Construction of chiral quaternary carbon centers by Pd-catalyzed asymmetric allylic substitution with P,N-1,1′-ferrocene ligands

Article abstract of DOI:10.1021/ol048729q

(Chemical equation presented) A chiral quaternary carbon center on allyl substrates was constructed by Pd-catalyzed allylic alkylation reaction in good to high regio- and enantioselectivities for a wide range of substrates for the first time.

Full text of DOI:10.1021/ol048729q

ORGANIC
LETTERS
2
004
Vol. 6, No. 24
399-4401
Construction of Chiral Quaternary
Carbon Centers by Pd-Catalyzed
Asymmetric Allylic Substitution with
4
P,N-1,1′-Ferrocene Ligands
Xue-Long Hou*,†,‡ and Na Sun‡
State Key Laboratory of Organometallic Chemistry and Shanghai-Hong Kong Joint
Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry,
The Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China
xlhou@mail.sioc.ac.cn
Received July 5, 2004 (Revised Manuscript Received September 21, 2004)
ABSTRACT
A chiral quaternary carbon center on allyl substrates was constructed by Pd-catalyzed allylic alkylation reaction in good to high regio- and
enantioselectivities for a wide range of substrates for the first time.
Construction of a chiral quaternary carbon center by catalytic
asymmetric reactions represents a demanding and challenging
area in organic synthesis because of its great importance for
the synthesis of enantiomerically pure natural products and
reaction is a powerful tool for carbon-carbon bond forma-
tion, one of its major limitations was that the reaction of
monosubstituted allylic substrates would lead to achiral linear
3
products. Only recently, some significant progress has been
1
4,5,6h
pharmaceuticals. Several protocols to construct an all-
made by Hayashi, Pfaltz, and us,
and for some substrates
carbon-substituted chiral quaternary carbon center such as
excellent regio- and enantioselectivities were obtained.
However, to the best of our knowledge, there has been no
report on the construction of an all-carbon-substituted chiral
quaternary carbon center on an allyl substrate using Pd-
catalyzed allylic alkylation. Obviously, this is a more
challenging issue. Recently, some encouraging results have
1c
1d
1e
Diels-Alder reaction, Heck reaction, Michael addition,
and metal-catalyzed allylic alkylation2 have been well
documented. Although palladium-catalyzed allylic alkylation
†
State Key Laboratory of Organometallic Chemistry.
Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis.
‡
6
been obtained by us using novel ferrocene ligands. It was
found that high regio- and enantioselectivities were realized
(
1) Review: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed.
1
998, 37, 388. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001,
4
0, 4591. (c) Corey, E. J.; Guzman-Perez, A.; Loh, T.-P. J. Am. Chem.
Soc. 1994, 116, 3611. (d) Lebsack, A. D.; Link, J. T.; Overman, L. E.;
Stearns, B. A. J. Am. Chem. Soc. 2002, 124, 9008. (e) Sasai, H.; Emori, E.;
Arai, T.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 5561.
(3) Reviews: (a) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996,
96, 395. (b) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds. ComprehensiVe
Asymmetric Catalysis; Springer: Berlin, 1999; Vol. 2.
(4) (a) Hayashi, T.; Kawatsura, M.; Uozumi, Y. Chem. Commun. 1997,
561. (b) Hayashi, T.; Kawatsura, M.; Uozumi, Y. J. Am. Chem. Soc. 1998,
120, 1681.
(2) Examples of metal-catalyzed allylic alkylation: (a) Rh: Evans, P.
A.; Nelson, J. D. Tetrahedron Lett. 1998, 39, 1725. (b) Ir: Bartels, B.;
Helmchen, G. Chem. Commun. 1999, 741. (c) Cu: Luchaco-Cullis, C. A.;
Mizutani, H.; Murphy, K. E.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2001,
4
0, 1456. (d) Pd: Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J.
(5) (a) Pr e´ t oˆ t, R.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 323. (b)
Hilgraf, R.; Pfaltz, A. Synlett 1999, 1814.
Org. Chem. 1988, 53, 113.
1
0.1021/ol048729q CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/30/2004

in Pd-catalyzed allylic substitution reactions using newly
designed chiral P,N-1,1′-ferrocene ligands.6h Now we show
that these ligands are also useful in construction of a chiral
quaternary carbon center with high regio- and enantioselec-
tivities by palladium-catalyzed allylic alkylation after some
modification.
Table 1. Pd-Catalyzed Regio- and Enantioselective Allylic
Alkylation of 1a with Various Ligandsa
time yield
(h)
4a ee
entry
ligand
(%)b 4a/(E)-5a/(Z)-5ac (%)d
1
2
3
4
5
6
7
8
(S,Sphos,R)-6
(S,Sphos,R)-7
(S,Sphos,R)-8
(S,Sphos, R)-9
(Sphos,R)-16
(Sphos,R)-17
(Rphos,R)-17
6
89
76
96
96
92
66
56
77
90/5/5
92/8/0
74/22/4
79/5/16
59/16/25
96/4/0
49
39
38
35
24
73
49
63
The branched and linear acetates and carbonate 1a-3a
were investigated using P,N-1,1′-ferrocene ligands 7, which
have been successfully applied to Pd-catalyzed regio- and
enantioselective allylic substitution reactions of monosub-
72
20
2.5
1
19
19
e
e
6h
stituted substrates (Scheme 1). Among four diastereomers,
96/4/0
90/10/0
(S,Sphos,R)-18 16
a
Reactions of entries 1-7 were performed in CH2Cl2 at 12 °C, while
Scheme 1. Pd-Catalyzed Allylic Substitution Reaction of
that of entry 8 proceeded in ethyl ether at 25 °C, all with a molar ratio of
1
a-3a
3
[
3
Pd(η -C3H5)Cl]2/ligand/KOAc/substrate/CH2(CO2Me)2/BSA ) 2/4/6/100/
00/300. b Isolated yield based on substrate. c Determined by 300 MHz H
1
d
NMR of the crude product after preparative TLC. Determined by chiral
HPLC. e Sign of optical rotation is opposite.
On the basis of the above results, ligands (S,Sphos,R)-7-9
were screened further using substrate 1a and the results are
showed in Table 1. The most profound feature is that the
steric effect of the substituent on the oxazoline ring has great
impact on the regio- and enantioselectivities of the reaction.
When the substituent on the oxazoline ring was changed from
iso-propyl to tert-butyl, the ee value of the product decreased
from 49 to 39%, although the regioselectivity was slightly
different (entry 1 vs entry 2). The reaction gave lower regio-
and enantioselectivities when the substituent was phenyl and
benzyl (entries 3 and 4). It is interesting that the product
gave the opposite sign of optical rotation when the ligand
(
S,Sphos,R)-8 with a phenyl group as a substituent on the
ligand (S,Sphos,R)-7 gave the best regio- and enantioselectivity
using 1a as a substrate (products 4a and 5a in a ratio of
oxazoline was used (entry 3). It seemed that the decrease in
the steric hindrance of the substituent would improve the
regio- and enantioselectivities of the reaction. Thus, ligands
1
1
cedures in 44, 20, and 39% total yields, respectively (Scheme
2
phosphorus atom of (Rphos,R)-16 was determined by X-ray
diffraction analysis.
90:10 with 49% ee for 4a) because of a match of different
chiralities. Branched acetate 1a reacted faster than linear
substrates 2a and 3a using ligand (S,Sphos,R)-7. Reaction of
acetate 1a was completed within 6 h, while that of branched
acetate 2a was incomplete after 72 h and the ratio of 4a and
6-18 with structural modification were synthesized from
-bromo-1′-oxazolidinylferrocenes 10-12 using known pro-
6
h
). The absolute configuration of chiral center on the
5
a was 38:62 with 52% ee for 4a. Similar regioselectivity
was given by linear carbonate 3a (ratio of 4a and 5a was
5:65 with 54% ee for 4a). These results differed from those
8
3
6h
of monosubstituted substrates. Moreover, the stereochem-
istry of the starting allylic esters 2a and 3a was retained to
a certain extent in the alkylation products due to the “memory
Scheme 2. Synthesis of Ligands 16-18a
7
effect”.
(6) (a) Dai, L. X.; Tu, T.; You, S. L.; Deng, W. P.; Hou, X. L. Acc.
Chem. Res. 2003, 36, 659. (b) You, S.-L.; Zhou, Y.-G.; Hou, X.-L.; Dai,
L.-X. Chem. Commun. 1998, 2765. (c) Deng, W.-P.; Hou, X.-L.; Dai, L.-
X.; Yu, Y.-H.; Xia, W. Chem. Commun. 2000, 285. (d) Deng, W.-P.; Hou,
X.-L.; Dai, L.-X.; Dong, X.-W. Chem. Commun. 2000, 1483. (e) Deng,
W.-P.; You, S.-L.; Hou, X.-L.; Dai, L.-X.; Yu, Y.-H.; Xia, W. J. Am. Chem.
Soc. 2001, 123, 6508. (f) You, S.-L.; Hou, X.-L.; Dai, L.-X.; Zhu, X.-Z.
Org. Lett. 2001, 3, 149. (g) You, S.-L.; Zhu, X.-Z.; Hou, X.-L.; Dai, L.-X.
Acta Chim. Sinica 2001, 10, 1667. (h) You, S. L.; Zhu, X. Z.; Luo, Y. M.;
Hou, X. L.; Dai, L. X. J. Am. Chem. Soc. 2001, 123, 7471. (i) Tu, T.;
Deng, W.-P.; Hou, X.-L.; Dai, L.-X.; Dong, X.-C. Chem. Eur J. 2003, 9,
a
2 2
Conditions: (a) BuLi; (b) (Et N) PCl; (c) (R)-binol.
3
073. (j) Tu, T.; Zhou, Y. G.; Hou, X. L.; Dai, L. X.; Dong, X. C.; Yu, Y.
H.; Sun, J. Organometallics 2003, 22, 125. (k) Tu, T.; Hou, X. L.; Dai, L.
X. Org. Lett. 2003, 5, 3651.
(
7) (a) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1996, 118, 235. (b)
Hayashi, T.; Kawatsura, M.; Uozumi, Y. J. Am. Chem. Soc. 1998, 120,
681. (c) Lloyd-Jones, G. C. Synlett 2001, 2, 161.
Then, the role of ligands 16-18 was also investigated
using substrate 1a (Table 1). When the substituent on the
1
4400
Org. Lett., Vol. 6, No. 24, 2004

oxazoline ring was changed from iso-propyl to methyl, the
ee value of the reaction were enhanced from 49 to 63% (entry
Table 2. Pd-Catalyzed Regio- and Enantioselective Allylic
Alkylation with Ligand (Sphos,R)-17a
1
vs entry 8). Alhough the ligand (Sphos,R)-16 with no
substituent on the oxazoline ring gave lower selectivity (entry
), the ligand (Sphos,R)-17 with two methyl groups on the
temp/time yield
4 ee
4/(E)-5c (%)d
5
entry
substrate Ar
(h)
(%)b
oxazoline ring provided a much better result. The reaction
gave a regioselectivity of 96/4 in favor of 4a with 73% ee
1
2
3
4
5
6
7
8
1a phenyl
25 °C/19
25 °C/96
35 °C/24
25 °C/72
25 °C/16
25 °C/5
66
13
46
31
90
90
86
92
96/4
73
91
78
79
78
69
78
86
e
1b 1-naphthyl
1b 1-naphthy
1c 4-MeO-C6H4
1d 4-Me- C6H4
1e 4-Cl- C6H4
1f 4-CN- C H
86/14
76/24
43/57
95/5
95/5
89/11
84/16
(entry 6). These results also showed that the chirality on the
oxazoline ring might not be necessary. In addition, when
the ligand (Rphos,R)-17 with a different configuration on the
phosphorus atom was used, the configuration of the product
was reversed (entry 6 vs entry7). This result gave us a hint
that the chirality of the phosphine might determine the
configuration of the product to some extent.
e
6
4
25 °C/2
25 °C/6
1g
a
3
[
Pd(η -C3H5)Cl]2/(Sphos,R)-17/KOAc/substrate/CH2(CO2Me)2/BSA )
b
Optimization of the reaction parameters (solvent, temper-
ature, and additive) showed that the reaction carried out at
2/4/6/100/300/300. Ethyl ether was the solvent. Isolated yield based on
substrate. c Determined by 300 MHz H NMR of the crude product after
preparative TLC. d Determined by chiral HPLC. e Reaction was not com-
plete.
1
2
5 °C gave the best result and the ethyl ether was the best
solvent among those tested (CH Cl , THF, CH CN, toluene,
Et O), while KOAc is the best additive among LiOAc,
NaOAc, Bu
2
2
3
2
t
NOAc, KF, K
2
CO
3
BuCO
2
K, and PrCO
2
K.
The absolute configuration of the product 4a was deter-
mined as R through converting it into substituted succinic
4
Under the optimized conditions using ligand (Sphos,R)-17, a
wide range of substrates were tested (Scheme 3, Table 2).
acid by oxidation using NaIO
of product with NaOH/MeOH then HCl
comparing the sign of optical rotation of the product with
4 4
/KMnO followed by treatment
9
,10
and through
1
1
Scheme 3. Pd-Catalyzed Allylic Substitution Reaction of
Various Substrates 1a-g
that of the authentic sample.
In summary, good to high regio- and enantioselectivities
were realized in palladium-catalyzed allylic alkylation to
construct chiral quaternary carbon centers for a wide range
of substrates for the first time. Investigations on the reaction
mechanism and reactions using different kinds of nucleo-
philes are in progress.
Acknowledgment. Financial support from the Major
Basic Research Development Program (Grant G2000077506),
the National Natural Science Foundation of China, Chinese
Academy of Sciences, the National Outstanding Youth Fund,
and the Shanghai Committee of Science and Technology.
Na Sun gratefully acknowledges the Hong Kong Croucher
Foundation for a Studentship. We thank Professor Li Xin
Dai for inspiring discussion.
All substrates including 1g derived from R-tetralone
entries 1,2, 5-7 and 8, Table 2) provided chiral quaternary
carbon center-containing products with high regioselectivity
and good enantioselectivity, except 1c with a strong electron-
donating group MeO as a substituent at the para position of
phenyl, which gave a low regioselectivity but still good
enantioselectivity (entry 4, Table 2). The reaction of substrate
(
Supporting Information Available: Synthetic procedure
and spectral data for ligands 16-18; X-ray structural
information on compound (Rphos,R)-16 as well as its X-ray
crystallographic file (CIF); general procedure for allylic
alkylation; and spectral data for 1b-f, 4, and 5. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
b gave good selectivity (4b/(E)-5b 86/14, 91% ee, entry 2,
Table 2) but could not be completed at room temperature,
perhaps due to steric reasons. If the reaction was carried out
at 35 °C, substrate 1b was consumed after 24 h but regio-
and enantioselectivities were decreased (entry 3, Table 2).
In addition, the low yield was caused by incremental
elimination byproduct. The electronic property of the sub-
stituent had superior effects on this reaction. An electron-
withdrawing group may accelerate the reaction (entries 6 and
OL048729Q
(
9) Dawson, G. J.; Williams, J. M. J.; Coote, S. J. Tetrahedron:
Asymmetry 1995, 6, 2535.
(10) (a) Buckwalter, B. L.; Burfitt, I. R.; Felkin, H.; Joly-Goudket, M.;
Naemura, K.; Salomon, M. F.; Wenkert, E.; Wovkulich, P. M. J. Am. Chem.
Soc. 1978, 100, 6445. (b) Herz, W.; Mohanraj, S. J. Org. Chem. 1980, 45,
7
, Table 2).
5
417.
(8) See Supporting Information.
(11) Gharpure, M. M.; Rao, A. S. Synthesis 1988, 410.
Org. Lett., Vol. 6, No. 24, 2004
4401