Convenient and highly efficient chromatographic resolution of BINOL and of 6,6′-dibromo-BINOL via N(α)-Boc-tryptophan esters

Article abstract of DOI:10.1016/S0040-4039(02)02268-2

Racemic [1,1′]binaphthalenyl-2,2′-diol (BINOL, (±)-1) has been esterified with various commercially available N-protected-L-amino acids, giving the corresponding diastereomeric esters. Their TLC separation factors were highly dependent on the amino acid pattern. Diesters of (±)-1 and N(α)-Boc-tryptophan (3a) showed unusually large separation factors, which allowed their efficient separation by simple column chromatography. Removal of the tryptophan moieties under very mild conditions furnished each enantiomer of 1 in high overall yield and 100% ee. This procedure was also successful for the resolution of racemic 6,6′-dibromo-[1,1′]binaphthalenyl-2,2′-diol (6,6′-dibromo-BINOL, (±)-2).

Full text of DOI:10.1016/S0040-4039(02)02268-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9245–9248
Convenient and highly efficient chromatographic resolution of
BINOL and of 6,6%-dibromo-BINOL via
N(a)-Boc-tryptophan esters
Bhavesh M. Panchal, Cathy Einhorn and Jacques Einhorn*
Laboratoire d% e´ tudes dynamiques et structurales de la s e´ lectivit e´ /UMR 5616, Universit e´ Joseph Fourier, BP 53,
38041 Grenoble Cedex 9, France
Received 5 September 2002; accepted 30 September 2002
Abstract—Racemic [1,1%]binaphthalenyl-2,2%-diol (BINOL, (±)-1) has been esterified with various commercially available N-pro-
tected-L-amino acids, giving the corresponding diastereomeric esters. Their TLC separation factors were highly dependent on the
amino acid pattern. Diesters of (±)-1 and N(a)-Boc-tryptophan (3a) showed unusually large separation factors, which allowed
their efficient separation by simple column chromatography. Removal of the tryptophan moieties under very mild conditions
furnished each enantiomer of 1 in high overall yield and 100% ee. This procedure was also successful for the resolution of racemic
6,6%-dibromo-[1,1%]binaphthalenyl-2,2%-diol (6,6%-dibromo-BINOL, (±)-2). © 2002 Elsevier Science Ltd. All rights reserved.
Resolution by conversion of a racemate to a mixture of
diastereomers remains of paramount importance to
obtain enantiomerically pure substances. In a large
majority of cases, this type of resolution is based on
solubility differences of crystalline solids. The major
drawbacks of this approach are that it involves neces-
sarily crystalline materials and that, often, only one
enantiomer (corresponding to the least soluble
diastereomer) can be obtained in a very high optical
purity. Comparatively, separations based on chromato-
graphic separation of covalent diastereomeric pairs are
much less frequent, though having, in favorable cases,
some decisive advantages over crystallization methods:
Mainly, there is no need to obtain crystalline materials
and, in principle, both enantiomers are obtainable opti-
racemic [1,1%]binaphthalenyl-2,2%-diol (BINOL, (±)-1)
and of racemic 6,6%-dibromo-[1,1%]binaphthalenyl-2,2%-
diol (6,6%-dibromo-BINOL, (±)-2) that fulfils all the
preceding requirements.
1
cally pure. To be of practical use, chromatographic
Various resolutions of (±)-1 and of other atropisomeric
resolutions on covalent diastereomers have to combine
the following characteristics: The resolving agent
should be readily (or, even better, commercially) avail-
able at a reasonable price. Covalent bonding to the
racemate should be simple, selective and high yielding.
diphenols via covalent derivatives have been described,
2
using for example menthyl carbonates, neomenthyl-
3
4
thioacetates, menthyl cyclic phosphites, cyclic phos-
phates or thiophosphates bearing the a-methyl-
2
c,f,5
6
benzylamine moiety,
camphorsulfonates,
and
R differences between the diastereomeric pairs should
7,8
f
camphanates. To our knowledge, amino acid deri-
vatives have not yet been used for chromatographic
resolution of atropisomeric diphenols via the corre-
sponding esters, with the notable exception of Fuji’s
be as large as possible. Lastly, removal of the chiral
auxiliary should be easy and should allow its recovery.
Herein we report a new chromatographic resolution of
resolution of [1,1%]binaphthalenyl-8,8%-diol via mono-
7
esters of N-Cbz-
L
-proline. a-Amino acids of the
L
Keywords: amino acids and derivatives; biaryls; column chromatogra-
phy; resolution.
series represent a natural source of optically pure
compounds with an outstanding structural diversity.
We have checked the resolution ability of various com-
*
Corresponding author. Tel.: 33 4 76 51 48 39; fax: 33 4 76 51 48 36;
e-mail: Jacques.Einhorn@ujf-grenoble.fr
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02268-2

9
246
B. M. Panchal et al. / Tetrahedron Letters 43 (2002) 9245–9248
mercially available N-protected-
via the corresponding diastereomeric esters. Each reac-
tion has been performed on an analytical scale (10
L
-amino acids on (±)-1,
1 equiv. of 3a, 1 equiv. of DCC and 10 mol% DMAP.
Column chromatography on silica gel (elution
CH Cl :ether, 95:5) gave 87% of monoester 4a with
2
2
mmol). R values and separation factors (h) were deter-
R =0.60 and 82% of monoester 4b with R =0.40
f
f1
f2
mined by TLC analysis, in order to select the most
promising candidates for efficient separations. Both
conversions into mono- and into diesters have been
attempted, using standard DCC/DMAP esterification
method. Table 1 summarizes the TLC data for the
various mono- and diesters tested. N-Boc- and N-Cbz-
proline gave readily monoesters with separation factors
of 1.21 and 1.15, but clean conversion into diesters
failed (entries 1 and 2). Amino acids with aliphatic side
chains like N-Boc-isoleucine and -valine gave easily
mono- or diesters, but with only negligible separation
factors (entries 3 and 4). N-Boc-asparagine and N(a)-
Boc-histidine failed to give significant amounts of esters
(Table 1, entry 11). Chromatographic separation also
furnished 12% of unreacted 1. Optical rotation of this
1
8
sample was [h] =+5.84 (c=1.0, THF), which reveals
D
an ee of 17% in the favor of (+)-1 and, consequently,
some degree of kinetic resolution during esterification.
Diesterification has next been performed on a 4 mmol
scale of (±)-1, using 2.2 equiv. of 3a, 2.3 equiv. of DCC
and 10 mol% of DMAP. Reaction was achieved after 3
h at room temperature. The large separation factor
allowed high loading of the chromatography column:
complete separation was performed on 60 g silica gel,
giving 1.66 g (97% yield) of diester 5a with R =0.54
f1
and 1.70 g (99% yield) of diester 5b with R =0.26.
f2
(
entries 5 and 6). Both mono and diesterification were
Each diester was diastereomerically pure (HPLC
easily performed with N-Boc-phenylglycine but separa-
tion factors were very low (entry 7). N-Boc- and N-
Cbz-phenylalanine gave monoesters, with separation
factors in the same range as for the corresponding
proline derivatives. The corresponding h factors were
somewhat lower for diesters (entries 8 and 9). Fmoc
nitrogen protection gave no advantage over Boc and
Cbz protection (entry 10). At last, unusually high sepa-
ration factors were observed in the tryptophan series
10
control).
(
entries 11–13): N(a)-Boc-, N(a)-Cbz- and N(a)-Fmoc-
tryptophan furnished monoesters with h values respec-
tively 1.50, 1.43 and 1.31, and diesters with 2.15, 1.89
and 1.50 values. Such high TLC h values are rather
uncommon and are generally indicative of easy chro-
matographic separations, even with the usual flash
Clean removal of the chiral auxiliaries after resolutions
via covalent diastereomeric pairs remain critical for the
global success of the processes. In fact, serious limita-
tions can arise from this final step: For example cam-
9
chromatography techniques.
7
Esterifications of (±)-1 with N(a)-Boc-tryptophan (3a)
have been scaled up without difficulties. Mono esterifi-
cation was performed on a 2 mmol scale of (±)-1, using
phanyl esters are best cleaved via reduction by LiAlH4.
Not only is this procedure destructive for the chiral
moiety, but it is also hard to use if sensitive functional-
Table 1. TLC data for mono- and diesters of (9)-1 and N-protected-L-amino acids
Entry
Amino acid derivative
Monoesters
Rf2a
Diesters
Rf1a
hb
Rf1a
Rf2a
hb
c
c
1
2
3
4
5
6
7
8
9
N-Boc-proline
N-Cbz-proline
N-Boc-isoleucine
N-Boc-valine
N-Boc-asparagine
N(a)-Boc-histidine
N-Boc-phenylglycine
N-Boc-phenylalanine
N-Cbz-phenylalanine
N-Fmoc-phenylalanine
N(a)-Boc-tryptophan
N(a)-Cbz-tryptophan
N(a)-Fmoc-tryptophan
0.46
0.46
0.66
0.62
0.36
0.38
0.40
0.66
0.60
0.36
1.21
1.15
1
1.03
1
–
–
–
–
–
–
1
1.06
–
c
c
0.76
0.74
0.76
0.70
d
d
d
d
–
–
–
–
e
e
e
e
–
–
–
–
0.66
0.62
0.64
0.68
0.60
0.60
0.68
0.65
0.52
0.54
0.62
0.40
0.42
0.52
1.01
1.19
1.18
1.10
1.50
1.43
1.31
0.76
0.78
0.80
0.84
0.54
0.68
0.78
0.74
0.70
0.74
0.80
0.26
0.36
1.03
1.11
1.08
1.05
2.15
1.89
1.50
10
11
12
13
f
f
f
f
f
f
f
f
f
f
f
f
0.52
a
b
c
d
e
f
Except when otherwise stated, elution with 95:5, CH Cl :ether mixtures.
2
2
h defined as: h=Rf1/Rf2
Complex mixture obtained.
Low conversion.
No esterification.
Elution with 90:10, CH Cl :ether mixtures.
2
2

B. M. Panchal et al. / Tetrahedron Letters 43 (2002) 9245–9248
9247
ities are present in the compound to be resolved. Simi-
lar limitations exist for the use of cyclic phosphorus
Fabbri, D.; Dettori, M. A.; Casalone, G.; Forni, A.
Tetrahedron: Asymmetry 2000, 11, 1827–1833; (d) Bandin,
M.; Casolari, S.; Cozzi, P. G.; Proni, G.; Schmohel, E.;
Spada, G. P.; Tagliavini, E.; Umani-Ronchi, A. Eur. J.
Org. Chem. 2000, 491–497; (e) Yudin, A. K.; Martyn, L.
J. P.; Pandiaraju, S.; Zheng, J.; Lough, A. Org. Lett.
2000, 2, 41–44; (f) Delogu, G.; Fabbri, D.; Dettori, M.
A.; Forni, A.; Casalone, G. Tetrahedron: Asymmetry
2001, 12, 1451–1458.
4
2
derivatives or of menthyl carbonates. Fuji’s resolution
of [1,1%]binaphthalenyl-8,8%-diol via N-Cbz- -proline
L
7
esters allowed hydrolytic cleavage by KOH. We first
applied the same procedure for the saponification of
diester 5a. Reaction was completed after 18 h at room
temperature, and furnished after conventional work-up,
1
1
6
2% (R)-(+)-1 (100% ee). Camphorsulfonates have
been cleaved after several hours refluxing in methanolic
3. Pakulski, Z.; Zamojski, A. Tetrahedron: Asymmetry 1995,
6, 111–114.
4. (a) Brunel, J.-M.; Buono, G. J. Org. Chem. 1993, 58,
7313–7314; (b) Anderson, S.; Neidlein, U.; Gramlich, V.;
Diederich, F. Angew. Chem. Int. Ed. Engl. 1995, 34,
1596–1600.
5. (a) Fabbri, D.; Delogu, G.; De Lucchi, O. J. Org. Chem.
1993, 58, 1748–1750; (b) Gelpke, A. E. S.; Fraanje, J.;
Goubitz, K.; Schenk, H.; Hiemstra, H. Tetrahedron 1997,
53, 5899–5908; (c) Delogu, G.; Fabbri, D. Tetrahedron:
Asymmetry 1997, 8, 759–763; (d) Delogu, G.; Fabbri, D.;
Dettori, M. A.; Forni, A.; Casalone, G. Tetrahedron:
Asymmetry 2000, 11, 4417–4427.
6
b
NaOH. Gratifyingly, we found that almost instanta-
neous cleavage of diesters occurred, using a stoichio-
metric amount of LiOH in methanol at room
temperature. In this procedure, aqueous work-up can
be avoided: After completion of the cleavage, stoichio-
metric amount of trifluoroacetic acid was added to the
reaction mixture and methanol removed at reduced
pressure. For 5a, column chromatography of the crude
material gave 91% of pure (R)-(+)-1 (100% ee). N-Boc-
L
-tryptophan was recovered as its methyl ester 3b (82%
12
recovery, 100% ee). In the same way, 93% of pure
(
S)-(−)-1 (100% ee) has been obtained, starting from
13
diester 5b (83% recovery of 3b).
6. (a) Chow, H.-F.; Wan, C.-W.; Ng, M.-K. J. Org. Chem.
1996, 61, 8712–8714; (b) Ducry, L.; Diederich, F. Helv.
This new method has also been applied successfully for
the resolution of (±)-2. Diesterification of (±)-2 with
Chim. Acta 1999, 82, 981–1004; (c) Tian, Y.; Chan, K. S.
Tetrahedron Lett. 2000, 41, 8813–8816.
7. Fuji, K.; Yang, X.-S.; Ohnishi, H.; Hao, X.-J.; Obata, Y.;
Tanaka, K. Tetrahedron: Asymmetry 1999, 10, 3243–
3248.
1
4
3
a furnished a mixture of diastereomeric diesters 6a and
b (TLC data: R =0.88, R =0.50, h=1.76, elution
6
f1
f2
with 85:15 CH Cl :ether). Column chromatographic
2
2
separation of the crude material gave pure 6a (98.5%
8. Various direct chromatographic resolutions of BINOL
and of other axially chiral biphenols have also been
described via chiral HPLC, some of them with very large
enantioseparations, see for example: (a) Yashima, E.;
Yamamoto, C.; Okamoto, Y. J. Am. Chem. Soc. 1996,
118, 4036–4048. Some of these separations have been
performed on stationary phases amenable to large-scale
simulated moving bed (SMB) technology. See: (b)
Negawa, M.; Shoji, F. J. Chromatogr. 1992, 590, 113–
117; (c) Ogawa, T.; Ohtsu, Y. Nippon Kagaku Kaishi
1997, 3, 201–206; (d) Kasuya, N.; Nakashima, J.; Kubo,
T.; Sawatari, A.; Habu, N. Chirality 2000, 12, 670–674.
For miscellaneous other resolutions of 1, see: (e) Du, H.;
Ji, B.; Wang, Y.; Sun, J.; Meng, J.; Ding, K. Tetrahedron
Lett. 2002, 43, 5273–5276, and references cited therein.
1
0
yield), followed by pure 6b (99%) yield). Hydrolysis of
a by LiOH in methanol gave 91% of pure (R)-(−)-2
6
1
1
(
100% ee). Similarly, 6b furnished (S)-(+)-2 (100% ee).
The present procedure combines all the desirable fea-
tures for efficient chromatographic resolution via cova-
lent derivatives. It allowed the resolution of (±)-1 and
-
2 with global yields close to 90% and 100% ee%s for
each of the enantiomers. Preliminary experiments indi-
cate that it should also be applicable to other types of
atropisomeric biphenols. Its scope and limitations, as
well as the origin of the high separation factors are
presently under investigation and will be reported in
due course.
9
. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
923–2925.
10. Although all mono- and diesters showed single signals on
HPLC analysis (performed on
2
Acknowledgements
a
mBondapack C18
reversed phase column, elution MeOH:H O, 85:15), they
2
Financial supports from CNRS and Universit e´ Joseph
Fourier are gratefully acknowledged.
exist, at room temperature, as mixtures of rotamers due
to restricted rotation across N-Boc bond, as determined
1
by H NMR spectroscopy. See Ref. 7 for similar
observations.
References
11. Enantiomeric purity has been determined by HPLC on a
Chiralpak AS column, elution hexane:i-PrOH, 9:1, 1 mL
−
1
1
. Lindner, W. In Indirect Separation of Enantiomers by
Liquid Chromatography; Zief, M.; Crane, L., Eds. Chro-
matographic chiral separations. Chapter 4, chromato-
graphic science series; Marcel Dekker: New York, Basel,
988; Vol. 40, pp. 91–130.
. (a) Fabbri, D.; Delogu, G.; De Lucchi, O. J. Org. Chem.
995, 60, 6599–6601; (b) Kolotuchin, S. V.; Meyers, A. I.
J. Org. Chem. 1999, 64, 7921–7928; (c) Delogu, G.;
min .
12. Cardillo, G.; Gentilucci, L.; Tomasini, C.; Tomasoni, L.
Tetrahedron: Asymmetry 1995, 8, 1947–1955. Enan-
tiomeric purity of 3b has been determined by HPLC on a
Chiralpak AS column, elution hexane:i-PrOH, 6:4, 1 mL
1
−
1
2
min . Furthermore, as variation of the enantiomeric
purity of the amino acid derivatives depending on the
supplier have been reported, we have also checked start-
1

9
248
B. M. Panchal et al. / Tetrahedron Letters 43 (2002) 9245–9248
ing 3a, after its preliminary derivatisation into 3b with
diazomethane.
3. Overall procedure for the resolution of 1: A solution of
racemic 1 (1.145 g, 4 mmol), 3a (2.618 g, 8.8 mmol)
(m, 6H), 7.20–7.35 (m, 4H), 7.40–7.65 (m, 6H), 8.00–8.20
13
(m, 4H), 10.69 (br s, 2H). C NMR (DMSO d ) l 25.58,
6
1
28.33, 55.03, 78.68, 109.83, 111.45, 117.67, 118.56, 121.05,
121.96, 122.78, 124.10, 127.48, 126.25, 126.71, 127.48,
128.71, 130.12, 131.58, 132.96, 136.13, 146.51, 155.68,
170.99. IR (KBr pellet) w 3412, 3331, 3061, 2971, 2931,
12
(100% ee, supplied by ACROS Organics), DCC (1.898
.
g, 9.2 mmol) and DMAP (0.048 g, 0.4 mmol) in anhy-
drous dichloromethane (80 mL) was stirred at room
temperature for 3 h. After filtration of dicyclohexylurea,
the solvent was removed at reduced pressure. The residue
was chromatographed over silica gel (60 g). Elution with
dichloromethane: ether (95:5) gave pure 5a (1.663 g, 97%
1763, 1714, 1502, 1363, 1159. MS (DCI, NH +isobutane)
3
m/z 875, 858, 759, 659, 473. Anal. calcd for C H N O :
52
48
4
8
C, 72.88; H, 5.64; N, 6.53. Found: C, 72.10; H, 5.87; N,
6.65. To a solution of diester 5a (1.663 g, 1.940 mmol) in
methanol (5 mL) was added a 1 M solution of LiOH·H O
2
2
5
yield) as an amorphous solid: [h] −68.3 (c=1.0, THF).
in methanol (3.88 mL, 3.88 mmol). After 5 min stirring at
room temperature, trifluoroacetic acid (0.29 mL, 3.88
mmol) was added. Removal of the solvent in vacuo gave
a solid residue, which was subjected to column chro-
D
1
H NMR (DMSO d ) l 1.19 and 1.27 (2br s in a 0.22:1
6
ratio, 18H), 1.85–2.20 (m, 4H), 4.00–4.20 (m, 2H), 6.90–
13
7
.59 (m, 20H), 8.04–8.17 (m, 4H), 10.74 (br s, 2H).
C
NMR (DMSO d ) l 24.90, 28.05, 54.47, 78.26, 109.58,
matography on silica gel (15 g). Elution with CH
gave R-(+)-1 (0.504 g, 91% yield): mp 206–207°C. [h]
D
2
Cl
2
6
2
5
1
1
1
3
11.37, 117.77, 118.42, 120.90, 121.83, 122.86, 123.61,
25.44, 125.89, 126.65, 126.95, 128.22, 129.98, 131.33,
32.64, 135.96, 146.51, 155.42, 171.01. IR (KBr pellet) w
412, 3053, 2980, 2931, 1763, 1706, 1502, 1371, 1159. MS
1
1
+34 (c=1.0, THF), ee=100%. Further elution with
CH Cl gave 3b (1.009 g, 3.169 mmol, 82% yield): mp
2
2
12
142–144°C (lit. : 142–144°C). In the same way, 5b (1.697
g, 1.979 mmol) gave S-(−)-1 (0.530 g, 93% yield): mp
(
DCI, NH +isobutane) m/z 875, 858, 759, 659, 473. Anal.
3
2
5
11
calcd for C H N O : C, 72.88; H, 5.64; N, 6.53. Found:
209–210°C; [h] −34.0 (c=1.0, THF), ee=100%. Fur-
D
52
48
4
8
C, 72.28; H, 5.82; N, 6.57. Further elution gave pure 5b
ther elution of the column gave 3b (1.049 g, 3.293 mmol,
83% yield) identical to the sample obtained from 5a.
14. (a) Vondenhof, M.; Mattay, J. Tetrahedron Lett. 1990,
31, 985–988; (b) Cai, D.; Hugues, D. L.; Verhoeven, T.
R.; Reider, P. J. Tetrahedron Lett. 1995, 36, 7991–7994.
25
(
(
1.697 g, 99% yield) as an amorphous solid: [h] −44.5
D
1
c=1.0, THF). H NMR (DMSO d ) l 1.15 and 1.29 (2
6
br s in a 0.27:1 ratio, 18H), 2.00–2.60 (m, 4H), 3.70–3.90
m, 2H), 6.30–6.40 (m, 2H), 6.70–6.80 (m, 2H), 6.95–7.05
(