Simple chiral diene ligands provide high enantioselectivities in transition-metal-catalyzed conjugate addition reactions

Article abstract of DOI:10.1021/ol801931v

(Chemical Equation Presented) Chiral dienes possessing the bicyclo[2.2.2]octadiene framework were prepared readily through the [4 + 2] cycloaddition of (R)-α-phellandrene with methyl propiolate as the key step. Diene 9, substituted with a tertiary alcohol

Full text of DOI:10.1021/ol801931v

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4387-4389
Simple Chiral Diene Ligands Provide
High Enantioselectivities in
Transition-Metal-Catalyzed Conjugate
Addition Reactions
Kazuhiro Okamoto,† Tamio Hayashi,*,† and Viresh H. Rawal*,‡
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto
606-8502, Japan, and Department of Chemistry, The UniVersity of Chicago, 5735
South Ellis AVenue, Chicago, Illinois 60637
thayashi@kuchem.kyoto-u.ac.jp; Vrawal@uchicago.edu
Received August 18, 2008
ABSTRACT
Chiral dienes possessing the bicyclo[2.2.2]octadiene framework were prepared readily through the [4 + 2] cycloaddition of (R)-r-phellandrene
with methyl propiolate as the key step. Diene 9, substituted with a tertiary alcohol on one of the two double bonds, is prepared in just one
step from the cycloadduct and is highly effective as a chiral ligand for rhodium-catalyzed asymmetric conjugate addition reactions, giving the
corresponding addition products with higher enantioselectivity than other chiral dienes.
The recent development of chiral diene ligands for transition-
metal-catalyzed asymmetric reactions has opened up new
vistas for ligand design.1 Chiral dienes have been found to
be superior to other types of chiral ligands, such as chiral
bisphosphines, in terms of both catalytic activity and
enantioselectivity, especially in rhodium-catalyzed asym-
metric carbon-carbon bond-forming reactions. The most
effective chiral dienes reported to date for catalytic asym-
metric reactions are those based on the bicyclic diene
frameworks, 1-5,2-7 as shown in Figure 1. Noteworthy
among these is Carreira’s diene (3), which has the advantage
that it is readily available from an inexpensive terpene, (-)-
carvone, through a seven-step sequence.4 The development
of even simpler routes to chiral diene ligands is expected to
spur further advances in transition-metal-mediated catalytic
asymmetric reactions.1b We report here an exceedingly
simple, two-step synthesis of a chiral diene from the
inexpensive terpene, (R)-R-phellandrene. The new diene is
(3) Diene 2: (a) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama,
K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584. (b)
Otomaru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org. Chem. 2005,
70, 2503. (c) Shintani, R.; Kimura, T.; Hayashi, T. Chem. Commun. 2005,
3213. (d) Shintani, R.; Tsurusaki, A.; Okamoto, K.; Hayashi, T. Angew.
Chem., Int. Ed. 2005, 44, 3909. (e) Shintani, R.; Okamoto, K.; Hayashi, T.
Org. Lett. 2005, 7, 4757. (f) Hayashi, T.; Tokunaga, N.; Okamoto, K.;
Shintani, R. Chem. Lett. 2005, 34, 1480. (g) Chen, F.-X.; Kina, A.; Hayashi,
T. Org. Lett. 2006, 8, 341. (h) Nishimura, T.; Yasuhara, Y.; Hayashi, T.
Org. Lett. 2006, 8, 979. (i) Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi,
T. Angew. Chem., Int. Ed. 2007, 46, 7277. (j) Shintani, R.; Ichikawa, Y.;
Hayashi, T.; Chen, J.; Nakao, Y.; Hiyama, T. Org. Lett. 2007, 9, 4643. (k)
So¨rgel, S.; Tokunaga, N.; Sasaki, K.; Okamoto, K.; Hayashi, T. Org. Lett.
2008, 10, 589.
† Kyoto University.
‡ The University of Chicago.
(1) For reviews, see: (a) Johnson, J. B.; Rovis, T. Angew. Chem., Int.
Ed. 2008, 47, 840. (b) Defieber, C.; Gru¨tzmacher, H.; Carreira, E. M. Angew.
Chem., Int. Ed. 2008, 47, 4482.
(2) Diene 1: (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K.
J. Am. Chem. Soc. 2003, 125, 11508. (b) Berthon-Gelloz, G.; Hayashi, T.
J. Org. Chem. 2006, 71, 8957. (c) Noe¨l, T.; Vandyck, K.; Van der Eycken,
J. Tetrahedron 2007, 63, 12961
.
10.1021/ol801931v CCC: $40.75
Published on Web 09/05/2008
2008 American Chemical Society

Scheme 1. Synthesis of Chiral Dienes
Figure 1. Chiral diene ligands for catalytic asymmetric reactions.
highly effective as a ligand for rhodium-catalyzed asym-
metric addition reactions, providing among the highest
enantioselectivities reported for these reactions.
One of the most efficient methods of constructing a
bicyclo[2.2.2]octadiene framework involves the [4 + 2] cy-
cloaddition of a 1,3-cyclohexadiene derivative with an acetylene.
We chose (R)-R-phellandrene, which is one of the most
inexpensive terpenes, as the chiral diene for construction of
enantiomerically enriched bicyclo[2.2.2]octadiene.8 Thus, tech-
nical grade (R)-R-phellandrene (∼70% chemical purity,9,10 1.05
equiv) was allowed to react with methyl propiolate in the
presence of chlorodimethylaluminum (1.0 equiv) in dichlo-
romethane at 0 °C for 6 h. The reaction mixture was
subjected to silica gel column chromatography to give 73%
isolated yield of the cycloaddition product 6, together with
an ene-type reaction product.11 The cycloaddition took place
with high regio- and diastereoselectivity to produce bicyclo-
[2.2.2]octadiene (R,R,R)-6 as a single diastereoisomer (Scheme
1). The enantiomeric purity of 6, determined using a chiral
stationary column (Chiralpak AD-H), was found to be 98.8
( 0.2% ee, coincident with the purity of the commercial
sample of (R)-R-phellandrene. An enantiomerically pure
sample of 6 was readily obtained using preparative chiral
HPLC. Alternatively, the cycloaddition can be performed
with R-phellandrene of higher enantiomeric purity.10
While cycloadduct 6 can itself be used as a chiral diene
ligand, the ester functionality can be easily modified to
generate derivatives. Thus, reduction of 6 with HAlBui2 gave
alcohol 7, subsequent methylation of which gave methyl ether
8. A quantitative yield of tertiary alcohol 9 was obtained by
treatment of 6 with methyllithium. The corresponding ether
(10) was also prepared.
(4) Diene 3: (a) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M.
J. Am. Chem. Soc. 2004, 126, 1628. (b) Defieber, C.; Paquin, J.-F.; Serna,
S.; Carreira, E. M. Org. Lett. 2004, 6, 3873. (c) Paquin, J.-F.; Defieber, C.;
Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 10850.
(d) Paquin, J.-F.; Stephenson, C. R. J.; Defieber, C.; Carreira, E. M. Org.
Lett. 2005, 7, 3821. (e) Fessard, T. C.; Andrews, S. P.; Motoyoshi, H.;
Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 9331. (f) Miura, T.;
Murakami, M. Org. Lett. 2005, 7, 3339. (g) Miura, T.; Murakami, M. Chem.
Commun. 2005, 5676. (h) Miura, T.; Takahashi, Y.; Murakami, M. Chem.
Commun. 2007, 595.
Chiral dienes 6-10, prepared in just one to three steps
from (R)-R-phellandrene, were examined as chiral ligands
for the rhodium-catalyzed asymmetric 1,4-additions (eq 1).12
Some of the results of this study are summarized in Table
1, which also contains the data reported with other dienes
for comparison. In the addition of phenylboronic acid (12m)
to 2-cyclohexen-1-one (11a), the (R,R,R)-dienes substituted
with an ester 6, alcohol 7, and its methyl ether 8 gave the
phenylation product 13am with 87%, 95%, and 94% ee,
(5) Diene 4: (a) Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T.
Org. Lett. 2005, 7, 307. (b) Otomaru, Y.; Kina, A.; Shintani, R.; Hayashi,
T. Tetrahedron: Asymmetry 2005, 16, 1673.
(6) Diene 5: (a) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H; Lin, G.-Q. J. Am.
Chem. Soc. 2007, 129, 5336. (b) Helbig, S.; Sauer, S.; Cramer, N.; Laschat,
S.; Baro, A.; Frey, W. AdV. Synth. Catal. 2007, 349, 2331.
(7) Other chiral diene ligands used for asymmetric reactions: (a) La¨ng,
F.; Breher, F.; Stein, D.; Gru¨tzmacher, H. Organometallics 2005, 24, 2997.
(b) Kina, A.; Ueyama, K.; Hayashi, T. Org. Lett. 2005, 7, 5889.
(8) Examples of the [4 + 2] cycloaddition of R-phellandrene: (a) Trost,
B. M.; Lunn, G. J. Am. Chem. Soc. 1977, 99, 7079. (b) Lauer, M.; Samuel,
O.; Kagan, H. B. J. Organomet. Chem. 1979, 177, 309. (c) Escher, S.; Keller,
U.; Willhalm, B. HelV. Chim. Acta 1979, 62, 2061. (d) Paquette, L. A.;
Doehner, R. F., Jr. J. Org. Chem. 1980, 45, 5105.
(11) (E)-Methyl 3-(5-isopropyl-2-methylenecyclohex-3-enyl)propenoate:
See: Supporting Information.
(12) For reviews: (a) Yoshida, K.; Hayashi, T. In Modern Rhodium-
Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim,
Germany, 2005; Chapter 3. (b) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003,
103, 2829. (c) Hayashi, T. Bull. Chem. Soc. Jpn. 2004, 77, 13. (d) Hayashi,
T. Pure Appl. Chem. 2004, 76, 465. (e) Darses, S.; Genet, J.-P. Eur. J.
Org. Chem. 2003, 4313. (f) Fagnou, K.; Lautens, M Chem. ReV. 2003, 103,
169. First report: (g) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.;
Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579.
(9) Kanto Chemicals Ltd. p-Cymene is a major component of the
impurity. The enantiomeric purity measured by a chiral GC column (CP-
Chiralsil-Dex CB) is 98.9 ( 0.2% ee
.
(10) (S)-R-Phellandrene is readily prepared, in three steps, from (R)-
(-)-carvone Sen, A.; Grosch, W. FlaVour Fragrance J. 1990, 5, 233. Also
see: Daubin, W. G.; Lorber, M. E.; Vietmeyer, N. D.; Shapiro, R. H.;
Duncan, J. H.; Tomer, K. J. Am. Chem. Soc. 1968, 90, 4762
.
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Org. Lett., Vol. 10, No. 19, 2008

Table 1. Asymmetric 1,4-Addition of PhB(OH)2 (12m) to 11a
and 11b Catalyzed by Rhodium-Diene Complexesa
diene
yieldc
(%)
entry ligandb enone conditions
% eed
ref
1
6e
6
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
11b
11b
11b
20 °C, 3 h
20 °C, 3 h
30 °C, 1 h
30 °C, 1 h
30 °C, 1 h
30 °C, 1 h
30 °C, 1 h
30 °C, 1 h
30 °C, 1 h
25 °C, s
93
89
96
88
90
90
94
97
97
87
95
90
94
86 (R)
87 (R)
95 (R)
94 (R)
99.3 (R)
99.1 (R)
96 (R)
95 (R)
96 (R)
95 (S)
2
3
7
4
8
9
10
1
2a
2b
3b
9
10
2a
5
6
7
2a
3b
3b
4b
8
9
10
11
12
13
Figure 2. Stereochemical pathway with Rh/(R,R,R)-9.
30 °C, 3 h
30 °C, 3 h
30 °C, 1 h
98.8 (S)
99.0 (S)
98 (S)
3b
a The reaction was carried out with enone 11 (0.30 mmol), PhB(OH)2
(0.45 mmol), [RhCl(C2H4)2]2 (3 mol % Rh), diene (3.3 mol %), and 1.5 M
aq KOH (0.1 mL) in dioxane (1.0 mL). b Dienes 6-10 had >99.8% ee.
c Isolated yield. d Determined by HPLC analysis with chiral stationary-phase
columns. e ee ) 98.8%.
Table 2. Asymmetric 1,4-Addition of Boronic Acids 12 to
Enones 11 Catalyzed by Rhodium/(R,R,R)-9 Complexa
yield
entry enone
boronic acid: R
conditions (%)b % eec
1
2
3
4
5
6
7
8
11a 12n: 4-MeOC6H4
11a 12o: 4-CF3C6H4
11a 12p: 2-MeC6H4
11a 12q: (E)-PhCH)CH
30 °C, 1 h 98 >99.5 (R)
30 °C, 1 h 97 99.1 (R)
30 °C, 1 h 95 99.4 (R)
30 °C, 3 h 97 99.3 (R)
respectively (entries 1-4). The enantioselectivity observed
here with 7 and 8 is comparable to that with the dienes 1-3
which had been the best diene ligands for this asymmetric
transformation (entries 7-10). To our delight, the dienes 9
and 10, which bear the tertiary alcohol and its methyl ether,
respectively, as a substituent on one of the two olefins, gave
13am with 99% ee (entries 5 and 6). The very high
enantioselectivity (99% ee) with dienes 9 and 10 was also
observed in the addition to linear enone, 3-nonen-2-one (11b)
(entries 11 and 12).
11a 12r: (E)-C5H11CH)CH 30 °C, 3 h 81 98.7 (R)
11c 12m: Ph
11d 12m: Ph
11e 12m: Ph
50 °C, 1 h 94 98 (R)
30 °C, 3 h 84 96 (R)
50 °C, 3 h 97 99.4 (S)
a The reaction was carried out with enone (0.30 mmol), RB(OH)2 (0.45
mmol), [RhCl(C2H4)2]2 (3 mol % Rh), (R,R,R)-9 (3.3 mol %), and 1.5 M
aq KOH (0.1 mL) in dioxane (1.0 mL). b Isolated yield. c Determined by
HPLC analysis with chiral stationary phase columns.
The high enantioselectivity of dienes 9 and 10 can be
ascribed to the steric bulkiness of the 1-hydroxy- or 1-meth-
oxy-1-methylethyl group attached to the double bond. The
comparable results obtained with 9 and 10 precludes
hydrogen bonding as playing a role in organizing the
transition state complex. The absolute configuration of the
products, (R) for cyclic enone 13am and (S) for acyclic enone
13bm, is consistent with the stereochemical pathway pro-
posed for the reactions using C2-symmetric diene
ligands.2,3,13 In the case of (R,R,R)-9, which is unsymmetri-
cally substituted with methyl and the tertiary alcohol,
phenyl-rhodium bond may be formed on the open methyl
side leaving the other, sterically congested, side for coordina-
tion of an enone (Figure 2). The sterically bulky tertiary
alcohol appears to better distinguish the enantiofaces of
enones than the primary alkyl groups or aryl groups which
are the substituents on the chiral dienes reported to date.2-6,14
Chiral diene ligand 9 also induced high enantioselectivity
in the conjugate addition of other substrates, as shown in
Table 2. Thus, the addition of arylboronic acids 12n-p
substituted with 4-methoxy, 4-trifluoromethyl, and 2-methyl
all proceeded with over 99% enantioselectivity (entries 1-3).
Ligand 9 is also very effective for alkenylboronic acids
(entries 4-5). 2-Cyclohepten-1-one (11c) and linear enones,
11d and 11e, undergo the 1,4-phenylation with high enan-
tioselectivities (entries 6-8).
In summary, chiral dienes possessing the bicyclo[2.2.2]-
octadiene framework can be easily prepared through the [4 +
2] cycloaddition of the inexpensive chiral terpene (R)-R-
phellandrene with an alkynyl dienophile. Simple further elabo-
ration of the cycloadduct, requiring just one or two steps,
provides dienes that are the most effective ligands reported so
far for the rhodium-catalyzed asymmetric addition reactions.
Acknowledgment. Support has been provided in part by
a Grant-in-Aid for Scientific Research, the Ministry of
Education, Culture, Sports, Science and Technology, Japan
(the Global COE Program “Integrated Materials Science”
on Kyoto University). K.O. thanks the Japan Society for the
Promotion of Science for the award of a fellowship for
graduate students. V.H.R. thanks the NIH for partial support
of this work.
(13) For the mechanism of rhodium-catalyzed 1,4-addition, see: Hayashi,
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002,
124, 5052
.
(14) For the asymmetric addition of PhB(OH)2 to 2-cyclopenten-1-one,
diene 9 is less enantioselective than Ph-bod* (2b), the latter giving the
corresponding phenylation products with 99% ee (ref 3b)
.
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