Asymmetric synthesis and structural elucidation of C2- Symmetrical optically active macrocycles consisting of two biaryl and two -amino acid moieties

Article abstract of DOI:10.1055/s-0030-1258582

A series of chiral C₂-symmetrical macrocycles containing two -amino acids and two biaryl subunits have been designed and synthesized in moderate yields (36-53%). The absolute configurations of biaryl motifs in these chiral macrocycles were established by X-ray crystal structure analysis and CD measurements. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258582

LETTER
2557
Asymmetric Synthesis and Structural Elucidation of C2-Symmetrical
Optically Active Macrocycles Consisting of Two Biaryl and Two a-Amino Acid
Moieties
S
ynthesis and Stru
o
c
tural Elucid
n
ation of
C
2-Sgymmetrical
w
O
ptically
A
ctive
M
u
acrocycles Zhao,* Shi Su, Jin Cui, Xiuqing Song, Xiao Qin, Hailong Li, Hong Yan, Rugang Zhong, Liming Hu
College of Life Science and Bio-engineering, Beijing University of Technology, Beijing 100124, P. R. of China
Fax +86(10)67396200; E-mail: hwzhao@bjut.edu.cn
Received 9 July 2010
attracted considerable attention from the above-men-
Abstract: A series of chiral C2-symmetrical macrocycles contain-
ing two a-amino acids and two biaryl subunits have been designed
and synthesized in moderate yields (36–53%). The absolute config-
urations of biaryl motifs in these chiral macrocycles were estab-
lished by X-ray crystal structure analysis and CD measurements.
tioned areas.6,7 Up to date, a number of biaryl-containing
chiral macrocycles with various chelating sites, asymmet-
ric elements, and tunable functionalities have been syn-
thesized and investigated aiming at developing the
efficient chiral ligands,8,9 artificial receptors,10 and potent
pharmaceutical agents.11–13 It has been demonstrated that
the spatial arrangement of the asymmetric elements
around the binding sites may serve as the key factors for
the successful asymmetric induction, chiral recognition,
and drug discovery.
Key words: chiral macrocycle, biaryl, C2-symmetrical, absolute
configuration, X-ray analysis
Optically active macrocycles containing biaryl subunits
have found a wide variety of applications in the fields of
asymmetric catalysis,1 host–guest chemistry,2–4 and drug
development.5 Due to the well-known advantages of
chiral macrocycles with respect to the preorganization of
binding sites and asymmetric elements as well, the design
and synthesis of biaryl-containing chiral macrocycles has
As a part of our project to develop optically active macro-
cycles as potential chiral ligands in the asymmetric cata-
lytic reactions, a series of novel chiral macrocycles 11a–c
were designed and synthesized as shown in Table 1. This
family of chiral macrocycles consists of two a-amino ac-
O
CHO
Pd(PPh3)4
Bu3Sn-SnBu3
NO2
Br
NO2
CHO
NO2
3
OH
Br
HO
O
toluene
110 °C
Pd(PPh3)4
TsOH, benzene
80 °C
SnBu3
NO2
CuBr, THF
reflux
90%
1
80%
4
2
80%
5
NHBoc
OH
O
O
O
O
R
TsOH, acetone
r.t.
MeI, Cs2CO3,
MeCN, r.t.
O
O
Me
H2, PtO2
EtOH, r.t.
O
7a–c
EDCI, CH2Cl2
r.t.
NH2
NHBoc
NHBoc
R
N
NH
6
O
R
94%
O
9a–c
78–90%
8a–c
83–97%
CHO
Me
(R)-10a: R = Me, 93%
(S)-10a: R = Me, 90%
(R)-10b: R = i-Bu, 98%
(S)-10b: R = i-Bu, 95%
(R)-10c: R = Bn, 96%
(S)-10c: R = Bn, 99%
NHBoc
R
N
O
10a–c
Scheme 1 Syntheses of key precursors 10a–c
SYNLETT 2010, No. 17, pp 2557–2560
x
x
.x
x
.2
0
1
0
Advanced online publication: 23.09.2010
DOI: 10.1055/s-0030-1258582; Art ID: W10810ST
© Georg Thieme Verlag Stuttgart · New York

2558
H. Zhao et al.
LETTER
ids and two biaryl residues. The key acyclic precursors
10a–c were prepared according to Scheme 1. We envi-
sioned that the introduction of the central chirality from a-
amino acid residues and the axial chirality from the biaryl
fragments into the skeleton of the chiral macrocycles can
play an important role in controlling the size, shape, and
orientation of the chiral cavity of the macrocyclic ligands.
Moreover, it was expected that the present amide and imi-
ne functionalities in such macrocycles may impart not
only the binding sites but also the high rigidity on the
chiral macrocyclic ligands.
Table 1 Syntheses of Macrocycles 11a–c
R
R
O
N
Me
CHO
C
N
N
1. TFA, CH2Cl2
H
Me
*
*
NHBoc
R
N
2. 5% AcOH,
CH2Cl2, reflux
N
C
H
Me O
O
10a–c
11a–c
Entry
Substrate
(R)-10a
(S)-10a
(R)--10b
(S)-10b
(R)-10c
(S)-10c
R
Product
Yield (%)a
1
2
3
4
5
6
Me
Me
i-Bu
i-Bu
Bn
(R,R,M,M)-11a
(S,S,P,P)-11a
(R,R,M,M)-11b
(S,S,P,P)-11b
(R,R,M,M)-11c
(S,S,P,P)-11c
36
43
53
48
44
50
Herein, we report the first syntheses of such macrocyclic
ligands by following a multistep reaction sequence. The
key precursors 10a–c for macrocyclization reactions were
synthesized as outlined in Scheme 1.
Starting from 1-bromo-2-nitrobenzene, tributylstannyl-2-
nitrobenzene (2) was prepared in 80% yield according to
a modified literature procedure (see Supporting Informa-
tion for details). The Stille coupling reaction of compound
2 with 2-bromobenzaldehyde proceeded smoothly to fur-
nish the desired compound 5 in 90% yield. In order to pre-
vent the unexpected intramolecular cyclization after
direct catalytic hydrogenation, compound 4 was protected
as an acetal 5 first in 80% yield upon treatment with glycol
in the presence of TsOH in refluxing benzene. Subse-
quently, compound 5 was successfully reduced to com-
pound 6 in 94% yield under a hydrogen atmosphere
catalyzed by PtO2.
Bn
a Isolated yield with flash column chromatography on silica gel.
Next, we turned our attention to the condensation reac-
tions of compound 6 with a wide range of enantiopure a-
amino acids 7a–c, providing compounds 8a–c in 83–97%
yields. Compounds 8a–c were reacted with MeI in the Figure 1 X-ray crystal structures of (S,S,P,P)-11b and (S,S,P,P)-
11c; hydrogen atoms are omitted for clarity
presence of Cs2CO3 in anhydrous acetonitrile at room
temperature giving rise to 9a–c in 78–90% yields. Depro-
tection of compounds 9a–c with TsOH in anhydrous ace-
tone at room temperature led to the formation of key
precusors 10a–c in 90–99% yields.
curred in the macrocyclization reactions of precursors
10a–c, and the desired macrocyclic products 11a–c were
formed as a single diastereoisomer. The possibility of the
free interconversion between the macrocyclic diastereoi-
With the acyclic precursors 10a–c in place, the stage was
1
somers were ruled out by the variable temperature H
now set to effect macrocyclization reactions. Treatment of
NMR experiments. As exemplified by macrocycle
compounds 10a–c with trifluoroacetic acid (TFA) in
(R,R,M,M)-11a, the 1H NMR spectra were recorded at at
CH2Cl2 at room temperature delivered the deprotected
–30, –50, and –70 °C, respectively. In all cases, analysis
crude products, which without further purifications were
1
of the H NMR spectra did not show any splitting of
easily cyclized to target compounds 11a–c in 36–53%
peaks. Using the racemic sample as reference, both
(R,R,M,M)-11a and (S,S,P,P)-11a were determined to
have an up to 99% ee, respectively, by analytical HPLC
on a chiral stationary phase [Chiralcel OD-H, 1.0 mL/min,
n-hexane–2-PrOH (90:10)]. As measured by HPLC with
a Chiralcel OD-H, no atropisomerization occurred after
(R,R,M,M)-11a was heated in toluene at 45 °C for 4 hours.
In contrast, an atropisomeric mixture was generated in a
ratio of about 7:17:76 with (R,R,M,M)-11a as the major
atropisomer after (R,R,M,M)-11a was heated in toluene at
80 °C for 4 hours. In view of the fact that (R,R,M,M)-11a
and its atropisomers could be easily resolved by a chiral
column, it is reasoned that the present axial configurations
in compound (R,R,M,M)-11a should be stable enough at
room temperature. Therefore, it is concluded that in the
yields by using 5% of acetic acid in refluxing CH2Cl2.14 It
is important to note that the cyclodimerization of the acy-
clic precusors 10a–c underwent smoothly without the
need of high-dilution reaction conditions, and only [1+1]
macrocyclization products 11a–c were isolated in moder-
ate yields without detection of any higher macrocycliza-
tion products. Therefore, it is rational to assume that the
desired macrocyclization is probably directed by the con-
formational preorganization of the linear precursors 10a–
c.15
1
The H NMR spectra for the synthesized macrocycles
11a–c presented only one set of signal peaks, not showing
any multiple sets of peaks. Based on this fact, it is safe to
say that an efficient center-to-axis chirality transfer oc-
Synlett 2010, No. 17, 2557–2560 © Thieme Stuttgart · New York

LETTER
Synthesis and Structural Elucidation of C2-Symmetrical Optically Active Macrocycles
2559
course of the macrocyclizations the stereogenic centers of enclosed chiral enviroments of the macrocycles, which
10a–c efficiently relayed their stereochemical informa- will contribute greatly to the effective asymmetric induc-
tion to the formed stereogenic axes of macrocycles 11a–c. tions, are closely associated with the axial chirality of the
biaryl systems and the central chirality of the a-amino
acid residues present in the synthesized macrocycles. The
circular dichroism (CD) measurement of (R,R,M,M)-11b
exhibited an Cotton effect of opposite sign and approxi-
mately equal intensity and shape in comparison with that
of its stereochemical counterpart (S,S,P,P)-11b (left,
Figure 3), and thus the absolute stereochemisy of the biar-
yl subunit of (R,R,M,M)-11b was assigned as M configu-
ration. In a similar way, the absolute configurations of the
present biaryls in compound (R,R,M,M)-11c were as-
signed as M configuration based on the comparison of CD
Figure 2 X-ray structure of macrocycle structure of (S,S,P,P)-11b:
spectra of (S,S,P,P)-11c and (R,R,M,M)-11c (right,
Figure 3). Overall, it should be addressed that there is a
strict stereochemical cooperativity of the present stereo-
genic centers and stereogenic axes in the macrocycles as
follows: the S configuration of the stereogenic center in-
duces the P configuration of the biaryl stereogenic axis;
the R configuration of the stereogenic center induce the M
configuration of the biaryl stereogenic axis. Based on this
concept, the absolute configurations of macrocycles 11a
were also determined as shown in Table 1 (entries 1 and
2).
top view (left) and side view (right)
The stereochemistry of macrocycle (S,S,P,P)-11b was un-
equivocally dertermined by X-ray crystallographic analy-
sis (Figure 1).16 The X-ray analysis disclosed that in the
solid-state macrocycle (S,S,P,P)-11b is C2-symmetrical
and has a chiral and elongated cavity with a dimension of
4.5 × 8.3 Å, which is defined as the cross-macrocycle dis-
tances between the four nitrogen atoms (left, Figure 2).
The side view of the molecule (S,S,P,P)-11b appears to
have a vase-like structure (right, Figure 2). As for the two
biaryl systems in (S,S,P,P)-11b, both of them are highly
twisted, and one biaryl has a 62° torsional angle and the
other one has a 65° torsional angle. In addition, it is inter-
esting to note that both of the biaryl subunits adopt P con-
figuration and exhibit almost the same orientation with
each other. We reasoned that these unique stereochemical
properties may favor the asymmetric induction behaviors
of such a type of macrocycles when they are used as chiral
ligands in the asymmetric catalysis reactions. Similarly,
the X-ray crystal structure of macrocycle (S,S,P,P)-11c
has clearly demonstrated that the macrocycle exhibits a
pair of highly restrained biaryls and thus again evidencing
P,P configurations at the two biaryl axes. It has been seen
that one of the two biaryls has a torsional angle of 57°, the
other one shows a torsional angle of 69°.
In conclusion, we have designed and synthesized novel
chiral macrocycles containing two a-amino acids and two
biaryl residues by following a multistep reaction sequence
in moderate yields. The absolute configurations of biaryl
subunits of these macrocycles were unequivocally estab-
lished by X-ray analysis and CD mesurements, indicating
that the macrocyclizations occurred in high diastereose-
lectivities. We are currently investigating the possibilities
offered by this kind of chiral macrocycles as chiral ligands
in asymmetric catalysis reactions, and the results will be
reported in short course.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank Beijing Municipal Commission of Education (No.
JC015001200902), Beijing Municipal Natural Science Foundation
(No. 7102010), Doctoral Scientific Research Start-up Foundation of
Beijing University of Technology (No. 52015001200701), National
Basic Research Program of China (No. 2009 CB930203).
References and Notes
Figure 3 CD spectra of (S,S,P,P)-11b vs. (R,R,M,M)-11b (left) and
(S,S,P,P)-11c vs. (R,R,M,M)-11c (right)
(1) Puglisi, A.; Benaglia, M.; Annunziata, R.; Bologna, A.
Tetrahedron Lett. 2003, 44, 2947.
(2) Lewandowski, B.; Jarosz, S. Chem. Commun. 2008, 6399.
(3) Yuan, Q.; Fu, E. Q.; Wu, X. J.; Fang, M. H.; Xue, P.; Wu,
C. T.; Chen, J. H. Tetrahedron Lett. 2002, 43, 3935.
(4) Ema, T.; Tanida, D.; Hamada, K.; Sakai, T. J. Org. Chem.
2008, 73, 9129.
(5) Montero, A.; Albericio, F.; Royo, M.; Herradón, B. Eur. J.
Org. Chem. 2007, 1301.
Accordingly, on the basis of the above-mentioned results,
we rationalized that the torsional angles of the biaryl sub-
units in the macrocycles can be finely tuned by the intro-
duction of the different R groups as summarized in
Table 1. It has been confirmed by the X-ray crystal struc-
ture analysis of (S,S,P,P)-11b and (S,S,P,P)-11c that the
Synlett 2010, No. 17, 2557–2560 © Thieme Stuttgart · New York

2560
H. Zhao et al.
LETTER
anhyd Na2SO4. After filtration and concentration, the
resulted residue was treated with 5% AcOH (aq) in CH2Cl2
at 40 °C overnight. The reaction mixture was diluted with
CH2Cl2, and washed with H2O three times. The organic
layers were dried over anhyd Na2SO4. After filtration and
concentration under reduced pressure, the resulted crude
products were purified with flash column to afford
(6) Colombo, F.; Annunziata, R.; Raimondi, L.; Benaglia, M.
Chirality 2006, 18, 446.
(7) Hopkins, R. B.; Albert, J. S.; Engen, D. V.; Hamilton, A. D.
Bioorg. Med. Chem. 1996, 4, 1121.
(8) Pàmies, O.; Net, G.; Widhalm, M.; Ruiz, A.; Claver, C.
J. Organomet. Chem. 1999, 587, 136.
(9) Yan, Y. Y.; Widhalm, M. Tetrahedron: Asymmetry 1998, 9,
3607.
macrocycles 11a–c in 36–53% yield.
(10) Lee, C. S.; Teng, P. F.; Wong, W. L.; Kwong, H. L.; Chan,
A. S. C. Tetrahedron 2005, 61, 7924.
(11) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T.
I.; Barrow, J. C.; Katz, J. L. Angew. Chem. Int. Ed. 1998, 37,
2700.
(12) Carbonnelle, A. C.; Zhu, J. P. Org. Lett. 2000, 2, 3477.
(13) Albrecht, B. K.; Williams, R. M. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 11949.
(14) General Procedure for the Syntheses of Chiral
Macrocycles of 11a–c
Analytical Data of Chiral Macrocycle (R,R,M,M)-11a
[a]D23 –296.0 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
d = 7.63 (dd, J = 8.0, 1.2 Hz, 2 H), 7.53 (s, 2 H), 7.23–7.49
(m, 10 H), 7.12 (d, J = 7.6 Hz, 2 H), 7.07 (dd, J = 7.6, 1.2 Hz,
2 H), 3.64 (q, J = 6.8 Hz, 2 H), 3.38 (s, 6 H), 1.15 (d, J = 6.8
Hz, 6 H). 13C NMR (100 MHz, CDCl3): d = 172.6, 160.3,
142.2, 138.1, 138.0, 133.5, 132.9, 130.2, 129.7, 128.9,
128.7, 128.3, 128.1, 127.6, 63.1, 39.8, 21.8. ESI-HRMS:
m/z calcd for C34H33N4O2 [M + H+]: 529.2598; found:
529.2601 (–0.5 ppm, –0.3 mmu).
To a well-stirred solution of 10a–c in anhyd CH2Cl2 was
added TFA. The resulting solution was stirred at r.t. for 2 h.
The excess TFA was removed under the reduced pressure.
The residue was dissolved in CH2Cl2 and washed with sat. aq
NaHCO3 three times. The organic layers were dried over
(15) Blankenstein, J.; Zhu, J. P. Eur. J. Org. Chem. 2005, 1949.
(16) The X-ray crystallographic data of compounds 11b and 11c
were deposited to the Cambridge Crystallographic Data
Centre, CCDC-773495 and CCDC-773496, respectively.
Synlett 2010, No. 17, 2557–2560 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.