Multinuclear Pd/Zn complex-catalyzed asymmetric alkylative ring-opening reaction of oxabicyclic alkenes

Article abstract of DOI:10.1021/ol102928q

A multinuclear palladium catalyst can be used to realize the efficient catalytic asymmetric alkylative ring-opening reaction of oxabicyclic alkenes using dimethylzinc. The use of (R)-BINOL-PHOS bearing bisphosphine and diol moieties is essential for achieving excellent catalytic performance; the corresponding monophosphine and hydroxy-protected derivatives showed lower catalytic activities and/or enantioselectivities. The generation of Pd/Zn-multinuclear complexes is a key feature of the present catalysis.(Figure Presented)

Full text of DOI:10.1021/ol102928q

ORGANIC
LETTERS
2
011
Vol. 13, No. 5
68–871
Multinuclear Pd/Zn Complex-Catalyzed
Asymmetric Alkylative Ring-Opening
Reaction of Oxabicyclic Alkenes
8
,
†
‡
‡
Kohei Endo,* Keisuke Tanaka, Mika Ogawa, and Takanori Shibata*
,‡
Waseda Institute for Advanced Study, Shinjuku, Tokyo, 169-8050, Japan, and
Department of Chemistry and Biochemistry, School of Advanced Science and
Engineering, Waseda University, Shinjuku, Tokyo, 169-8555, Japan
kendo@aoni.waseda.jp; tshibata@waseda.jp
Received December 3, 2010
ABSTRACT
A multinuclear palladium catalyst can be used to realize the efficient catalytic asymmetric alkylative ring-opening reaction of oxabicyclic
alkenes using dimethylzinc. The use of (R)-BINOL-PHOS bearing bisphosphine and diol moieties is essential for achieving excellent catalytic
performance; the corresponding monophosphine and hydroxy-protected derivatives showed lower catalytic activities and/or enantioselectivities.
The generation of Pd/Zn-multinuclear complexes is a key feature of the present catalysis.
2
The development of a multimetallic synergism contri-
butes to new catalyst design as a novel and remarkably
1
enhanced catalytic approach in organic chemistry. We
enones. The incorporation of Cu and Zn atoms in the
catalyst was confirmed by ESI-MS analyses and was
fundamental for the excellent catalytic performance. The
present paper describes the asymmetric alkylative ring-
opening reaction of oxabicyclic alkenes. As part of our
ongoing studies on a new combination of transition metals
and main group metals, we discovered that Pd and Zn
atoms have cooperative effects in the catalyst (Figure 1).
Our strategy using BINOL-PHOS ligands could be used to
generate Zn-linked ligands with dialkylzinc reagents, the
phosphorus moieties of which coordinate to Pd centers to
form multinuclear complexes. There have been several
reports on asymmetric alkylative ring-opening reactions
using Pd catalyst, which can be used to achieve the highly
enantioselective synthesis of optically active alcohols bear-
previously reported the BINOL scaffold for the generation
of multinuclear complexes and achieved excellent catalytic
performance in the Cu-catalyzed asymmetric conjugate
addition of organozinc reagents to acyclic and cyclic
†
Waseda Institute for Advanced Study.
Waseda University.
‡
(
1) (a) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187. (b)
Majima, K.; Takita, R.; Okada, A.; Oshima, T.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 15837. (c) Matsunaga, S.; Yoshida, T.; Morimoto,
H.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8777. (d)
Takacs, J. M.; Reddy, D. S.; Moteki, S. A.; Wu, D.; Palencia, H. J. Am.
Chem. Soc. 2004, 126, 4494. (e) Shibasaki, M.; Matsunaga, S. Chem.
Soc. Rev. 2006, 35, 269. (f) Chen, Z.; Morimoto, H.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170. (g) Trost, B. M.;
M
3
,4
u€ ller, C. J. Am. Chem. Soc. 2008, 130, 2438. (h) Shibasaki, M.; Kanai,
ing contiguous chiral centers. We describe here a multi-
nuclear catalysis including Pd and Zn atoms for highly
efficient asymmetric alkylative ring-opening reactions
using organozinc reagents (Figure 2). The previously
M.; Matsunaga, S.; Kumagai, N. Acc. Chem. Res. 2009, 42, 1117 and
references therein.
(2) Endo, K.; Ogawa, M.; Shibata, T. Angew. Chem., Int. Ed. 2010,
9, 2410.
4
1
0.1021/ol102928q r 2011 American Chemical Society
Published on Web 01/24/2011

Table 1. Screening of Reaction Conditions
a,b
c
entry
Pd salt
solvent
time (h) yield, ee (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)
2
THF (0.1)
THF (0.1)
THF (0.1)
THF (0.1)
THF (0.1)
24
24
24
24
24
24
24
24
24
24
16
24
20
8
48, 56
51, 57
42, 54
23, 47
-
2 3 2
PdCl (CH CN)
Pd(TFA)
[Pd(allyl)Cl]
2
2
Pd
2
dba
3
3 CHCl3
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
Et O (0.1)
-
DCM (0.1)
DCE (0.1)
63, 85
49, 10
63, 97
70, 97
93, 97
-
Figure 1. Design of multi-Pd/Zn-complexes.
toluene (0.1)
toluene (0.2)
toluene (0.5)
toluene (0.5)
THF (0.5)
10
reported ligands are expensive and somewhat difficult to
synthesize; thus, a simple procedure for the synthesis of
11
Pd(OAc)
2
d
d
d
d
d
d
d
12
13
Pd(OAc)2
(
R)-BINOL-PHOS (BP1) (3 steps without column chro-
matography, 65% yield from inexpensive (R)-BINOL)
Pd(OAc)
Pd(OAc)
2
2
47, 64
66, 69
88, 69
86, 60
-
14
dioxane (0.5)
DCM (0.5)
DCE (0.5)
2,5
15
Pd(OAc)2
8
could broaden the utility of the present catalysis.
1
1
1
6
7
8
Pd(OAc)
Pd(OAc)
2
2
8
DMF (0.5)
DCM (0.5)
20
24
2
PdCl (CH
3
CN)
2
85, 59
a
b
The concentration of 1a is in parentheses. DCM, dichloro-
methane; DCE, 1,2-dichloroethane; DMF, N,N-dimethylformamide.
NMR yields. The enantiomeric excess was determined by chiral HPLC
(5 mol %) was added.
c
d
analyses (see Supporting Information). Zn(OTf)
2
screening of Pd(II) salts showed the comparable enantio-
selectivities (entries 2-4); however, Pd(0) precursor did
not work at all (entry 5). Thus, Pd(OAc) was used as the
2
catalyst precursor for the subsequent screening of solvents.
Further examination showed that toluene could be used to
achieve excellent ee (entry 9). A higher concentration of 1a
in toluene improved the yield of product; 0.5 M gave the
best results, and the product 2a was obtained in 93% yield
with 97% ee (entry 11). To improve the reaction rate, the
use of PdCl (CH CN) or Pd(OAc) in the presence of a
2
3
2
2
e,6
4
Zn(OTf)2 system was examined.
reaction with Zn(OTf) in toluene did not proceed at all
Unexpectedly, the
2
(entry 12). Although the reaction in THF, dioxane, DCM,
or DCE proceeded, the yield and enantioselectivity were
4c,d
lower than those in entry 11 (entries 13-16). The reaction
(
4) (a) Lautens, M.; Renaud, J.-L.; Hiebert, S. J. Am. Chem. Soc.
Figure 2. Representative ligands for Pd-catalyzed asymmetric
alkylative ring opening of oxabicyclic alkenes.
2
000, 122, 1804. (b) Lautens, M.; Hiebert, S.; Renaud, J.-L. Org. Lett.
2000, 2, 1971. (c) Lautens, M.; Hiebert, S.; Renaud, J.-L. J. Am. Chem.
Soc. 2001, 123, 6834. (d) Priego, J.; Manche n~ o, O. G.; Cabrera, S.;
Array ꢀa s, R. G.; Llamas, T.; Carretero, J. C. Chem. Commun. 2002, 2512.
The initial screening of reaction conditions is described
in Table 1. The reaction of oxanorbornadiene 1a and
Me Zn (1.5 equiv) was carried out in the presence of Pd
2
salt (5 mol %) and (R)-BINOL-PHOS (BP1) (5 mol %) at
room temperature. The use of THF as a solvent gave the
product 2a in 48% yield with 56% ee (entry 1). The
(
e) Lautens, M.; Hiebert, S. J. Am. Chem. Soc. 2004, 126, 1437. (f) Dotta,
P.; Kumar, P. G. A.; Pregosin, P. S.; Albinati, A.; Rizzato, S. Organo-
metallics 2004, 23, 2295. (g) Cabrera, S.; Array ꢀa s, R. G.; Carretero, J. C.
Angew. Chem., Int. Ed. 2004, 43, 3944. (h) Imamoto, T.; Sugita, K.;
Yoshida, K. J. Am. Chem. Soc. 2005, 127, 11934. (i) Cabrera, S.;
Arrayas, R. G.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 2005,
27, 17938. (j) Imamoto, T.; Kumada, A.; Yoshida, K. Chem. Lett. 2007,
6, 500. (k) Imamoto, T.; Saitoh, Y.; Koide, A.; Ogura, T.; Yoshida, K.
ꢀ
1
3
Angew. Chem., Int. Ed. 2007, 46, 8636. (l) Ogura, T.; Yoshida, K.;
Yanagisawa, A.; Imamoto, T. Org. Lett. 2009, 11, 2245.
(5) (R)-BINOL (>99.0% ee) was purchased from Fuji Molecular
Planning Co., Ltd. at JPY50,000/500 g.
(
3) For reviews, see: (a) Lautens, M. Synlett 1993, 177. (b) Chiu, P.;
Lautens, M. Top. Curr. Chem. 1997, 190, 1. (c) Lautens, M.; Fagnou, K.;
Hiebert, S. Acc. Chem. Res. 2003, 36, 48.
Org. Lett., Vol. 13, No. 5, 2011
869

bisphosphine and diols in (R)-BINOL-PHOS (BP1) are
important for realizing excellent catalytic activity and
enantioselectivity.
Scheme 1. Effect of Ligand
In our previous report, ESI-MS analyses of Zn- and Cu/
Zn-complexes derived from BP1 showed the existence of a
2
Zn -complex and Cu /Zn -complex. Thus, ESI-MS ana-
2
2
2
lyses were performed for the corresponding Pd/Zn-com-
plexes derived from BP1. Part of the spectrum is shown in
Figure 3 (see the Supporting Information for the large
spectrum). The peak found in the spectrum indicated the
generation of Pd/Zn-multinuclear complex, the isotope dis-
tribution pattern of which was very complicated and unclear.
Uncharacterized peaks around m/z 1500 were observed, and
a major peak in the range of m/z 2000-4000 for m/z 3170.5
þ
seems to be [Pd Zn (BP1-2H) (dba) ] (exact mass 3168.3)
3
3
3
3
derived from Pd precursor. In this context, the multicationic
2þ
complexes, such as [Pd Zn (BP1-2H) (dba) ] and others,
6
6
6
6
could be possible. Although we could not determine the
Table 2. Scope of Oxanorbornadienes
Figure 3. ESI-MS analysis of Pd/Zn-complex derived from BP1.
in DMF did not proceed (entry 17). The enantioselectivity
with the use of PdCl (CH CN) was less than that with
Pd(OAc) (entry 18).
2
3
2
2
The choice of ligand was important. Scheme 1 presents
the excellent performance of (R)-BINOL-PHOS (BP1)
with regard to catalytic activity and stereoselectivity. The
reaction in the presence of monophosphine BP2 was not
complete even after 24 h and gave the product 2a in 39%
yield with a reduced enantioselectivity of 89% ee. The
methoxy methyl-protected ligand BP3 required a longer
reaction time to give the corresponding product 2a in
2
7% yield with 24% ee. These results clarified that the
(
6) The use of Et
catalytic activity and stereoselectivity. The reaction of 1a with Et
under the optimized conditions for Me Zn gave a trace amount of
desired product; the reductive ring-opening product formed. In contrast,
the reaction in the presence of PdCl (CH CN) (5 mol %), BP1 (5 mol
), and Zn(OTf) (5 mol %) gave the desired product in 48% yield with
7% ee. The use of mixed reagents, Et Zn (1.5 equiv) and Me Zn (1.5
2
Zn or n-Bu
2
Zn instead of Me
2
Zn diminished the
2
Zn
2
a
2
Me Zn (1.5 equiv in entry 1; 3 equiv in entries 2, 3, 5, 6, and 7; 5
b
2
3
2
equiv in entries 4, 8, and 9) was used. Isolated yields. The enantiomeric
excess was determined by chiral HPLC analyses (see Supporting
Information). Absolute configuration was not determined. A toluene
%
1
2
2
2
c
d
equiv), under the same reaction conditions gave the ethylated product
exclusively in 31% yield with 44% ee. Furthermore, the reaction using
Et Zn (3 equiv) gave the product in 21% yield with 13% ee. The details
e
solution of 1 M Me
2
Zn (3 equiv) was used. A hexane solution of 1 M
Me Zn (3 equiv) was used.
2
2
are under examination.
8
70
Org. Lett., Vol. 13, No. 5, 2011

exact structures of the active complexes, we confirmed that
the complex included multi-Pd and -Zn atoms.
In conclusion, we have demonstrated an efficient Pd-
catalyzed asymmetric alkylative ring-opening reaction using
the readily accessible BINOL-PHOS ligand. The incorpora-
tion of bisphosphine and diols definitely enhanced both the
catalytic activity and the stereoselectivity. Therefore, Pd/
Zn-multimetallic synergism based on our originally devel-
oped BINOL-PHOS plays an important role in the present
reactions. The further modification of ligand architectures
to achieve a pliable catalyst system for metal-catalyzed
asymmetric reactions is underway in our laboratory.
Various types of substituted oxanorbornadienes can be
used for the present asymmetric alkylative ring-opening
reaction (Table 2). Since an excess amount of Me Zn
2
improved the yields and enantioselectivities in the reaction
of substituted oxanorbornadienes, 3-5 equiv of Me Zn
2
was used. Thereactions of 5,8-disubstitutedcompounds1b
and 1c gave the corresponding alcohols 2b and 2c, respec-
tively, in high to excellent yields with excellent enantio-
selectivities (entries 2 and 3). The use of a 1 M solution of
Me Zn in toluene diminished the yield of product 2c to
2
Acknowledgment. This work was financially supported
by Grant-in-Aid for Young Scientists (B) (No. 21750108)
from the Japan Society for the Promotion of Science, The
Kurata Memorial Hitachi Science and Technology Foun-
dation, and Waseda University Grant for Special Research
Project. K.E. thanks the Society of Synthetic Organic
Chemistry, Japan for a Teijin Pharma Award.
2
1% with 89% ee; thus, the co-presence of hexane seems to
7
be favorable. In contrast, the reaction using 5,8-difluoro
compound 1d gave 2d in low yield, albeit with high
enantioselectivity (entry 4). The electronic effects are gen-
erally inconsequential in other cases. The reactions of 6,7-
disubstituted compounds 1e-h gave the corresponding
products 2e-h in excellent yields with excellent enantioselec-
tivities (entries 5-8). Furthermore, the reaction of 5,6,7,8-
tetrasubstituted oxabicyclic alkene 1i gave the corresponding
product 2i in 83% yield with 97% ee (entry 9).
Supporting Information Available. Experimental pro-
cedure and HPLC analyses of the racemic and chiral
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(
7) Almost no reaction occurred in a single solvent of hexane.
Org. Lett., Vol. 13, No. 5, 2011
871