Organic Syntheses, CV 9, 77
(S)-(−)- AND (R)-(+)-1,1'-BI-2-NAPHTHOL
Submitted by Romas J. Kazlauskas
1
Checked by Mark R. Sivik and Leo A. Paquette.
1. Procedure
A.
Racemic 1,1'-bi-2-naphthyl pentanoate. A suspension of
203 g (0.71 mol) of racemic 1,1'-bi-2-naphthol (Note
1) and
215 mL (1.54 mol) of triethylamine in
2 L of ethyl ether is stirred magnetically in a
4-L Erlenmeyer flask. Over a period of 20 min
185 mL (1.56 mol) of pentanoyl chloride is added (Note
2) and the suspension is stirred for an additional hour to ensure complete reaction (Note
3). The mixture is poured into a
6-L separatory funnel and washed twice with
2-L portions of aqueous 1 M sodium bicarbonate and once with a 2-L portion of water resulting in a clear yellow-orange
ether solution.
B.
(S)-(−)-1,1'-Bi-2-naphthol. In a
12-L, round-bottomed flask the above
ether solution is diluted to 4 L with additional
ethyl ether. A 5.0-mL aliquot of this solution is used to assay the enzyme (Note
4). The remaining
ether solution is stirred using an
overhead stirrer with
4 L of aqueous 0.1 M phosphate buffer (pH 7.5) containing 60 g of crude sodium taurocholate (Note
5). An opaque emulsion forms. The reaction is started by adding 2000 units of cholesterol esterase activity (
100–150 g of bovine pancreas acetone powder, (Note
4)). Stirring is continued at

25°C and the flask is stoppered to minimize evaporation of
ether. The pH of the emulsion is measured occasionally and readjusted to 7.2 ± 0.3 by adding aqueous
1 M sodium hydroxide. Approximately 250 mL of base is consumed during the first 3 hr; an additional 400 mL is consumed over the next 20 hr. Although the consumption of base virtually ceases after 24 hr, stirring is continued for a total of 3 days (Note
6).
To break the emulsion
400 mL of ethanol is added and the mixture is transferred to separatory funnels and allowed to settle for 4 hr. Three layers form: at the top—a clear yellow ether phase, at the bottom—a brown aqueous phase and in between—an opaque emulsion layer. The brown aqueous layer is discarded. The emulsion layer (

1 L) is transferred to a flask and broken up by addition of
200 g of magnesium sulfate in portions. Heat is evolved, the
ether boils and two layers form. This
ether layer is combined with the first
ether layer, dried over
50 g of magnesium sulfate, filtered and concentrated by rotary evaporation to

300 mL of an orange oil.
Toluene (500 mL) is added and the solution cooled to 4°C overnight. Fine white crystals (
70–71 g) are collected by filtration and washed twice with
20-mL portions of cold toluene (Note
7). The filtrate is concentrated to

600 mL by rotary evaporation and cooled once again to 4°C. The additional
10 g of crystals which form are collected by filtration and washed twice with
20-mL portions of toluene. Recrystallization of the combined crystals from
375–400 mL of toluene yields
65–68 g (
64–67%) of white crystals, mp
211–213.5°C;
[α]D19 −33.2 ± 0.8° (THF,
c 0.2); >99% diol (see (Note
3)), >99.9% enantiomeric purity (Note
8).
C.
(R)-(+)-1,1'-Bi-2-naphthol.
Toluene in the above filtrate is removed by rotary evaporation, and the residue is recrystallized from
methanol (500 mL) overnight at 4°C. Yellow crystals (
125–141 g) form and are collected by filtration and washed twice with
20 mL of hexane. Recrystallization from
500 mL of methanol yields pure
(R)-binaphthol dipentanoate [mp
63–65°C,
89–102 g, >99% ee (R),
[α]D19 +15.0 ± 0.3° (CHCl
3,
c 0.4), (Note
9)]. If desired, an additional
25 g of dipentanoate can be isolated from the filtrate by column chromatography on
1 kg of silica gel eluted with
methylene chloride followed by crystallization (Note
9).
The crystalline
dipentanoate (89–102 g, 0.20 mol) is dissolved in
1 L of methanol containing
6.6 g (0.12 mol) of sodium methoxide. After 4 hr at room temperature, analysis of the solution by thin layer chromatography (Note
3) shows only traces of the mono- and diester. The solution is neutralized to pH <7 (test paper) with
10 mL of concd hydrochloric acid. The solution is diluted with
1 L of 0.1 M phosphate buffer (pH 7), transferred to a
4-L separatory funnel and extracted with a mixture of
1 L of ethyl ether and 500 mL of toluene. The organic layer is washed with a 1-L portion of water, dried over
magnesium sulfate, concentrated to 300 mL and cooled to 4°C. White crystals (
48–64 g) separate and are collected by filtration and washed twice with
20-mL portions of cold toluene, mp
211–213.5°C;
[α]D19 +33.9 ± 0.2° (THF,
c 0.2); 99% chemical purity (Note
3), >99% enantiomeric purity (Note
8).
2. Notes
2. The initial suspension is thick and can sometimes be difficult to stir magnetically. In this case, occasional swirling by hand is sufficient. The mixture thins as the reaction proceeds.
Caution: This exothermic reaction causes the ether to boil; pentanoyl chloride should be added slowly, allowing the heat of reaction to dissipate. The checkers cooled the reaction mixture in an
ice bath during addition of the acid chloride.
Pentanoyl chloride was obtained from Aldrich Chemical Company, Inc.
3. To ensure high enantiomeric purity of the product there should be <0.5%
1,1'-bi-2-naphthol or its monoester in this solution. The relative amounts of
binaphthol species can be accurately determined by HPLC on a reverse-phase column eluted with a
water-acetonitrile gradient (50–100% over 10 min). Both
1,1'-bi-2-naphthol and its dipentanoate have equal (within 2%) extinction coefficients at 254 nm. The monopentanoate absorbs more strongly: the relative extinction coefficient at 254 nm is 1.13. Alternatively, the solution composition can be estimated using thin layer chromatography: silica gel eluted with
1:4 ethyl acetate/cyclohexane:
1,1'-bi-2-naphthol, R
f 0.39; monopentanoate, R
f 0.56; dipentanoate, R
f 0.71.
4. The catalyst for this reaction is the enzyme cholesterol esterase (EC 3.1.1.13).
Bovine pancreas acetone powder (Sigma Chemical Company), a crude extract from pancreas, is an inexpensive source of cholesterol esterase activity. This extract contains

15 units of cholesterol esterase activity/gram; unit = μmol of ester hydrolyzed/min. To measure the activity, the ethereal aliquot of
binaphthol dipentanoate is stirred rapidly using a magnetic stirrer with
5.0 mL of 10 mM phosphate buffer (pH 7.0) containing 75 mg of crude sodium taurocholate (Sigma Chemical Company). Approximately
200 mg of acetone powder is added and the pH of the emulsion is monitored with a pH meter and maintained at 7.0 by addition of aqueous
0.1 M sodium hydroxide in portions of 50 μL until

200 μL has been added,

70 min. The slope of a plot of μmoles of base consumed vs. time gives the activity of the acetone powder. (The amount of base needed to readjust the pH to 7.0 after the addition of the slightly acidic acetone powder is ignored in the activity calculation.)
5. Directions for the preparation of this buffer solution are given in reference
3.
6. After 24 hr, analysis by HPLC shows 37%
binaphthol, 10% monopentanoate and 53% dipentanoate, after an additional 2 days of stirring, analysis shows 45%, 3%, and 52%. Isolation of
binaphthol and diester by crystallization is substantially more difficult and less efficient from reaction mixtures containing <40 mol %
binaphthol.
7.
Binaphthol may not crystallize if the solution is wet. If no crystals form, water can be removed by rotary evaporation of the water-
toluene azeotrope.
8. Enantiomeric purity of
binaphthol is determined using chiral stationary phase HPLC:
Pirkle Type 1-A column (Regis Chemical Company) eluted with
20:1 hexane/2-propanol4 or poly(triphenylmethyl)methacrylate on
silica gel (Chiralpak OT, Daicel Chemical Industries, LTD) eluted with
methanol.
5 To determine enantiomeric purities >99% ee an HPLC trace of the unknown is compared to the HPLC trace of unknown containing 0.2% deliberately-added racemic material.
9. Crystallization of
(R)-binaphthyl dipentanoate increases its enantiomeric purity from

92% ee in the reaction mixture to >99% ee. The enantiomeric purity of the final product,
binaphthol, is not increased by crystallization. The recrystallization step for the dipentanoate ensures high enantiomeric purity. Usually crystallization from
methanol must be induced by scratching the side of the flask with a
glass rod. The enantiomeric purity of the dipentanoate is determined after cleavage to
binaphthol. A sample of dipentanoate is treated with an equivalent of
sodium methoxide in
methanol. After 30 min the solution is neutralized with excess
acetic acid and analyzed by HPLC as in (Note
8).
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
Enantiomerically pure
binaphthol is used as a chiral auxiliary.
6 For example, it has been used to prepare chiral aluminum hydride reducing agents,
7 chiral Lewis acids catalysts,
8 and chiral crown ethers.
9
The best previous resolution of
binaphthol uses fractional crystallization of the diastereomeric cinchonine salts of binaphthol cyclic phosphate ester.
10 The resolution using cholesterol esterase involves fewer manipulations and thus is simpler and faster than the cinchonine method. Fewer manipulations also enable the resolutions using cholesterol esterase to be carried out on a larger scale. The high enantioselectivity of cholesterol esterase assures high ee for the (S)-enantiomer, while crystallization of
(R)-binaphthyl dipentanoate assures high enantiomeric purity for the (R)-enantiomer.
Octahydrobinaphthol and several spirobiindanols can also be resolved using this method, but several bromo-substituted binaphthols could not be resolved because their esters were not hydrolyzed.
11
This preparation is referenced from:
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
silica gel
(S)-(−)- AND (R)-(+)-1,1'-BI-2-NAPHTHOL
poly(triphenylmethyl)methacrylate
ethanol (64-17-5)
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
ethyl acetate (141-78-6)
methanol (67-56-1)
ether,
ethyl ether (60-29-7)
acetonitrile (75-05-8)
sodium hydroxide (1310-73-2)
sodium bicarbonate (144-55-8)
2-naphthol (135-19-3)
cyclohexane (110-82-7)
sodium methoxide (124-41-4)
toluene (108-88-3)
2-propanol (67-63-0)
methylene chloride (75-09-2)
magnesium sulfate (7487-88-9)
hexane (110-54-3)
triethylamine (121-44-8)
binaphthol
(R)-(+)-1,1'-Bi-2-naphthol,
1,1'-bi-2-naphthol,
[1,1'-Binaphthalene]-2,2'-diol, (R)-,
(±)-1,1'-bi-2-naphthol,
[1,1'-Binaphthalene]-2,2'-diol, (S)-,
(S)-(−)-1,1'-Bi-2-naphthol (18531-99-2)
1,1'-bi-2-naphthyl pentanoate (110902-38-0)
pentanoyl chloride (638-29-9)
sodium taurocholate
binaphthol dipentanoate,
(R)-binaphthol dipentanoate
(R)-binaphthyl dipentanoate
Octahydrobinaphthol
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