Diastereoselective synthesis of rotationally restricted chiral phenylpyridines via intramolecular cascade cyclization of n-acyliminium ions containing α-amino acid residues

Article abstract of DOI:10.1080/00397911.2013.771403

A series of chiral phenylpyridines possessing a fused chiral bridge were synthesized diastereoselectively via cascade cyclizations, where N-acyliminium ions including an enantiopure α-amino acid residue were involved. The absolute configuration of the synthesized phenylpyridines was identified unambiguously by using nuclear Overhauser effect difference and circular dichroism (CD) measurements on the basis of literature methods. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2013.771403

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Diastereoselective Synthesis of
Rotationally Restricted Chiral
Phenylpyridines via Intramolecular
Cascade Cyclization of N-Acyliminium
Ions Containing α-Amino Acid Residues
Jin-Ling Li a , Hong-Wu Zhao b , Xiao Qin b , Jin Cui b , Shi Su b , Hai-
Long Li b , Yuan-Yuan Yue b & Xiu-Qing Song b
a Department of Materials and Mineral Resources , Jilin Technology
College of Electronic Information , Jilin , China
b College of Life Science and Bio-engineering, Beijing University of
Technology , Beijing , China
Accepted author version posted online: 03 Jul 2013.Published
online: 04 Sep 2013.
To cite this article: Jin-Ling Li , Hong-Wu Zhao , Xiao Qin , Jin Cui , Shi Su , Hai-Long Li , Yuan-
Yuan Yue & Xiu-Qing Song (2013) Diastereoselective Synthesis of Rotationally Restricted Chiral
Phenylpyridines via Intramolecular Cascade Cyclization of N-Acyliminium Ions Containing α-Amino
Acid Residues, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 43:23, 3175-3180, DOI: 10.1080/00397911.2013.771403
To link to this article: http://dx.doi.org/10.1080/00397911.2013.771403
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Synthetic Communications1, 43: 3175–3180, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.771403
DIASTEREOSELECTIVE SYNTHESIS
OF ROTATIONALLY RESTRICTED CHIRAL
PHENYLPYRIDINES VIA INTRAMOLECULAR
CASCADE CYCLIZATION OF N-ACYLIMINIUM
IONS CONTAINING a-AMINO ACID RESIDUES
Jin-Ling Li,1 Hong-Wu Zhao,2 Xiao Qin,2 Jin Cui,2 Shi Su,2
Hai-Long Li,2 Yuan-Yuan Yue,2 and Xiu-Qing Song2
1Department of Materials and Mineral Resources, Jilin Technology College
of Electronic Information, Jilin, China
2College of Life Science and Bio-engineering, Beijing University of
Technology, Beijing, China
GRAPHICAL ABSTRACT
Abstract A series of chiral phenylpyridines possessing a fused chiral bridge were synthesized
diastereoselectively via cascade cyclizations, where N-acyliminium ions including an enan-
tiopure a-amino acid residue were involved. The absolute configuration of the synthesized
phenylpyridines was identified unambiguously by using nuclear Overhauser effect difference
and circular dichroism (CD) measurements on the basis of literature methods.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resources: Full
experimental and spectral details.]
Keywords Absolute configuration; bridged phenylpyridine; cascade cyclization; CD
measurements; diastereoselectivity; N-acyliminium ion; NOE difference
INTRODUCTION
Bridged phenylpyridines are a class of interesting compounds that have found
a wide range of applications in asymmetric catalysis[1] and medicinal chemistry.[2–8]
It has been demonstrated that the catalytic and biological activities of bridged
phenylpridines are mainly governed by the substitution pattern and stereochemical
Received December 28, 2012.
Address correspondence to Hong-Wu Zhao, College of Life Science and Bio-engineering, Beijing
University of Technology, No. 100 Pingleyuan, Chaoyang District, Beijing 100124, China. E-mail:
hwzhao@bjut.edu.cn
3175

3176
J.-L. LI ET AL.
arrangement of the phenylpyridinyl and bridge scaffolds, respectively. Up to now,
many different strategies have been developed for the construction of rotationally
restrained phenylpyridines.[9,10] However, the stereoselective synthesis of bridged
phenylpyridines has rarely been reported in the literature. Levacher and coworkers
presented the first examples of diastereoselective synthesis of axially chiral bridged
phenylpridines starting from enantiopure a-amino alcohols.[1–11] Therefore, the
development of asymmetric synthetic methodologies for access to the novel bridged
phenylpyridines remains in great demand in part for drug discovery and asymmetric
catalysis.
RESULTS AND DISCUSSION
Herein, we report our recent studies on the diastereoselective synthesis of rota-
tionally restrained phenylpyridines, which may find some potential biological and
catalytical activities. Based on our previous work,[12] it is reasoned that the synthesis
of the titled phenylpyridines was completed via the intramolecular cyclization
reaction of chiral cyclic N-acyliminium ions formed in situ.[13] The access to the
key acyclic precursors 11a–e was realized according to a sequence of chemical trans-
formations as shown in Scheme 1. Based on the literature method, compound 3 was
readily prepared on treatment of compound 1 with N-bromosuccinimide (NBS) in
CCl4 at 80 ꢀC, followed by the basic hydrolysis in the presence of CaCO3 at reflux.[14]
The reaction of compound 4 with concentrated nitric acid led to the formation of
compound 5 in a good yield of 95%.[15] Catalyzed by Pd(PPh3)4, compound 5 was
Scheme 1. Synthesis of a-amino acid–based phenylpyridines 11a–e. (Figure is provided in color online.)

BRIDGED PHENYLPYRIDINE
3177
smoothly converted into compound 6 in 95% yield by the reaction with Bu3Sn-SnBu3
in degassed toluene at 110 ꢀC. The coupling reaction of compound 3 with 6 was car-
ried out successfully, furnishing the desired phenylpyridine 7 in 57% yield. Promoted
by TsOH, the exposure of compound 7 to ethylene glycol in anhydrous benzene at
80ꢀC gave compound 8 in a yield of 75%. Using PtO2 as catalyst, compound 8
was hydrogenated into compound 9 in 94% yield. Finally, the acyclic precursors
11a–e were synthesized by the reaction of compound 9 with a series of enantiopure
N-Boc- or N-Cbz-a-amino acids 10a–e in 66–98% yields.
Using the optimal reaction conditions (TsOH.H2O = i-PrOH = 70 ꢀC), the
intramolecular cyclization of compounds 11 was carried out as shown in Table 1.
The intramolecular cyclization of 11a, which is devoid of a chiral center, provided
the desired product 12a in 46% yield. As for compounds 11b–e with a chiral a-amino
acid residue, it has been indicated that the identified diastereoselectivities in the
cyclization reactions were highly dependent on the steric size of the substituents at
the stereogenic center of compounds 11. The cyclization reaction of substrates such
as (2R)- or (2S)-11b and (2R)- or (2S)-11e bearing a benzyl group has shown excel-
lent diastereoselectivity (Table 1, entries 2, 3, 7, and 8). For example, the cyclization
of compound (2S)-11b with a Cbz protective group provided product (2S,12bR,M)-
12b as a single diastereoisomer. In comparison, the cyclization reaction of substrates
(2S)-11c and (2R)- or (2S)-11d, which possess a methyl or iso-butyl group with less
Table 1. Cascade cyclizations of a-amino acid-based phenylpyridines 11a–e
Entry
Sub.
R1
R2
Product (% yield)
de (%)
1
2
3
4
5
6
7
8
11a
Boc
H
(2R)-11b Cbz Bn
12a (46)
0
100
100
44
(2R,11bR,M)-12b (0) (2R,11bS,P)-12b (27)
(2S,11bS,P)-12b (0) (2S,11bR,M)-12b (25)
(2S,11bS,P)-12c (10) (2S,11bR,M)-12c (26)
(2R,11bR,M)-12d (12) (2R,11bS,P)-12d (23)
(2S,11bS,P)-12d (10) (2S,11bR,M)-12d(22)
(2R,11bR,M)-12e (0) (2R,11bS,P)-12e (34)
(2S,11bS,P)-12e (0) (2S,11bR,M)-12e (29)
(2S)-11b
(2S)-11c
Cbz Bn
Cbz i-Bu
(2R)-11d Boc
(2S)-11d Boc
(2R)-11e Boc
(2S)-11e Boc
Me
Me
Bn
Bn
31
38
100
100

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J.-L. LI ET AL.
Scheme 2. Removal of Cbz group by catalytic hydrogenation.
steric demand at the stereogenic center, afforded the desired products with de values
ranging from 31% to 44% (Table 1, entries 4–6).
As shown in Scheme 2, (2S,11bS,P)-12c and (2S,11bR,M)-12c were hydroge-
nated to provide compounds (2S,11bS,P)-13 and (2S,11bR,M)-13, respectively.
The relative stereochemistry between C2-H and C11b-H in compounds
(2S,11bS,P)-13 and (2S,11bR,M)-13 were determined by nuclear Overhauser effect
(NOE) difference measurements. As for compound (2S,11bR,M)-13, a spatial corre-
lation was observed between C2-H and C11b-H, indicating that C2-H and C11b-H rep-
resent an cisrelationship. However, such a spatial correlation was not discovered
with compound (2S,11bS,P)-13 between C2-H and C11b-H, showing that C2-H and
C
11b-H are in a trans-relationship (see Supporting Information for details). There-
fore, according to the known (S)-configuration at C2 in the a-amino acid residues,
it is reasonable to assign the absolute configuration at C12b as (S)-configuration in
(2S,11bS,P)-13 and (R)-configuration in (2S,11bR,M)-13, respectively.
At the same time, for the sake of the identification of absolute configuration of
stereogenic axis in the target molecules 12, the circular dichroism (CD) spectra of
both (2S,11bS,P)-13 and (2S,11bR,M)-13 were recorded in MeOH, respectively
(see Supporting Information for details). The CD spectra of (2S,11bS,P)-13 dis-
played a strongly negative Cotton effect at 286 nm and a weak positive Cotton effect
at 230 nm. The CD spectrum of (2S,11bR,M)-13 has shown a strong positive Cotton
effect at 287 nm and a weak negative Cotton effect at 231 nm. It can be definitely pre-
dicted that the strong Cotton effects at 286 nm and 287 nm contributed to the twisted
phenylpyridine chromophore in compounds (2S,11bS,P)-13 and (2S,11bR,M)-13
respectively and can be used as a probe to evaluate the helical chirality in both mole-
cules. Together with the literature methods,[16–18] the CD evidence allowed us to
assign (2S,11bS,P)-13 with (P)-helicity and (2S,11bR,M)-13 with (M)-helicity.
Accordingly, on the basis of the determined absolute stereochemistry of compounds
(2S,11bS,P)-13 and (2S,11bR,M)-13, the absolute stereochemistry of compounds 12
was conclusively deduced as depicted in Table 1.
In conclusion, a series of rotationally restricted phenylpyridines bearing a fused
chiral bridge were synthesized diastereoselectively via the cyclization of a cyclic

BRIDGED PHENYLPYRIDINE
3179
N-acyliminium ion. The absolute stereochemistry of target molecules was
conclusively assigned on the basis of NOE difference and CD measurements together
with literature methods. In our group, further studies on the synthesis of structurally
diverse bridged biaryls are in progress by means of this methodology, and the
corresponding results will be reported in due course.
EXPERIMENTAL
General Procedure for the Conversion of 11a to 12a
TsOH.H2O (37.0 mg, 0.19 mmol, 0.5 equiv) was added in one portion under
nitrogen to a well-stirred solution of compound 11a (150.0 mg, 0.37 mmol, 1.0equiv)
in 2-propanol (10.0 mL). The resulted reaction mixture was stirred at 70 ꢀC for 4 h.
The reaction solution was concentrated under reduced pressure, and the resulted
residue was purified with flash column chromatography on silica gel (eluent:
EtOAc=petroleum ether ¼ 3:2) to afford compound 12a (59.0 mg, 46.0% yield) as
white solid. Compound 12a: mp 110–112 ꢀC; 1H NMR (CDCl3): (8.61 (s, 1H),
7.88 (s, 1H), 7.65 (d, J ¼ 7.6 Hz, 1H), 7.41 (s, 1H), 7.22–7.30 (m, 1H), 6.46 (br,
1H), 4.30–4.70 (m, 1H), 4.02 (s, 3 H), 4.02 (s, 3 H), 1.68–1.21 (br, 9H); 13C NMR
(CDCl3): d166.0, 155.0, 151.1, 149.7, 148.8, 148.0, 132.5, 128.1, 127.4, 122.3,
119.9, 107.4, 105.6, 82.5, 72.2, 56.5, 56.4, 53.6, 49.3, 28.5. HRMS (ESI) calculated
for C21H23N3O5 (M þ Hþ): 398.1710; found 398.1738.
SUPPORTING INFORMATION
Full experimental detail, characterization data for intermediates and target
molecules, and copies of CD and NOE difference spectra for compounds
(2S,11bS,P)-13 and (2S,11bR,M)-13 are available online.
ACKNOWLEDGMENTS
We thank the Beijing Municipal Commission of Education (No.
JC015001200902), Beijing Municipal Natural Science Foundation (No. 710201
and No. 2122008), Basic Research Foundation of Beijing University of Technology
(X4015001201101), Funding Project for Academic Human Resources Development
in Institutions of Higher Learning under the Jurisdiction of Beijing Municipality
(No. PHR201008025), and Doctoral Scientific Research Start-up Foundation of
Beijing University of Technology (No. 52015001200701) for financial support.
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