Facile synthesis of C2-symmetric chiral binaphthyl ketone catalysts

Article abstract of DOI:10.1016/S0040-4039(00)00120-9

C₂-Symmetric chiral binaphthyl ketones, efficient catalysts for asymmetric epoxidation, have been synthesized through an intramolecular Ullmann reaction and/or a lipase-catalyzed enantioselective hydrolysis of the 11-membered cyclic binaphthyl acetate. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00120-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2149–2152
Facile synthesis of C2-symmetric chiral binaphthyl
ketone catalysts
Masahiko Seki,∗ Toshiyuki Furutani, Masanori Hatsuda and Ritsuo Imashiro
Product & Technology Development Laboratory, Tanabe Seiyaku Co., Ltd, 3-16-89, Kashima, Yodogawa-ku,
Osaka 532-8505, Japan
Received 20 October 1999; revised 11 January 2000; accepted 14 January 2000
Abstract
C2-Symmetric chiral binaphthyl ketones, efficient catalysts for asymmetric epoxidation, have been synthesized
through an intramolecuar Ullmann reaction and/or a lipase-catalyzed enantioselective hydrolysis of the 11-
membered cyclic binaphthyl acetate. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: epoxidation; Ullmann reactions; biaryls; enzymes and enzyme reactions.
Optically active epoxides have received considerable attention as useful chiral building blocks for
drugs and natural products. The asymmetric epoxidation of olefins with chiral dioxiranes, generated
in situ from the corresponding ketones, has recently emerged as a prominent synthetic method for
the optically active epoxides.1,2 Yang has developed C2-symmetric chiral binaphthyl ketones 1 and
has demonstrated their efficiency for the dioxirane-mediated catalytic asymmetric epoxidation.2 The
ketones 1a (X=H) and 1b (X=Cl) have been synthesized via condensation of optically active 1,10-
binaphthyl-2,20-dicarboxylic acid derivatives with 1,3-dihydroxyacetone or 3-chloro-2-chloromethyl-1-
propene, respectively. However, the methods are unsatisfactory for practical use because of the following
drawbacks: (1) a poor yield (28%) for the condensation step in the synthesis of the unsubstituted ketone
1a even by the use of Mukaiyama reagent and a high dilution method (ca. 300 volume of solvent per
weight of the substrate was employed);2a (2) preparation of the optically active 1,10-binaphthyl-2,20-
dicarboxylic acid derivatives requires very toxic brucine or quinine for the resolution.3 We describe
herein a facile synthesis of the ketones 1a and 1b by means of an intramolecular Ullmann reaction and/or
a lipase-catalyzed kinetic resolution.
∗
Corresponding author. E-mail: m-seki@tanabe.co.jp (M. Seki)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00120-9
tetl 16400

2150
We first investigated synthesis of the unsubstituted ketone 1a (Scheme 1). The intramolecular Ullmann
reaction of a dibromide 4a was attempted to improve the condensation step in the synthesis of 1a. The
dibromide 4a was readily prepared in two steps from 1-bromo-2-naphthoic acid 2a through sequential
addition of two molecules of 2a to epichlorohydrin.4 Addition of the dibromide 4a in DMF to a
suspension of copper powder5 in refluxing DMF for 6 h and an additional refluxing for 1 h provided the
cyclized product (±)-5a in only 9% yield accompanied by considerable side reactions such as reductive
cleavage of the bromo group. In order to improve the yield, we then employed more reactive diiodide
4b derived from 1-iodo-2-naphthoic acid 2b.6 As expected, the cyclization of the diiodide 4b gave the
desired product (±)-5a in good yield (67%) using the same reaction procedure as with 4a. It should
be noted that the reaction can provide the 11-membered ring system without the need for high dilution
methods (the total volume of the reaction solvent (DMF) is 40 v/w).
We then examined the lipase-catalyzed kinetic resolution of the acetate (±)-5a. Although recognition
of the axial chirality in biaryls by enzymes has scarcely been studied,8 treatment of (±)-5a with
Lipoprotein lipase (Toyobo Co., Ltd) at 30°C for 48 h in a mixed solvent of toluene and 0.1 M Tris-HCl
buffer (pH 7.5) (1:1) was found to selectively hydrolyze (R)-5a to give an alcohol (R)-6a in enantiopure
form (>99% e.e.,9 46% yield) and the recovery of a homochiral acetate (S)-5 (>99% e.e.,8 50% yield) (E-
value=670). The alcohol (R)-6a was cleanly oxidized with MnO2 at ambient temperature to provide
the desired ketone (R)-1a (>99% e.e.10) in 96% yield.11 The antipode (S)-1a was prepared through
aminolysis of the acetate (S)-5a followed by the oxidation with MnO2 (>99% e.e.,10 80% yield, two
steps).
The present synthetic method based on the enzymatic resolution was applicable to the synthesis of a
3,30-dichloro derivative (R)-1b, a better epoxidation catalyst for some olefins (Scheme 2).2b Although
the racemic acetate (±)-5b could not be obtained through the intramolecular Ullmann reaction shown
in Scheme 1, it was prepared from a racemic ketone (±)-1b2b,12 by reduction of the carbonyl group
followed by acetylation (1. NaBH4; 2. Ac2O, Et3N, DMAP (cat.), 86% (two steps)). The compound (±)-
5b was allowed to react with Lipoprotein lipase (Toyobo Co., Ltd) at 30°C for 48 h in a mixed solvent of
toluene and 0.1 M Tris-HCl buffer (pH 7.5) (1:1) provided an alcohol (R)-6b in high enantioselectivity
(>99% e.e.,9 45% yield) while the homochiral acetate (S)-5b was recovered in 52% yield (93% e.e.9)
(E-value=85). The alcohol (R)-6b was oxidized with MnO2 to provide the desired ketone (R)-1b (>99%
e.e.10) in 92% yield.13
In conclusion, efficient syntheses of C2-symmetric chiral binaphthyl ketones 1a and 1b were accomp-
lished by the use of the intramolecular Ullmann reaction of the diiodide 4b (for the synthesis of 1a) and
the lipase-catalyzed kinetic resolution of the acetates (±)-5a and (±)-5b. The present synthesis is efficient
in terms of the high enantioselectivities and the versatilty of the enzymatic reactions. Both unsubstituted
and 3,30-dichloro binaphthyl ketones 1a and 1b are readily accessible in enantiopure form through the
Lipoprotein lipase-catalyzed kinetic resolution. Further efforts to improve the present synthesis are in
progress and will be reported elsewhere in due course.

2151
Scheme 1.
Scheme 2.

2152
References
1. (a) Murray, R. W. Chem. Rev. 1989, 89, 1187. (b) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806. (c)
Denmark, S. E.; Wu, Z. Synlett 1999, 847.
2. (a) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-H.; Cheung, K.-K. J. Am. Chem. Soc. 1996, 118, 491. (b)
Yang, D.; Wang, X.-C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J. Am. Chem. Soc. 1996, 118, 11 311. (c) Yang, D.; Wong,
M.-K.; Yip, Y.-C.; Wang, X.-C.; Tang, M.-W.; Zheng, J.-H.; Cheung, K.-K. J. Am. Chem. Soc. 1998, 120, 5943.
3. (a) Hall, D. M.; Turner, E. E. J. Chem. Soc. 1955, 1242. (b) Kanoh, S.; Hongoh, Y.; Motoi, M.; Suda, H. Bull. Chem. Soc.
Jpn. 1988, 61, 1032.
4. (a) Zlatanos, S. N.; Sagredos, A. N. J. Am. Oil Chem. Soc. 1990, 67, 661. (b) Ikeda, I.; Gu, X.-P.; Miyamoto, I.; Okahara,
M. J. Am. Oil Chem. Soc. 1989, 66, 822.
5. The copper powder (particle size: 100–200 mesh) was purchased from Kanto Chemicals Co., Inc. and used without further
purification.
6. 1-Iodo-2-naphthoic acid 2b was prepared from 1-bromo-2-hydroxymethylnaphthalene7 through iodination [(i) n-BuLi (2.2
equiv.), THF, −60°C, 10 min, (ii) I2, −50–60°C, 1.5 h (80%)] followed by oxidation of the hydroxymethyl group to the
carboxylic acid [1. MnO2, toluene (63%); 2. NaClO2, H2O2, NaH2PO4, CH3CN, H2O (95%)].
7. Smith, J. G.; Dibble, P. W.; Sandborn, R. E. J. Org. Chem. 1986, 51, 3762.
8. Enzymatic kinetic resolution of 2,20-dihydroxy-1,10-binaphthyl was reported: (a) Kazlauskas, R. J. J. Am. Chem. Soc. 1989,
111, 4953. (b) Inagaki, M.; Hiratake, J.; Nishioka, T.; Oda, J. Agric. Biol. Chem. 1989, 53, 1879.
9. The e.e.s of the products were determined by HPLC: Chiralcel OD (Daicel), n-hexane:2-propanol=10:1, 1 mL/min, 40°C,
224 nm.
10. IR, 1H NMR and MS spectra of the products 1a and 1b are in good accordance with those of the literature.2a,b The mp and
specific rotation of 1a and 1b are not reported. Absolute configuration and optical purities of the products 1a and 1b were
determined by comparing the retention time in the chiral HPLC with those of the authentic samples prepared according to
the literature.2a,b HPLC: Chiralcel OD (Daicel), n-hexane:2-propanol=10:1, 1 mL/min, 40°C, 224 nm.
1
11. (R)-6a: mp 256–257°C; IR (KBr) 1744, 1720, 1592 cm−1; H NMR (CDCl3) δ 2.11 (d, J=8.4 Hz, 1H), 4.03 (dd, J=1.3,
12.4 Hz, 1H), 4.25–4.35 (m, 1H), 4.57 (dd, J=8.3, 10.7 Hz, 1H), 4.85 (dd, J=3.2, 12.4 Hz, 1H), 7.17 (d, J=8.6 Hz, 2H), 7.31
25
(d, J=7.4 Hz, 2H), 7.49–7.56 (m, 2H), 7.65 (dd, J=8.5, 11.4 Hz, 2H), 7.93–8.02 (m, 4H); MS (m/z) 398 (M+); [α]D −230
(c, 1.01, CHCl3). (S)-5a: mp 256°C; IR (KBr) 1746 cm−1; 1H NMR (CDCl3) δ 2.11 (s, 3H), 4.00 (d, J=13.1 Hz, 1H), 4.15
(dd, J=7.2, 10.9 Hz, 1H), 4.66 (dd, J=9.8, 10.8 Hz, 1H), 4.99 (d, J=3.9, 13.1 Hz, 1H), 5.32–5.42 (m, 1H), 7.18–7.34 (m,
25
4H), 7.49–7.71 (m, 4H), 7.93–8.04 (m, 4H); MS (m/z) 440 (M+); [α]D +171 (c, 1.0, CHCl3).
12. Reported synthesis of (±)-1b involves condensation of 3,30-dichloro-1,10-binaphthyl-2,20-dicarboxylic acid with 3-chloro-
2-chloromethyl-1-propene and oxidative cleavage of the double bond.2b While the yield of the cyclization is moderate (60%
yield), that of the oxidation step is poor (21% yield).
13. (R)-6b: mp >300°C; IR (KBr) 1740 cm−1; 1H NMR (CDCl3) δ 2.05 (d, J=1.1 Hz, 1H), 4.07 (dd, J=12.3 Hz, 1H), 4.19 (dd,
J=6.5, 10.3 Hz, 1H), 4.41 (m, 1H), 4.57 (dd, J=8.8, 10.2 Hz, 1H), 4.91 (dd, J=3.4, 12.2 Hz, 1H), 6.91 (d, J=8.5 Hz, 2H),
21
7.28 (t, J=7.7 Hz, 2H), 7.53 (t, J=7.6 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H), 8.05 (d, J=2.8 Hz, 1H); MS (m/z) 467 (M+); [α]D
−97 (c, 0.1, CHCl3). (S)-5b: mp 300°C (dec); IR (KBr) 1747 cm−1; 1H NMR (DMSO-d6) δ 2.08 (s, 3H), 4.02 (d, J=13.0
Hz, 1H), 4.23 (dd, J=7.2, 10.8 Hz, 1H), 4.42 (dd, J=10.1, 10.7 Hz, 1H), 4.87 (dd, J=3.8, 13.1 Hz, 1H), 5.37–5.56 (m, 1H),
6.78 (d, J=8.5 Hz, 1H), 7.39 (ddd, J=1.1, 7.0, 7.7 Hz, 2H), 7.66 (ddd, J=1.0, 6.9, 7.5 Hz, 2H), 8.10 (d, J=8.2 Hz, 2H), 8.45
21
(s, 2H); MS (m/z) 509 (M+); [α]D +71 (c, 1.01, CHCl3).