Heterocomplexation of a chiral dipeptide and quantitative enantiomeric enrichment of nonracemic 1,1′-Bi-2-naphthol

Article abstract of DOI:10.1021/jo801547j

(Chemical Equation Presented) Heterocomplexation of a chiral host to a racemic guest has been discovered. A cyclic dipeptide generated from (S)-proline alkyl ester undergoes an achiroselective complexation to both the enantiomers of racemic BINOL in benzene to yield a crystalline heterocomplex bearing the solvent molecules. However, complexation crystallization does not occur between the diptide and either enantiomer of BINOL under similar conditions. The difference in complexation behavior has been successfully applied in the enantiomeric enrichment of nonracemic BINOLs, and almost quantitative separation of the excess enantiomer from racemic BINOL was achieved.

Full text of DOI:10.1021/jo801547j

Heterocomplexation of a Chiral Dipeptide and
Quantitative Enantiomeric Enrichment of
Nonracemic 1,1′-Bi-2-naphthol
Zixing Shan,* Ying Xiong, Jing Yi, and Xiaoyun Hu
Department of Chemistry, Wuhan UniVersity,
FIGURE 1. Cyclic tricyclic dipeptide (3S,6S)-1 and 1,1′-bi-2-naphthol.
Wuhan 430072, China
of an achiral host to a racemic guest has been recently reported.2
In an attempt to prepare an enantiopure diol via enantioselective
complexation of a chiral tricyclic dipeptide host (3S,6S)-1
(Figure 1) to an axially chiral guest racemic 1,1′-bi-2-naphthol
(rac-2), we unexpectedly observed an achiroselective complex-
ation crystallization of the dipeptide to the two enantiomers of
rac-2. Further investigation found that no complexation crystal-
lization occurred between (3S,6S)-1 and enantiopure (R)- or (S)-
1,1′-bi-2-naphthol [(R)-2 or (S)-2] under similar conditions. This
difference in complexation behaviors naturally aroused our
interest in the enrichment of the excess enantiomer in (R)-2 or
(S)-2 with lower ee via the heterocomplexation strategy. We
successfully applied the strategy and realized almost quantitative
separation of the excess enantiomer from the racemate. We
herein report the novel enrichment of the excess enantiomer in
nonracemic 1,1′-bi-2-naphthols (non-rac-2).
zxshan@whu.edu.cn
ReceiVed July 14, 2008
Heterocomplexation of a chiral host to a racemic guest has
been discovered. A cyclic dipeptide generated from (S)-
proline alkyl ester undergoes an achiroselective complexation
to both the enantiomers of racemic BINOL in benzene to
yield a crystalline heterocomplex bearing the solvent mol-
ecules. However, complexation crystallization does not occur
between the diptide and either enantiomer of BINOL under
similar conditions. The difference in complexation behavior
has been successfully applied in the enantiomeric enrichment
of nonracemic BINOLs, and almost quantitative separation
of the excess enantiomer from racemic BINOL was achieved.
The tricyclic dipeptide (3S,6S)-13 generated from (S)-proline
methyl ester was allowed to mix with rac-2 in benzene with
heating until the solids dissolved completely, followed by reflux
for an additional 1 h, and then cooled to ambient temperature
to give a colorless crystalline material SC-34 with [R]D
)
25
1
-18.3° (c ) 1, THF). The H NMR spectrum of SC-3 clearly
indicates that it is a 1:2:3 complex consisting of the dipeptide,
1,1′-bi-2-naphthol, and benzene, and the dipeptide retains its
configuration under the solution NMR condition. However,
decomplexation of SC-3 yielded almost quantitative rac-2,
meaning that two opposite configurational 1,1′-bi-2-naphthol
molecules are included in the complex. This fact reveals that
an achiroselective complexation of (3S,6S)-1 to both the
enantiomers of rac-2 occurs in this system.
Chiral discrimination of a chiral host to a racemic guest is
one of the most important forms of molecular recognition. In
the molecular recognition, the chiral host stereoselectively
interacts with one enantiomer of the racemic guest, leading to
chiral separation of the racemic compound. This chiral recogni-
tion has been developed into an effective method for preparing
optically active organic materials.1 However, simultaneous
complexation of a chiral host to two enantiomers of a racemic
guest has never been observed to date, though heterorecognition
Single crystal X-ray diffraction analysis5 of SC-3 further
confirmed the composition of the complex (Figure 2 on left).
In the crystal, it can be observed that both OH groups of
each 1,1′-bi-2-naphthol molecule are involved in H-bonds
with neighboring carbonyl groups of the dipeptides, and that
each peptide carbonyl group is hydrogen-bonded with two
1,1′-bi-2-naphthols having different chirality, namely, each
(3) (a) Nakamura, D.; Kakiuchi, K.; Koga, K.; Shirai, R. Org. Lett. 2006, 8
(26), 6139–6142. (b) Tang, H. Y.; Zhao, G. F.; Zhou, Z. H.; Zhou, Q. L.; Tang,
C. C. Tetrahedron lett. 2006, 47, 5717–5721.
(4) When the molar ration of racemic 1,1′-bi-2-naphthol and (3S,6S)-1 is
higher than 2:1, a co-precipitation of the complex and racemic 1,1′-bi-2-naphthol
occurred. The co-precipitate was treated by recrystallization in benzene to offer
pure complex SC-3.
(5) Final atomic coordinates of the crystal, along with lists of anisotropic
thermal parameters, hydrogen coordinates, bond lengths, and bond angles, have
been deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC-287999. Data can be obtained, on request, from
the Director, Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK (Fax: (+44) 1223-336-033. E-mail: deposit@
ccdc.cam.cn. Web: http//www.ccdc.cam.ac.uk).
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10.1021/jo801547j CCC: $40.75 2008 American Chemical Society
Published on Web 10/22/2008

FIGURE 2. (Left) Molecular packing diagram of the complex SC-3 (hydrogen bonds are shown as dotted lines). (Right) Chain structure of SC-3.
SCHEME 1. Enrichment of Non-rac-2 via Hetereocamplexation of (3S,6S)-1
TABLE 1. Enantiomeric Enrichment of Non-Racemic BINOLs by Heterocomplexation of (3S,6S)-1
yield of the enantiomer
enriched (%)b
[R]D of the
enantiomer enriched (THF, c 1)
ee of the enantiomer
enriched (%)c
entry
nonrac-2a
yield of SC-3 (%)
1
2
3
4
80% ee (R)-2
80% ee (S)-2
50% ee (S)-2
20% ee (S)-2
96
98
97
98
96
97
96
95
[R]D25 ) +35.6
[R]D25 ) -35.4
[R]D25 ) -35.6
[R]D25 ) -35.5
>99
>99
>99
>99
a Nonracemic BINOLs were made up by mixing of rac-2 with an appropriate amount of enantiopure (R)- or (S)-2. b Yield of optically active BINOL
is calculated based on the sum of two or three crops by crystallization. c Ee of optically active BINOL is obtained based on chiral HPLC determination
and the specific rotation.
peptide CdO group actually accepted two H-bonds, and the
OH · · · O distances are 2.014 and 2.149 Å, respectively, and
in one H-bond, the three atoms are nearly collinear with a
bond angle of 178°. This molecular assembly results in the
formation of an infinite chain, where each link is composed
of the peptide molecules doubly bridged by two BINOL
molecules, and the solvent molecules (benzenes) are locked
between the chains to form a more stable three-dimensional
network (Figure 2 on right). To the best of our knowledge,
this interesting supramolecular construction has never been
observed before.
in the non-rac-2 precipitated from the solution as a crystalline
complex (SC-3). The benzene solution removed from the
crystals was concentrated to give massy transparent crystals6
of enantiopure (R)-2 or (S)-2. Some results obtained by the
heterocomplexation enrichment were summarized in Table 1.
It may be seen that efficient separation of the excess enantiomer
from rac-2 is realized.
Theoretically, this enrichment method is suitable for any
enantiomerically impure 1,1′-bi-2-naphthol; however, in
consideration of preparative efficiency, it is more suitable
for nonracemic 1,1′-bi-2-naphthols with medium or higher
enantiomeric purity.7
In contrast to the above, enantiopure (R)-2 or (S)-2 can
not undergo complexation crystallization with (3S,6S)-1 under
similar condition.
(6) We early observed that enantiopure (R)- or (S)-BINOL has different
crystalline behavior from racemic BINOL in benzene or toluene. In both the
solvents, enantiopure (R)- or (S)-BINOL is isolated as a massy colorless
transparent crystal, whereas racemic BINOL is obtained as a light, white needle.
However, in Et2O, they are isolated as a massy colorless transparent crystal.
Therefore, benzene and toluene are selected as solvent for the enrichment of the
excessive enantiomer in nonracemic BINOL.
(7) Our enrichment is more suitable for the (R)- or (S)-BINOLs in higher
than 50% ee. That is because the (R)- and (S)-BINOLs with low ee include high
ratio of racemic BINOL, whereas racemic BINOL has low solubility in benzene
even under reflux condition. Thus, a great amount of the solvent, bulky
equipment, and long time are required for their dissolution. On the other hand,
it is low efficiency to obtain relative small amount of enantiopure (R)- or (S)-
BINOL by evaporation of plentiful low-concentration solution.
The strikingly different complexation behavior of rac-2 from
enantiopure (R)-2 or (S)-2 was applied to enrich the excess
enantiomer in 1,1′-bi-2-naphthols with lower ee (Scheme 1).
For a non-rac-2, the amount of the rac-2 included can be readily
calculated based on the ee value of the non-rac-2, thus the
appropriate (3S,6S)-1 loading requested for the formation of a
1:2 complex with the rac-2 can be determined. When a
stoichiometric (3S,6S)-1 was added to a benzene solution of
the non-rac-2, refluxed, and then cooled, the rac-2 contained
J. Org. Chem. Vol. 73, No. 22, 2008 9159

In addition, it is noteworthy that the heterocomplex SC-3 is
easily dissociated by a H2O-CH3COOEt mixture, from which
(3S,6S)-1 and rac-2 can be recovered almost quantitatively for
reuse.
In summary, an achiroselective complexation of chiral host
(3S,6S)-1 to racemic guest rac-2 has been discovered, and the
heterocomplexation has been successfully applied to enantio-
meric enrichment of a wide range of nonracemic 1,1′-bi-2-
naphthols, where stoichiometric separation of the excess enan-
tiomer from the racemate is realized.
Enantiomerically pure (R)-2 and (S)-2 have been widely
used in asymmetric synthesis,8 supramolecular chemistry,9
chiral separation10 and preparation of a variety of chiral
materials.11 However, most of the reported preparations for
them cannot directly offer high-yieldingly enantiopure prod-
ucts, and further purification or enrichment is generally
required. It must be pointed out that the known purifica-
tions, including chiral12a,b or achiral stationary phase
chromatography,12c fractional crystallization,12d-f “kinetic”
crystallization12g and chiral discrimination of bovine serum
albumin,12h,i often are not satisfied in cost or in efficiency.
Our enrichment possesses some remarkable advantages, such
as simple procedure, stoichiometric separation, lower cost
and higher efficiency.
Experimental Section
Representative Procedure for the Enrichment of the
Excessive Enantiomer in a Nonracemic 1,1′-Bi-2-naphthol. A
mixture of (3S,6S)-1 (0.1 g, 0.515 mmol) and 80% ee (S)-1,1′-bi-
2-naphthol (1.44 g, 5.035 mmol) was refluxed in benzene (15 mL)
for 1.5 h. The resulting solution was cooled to rt and stood for
24 h to isolate a white solid. The solid was filtered, washed with
benzene, collected, and then dried under reduced pressure to weigh
20
0.495 g, mp 170-172 °C, [R]D ) -18.6 (c 1, in THF), 98%
yield (calcd based on a 1:2:3 complex consisting of the dipeptide,
1,1′-bi-2-naphthol and benzene). IR (KBr, cm-1): 3358, 3224, 1623.
1H NMR (DCCl3, 300 MHz): 1.85-2.33 (m, 8H); 3.49-3.54 (dd,
J ) 9.0 Hz, J ) 6.0 Hz, 4H); 4.13 (t, J ) 8.1 Hz, 2H); 5.18 (s,
4H); 7.15 (d, J ) 8.1 Hz, 4H); 7.40-7.28 (m, 30 H); 7.90 (d, J )
7.2 Hz, 4H), 7.98 (d, J ) 9.3 Hz, 4H). The benzene mother liquor
removed from the solid was concentrated and slowly cooled to
furnish massy transparent crystals of enantiopure (S)-2 (1.102 g),
mp 208-210, 96% yield, [R]D20 )-35.6 (c 1, in THF). >99% ee.
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Acknowledgment. We thank the National Natural Science
Foundation of China (20372053 and 20672083) for financial
support.
Supporting Information Available: The preparative pro-
cedure of (3S,6S)-1 and the IR, 1H NMR spectra, crystal
structure and CIF for SC-3. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO801547J
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