Asymmetric synthesis of 5-arylcyclohexenones by rhodium(I)-catalyzed conjugate arylation of racemic 5-(trimethylsilyl)cyclohexenone with arylboronic acids

Article abstract of DOI:10.1021/ol051704m

(Chemical Equation Presented) A catalytic asymmetric conjugate arylation of racemic 5-(trimethylsilyl)cyclohex-2-enone with arylboronic acids was catalyzed by 3 mol % chiral amidophosphane- or BINAP-Rh(I) in dioxane-water (10:1) to afford trans- and cis-3-aryl-5-(trimethylsilyl)cyclohexanones in high enantioselectivity. Dehydrosilylation of the product mixture with cupric chloride in DMF gave 5-arylcyclohex-2-enones with up to 93% ee in good yield. Enantiofacial selectivity with chiral phosphane-Rh(I) exceeds the trans-diastereoselectivity that is maintained in the achiral or racemic phosphane-Rh(I)-catalyzed conjugate arylation of 5-(trimethylsilyl) cyclohexenone.

Full text of DOI:10.1021/ol051704m

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4439-4441
Asymmetric Synthesis of
5-Arylcyclohexenones by
Rhodium(I)-Catalyzed Conjugate
Arylation of Racemic
5-(Trimethylsilyl)cyclohexenone with
Arylboronic Acids
Qian Chen, Masami Kuriyama, Takahiro Soeta, Xinyu Hao, Ken-ichi Yamada, and
Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
Received July 20, 2005
ABSTRACT
A catalytic asymmetric conjugate arylation of racemic 5-(trimethylsilyl)cyclohex-2-enone with arylboronic acids was catalyzed by 3 mol %
chiral amidophosphane- or BINAP-Rh(I) in dioxane water (10:1) to afford trans- and cis-3-aryl-5-(trimethylsilyl)cyclohexanones in high
−
enantioselectivity. Dehydrosilylation of the product mixture with cupric chloride in DMF gave 5-arylcyclohex-2-enones with up to 93% ee in
good yield. Enantiofacial selectivity with chiral phosphane-Rh(I) exceeds the trans-diastereoselectivity that is maintained in the achiral or
racemic phosphane-Rh(I)-catalyzed conjugate arylation of 5-(trimethylsilyl)cyclohexenone.
Enantiomerically enriched substituted cyclohexenones have
been utilized as versatile chiral building blocks for the
synthesis of biologically important compounds.1 Among a
variety of methods for the preparation of these chiral
cyclohexenones,2,3 kinetic resolution of racemic substituted
cyclohexenones by catalytic asymmetric reactions4 and
enzymatic reactions5 has proven to be the most effective
method, resulting in recovery of a nearly pure enantiomer.
(3) Asymmetric synthesis: (a) Taylor, M. S.; Zalatan, D. N.; Lerchner,
A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313-1317. (b)
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10.1021/ol051704m CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/01/2005

However, kinetic resolution involves a fatal disadvantage
because half of the starting material is discarded. It should
also be emphasized that careful control of the reaction
progress is required to maximize the recovery yield and ee
of the unreacted starting material. Since the enantioenriched
5-(trialkylsilyl)cyclohexenones themselves have been the
choice of starting material for the preparation of 5-substituted
cyclohexenones, 5-(trialkylsilyl)cyclohexenones have been
the target of kinetic resolution.4a,f,5a We describe herein the
straightforward asymmetric synthesis of 5-arylcyclohex-
enones 4 with high ee from racemic 5-(trimethylsilyl)-
cyclohexenone 1 via chiral phosphane-rhodium(I)-catalyzed
conjugate arylation6,7 and subsequent oxidative dehydrosi-
lylation (Scheme 1). Namely, the idea is based on the utility
Scheme 2. Substrate Control versus Chiral Catalyst Control in
Conjugate Arylation of Racemic 1
Scheme 1. Two-Step Catalytic Asymmetric Synthesis of 4
from Racemic 1
We anticipated that the high enantioselectivity up to 97%
ee observed with an amidophosphane 5-rhodium(I) catalyst
in the conjugate arylation of cyclohexenone10 would over-
come the trans-diastereoselectivity, providing a mixture of
2 and ent-3 with high ee (Figure 1). The difference of the
of racemic 1 as a synthetic equivalent of cyclohex-2,5-
dienone, which readily isomerizes to phenol.
Generally, 5-substituted cyclohexenones undergo trans-
selective conjugate addition.2a,8 Although this substrate
control is operative in the reaction of racemic 1 (1 and ent-
1) to stereoselectively produce racemic 2 (2 and ent-2), the
enantiofacial control of a chiral catalyst, if favoring si face
addition, produces 2 as a major product over ent-2, allowing
kinetic resolution to recover ent-1 as has been reported
(Scheme 2).4,5 However, if the chiral catalyst control
overcomes the trans-diastereoselectivity of the substrate
control,9 2 and ent-3 are the major products that bear the
same stereochemistry at the newly created chiral centers.
Dehydrosilylation4f,5a thereof completes an asymmetric syn-
thesis of 5-substituted cyclohexenones 4 from the racemic
mixture of 1 and ent-1.
Figure 1. Chiral phosphane ligands 5 and 6 for Rh(I).
present proposal from kinetic resolution protocol is the full
conversion of racemic 1 to ideally a 1:1 mixture of 2 and
ent-3, whereas in the kinetic resolution the formation of ent-3
is suppressed to recover ent-1.
The trans-diastereoselectivity by the substrate control was
confirmed by the dppb-[RhCl(C2H4)2]2-KOH-catalyzed
Miyaura arylation11 of racemic 14f with phenylboronic acid
in dioxane-water at 100 °C, giving a 91:9 racemic mixture
of trans-2a (Ar ) Ph) and cis-3a (Ar ) Ph) in 57% yield,
apparently indicating that trans-diastereoselectivity is main-
tained in the Rh(I)-catalyzed arylation of 1. With dl-BINAP
6 in place of dppb, the same substrate control was observed
to give a 89:11 trans major mixture in 90% yield.
(6) (a) Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T. J. Am. Chem.
Soc. 2004, 126, 6240-6241. (b) Fischer, C.; Defieber, C.; Suzuki, T.;
Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 1628-1629. (c) Hayashi, T.;
Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125,
11508-11509. (d) Boiteau, J.-G.; Minnaard, A. J.; Feringa, B. L. J. Org.
Chem. 2003, 68, 9481-9484. (e) Iguchi, Y.; Itooka, R.; Miyaura, N. Synlett
2003, 1040-1042. (f) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103,
2829-2844. (g) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.;
Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579-5580.
(7) Reviews on asymmetric conjugate addition: (a) Tomioka, K. in
ComprehensiVe Asymmetric Catalysis, Supplement to Chapter 31.1; Jacob-
sen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 2004, pp
109-124. (b) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171-196.
(c) Kanai, M.; Shibasaki, M. In Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; VCH: Weinheim, 2000, p 569. (d) Tomioka, K. Synthesis 1990, 541-
549.
(8) (a) Yamamoto, Y. In Methoden Organischen Chemie, Engl. Ed.;
Helmchen, G., Houben, J., Wely, T., Eds.; Georg Thieme: Stuttgart, 1995;
Vol. E21b, pp 2041-2067. (b) Lipshutz, B. H.; Sengupta, S. Org. React.
1992, 41, 135-631. (c) Corey, E. J.; Hannon, F. J. Tetrahedron Lett. 1990,
31, 1393-1396.
(9) cis-Diastereoseletivity by chiral catalyst- and reagent-control has been
reported in the reaction of cyclohexenones bearing an ether appendage:
Imbos, R.; Minnaard, A. J.; Feringa, B. L. Tetrahedron 2001, 57, 2485-
2489. See also ref 2a.
The reaction of racemic 1 with phenylboronic acid was
successfully catalyzed by 3 mol % 5-[RhCl(C2H4)2]2 and 1
(10) (a) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa, Y.; Taga, T.;
Tomioka, K. J. Am. Chem. Soc. 2002, 124, 8932-8939. (b) Kuriyama, M.;
Tomioka, K. Tetrahedron Lett. 2001, 42, 921-923.
(11) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4229-4231.
4440
Org. Lett., Vol. 7, No. 20, 2005

Table 1. Phosphane-Rh(acac)(C2H4)2-Catalyzed Asymmetric Arylation of Racemic 1 at 100 °C and Dehydrosilylation to 4a
2 + ent-3
yield
(S)-4b
time
(h)
2 ee
(%)
ent-3 ee
(%)
yield
(%)
ee
(%)
entry
Ar
5/6
(%)
ratio
4
1
2
3
4
5
6
7
8
9
10
Ph
Ph
5c,d
6
3
10
2
5
2
91
91
93
92
93
82
88
82
55
94
59:41
61:39
65:35
61:39
67:33
63:37
68:32
63:37
87:13
51:49
76
89
72
83
70
98
99
99
99
97
4a
4a
4b
4b
4c
4c
4d
4d
73
75
73
73
72
77
74
74
83
93
84
93
78
90
80
93
3-MeOC6H4
3-MeOC6H4
3-ClC6H4
3-ClC6H4
4-CF3C6H4
4-CF3C6H4
2-Naph
5c
6
5c
6
5c
6
5c,d
6c
6
11
22
32
3
72
88
50
83
99
99
98
99
2-Naph
4e
70
90
a Percent ee was determined by HPLC (Supporting Information). b The absolute configuration was assigned to be (S) by comparing specific rotation of
the 3-arylcyclohexanones obtained by hydrogenation of 4. c [RhCl(C2H4)2]2 (1.5 mol %) and KOH (1 equiv) were used. d At 60 °C.
equiv of KOH in dioxane-water (10:1) at 60 °C to afford a
59:41 mixture of 2a and ent-3a in 91% yield (Table 1, entry
1). The enantioselectivity was determined by chiral stationary
phase HPLC to be 76% and 98% ee, respectively. Treatment
of the above mixture of 2a and ent-3a with cupric chloride
in DMF12 at 60 °C for 5 h gave (S)-4a (Ar ) Ph) with 83%
ee in 73% yield. (S)-BINAP 6 was more effective to give a
61:39 mixture of 2 with 89% ee and ent-3 with 99% ee in
91% combined yield. Dehydrosilylation to (S)-4a with 93%
ee was carried out in 68% overall yield from racemic 1 (entry
2).
Aryl groups having electron-donating and -withdrawing
substituents, for example, 3-methoxyphenyl, 3-chlorophenyl,
4-trifluoromethylphenyl, and 2-naphthyl groups, were suc-
cessfully introduced into racemic 1, giving the corresponding
2 and ent-3 with reasonably high ee (50-99%) in high yields
(55-94%). In the production of 2, 6 is superior to 5, giving
higher enantioselectivity (entries 2, 4, 6, 8, and 10). In the
production of ent-3 both phosphanes 5 and 6 behave equally
efficiently, giving selectivity over 97% ee. Dehydrosilylation
of a mixture of 2b-e and ent-3b-e successfully afforded
the corresponding 4b-e with 90-93% ee by 6 and 78-
84% ee by 5 in 70-77% yield. It is also important to note
that with use of dl-6 as a ligand trans-diastereoselectivity
(racemic 2:3 ) 83:17-89:11) due to the conformational and
stereoelectronic effects of 1 was confirmed without excep-
tion.
In conclusion, a chiral phosphane-Rh(I)-catalyzed asym-
metric conjugate arylation of racemic 5-(trimethylsilyl)-
cyclohexenone with arylboronic acids and subsequent de-
hydrosilylation gave 5-arylcyclohex-2-enones in high enantio-
selectivity and good two-step yield. The present asymmetric
reaction protocol overcomes the drawback involved in
catalytic kinetic resolution. Enantiofacial selectivity with
chiral phosphane-Rh(I) exceeds the trans-diastereoselectivity
that is maintained in achiral or racemic phosphane-rhodium-
catalyzed conjugate arylation of 5-(trimethylsilyl)cyclohex-
enone.
Acknowledgment. This research was supported by the
COE Program “Knowledge Information Infrastructure for
Genome Science” and a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Supporting Information Available: Reaction procedure
and characterization data of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Asaoka, M.; Shima, K.; Takei, H. J. Chem. Soc., Chem. Commun.
1988, 430-431.
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