Catalytic enantioselective meso-epoxide ring opening reaction with phenolic oxygen nucleophile promoted by gallium heterobimetallic multifunctional complexes

Article abstract of DOI:10.1021/ja993650f

The catalytic enantioselective meso-epoxide ring opening reaction with phenolic oxygen nucleophile (4-methoxyphenol) is described for the first time herein. This reaction was first found to be promoted by (R)-GaLB (Ga = gallium, L = lithium, B = (R)-BINOL), giving a variety of epoxide opening products in good to high ee (67-93% ee). However, chemical yield was only modest (yield 31-75%), despite the use of more than 20 mol % GaLB. This was due to the undesired ligand exchange between BINOL and 4-methoxyphenol, which resulted in the decomplexation of GaLB. Application of various known chiral ligands such as 6,6'-bis((triethylsilyl)ethynyl)-BINOL and H₈-BINOL were examined, but satisfactory results were not obtained. To overcome this problem a novel linked-BINOL containing coordinative oxygen atom in the linker has been developed. By linking two BINOL units in GaLB, the stability of the Ga-complex was greatly improved. Using 3-10 mol % (R,R)-Ga-Li-linked- BINOL complex, a variety of epoxide opening reactions were found to proceed smoothly, affording products in analogous ee (66-96% ee) and in much higher yield (yield 67-94%) compared to (R)-GaLB. The structure of the LiCl free Ga- Li-linked-BINOL complex was elucidated by X-ray analysis. This is the first X-ray data for an asymmetric catalyst containing gallium. The possible mechanism of the entitled reaction is also discussed, based on the X-ray structure of the Ga-complex.

Full text of DOI:10.1021/ja993650f

2252
J. Am. Chem. Soc. 2000, 122, 2252-2260
Catalytic Enantioselective meso-Epoxide Ring Opening Reaction with
Phenolic Oxygen Nucleophile Promoted by Gallium Heterobimetallic
Multifunctional Complexes
Shigeki Matsunaga,† Jagattaran Das,† Jochen Roels,† Erasmus M. Vogl,†
Noriyoshi Yamamoto,† Takehiko Iida,† Kentaro Yamaguchi,‡ and Masakatsu Shibasaki*,†
Contribution from the Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and Chemical Analysis Center, Chiba UniVersity Yayoicho,
Inage-ku, Chiba-shi 263-0022, Japan
ReceiVed October 12, 1999
Abstract: The catalytic enantioselective meso-epoxide ring opening reaction with phenolic oxygen nucleophile
(4-methoxyphenol) is described for the first time herein. This reaction was first found to be promoted by
(R)-GaLB (Ga ) gallium, L ) lithium, B ) (R)-BINOL), giving a variety of epoxide opening products in
good to high ee (67-93% ee). However, chemical yield was only modest (yield 31-75%), despite the use of
more than 20 mol % GaLB. This was due to the undesired ligand exchange between BINOL and
4-methoxyphenol, which resulted in the decomplexation of GaLB. Application of various known chiral ligands
such as 6,6′-bis((triethylsilyl)ethynyl)-BINOL and H8-BINOL were examined, but satisfactory results were
not obtained. To overcome this problem a novel linked-BINOL containing coordinative oxygen atom in the
linker has been developed. By linking two BINOL units in GaLB, the stability of the Ga-complex was greatly
improved. Using 3-10 mol % (R,R)-Ga-Li-linked-BINOL complex, a variety of epoxide opening reactions
were found to proceed smoothly, affording products in analogous ee (66-96% ee) and in much higher yield
(yield 67-94%) compared to (R)-GaLB. The structure of the LiCl free Ga-Li-linked-BINOL complex was
elucidated by X-ray analysis. This is the first X-ray data for an asymmetric catalyst containing gallium. The
possible mechanism of the entitled reaction is also discussed, based on the X-ray structure of the Ga-complex.
Introduction
The catalytic enantioselective meso-epoxide ring opening
reaction is an attractive method in asymmetric synthesis,1 since
it simultaneously constructs two contiguous stereogenic centers.
A few years ago, we reported an asymmetric epoxide ring
opening reaction with tBuSH catalyzed by a Ga-Li-bis(binaph-
thoxide) complex (1: GaLB, Figure 1) in up to 90% yield and
97% ee.2a Recently several chiral asymmetric catalyst systems
have been reported which promote enantioselective meso-
epoxide ring opening in high enantiomeric excess utilizing
various nucleophiles, such as trialkylsilyl azide,3 trimethylsilyl
cyanide,4 aryllithium,5 halides,6 and alkylamine.7 Oxygen nu-
Figure 1. Proposed structure of (R)-Ga-Li-bis(binaphthoxide) (GaLB,
1) and (R)-Ga-Li-bis((6,6′-bis(triethylsilyl)ethynyl)binaphthoxide) (GaLB*,
15).
cleophiles such as alcohols, phenols, and carboxylic acids can
also be the candidates for this type of reactions. The enanti-
oselective epoxide opening reactions with such oxygen nucleo-
philes are very useful methods to provide valuable chiral
building blocks such as 1,2-diol derivatives.8 Quite recently
Jacobsen et al. reported excellent kinetic resolutions of racemic
terminal epoxides with water9,10b and phenols10 by using a
† The University of Tokyo.
‡ Chiba University.
(1) Review: (a) Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron
1996, 52, 14361. (b) Willis, M. C. J. Chem. Soc., Perkin Trans 1 1999,
1765.
(2) (a) Iida, T.; Yamamoto, N.; Sasai, H.; Shibasaki, M. J. Am. Chem.
Soc. 1997, 119, 4783. This reaction was used in the synthesis of a useful
chiral phosphinite, sulfur ligand, see: (b) Evans, D. A.; Campos, K. R.;
Tedrow, J. S.; Michael, F. E.; Gagne´, M. R. J. Org. Chem. 1999, 64, 2994.
(3) (a) Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768. For
mechanistic study by Nugent: (b) McCleland, B. W.; Nugent, W. A.; Finn,
M. G. J. Org. Chem. 1998, 63, 6656. (c) Martinez, L. E.; Leighton, J. L.;
Carsten, D. H.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5897. For
mechanistic studies by Jacobsen: (d) Hansen, H. B.; Leighton, J. L.;
Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 10924. (e) Konsler, R. G.;
Jo¨rn, K.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 10780.
(4) (a) Cole, B. M.; Shimizu, K. D.; Krueger, C. A.; Harrity, J. P. A.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1996, 35,
1668. (b) Shimizu, K. D.; Cole, B. M.; Krueger, C. A.; Kuntz, K. W.;
Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed. Engl. 1997, 36,
1704.
(5) Oguni, N.; Miyagi, Y.; Itoh, K. Tetrahedtron Lett. 1998, 39, 9023.
(6) (a) Nugent, W. A. J. Am. Chem. Soc. 1998, 120, 7139. (b) Denmark,
S. E.; Barsanti, P. A.; Wong, K.-T.; Stavenger, R. A. J. Org. Chem. 1998,
63, 2428.
(7) Sagawa, S.; Abe, H.; Hase, Y.; Inaba, T. J. Org. Chem. 1999, 64,
4962.
(8) For an alternative approach to the synthesis of optically active 1,2-
diols by the catalytic asymmetric dihydroxylations of olefins, which was
realized by Sharpless, K. B., et al., see: Kolb, H. C.; VanNieuwenhze, M.
S.; Sharpless K. B. Chem. ReV. 1994, 94, 2483.
(9) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 277, 936.
(10) (a) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121,
6086. (b) Annis, D. A.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 4147.
10.1021/ja993650f CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/26/2000

meso-Epoxide Ring Opening Reaction
J. Am. Chem. Soc., Vol. 122, No. 10, 2000 2253
Table 1. Enantioselective Ring Opening of Various meso-Epoxides
with 4-Methoxyphenol (2) Promoted by GaLB
Scheme 1. Working Model for the Ring Opening of
Cyclohexene Oxide with t-BuSH Catalyzed by GaLB (1)
(salen)-Co catalyst. The (salen)-Co catalyst was also utilized
for the enantioselective ring opening of meso-epoxides with
carboxylic acid.11 However, in the latter case the (salen)-Co
catalyst left room to be improved in terms of substrate
generalitysonly 2 meso-epoxides were ring-opened in high
enantiomeric excess and others in moderate (<80%) ee’s. So
development of practical methods for the asymmetric ring
opening of meso-epoxides with oxygen nucleophiles has been
well desired.12 The key issue to achieve this type of reaction is
how to overcome the normal poor reactivity of oxygen nucleo-
philes toward epoxides. From the analogy of our and other
groups’ works, the activation of both epoxides and nucleophiles
seems to be very important to obtain products in good yield
and ee.2a,3,6a,9,10,12 We speculated that it might be possible to
develop the catalytic enantioselective meso-epoxide ring opening
reactions with oxygen nucleophiles by using heterobimetallic
multifunctional catalysts13 in a similar manner as with tBuSH.
A proposed working model for the GaLB catalyzed epoxide
opening reaction with tBuSH is shown in Scheme 1. We believe
that gallium center metal would act as a Lewis acid and activate
epoxides (I), while at the same time, the lithium binaphthoxide
moiety would function as a Brønsted base to activate tBuSH
(II). Activated nucleophile would then react with epoxide to
give III. Proton exchange between gallium alkoxide and an
aromatic hydroxyproton leads to the epoxide opening adduct
and regeneration of catalyst. Considering the Brønsted basicity
of the alkali-metal binaphthoxide moiety in the heterobimetallic
complex (pKa value of BINOL ) ∼10), phenolic oxygen
nucleophiles (pKa value of 4-methoxyphenol ) 10.2) might also
be activated to react with epoxides in a similar catalytic cycle
as tBuSH (pKa value of tBuSH ) 10.6). Herein we report an
efficient catalytic enantioselective ring opening of various meso-
epoxides with 4-methoxyphenol promoted by gallium hetero-
bimetallic catalysts. These systems afforded optically actiVe 1,2-
diol monoethers with broad generality in up to 94% yield and
in up to 96% ee.
a Isolated yield. b Determined by HPLC analysis. c GaLB* (20 mol
%) was used. d No reaction. e R1 ) CH2OSiPh2tBu. f 30 mol % catalyst
was used. Mts ) 2,4,6-trimethylbenzenesulfonyl.
Results and Discussion
A. Catalytic Enantioselective Epoxide Ring Opening
Reaction with 4-Methoxyphenol Promoted by Gallium
Heterobimetallic Complexes. As phenolic oxygen nucleophile,
we chose 4-methoxyphenol (2) because the corresponding 1,2-
diol monoether adducts can be converted easily into 1,2-diols.14
However, in general, reactions of epoxides with oxygen
nucleophiles are rather difficult, and therefore the epoxide ring
opening with phenolic oxygen nucleophiles is quite challenging.
In fact, the reaction of cyclohexene oxide (3) with 4-methoxy-
phenol (2) using catalytic and/or stoichiometric amounts of
BuLi, NaOtBu, KOtBu, K2CO3, and Cs2CO3 at 50 °C did not
proceed at all. Similarly Lewis acids such as BF3‚Et2O or ZnCl2
were also ineffective for this reaction. After several attempts
we found that the reaction proceeded by using ZnCl2 (2 equiv;
Lewis acid) and Et3N (5 equiv; Brønsted base) at the same time,
although chemical yield was only 6% after 23 h. These results
are quite consistent with our initial assumption that dual
activation of both substrates is very important.
(11) Jacobsen, E. N.; Kakiuchi, F.; Konsler, R. G.; Larrow, J. F.;
Tokunaga, M. Tetrahedtron Lett. 1997, 38, 773.
(12) Quite recently Jacobsen reported an asymmetric intramolecular
cyclization of meso-epoxy alcohol using the (salen) Co catalyst. Wu, M.
H.; Hansen, K. B.; Jacobsen, E. N. Angew. Chem., Int. Ed. Engl. 1999, 38,
2012.
(13) For review, see: (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 6, 1236. (b) Steinhagen, H.; Helmchen, G. Angew.
Chem., Int. Ed. Engl. 1996, 35, 5, 2339. For recent representative examples,
see: (c) Arai, T.; Sasai, H.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem.
Soc. 1998, 120, 441. (d) Gro¨ger, H.; Saida, Y.; Sasai, H.; Yamaguchi, K.;
Martens, J.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 3089. (e) Emori,
E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043.
(f) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J.
Am. Chem. Soc. 1999, 121, 4168.
Encouraged by the results mentioned above, we next exam-
ined the epoxide opening reaction with 4-methoxyphenol using
(R)-GaLB which was effective in the thiol case. We were
pleased to find that the reaction of 3 with 2 proceeded in the
presence of (R)-GaLB (20 mol %) and MS 4A (toluene, 50 °C)
to afford 1,2-diol monoether 9 in 48% yield and in 93% ee
(Table 1, entry 1). GaLB catalyst was applicable to several
(14) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991; p 46.

2254 J. Am. Chem. Soc., Vol. 122, No. 10, 2000
Matsunaga et al.
Scheme 2. Preparation of Ga-Na-bis(H8-binaphthoxide)
unfuntionalized and funtionalized meso-epoxides affording
products in good to high ee (67-93% ee), although chemical
yields were only modest (31-75% yield). The results are
summarized in Table 1 (entries 1 and 5-9). The addition of
MS 4A, which might assist the dissociation of products from
the catalyst, was extremely effective in enhancing the reaction
rate. The reaction of cyclohexene oxide in the absence of MS
4A afforded product 9 in only 5% yield but in 95% ee.15
The GaLB catalyzed epoxide ring opening gave products in
good to excellent ee’s, but chemical yield was only modest
despite the use of more than 20 mol % catalyst. Attempts to
increase the reactivity of GaLB by using more equivalents of
4-methoxyphenol (2) or by heating the reaction mixture at higher
temperature failed. When 2.4 mol equiv of 2 was used, both
chemical yield and ee of 9 decreased (yield 41%, 86% ee, Table
1, entry 2). In the presence of 5.0 mol equiv of 2, the reaction
did not proceed at all (entry 3). Even at higher temperature (85
°C) chemical yield was still moderate and ee decreased (yield
52%, 76% ee, entry 4). These results can probably be attributed
to an undesired ligand exchange between BINOL and 4-meth-
oxyphenol (2), resulting in the decomplexation of the GaLB
and the formation of unavoidable side products.16 So preparation
of a more stable gallium heterobimetallic complex seemed to
be the solution to this problem. Therefore we started to examine
various modified BINOLs as chiral ligands. After several
attempts,17 we found that the use of GaLB* (Figure 1, 15), which
was prepared from (R)-6,6′-bis((triethylsilyl)ethynyl)binaphthol,
slightly improved the yield of the ring opening of 3 (60% yield)
without loss in enantiomeric excess (94% ee) (Table 1, entry 1
in parentheses).19 This may be due to the higher stability of
GaLB* with respect to ligand exchange than that of GaLB.
However, this GaLB* complex was also not stable enough to
suppress the undesired ligand exchange completely, and so the
use of as much as 20 mol % catalyst was needed to obtain
products in acceptable yield.
(GaSO, 16)
Table 2. Enantioselective Ring Opening of Various meso-Epoxides
with 4-Methoxyphenol (2) Promoted by Ga-Na-bis(H8-binaphthox-
ide) (GaSO)
To develop more efficient catalysts, we then prepared a
number of new gallium complexes with various known chiral
ligands.20 Among those, the gallium complexes prepared from
(R)-5,5′,6,6′,7,7′,8,8′-octahydro-BINOL (H8-BINOL)24 showed
much higher catalytic activities for the present reaction. The
proposed structure of the Ga-Na-bis(H8-binaphthoxide) complex
(16: GaSO) is shown in Scheme 2. The reaction of 3 with 2
catalyzed by GaSO proceeded smoothly in toluene at 50 °C in
a Isolated yield. b Determined by HPLC analysis. c R1 ) CH2OSi-
Ph2tBu. d 30 mol % catalyst was used. Mts ) 2,4,6-trimethylbenzene-
sulfonyl.
only 4 h to afford 9 (73% yield), albeit in modest ee (56% ee).
A wide range of meso-epoxides could be subjected to GaSO
catalyzed ring opening with 2 to give products in good to
excellent yields (except entry 6, Table 2) although the enanti-
oselectivities were only modest (34-58% ee). The results are
summarized in Table 2. In contrast to heterobimetallic gallium
binaphthoxide complex (GaLB), sodium was the most suitable
alkali metal to make the heterobimetallic gallium H8-binaph-
thoxide complex effective.25 It seems likely that different Ga-O
bond lengths account for the observed alkali metal ion effects.
Furthermore GaSO and GaLB catalysts seem to be equipped
with characteristic dihedral angles of the axial biaryl groups.26
Difference in dihedral angles between H8-BINOL and BINOL
may be crucial for enantioselection, resulting in poor ee in the
former system.27
(15) The same phenomenon was observed in GaLB catalyzed enanti-
oselective epoxide opening with tBuSH. See ref 2a.
(16) The product from the ring opening of cyclohexene oxide with
BINOL was obtained in 24% yield based on BINOL.
(17) The use of (R)-6,6′-bis(trimethylsilyl)-, dibromo-, or dimethoxy-
BINOL, 3,3′-dimethyl-, or difluoro-BINOL, 3-hydroxymethyl-BINOL,18 and
4,4′-dibromo- or dimethyl-BINOL gave less satisfactory results.
(18) Bougauchi, M.; Watanabe, S.; Arai, T.; Sasai, H.; Shibasaki, M. J.
Am. Chem. Soc. 1997, 119, 2329.
(19) Another application of 6,6′-bis((triethylsilyl)ethynyl)binaphthol is
in catalytic asymmetric nitroaldol reactions: (a) Sasai, H.; Tokunaga, T.;
Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org. Chem. 1995, 60,
7388. (b) Takaoka, E.; Yoshikawa, N.; Yamada, Y. M. A.; Sasai, H.;
Shibasaki, M. Heterocycles 1997, 46, 157.
(20) The use of 10,10′-dihydroxy-9,9′-biphenanthryl,21 3,3′-dihyroxy-
4,4′-biphenanthryl (BIPOL),22 and R,R,R′,R′-tetraphenyl-2-methyl-2-phenyl-
1,3-dioxolane-4,5-dimethanol (TADDOL)23 gave unsatisfactory results.
(21) Toda, F.; Tanaka, K. J. Org. Chem. 1988, 53, 3607.
B. Development of a Novel Linked-BINOL for the
Improved Catalytic Enantioselective Epoxide Ring Opening
(22) Yamamoto, K.; Nada, K.; Okamoto, K. J. Chem. Soc., Chem.
Commun. 1985, 1065.
(23) (a) Seebach, D.; Beck, A. K.; Imwinkelried, R.; Roggo, S.;
Wonnacott, A. HelV. Chim. Acta 1987, 70, 954. (b) Narasaka, K.; Iwasawa,
N.; Inoue, M.; Yamada, T.; Nakashima, M.; Sugimori, J. J. Am. Chem.
Soc. 1989, 111, 5340.
(24) Cram, D. J.; Helgeson, R. C.; Peacock, S. C.; Kaplan, L. J.; Domeier,
L. A.; Moreau, P.; Koga, K.; Mayer, J. M.; Chao, Y.; Siegel, M. G.;
Hoffman, D. H.; Sogah, G. D. Y. J. Org. Chem. 1978, 43, 1930.
(25) Ga-Li-bis(H8-binaphthoxide) (39% yield, 33% ee) and Ga-K-bis-
(H8-binaphthoxide) (58% yield, 52% ee) gave less satisfactory results.
(26) By comparison with Takaya’s catalytic enantioselective hydrogena-
tions with the H8-(S)-[2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl] complex
(H8-BINAP): Uemura, T.; Zhang, X.; Matsumura, K.; Sayo, N.; Kumoba-
yashi, H.; Ohta, T.; Nozaki, K.; Takaya, H. J. Org. Chem. 1996, 61, 5510.

meso-Epoxide Ring Opening Reaction
J. Am. Chem. Soc., Vol. 122, No. 10, 2000 2255
Scheme 3. Synthesis of Oxygen Containing
(R,R)-Linked-BINOL 22a
Figure 2. Linked-BINOLs (19-22).
Reaction. As described above, we have achieved success in
carring out catalytic enantioselective meso-epoxide opening
reaction with phenolic oxygen nucleophile for the first time
utilizing heterobimetallic catalyst GaLB, GaLB* (high ee but
modest yield), and GaSO (high yield but modest ee).28 However,
to make this methodology synthetically useful, it is indispensable
to develop a new catalyst which affords epoxide opening adducts
both in high chemical yield and in high ee even with reduced
amounts of catalyst. In this section we report our efforts in this
direction utilizing a novel linked-BINOL concept.
We assumed that by linking two BINOL units in GaLB the
complex would become more stable against ligand exchange
without any adverse effects on the asymmetric environment.
As a first trial, we designed carbon linked-BINOLs (Figure 2,
19-21).29 One of the key issues for designing the linked-
BINOLs is the length of its linker. The linker should be
relatively short to limit the flexibility of BINOL units since
details of the geometry might be crucial for enantioselection.
We prepared Ga-Li-carbon-linked-BINOL complexes using 19,
20, and 21; however, none of these were effective in the
enantioselective epoxide opening reaction of 3 with 2 (19, yield
28%, 27% ee; 20, yield 43%, 10% ee; 21, yield 40%, -1%
ee).30 We assumed that these unsatisfactory results might be
attributed to the undesired oligomeric structure of these linked-
BINOL complexes. With carbon linker, each BINOL unit of
linked-BINOLs would rotate freely during the formation of Ga-
complexes and so they would not settle down to the desired
monomeric species. To overcome this problem, we then
designed a novel oxygen-containing linked-BINOL (Figure 2,
22). This new linked-BINOL 22 was designed by considering
the related works by Cram et al. regarding crown ether
incorporating chiral BINOL units.32a We supposed that the
a (a) NaH, MOMCl, DMF, 0 °C, 5 h; (b) i) BuLi, TMEDA, THF,
-78 to 0 °C; (ii) DMF, -78 to 0 °C; (c) NaBH4, THF, MeOH, 0 °C,
15 min; (d) (i) MsCl, toluene, AcOEt, 0 °C, 90 min; (ii) LiBr, DMF,
room temperature, 10 min; (e) (i) NaH, THF, DMF, 0 °C, 60 min; (ii)
25, room temperature, 64 h; (f) TsOH‚H2O, CH2Cl2, MeOH, 40 °C,
36 h.
Scheme 4. Preparation of (R,R)-Ga-Li-linked-BINOL‚3 LiCl
Complex 26 and LiCl Free (R,R)-Ga-Li-linked-BINOL
Complex 36
(27) For other examples in which H8-binaphthyl ligands gave better
results than binaphthyl ligands, see, for the Ti(H8-binaphthoxide) com-
plex: (a) Chan, A. C. S.; Zhang, F.-Y.; Yip, C.-W. J. Am. Chem. Soc.
1997, 119, 4080. For the [Rh(2,2′-bis(diphenylphosphinoamino)-H8-bi-
naphthyl)COD]BF4 complex: (b) Zhang, F.-Y.; Pai, C.-C.; Chan, A. C. S.
J. Am. Chem. Soc. 1998, 120, 5808.
(28) The result was reported previously, see: Iida, T.; Yamamoto, N.;
Matsunaga, S.; Woo, H.-G.; Shibasaki, M. Angew. Chem., Int. Ed. Engl.
1998, 37, 7, 2223.
(29) The synthesis of the carbon linked-BINOLs 19 and 20 were reported
previously, see: (a) Vogl, E. M.; Matsunaga, S.; Kanai, M.; Iida, T.;
Shibasaki, M. Tetrahedron Lett. 1998, 39, 7917. For other group’s related
works using 19: (b) Ishitani, H.; Kitazawa, T.; Kobayashi, S. Tetrahedron
Lett. 1999, 40, 2161. For the synthesis of 21 (n ) 3), see the supporting
information.
(30) In the case of 20 (n ) 2), we could not get reproducibility for the
data reported in ref 29a (yield 37%, 86% ee). We found that the results
were very sensitive to the amount of BuLi used in the preparation of the
catalyst. By adding a small excess (0.5 equiv) of BuLi, the result was greatly
improved and 9 was obtained in 69% yield, 99% ee. However, this catalyst
system was not effective for other epoxides at all and gave unsatisfactory
results (yield <50%). Furthermore a positive nonlinear effect31 was observed
in this catalyst system, suggesting the oligomeric structure of the Ga-Li-
carbon-linked-BINOL complex. For detailed results and discussion, see the
supporting information (Table S-1, Table S-2, and Figure S-1).
(31) For review see: Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed.
1998, 37, 2922.
oxygen atom in the linker might coordinate to gallium during
the Ga-complex formation, thus helping the formation of the
desired monomeric Ga-complex. The preparation of 22 is shown
in Scheme 3. Starting from (R)-BINOL, 24 and 25 could easily
be prepared on a multigram scale following our procedure.18,29a
Coupling reaction between 24 and 25 proceeded smoothly. After
deprotection of the MOM group and 2 times recrystallization,
(R,R)-linked-BINOL 22 was obtained on a gram scale (total
yield 47% from (R)-BINOL). Complex 26 (prepared from GaCl3
(1 mol equiv), 22 (1 mol equiv), and BuLi (4 mol equiv):
Scheme 4) was found to be far more stable than GaLB and
very effective for the epoxide opening reaction. The results are
summarized in Table 3. Unlike GaLB, complex 26 was stable
even in the presence of excess 4-methoxyphenol (2) and/or at
higher temperature. By using complex 26, the catalyst amount
could be reduced for the first time. Under the optimized
conditions (toluene, 75 °C, 3 equiv of 2), 6 reacts with 2
smoothly in the presence of 10 mol % catalyst, half the amount
(32) (a) Helgeson, R. C.; Tarnowski, T. L.; Cram, D. J. J. Org. Chem.
1979, 44, 2538. For review about BINOL, see also: (b) Pu, L. Chem. ReV.
1998, 98, 2405.

2256 J. Am. Chem. Soc., Vol. 122, No. 10, 2000
Matsunaga et al.
Table 3. Enantioselective Ring Opening of Various meso-Epoxides
with 4-Methoxyphenol (2) Promoted by Ga-Li-Linked-BINOL
Complex (26)
Scheme 5. Transformations of 9 into the Optically Active
1,2-Diol 33, Ketone 34, and Azide 35
Figure 3. X-ray structure of LiCl-free Ga-Li-linked-BINOL 36.
thesis. Corresponding 1,2-diol 33 was readily obtained in 76%
yield from 9 by treatment with ammonium cerium(IV) nitrate
(CAN).33 In addition, since 9 was obtained as a monoprotected
diol, it could also be converted into R-aryloxyketone 34 and
â-aryloxy azide 35 without any reduction in its optical purity.
C. Catalyst Structure and the Mechanism of the Epoxide
Opening Reaction. Having succeeded in improving the catalytic
enantioselective epoxide opening reaction, we then turned our
attention to the elucidation of the catalyst structure. Although
13C NMR,34 FAB mass (GaLB: M+ ) 644 for Ga69 and 646
for Ga71), and (-)-LDI TOF mass (Ga-Li-linked-BINOL 26:
M - Li+ ) 679 for Ga69) data suggested the assumed
monomeric structures, all attempts to obtain X-ray grade crystal
of these catalysts, prepared from GaCl3, were unsuccessful. After
several trials, we succeeded in getting an X-ray grade crystal
of LiCl free Ga-Li-linked-BINOL complex. The LiCl free Ga-
Li-linked-BINOL complex (36) was prepared from Ga(O-i-Pr)3
(1 mol equiv), linked-BINOL 22 (1 mol equiv), and BuLi (1
mol equiv) (Scheme 4), and the crystal of 36 was grown from
toluene solution in the presence of a small amount of THF and
diethyl ether. This crystal of 36 also catalyzed the ring opening
reaction of epoxide 3 to give 9 (20 mol % catalyst, toluene, 50
°C, 40 h, yield 85%), although in somewhat lower ee (74%)
compared to catalyst 26. By treating this crystal with 3 mol
equiv of LiCl in THF prior to use, the enantiomeric excess
increased to 90%, suggesting the formation of the same catalyst
as the one from GaCl3. The role of LiCl is not clear, but it is
well-known that lithium halide functions effectively as an achiral
additive to increase enantioselectivity.35 Therefore it might be
possible that LiCl could coordinate to the Ga-Li-linked-BINOL
complex, slightly affecting the asymmetric environment of the
complex in solution phase. As shown in Figure 3, Ga-Li-linked-
BINOL complex has a monomeric tetracoordinated structure,
which is similar to the structure of Al-Li-bis(binaphthoxide)-
a Isolated yield. b Determined by HPLC analysis. c 3 mol % catalyst
was used. d R1 ) CH2OSiPh2tBu. e 30 mol % catalyst was used. Mts
) 2,4,6-trimethylbenzenesulfonyl.
of GaLB, to afford 12 (36 h, yield 94%, 85% ee, entry 4). Entries
1-5 show that the new catalyst 26 (10 mol %) afforded products
(9-13) in analogous ee’s (66-91%) but in much higher
chemical yields (72-94%) compared to GaLB (20 mol %, Table
1). After the reaction ligand 22 was recovered in almost
quantitative yield by extracting with 1 N aq NaOH. This
situation was very different for the GaLB catalyzed reaction
because BINOL itself reacted with epoxide. The catalyst 26 was
also effective for epoxides 27 and 28 (entry 7, yield 67%, 87%
ee; entry 8, yield 85%, 96% ee). It is noteworthy that even the
reaction between 2 and the less reactive acyclic epoxide 29
proceeded with this catalyst (entry 9, yield 72%, 91% ee).
Importantly, using only 3 mol % of catalyst 26, epoxide 6 gave
12 in 80% yield and in 91% ee; however, the reaction time
was long (117 h, entry 4 in parentheses). It seems that all of
these results can be attributed to the stability of complex 26,
obtained by linking the two BINOL units in GaLB. The stable
catalyst 26 remained unchanged during the course of the
reaction, whereas GaLB was decomposed by severe ligand
exchange with 4-methoxyphenol and the reaction stopped on
the way.
(33) Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetrahedron Lett.
1985, 26, 6291.
(34) 13C NMR of GaLB gave only 10 peaks in aromatic region,
suggesting symmetric structure of GaLB. 13C NMR chart of GaLB is
available. See the supporting information.
As shown in Scheme 5, epoxide ring-opened product 9 was
transformed into various useful intermediates in organic syn-
(35) Sugasawa, K.; Shindo, M.; Noguchi, H.; Koga, K. Tetrahedron Lett.
1996, 37, 7377 and references therein.

meso-Epoxide Ring Opening Reaction
J. Am. Chem. Soc., Vol. 122, No. 10, 2000 2257
Scheme 6. Working Model for the Ring Opening of
Cyclohexene Oxide with 4-Methoxyphenol (2, ArOH)
Catalyzed by Gallium Heterobimetallic Complexes
Figure 4. Working transition state model for meso-epoxide opening
reaction promoted by gallium heterobimetallic complexes.
(thf)3 complex (ALB).36 This is the first X-ray crystal analysis
of an asymmetric catalyst containing gallium, and this result
also strongly supports the proposed monomeric structures of
other gallium heterobimetallic catalysts which were reported
by our group2a,37 and others.38
with phenolic oxygen nucleophile by utilizing heterobimetallic
multifunctional catalysts. A novel linked-BINOL containing a
coordinative oxygen atom in its linker was developed for
preparing a more stable gallium heterobimetallic complex. By
using this Ga-Li-linked-BINOL complex, the present reaction
was greatly improved to afford 1,2-diol monoethers in up to
94% yield and in up to 96% ee. These 1,2-diol monoethers could
easily be converted not only into optically active 1,2-diols but
also into other chiral compounds. Furthermore we have suc-
ceeded in getting X-ray data of LiCl free Ga-Li-linked-BINOL
complex. This is the first X-ray analysis of an asymmetric
catalyst containing gallium. Although more detailed mechanistic
studies are needed for clear understanding, these X-ray data
contribute a lot to understanding the mechanism of various
reactions catalyzed by other gallium heterobimetallic complexes
as well as the mechanism of the present epoxide opening
reaction. The linked-BINOL has opened up the possibility of
developing various catalysts containing several types of Lewis
acidic metals other than gallium. In addition, we consider that
this new linked-BINOL concept makes it easy to develop a
solid-phase asymmetric catalyst that contains several BINOL
units.43 These are now under intense investigation in our group.
On the basis of mechanistic studies of other asymmetric
reactions catalyzed by various heterobimetallic com-
plexes,13a,13d,13f,36,39 especially those of ALB,36,39b which has a
group 13 element Al as a center metal, it is quite reasonable to
consider that group 13 element Ga would also function as a
Lewis acid in a similar manner as Al to activate epoxides40 and
lithium binaphthoxide would act as a Brønsted base to activate
4-methoxyphenol. Furthermore, as mentioned previously (sec-
tion A), dual activation of both epoxides and 4-methoxyphenol
seems very important. So the proposed catalytic cycle for the
present epoxide opening reaction appears to be reasonable
(Scheme 6). In the meso-epoxide ring opening reaction, fixing
the position of epoxides coordinating to the Lewis acid and
controlling the orientation of nucleophiles are necessary to
achieve high enantiomeric induction. Based on the X-ray
structure of LiCl free (R,R)-Ga-Li-linked-BINOL complex 36
and the absolute configuration of the product obtained by this
catalyst (74% ee for (R,R)-9), enantiomeric induction in the
present system can be understood by assuming the transition
state in Figure 4.41 Due to the steric hindrance, the epoxide
coordinating to gallium would be fixed in (A) form rather than
(B) form. Lithium binaphthoxide then activates and controls
the orientation of ArOH 2 so that lithium phenoxide should
attack the epoxide selectively from one side to afford (R,R)-
1,2-diol monoether.42
Experimental Section
General. Infrared (IR) spectra were recorded on a JASCO FT/IR
410 Fourier transform infrared spectrophotometer. NMR spectra were
recorded on a JEOL JNM-LA500 spectrometer, operating at 500 MHz
for 1H NMR and 125.65 MHz for 13C NMR. Chemical shifts in CDCl3
were reported downfield from TMS ()0) for 1H NMR. For 13C NMR,
chemical shifts were reported on the scale relative to CHCl3 (77.00
ppm for 13C NMR) as an internal reference. Optical rotations were
measured on a JASCO P-1010 polarimeter. EI mass spectra were
measured on JEOL JMS-DX303 or JMS-BU20 GCmate. LDI-TOF
mass spectra were measured on Shimadzu MALDI IV. Column
chromatography was performed with silica gel Merck 60 (230-400
mesh ASTM). The enantiomeric excess (ee) was determined by HPLC
analysis. HPLC was performed on JASCO HPLC systems consisting
of the following: pump, 880-PU or PU-980; detector, 875-UV or UV-
970, measured at 254 nm; column, DAICEL CHIRALPAK AS, AD,
Conclusion
In conclusion, we have succeeded in carrying out the first
catalytic enantioselective meso-epoxide ring opening reaction
(36) Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki,
M. Chem. Eur. J. 1996, 2, 1368.
(37) Ga-Na-bis(binaphthoxide) (GaSB) complex was used for catalytic
asymmetric Michael reaction; see ref 36.
(38) Ford, A.; Woodward, S. Angew. Chem., Int. Ed. Engl. 1999, 38,
335.
(39) (a) Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M. J.
Am. Chem. Soc. 1995, 117, 6194. (b) Arai, T.; Sasai, H.; Aoe, K.; Okamura,
K.; Date, T.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 5, 104.
(40) ALB can also promote the epoxide opening reaction with 2, although
the result was inferior to GaLB and 26. Epoxide 3 gave 9 in 20% yield and
72% ee (20 mol % ALB, toluene, MS 4A, 50 °C, 115 h).
(41) LiCl effect as an achiral additive to enhance enantiomeric excess
has already been discussed in this section. However, since its role is not
yet clear, LiCl is not included into the proposed transition state.
(42) Probably in the case of GaSO, H8-BINOL has a larger dihedral angle
and so fixation of epoxides might not be rigid enough, thus resulting in
low enantiomeric excess.
(43) With two nonlinked BINOL units, the relative spatial relationship
between two BINOL units on the resin should be finely controlled to make
an active catalytic species formation possible. However, such control
probably is not so easy. Seebach reported various polymer supported Ti-
TADDOL catalysts. The polymer supported Ti catalysts afforded products
in comparable ee with homogeneous analogues in the reaction where the
active species was a Ti:TADDOL ) 1:1 complex. On the other hand, the
catalysts gave products only in poor ee in the reaction where the active
species was different from the Ti:TADDOL ) 1:1 complex. See: Seebach,
D.; Marti, R. E.; Hintermann, T. HelV. Chim. Acta 1996, 79, 1710.

2258 J. Am. Chem. Soc., Vol. 122, No. 10, 2000
Matsunaga et al.
DAICELCHIRALCEL OD or OJ; mobile phase, hexane-2-propanol;
flow rate, 0.50-1.0 mL/min. Reactions were carried out in dry solvents
under an argon atmosphere, unless otherwise stated. Tetrahydrofuran
(THF) and diethyl ether were distilled from sodium benzophenone ketyl.
Toluene was distilled from sodium. GaCl3 and Ga(O-i-Pr)3 were
purchased from Kojundo Chemical Laboratory Co., Ltd., 5-1-28,
Chiyoda, Sakado-shi, Saitama 350-0214, Japan (fax, ++(81)-492-84-
1351). Other reagents were purified by the usual methods.
Procedure for the Preparation of (R)-Ga-Li-bis(binaphthoxide)
Complex (GaLB: 1). To an ice-cooled solution of (R)-binaphthol
(1.145 g, 4.00 mmol) in THF (24 mL) was added BuLi (5.00 mL, 8.00
mmol, 1.60 M in hexane), and the mixture was stirred at 0 °C for 10
min and at room temperature for 30 min. The resultant solution was
added to a mixture of GaCl3 (4.67 mL, 2.00 mmol, 0.428 M in diethyl
ether) and THF (15 mL) at room temperature. The reaction mixture
was then stirred at room temperature for 3 h. This catalyst solution
can be stored for a couple of months under argon at room temperature.
13C NMR (THF, external D2O was used to obtain lock signal) δ 121.0,
121.3, 124.0, 125.2, 126.3, 127.0, 127.3, 128.4, 134.6, 157.4; FAB-
MS, m/z 653 (for 71Ga) and 651 (for 69Ga) [M+ + Li], 646 (for 71Ga)
and 644 (for 69Ga) [M+].
General Procedure for the Catalytic Enantioselective Epoxide
Ring Opening Reactions with 4-Methoxyphenol using GaLB 1. A
mixture of powdered MS 4A (400 mg), dried at 180 °C under reduced
pressure (ca. 5 mmHg) for 6 h prior to use, and a 0.05 M solution of
(R)-GaLB 1 (4.0 mL, 0.20 mmol, prepared by the procedure described
above) was evaporated in vacuo to remove the solvents. A solution of
4-methoxyphenol (2) (149 mg, 1.2 mmol) in toluene (2.0 mL) and
cyclopentene oxide (4) (87.5 µL, 1.0 mmol) was added to the residue
at room temperature, and the mixture was stirred at 50 °C for 72 h.
The resultant mixture was diluted with diethyl ether (30 mL) and filtered
over a Celite pad to remove MS 4A. The filtrate was washed
successively with 5% aq citric acid (10 mL), 1 N aq NaOH (10 mL),
saturated aq NH4Cl (10 mL), and brine (10 mL) and then dried over
MgSO4. After evaporation of the volatiles, the residue was purified by
flash column chromatography (SiO2, hexane/acetone 10/1) to give 10
(157 mg, 0.75 mmol, yield 75%) in 86% ee as a colorless oil.
Procedure for the Preparation of (R)-Ga-Na-bis(H8-binaphthox-
ide) Complex (GaSO: 16). To an ice-cooled solution of (R)-H8-BINOL
(294 mg, 1.00 mmol) in THF (11.52 mL) was added t-BuONa (4.48
mL, 2.00 mmol, 0.446 M in THF) and the mixture was stirred at room
temperature for 30 min. The resultant suspension was added to a mixture
of GaCl3 (1.00 mL, 0.500 mmol, 0.500 M in diethyl ether) and THF
(3.00 mL) at room temperature. The mixture was stirred for 10 h at
room temperature. Then the resultant suspension was kept standing at
the same temperature until NaCl salt precipitated. The supernatant
solution was used as (R)-GaSO catalyst (0.025 M). This catalyst can
be stored for couple of months under argon at room temperature.
General Procedure for the Catalytic Enantioselective Epoxide
Ring Opening Reactions with 4-Methoxyphenol Using GaSO 16.
A mixture of powdered MS 4A (200 mg), dried at 180 °C under reduced
pressure (ca. 5 mmHg) for 6 h prior to use, and a 0.025 M supernatant
of (R)-GaSO 16 (4.0 mL, 0.10 mmol, prepared by the procedure
described above) was evaporated in vacuo to remove the solvents. A
solution of 4-methoxyphenol (2) (74.5 mg, 0.60 mmol) in toluene (2.0
mL) and cyclohexene oxide (3) (51 µL, 0.50 mmol) was added to the
residue at room temperature, and the mixture was stirred at 50 °C for
4 h. The resultant mixture was diluted with diethyl ether (30 mL) and
filtered over a Celite pad to remove MS 4A. The filtrate was washed
successively with 5% aq citric acid (10 mL), 1 N aq NaOH (10 mL),
saturated aq NH4Cl (10 mL), and brine (10 mL) and then dried over
MgSO4. After evaporation of the volatiles, the residue was purified by
flash column chromatography (SiO2, hexane/acetone 15/1) to give 9
(81.1 mg, 0.365 mmol, yield 73%) in 56% ee as colorless solid.
Procedure for the Preparation of (R,R)-Ga-Li-linked-BINOL
Complex 26. To a stirred solution of (R,R)-linked-BINOL 22 (1.09 g,
(15.5 w/w % diethyl ether and hexane), 1.5 mmol), in THF (22.7 mL)
at 0 °C was added BuLi (4.0 mL, 6.0 mmol, 1.50 M in hexane) and
the mixture was stirred at 0 °C for 2 h. GaCl3 (3.3 mL, 1.5 mmol,
0.455 M in diethyl ether) was then added at 0 °C. After stirring for 90
min at 0 °C, the reaction mixture became a white suspension and was
then stirred at room temperature for another 90 min. The resultant
suspension was used as (R,R)-Ga-Li-linked-BINOL catalyst. This
catalyst suspension can be stored for at least 1 month under an argon
atmosphere at 0 °C. GaCl3 can be stored as diethyl ether solution for
several months at -20 °C.
General Procedure for the Catalytic Enantioselective Epoxide
Ring Opening Reactions with 4-Methoxyphenol Using Ga-Li-linked-
BINOL Complex 26. A mixture of powdered MS 4A (100 mg), dried
at 180 °C under reduced pressure (ca. 5 mmHg) for 6 h prior to use,
and a 0.05 M suspension of (R,R)-Ga-Li-linked-BINOL complex 26
(1.0 mL, 0.05 mmol, prepared by the procedure described above) was
evaporated in Vacuo. A solution of 4-methoxyphenol (2) (186 mg, 1.5
mmol) in toluene (2.0 mL) and cyclopentene oxide (4) (43.7 µL, 0.50
mmol) was added to the residue at room temperature, and the mixture
was stirred at 75 °C for 96 h. The resultant mixture was diluted with
diethyl ether (30 mL) and filtered over a Celite pad to remove MS 4A.
The organic layer was washed successively with 5% aq citric acid (10
mL), 1 N aq NaOH (15 mL × 2), saturated aq NH4Cl (10 mL), and
brine (10 mL) and then dried over MgSO4. After evaporation, the
residue was purified by flash column chromatography (SiO2, hexane/
diethyl ether 5/1) to give 10 (91.8 mg, 0.44 mmol, yield 88%) in 85%
ee as a colorless oil. Linked-BINOL 22 was recovered in the following
manner: aq NaOH layers were acidified with 1 N aq HCl and then
extracted with diethyl ether (20 mL). The organic layer was washed
with saturated aq NaHCO3 (10 mL) and brine (10 mL) and then dried
over MgSO4. After evaporation, the residue was purified by flash
column chromatography (SiO2, hexane/diethyl ether 2/1) to give 22 in
quantitative yield.
Synthesis of the 1,2-Diol Monoethers 9-14, 18, and 30-32 Using
Gallium Heterobimetallic Complexes. The absolute configurations
of 9 and 10 were determined by converting them into known chiral
diols. 12 was transformed into 9 and 14 was transformed into a known
compound.44a Mosher’s method44b was used for 11, 13, 18, and 31.
The absolute configurations of 30 and 32 have not yet been determined.
(1R,2R)-2-(4-Methoxyphenyloxy)cyclohexanol (9): colorless solid;
1
mp 84-86 °C; IR (KBr) ν 3398, 2933, 2056, 1982 cm-1; H NMR
(CDCl3) δ 1.21-1.43 (m, 4 H), 1.73 (m, 2 H), 2.02-2.17 (m, 2 H),
2.62 (br, 1 H), 3.68 (ddd, J ) 4.6, 8.6, 10.5 Hz, 1 H), 3.76 (s, 3 H),
3.84 (ddd, J ) 4.6, 8.6, 10.5 Hz, 1 H), 6.79-6.92 (m, 4 H); 13C NMR
(CDCl3) δ 23.9, 24.0, 29.3, 32.0, 55.7, 73.5, 83.6, 114.6, 118.1, 151.7,
154.4; MS m/z 222 [M+]; [R]D -56.6° (c 1.10, CHCl3); HPLC
25
(DAICEL CHIRALCEL OJ, 2-propanol/hexane 1/9, flow 1.0) tR 14.2
and 16.5 min. Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found:
C, 69.95; H, 8.29.
(1R,2R)-2-(4-Methoxyphenyloxy)cyclopentanol (10): colorless oil;
1
IR (neat) ν 3408, 2954, 1507 cm-1; H NMR (CDCl3) δ 1.58-1.84
(m, 4 H), 2.01-2.16 (m, 3 H), 3.75 (s, 3 H), 4.28 (m, 1 H), 4.43 (m,
1 H), 6.83 (m, 4 H); 13C NMR (CDCl3) δ 21.0, 29.8, 32.5, 55.7, 77.2,
85.2, 114.6, 116.6, 151.9, 153.8; MS m/z 208 [M+]; [R]D -36.0° (c
25
1.08 CHCl3); HPLC (DAICEL CHIRALPAK AS, 2-propanol/hexane
1/9, flow 1.0) tR 10.1 and 25.5 min; HRMS [M+] calcd for C12H16O3,
208.1100; found, 208.1099.
(1R,2R)-2-(4-Methoxyphenyloxy)cycloheptanol (11): colorless solid;
mp 89-91 °C; IR (KBr) ν 3457, 2936, 1509 cm-1; 1H NMR (CDCl3)
δ 1.42-1.76 (m, 8H), 1.89-2.00 (m, 2 H), 2.70 (br, 1 H), 3.77 (s, 3
H), 3.86 (dt, J ) 4.0, 8.5 Hz, 1 H), 3.96 (dt, J ) 3.1, 8.9 Hz, 1 H),
6.84 (m, 4 H); 13C NMR (CDCl3) δ 22.27, 22.34, 27.3, 28.2, 31.8,
55.7, 75.9, 85.7, 114.8, 117.8, 151.5, 154.3; MS m/z 236 [M+]; [R]D
23
-28.1° (c 0.206 CHCl3 (67% ee)); HPLC (DAICEL CHIRALPAK AD,
2-propanol/hexane 1/9, flow 1.0) tR 13.0 and 16.0 min; HRMS [M+]
calcd for C14 H20O3, 236.1413; found, 236.1412.
(1R,2R)-2-(4-Methoxyphenyloxy)-4-cyclohexen-1-ol (12): colorless
1
solid; mp 98-100 °C; IR (KBr) ν 3376, 2925, 1508 cm-1; H NMR
(CDCl3) δ 2.08-2.22 (m, 2 H), 2.55-2.63 (m, 2 H), 3.77 (s, 3 H),
4.02 (ddd, J ) 5.9, 9.2, 9.2 Hz, 1 H), 4.19 (ddd, J ) 5.7, 9.2, 9.2 Hz,
1 H), 5.52-5.56 and 5.59-5.62 (m, 1 H each), 6.82-6.94 (m, 4 H);
(44) (a) Ballini, R.; Marcantoni, E.; Petrini, M. J. Org. Chem. 1992, 57,
1316. (3S,4S)-1-Benzyl-3,4-bis(methoxymethoxy)pyrrolidine: [R]D20 + 11.9°
(c 2.4, CHCl3). (b) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Org.
Chem. 1991, 56, 1296.

meso-Epoxide Ring Opening Reaction
J. Am. Chem. Soc., Vol. 122, No. 10, 2000 2259
13C NMR (CDCl3) δ 30.3, 32.5, 55.7, 69.9, 79.6, 114.7, 117.9, 123.8,
(91% ee)); HPLC (DAICEL CHIRALPAK AS, 2-propanol/hexane 1/9,
flow 1.0) tR 7.3 and 28.9 min; HRMS [M+] calcd for C11H16O3,
196.1099; found, 196.1104.
124.6, 151.7, 154.5; MS m/z 220 [M+]; [R]D -56.5° (c 0.74 CHCl3
25
(47% ee)); HPLC (DAICEL CHIRALCEL OJ, 2-propanol/hexane 1/9,
flow 1.0) tR 18.5 and 26.3 min; HRMS [M+] calcd for C13H16O3,
222.1100; found, 222.1099.
Synthesis of Linked-BINOL 22. 2,2′-Bis(methoxymethyloxy)-1,1′-
binaphthalene-3-carboxaldehyde (23). To a stirred solution of MOM-
protected (R)-binaphthol (32.05 g, 85.6 mmol), in THF (320 mL) at
-78 °C was added TMEDA (15.5 mL, 103 mmol) and then BuLi (60.8
mL, 96.7 mmol, 1.59 M in hexane) over 15 min. The mixture was
warmed to 0 °C and stirred for 30 min. After cooling to -78 °C, DMF
(7.58 mL, 103 mmol) in THF (40 mL) was added dropwise over 10
min. The mixture was stirred at the same temperature for 30 min and
then was warmed to 0 °C and stirred for further 40 min. The resultant
yellow solution was quenched with saturated aq NH4Cl (50 mL). After
addition of 1 N aq HCl (50 mL), the solution was extracted with diethyl
ether (500 mL), and the combined organic layers were washed with
saturated aq NaHCO3 (50 mL) and brine and then dried over MgSO4.
The solvent was evaporated under reduced pressure, and the residue
was purified by flash column chromatography (SiO2, hexane/ethyl
acetate 10/1) to give 23 (26.03 g, 64.7 mmol, yield 76%). 23 has already
been reported. See ref 18.
3-Hydroxymethyl-2,2′-bis(methoxymethyloxy)-1,1′-binaphtha-
lene (24). To an ice-cooled solution of 23 (5.15 g, 12.8 mmol) in THF
(80 mL)/CH3OH (80 mL) was added NaBH4, and the mixture was
stirred at 0 °C for 15 min. H2O was added and the mixture was
concentrated under reduced pressure and then extracted with ethyl
acetate (100 mL × 2). The combined organic extracts were washed
with brine, dried over MgSO4, and evaporated under reduced pressure.
The residue was then dried in vacuo to afford 24 as a colorless foam,
which was used for the next step without further purification. 24 has
already been reported. See ref 18.
(1R,2R,4R,5S)-4,5-bis((tert-Butyldiphenylsilyloxy)methyl)-2-(4-
methoxyphenyloxy)cyclohexanol (13): colorless foam; IR (neat) ν
1
3437, 2930, 1507 cm-1; H NMR (CDCl3) δ 0.96 (s, 9H), 0.98 (s,
9H), 1.37 (m, 1 H), 1.45 (m, 1 H), 1.97 (m, 1 H), 2.21 (br s, 1 H), 2.59
(m, 1 H), 3.48 (d, J ) 6.4 Hz, 2 H), 3.68 (dd, J ) 9.8, 10.1 Hz, 1 H),
3.74 (s, 3 H), 3.73-3.81 (m, 3 H), 4.19 (ddd, J ) 4.3, 8.5, 11.6 Hz, 1
H), 6.75 (dt, J ) 4.0, 9.2 Hz, 2 H), 6.91 (dt, J ) 3.7, 9.2 Hz, 2 H),
7.24-7.42 (m, 12 H), 7.52-7.62 (m, 8H); 13C NMR (CDCl3) δ 19.1,
26.8, 29.8, 30.9, 37.5, 39.8, 55.7, 62.1, 65.6, 73.3, 80.0, 114.7, 117.8,
127.66, 127.72, 129.6, 129.7, 133.4, 133.5, 135.5, 151.8, 154.3; MS
m/z 758 [M+]; [R]D21 -13.9° (c 1.07 CHCl3 (80% ee)); HPLC (DAICEL
CHIRALPAK AD, 2-propanol/hexane 1/99, flow 1.0) tR 21.0 and 26.0
min; HRMS [M+] calcd for C47H58O5Si2, 758.3823; found, 758.3821.
(1R,2R)-4-(4-Methoxyphenyloxy)-1-(2,4,6-trimethylphenylsulfo-
nyl)-3-pyrrolidin-3-ol (14): MS 4A was used without prior activation;
1
colorless solid; IR (KBr) ν 3449, 2960, 1509, 1315, 1146 cm-1; H
NMR (CDCl3) δ 2.31 (s, 3 H), 2.64 (s, 6H), 3.36 (dd, J ) 2.0, 11.5
Hz, 1 H), 3.42 (br s, 1 H), 3.53 (dd, J ) 4.0, 12.0 Hz, 1 H), 3.76 (s,
3 H), 3.81 (dd, J ) 5.0, 11.5 Hz, 1 H), 4.38 (m, 1 H), 4.64 (m, 1 H),
6.81 (s, 4 H), 6.96 (s, 2 H); 13C NMR (CDCl3) δ 20.9, 22.8, 50.0,
52.7, 55.7, 73.8, 82.0, 114.8, 116.9, 131.9, 132.3, 140.2, 142.8, 150.6,
27
154.6; MS m/z 391 [M+]; [R]D -19.6° (c 1.04 CHCl3 (79% ee));
HPLC (DAICEL CHIRALCEL OD, 2-propanol/hexane 1/9, flow 1.0)
tR 26.4 and 31.6 min; HRMS [M+] calcd for C20H25O5, 391.1453; found,
391.1450.
(2R,3R)-2-Hydroxy-3-(4-methoxyphenyloxy)-1,4-butanediol Bis-
(triphenylmethyl) Ether (18): colorless foam; H NMR (CDCl3) δ
3-Bromomethyl-2,2′-bis(methoxymethyloxy)-1,1′-binaphtha-
lene (25). To an ice-cooled solution of crude 24 in toluene (50 mL)/
ethyl acetate (50 mL) were added successively Et3N (7.14 mL, 51.2
mmol) and MsCl (1.98 mL, 25.6 mmol). The mixture was stirred at 0
°C for 90 min. The resultant suspension was filtered to remove solid
Et3NH+Cl- and the solid was washed with ethyl acetate (50 mL). The
combined filtrate and washings were cooled to 0 °C and then LiBr
(11.1 g, 128 mmol) and DMF (100 mL) were added. The mixture was
stirred at room temperature for 10 min. It was diluted with diethyl ether
(200 mL) and washed with water (100 mL × 2), 1 N aq HCl (50 mL
× 2), saturated aq NaHCO3 (50 mL), and brine. It was dried over
MgSO4 and evaporated in vacuo to give 25 as a colorless solid (5.568
g, 11.9 mmol, yield 93% from 23) which was pure enough to be used
in next step without further purification. 25 has already been reported.
See ref 29a.
1
2.51 (d, J ) 6.1 Hz, 1 H), 3.16 (dd, J ) 6.1, 9.2 Hz, 1 H), 3.24 (dd,;
J ) 6.4, 9.2 Hz, 1 H), 3.28 (dd, J ) 5.2, 10.8 Hz, 1 H), 3.45 (dd, J )
5.5, 10.1 Hz, 1 H), 3.76 (s, 3 H), 4.06 (m, 1 H), 4.42 (dt, J ) 3.4, 4.0
Hz, 1 H), 6.71-6.78 (m, 4 H), 7.17-7.25 (m, 18H), 7.33-7.39 (m,
12 H); 13C NMR (CDCl3) δ 55.7, 62.8, 64.0, 70.9, 78.0, 86.8, 87.1,
114.5, 114.7, 117.5, 127.0, 127.2, 127.3, 127.78, 127.81, 127.9, 128.6,
23
128.7, 143.76, 143.81, 152.5, 154.2; MS m/z 712 [M+]; [R]D +1.9°
(c 0.579 CHCl3 (50% ee)); HPLC (DAICEL CHIRALCEL OD,
2-propanol/hexane 1/9, flow 0.8) tR 28.0 and 35.0 min.
(1R,2R,4S)-4-(tert-Butyldimethylsilyloxy)-2-(4-methoxyphenyloxy)-
cyclopentanol (30): colorless oil; IR (neat) ν 3508, 2930, 1507 cm-1
;
1H NMR (CDCl3) δ 0.10 (s, 6H), 0.90 (s, 9H), 1.86 (ddd, J ) 1.5, 1.8,
14.0 Hz, 1 H), 1.97 (ddd, J ) 4.3, 4.7, 15.0 Hz, 1 H), 2.05 (ddd, J )
4.9, 4.9, 14.0 Hz, 1 H), 2.34 (dddd, J ) 1.8, 1.8, 7.0, 15.0 Hz, 1 H)
3.24 (br s, 1 H), 3.75 (s, 3 H), 4.19 (brd, J ) 4.9 Hz, 1 H), 4.51-4.53
(m, 1 H), 4.71-4.73 (m, 1 H), 6.80-6.87 (m, 4 H); 13C NMR (CDCl3)
δ -5.0, -4.9, 17.9, 25.7, 41.5, 42.2, 55.7, 74.3, 77.0, 84.8, 114.7, 116.3,
151.9, 153.8; MS m/z 338 [M+]; [R]D25 -6.2° (c 1.08 CHCl3(87% ee));
HPLC (DAICEL CHIRALPAK AD, 2-propanol/hexane 1/9, flow 1.0)
tR 9.9 and 10.9 min; HRMS [M+] calcd for C30H18O4Si, 338.1913;
found, 338.1906.
3,3′′-(Oxydimethylene)-di-1,1′-bi-2-naphthol (22). To a stirred
solution of 24 (4.0 g, 9.89 mmol), in THF (50 mL)/DMF (30 mL) at
0 °C, was added NaH in oil (482 mg, 12.6 mmol as 60% purity). The
mixture was stirred at the same temperature for 60 min, and then 25
(4.62 g, 9.89 mmol) in DMF (30 mL) was added. The mixture was
stirred at room temperature for 64 h and then cooled to 0 °C and
quenched with H2O. It was diluted with diethyl ether (400 mL), washed
with H2O (100 mL) and brine (100 mL), and then dried over MgSO4.
After evaporation of solvent, the residue was purified by flash column
chromatography (SiO2, hexane/ethyl acetate 4/1) to give MOM-
protected linked-BINOL (6.63 g (4.0 w/w % ethyl acetate was included
(1R,2R)-5,8-Dimethoxy-3-(4-methoxyphenyloxy)-1,2,3,4-tetrahy-
dronaphthalene-2-ol (31): colorless foam; mp 155-156 °C; IR (KBr)
ν 3406, 2942, 1508 cm-1; 1H NMR (CDCl3) δ 2.56 (dd, J ) 9.2, 17.1
Hz, 1 H), 2.64 (dd, J ) 9.2, 17.7 Hz, 1 H), 3.37 (dd, J ) 6.1, 17.1 Hz,
1 H), 3.38 (dd, J ) 5.5, 17.7 Hz, 1 H), 4.15 (ddd, J ) 6.1, 9.2, 9.2 Hz,
1 H), 4.32 (ddd, J ) 5.5, 9.2, 9.2 Hz, 1 H), 6.63 (d, J ) 8.9 Hz, 1 H),
6.65 (d, J ) 8.9 Hz, 1 H), 6.83-6.98 (m, 4 H); 13C NMR (CDCl3) δ
28.1, 30.4, 55.5, 55.7, 69.8, 79.2, 107.4, 107.7, 114.8, 117.9, 123.7,
1
based on H NMR), 8.04 mmol, yield 82%) as a yellow foam.
To a stirred solution of this yellow foam (3.01 g, 3.65 mmol) in
CH2Cl2 (40 mL)/CH3OH (40 mL) was added TsOH‚H2O (300 mg, 1.58
mmol). The solution was stirred at 40 °C for 36 h. It was then diluted
with CH2Cl2 (250 mL), washed with saturated NaHCO3 (100 mL) and
brine (100 mL), and dried over MgSO4. After removing the solvent
under reduced pressure the residue was purified by flash column
chromatography (SiO2, hexane/ethyl acetate 4/1). The product was
further purified by recrystallization using diethyl ether/hexane to give
22 (2.03 g, 5.6 w/w % diethyl ether and hexane were included based
on 1H NMR), 3.12 mmol, yield 85%) as a colorless powder: IR (KBr)
ν 3375, 3069, 1507, 1106 cm-1; 1H NMR (CDCl3) δ 5.00 (br s, 2 H),
5.05 (d, J ) 12.6 Hz, 2 H), 5.06 (d, J ) 12.6 Hz, 2 H), 6.31 (s, 2 H),
7.10 (d, J ) 8.3 Hz, 2 H), 7.14 (d, J ) 8.5 Hz, 2 H), 7.22 (ddd, J )
1.5, 6.8, 8.3 Hz, 2 H), 7.28-7.38 (m, 8H), 7.85 (d, J ) 8.0 Hz, 2 H),
124.1, 151.1, 151.2, 151.8, 154.5; MS m/z 330 [M+] 207; [R]D
25
-131.93° (c 0.42, CHCl3 (96% ee)); HPLC (DAICEL CHIRALCEL
OD, 2-propanol/hexane 1/9, flow 0.5) tR 39.0 and 42.7 min. Anal. Calcd
for C19H22O5: C, 69.07; H, 6.71. Found: C, 68.89; H, 6.59.
(2R,3R)-3-(4-Methoxyphenyloxy)-2-butanol (32): colorless oil; IR
(neat) ν 3433, 2976, 1507 cm-1; 1H NMR (CDCl3) δ 1.18 (d, J ) 6.1
Hz, 3 H), 1.22 (d, J ) 6.1 Hz, 3 H), 2.63 (br s, 1 H), 3.75 (s, 3 H),
3.79 (dq, J ) 6.1, 6.4 Hz, 1 H), 3.98 (dq, J ) 6.1, 6.4 Hz, 1 H), 6.79-
6.86 (m, 4 H); 13C NMR (CDCl3) δ 15.6, 18.4, 55.6, 70.9, 80.3, 114.7,
117.8, 151.6, 154.3; MS m/z 196 [M+]; [R]D26 -52.3° (c 1.93, CHCl3

2260 J. Am. Chem. Soc., Vol. 122, No. 10, 2000
Matsunaga et al.
7.87 (d, J ) 7.3 Hz, 2 H), 7.93 (d, J ) 8.9 Hz, 2 H), 7.98 (s, 2 H); 13
C
(SiO2, hexane/ethyl acetate 10/1) to give 35 (7.8 mg, yield 59% 2 steps)
as colorless oil: IR (neat) ν 2939, 2097, 1507 cm-1; 1H NMR (CDCl3)
δ 1.32-1.43 (m, 2 H), 1.58-1.73 (m, 4 H), 1.92-2.05 (m, 2 H), 3.61-
3.62 (m, 1 H), 3.75 (s, 3 H), 4.29-4.32 (m, 1 H), 6.79-6.83 (m, 2 H),
6.88-6.91 (m, 2 H); 13C NMR (CDCl3) δ 21.5, 22.1, 27.3, 27.5, 55.7,
60.6, 77.8, 114.7, 117.8, 151.3, 154.4; MS m/z 247 [M+]; [R]D23 +2.26°
(c 0.58, CHCl3(94% ee)); HPLC (DAICEL CHIRALCEL OD, 2-pro-
panol/hexane 1/99, flow 1.0) tR 7.3 and 9.6 min; HRMS [M+] calcd
for C13H17O2N3, 247.1321; found, 247.1323.
NMR (CDCl3) δ 70.2, 112.1, 112.5, 117.7, 123.7, 124.2, 124.4, 125.6,
127.1, 127.4, 128.2, 128.3, 128.9, 129.3, 130.0, 130.8, 133.4, 133.6,
151.8, 152.2; MS m/z 614 [M+] 299; [R]D + 67.4° (c 0.90, CHCl3);
27
HPLC (DAICEL CHIRALPAK AS, 2-propanol/hexane 1/4, flow 0.75)
tR 24.8 and 46.5 min. Anal. Calcd for C42H30O5 (1.00 mol equiv), diethyl
ether (C4 H10O, 0.265 mol equiv), and hexane (C6H14, 0.200 mol
equiv): C, 81.59; H, 5.48. Found: C, 81.30; H, 5.51.
Transformation of 9 into 1,2-Cyclohexanediol (33), r-Aryloxy-
ketone 34, and â-Aryloxy Azide 35. (1R,2R)-Cyclohexane-1,2-diol
(33). To a stirred solution of 9 (47.5 mg, 0.214 mmol) in CH3CN (2.0
mL)/H2O (0.5 mL) at 0 °C was added (NH4)2Ce(NO3)6 (293 mg, 0.534
mmol). The mixture was stirred at the same temperature for 40 min;
then 6 N aq HCl was added. The resultant mixture was continuously
extracted with CHCl3 for 12 h. The organic layer was washed with
brine and then dried over MgSO4. After evaporation, 33 was obtained
Preparation of LiCl free (R,R)-Ga-Li-linked-BINOL Complex
for the X-ray Structure Analysis. To a stirred solution of (R,R)-linked-
BINOL 22 (357.2 mg (14.2 w/w % diethyl ether and hexane included),
0.5 mmol), in THF (4.6 mL) at 0 °C was added Ga(O-i-Pr)3 (123.49
mg, 0.5 mmol) in THF (5 mL), and the solution was stirred for 12 h
at room temperature. It was cooled to 0 °C and BuLi (0.333 mL, 0.5
mmol, 1.5 M in hexane) was added. The reaction mixture was stirred
at room temperature for 3 h. Ga(O-i-Pr)3 CANNOT be stored as a THF
solution, it should be stored as a toluene solution or powder under an
argon atmosphere.
25
as a colorless oil (yield 76%). [R]D -40° (c 0.19, H2O (94% ee));
literature value [R]D -46.5° (c 1.6, H2O).45
25
(2R)-2-(4-Methoxyphenyloxy)cyclohexan-1-one (34). To a stirred
solution of 9 (32.0 mg, 0.144 mmol) and Et3N (60.0 µL, 0.430 mmol)
in DMSO (1.0 mL) was added SO3‚pyridine, and the mixture was stirred
at room temperature for 30 min. The resultant mixture was poured into
ice-cooled water (20 mL) and then extracted with ethyl acetate (10
mL × 3). The combined organic layers were washed with brine and
dried over MgSO4. The solvent was evaporated under reduced pressure
and the residue was purified by flash column chromatography (SiO2,
hexane/ethyl acetate 15/1) to give 34 (32.0 mg, 0.144 mmol, yield
Preparation of the Crystal of (R,R)-Ga-Li-linked-BINOL(thf)3.
The LiCl free Ga-Li-linked-BINOL complex 36 in THF (0.05 M, 1
mL) was evaporated in vacuo. The resulting foam was dissolved in
toluene (0.4 mL). An X-ray quality crystal of LiCl free Ga-Li-linked-
BINOL(thf)3 complex (colorless prism) was grown at room temperature
from toluene solution (0.125 M, 0.4 mL) under argon in the presence
of a trace amount of THF and diethyl ether.
1
100%) as a colorless solid: IR (KBr) ν 2944, 1721, 1508 cm-1; H
(R,R)-Ga-Li-linked-BINOL(thf)3: Collected at 135 K; C65H70O10-
GaLi ) 1087.92; colorless prism, a ) 10.013(5) Å, b ) 19.02(1) Å,
c ) 15.34(1) Å, â ) 106.32(3)°, V ) 2802(3) Å3, monoclinic, P21 (Z
) 2), Dx ) 1.289 g/cm3, R(F) ) 0.067. Other than (thf)3, diethyl ether
× 1, water × 1, and toluene × 1 were incorporated in the crystal. For
data collection and solution and refinement of the structure, see the
supporting information.
NMR (CDCl3) δ 1.69-1.80 (m, 2 H), 1.97-2.07 (m, 3 H), 2.25-2.36
(m, 2 H), 2.58-2.61 (m, 1 H), 3.73 (s, 3 H), 4.50-4.52 (m, 1 H),
6.76-6.95 (m, 4 H); 13C NMR (CDCl3) δ 22.8, 27.8, 34.5, 40.5, 55.7,
23
81.8, 114.6, 117.0, 151.7, 154.4; MS m/z 220 [M+]; [R]D +60.5° (c
0.65, CHCl3 (94% ee)); HPLC (DAICEL CHIRALPAK AD, 2-pro-
panol/hexane 1/99, flow 1.0) tR 14.6 and 16.9 min; HRMS [M+] calcd
for C13H16O3, 220.1099; found, 220.1105.
(1S,2R)-1-Azido-2-(4-methoxyphenyloxy)cyclohexane (35). To a
stirred solution of 9 (36.6 mg, 0.163 mmol) in CH2Cl2 (1.0 mL) at 0
°C were added pyridine (0.5 mL, 6.2 mmol) and MsCl (65 µL, 0.84
mmol). The mixture solution was stirred at room temperature for 2.5
h. The resultant solution was washed successively with 1 N HCl (10
mL × 2), saturated aqueous NaHCO3 (10 mL), and brine (10 mL) and
then dried over MgSO4. After evaporation of solvent, the residue was
purified by flash column chromatography (SiO2, hexane/ethyl acetate
10/1) to give the corresponding mesylate as colorless oil. A portion of
this mesylate (16.0 mg, 0.0533 mmol) was dissolved in DMF (1.0 mL),
and then NaN3 was added at room temperature. The suspension was
stirred at 120 °C for 48 h. The reaction mixture was cooled and diluted
with H2O (20 mL) and then extracted with CH2Cl2 (15 mL × 3). The
combined organic layers were dried over MgSO4 and then evaporated
in Vacuo. The residue was purified by flash column chromatography
Acknowledgment. This study was financially supported by
CREST, The Japan Science and Technology Corporation (JST),
and by a Grant-in Aid for Scientific Research from the Ministry
of Education, Science, and Culture, Japan. J.D. thanks JST and
E.M.V. thanks JSPS.
Supporting Information Available: Detailed results and
discussion about the epoxide opening reaction with Ga-Li-
carbon-linked-BINOL 20 complex, synthetic scheme for 21,
X-ray structural information for 36, 1H NMR spectra of 22, 13
C
NMR spectra of GaLB, 14, 22, 30-32, 34, 35 (PDF), and an
X-ray crystallographic file (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(45) Wilson, N. A. B.; Read, J. J. Chem. Soc. 1935, 1269.
JA993650F