Asymmetric synthesis of novel biaryl analogues with a fused chiral bicyclic bridge using -amino acids as chiral sources

Article abstract of DOI:10.1055/s-0030-1261235

A series of biaryl anologues with a fused bicyclic bridge were synthesised in a diastereoselectivity of up to 14:86 via an intramolecular cyclisation of an in situ generated N-acyliminium ion. The absolute configuration of products 9b-d and 10b-d was clea

Full text of DOI:10.1055/s-0030-1261235

LETTER
2415
Asymmetric Synthesis of Novel Biaryl Analogues with a Fused Chiral Bicyclic
Bridge Using a-Amino Acids as Chiral Sources
Synthesis of
N
ove
o
l
Biaryl
A
nal
n
ogues
w
ith
a
g
F
used Chira
-
l
Bicycli
W
c
Bridge u Zhao,*a Xiao Qin,a Jin Cui,a Shi Su,a Xiu-Qing Song,a Hai-Long Li,a Hong Yan,a Ru-Gang Zhong,a
Ning-Bo Gong,b Yong-Hui Guo,b Yang Lvb
a
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
Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing 100050, P. R. of China
b
Received 10 July 2011
diastereoisomeric mixture of (2R,12bR,P)-9b and
Abstract: A series of biaryl anologues with a fused bicyclic bridge
were synthesised in a diastereoselectivity of up to 14:86 via an in-
tramolecular cyclisation of an in situ generated N-acyliminium ion.
The absolute configuration of products 9b–d and 10b–d was clearly
(2R,12bS,M)-10b, and the two diastereoisomers can be
readily separated by flash column chromatography on sil-
ica gel. For compound (R)-8c, diastereoisomers
defined by a combination of X-ray crystal-structural analysis, NOE (2R,12bR,P)-9c and (2R,12bS,M)-10c were obtained in a
difference, and CD experiments.
diastereoisomeric ratio of 14:86. Apparently, the cyclisa-
tion of (R)-8c gave the products with higher diastereose-
lectivity as compared to that of compound (R)-8b.
Key words: biaryl, diastereoselectivity, cyclisation mechanism, N-
acyliminium ion, absolute configuration
Axially enantiopure biaryls are highly important mole-
cules and are widely used in asymmetric catalysis,1,2 me-
dicinal,3–9 and supramolecular chemistry.10 It has been
documented that the pharmacological properties of bioac-
tive chiral biaryls are mainly governed by the stereogenic
configuration of biaryl axes11,12 and that the catalytic reac-
tivity and stereoselectivity of biaryl catalysts are also sig-
nificantly affected by the axial chirality. Due to the unique
stereochemical characteristics of biaryl compounds, a
number of excellent asymmetric methodologies have
been developed for the atroposelective synthesis of rota-
tionally hindered biaryl compounds.13–18
CHO
Pd(PPh3)4
Br
NO2
NO2
Br
Bu3Sn-SnBu3
3
toluene
110 °C
Pd(PPh3)4
CuBr, THF
reflux
SnBu3
2 80%
1
O
OH
H2, PtO2
EtOH, r.t.
HO
CHO
NO2
O
TsOH, benzene
80 °C
NO2
4 90%
5 80%
In this work, we wish to report a new approach to the syn-
thesis of a series of conformationally restrained biaryls 9
and 10 containing a fused chiral bicyclic bridge (Table 1).
Using a-amino acids as chiral sources, the construction of
the target molecules was accomplished diastereoselec-
tively via a cascade cyclisation involving the initial for-
mation of a cyclic N-acyliminium ion intermediate,
followed by a second diastereoselective intramolecular
cyclisation with a nitrogen-based nucleophile.19
NHBoc
OH
R
O
O
O
O
7a–d
O
NHBoc
EDCI, CH2Cl2
r.t.
NH
NH2
O
R
6 94%
8a–d
8a: R = H, 83%
The key acyclic precursors 8a–d were synthesised in 83–
97% yields based on the strategy developed by us previ-
ously (Scheme 1).20 It was indicated by 1H NMR spectral
data that compounds 8b–d existed as a mixture of two in-
separable diastereoisomers in a ratio of about 70:30. The
cyclisation reaction of compounds 8b–d were carried out
in the presence of TsOH (Table 1).21 In the cyclisation re-
actions, compounds 10b–d were obtained as major diaste-
reoisomers and 9b–d as minor diastereoisomers. For
example, compound (R)-8b was cyclised to give a 35:65
(R)-8b R = Me, 92%
(S)-8b R = Me, 95%
(R)-8c R = i-Bu, 86%
(S)-8c R = i-Bu, 93%
(R)-8d R = Bn, 97%
(S)-8d R = Bn, 90%
Scheme 1 Synthesis of a-amino acid based biaryls 8a–d
In the case of compound (R)-8d, a diastereoisomeric mix-
ture of (2R,12bR,P)-9d and (2R,12bS,M)-10d was provid-
ed in a 15:85 ratio. Accordingly, compounds (R)-8c and
(R)-8d exhibited a similar degree of diastereoselectivity in
the cyclisation reactions. Obviously, the diastereoselec-
tivities of the products from the antipodal (S)-8b–d were
the same as those of (R)-8b–d. It should be pointed out
SYNLETT 2011, No. 16, pp 2415–2419
x
x
.x
x
.2
0
1
1
Advanced online publication: 13.09.2011
DOI: 10.1055/s-0030-1261235; Art ID: W15111ST
© Georg Thieme Verlag Stuttgart · New York

2416
H.-W. Zhao et al.
LETTER
Table 1 Cascade Cyclisations of a-Amino Acid Based Biaryls
O
Boc
Boc
H
H
N
N
(R)
TsOH
(R)
2
(R)
2
O
12b
12b
(S)
(M)
+
R
R
(P)
NHBoc
N
N
NH
acetone, r.t.
4
4
(R)
O
O
2
O
R
(R)-8b–d
(2R,12bR,P)-9b–d
(2R,12bS,M)-10b–d
O
Boc
H
Boc
H
N
(S)
N
(R)
TsOH
(S)
O
(S)R
12b
12b
(M)
R
(P)
+
2
2
N
N
NHBoc
NH
acetone, r.t.
4
4
(S)
O
O
2
R
O
(S)-8b–d
(2S,12bS,M)-9b–d
(2S,12bR,P)-10b–d
Substrate
R
Product
Yield (%)a
Product
Yield (%)a
dr (9/10)
35:65
34:66
14:86
16:84
15:85
17:83
(R)-8b
(S)-8b
(R)-8c
(S)-8c
(R)-8d
(S)-8d
Me
Me
i-Bu
i-Bu
Bn
(2R,12bR,P)-9b
(2S,12bS,M)-9b
(2R,12bR,P)-9c
(2S,12bS,M)-9c
(2R,12bR,P)-9d
(2S,12bS,M)-9d
16
17
5
+ (2R,12bS,M)-10b
+ (2S,12bR,P)-10b
+ (2R,12bS,M)-10c
+ (2S,12bR,P)-10c
+ (2R,12bS,M)-10d
+ (2S,12bR,P)-10d
30
33
30
51
40
43
10
7
Bn
9
a Isolated yield with flash column chromatography on silica gel.
that the diastereoselectivities in the cyclisations of com- To simplify their 1H NMR spectral properties, compounds
pounds 8b–d are significantly influenced by the steric size (2S,12bS,M)-9e and (2S,12bR,P)-10e, devoid of Boc
of R group at C2 position. Generally, among the examined functionality, were prepared upon treatment of
substrates 8b–d, the one with a bulky substituent at C2 po- (2S,12bS,M)-9b and (2S,12bR,P)-10b with TFA, respec-
sition always afforded products with a higher diastereose- tively, in CH2Cl2 at room temperature (Scheme 2). The 1H
lectivity. The optical purities of products (2R,12bR,P)-9b, NMR spectra of (2S,12bS,M)-9e and (2S,12bR,P)-10e
(2S,12bS,M)-9b, (2R,12bS,M)-10b, and (2S,12bR,P)-10b showed a much more simplified splitting pattern that
were determined to be more than 99% ee by HPLC anal- could be explained based on the (n + 1) spin-coupling
ysis on a chiral stationary phase, indicating that the cycli- rules.
sation reactions did not cause epimerization at the a-
amino acid residues.
The 1H NMR spectra of (2S,12bS,M)-9b and (2S,12bR,P)- figuration at the C2 position, the absolute configuration of
10b were conducted in CDCl3 and both of them showed a (2S,12bS,M)-9d was assigned as (2S,12bS,M) by X-ray
complex splitting pattern due to the presence of rotamers. analysis as shown in Figure 1.22 In the solid state, com-
pound (2S,12bS,M)-9d exhibited a twisted frame struc-
Crystals of the minor diastereoisomer (2S,12bS,M)-9d
were grown in ethanol solution. Based on the known con-
ture, and the dihedral angle of the biaryl subunit was 20°.
Boc
H
H
H
TFA,
CH2Cl2, r.t.
Moreover, as confirmed by the X-ray crystal structure, the
six-membered bridge adopts a half-chair conformation
and the fused five-membered heterocycle adopts an enve-
lope conformation.
N
N
(S)
2
(S)
12b (S)
12b
(R)
(M)
(M)
Me
Me
2
N
N
4
4
O
O
(2S,12bS,M)-9b
(2S,12bS,M)-9e
The CD spectra of (2S,12bS,M)-9d and (2S,12bR,P)-10d
were recorded in MeOH, respectively. In both cases, a
Cotton effect was observed at about 240 nm correspond-
ing to the A band of biphenyl chromophore.23 The (M)-
torsion of the biphenyl subunit was determined with
(2S,12bS,M)-9d by the positive Cotton effect at about 242
nm. In contrast, the (P)-torsion of the biphenyl motif was
identified with compound (2S,12bR,P)-10d due to the
presence of a negative Cotton effect at about 242 nm (see
H
H
Boc
H
TFA,
CH2Cl2, r.t.
N
N
(S)
(S)
12b
(S)
12b
(R)
(P)
(P)
Me
Me
2
2
N
N
4
4
O
O
(2S,12bR,P)-10b
(2S,12bR,P)-10e
Scheme 2 Removal of Boc group in the presence of TFA
Synlett 2011, No. 16, 2415–2419 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Biaryl Analogues with a Fused Chiral Bicyclic Bridge
2417
Supporting Information for details). The (M)-torsion of spatial correlation was found with compound
(2S,12bS,M)-9d characterised by CD spectra was in full (2S,12bS,M)-9d between C2–H and C12b–H, showing that
agreement with the one assigned by X-ray analysis of C2–H and C12b–H are in the trans relationship. Therefore,
(2S,12bS,M)-9d. Accordingly, based on the above exper- according to the known configuration at C2 position of a-
imental results, the absolute configuration of chiral axis of amino acid residues it is rational to assign the absolute
compounds 9b–d and 10b–d was assigned as depicted in configuration at C12b, which is a newly formed stereogenic
Table 1 in the combination of CD and X-ray experiments. center, of compounds 9b–d and 10b–d as listed in
Table 1.
Subsequently, we turned our attention to the investigation
of the mechanism of the cascade cyclisation of com-
pounds 8a–d. It has been proven that the condensation of
secondary amides and O,O-acetals can offer N-acylimini-
um ions in an intramolecular or intermolecular way.19
In the attempted cyclisations, two plausible cyclisation
paths may account for the formation of compounds 9a–d
and 10b–d as outlined in Scheme 3. In path A, compounds
8a–d cyclise into target molecules through a six-mem-
bered ring N-acyliminium ion 11; in path B, a nine-mem-
bered ring N-acyliminium ion 12 is involved in the
cyclisation of compounds 8a–d. Although both path A
and path B involve a geometrically unfavourable 5-endo-
trig cyclisation, the observed cyclisations do proceed
smoothly when the amide nitrogen atom acts as a nucleo-
phile to add onto an N-acyliminium ion intramolecular-
Figure 1 ORTEP representation of the X-ray crystal structure of
(2S,12bS,M)-9d. Hydrogen atoms are omitted for clarity.
ly.24–26 Apparently, in the presence of TsOH, compounds
8a–d prefer to cyclise into 11 rather than producing 12
due to the presence of a more extensive p-conjugated sys-
The relative stereochemistry between C2–H and C12b–H of
compounds (2S,12bS,M)-9d and (2S,12bR,P)-10d were
tem in 11.
To verify the possible involvement of path A or B in the
supported by NOE difference experiments as presented in
cyclisations, the cyclisation of an acyclic precursor 8a
the Supporting Information, respectively. As for com-
pound (2S,12bR,P)-10d, a spatial correlation was ob-
served between C2–H and C12b–H, indicating that C2–H
and C12b–H have a cis relationship. However, no such a
was carried out as shown in Scheme 4. In this reaction, an-
hydrous EtOH was chosen to function as both reaction
solvent and an external nucleophile in the cyclisation re-
action. In the presence of TsOH, the cyclisation of 8a gave
compound 9a and 10f in 35% and 25% yields, respective-
ly. On the basis of the obtained experimental data, it was
Path A
Boc
HN
N+
TsOH
firmly confirmed that path A was involved in the cyclisa-
tion of 8a–d, and path B did not take place in the cyclisa-
tions. Obviously, by following path A, starting from
compound 8a, the in situ generated N-acyliminium ion
11a (R = H) can be trapped either in an intramolecuclar or
intermolecular way. The intramolecular trapping of the N-
acyliminium ion 11a by the present NHBoc group con-
tributed to the formation of compound 9a. Alternatively,
the intermolecular trapping of 11a by EtOH as an external
nucleophile furnished compound 10f.
R
O
Boc
O
H
N
N
O
11
R
NHBoc
R
NH
Boc
N+
O
O
8a–d
9a–d and
10b–d
H
N
R
TsOH
O
Path B
12
In order to establish whether the cyclisation reaction of
(R)-8b–d is under thermodynamic or kinetic control,
Scheme 3 The proposed mechanism of the cascade cyclisation
O
Boc
H
OEt
N
TsOH, EtOH
O
+
NHBoc
N
NHBoc
N
r.t.
NH
O
O
O
8a
9a 35%
10f 25 %
Scheme 4 Investigation on the reaction mechanism by additional experiments
Synlett 2011, No. 16, 2415–2419 © Thieme Stuttgart · New York

2418
H.-W. Zhao et al.
LETTER
D
H
H
O
Boc
N
slower,
lower
yield
H
2
restricted rotation
on this bond
R
12b
(R)
TsOH
O
12b
(R)
(P)
(P)
HN
N+
R
(P)
2
Boc
N
30%
NHBoc
NH
4
O
(R)
O
2
B
O
R
O
(2R,12bR,P)-9b–d
absolute yield cannot
be >30%
O
noninterconvertible
axial chirality is preserved
during cyclisation
NHBoc
NH
(R)
2
O
R
(R)-8b–d
H
H
O
faster,
higher
yield
Boc
H
70%
2
12b
(R)
N
TsOH
R
Boc
(M)
O
(M)
12b
(S)
HN
HN+
R
(M)
2
N
NHBoc
NH
4
(R)
O
2
O
O
R
A
C
(2R,12bS,M)-10b–d
absolute yield cannot
be >70%
axial chirality is preserved
during cyclisation
Scheme 5 Proposed transition states for the stereoselective tandem cyclisation of (R)-8b–d
equilibration experiments were carried out with the single states. The stereochemistry of target molecules were con-
diastereoisomers (2R,12bS,M)-10b and (2R,12bS,M)- clusively assigned on the basis of X-ray crystal analysis,
10d, respectively. Treatment of compound (2R,12bS,M)- NOE difference, and CD experiments. Further studies on
10b with TsOH for 10 hours in acetone at room tempera- the synthesis of biologically active chemical entities using
ture did not result in the formation of an equilibrium mix- the developed methodology are in progress, and the data
ture of (2R,12bR,P)-9b and (2R,12bS,M)-10b as shown in will be reported in due course.
Table 1. Similarly, an equilibrium mixture of
(2R,12bR,P)-9d and (2R,12bS,M)-10d was not formed
Supporting Information for this article is available online at
when the single diastereoisomer (2R,12bS,M)-10d was
http://www.thieme-connect.com/ejournals/toc/synlett.
exposed to the same reaction conditions. On the basis of
the experimental data, it was believed that the cyclisation
reaction of (R)-8b–d is controlled kinetically, but not ther-
modynamically.
Acknowledgment
We thank Beijing Municipal Commission of Education (No.
JC015001200902), Beijing Municipal Natural Science Foundation
To clarify the stereochemical course of the cascade cycli-
sation of compounds (R)-8b–d, two diastereoisomeric (No. 7102010), Funding Project for Academic Human Resources
Development in Institutions of Higher Learning Under the Jurisdic-
tion of Beijing Municipality (No. PHR201008025), Doctoral Scien-
transition states C and D were proposed to account for the
observed diastereoselectivities as shown in Scheme 5. As
tific Research Start-up Foundation of Beijing University of
mentioned above, compounds (R)-8b–d were obtained as
Technology (No. 52015001200701) for financial supports.
an inseparable mixture of diastereomers A (70%) and B
(30%). Under cyclisation conditions, the major diastereoi-
References and Notes
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(2R,12bS,M)-10b–d via transition state C with the reten-
tion of axial chirality; whereas the minor diastereoisomer
B underwent cyclisation to give the minor diastereoiso-
mers (2R,12bR,P)-9b–d through transition state D also
with retention of axial chirality. On the basis of the ob-
tained experimental results, it was reasonable to assume
that the formation of major diastereoisomers
(2R,12bS,M)-10b–d should be kinetically favourable be-
cause of the likely involvement of the least-hindered tran-
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Synlett 2011, No. 16, 2415–2419 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Biaryl Analogues with a Fused Chiral Bicyclic Bridge
2419
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