2.2.2] bicyclic cycloocta-
dienes substituted at C-2 with a phenyl group, variation at
C-5 was examined. In this series, the presence of a CdC in
the substituents at C-5 leads to improvement in selectivity
(compare 4 at 82% ee with 3 at 91% ee). This effect is not
present if the olefin is absent (cf. 4 at 82% ee and 2 at 88%
ee) or is attenuated with a more flexible spacer (cf. 5 at 93%
ee). Interestingly, a study of the Rh‚1 complex by 1H NMR
spectroscopy indicates coordination by all three double
bonds, with potential implications for the enantiodetermining
step. When the phenyl group was replaced by an isobutyl
group (cf. 1), improvement in the product enantioselectivity
was observed.
(4) For reviews involving the addition of boronic acids to acceptors using
complexes derived from chiral phosphines, see: (a) Hayashi, T. Bull. Chem.
Soc. Jpn. 2004, 77, 13. (b) Hayashi, T. Pure Appl. Chem. 2004, 76, 465.
(c) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829. (d) Fagnou,
K.; Lautens, M. Chem. ReV. 2003, 103, 169.
Scheme 1
(5) Mechanistic study: Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara,
M. J. Am. Chem. Soc. 2002, 124, 5052.
(6) For additions of boronic acids to unsaturated ketones employing
phosphine ligands, see: (a) Ma, Y.; Song, C.; Ma, C.; Sun, Z.; Chai, Q.;
Andrus, M. B. Angew. Chem., Int. Ed. 2003, 42, 5871; Angew. Chem. 2003,
115, 6051. (b) Amengual, R.; Michelet, V.; Geneˆt, J.-P. Synlett 2002, 11,
1791. (c) Iguchi, Y.; Itooka, R.; Miyaura, N. Synlett 2003, 7, 1040. (d)
Pucheault, M.; Darses, S.; Geneˆt, J.-P. Eur. J. Org. Chem. 2002, 3552. (e)
Reetz, M.; Moulin, D.; Gosberg, A. Org. Lett. 2001, 3, 4083. (f) Boiteau,
J.-G.; Imbos, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 685.
(f) Duursma, A.; Hoen, R.; Schuppan, J.; Hulst, R.; Minnaard, A. J.; Feringa,
B. L. Org. Lett. 2003, 5, 3111. (g) Kuriyama, M.; Nagai, K.; Yamada,
K.-i.; Miwa, Y.; Taga, T.; Tomioka, K. J. Am. Chem. Soc. 2002, 124, 8932.
(i) Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998, 120,
5579.
(7) Meyer, O.; Becht, J.-M.; Helmchen, G. Synlett 2003, 10, 1539.
(8) For additions of boronic acids to unsaturated esters employing
phosphine ligands with control at both R and â carbons, see: (a) Navarre,
L.; Darses, S.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719; Angew.
Chem. 2004, 116, 737. (b) Navarre, L.; Darses, S.; Geneˆt, J.-P. Eur. J.
Org. Chem. 2004, 69. (c) Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N.
J. Org. Chem. 2000, 65, 5951. (d) Takaya, Y.; Senda, T.; Kurushima, H.;
Ogasawara, M.; Hayashi, T. Tetrahedron: Asymmetry 1999, 10, 4047.
(9) For the addition of boronic acids to amides and vinylogous amides
employing phosphine ligands, see: (a) Shintani, R.; Tokunaga, N.; Doi,
H.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 6240. (b) Senda, T.;
Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66, 6852. (c) Sakuma,
S.; Miyaura, N. J. Org. Chem. 2001, 66, 8944.
the substituents at C-2 and C-5. There are two key differences
with respect to our earlier route: an initial addition/
transposition sequence with carvone (8 f 9) and subsequent
alkylation of the [2.2.2] ketone (10 f 11).10 Although a
separable mixture of C-8 diastereomers is obtained for 10,
the derived Rh(I) complexes for both lead to identical results.
(10) As shown in Scheme 1, the final step in the synthesis of 1 furnishes
the diene ligand in good yields. The conversions of 11b-e to 2-5 proceeded
in considerably poorer yields (18-42%); however, these yields were
unoptimized, as the ligands were shown to be inferior (Table 1).
3874
Org. Lett., Vol. 6, No. 21, 2004

We conducted further preliminary investigations of the
unexpected effect of an additional CdC with ligands 12 and
13 (Scheme 2). Interestingly, the use of 12 fails to give any
Table 2. Reactions of Acceptors and Boronic Acids Catalyzed
by Rh(I)‚1
Scheme 2
significant amount of product; by contrast, 13 furnishes
adduct in 93% yield and 58% ee. Although the latter result
is inferior to those described above, it does open up new
potential avenues of investigation involving the synthesis and
screening of ligands with varied exocyclic olefin substituents.
We then proceeded to examine the addition reaction for a
range of acceptors utilizing the optimal ligand 1 (Table 2).
Additions to cyclohexenone afforded products in high
selectivity (94-97% ee) and 83-96% yield, employing 4-,
3-, and 2-substituted phenylboronic acids. The use of
2-substituted phenylboronic acids has not been peviously
examined in these reactions with diene ligands. When
cyclopentenones were subjected to additions with both
substituted phenyl as well as 2-styrylboronic acids, adducts
were isolated in 90-97% ee and 91-98% yield. Conjugate
additions to cyclopentenone have historically proven difficult
to effect in high selectivities under a variety of conditions.
It is important to note that the selectivities we obtained for
3-phenylcyclopentanone (97% ee with 1; when the addition
is carried out with 3 the same adduct is obtained in 98% ee)
represent to the best of our knowledge the highest observed
to date using any of the available methods.11 In previous
reports involving chiral dienes as ligands, acceptors such as
coumarin, 2-(5H)-furanone, unsaturated amides, and the
simple 3-penten-2-one were not examined. Using Rh(I)‚1,
these additions are all executed successfully (88-98% ee).
a See eq 2 for conditions; reaction times 1-18 h. b Reaction carried out
with ent-1 to facilitate analysis by chiral HPLC. c Conducted at 50 °C.
In summary, we have documented for the first time the
successful use of a [2.2.2]bicyclooctadiene ligand in the Rh-
(I)-catalyzed addition of aryl and styryl boronic acids to a
variety of acceptors. Included in the set of substrates that
were investigated are unsaturated lactones, an acyclic amide,
and a simple ketone, none of which had been previously
examined with diene ligands. Within this ligand family, we
have observed interesting and unexpected observations that
result from the introduction of a third CdC, underscoring
the dramatic effects that can ensue with relatively minor
structural modifications of the scaffold. In particular, this
study establishes the versatility of the [2.2.2] ligands derived
from (R)- or (S)-carvone using a new synthetic sequence,
which may lead to the potential wider study and use of
diene-metal complexes in asymmetric catalysis.
Acknowledgment. This research is supported by a Swiss
National Science Foundation Grant and ETH-Z. J.-F.P. is
grateful to the National Sciences and Engineering Research
(11) (a) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 17. (b)
Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221.
Org. Lett., Vol. 6, No. 21, 2004
3875

Council of Canada (NSERC) for a postdoctoral fellowship.
S.S. thanks the Basque Government for a predoctoral
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,
OL048240X
3876
Org. Lett., Vol. 6, No. 21, 2004