Rhodium-catalyzed asymmetric 1,6-addition of aryl zinc reagents to dienones

Article abstract of DOI:10.1002/anie.200500678

(Chemical Equation Presented) A highly enantioselective methodology allows the preparation of α,β-unsaturated ketones that contain a new stereogenic center at the C5 position. This approach is realized through the title reaction in the presence of chlorotrimethylsilane as a Lewis acid and a rhodium/(S)-binap complex as the catalyst followed by acidic hydrolysis (see scheme). binap = 2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl.

Full text of DOI:10.1002/anie.200500678

Communications
Asymmetric Catalysis
Rhodium-Catalyzed Asymmetric 1,6-Addition of
Aryl Zinc Reagents to Dienones**
Tamio Hayashi,* Shohei Yamamoto, and
Norihito Tokunaga
The catalytic asymmetric 1,4-addition of organometallic
reagents to electron-deficient olefins is one of the most
important methods of forming stereogenic centers in carbon–
carbon bond-forming reactions.[1] In this field, attention has
focused on asymmetric 1,4-additions catalyzed by copper,[2,3]
rhodium,[4–8] palladium,[9] and nickel[10] complexes. On the
other hand, asymmetric 1,6-addition to extended conjugate
systems has developed less rapidly.[11] Although several
reports have appeared on diastereoselective 1,6-additions,[12]
the use of a chiral catalyst for this asymmetric transformation
remains to be studied. Herein, we report the first example of a
catalytic asymmetric 1,6-addition to 2,4-dien-1-ones, in which
a stereogenic center at the C5 position is also formed; this
reaction is realized by a rhodium-catalyzed addition of aryl
zinc reagents to dienones in the presence of chlorotrimethyl-
silane.
To investigate conjugate addition to 3-((E)-hexenyl)-2-
cyclohexenone (1), several phenyl organometallic reagents
that had been successfully used in rhodium-catalyzed asym-
metric 1,4-addition reactions to electron-deficient alkenes[4–7]
were examined for their reactivity and selectivity (Scheme 1
and Table 1). When the reaction was carried out with
phenylboronic acid under reaction conditions that have
been shown to be very efficient for asymmetric 1,4-additions
Scheme 1. Rhodium-catalyzed addition of phenyl organometallic
reagents (PhM) to dienone 1.
[*] Prof. T. Hayashi, S. Yamamoto, N. Tokunaga
Department of Chemistry
Graduate School of Science, Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
Fax: (+81)75-753-3988
E-mail: thayashi@kuchem.kyoto-u.ac.jp
[**] This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan (21 COE on Kyoto University Alliance for
Chemistry). N.T. thanks the Japanese Society for the Promotion of
Science for the award of a fellowship for graduate students.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200500678
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Chemie
Table 1: Rhodium-catalyzed asymmetric 1,6-addition to
products 3a–e.[a]
1 forming
quantitative yield with 96% ee after acidic hydrolysis
(Scheme 2; Table 1, entry 5). The 1,6-addition product
before hydrolysis was a 1,3-dienyl silyl ether 4 (Z/E = 4:1).
The high yield of the addition product may be ascribed to the
Entry PhM (equiv)
Conditions[b] Yield [%][c] ee [%][d]
–
1
2
3
PhB(OH)2 (2.5)
A
B
C
0[e]
–
PhTi(OiPr)3 (1.6)
PhTi(OiPr)4Li/Me3SiCl
(1.5/2.0)
0[f]
78 (3a)
88
4
5
6
7
PhZnCl[g] (1.4)
D
D
D
D
18 (3a)
99 (3a)
94 (3a)
90 (3b)
96
96
94
98
PhZnCl[g]/Me3SiCl (1.4/1.5)
PhZnX[h]/Me3SiCl (1.4/1.5)
4-FC6H4ZnX[h]/Me3SiCl
(1.4/1.5)
8
9
4-MeOC6H4ZnCl[g]/Me3SiCl
(1.4/1.5)
D
D
D
94 (3c)
86 (3d)
85 (3e)
91
86
91
3-MeOC6H4ZnCl[h]/Me3SiCl
(1.4/1.5)
10
2-naphthylZnCl[h]/Me3SiCl
(1.4/1.5)
[a] The reactions were carried out with 0.30 mmol of 1 in the presence of
3 mol% of the rhodium catalyst. [b] Conditions A: [{Rh(OH)[(S)-
binap]}2], dioxane/H2O (10:1), 508C, 3 h. Conditions B: [{Rh(OH)[(S)-
binap]}2], THF, 308C, 1 h; hydrolysis with dilute HCl. Conditions C:
[{RhCl[(S)-binap]}2], THF, 208C, 0.5 h; hydrolysis with dilute HCl.
Conditions D: [{RhCl[(S)-binap]}2], THF, 208C, 2 h; hydrolysis with
dilute HCl. [c] Yield of product isolated by column chromatography on
silica gel (hexane/ethyl acetate, 4:1). [d] Determined by HPLC analysis
with a chiral stationary-phase column (chiralpak OJ: hexane/2-propanol,
95:5); ee value for R enantiomer. [e] Dienone 1 was recovered. [f] A 1,2-
addition product 2 was formed in 70% yield. [g] Generated from ArLi and
ZnCl2. [h] Generated from ArMgBr and ZnCl2.
Scheme 2. Rhodium-catalyzed asymmetric 1,6-addition of ArZnCl to
dienone 1 in the presence of Me3SiCl.
activation of 1 by the chlorosilane acting as a Lewis acid,[13]
which accelerates the addition of 1 to a phenylrhodium
species in the catalytic cycle (see below). The asymmetric
addition of aryl zinc reagents generated from 4-FC6H4MgBr,
4-MeOC6H4Li, 3-MeOC6H4MgBr, and 2-naphthylMgBr also
gave the corresponding 1,6-addition products 3b–e, respec-
tively, in high yields and with high enantioselectivities
(Table 1, entries 7–10). The formation of any 1,4- or 1,2-
addition products was not detected in the reaction of 1 under
the current conditions.
The absolute configuration of the 1,6-addition product 3a
was determined to be R after its conversion into (R)-1,2-
diphenylhexane[14] (5d). The key step in the synthetic pathway
to 5d is the oxidation of the cyclohexenone moiety in 3a into
the methoxyphenyl group in 5a (Scheme 3).[15]
(3 mol% (Rh) of [{Rh(OH)[(S)-binap]}2] (binap = 2,2’-bis-
(diphenylphosphanyl)-1,1’-binaphthyl) as the catalyst in diox-
ane/H2O (10:1) at 508C for 3 h),[5b] the starting dienone 1 was
recovered quantitatively (Table 1, entry 1). The use of the
phenyltitanium reagent PhTi(OiPr)3 in the presence of
[{Rh(OH)[(S)-binap]}2] in THF at 308C, which gives titanium
enolates as 1,4-addition products with high enantioselectiv-
ities from a,b-unsaturated ketones,[6a] does not react in the
same way with the present substrate 1. Instead, titanium
reagent reacted to give the tertiary alcohol 2 (70% yield;
Table 1, entry 2) by a noncatalyzed 1,2-addition. The lithium
titanate reagent PhTi(OiPr)4Li (1.5 equiv), used in the
presence
of
chlorotrimethylsilane
(2.0 equiv)
and
[{RhCl[(S)-binap]}2] (3 mol% Rh) in THF at 208C, proved
more promising.[6c] The 1,6-addition product (R)-3-(2-phenyl-
hexyl)-2-cyclohexenone (3a) was afforded after acidic hydrol-
ysis in 78% yield and with 88% ee (Table 1, entry 3). The zinc
reagent PhZnCl (1.4 equiv), which has been recently found to
be more efficient than boron or titanium reagents in rhodium-
catalyzed asymmetric 1,4-addition reactions to enones,[7] gave
the 1,6-addition product 3a with higher enantioselectivity
(96% ee (R)), although its yield was as low as 18% (Table 1,
entry 4).
We have found, therefore, that chlorotrimethylsilane
greatly accelerates[13] the rhodium-catalyzed 1,6-addition of
aryl zinc reagents to dienone 1. Thus, 1 was treated with
PhZnCl (1.4 equiv; generated from PhLi and ZnCl2 in THF)
in the presence of chlorotrimethylsilane (1.5 equiv) and
[{RhCl[(S)-binap]}2] (3 mol% Rh) in THF at 208C for 2 h,
and the phenylation product (R)-3a was obtained in a
Scheme 3. Determination of the absolute configuration of the 1,6-addi-
tion product 3a. a) I2, MeOH, reflux (99%); b) BBr3, CH2Cl2, room
temperature (90%); c) Tf2O, pyridine, ClCH2CH2Cl, room temperature
(99%); d) H2, Pd/C, EtOH, EtN(iPr)2, room temperature (86%).
Tf =trifluoromethanesulfonyl.
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Communications
The treatment of the linear dienone 4-methylundeca-3,5-
reagents (Scheme 6), as this mechanism involves the reaction
of an oxo-p-allyl rhodium intermediate with chlorosilane to
afford a chlororhodium complex and a silyl enolate as the
product. With a dienone as the substrate, insertion of its g,d-
double bond into the phenyl–rhodium bond in A is slow
dien-2-one (6) with PhZnCl and chlorotrimethylsilane in the
presence of the Rh/(S)-binap (3 mol% Rh) catalytic system
also proceeded with perfect 1,6-selectivity to give the phenyl-
ation product in high yield (Scheme 4). Hydrolysis with
Scheme 6. The catalytic cycle for the rhodium-catalyzed 1,6-addition
reaction. [Rh]=[Rh{(S)-binap}].
compared with the insertion of the a,b-double bond of an a,b-
unsaturated ketone; therefore, insertion of the dienone g,d-
double bond takes place more smoothly with the assistance of
a chlorosilane as a Lewis acid. An alkyl rhodium intermediate
B is formed by the insertion reaction and undergoes isomer-
ization to a thermodynamically stable oxo-p-allyl rhodium
complex C. A silylation reaction of C with chlorotrimethylsi-
lane yields a chlororhodium species D and a silyl dienyl ether
as the 1,6-addition product. Transmetalation between D and
PhZnCl regenerates the phenylrhodium species A.
The absolute configuration R of the 1,6-addition product
3, obtained with (S)-binap as a chiral ligand, was rationalized
by using the stereochemical pathway shown in Scheme 7. At
the insertion step, coordination of the g,d-double bond at the
Re face is more favorable than coordination at the Si face
because of the steric repulsions between one of the phenyl
rings of the binap ligand and the cyclohexene moiety.
Scheme 4. Rhodium-catalyzed asymmetric 1,6-addition of PhZnCl to
dienone 6 in the presence of Me3SiCl.
hydrochloric acid afforded a,b-unsaturated ketone 7 and b,g-
unsaturated ketone 8 as a mixture of olefinic isomers in a ratio
of 21:79. Treatment of the mixture with sodium bicarbonate in
ethanol at reflux for 48 h shifted the ratio of 7/8 to 67:33. Both
7 and 8 were found to be R enantiomers in 95% ee. The
configuration was determined by correlation with (R)-3-
phenylnonen-2-one[5a] ((R)-9), which was obtained by oxida-
tive cleavage of the double bond in 7.
The selectivity of the 1,6-addition was not as high in the
reaction of hepta-3,5-dien-2-one (10); the 1,4-addition prod-
uct was formed as a by-product because 10 lacks a substituent
at the b position. Thus, the addition of PhZnCl to 10 in the
presence of chlorotrimethylsilane under similar conditions
gave the 1,6-addition products 11 (77% ee) and 12 in a
combined yield of 58% together with the 1,4-addition
product 13 in 25% yield (Scheme 5).
In summary, catalytic asymmetric 1,6-additions to 2,4-
dien-1-ones has been realized with up to 98% ee using a chiral
The catalytic cycle proposed for the rhodium-catalyzed
1,4-addition of aryl titanates in the presence of chlorotrime-
thylsilane[6c] can be applied to the 1,6-addition of aryl zinc
Scheme 5. Rhodium-catalyzed asymmetric addition of PhZnCl to
dienone 10 in the presence of Me3SiCl.
Scheme 7. The stereochemical pathway in the rhodium-catalyzed
asymmetric 1,6-addition reaction.
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Chem. 2004, 116, 737; Angew. Chem. Int. Ed. 2004, 43, 719; u) M.
bisphosphine/rhodium catalyst, aryl zinc reagents, and a
chlorosilane. Further studies on the scope and limitations of
this new catalytic asymmetric carbon–carbon bond-forming
reaction are underway.
Pucheault, V. Michaut, S. Darses, J.-P. GenÞt, Tetrahedron Lett.
2004, 45, 4729; v) A. Duursma, J.-G. Boiteau, L. Lefort, J. A. F.
Boogers, A. H. M. De Vries, J. G. De Vries, A. J. Minnaard,
B. L. Feringa, J. Org. Chem. 2004, 69, 8045; w) K. M. Belyk,
C. D. Beguin, M. Palucki, N. Grinberg, J. DaSilva, D. Askin, N.
Yasuda, Tetrahedron Lett. 2004, 45, 3265; x) P. Mauleon, J. C.
Carretero, Org. Lett. 2004, 6, 3195; y) R. J. Moss, K. J. Wads-
worth, C. J. Chapman, C. G. Frost, Chem. Commun. 2004, 1984;
z) B. M. Bocknack, L.-C. Wang, M. J. Krische, Proc. Natl. Acad.
Sci. USA 2004, 101, 5421.
Received: February 23, 2005
Published online: June 1, 2005
Keywords: 1,6-addition · asymmetric catalysis ·
.
organometallic reagents · rhodium · zinc
[6] For organotitanium reagents, see: a) T. Hayashi, N. Tokunaga, K.
Yoshida, J. W. Han, J. Am. Chem. Soc. 2002, 124, 12102; b) K.
Yoshida, T. Hayashi, J. Am. Chem. Soc. 2003, 125, 2872; c) N.
Tokunaga, K. Yoshida, T. Hayashi, Proc. Natl. Acad. Sci. USA
2004, 101, 5445.
[1] For recent reviews on catalytic asymmetric 1,4-addition reac-
tions, see: a) N. Krause, A. Hoffmann-Roder, Synthesis 2001,
171; b) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033; c) K.
Tomioka, Y. Nagaoka in Comprehensive Asymmetric Catalysis,
Vol. 3 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, chap. 31.1; d) M. Kanai, M. Shibasaki in Catalytic
Asymmetric Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley, New York,
2000, p. 569.
[2] For selected reviews on enantioselective copper-catalyzed con-
jugate addition, see: a) A. Alexakis, C. Benhaim, Eur. J. Org.
Chem. 2002, 3221; b) B. L. Feringa, R. Naasz, R. Imbos, L. A.
Arnold, Modern Organocopper Chemistry (Ed.: N. Krause),
Wiley-VCH, Weinheim, 2002, p. 224; c) B. L. Feringa, Acc.
Chem. Res. 2000, 33, 346.
[3] For recent examples, see: a) L. A. Arnold, R. Naasz, A. J.
Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2001, 123, 5841;
b) C. A. Luchaco-Cullis, A. H. Hoveyda, J. Am. Chem. Soc.
2002, 124, 8192; c) S. J. Degrado, H. Mizutani, A. H. Hoveyda, J.
Am. Chem. Soc. 2002, 124, 13362; d) A. Duursma, A. J.
Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2003, 125, 3700;
e) A. W. Hird, A. H. Hoveyda, Angew. Chem. 2003, 115, 1314;
Angew. Chem. Int. Ed. 2003, 42, 1276; f) K. Agapiou, D. F.
Cauble, M. J. Krische, J. Am. Chem. Soc. 2004, 126, 4528.
[4] For reviews, see: a) T. Hayashi, Synlett 2001, 879; b) K. Fagnou,
M. Lautens, Chem. Rev. 2003, 103, 169; c) T. Hayashi, K.
Yamasaki, Chem. Rev. 2003, 103, 2829; d) T. Hayashi, Bull.
Chem. Soc. Jpn. 2004, 77, 13.
[7] For organozinc reagents, see: R. Shintani, N. Tokunaga, H. Doi,
T. Hayashi, J. Am. Chem. Soc. 2004, 126, 6240.
[8] Other organometallic reagents: for silicon, see: a) S. Oi, A.
Taira, Y. Honma, Y. Inoue, Org. Lett. 2003, 5, 97; b) Y. Otomaru,
T. Hayashi, Tetrahedron: Asymmetry 2004, 15, 2647; for zirco-
nium, see: c) S. Oi, T. Sato, Y. Inoue, Tetrahedron Lett. 2004, 45,
5051.
[9] T. Nishikata, Y. Yamamoto, N. Miyaura, Chem. Commun. 2004,
1822.
[10] For a recent example, see: Y.-S. Kwak, E. J. Corey, Org. Lett.
2004, 6, 3385.
[11] A rhodium-catalyzed asymmetric 1,6-addition to 3-alkynyl-2-en-
1-ones that affords axially chiral allenes has been reported: T.
Hayashi, N. Tokunaga, K. Inoue, Org. Lett. 2004, 6, 305.
[12] For organocopper reagents, see: a) J. A. Marshall, H. Roebke, J.
Org. Chem. 1966, 31, 3109; b) J. A. Marshall, R. A. Ruden, L. K.
Hirsch, M. Phillippe, Tetrahedron Lett. 1971, 12, 3795; c) N.
Krause, J. Org. Chem. 1992, 57, 3509; d) N. Krause, S. Thorand,
Inorg. Chim. Acta 1999, 296, 1; e) M. Uerdingen, N. Krause,
Tetrahedron 2000, 56, 2799; for an iron-catalyzed reaction, see:
f) K. Fukuhara, H. Urabe, Tetrahedron Lett. 2005, 46, 603.
[13] For the acceleration of a 1,4-addition reaction of organocuprates
by chlorotrimethylsilane, see: a) E. J. Corey, N. W. Boaz, Tetra-
hedron Lett. 1985, 26, 6015; b) E. J. Corey, N. W. Boaz,
Tetrahedron Lett. 1985, 26, 6019.
[5] For organoboron reagents, see: a) Y. Takaya, M. Ogasawara, T.
Hayashi, M. Sakai, N. Miyaura, J. Am. Chem. Soc. 1998, 120,
5579; b) T. Hayashi, M. Takahashi, Y. Takaya, M. Ogasawara, J.
Am. Chem. Soc. 2002, 124, 5052; c) T. Hayashi, K. Ueyama, N.
Tokunaga, K. Yoshida, J. Am. Chem. Soc. 2003, 125, 11508; d) R.
Shintani, K. Ueyama, I. Yamada, T. Hayashi, Org. Lett. 2004, 6,
3425; e) S. Sakuma, M. Sakai, R. Itooka, N. Miyaura, J. Org.
Chem. 2000, 65, 5951; f) S. Sakuma, N. Miyaura, J. Org. Chem.
2001, 66, 8944; g) M. Kuriyama, K. Tomioka, Tetrahedron Lett.
2001, 42, 921; h) M. Kuriyama, K. Nagai, K.-i. Yamada, Y. Miwa,
T. Taga, K. Tomioka, J. Am. Chem. Soc. 2002, 124, 8932; i) M. T.
Reetz, D. Moulin, A. Gosberg, Org. Lett. 2001, 3, 4083; j) R.
Amengual, V. Michelet, J.-P. GenÞt, Synlett 2002, 1791; k) M.
Pucheault, S. Darses, J.-P. GenÞt, Tetrahedron Lett. 2002, 43,
6155; l) M. Pucheault, S. Darses, J.-P. GenÞt, Eur. J. Org. Chem.
2002, 3552; m) R. Itooka, Y. Iguchi, N. Miyaura, J. Org. Chem.
2003, 68, 6000; n) J.-G. Boiteau, R. Imbos, A. J. Minnaard, B. L.
Feringa, Org. Lett. 2003, 5, 681; J.-G. Boiteau, R. Imbos, A. J.
Minnaard, B. L. Feringa, Org. Lett. 2003, 5, 1385; o) Q. , Shi, L.
Xu, X. Li, X. Jia, R. Wang, T. T.-L. Au-Yeung, A. S. C. Chan, T.
Hayashi, R. Cao, M. Hong, Tetrahedron Lett. 2003, 44, 6505;
p) Y. Iguchi, R. Itooka, N. Miyaura, Synlett 2003, 1040; q) J.-G.
Boiteau, A. J. Minnaard, B. L. Feringa, J. Org. Chem. 2003, 68,
9481; r) Y. Ma, C. Song, C. Ma, Z. Sun, Q. Chai, M. B. Andrus,
Angew. Chem. 2003, 115, 6051; Angew. Chem. Int. Ed. 2003, 42,
5871; s) C. Defieber, J.-F. Paquin, S. Serna, E. M. Carreira, Org.
Lett. 2004, 6, 3873; t) L. Navarre, S. Darses, J.-P. GenÞt, Angew.
[14] S. Norsikian, I. Marek, S. Klein, J. F. Poisson, J. F. Normant,
Chem. Eur. J. 1999, 5, 2055; [a]2D0 = À70 (c = 1.1, Et2O).
[15] A. S. Kotnis, Tetrahedron Lett. 1990, 31, 481.
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