Linker-oriented design of binaphthol derivatives for optical resolution using lipase-catalyzed reaction

Article abstract of DOI:10.1021/jo800351h

(Chemical Equation Presented) Candida antarctica lipase B (CAL-B) is one the most frequently used enzymes in organic synthesis for the preparation of optically active alcohols. However, it has not been used for the optical resolution of (±)-2,2′-binaphthol. We established an efficient linker-oriented design of 2,2′-binaphthol derivatives that is appropriate for optical resolution using CAL-B-catalyzed hydrolysis reaction. Methyl 4-(1-(6-bromo-2-methoxymethoxynaphthalen-1-yl)-6-bromonaphthalen-2-yloxy) butanoate was hydrolyzed by CAL-B to afford a corresponding acid with excellent enantioselectivity (E > 200). Two types of optically active binaphthol derivatives, 1-(2-hydroxy-6-(naphthalen-1-yl)naphthalen-1-yl)-6-(naphthalen-1- yl)naphthalen-2-ol and 6-butyl-1-(6-butyl-2-hydroxynaphthalen-1-yl)naphthalen-2- ol, were prepared by this chemoenzymatic reaction protocol and were used as chiral templates for symmetric reactions.

Full text of DOI:10.1021/jo800351h

Linker-Oriented Design of Binaphthol Derivatives for Optical
Resolution Using Lipase-Catalyzed Reaction
Tomohiro Taniguchi,† Taka-aki Fukuba,† Shuhei Nakatsuka,† Shuichi Hayase,†
Motoi Kawatsura,† Hidemitsu Uno,‡ and Toshiyuki Itoh*,†
Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori UniVersity, 4-101
Koyama-minami, Tottori 680-8552, Japan, and Integrated Center for Sciences, Ehime UniVersity, 2-5
Bunkyo-cho, Matsuyama 790-8577, Japan
titoh@chem.tottori-u.ac.jp
ReceiVed February 15, 2008
Candida antarctica lipase B (CAL-B) is one the most frequently used enzymes in organic synthesis for
the preparation of optically active alcohols. However, it has not been used for the optical resolution of
(()-2,2′-binaphthol. We established an efficient linker-oriented design of 2,2′-binaphthol derivatives that
is appropriate for optical resolution using CAL-B-catalyzed hydrolysis reaction. Methyl 4-(1-(6-bromo-
2-methoxymethoxynaphthalen-1-yl)-6-bromonaphthalen-2-yloxy)butanoate was hydrolyzed by CAL-B
to afford a corresponding acid with excellent enantioselectivity (E > 200). Two types of optically active
binaphthol derivatives, 1-(2-hydroxy-6-(naphthalen-1-yl)naphthalen-1-yl)-6-(naphthalen-1-yl)naphthalen-
2-ol and 6-butyl-1-(6-butyl-2-hydroxynaphthalen-1-yl)naphthalen-2-ol, were prepared by this chemo-
enzymatic reaction protocol and were used as chiral templates for symmetric reactions.
Introduction
for industrial scale syntheses,6 although several methodologies
have been developed for preparing optically active binaphthol
compounds by many groups. 7–9 Therefore, development of an
Axially chiral 2,2′-binaphthol is well respected as a milestone
compound for modern asymmetric synthesis,1,2 and numerous
asymmetric reactions have been developed using chiral 2,2′-
binaphthol derivatives as chiral templates.1–5 However, tedious
classical optical resolution of racemic binaphthol is employed
(2) For examples, see: (a) Noyori, R.; Tomino, I.; Tanimoto, Y. J. Am. Chem.
Soc. 1979, 101, 3129–3131. (b) Noyori, T.; Ohkuma, T. Angew. Chem., Int. Ed.
2001, 40, 40–73. (c) Nishizawa, M.; Yamada, M; Noyori, R. Tetrahedron Lett.
1981, 22, 247–250. (d) Noyori, R. Pure Appl. Chem. 1981, 53, 2315–2322. (e)
Noyori, R.; Tomino, I.; Yamada, M. J. Am. Chem. Soc. 1984, 106, 6717–6725.
(f) Noyori, R.; Tomino, I.; Tanimoto, Y. J. Am. Chem. Soc. 1984, 106, 6709–
6716. (g) Ohkuma, T; Doucet, H; Pham, T. J. Am. Chem. Soc. 1998, 120, 1086–
1087. (h) Kitamura, M; Oka, H; Noyori, R. Tetrahedron 1999, 55, 3605–3614.
(3) For reviews, see: (a) Maruoka, K; Ooi, T; Kano, T Chem. Commun. 2007,
1487–1495. (b) Ooi, T; Maruoka, K. Aldrichim. Acta 2007, 40, 77–86. (c) Ooi,
T; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222–4266. (d) For the original
reaction see: (e) RajOoi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999,
121, 6519–6520.
* To whom correspondence should be addressed. Phone and Fax: +81-857-
31-5259.
† Tottori University.
‡ Ehime University.
(1) For reviews, see: (a) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; John Wiley & Sons, New York, 1994; Chapter 2. (b) Rosini, C.;
Franzini, L.; Raffaelli, A.; Salvadori, P Synthesis 1992, 503–519.
10.1021/jo800351h CCC: $40.75
Published on Web 04/22/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3875–3884 3875

Taniguchi et al.
efficient practical method for chiral 2,2′-binaphthol derivatives
has been awaited.
The enzymatic reactions are now well recognized as an easy
and dependable means of providing enantiomerically pure
products,10 and optical resolution of (()-1 was demonstrated
by enantiospecific hydrolyses using microorganisms.11 Esterases
are the most frequently used enzymes for asymmetric organic
syntheses because of their acceptance of a broad range of
substrates, stability, and availability. The first successful optical
resolution of (()-2,2′-binaphthol (1) by the esterase-catalyzed
reaction was reported by Miyano and co-workers using porcine
pancreatic lipase (PPL).12 Kazlauskas next reported an efficient
example of enantioselctive hydrolysis of dipentanoate of 1 using
cholesterol esterase (EC 3.1.1.3).13 Oda and co-workers further
demonstratedenzymaticresolutionofbinaphthol1usingPseudomo-
nas aeruginosa lipase (LPL-A or LIP, Toyobo).14 After these
works, two types of indirect methods were also developed by
Lin15 and Hauser,16 respectively. However, development of a
more efficient biocatalyst reaction protocol using commercially
available enzymes for preparing chiral binaphthol has remained
a challenging topic in organic synthesis.
We were especially interested in the poor reactivity of lipases
for 2,2′-binaphthol derivatives and recognized that three types
of typical commercially available lipase, C. antarctica lipase
B (CAL-B: Novozym435 and Chirazyme L-2), lipase PS from
Burkholderia cepacia, and Candida rugosa lipase, in fact,
showed no reactivity for 2,2′-binaphthol (1) or binaphthyl
(4) For a review, see: (a) Matsunaga, S; Ohshima, T; Shibasaki, M. AdV.
Synth. Catal. 2002, 344, 3–15. For typical examples, see: (b) Sasai, H.; Itoh,
N.; Suzuki, T.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 855–858. (c) Sasai,
H.; Arai, S.; Tahara, Y.; Shibasaki, M. J. Org. Chem. 1995, 60, 6656–6657. (d)
Sasai, H; Watanabe, S; Shibasaki, M. Enantiomer 1997, 2, 267–271. (e)
Shibasaki, M; Sasai, H; Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 1237–
1256. (f) Vogl, E. M.; Matsunaga, S; Kanai, M.; Iida, T.; Shibasaki, M.
Tetrahedron Lett. 1998, 39, 7917–7920. (g) Yoshikawa, N; Yamada, Y.; Das,
J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168–4178. (h)
Yoshikawa, N.; Kumagai, N.; Matsunaga, S.; Moll, G.; Oshima, T.; Suzuki, T.;
Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466–2467.
(5) For typical examples, see: (a) Evans, D. A.; Dinsmore, C. J.; Evrard,
D. A.; DeVries, K. M. J. Am. Chem. Soc. 1993, 115, 6426–6427. (b) Lipshutz,
B. H.; Liu, Z. -P.; Kayser, F. Tetrahedron Lett. 1994, 35, 5567–5570. (c)
Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S. J. Org. Chem. 1999,
64, 2264–2271. (d) Luo, Z.; Liu, Q.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y. Angew.
Chem., Int. Ed. 2002, 41, 4532–4535.
FIGURE 1. Working hypothesis of linker-oriented design of binaphthol
derivatives applicable to CAL-B-catalyzed reaction. The 3D structure
of CAL-B was produced by RasMol using X-ray structure data reported
by Jones et al.20
(6) (a) Jacques, J.; Fouguey, C. Org. Synth. 1988, 67, 1–12. (b) Truesdale,
L. K. Org. Synth. 1988, 67, 13–19. (c) Gong, B.-Q.; Chen, W.-Y.; Hu, B. -F. J.
Org. Chem. 1991, 56, 423–425.
carboxylic methyl ester (()-2a. Sih17a and Achiwa17b indepen-
dently reported the successful protocol for designing 4-aryl-
1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylates as substrate
for the enzymatic hydrolysis reaction: modification of the
carbonyl group as acyloxymethyl ester made possible smooth
hydrolysis by the Pseudomonas lipase with high enantioselec-
tivity, while lipases showed poor reactivity vs a simple methyl
ester.17 However, we found that both CAL-B and lipase PS were
inactive to binaphthyl diester 2b (Figure 1).17a
Recently, Aoyagi and co-workers reported interesting results
for the lipase-catalyzed reaction using binaphthol derivatives
as substrates;18 P. aeruginosa lipase-catalyzed acylation pro-
ceeded smoothly when (()-3c (n ) 2) was subjected to the
reaction, while the lipase showed no reactivity for 3a (n ) 0)
or 3b (n ) 1).19 In addition, the same authors reported that
compound 4c (n ) 2) was converted to the corresponding amide
(7) (a) Hattori, T.; Suzuki, T.; Miyano, S. J. Chem. Soc., Chem. Commun.
1991, 1375–1376. (b) Meyer, A. I.; Moorlag, H. Tetrahedron Lett. 1993, 34,
6989–6992.
(8) (a) Hall, D. M.; Turner, E. E. J. Chem. Soc. 1955, 1242. (b) Toda, F.;
Tanaka, K.; Stein, Z.; Goldberg, I. J. Org. Chem. 1994, 59, 5748–5751. (c) Itoh,
T.; Chika, J.; Shirakami, S.; Ito, H.; Yoshida, T.; Kubo, Y.; Uenishi, J. J. Org.
Chem. 1996, 61, 3700–3705.
(9) (a) Toda, F.; Tanaka, K.; Iwata, S. J. Org. Chem. 1989, 54, 3007–3011.
(b) Doussot, J.; Guy, A.; Ferroud, C. Tetrahedron Lett. 2000, 41, 2545–2545.
(10) For reviews, see: (a) Wong C.-H., Whitesides G. M., Enzymes in
Synthetic Organic Chemistry; Pergamon, Oxford, 1994. (b) Bornscheuer, U. T.;
Kazlauskas, R. J. Hydrolases in Organic Synthesis: Regio-And StreoselectiVe
Biotransformation; John Wiley & Sons, Inc.: Chichester, 1999. (c) Matsuda, T.,
Ed. Future Directions in Biocatalysis; Elsevier: The Netherlands, 2007.
(11) (a) Fujimoto, Y.; Iwadate, H.; Ikekawa, N. J. Chem. Soc., Chem.
Commun. 1985, 1333–1334. (b) Wu, S.-H.; Zhang, L.-Q.; Chen, C.-S.;
Girdauskas, G.; Sih, C. J. Tetrahedron Lett. 1985, 26, 4323–4326.
(12) Miyano, S.; Kawahara, K.; Imone, Y.; Hashimoto, H. Chem. Lett. 1987,
355–356.
(13) (a) Kazlauskas, R. J. Am. Chem. Soc. 1989, 111, 4955–4959. (b)
Kazlauskas, R. Org. Synth. 1991, 70, 60–67. (c) Kazlauskas, R. Organic
Syntheses; Wiley: New York, 1998; Collect. Vol. IX, pp 77-84.
(14) Inagaki, M.; Hiratake, J.; Nishioka, T.; Oda, J. Agric. Biol. Chem. 1989,
53, 1879–1884.
(17) (a) Holdgru¨n, X. K.; Sih, C. J. Tetrahedron Lett. 1991, 32, 3465–3468.
(b) Ebiike, H.; Terao, Y.; Achiwa, K. Tetrahedron Lett. 1991, 32, 5805–5808.
(c) Salazar, L.; Sih, C. J. Tetrahedron: Asymmetry 1995, 6, 2917–2920. (d)
Hirose, Y.; Kariya, K.; Nakanishi, Y.; Kurono, Y.; Achiwa, K. Tetrahedron Lett.
1995, 36, 1063–1066.
(15) Lin, G.; Liu, S.-H.; Chen, S.-J.; Wu, F.-C.; Sun, H.-L. Tetrahedron Lett.
1993, 34, 6057–6058.
(16) Hauser, F. M.; Sengupta, D.; Corlett, S. A. J. Org. Chem. 1994, 59,
1967–1969.
(18) Aoyagi, N.; Izumi, T. Tetrahedron Lett. 2002, 43, 5529–5531.
3876 J. Org. Chem. Vol. 73, No. 10, 2008

Design of Binaphthols for Enzymatic Resolution
with acceptable enantioselectivity by the reaction with 3-ami-
nopropanenitrile using CAL-B, while no reaction took place
for biaryl compounds 4a (n ) 0) and 4b (n ) 1) (Figure 1).19
These results clearly suggested that the chain length between
the binaphthyl ring with the reaction point of the carboxyl group
critically influenced reactivity of the lipase. We were fascinated
by these interesting phenomena of lipase reactivity to the
binaphthol derivatives and decided to investigate the designs
of binaphthol derivatives that are appropriate for CAL-B-
catalyzed transformation. We expected that useful information
about the origin of enantioselectivity of the lipase might be
obtained through this study.
and the resulting mixture was stirred at 35 °C (eq 1). The
reaction was monitored by silica gel thin-layer chromatog-
raphy (TLC), and lipase was removed by filtration through a
glass sintered filter and washed with ethyl acetate. The
combined organic layers were dried and evaporated, and the
acid produced and remaining ester were purified by silica
gel thin-layer chromatography (TLC). The results are sum-
marized in Table 1.
It is reported that there exists a crevice in CAL-B and that
the substrate is taken into the enzyme through this crevice.
According to the results of X-ray crystallographic analysis
(Figure 1), the area of the crevice was estimated to be 10 × 25
Å and the distance between the entryway from the active site
of the enzyme (Ser 105) to be 8 Å.20
Although the size of the crevice seemed to be large enough
for entry of the binaphthyl compounds 1 and 2, no reaction took
place when these compounds were treated with CAL-B. It is
therefore anticipated that there is a certain narrow area within
the crevice which might prevent hydroxyl groups on the
binaphthyl rings from accessing the active site of the enzyme
because the two naphthyl rings are twisted and act as a very
bulky molecule. Ema proposed that the enantioselectivity of the
lipase-catalyzed reaction might be determined mainly by the
kinetic preference due to the conformational requirements and
repulsive interaction in the transition state.21 Kazlauskas and
co-workers reported an efficient design of primary alcohols that
are appropriate for the lipase-catalyzed reaction by tuning of
acyl chain length.22 Based on these results, we hypothesized
that a binaphthol-substituted carboxylic acid methyl ester that
has an appropriate linker group between the 2-hydroxyl group
of binaphthol and the terminal methoxycarbonyl group might
become a good substrate for lipase-catalyzed enantiospecific
hydrolysis reaction. We tested the reaction of binaphthyl-
substituted glycolic acid derivatives 5a and 5b and confirmed
that no reaction took place for these compounds. Therefore, it
was anticipated that at least two or three of the methylene groups
might be required as a linker between the naphthyl ring and
terminal carboxyl group for the enzymatic hydrolysis. In this
paper we wish to report our successful design of binaphthol
derivatives that are appropriate for efficient optical resolution
by commercial CAL-B-catalyzed reaction.
As anticipated, the alkyl chain length of the linker group was
very important for the reaction. We found that binaphthyl-
substituted butanoic acid methyl ester (()-6a was hydrolyzed
smoothly by the lipase, but poor enantioselectivity was recorded
(entry 1).
On the other hand, the desired enantioselective hydrolysis
reaction was accomplished when methoxymethyl-protected 2,2′-
binaphthol derivative (()-6b was used as substrate for the CAL-
B-catalyzed reaction; the desired acid (R)-(+)-7b was obtained
in 66% yield with 75% ee and unreacted ester (S)-6b was
obtained in 34% yield with 92% ee (entry 2).
The E value23 was estimated as 21; although this value seems
to be modest, this is an amazing selectivity because there is a
great distance between the hydrolysis point and the chiral point
of 6b. To confirm the absolute configuration of the lipase-
catalyzed reaction, (+)-7b (75% ee) was converted to 2,2′-
binaphthol (1) by the reaction with boron tribromide (BBr3) in
dichloromethane (CH2Cl2) with 80% yield. Since the resulting
2,2′-binaphthol (1) showed a positive sign of optical rotation
([R]22 +27 (c 1.0, THF); lit.14 [R]22 +31 (R)), the absolute
D
D
configuration of (+)-7b produced was determined to be the (R)-
form.
Design of the protecting group of the hydroxyl group on the
binaphthyl ring was also important; no reaction for compound
(()-6c (entry 3) or (()-6d (entry 4) was obtained, although
these have the same alkylcarboxylic acid moiety to be hydro-
lyzed. It was thus established that protection of the 2′-hydroxy
group on the binaphthyl ring as methoxymethyl (MOM) ether
was essential for realization of the enantioselective reaction;
the methoxymethyl (MOM) group of the hydroxyl group of
BINOL seemed to play a very important role in the enantiomer
discrimination step of the enzymatic reaction.
Flexibility of the linker portion was also a very important
factor for the lipase-catalyzed reaction because lipase could not
hydrolyze (()-6e (entry 5). On the other hand, the hydrolysis
reaction of octanoic ester derivative (()-6f proceeded rapidly
but with no enantioselectivity (entry 6). Since the chain length
of (()-6f is very long compared to the distance between the
active site and entryway of the enzyme, these results might
suggest that the origin of the enantioselectivity of the present
Results and Discussion
1. Design of Binaphthol Derivatives for CAL-B-Catalyzed
Reaction. We expected that CAL-B-catalyzed optical resolution
of binaphthol derivatives might be possible using appropriately
modified binaphthol (()-6. Typically, the reaction was carried
out as follows: to a mixture of substrate ester (()-6 in a mixed
solvent of a buffer (0.1 M potassium phosphate buffer pH 7.2)
and acetone (1:10) was added lipase (50 wt % vs substrate),
(19) Aoyagi, N.; Kawauchi, S.; Izumi, T. Tetrahedron Lett. 2003, 44, 5609–
5612.
(20) Uppenberg, J.; Hansen, M. T.; Patkar, S.; Jones, T. A. Structure 1994,
2, 293–308.
(21) (a) Ema, T.; Kobayashi, J.; Maeno, S.; Sakai, T.; Utaka, M. Bull. Chem.
Soc. Jpn. 1998, 71, 443–453. (b) Ema, T. Tetrahedron: Asymmetry 2004, 15,
2765–2720.
(22) Mezzetti, A.; Keith, C.; Kazlauskas, R. J. Tetrahedron: Asymmetry 2003,
14, 3917–3924.
(23) Chen, C. -S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc.
1982, 102, 7294–7298.
J. Org. Chem. Vol. 73, No. 10, 2008 3877

Taniguchi et al.
TABLE 1. Results of CAL-B-Catalyzed Hydrolysis of Binaphthol Derivatives (()-6
a Determined by HPLC analysis (Chiralcel AD, hexane/2-propanol/TFA ) 9:1:0.01). b E) ln[1 - c(1 + eep)]/ln[1 - c(1 - eeP)], where c ) eeS/(eeP
+ eeS). c c ) conv. See ref 23.
enzymatic reaction is basically caused by interaction of the
axially chiral binaphyl group with the entryway of the lipase
protein as we initially hypothesized.
of the lipase.24 Introduction of the hydroxy group at the 7,7′-
position of binaphthyl was effective to increase enantioselectivity
(24) (a) Taniguchi, T.; Fukuba, T.; Hayase, S.; Itoh, T. Abstract. 85th CSJ
Annual Meeting, Kanagawa, Japan, 2005, 2F2-29. Taniguchi, T.; Kawatsura,
M.; Hayase, S.; Itoh, T. Abstract. Pacifichem, Hawaii, 2005.
We next discovered that the functional group existing on the
B-ring of the naphthyl group significantly affected the reactivity
3878 J. Org. Chem. Vol. 73, No. 10, 2008

Design of Binaphthols for Enzymatic Resolution
SCHEME 1. Synthesis of Binaphthol Derivative (S)-9
of the enzymatic reaction; a highly enantioselective reaction (E
value 74) was accomplished for compound 6g (entry 7).
However, no reaction took place for benzyl-protected compound
6h (Entry 8). We finally found that 6,6′-dibromobinaphthyl
derivative 6i was the best substrate for CAL-B catalyzed reaction
(entry 9);24 optically pure acid (R)-7i was obtained in 35% yield
with over 99% ee, and the E value reached over 200. These
results are very interesting in that such an excellent enantiose-
lective hydrolysis was accomplished for the hydrolysis of the
methoxycarbonyl group apart from the chiral binaphthyl moiety.
Since a reduced reaction rate was obtained for 6i compared to
that of 6b, we are assuming that presence of the appropriate
functional group at the 6- and 7-positions of the naphthyl ring
might play an important role in the arrangement of the
compound to fit the active site correctly or may contribute to
enhance the difference in transition-state energy over the course
of the hydrolysis reaction between two enantiomers. It was thus
found that 4-binaphthyloxybutanoates were suitable substrates
for CAL-B-catalyzed reaction, and compounds 6j, 6k, and 6l
were next prepared and tested as substrates for this reaction.
However, no reaction took place when methyl succinate (()-
6j was used as substrate (entry 10), although it was estimated
that the distance between the reaction point and the binaphthyl
ring was almost the same as that of (()-6b (7.29 Å estimated
by the PM3 calculation). Fortunately, good results were obtained
when methyl glutarate derivatives, (()-6k and (()-6l, were
subjected to the reaction; the E value reached 40 for the reaction
of 6l (entry 12) and 17 for the reaction of 6k (entry 11). Since
the present reaction is a kinetic resolution of racemic com-
pounds, it is easy to obtain both enantiomers with optically pure
form by stopping the reaction at an appropriate conversion.
Because CAL-B is an economical and a commercially available
enzyme, we thus established a practical method to prepare
optically active 2,2′-binaphthol derivatives.
(S)-9 was next demonstrated using Suzuki-Miyaura coupling
protocol (Scheme 1).27
Binaphthyl (S)-7i (97% ee) which was derived from (S)-6i
was reacted with 1-naphthylboronic acid in the presence of 10
mol % of tetrakistriphenylphosphinepalladium (Pd(PPh3)4) in
a mixed solvent of 2 M NaOH aqueous solution and THF at 60
°C for 24 h to give the corresponding coupling product (S)-8 in
99% yield. This was treated with boron tribromide (BBr3) in
CH2Cl2 at 78 °C and allowed to warm to room temperature (rt)
for 5 h. However, unfortunately, we encountered the unexpected
problem that removal of the linker moiety of (S)-8 was difficult
and deprotection of the MOM group took place easily under
the conditions used, so that desired (S)-928 was obtained in low
yield with an unidentified complex mixture (Scheme 1).
On the other hand, we did succeed in removing the linker
moiety more conveniently through hydrolysis of (R)-7l under
basic conditions, and (R)-1029 was obtained in 99% yield. (R)-
10 was then converted to di-MOM ether (R)-11, which was next
converted to (R)-12 using Pd-catalyzed alkylation by the reaction
with butylmagnesium bromide (Scheme 2).30 We next prepared
(R)-9 again using (R)-11 following the Suzuki-Miyaura cou-
pling reaction: Pd-catalyzed coupling reaction of (R)-11 with
1-naphthylboronic acid proceeded very smoothly to give (R)-
13, and subsequent deprotection of the MOM group gave (R)-
930 in 77% yield (two steps). X-ray crystallographic analysis
of (R)-12 was successful, and the ORTEP view is shown in
Figure 2.31 (S)-9 and (S)-12 were also prepared following the
same route from (S)-6l.
It is recognized that lipases are generally inactive to bulky
substrates at room temperature. Recently, Sakai and Ema
provided a surprisingly simple solution to this problem: they
demonstrated that several bulky alcohols were acylated by a
lipase under high temperature conditions (60-80 °C) while
maintaining good enantioselectivity.21b,25 It was, therefore,
expected that high-temperature lipase-catalyzed reaction might
be applicable to bulky binaphthol derivatives; this idea was
realized by Aoyagi and co-workers recently: 1-(2-hydroxynaph-
thalen-1-yl)naphthlen-2-yl butyrate was converted to (R)-2,2′-
binaphthol by CAL-B-catalyzed alcoholysis reaction at 80 °C,
and no reaction took place if the reaction was carried out at 30
°C.26
On the other hand, we have established that lipase can
hydrolyze binaphthol derivatives that connected with an ap-
propriate linker even at 35 °C. Although our chemical modifica-
tion protocol of binaphthol may be less convenient than the high-
temperature method, it obviously provides another solution of
enzymatic reactions for bulky compounds.
Since compound 7i has two bromide groups at the 6,6′-point,
various types of binaphthol derivatives could be converted from
this compound. Synthesis of 6- and 6′-aryl-substituted binaphthol
(27) (a) Hoshino, Y.; Miyaura, N.; Suzuki, A. Bull. Chem. Soc. Jpn. 1988,
61, 3008–3010. For a recent review, see: (b) Miyaura, N. Top. Curr. Chem.
2002, 219, 11. (c) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(28) Chen, R.-F.; Qian, C.-T.; Johannes, G. V.; Sun, P. P.; Wang, L.-M.
Chin. J. Chem. 2001, 19, 1225–1231.
(25) (a) Ema, T.; Kageyama, M.; Korenaga, T.; Sakai, T. Tetrahedron:
Asymmetry 2003, 14, 3943–3947. (b) Sakai, T.; Matsuda, A.; Tanaka, Y.;
Korenaga, T.; Ema, T. Tetrahedron: Asymmetry 2004, 15, 1929–1932. (c) Ema,
T.; Doi, T.; Sakai, T. Chem. Lett. 2008, 37, 90–91.
(29) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122,
8180–8186.
(30) Brunkan, N. M.; Gague, M. R. J. Am. Chem. Soc. 2000, 122, 6217–
6225.
(26) Aoyagi, N.; Ogawa, N.; Izumi, T. Tetrahedron Lett. 2006, 47, 4797–
4801.
(31) The crystallographic data of (R)-12 is available as a CIF file (Supporting
Information).
J. Org. Chem. Vol. 73, No. 10, 2008 3879

Taniguchi et al.
TABLE 2. Results of La-BINOL-Catalyzed Asymmetric Henry
Reaction
entry
catalyst
yield of 14 (%)
% eea
1
2
3
(S)-BINOL (1)
(S)-9
(S)-12
63
70
81
74
79
73
a Determined by HPLC analysis (Chiralcel AD, hexane/2-propanol )
9:1, 35 °C).
2. Application of BINOL Derivatives As Templates for
Asymmetric Reactions. We then investigated the applicability
of BINOL derivatives 9 and 12 as chiral ligands for the
asymmetric Henry reaction of 3-phenylpropionaldehyde cata-
lyzed La-BINOL complex that was developed by Shibasaki
(eq 2).32
FIGURE 2. ORTEP view of (R)-12. C28H30O2, formula weight )
398.54, monoclinic, space group P21(#4), a ) 10.195(6) Å, b )
8.387(5) Å, c ) 13.540(9) Å, b )108.076(17)°, V) 1100.6(11)3, Z )
2, dcalc ) 1.203 g cm-3, R(Rw) ) 0.0500 for 11705 diffraction data
with I > 2.00σ(I) and 281 valuable.
SCHEME 2. Synthesis of Two Types of Binaphthol
Derivatives, (R)-9 and (R)-12
We anticipated that La complexes prepared from (S)-12 might
be easily dissolved in a conventional organic solvent such as
THF and thus contribute to increase the efficiency of the catalyst
system. As expected, La complex made by (S)-12 was easily
dissolved in THF and chemical yield of the product nitro alcohol
14 was indeed improved to 81% (entry 3) from 63% (entry 1),
which was obtained for the La complex made from (S)-BINOL
((S)-1) while maintaining the enantioselectivity (Table 2). On
the other hand, a slightly enhanced enantioselectivity was
recorded when the La complex made from (S)-9 was used as
catalyst (entry 2).
We next tested asymmetric diethyl zinc reaction with ben-
zylaldehyde in the presence of Ti-BINOL complex developed
by Mori and Nakai (eq 3).33 In the reaction, it was again
anticipated that solubility of the Ti complex toward the solvent
system might affect the efficiency of the reaction. As expected,
improved chemical yield of product 15 was obtained when the
Ti complex made from (S)-12 was used as catalyst (Table 3,
entry 3), although no difference in the enatioselectivity was
recorded. In this reaction, both chemical yield and enantiose-
(32) (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem.
Soc. 1992, 114, 4418–4420. (b) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki,
T.; Itoh, N.; Shibasaki, M. J. Org. Chem. 1995, 60, 7388–7389.
(33) Mori, M.; Nakai, T. Tetrahedron Lett. 1997, 38, 6233–6236.
3880 J. Org. Chem. Vol. 73, No. 10, 2008

Design of Binaphthols for Enzymatic Resolution
TABLE 3. Results of Ti-BINOL-Mediated Asymmetric Addition
of Benzaldehyde with Diethylzinc
s), 3.12 (3H, s), 3.92-4.08 (2H, m), 4.93 (1H, d, J ) 6.7 Hz),
5.08 (1H, d, J) 6.7 Hz), 7.05-7.28 (6H, m), 7.35 (1H, d, J ) 9.1
Hz), 7.50 (1H, d, J ) 9.1 Hz), 7.80 (2H, q, J ) 5.5 Hz), 7.88 (2H,
dd, 1.9 Hz, J ) 8.7 Hz); 13C NMR (125 MHz, CDCl3) δ 24.2 (3C),
29.6 (2C), 55.7 (Me-MOM), 68.3 (4C), 95.0 (CH2-MOM), 115.8,
117.1, 120.6, 121.2, 123.7, 124.0, 125.3, 125.4, 126.2, 126.3, 127.8,
127.9, 129.3, 129.4, 129.8, 133.9, 134.0, 152.5, 154.0, 179.3 (1C).
Anal. Calcd for C26H24O5: C, 74.98; H,5.81. Found: C, 74.69; H,
5.85.
entry
catalyst source
yield of 15 (%)
% eea
1
2
3
(S)-BINOL (1)
(S)-9
(S)-12
79
76
85
84
72
82
a Determined by HPLC analysis (Chiralcel OD-H, hexane/2-propanol
) 100:1, 35 °C).
(S)-6b: 92% ee (Chiralpak AD, hexane/2-propanol ) 9:1, 35
°C); tR ) 5.9 min for (S)-isomer, 6.9 min for (R)-isomer; [R]28
D
lectivity were slightly reduced when the Ti complex made from
(S)-9 was used as catalyst to the reaction (entry 2).
-42.6 (c 1.0, CHCl3) .
(R)-(+)-7b (75% ee) was treated with BBr3 in dichloromethane
at -78 °C to give (R)-(+)-2,2′-binaphthol (1): [R]22 +26 (c 1.0,
D
THF) (lit.14 [R]22 +31 (c 1.0, THF)) for 98% ee of (R)-1a. (S)-
Conclusion
D
(-)-6b (92% ee) was converted to (S)-(-)-1a by the same
procedure: [R]22 -32 (c 1.0, THF) (lit.12 -35 (c 1.18, THF)),
In summary, we established a linker-oriented design of
binaphthol derivatives that made it possible to modify binaphthol
applicable for kinetic resolution of commercially available C.
antarctica lipase B; methyl 4-(1-(2-(methoxymethoxy)-6-bro-
monaphthalen-1-yl)-6-bromonaphthalen-2-yloxy)butanoate (6i)
and 6-bromo-1-(6-bromo-2-(methoxymethyloxy)naphthalen-1-
yl)naphthalen-2-yl glutaric acid methyl ester (6l) were thus
prepared as appropriate substrates for CAL-B-catalyzed reaction.
CAL-B-catalyzed hydrolysis of (()-6i or 6l was very successful,
and the corresponding acid (R)-7i or (R)-7l was obtained with
excellent enantioselectivity. It is amazing that such an excellent
enantioselective hydrolysis was accomplished by the hydrolysis
of the methoxy carbonyl group of compounds 6i or 6l, both of
which are apart from the chiral binaphthyl moiety. Since both
compounds 7i and 7l have two bromide groups at 6,6′-points
on the binaphthyl rings, it is possible to convert them to various
types of binaphthol derivatives. Two types of 2,2′-binaphthol
derivatives, 9 and 12, were thus prepared and used as chiral
templates for symmetric reactions. We believe that the present
results provide not only a solution for preparation of chiral
binaphthol derivatives using an enzymatic reaction but also
provide a hint to the consideration of the origin of the enantiomer
recognition of the lipase-catalyzed reaction.
D
100% ee .
(()-6b: bp 198-200 °C, 3.0 mmHg (Kugelrohr); Rf 0.38
(hexane/ethyl acetate ) 3/1); IR (KBr) 2902, 2825, 1732 (CO),
1622, 1591, 1433, 1015, 810 cm-1; 1H NMR (500 MHz, CDCl3) δ
1.59-1.72 (2H, m), 1.74-1.88 (2H, m), 3.06 (3H, s), 3.46 (3H,
s), 3.85-4.00 (2H, m), 4.88 (1H, d, J ) 6.7 Hz), 5.02 (1H, d, J)
6.7 Hz) 7.05-7.28 (6H, m), 7.35 (1H, d, J ) 9.1 Hz), 7.50 (1H, d,
J ) 9.1 Hz), 7.80 (2H, q, J ) 5.5 Hz), 7.88 (2H, dd, 1.9 Hz, J )
8.7 Hz); 13C NMR (125 MHz, CDCl3) δ 24.7 (3C), 29.8 (2C), 51.59
(OMe), 55.9 (Me-MOM), 68.6 (4C), 95.3 (CH2-MOM), 115.9,
117.4, 120.7, 121.4, 123.9, 124.1, 125.6, 126.3, 126.4, 128.0, 129.4,
129.4, 129.5, 130.0, 134.1, 134.2, 152.7, 154.2, 173.8 (1C). Anal.
Calcd for C27H26O5: C, 75.33; H,6.09. Found: C, 75.16; H, 6.14.
Optical Resolution of (()-6g. (R)-7g: 92% ee (Chiralpak AD,
hexane/2-propanol/TFA ) 4:1:0.01, 35 °C), tR ) 18.7 min for (R)-
isomer, 12.8 min for (S)-isomer; [R]25D +27.8 (c 1.0, MeOH); mp
215 °C (recrystallized from CH2Cl2); Rf 0.11 (hexane/ethyl acetate/
MeOH ) 20:20:1); IR (KBr) 3320, 2941, 1701 (CO), 1624, 1238,
1
1217, 1029, 966, 830 cm-1; H NMR (500 MHz, δ, methanol-d4)
δ 1.54-1.67 (2H, m), 1.80-1.92 (2H, m), 3.04 (3H, s), 3.84-3.96
(2H, m), 4.77 (b), 4.89 (1H, d, J ) 6.4 Hz), 5.08 (1H, d, J) 6.4
Hz), 6.31 (1H, d, J ) 2.3 Hz), 6.33 (1H, d, J ) 2.8 Hz), 6.78 (1H,
dd, J ) 2.8 Hz, 9.0 Hz), 6.80 (1H, dd, J ) 2.3 Hz, 9.0 Hz), 7.16
(1H, d, J ) 9.1 Hz), 7.25 (1H, d, J ) 8.7 Hz), 7.61 (1H, d, J ) 6.4
Hz), 7.63 (1H, d, J ) 6.4 Hz), 7.71 (1H, d, J ) 7.3 Hz), 7.73 (1H,
d, J ) 7.3 Hz); 13C NMR (125 MHz, acetone-d6) δ 25.1 (3C),
29.5 (2C), 55.2 (Me-MOM), 68.3 (4C), 95.0 (CH2-MOM), 106.9,
107.1, 112.8, 114.3, 116.4, 116.7, 119.2, 120.1, 124.9, 125.3, 129.0,
129.3, 129.9, 130.0, 136.1, 136.2, 153.5, 155.1, 156.0, 156.1,
174.0(1C). Anal. Calcd for C24H26O7: C, 69.63; H, 5.39. Found:
C, 69.25; H, 4.94. (S)-6g: 90%ee (Chiralpak AD, hexane/2-propanol
) 4:1, 35 °C), tR ) 16.7 min for (R)-isomer, 10.5 min for (S)-
Experimental Section
Using CAL-B-catalyzed hydrolysis, optical resolution of (()-
6g, (()-6i, (()-6k, and (()-6l was accomplished. However, no
reaction took place when (()-6c, 6d, 6e, 6h, or 6j was subjected
to the CAL-B-catalyzed reaction. For the syntheses of substrates
6a-l for the enzymatic reaction, see the Supporting Information.
CAL-B-Catalyzed Enantioselective Hydrolysis of (()-6b. To
a solution of (()-6b (50 mg, 0.12 mmol) in acetone (1 mL) and
0.1 mL of 0.1 M potassium phosphate buffer (pH7.2) was added
CAL-B (Novozym435: 25 mg, 50 wt %). After being stirred at 35
°C for 48 h, the reaction mixture was filtered though a glass sintered
filter with a Celite pad to remove the lipase. The filtrate was dried
(MgSO4), evaporated, and purified by silica gel thin-layer chro-
matography (TLC) (hexane/ethyl acetate/methanol ) 10:10:1) to
give (R)-7b (26 mg, 0.060 mmol, 66%) and (S)-6b (19.5 mg, 0.040
mmol, 34%). It was possible to reduce the amount of CAL-B while
maintaining high enantioselectivity, but it took a longer reaction
time (4 days) to reach ca. 50% conversion when 10 wt % of CAL-B
was used. From a practical standpoint, we decided to test the
reactions using 50 wt % of enzyme vs substrate.
isomer; [R]25 -31.0 (c 1.0, MeOH).
D
(()-6g: mp 145 °C (recrystallized from CH2Cl2); Rf 0.49 (hexane/
ethyl acetate/methanol ) 20/20/1); IR (KBr) 3377, 1709 (CO),
1624, 1510, 1439, 1217, 1146, 1030, 966, 829 cm-1; 1H NMR (500
MHz, CDCl3) δ 1.72 (2H, qu, J ) 6.0 Hz), 1.85-1.97 (2H, m),
3.10 (3H, s), 3.52 (3H, s), 3.92-4.02 (2H, m), 4.89 (1H, d, J )
6.9 Hz), 5.04 (1H, d, J) 6.9 Hz), 5.04 (1H, s), 5.26 (1H, brs), 6.40
(1H, d, J ) 2.3 Hz), 6.41 (1H, d, J ) 2.2 Hz), 6.91 (1H, dd, J )
2.3 Hz, 8.8 Hz), 6.94 (1H, dd, J ) 2.3 Hz, 8.8 Hz), 7.20 (1H, d, J
) 9.1 Hz), 7.32 (1H, d, J) 9.1 Hz), 7.72 (1H, d, J ) 5.1 Hz), 7.74
(1H, d, J ) 5.1 Hz), 7.80 (1H, s), 7.82 (1H, s); 13C NMR (125
MHz, CDCl3) δ 24.2 (3C), 29.5 (2C), 51.6 (OMe), 55.5 (Me-
MOM), 68.0 (4C), 94.7 (CH2-MOM), 107.0, 107.2, 112.8, 114.4,
115.8, 116.1, 118.7, 119.9, 124.6, 125.2, 129.0, 129.7, 135.1, 135.2,
152.7, 154.3, 174.5(1C). Anal. Calcd for C27H26O7: C, 70.12; H,
5.67. Found: C, 70.06; H, 5.50.
(R)-7b: 75% ee (Chiralpak AD, hexane/2-propanol/trifluoroacetic
acid (TFA) ) 9:1:0.01, 35 °C); tR ) 10.2 min for (R)-isomer, 8.1
min for (S)-isomer; [R]28 +17.0 (c 1.0, CHCl3); Rf 0.4 (hexane/
Optical Resolution of (()-6i. Since the enantioselectivity of the
CAL-B-catalyzed reaction of (()-6i was extremely high, we
conducted the a multigram scale reaction for this compound as
follows: To the solution of (()-6i (2.95 g, 5.01 mmol) in acetone
D
ethyl acetate ) 3:1) ; IR (KBr) 3010 (OH), 2936, 1705 (CO), 1622,
1593, 1506, 1355, 1240, 1015, 920, 810, 752 cm-1; 1H NMR (500
MHz, CDCl3) δ 1.65-1.79 (2H, m), 1.82-1.95 (2H, m), 3.06 (3H,
J. Org. Chem. Vol. 73, No. 10, 2008 3881

Taniguchi et al.
(50 mL) and pH 7.2 buffer (5.0 mL) was added CAL-B (No-
vozym435: 1.45 g, 50 wt %). After being stirred at 35 °C for 64 h,
the reaction mixture was filtered though a glass sintered filter with
a Celite pad to remove the lipase. The filtrate was evaporated under
vacuum, and then the residue was diluted with ether and washed
with brine. The ether layer was dried (MgSO4), evaporated, and
chromatographed on a silica gel flash column (hexane/acetone )
5/1 and hexane/acetone ) 2/1) to give (R)-7i (1.00 g, 1.75 mmol,
35%) and (S)-6i (1.42 g, 2.40 mmol, 48%). Since the reaction is a
kinetic resolution, we succeeded in obtaining optically pure (S)-6i
in 44% yield when (()-6i was treated with lipase for 72 h.
(R)-7i: >99% ee (Chiralpak AD, hexane/2-propanol/TFA ) 9:1:
0.01, 35 °C), tR ) 13.5 min for (R)-isomer, 14.3 min for (S)-isomer;
(1H, s), 7.95 (1H, s), 7.99 (1H, d, J ) 8.7 Hz); 13C NMR (125
MHz, CDCl3) δ 19.6 (3C), 32.2 (4C), 33.0 (2C), 51.4 (OMe), 55.8
(Me-MOM), 94.9 (CH2-MOM), 116.5, 119.2, 121.8, 124.1, 125.1,
125.4, 125.5, 126.1, 126.4, 126.5, 127.7, 128.0, 129.0, 129.5, 129.9,
131.7, 133.5, 133.6, 146.6, 152.6, 170.9(5C), 173.0(1C). Anal.
Calcd for C28H26O6: C, 73.35; H, 5.72. Found: C, 73.70; H, 5.65.
Optical Resolution of (()-7l. (R)-7l: 92% ee (Chiralpak AD,
hexane/2-propanol/TFA ) 4:1:0.01, 35 °C), tR ) 18.7 min for (R)-
isomer, 12.7 min for (S)-isomer; [R]25D +28 (c 1.0, MeOH); Rf 0.2
(hexane/ethyl acetate/MeOH ) 20:20:1); IR (KBr) 2950, 1757
(CO), 1709 (CO), 1585, 1492, 1201, 1024, 878, 756 cm-1; 1H NMR
(500 MHz, CDCl3) δ 1.40-1.53 (2H, m), 1.87-1.99 (2H, m), 2.15
(2H, t, 7.3 Hz), 3.19 (3H, s), 5.00 (1H, d, J) 6.9 Hz), 5.08 (1H, d,
J ) 6.9 Hz), 6.97 (1H, d, J ) 8.7 Hz), 7.10 (1H, d, J ) 9.2 Hz),
7.31 (1H, dd, J ) 2.3 Hz, 9.0 Hz), 7.37 (1H, dd, J ) 1.8 Hz, 9.2
Hz), 7.44 (1H, d, J ) 9.1 Hz), 7.58 (1H, d, J ) 9.2 Hz), 7.86 (1H,
d, J ) 9.1 Hz), 7.91 (1H, d, J ) 9.2 Hz), 8.01 (1H, d, J ) 2.3 Hz),
8.11 (1H, d, J ) 1.8 Hz); 13C NMR (125 MHz, CDCl3) δ 19.3
(3C), 32.2 (4C), 32.8 (2C), 56.0 (Me-MOM), 94.8 (CH2-MOM),
117.4, 118.2, 118.6, 119.8, 123.0, 125.0, 127.0, 127.7, 128.4, 129.4,
129.8, 129.9, 130.0, 130.1, 130.5, 131.9, 132.0, 132.8, 146.9, 152.9,
170.7 (5C), 178.3 (1C). Anal. Calcd for C27H22Br2O6: C, 53.84; H,
3.68. Found: C, 53.94; H, 3.68.
[R]24 +20.4 (c 1.0, CHCl3): mp 156 °C (ether); Rf 0.3 (hexane/
D
ethyl acetate/MeOH ) 20:20:1); IR (KBr) 3433, 2920, 1705(CO),
1583, 1490, 1238, 1020, 875, 810 cm-1 1H NMR (500 MHz,
;
CDCl3) δ 1.66-1.83 (2H, m), 1.87-2.00 (2H, m), 3.12 (3H, s),
3.93-4.06 (2H, m), 4.95 (1H, d, J ) 6.9 Hz), 5.09 (1H, d, J ) 6.9
Hz), 6.93 (1H, d, 9.1 Hz), 7.00 (1H, d, J ) 9.2 Hz), 7.25-7.30
(2H, m), 7.41 (1H, d, J ) 9.1 Hz), 7.56 (1H, d, J ) 9.2 Hz), 7.84
(2H, t, J ) 9.2 Hz), 8.00 (1H, s), 8.01 (1H, s); 13C NMR (125
MHz, CDCl3) δ 24.2 (3C), 29.5 (2C), 55.9 (Me-MOM), 68.2 (4C),
94.9 (CH2-MOM), 116.4, 117.7, 118.0, 120.0, 120.7, 127.0, 128.7,
128.8, 129.7, 129.7, 129.9, 130.4, 130.8, 132.3, 132.4, 152.8, 154.3,
178.8 (1C). Anal. Calcd for C26H22Br2O5: C, 54.38; H, 3.86. Found:
C, 54.37; H, 3.85.
(S)-6l: 90% ee (Chiralpak AD, hexane/2-propanol)4/1, 35 °C),
tR )16.7 min for (R)-isomer, 10.5 min for (S)-isomer; [R]25D -31
(c 1.0, MeOH).
(S)-6i: 83% ee (Chiralpak AD, hexane/2-propanol ) 9:1, 35 °C),
(()-6l: mp 106 °C (recrystallized from ether); Rf 0.48 (hexane/
ethyl acetate ) 2/1); IR (KBr) 2950, 1757 (CO), 1736 (CO), 1585,
1493, 1200, 1022, 943, 812 cm-1; 1H NMR (500 MHz, δ, CDCl3)
δ 1.36-1.54 (2H, m), 1.79-1.90 (2H, m), 2.08-2.18 (2H, m), 3.19
(3H, s), 3.62 (3H, s), 5.00 (1H, d, J) 6.9 Hz), 5.08 (1H, d, J ) 6.9
Hz), 6.96 (1H, d, J ) 9.1 Hz), 7.09 (1H, d, J ) 8.7 Hz), 7.31 (1H,
dd, J ) 1.9 Hz, 8.9 Hz), 7.36 (1H, dd, J ) 1.9 Hz, 8.9 Hz), 7.44
(1H, d, J ) 8.7 Hz), 7.59 (1H, d, J ) 9.2 Hz), 7.86 (1H, d, J ) 9.2
Hz), 7.91 (1H, d, J ) 8.7 Hz), 8.01 (1H, d, J ) 2.3 Hz), 8.11 (1H,
d, J ) 1.8 Hz); 13C NMR (125 MHz, CDCl3) δ 19.6 (3C), 32.2
(4C), 32.9 (2C), 51.5 (OMe), 56.0 (Me-MOM), 94.8 (CH2-MOM),
117.4, 118.2, 119.8, 123.1, 125.0, 127.0, 127.7, 128.4, 129.3, 129.8,
129.9, 130.0, 130.1, 130.5, 131.9, 132.0, 132.8, 147.0, 152.9, 170.8
(5C), 172.9 (1C). Anal. Calcd for C28H24Br2O6: C, 54.57; H, 3.93.
Found: C, 54.68; H, 3.93.
tR ) 10.6 min for (R)-isomer, 9.1 min for (S)-isomer; [R]23D -11.6
(c 1.0, CHCl3); [R]23 -24.6 (c 1.0, CHCl3) for >99% ee of (S)-
D
6i.
(()-6i: mp 107 °C (recrystallized from ether); Rf 0.33 (hexane/
ethyl acetate ) 3/1); IR (KBr) 3500, 2900, 1751 (CO), 1701 (CO),
1136, 1086, 1015, 802, 750 cm-1; 1H NMR (500 MHz, δ, CDCl3)
δ 1.67-1.79 (2H, m), 1.81-1.96 (2H, m), 3.15 (3H, s), 3.56 (3H,
s), 3.93-4.07 (2H, m), 4.93 (aH, d, J ) 6.9 Hz), 5.08 (1H, d, J)
6.9 Hz), 6.93 (1H, d, J ) 9.1 Hz), 7.00 (1H, d, J ) 9.1 Hz), 7.28
(2H, dt, J)1.8 Hz, 8.8 Hz), 7.42 (1H, d, J ) 9.2 Hz), 7.58 (1H, d,
J ) 9.2 Hz), 7.86 (2H, dd, J ) 6.9 Hz, 9.2 Hz), 8.02 (2H, dd, J )
2.3 Hz, 5.0 Hz) ; 13C NMR (125 MHz, CDCl3) δ 24.4 (3C), 29.5
(2C), 51.5 (OMe), 55.9 (Me-MOM), 68.2 (4C), 94.9 (CH2-MOM),
116.3, 117.5, 117.9, 118.0, 119.9, 120.7, 127.0, 128.6, 128.7, 129.6,
129.7, 129.8, 130.7, 130.8, 132.3, 132.4, 152.8, 154.3, 173.4 (1C).
Anal. Calcd for C27H24Br2O5: C, 55.12; H, 4.11. Found: C, 55.04;
H, 3.72.
Preparation of (S)-1-(2-Hydroxy-6-(naphthalen-1-yl)naph-
thalen-1-yl)-6-(naphthalen-1-yl)naphthalen-2-ol (9)28 by the
Suzuki-Miyaura Coupling Reaction27 (Scheme 1). A mixture
of (S)-7i (574 mg, 1.0 mmol, 97% ee), 1-naphthylboronic acid (378
mg, 2.2 mmol), Pd(PPh3)4 (116 mg, 0.10 mmol), 2 M NaOH aq
(3.3 mL), and THF (15 mL) was heated at 60 °C for 24 h with
stirring. After being cooled to rt, 2 M HCl was added to the reaction
mixture, and then the organic layer was extracted with ethyl acetate,
dried (MgSO4), and evaporated. Silica gel flash column chroma-
tography using hexane/acetone (3:1) gave (S)-8 (666 mg, 0.99
mmol, 99%). This compound was then converted to (S)-9.28 To
the solution of (S)-8 (134 mg, 0.20 mmol) in CH2Cl2 (2.0 mL)
was added BBr3 (1.0 mL) at -78 °C, and then the mixture was
warmed to rt for 3 h with stirring. The reaction was quenched by
addition of 2 M HCl and extracted with CH2Cl2. The combined
organic layers were dried (MgSO4) and evaporated to give a brown
solid. This was purified by silica gel TLC using hexane/ethyl acetate
(2:1) to give (S)-9 (40 mg, 0.074 mmol, 34%). However, a large
amount of unidentified byproduct was formed.
Optical Resolution of (()-7k. (R)-7k: 85% ee (Chiralpak AD,
hexane/2-propanol/TFA ) 9/1/0.01, 35 °C), tR ) 23.2 min for (R)-
isomer, 10.1 min for (S)-isomer; [R]24 -34 (c 1.0, CHCl3); Rf
D
0.27 (hexane/ethyl acetate/MeOH ) 20:20:1); IR (KBr) 3500
(broad), 2900, 1751 (CO), 1701 (CO), 1136, 1086, 1015, 802, 750
cm-1 1H NMR (500 MHz, CDCl3) δ 1.35-1.48 (2H, m),
;
1.77-1.91 (2H, m), 2.08-2.18 (2H. m), 3.16 (3H, s), 4.98 (1H, d,
J) 6.9 Hz), 5.06 (1H, d, J ) 6.9 Hz), 7.14 (1H, d, J ) 8.7 Hz),
7.22-7.46 (6H, m), 7.56 (1H, d, J ) 9.2 Hz), 7.83 (1H, d, J ) 8.3
Hz), 7.92 (1H, s), 7.94 (1H, d, J ) 2.7 Hz), 7.99 (1H, d, J ) 9.2
Hz); 13C NMR (125 MHz, CDCl3) δ 19.3 (3C), 32.1 (4C), 32.9
(2C), 55.8 (Me-MOM), 94.9 (CH2-MOM), 116.6, 119.2, 121.8,
124.2, 125.2, 125.4, 125.6, 126.2, 126.5, 126.6, 1278, 128.1, 129.1,
129.6, 130.0, 131.7, 133.5, 133.6, 146.6, 152.6, 170.9 (1C), 178.7
(5C). Anal. Calcd for C27H24O6: C, 72.96; H, 5.44. Found: C, 72.74;
H, 5.63.
(S)-9: [R]25 +173.2 (c 1.0, CHCl3), <99% ee after recrystal-
(S)-6k: 33% ee (Chiralpak AD, hexane/2-propanol ) 9:1, 35
D
lization, lit.28 [R]20589 +357 (CHCl3) for (S): mp 140 °C (recrystal-
lized from cyclohexane/CHCl3); Rf 0.22 (hexane/ethyl acetate )
3:1) ; IR (KBr) 3414 (broad s), 3013, 1697, 1597, 1477, 1352,
°C), tR ) 18.0 min for (R)-isomer, 11.7 min for (S)-isomer; [R]23
-12 (c 1.0, CHCl3) .
D
(()-6k: Rf 0.40 (hexane/ethyl acetate ) 2/1); IR (KBr) 2950,
1734 (CO), 1593, 1508, 1434, 1146, 1015, 814, 754 cm-1; 1H NMR
(500 MHz, δ, CDCl3) δ 1.36-1.50 (2H, m), 1.77-1.89 (2H, m),
2.05-2.17 (2H, m), 3.17 (3H, s), 3.60 (3H, s), 4.99 (1H, d, J) 6.9
Hz), 5.83 (1H, d, J ) 6.9 Hz), 7.13 (1H, d, J ) 8.3 Hz), 7.22-7.47
(7H, m), 7.56 (1H, d, J ) 9.2 Hz), 7.85 (1H, d, J ) 8.3 Hz), 7.93
1
1020, 930, 756 cm-1; H NMR (500 MHz, CDCl3) δ 5.15 (2H,
brs), 7.30-7.99 (22H, m); 13C NMR (125 MHz, acetone-d6) δ
115.1, 120.0, 125.4, 126.3, 126.6, 126.9, 128.0, 128.3, 129.2, 129.5,
129.7, 129.9, 130.8, 132.5, 134.6, 134.9, 136.0, 141.0, 154.9. Anal.
Calcd for C40H26O2: C, 89.19, H, 4.87. Found: C, 89.24, H, 4.79.
3882 J. Org. Chem. Vol. 73, No. 10, 2008

Design of Binaphthols for Enzymatic Resolution
(S)-4-(1-(2-(Methoxymethoxy)-6-(naphthalen-1-yl)naphthalen-
1-yl)-6-(naphthalen-1-yl)naphthalen-2-yloxy)butanoic Acid (8):
[R]25D -24 (c 1.0, CHCl3), 97% ee; mp 132 °C (recrystallized from
CHCl3); Rf 0.3 (hexane/ethyl acetate/methanol ) 20:20:1); IR (KBr)
evaporated to dryness. Silica gel flash column chromatography using
hexane/ethyl acetate (30:1) gave the corresponding coupling product
(421 mg, 0.87 mmol, 87%) as a colorless oil: [R]25 +19 (c 1.0,
D
CHCl3) . This compound was treated with concd. HCl (0.40 mL)
in dioxane (2.0 mL) and the mixture was stirred at 60 °C for 24 h.
After being cooled to rt, the reaction mixture was poured into water,
and was extracted with ether. The combined organic layers were
dried and purified by silica gel flash column chromatography
(hexane/ethyl acetate ) 10:1) and recrystallization from hexane to
give optically pure (R)-12 (344 mg, 0.86 mmol) as a colorless
3433, 2920, 1705 (CO), 1576, 1479, 1240, 1020, 777, 754 cm-1
;
1H NMR (500 MHz, δ, CDCl3) δ 1.76-1.87 (2H, m), 1.97-2.05
(2H, m), 3.24 (3H, s), 4.03-4.17 (2H, m), 5.06 (1H, d, J ) 6.9
Hz), 5.18(1H, d, J ) 6.9 Hz), 7.33-8.04 (22H, m); 13C NMR (125
MHz, CDCl3) δ 24.3 (3C), 29.7 (2C), 55.9 (Me-MOM), 68.3 (4C),
95.2 (CH2-MOM), 115.9, 117.6, 120.5, 121.2, 125.2, 125.3, 125.4,
125.7, 126.0, 126.1, 126.2, 127.2, 127.2, 127.5, 128.2, 128.3, 128.8,
128.9, 129.0, 129.4, 129.6, 129.7, 129.9, 131.7, 133.2, 133.2, 133.7,
133.8, 136.2, 136.4, 140.2, 152.8, 154.2, 179.1(1C). Anal. Calcd
for C46H36O5: C, 82.61, H, 5.43. Found: C, 82.64, H, 5.36.
Preparation of (R)-9 and (R)-12 starting from (R)-7l. (R)-6-
Bromo-1-(6-bromo-2-(methoxymethoxy)naphthalen-1-yl)naph-
thalen-2-ol (10) (Scheme 2). To the solution of (R)-7l(4.33 g, 7.02
mmol, 85% ee) in a mixed solvent (9.0 mL of water and 26 mL of
THF) was added LiOH ·H2O (1.18 g, 28.1 mmol) at 0 °C, and then
the mixture was allowed to warm to rt with stirring for 40 h. The
reaction was quenched by addition of 2 M HCl at 0 °C and then
extracted with ethyl acetate, and the organic layer was washed with
brine. The combined organic layers were dried (MgSO4), evapo-
rated, and chromatographed on silica gel flash column (hexane/
ethyl acetate ) 5:1) and gave (R)-10 (3.39 g, 6.94 mmol, 99%) as
needle: [R]28 -68.6 (c 1.0, CHCl3), >99% ee; Rf 0.43 (hexane/
D
ethyl acetate ) 3:1); IR (KBr) 3440, 2860, 1600, 1510, 1460, 1360,
1310, 1240, 1260, 1220, 1160, 950, 880, 830, 680 cm-1; 1H NMR
(500 MHz, CDCl3) δ 0.94 (6H, t, J ) 7.3 Hz), 1.38 (4H, sext, J )
7.3 Hz), 1.65 (4H, qu, J ) 7.8 Hz), 2.72 (4H, t, J ) 7.8 Hz), 4.97
(2H, brs), 7.09 (2H, d, J ) 8.8 Hz), 7.16 (2H, dd, J ) 1.8 Hz, 8.8
Hz), 7.34 (2H, d, J) 9.1 Hz), 7.66 (2H, s), 7.090 (2H, d, J) 9.1
Hz) ; 13C NMR (125 MHz, CDCl3) δ 13.9, 22.4, 33.5, 35.4, 55.7,
110.9, 117.6, 124.2, 126.8, 129.0, 129.6, 130.7, 131.7, 138.5, 152.0.
We also prepared (S)-12 ([R]25 +69.4 (c 1.0, CHCl3), >99%
D
ee) from (S)-7l through the same route. X-ray crystallographic
analysis of (R)-12 was successfully carried out. Crystal and
refinement data for (R)-12: C28H30O2, formula weight ) 398.54,
monoclinic, space group P21(#4), a ) 10.195(6) Å, b ) 8.387(5)
Å, c ) 13.540(9) Å, b ) 108.076(17)°, V ) 1100.6(11)3, Z ) 2,
dcalc ) 1.203 g cm-3, R(Rw) ) 0.0500 for 11705 diffraction data
with I > 2.00σ(I) and 281 valuable.
a colorless oil: [R]23 -86 (c 1.0, CHCl3); 85% ee, Chiralcel AD
D
(hexane/2-propanol ) 4:1) tR ) 6.2 min for (S)-isomer, 8.1 min
1
for (R)-isomer; H NMR (500 MHz, CDCl3) δ 3.16 (3H, s), 5.03
(R)-6-(Naphthalen-1-yl)-1-(6-(naphthalen-1-yl)-2-hydroxynaph-
thalen-1-yl)naphthalen-2-ol (9)28 (Scheme 2). A mixture of (R)-
1129 (532 mg, 1.0 mmol), 1-naphthylboronic acid (344 mg, 2.0
mmol), Pd(PPh3)4 (116 mg, 0.10 mmol), 2 M NaOH (3.0 mL, 6.0
mmol), and THF (10 mL) was heated under reflux conditions for
24 h. After being cooled to rt, the reaction mixture was quenched
by the addition of water and then extracted with ethyl acetate. The
combined organic layers were washed with brine and dried
(MgSO4), and the solvent was removed by evaporation. The residue
was purified by silica gel flash column chromatography (hexane/
ethyl acetate ) 10:1) to give di-MOM ether (R)-13 (570 mg, 0.91
mmol, 91%) as a white solid. This di-MOM ether was then treated
with 0.55 mL of concd HCl in 1,4-dioxane (3.0 mL) at 60 °C for
16 h to give (R)-9 (400 mg, 0.74 mmol) in 94% yield: mp 300 °C
(recrystallized from hexane and ethyl acetate): Rf 0.22 (hexane/
ethyl acetate ) 3:1) ; IR (KBr) 3520, 3410, 3010, 1700, 1600, 1480,
(1H, b), 4.98 (1H, d, J) 6.9 Hz), 5.08 (1H, d, J) 6.9 Hz), 6.89
(1H, d, J ) 8.7 Hz), 7.00 (1H, d, J ) 8.7 Hz), 7.24-7.35 (3H, m),
7.59 (1H, d, J ) 8.7 Hz), 7.79 (1H, d, J ) 6.9 Hz), 7.90 (1H, d,
J ) 9.0 Hz), 8.00 (1H, d, J ) 2.3 Hz), 8.04 (1H, d, J ) 1.8 Hz);
13C NMR (125 MHz, CDCl3) δ 56.2, 56.2, 94.8, 114.8, 117.2, 117.9,
118.7, 118.8, 126.4, 126.7, 129.1, 129.8, 130.0, 130.1, 130.2, 131.1,
132.2, 132.3, 151.6, 153.8.
(R)-6-Bromo-1-(6-bromo-2-(methoxymethoxy)naphthalen-1-
yl)-2-(methoxymethoxy)naphthalene (11).29 To the suspension of
NaH (224 mg, 9.34 mmol) in THF (10 mL) was added a THF (8.0
mL) solution of (R)-10 (2.28 g, 4.67 mmol, 85% ee) at 0 °C, the
mixture was stirred at 0 °C for 2 h, and then MOMCl (1.12 mg,
13.9 mmol) was added to this mixture at 0 °C and allowed to warm
to rt with stirring for 3 h. The reaction was quenched by saturated
NH4Cl aqueous solution and acidified with 2 M HC, and filtered
though a glass filter. The filtrate was extracted with ether and the
combined organic layers were washed with brine, dried over
MgSO4, and evaporated to dryness. Silica gel flash column
chromatography (hexane/ethyl acetate ) 10:1) and subsequent
recrystallization from ether gave (R)-11 (2.06 g, 3.87 mmol, 83%)
1460, 1350, 1130, 1020, 960, 930, 890, 870, 760, 690, 670 cm-1
;
1H NMR (500 MHz, CDCl3) δ 5.15 (2H, brs), 7.30-7.99 (22H,
m); 13C NMR (125 MHz, CDCl3) δ 115.1, 120.0, 125.4, 126.3,
126.6, 126.9, 128.0, 128.3, 129.2, 129.5, 129.7, 129.9, 130.8, 132.5,
134.6, 134.9, 136.0, 141.0, 154.9; [R]26D -173.10 (c 1.0, CHCl3),
26
as a colorless plate: [R]23 +20.2 (c 1.0, CHCl3), >99% ee after
>99% ee (lit. [R]20 +357 (c 0.89, CHCl3) (S)).
D
589
recrystallization from ether (lit.29 [R]D +23.1 (c 1.0, THF); mp
Di-MOM-ether of (R)-13: mp 197 °C (recrystallized from ether);
[R]26D -43.2 (c 1.0, CHCl3), >99% ee; Rf 0.49 (hexane/ethyl acetate
) 3:1); IR (KBr) 2900, 2780, 1580, 1470, 1330, 1230, 1190, 1140,
1
147 °C (ether); Rf 0.53 (hexane/ethyl acetate ) 3:1) ; H NMR
(500 MHz, CDCl3) δ 3.16 (6H, s), 5.03 (4H, dd, J ) 6.9 Hz, 53.2
Hz), 6.98 (2H, d, J ) 9.2 Hz), 7.29 (2H, dd, J ) 1.8 Hz, 9.2 Hz),
7.59 (2H, d, J ) 9.1 Hz), 7.86 (2H, d, J ) 9.1 Hz), 8.03 (2H, d,
J ) 1.8 Hz); 13C NMR (125 MHz, CDCl3) δ 55.9, 95.0, 118.0,
118.0, 120.7, 127.1, 128.7, 129.7, 129.9, 130.8, 133.4, 152.9. Anal.
Calcd for C24H20Br2O4: C, 54.16; H, 3.79. Found: C, 53.87; H,
3.72. We prepared (S)-11 through the same route starting from (S)-
7l (78% ee). Although the starting material (S)-7l was not an
optically pure form, it was successful to enhance the optical purity
of (S)-11 (99% ee) by recrystallization from ether.
1
1070, 1010, 950, 920, 890, 770, 420 cm-1; H NMR (500 MHz,
CDCl3) δ 3.27 (6H, s), 5.010 (1H, d, J ) 6.9 Hz), 5.18 (1H, d, J
) 6.9 Hz), 7.38-7.56 (12H, m), 7.68 (2H, d, J ) 9.1 Hz), 7.87
(2H, d, J ) 7.8 Hz), 7.92 (2H, d, J ) 8.2 Hz), 7.98 (2H, d, J ) 8.2
Hz), 8.02 (2H, s), 8.03 (2H, d, J ) 8.7 Hz); 13C NMR (125 MHz,
CDCl3) δ 55.9, 95.3, 117.6, 121.2, 125.7, 126.0, 126.1, 127.2, 127.6,
128.3, 128.8, 129.0, 129.6, 129.9, 131.7, 133.2, 133.8, 136.5, 140.1,
152.9. Anal. Calcd for C44H34O4: C, 84.32; H, 5.47. Found: C,
84.11; H, 5.47.
(R)-6-Butyl-1-(6-butyl-2-hydroxynaphthalen-1-yl)naphthalen-
2-ol (12).30 To a mixture of (R)-11 (532 mg, 1.0 mmol),
PdCl2(dppf)·CH2Cl2 (41 mg, 0.05 mmol), and THF (5.0 mL) was
added a THF solution of n-BuMgBr (1.0 M THF solution, 3.5 mL,
3.5 mmol) at 0 °C, and the mixture was stirred at 60 °C for 24 h.
After being cooled to rt, the reaction was quenched by addition of
saturated NH4Cl aqueous solution and was extracted with ethyl
acetate. The combined organic layers were dried (MgSO4) and
Asymmetric Henry Reaction Catalyzed by La-BINOL Com-
plex.32 Synthesis of (S)-1-Nitro-4-phenylbutan-2-ol (14).32
La-BINOL complex was prepared following the method reported
by Shibasaki et al:32 (S)-BINOL derivatives (0.15 mmol) were dried
under a vacuum at 60 °C for 2 h prior to the La complex. To a
solution of dried BINOL derivatives in THF (1.35 mL) was added
a 0.2 M THF solution of La(O-i-Pr)3 (0.25 mL, 0.05 mmol) at 0
°C, the mixture was stirred for 30 min at rt, and then to this mixture
J. Org. Chem. Vol. 73, No. 10, 2008 3883

Taniguchi et al.
was added 0.1 mL of n-BuLi (1.52 M in hexane, 0.15 mmol) at 0
°C. After being stirred at rt for 12 h, 0.05 mL of 1.0 M THF solution
of H2O (0.05 mmol) was added at rt to give a THF solution of
La-BINOL complex (0.03 M). This solution was immediately used
for the reaction.
-78 °C, the mixture was stirred for 30 min, and then benzaldehyde
(0.5 mmol) was added to this mixture at the same temperature.
The resulting mixture was allowed to warm to 0 °C and stirred for
1 h at rt, and the reaction was quenched by addition of saturated
NH4Cl aqueous solution at 0 °C. The resulting mixture was next
filtered through a glass filter with a Celite pad to remove the solid
formed. The filtrate was dried (MgSO4), evaporated, and purified
A 0.03 M THF solution of La-BINOL complex (0.67 mL, 0.02
mmol) was diluted with 2.0 mL of THF, and then the solution was
cooled to -50 °C and stirred for 30 min at the same temperature.
To the mixture was added nitromethane (366 mg, 6.0 mmol), the
mixture was stirred for 30 min at -50 °C, and then 3-phenylpro-
rionaldehyde (80.6 mg, 0.6 mmol) was added to the mixture. After
being stirred for 24 h at -50 °C, the reaction was quenched by
addition of 2 M HCl and extracted with ethyl acetate. The combined
organic layer was dried (MgSO4), filtered, evaporated, chromato-
graphed on silica gel TLC, using hexane/ethyl acetate )3:1, and
gave (S)-1-nitro-4-phenylbutan-2-ol (14):32b 1H NMR (500 MHz,
CDCl3) δ 1.76-1.91(2H, m), 2.60 (1H, d, J) 5.1 Hz), 2.72-2.89
(2H, m), 4.47-4.34 (1H, m), 4.36-4.44 (2H, m), 7.32-7.55 (5H,
m); 13C NMR (125 MHz, CDCl3) δ 31.2, 35.1, 67.8, 80.5, 126.2,
128.3, 128.5, 140. 6; enantiomeric excess of 14 was determined
by HPLC analysis (Chiralpak AD, hexane/2-propanol ) 9:1, 35
°C), tR ) 11.0 min for (R)-isomer, 12.8 min for (S)-isomer.
Asymmetric Ethylation Catalyzed by Ti-BINOL Complex.33
Synthesis of (S)-1-Phenylpropan-1-ol (15).33 A mixture of (S)-
BINOL derivatives (0.05 mmol) and Ti(O-i-Pr)4 (0.6 mmol) in
toluene (1.5 mL) was stirred at rt for 30 min. To this solution was
added 1.5 mL of a hexane solution of diethylzinc (1.5 mmol) at
1
by silica gel TLC (hexane/ethyl acetate ) 3:1) to give (S)-15: H
NMR (400 MHz, δ, CDCl3) δ 0.92 (3H, t, J ) 7.4 Hz), 1.70-1.88
(2H, m), 2.20 (1H, brs), 4.60 (1H, t, J ) 7.0H z), 7.33-7.37 (5H,
m). Enantiomeric excess of (S)-14 was determined by HPLC
analysis (Chiralcel OD-H, hexane/2-propanol ) 100:1, 35 °C): tR
) 18.6 min for (R)-isomer, 21.6 min for (S)-isomer.
Acknowledgment. This work is dedicated to Dr. Yoshihiko
Ito, Emeritus Professor of Kyoto University. The present work
was supported by a Grant-in-Aid for Scientific Research in the
Asahi Glass Foundation.
Supporting Information Available: Experimental procedure
for the syntheses of compounds 6a-l. Enzymatic resolution of
1
(()-6g, 6k, and 6l. H and 13C NMR spectra for 6a-l, 7g-l,
and 8. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO800351H
3884 J. Org. Chem. Vol. 73, No. 10, 2008