Highly efficient chromatographic resolution of α,α′- dihydroxybiaryls

Article abstract of DOI:10.1021/ol052309z

(Graph Presented) Separation factors as high as 115 were observed for the chromatographic resolution of many α,α′-dihydroxybiaryls with a single chiral stationary phase made from readily available amino acid derivatives. The stationary phase works well for biphenyl-type compounds. It works extremely well for larger bis-aromatic compounds, such as binaphthyl-type compounds.

Full text of DOI:10.1021/ol052309z

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ORGANIC
LETTERS
2005
Vol. 7, No. 26
5821-5823
Highly Efficient Chromatographic
Resolution of
r,r′-Dihydroxybiaryls
Junmin Huang and Tingyu Li*
Department of Chemistry, Box 9573, Mississippi State UniVersity,
Mississippi State, Mississippi 39762
TL45@ra.msstate.edu
Received September 22, 2005
ABSTRACT
Separation factors as high as 115 were observed for the chromatographic resolution of many
r
,
r′-dihydroxybiaryls with a single chiral
stationary phase made from readily available amino acid derivatives. The stationary phase works well for biphenyl-type compounds. It works
extremely well for larger bis-aromatic compounds, such as binaphthyl-type compounds.
Enantiomerically pure R,R′-dihydroxybiaryls (Figure 1), such
as 1,1′-bi-2-naphthol (8), are widely used as chiral auxiliaries
and ligands in asymmetric synthesis and have shown high
stereocontrol properties in a wide range of asymmetric
transformations.1-3 They are also valuable precursors to
enantiomerically pure phosphine-type chiral ligands, such as
binap (Scheme 1), which are highly versatile and useful
pure R,R′-dihydroxybiaryls and the corresponding phosphine-
type ligands are commercially available, possibly due to
difficulty in their preparation. Ready access to these com-
pounds is clearly important, as it will allow a greater number
of such compounds to be examined in catalytic reactions.
Although asymmetric synthesis of enantiomerically pure
R,R′-dihydroxybiaryls has been reported, they are frequently
obtained in enantiomerically pure forms by resolution of the
racemic mixture.1 The successful resolution methods often
involves (1) chemical modification of the target compound
to a derivative, (2) resolution of the derivative by fractional
crystallization or enzymatic method, and (3) conversion of
the derivative back to the target compound. For each
compound, a different resolution procedure needs to be
developed. Apparently, a resolution method that does not
require the chemical modification and that is applicable to
many different compounds is very desirable.
Scheme 1. Merck (a) or Monsanto (b) Process of Preparing
Enantiomerically Pure Binap
In this respect, chromatographic resolution, which usually
does not require chemical derivatization, is an attractive
alternative. However, for this method to be competitive, a
column that can resolve many different compounds with high
ligands for asymmetric transformations.4 Despite their cata-
lytic effectiveness, only a small number of enantiomerically
(1) Periasamy, M. Aldrichimica Acta 2002, 35, 89-101.
(2) Brunel, J. M. Chem. ReV. 2005, 105, 857-897.
(3) Kocovsky, P.; Vyskocil, S.; Smrcina, M. Chem. ReV. 2003, 103,
3213-3245.
(4) Berthod, M.; Mignani, G.; Woodward, G.; Lemaire, M. Chem. ReV.
2005, 105, 1801-1836.
10.1021/ol052309z CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/01/2005

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Figure 2. Structure of the Fmoc-Asn(Trt)-Asn(Trt)-NH(CH2)6CO-
APS chiral stationary phase. APS, 3-aminopropylsilica gel.
known analyte.6-12 Encouraged by this finding, we decided
to study the chiral resolution of other R,R′-dihydroxybiaryls
with this stationary phase.
Before studying other R,R′-dihydroxybiaryls, the impact
of the mobile phase on the resolution of 1,1′-bi-2-naphthol
(8) was studied. With 2-propanol/hexanes (86.1% n-hexane,
9.7% methylcyclopentane, 4.2% various methylpentanes) as
the mobile phase, the separation factor dropped to 2.11.
However, the separation factor increased to 15.5 when the
mobile phase was switched to CHCl3 (containing 50 ppm
pentene, no ethanol). The large increase in separation factor
with CHCl3 as the mobile phase is unexpected, considering
the similarity between CHCl3 and CH2Cl2. The separation
factor, however, is not sensitive to the presence of hexanes.
For 1,1′-bi-2-naphthol (8), the separation factor changed
slightly to 13.5 when 50% chloroform in hexanes was used
as the mobile phase. Similar results were observed for
compound 16. With 100% chloroform as the mobile phase,
the separation factor is 65.4. With 50% chloroform in
hexanes as the mobile phase, the separation factor becomes
65.7.
The resolution of other R,R′-dihydroxybiaryls in Figure 1
was subsequently studied with CHCl3 or CHCl3/hexanes as
the mobile phase, and the separation factors obtained are
listed in Figure 1 besides compound numbers. These R,R′-
dihydroxybiaryls were chosen based on their availability and
structural representation regarding size and substitution of
the aromatic ring. Some of the compounds (3, 4, 8, 9, 17,
20, 21, 23, 26, 27) are commercially available, and many
were made by following literature procedures.
Figure 1. Structures and separation factors for the R,R′-dihydroxy-
biaryls and other compounds studied. Separation factors are listed
after compound number (bold). See Supporting Information for
complete chromatographic data.
The stationary phase works very well for biphenyl-type
compounds (1-4). It works extremely well for larger bis-
separation factors [ratio of the retention times (TR, TS) of
the two enantiomers, after subtracting dead time (T0), (TR -
T0)/(TS - T0)] is required. Herein we would like to report a
chiral column that resolves many racemic R,R′-dihydroxy-
biaryls with unusually high enantioselectivity.
By screening a small peptide library, we discovered a
chiral stationary phase, Fmoc-Asn(Trt)-Asn(Trt)-NH(CH2)6-
CO-APS (Figure 2), that resolved racemic 1,1′-bi-2-naphthol
(8) with a separation factor of 7.2 when CH2Cl2 was used
as the mobile phase.5 This separation factor is significantly
higher than other separation factors reported for this well-
(5) Huang, J.; Li, T. J. Chromatogr., A 2005, 1062, 87-93.
(6) Kubota, T.; Yamamoto, C.; Okamoto, Y. Chirality 2002, 14, 372-
376.
(7) Yashima, E.; Yamamoto, C.; Okamoto, Y. J. Am. Chem. Soc. 1996,
118, 4036-4048.
(8) Kosjek, B.; Uray, G. Chirality 2001, 13, 657-667.
(9) Kasuya, N.; Nakashima, J.; Kubo, T.; Sawatari, A.; Habu, N. Chirality
2000, 12, 670-674.
(10) Vaton-Chanvrier, L.; Oulyadi, H.; Combret, Y.; Coquerel, G.;
Combret, J. C. Chirality 2001, 13, 668-674.
(11) Andersson, S.; Allenmark, S.; Moeller, P.; Persson, B.; Sanchez,
D. J. Chromatogr., A 1996, 741, 23-31.
(12) Krause, K.; Chankvetadze, B.; Okamoto, Y.; Blaschke, G. Elec-
trophoresis 1999, 20, 2772-2778.
5822
Org. Lett., Vol. 7, No. 26, 2005

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aromatic compounds, such as binaphthyl-type compounds.
Separation factors as high as 115 were observed (Figure 3)!
dropped to 1.33. In compound 21, in which both OH groups
are converted to OCH3 groups, no separation was observed.
No separation was observed for compound 23, in which both
OH groups are converted to OCOCH3 groups. As both
conversions remove the acidic hydrogen atom, these results
suggest that the hydrogen bonding donor ability of the HO
groups is important in the chiral recognition, although steric
effects cannot be ruled out. Studies of compound 24 or 25,
in which one OH group is replaced with a SH or a NH2,
support such a hydrogen bond donor argument, as separation
factors in both cases dropped significantly. When compared
with OH groups, SH and NH2 are generally considered as
weaker hydrogen bond donors. Interestingly, a modest
separation factor of 2.55 was observed when both HO groups
are replaced with NH2 groups as in compound 26. Location
of the two OH groups is also important, as no separation
was observed for compound 27.
Figure 3. Resolution of compound 19. Column size, 5 cm × 4.6
mm. Flow rate, 1 mL/min. Mobile phase, 100% CHCl3. Peaks A
and B are the enantiomers.
Severe peak tailing was observed for the latter eluting
enantiomer for the compound shown in Figure 3. Such peak
tailing is common for resolution with high separation factors
and can be readily eliminated by switching to a more polar
mobile phase after the first enantiomer is eluted.
The chiral stationary phase is made readily from com-
mercially available amino acid derivatives by stepwise solid-
phase synthesis. The ready availability of the stationary phase
and the large separation factors bode well for large-scale
preparative separations. Preliminary examination with an
analytical column (25 cm × 4.6 mm) looks promising; 10
mg of compound 9 was base-line resolved in one injection
using a simple isocratic elution with quantitative recovery.
Other elution conditions and techniques more suitable for
large-scale separation will be investigated.
These separation factors are among the highest ever reported
for chiral separation, where the typical separation factors are
often less than 1.5. Compound 20, which contains two
binaphthyl units, was also resolved with high separation
factor.
Steric properties of the substituents seem to influence the
separation factors more than the electronic properties of the
substituents. In compounds 13-16, which contain electron-
donating alkyl groups, excellent separation factors were
observed and they increased with the steric bulkiness of the
alkyl substituents. Excellent separation factors were also
observed for compounds 10-12, in which strong electron-
withdrawing groups exist. The separation factors for com-
pounds 12 and 15, one containing an electron-withdrawing
and another one containing an electron-donating group of
similar size, are not very different. Position of the substitution
can have a significant impact on the separation factor. For
the four dibromo-substituted binaphthols (9, 17, 18, 19), the
separation factors range from 1 to 115. No separation was
observed for compound 17, in which the two bromo
substituents are R to the OH groups. However, a separation
factor of 115 was observed when the bromo substituents are
at 7,7′ positions.
Acknowledgment. The financial support from NIH (1
R01 GM63812-01) is greatly appreciated. We also would
like to thank Professor Tamio Hayashi of Kyoto University
for sending us several analyte precursors.
Supporting Information Available: Chromatograms and
chromatographic data (dead time, retention times, retention
factors, separation factors, mobile phase), literature references
for the preparation of analytes. This material is available free
of charge via the Internet at http://pubs.acs.org.
Modification of two hydroxyl groups drastically reduces
the separation factors. In compound 22, in which one of the
OH is converted to an OCH3 group, the separation factor
OL052309Z
Org. Lett., Vol. 7, No. 26, 2005
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