Asymmetric construction of quaternary carbon stereocenter by Pd-hemilabile ligand-catalyzed allylic substitution

Article abstract of DOI:10.1016/j.tetlet.2007.03.065

The catalyst comprised [PdCl(η³-C₃H₅)]₂ and a simple chiral hemilabile ferrocene ligand, 1′,2-bis(diphenylphosphinoethyl)ferrocenyl alcohol, provides synthetically acceptable results for an enantioselective Pd-catalyzed allylic alkylation of cyclohexanone derivatives bearing an electron-withdrawing group at the α-position to form the quaternary carbon with up to 90% enantioselectivity under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2007.03.065

Tetrahedron Letters 48 (2007) 3389–3391
Asymmetric construction of quaternary carbon stereocenter by
Pd-hemilabile ligand-catalyzed allylic substitution
Yoshimasa Fukuda, Kazuhiro Kondo* and Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 16 February 2007; revised 6 March 2007; accepted 9 March 2007
Available online 14 March 2007
Dedicated to the memory of Professor Yoshihiko Ho, deceased on 23 December 2006
Abstract—The catalyst comprised [PdCl(g3-C3H5)]2 and a simple chiral hemilabile ferrocene ligand, 10,2-bis(diphenylphosphino-
ethyl)ferrocenyl alcohol, provides synthetically acceptable results for an enantioselective Pd-catalyzed allylic alkylation of cyclohex-
anone derivatives bearing an electron-withdrawing group at the a-position to form the quaternary carbon with up to 90%
enantioselectivity under mild reaction conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
Creating quaternary carbon centers in which the abso-
lute stereochemistry can be controlled by allylic alkyl-
At first, the Pd-catalyzed enantioselective allylic alkyl-
ation of 2-carboethoxycyclohexanone (2) with cinnamyl
acetate (1) using a variety of chiral hemilabile ligands
was examined: nonhemilabile-type BINAP, Segphos,
DIOP, Binaphane, and i-Pr-Duphos were not good li-
gands. The selected results are shown in Table 1.8 As
can be seen, among the hemilabile ligands screened, only
ligand 10 bearing an OH group exhibited good asym-
metric induction (3: 85% ee, entry 7).
ation represents
a
major challenge in organic
synthesis.1 We have quite recently constructed quater-
nary carbon stereocenters with up to 65% enantioselec-
tivity in Pd-catalyzed enantioselective intramolecular
a-arylation of N-(2-bromophenyl)-N-methyl-2-arylpro-
panamides:2 the enantioselectivity obtained is of the
good level reported in the literature.3 And we have
developed hemilabile ligands4 with both soft and hard
coordinated centers within one molecule.5 As part of
our research program in relation to the above described
methodology, we planned to construct chiral quaternary
carbon centers by enantioselective Pd-catalyzed allylic
alkylation with a hemilabile ligand. Since, in general,
enantioselective Pd-catalyzed allylic alkylations involv-
ing prochiral nucleophiles are a formidable challenge,6
we became interested in these reactions with prochiral
nucleophiles, cyclohexanone derivatives bearing an elec-
tron-withdrawing group at the a-position. We herein
would like to describe that a chiral hemilabile ligand,
Encouraged by the good results with ligand 10, the reac-
tion of several cinnamyl acetates with the cyclohexanone
derivatives bearing various a-electron-withdrawing
groups was examined (Table 2). As can be seen in all en-
tries, the reactions were completed within 30 min at rt,
affording the corresponding products in 99% yield. In
terms of enantioselectivity, the electronic effect in the
cinnamyl acetates was not observed (entry 1 vs entry
2, entry 5 vs entry 6). The acetate bearing a 1-naphthyl
group in place of a phenyl group gave good enantio-
selectivity (entries 3, 7, and 12). Among the pronucleo-
philes examined, cyclohexanone derivative 12 bearing
an a-tosyl group led to the best enantioselectivity (up
to 90% ee, entries 4–7). To the best of our knowledge,
this is the first example of Pd-catalyzed enantioselective
allylic alkylations using cyclohexanone derivative bear-
ing an a-tosyl group as a pronucleophile. And the
enantioselectivity obtained by a-nitroketone and a-dike-
tone as pronucleophiles is of the good level reported in
the literature.9 A reaction that the simple chiral hemila-
bile ferrocene 10 serves as a good ligand exhibiting good
enantioselectivity is a rare case,10,11 although many
10,2-bis(diphenylphosphinoethyl)ferrocenyl
alcohol,7
was found to serve as a good ligand for a Pd-catalyzed
enantioselective allylic alkylation of cyclohexanone
derivatives bearing an electron-withdrawing group at
the a-position.
Keywords: Asymmetric quaternary carbon; Chiral hemilabile ligand;
Enantioselective Pd-catalyzed allylic substitution.
*
Corresponding authors. Fax: +81 52 836 3439 (K.K.); e-mail
addresses: kazuk@phar.nagoya-cu.ac.jp; aoyama@phar.nagoya-cu.
ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.065

3390
Y. Fukuda et al. / Tetrahedron Letters 48 (2007) 3389–3391
Table 1. Effects of hemilabile ligandsa
O
CO2Et
O
CO2Et
2 (1.5 equiv)
*
OAc
Ph
[PdCl(η3-C3H5)]2 (2.5 mol%)
Ligand (5 mol%)
1
Ph
3
BSA (1.5 equiv), KOAc (5 mol%)
toluene, rt
Entry
Ligand
Time
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
4
5
12 h
12 h
99
99
99
99
99
99
99
51c
22 (S)
30 (S)
8 (S)
53 (S)
23 (S)
29 (S)
85 (R)
11 (S)
BPPFA (6)
7
<5 min
<5 min
<5 min
<5 min
<5 min
12 h
8
9
10
11
a K2CO3, Cs2CO3, and i-Pr2NEt in place of BSA as a base, Zn(OAc)2, and Co(OAc)2 as an additive, and other solvents such as THF, CH2Cl2, and
DMF gave less satisfactory results.
b Determined by HPLC analysis.
c Remainder of mass balance was the starting cinnamyl acetate.
O
Me
Ph
Me2N
H
Me2N
H
PPh2
PPh2
O
O
PPh2
PPh2
O
PPh2
PPh2
O
Fe
Fe
Ph2P
Ph2P
O
7
4
5
BPPFA (6)
Me
Ph
Ph
Me
AcO
H
MeO
HO
HO
H
PPh2
PPh2
PPh2
H
H
Fe
Fe
Fe
Fe
Ph2P
Ph2P
Ph2P
Ph2P
8
9
10
11
Table 2. Generality of substrate and pronucleophile
O
Pronucleophile (1.5 equiv)
[PdCl(η3-C3H5)]2 (2.5 mol%)
X
*
Ar
OAc
Ligand 10 (5 mol%)
BSA (1.5 equiv), KOAc (5 mol%)
toluene, rt
Ar
Entry
1
Pronucleophile
Time (min)
Yield (%)
99
eea (%)
OAc
Ar
Ar=
O
CO2Et
4-Cl–C6H4–
<5
83
2
2
3
4-MeO–C6H4–
1-Naphthyl
2
<5
<5
99
99
81
79
2
O
Ts
4
Ph
30
99
86
12
5
6
7
4-Cl–C6H4–
4-MeO–C6H4–
1-Naphthyl
12
20
20
30
99
99
99
85
85
90
12
12

Y. Fukuda et al. / Tetrahedron Letters 48 (2007) 3389–3391
3391
Table 2 (continued)
Entry
Pronucleophile
Time (min)
<5
Yield (%)
99
eea (%)
OAc
Ar
Ar=
O
NO2
8
Ph
77
13
9
4-MeO–C6H4–
Ph
13
<5
<5
99
99
73
74
O
O
10
14
11
12
4-Cl–C6H4–
1-Naphthyl
14
14
<5
<5
99
99
71
83
a Determined by HPLC analysis.
H.; Murakami, Y.; Aoyama, T. Synlett 2003, 2047–2051;
(c) Kondo, K.; Kazuta, K.; Saitoh, A.; Murakami, Y.
Heterocycles 2003, 59, 97–100; (d) Horibe, H.; Fukuda,
Y.; Kondo, K.; Okuno, H.; Murakami, Y.; Aoyama, T.
Tetrahedron 2004, 60, 10701–10709; (e) Suzuki, K.; Ishii,
S.; Kondo, K.; Aoyama, T. Synlett 2006, 648–650; (f)
Arao, T.; Suzuki, K.; Kondo, K.; Aoyama, T. Synthesis
2006, 3809–3814.
examples using highly tuned and functionalized ferro-
cene ligands have been reported.9
In summary, we have shown that a simple chiral
hemilabile ferrocene ligand is efficient in forming a chi-
ral quaternary carbon center12 by an enantioselective
Pd-catalyzed allylic alkylation of cyclohexanone deriva-
tives bearing an a-electron-withdrawing group. Devel-
opment and research of hemilabile ligands are now in
progress for constructing chiral quaternary carbon
centers.
6. For successful examples (>90% ee), see: (a) Sawamura,
M.; Sudoh, M.; Ito, Y. J. Am. Chem. Soc. 1996, 118, 3309–
3310; (b) Trost, B. M.; Radinov, R.; Grenzer, E. M. J.
Am. Chem. Soc. 1997, 119, 7879–7880; (c) Nemoto, T.;
Matsumoto, T.; Masuda, T.; Hitomi, T.; Hatano, K.;
Hamada, Y. J. Am. Chem. Soc. 2004, 126, 3690–3691.
7. Hayashi, T.; Mise, T.; Kumada, M. Tetrahedron Lett.
1976, 4351–4354.
Acknowledgments
8. Ligand 5, 8, and 9 are new compounds.
We thank the Ministry of Education, Culture, Sports,
Science and Technology, Japan for support. K.K. was
financially supported by the Takeda Science Founda-
tion. We are grateful to Takasago International Corpo-
ration for gifts of BINAP and SEGPHOS derivatives.
9. For a review, see: (a) Sawamura, M.; Ito, Y. Chem. Rev.
1992, 92, 857–871; For selected examples, see: (b) Hayashi,
T.; Yamamoto, A.; Ito, Y. Chem. Lett. 1987, 177–180; (c)
Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M.
J. Org. Chem. 1988, 53, 113–120; (d) Sawamura, M.;
Nagata, H.; Sakamoto, H.; Ito, Y. J. Am. Chem. Soc.
1992, 114, 2586–2592; (e) Sawamura, M.; Nakayama, Y.;
Tang, W.-M.; Ito, Y. J. Org. Chem. 1996, 61, 9090–9096;
(f) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito,
Y. J. Am. Chem. Soc. 2000, 122, 7614–7615.
10. (a) For successful examples, see: Ref. 7; (b) Nukui, S.;
Sodeoka, M.; Shibasaki, M. Tetrahedron Lett. 1993, 34,
4965–4968.
11. The Pd-10-catalyzed asymmetric allylic alkylation of
allylacetate with b-diketone has been reported by Hayashi,
but the enantioselectivity was 30%: Hayashi, T.; Kanehira,
K.; Hagihara, T.; Kumada, M. J. Org. Chem. 1988, 53,
113–120.
References and notes
1. (a) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1–14; (b)
Trost, B. M.; Lee, C. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; Wiely-VCH: New York, 2000; pp 593–649.
2. (a) Arao, T.; Kondo, K.; Aoyama, T. Tetrahedron Lett.
2006, 47, 1417–1420; (b) Arao, T.; Satoh, K.; Kondo, K.;
Aoyama, T. Chem. Pharm. Bull. 2006, 54, 1743–1744; (c)
Arao, T.; Sato, K.; Kondo, K.; Aoyama, T. Chem. Pharm.
Bull. 2006, 47, 1576–1581.
3. (a) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402–
3415; (b) Glorius, F.; Altenhoff, G.; Goddard, R.;
Lehmann, C. Chem. Commun. 2002, 2704–2705.
4. For the definition of hemilabile ligands, see: Braunstein,
P.; Naud, F. Angew. Chem., Int. Ed. 2001, 40, 680–699.
5. (a) Kondo, K.; Kazuta, K.; Fujita, H.; Sakamoto, Y.;
Murakami, Y. Tetrahedron 2002, 58, 5209–5214; (b)
Horibe, H.; Kazuta, K.; Kotoku, M.; Kondo, K.; Okuno,
12. For successful examples of constructing a quaternary
carbon stereo center by other asymmetric allylic alkyl-
ations: (a) Trost, B. M.; Xu, J.; Reichle, M. J. Am. Chem.
Soc. 2007, 129, 282–283; (b) Trost, B. M.; Xu, J. J. Am.
Chem. Soc. 2005, 127, 2846–2847; (c) Behenna, D. C.;
Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044–
15045.