Multifunctional isoquinoline-oxazoline ligands of chemical and biological importance

Article abstract of DOI:10.1039/c9cc01790a

Multifunctional isoquinoline-oxazolines (MIQOXs) were conceived and synthesized from commercially available chiral amino acids. The multifunctional role of MIQOXs was demonstrated by Pd-catalyzed highly enantioselective addition of arylboronic acids to nitrostyrenes, and by the discovery of novel antifungal candidates.

Full text of DOI:10.1039/c9cc01790a

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
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DOI: 10.1039/C9CC01790A
COMMUNICATION
Multifunctional Isoquinoline-Oxazolines Ligands of Chemical and
Biological Importance
Received 00th January 20xx,
Accepted 00th January 20xx
Wei Li, Guotong Wang, Jixing Lai, and Shengkun Li*
DOI: 10.1039/x0xx00000x
Multifunctional isoquinoline-oxazolines (MIQOX) were conceived by Isoquinoline-oxazolines to conduct a proof-of-principle
and synthesized from commercially available chiral amino acids. study for the discovery of multifunctional ligands. The
The multifunctional role of MIQOX was demonstrated by Pd combination of these two segments can be achieved by
catalyzed highly enantioselective addition of arylboronic acids to tethering the 2-position of oxazoline to the 1-position or the 3-
nitrostyrenes, and by the discovery of novel antifungal candidates. position of isoquinoline, to give IsoQuinox type ligands7 and
MIQOX type ligands, respectively (Fig. 1B). Comparison of the
In pharmacology or biochemistry, the ligand is a special
substance that can bind to a biomolecule (e.g. protein) to form
a complex for the biological purpose; in chemistry, it refers to
a particular molecule that can coordinate to a central metal to
establish a coordination complex for the chemical application
(Fig. 1A). It is widely-accepted that ligands play a pivotal role in
both biology and chemistry, in terms of accelerating and
diversifying novel therapeutics and transformations. Based on
this general knowledge, we envision that the discovery of
multifunctional ligands of both chemical and biological
importance will be highly desirable. Specifically, Hansen and
Weix reported the elegant and efficient mining bioactive
heterocycles from the pharmaceutical library as chemical
ligands for nickel-catalysed cross-electrophile coupling.1 which
will not only solve the challenging transformation but also in
turn facilitate the synthesis of pharmaceutically important
scaffolds. We envisage some ligands in chemistry may possess
pharmaceutical potentials. Herein, the practice of
multifunctional ligands will be documented by the discovery of
new isoquinoline-oxazolines for asymmetric catalysis and
antifungal application (Fig. 1A).
isomers showed that the current MIQOX ligands are
underexplored both in chemistry and biology. To the best of
our knowledge, only one MIQOX (tBu-MIQOX) was reported in
enantioselective transformation.8
A
. Initial Inspiration and Rational Design
Chemistry
Biology
Multifunctional
Ligands
Chemical
Application
Biological
Purpose
O
Enantioselective Addition
Antifungal candidates
N
N
R
MIQOX
Multifunctional isoquinoline-oxazolines (
)
B
. Pyridine-Oxazoline as Priviledged Scaffolds: Benzo-Catalogues
O
O
O
N
N
N
N
N
N
R
R
R
Quinox
IsoQuinox
MIQOX
One Asymmetric Example
Versatile Asymmetric Transformations
C
. Selected Transformation
Ar1

Ar1

Pd/L
NO2
NO2
NH2
Ar1BH(OH)2
Ar2
+
Ar2
Ar2
Quinox
: NO ; L =
IsoQuinox
: YES
MIQOX UNKNOWN
L =
L =
:
Fig. 1 Design and exploration of MIQOX as multifunctional ligands
The initial idea in the multifunctional ligands burgeoned
three years ago when we explored chiral amides containing
oxazolines as antifungal candidates.2 Beside the excellent
catalytic performance, oxazolines also demonstrated huge
potential in the development of new therapeutics. The 2-aryl-
oxazoline was verified as a promising pharmacophore3 and the
promising backbone for catalysis.4 Inspired by the renaissance
of pyridine-oxazoline ligands5 in catalysis and the biologically
important isoquinolines.6 Our research interest was attracted
The fused position of the phenyl ring to pyridine-oxazoline is
crucial for catalytic performance.5 The significant variation
between Quinox and IsoQuinox ligands in the asymmetric
addition of boronic acids to 2-nitrostyrenes7a questioned
whether the isomer MIQOX is compatible (Fig. 1C). We
envisaged any success in this transformation will rationalize
the design and first general asymmetric application of MIQOX,
and enrich our tactics to β-chiral nitrocompounds.9 Moreover,
the resultant products are versatile building blocks which can
be readily transformed to chiral β-arylamines or α-chiral
carbonyl compounds. The prevalence of this enantioselective
transformation is evidenced mainly by the increasing
appearance of different rhodium catalyst with versatile
ligands, including phosphoramidite,10 dienes,11 sulfinyl
a. Department of Pesticide Science, College of Plant Protection, Nanjing Agricultural
University, Weigang 1, Xuanwu District, Nanjing 210095, People’s Republic of
China. E-mail: skl505@outlook.com
† Electronic Supplementary Information (ESI) available: Experimental details and
characterization data, including 1H NMR and 13C NMR spectra of all the new
compounds, HRMS, HPLC traces, and X-ray crystallographic data (CCDC 1893343).
See DOI: 10.1039/x0xx00000x
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phosphine,12 olefin-sulfoxide,13 biaryl phosphites,14 and inert for this translation, albeit with up to 71% ee. The
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phosphine-olefin.15 The first Pd catalytic system was counterions of palladium salts projected a crucial role in the
DOI: 10.1039/C9CC01790A
developed by Yang and Zhang,7a and then applied efficiently in reaction efficiency, and the chloridion inhibited this
the synthesis of isopavine alkaloids by Chen.16 Exploration of transformation almost completely (entry 18). Non-precious
the less expensive Pd catalysis with MIQOX ligands would be metal salts, including Cu(OTf)2, Cu(OAc)2, Zn(OTf)2, Zn(OAc)2,
highly useful to complement the established methodologies. Co(OAc)2, and Mn(OAc)2 were also tested, while no obvious
Structural optimization and discovery of new MIQOX ligands 3aa was obtained. After extensive optimization, the chiral 3aa
are also highly desirable both in catalysis and in biology.
can be furnished in 84% yield and 93% ee, when the
nitrostyrene 2a was treated with 1.5 equiv. of 1a in MeOH
(0.17 M) at 40 ℃ by the Pd(TFA)2/MIQOX4 catalyst.
COOH
1
2
3
4
5
O

NH2
N
N
R
Table
1 Optimization of the reaction conditions of the asymmetric addition of
phenylalanine
MIQOX
arylboronic acid 1a to nitrostyrene 2a a
1, 37% formalin,conc. HCl, 95 oC; 2, KMnO4, DMF, 0 oC to r.t.;
3, chiral amino alcohol, anhydrous DCM, HOBt, EDCI-HCl;
4, SOCl2, DCM, 0 oC; 5, NEt3, CH3CN, r.t. to reflux.
O2N
O2N
Metal

MIQOX
B(OH)2
R = Me: MIQOX1
R = Et: MIQOX2
R = iPr: MIQOX3
R = tBu: MIQOX4
R = iBu: MIQOX5
R = sBu: MIQOX6
R = Ph: MIQOX7
R = Bn: MIQOX8
+
Solvent
O
40 o
C
MeO
MeO
1a
2a
3aa
N
N
Yieldb (%)
eec (%)
R
Entry
Metal
MIQOX
Solvent
1
2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(OAc)2
PdCl2
1
2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DCM
68
76
87
85
83
86
78
76
86
73
14
63
54
77
48
17
34
<5
89
78
84
70
67(S)
80(S)
91(S)
92(S)
82(S)
88(S)
83(S)
86(S)
85(S)
79(R)
71(S)
68(S)
3(S)
O
O
N
N
N
N
3
3
Et
MIQOX9
ent-MIQOX2
4
4
Scheme 1 Synthesis of MIOQX ligands
5
5
6
6
7
7
The MIQOX ligands were synthesized starting from
commercially inexpensive phenylalanine (Scheme 1).
Isoquinoline-3-carboxylic acid was synthesized through
Brønsted acid-mediated Pictet-Spengler cyclization followed by
Oxidation. The obtained acid intermediate underwent Steglich-
type condensation with chiral amino alcohols to form amides,
which were used to install the MIQOX ligands smoothly
through the sequential chlorination and the base-mediated
cyclization. Gratifyingly, MIQOX5 was unambiguously
determined by X-ray crystallography (CCDC 1893343).
With para-anisylboronic acid 1a and the nitrostyrene 2a as
the standard nucleophile and electrophile respectively,
reaction parameters were optimized for asymmetric addition
employing 5 mol % of metal salts with 7.5 mol % of the MIQOX
ligands. As shown in Table 1, this transformation went
smoothly and enantioselectively with the Pd(TFA)2/MIQOX
combination in MeOH (entries 1-10). The enantiopurity of the
desired β-chiral aryl-nitroethane 3aa increased with the steric
bulkiness of the substituent on the oxazoline ring of the
MIQOX ligands (entires 1-4). We speculated that substitution
proximal to the chiral center of MIQOX ligands will be
beneficial for the chirality introduction (entry 5 vs entry 6).
Interestingly, the configuration of 3aa is also dependent on the
chirality of MIQOX, and the enantiomer of 3aa can be easily
achieved by variation of the chirality of MIQOX (entry 10).
MIQOX4 was selected as the optimal chiral ligand for the
optimization of other parameters. This reaction proceeded
smoothly in polar solvents, while both yield and ee values
decreased with the improvement of pKa values of alcohols
(entries 4, 15 and 16). Both the nonpolar solvent toluene and
the polar solvent DMF can afford the desired 3aa in satisfying
yields, while a sharp decline in the enantioselectivity was
detected with toluene (entries 13 and 14). DCM seems to be
8
8
9
9
10
11
12
13
14
15
16
17
18
19d
20e
21f
22g
ent-2
4
4
THF
4
Tol
4
DMF
72(S)
80(S)
60(S)
88(S)
n.d.
4
EtOH
4
tBuOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
4
4
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
4
84(S)
87(S)
93(S)
88(S)
4
4
4
a
unless otherwise mentioned, reactions were carried out on a 0.25 mmol of
2a, 0.375 mmol of para-MeO-C6H4B(OH)2 using 5 mol % Pd(TFA)2 and 7.5
mol % MIQOX ligand in 3 mL solvent at 40 °C for 24 h under N2
atmosphere. bIsolated yield. cDetermined by HPLC using a Daicel column
(OD-H). The absolute configuration was assigned by comparing the retention
time of 3aa with that reported in the literature (Ref. 11a,15a). n.d. = not
determined. Under O2 atmosphere (5# balloon). 48h. 1.5 mL MeOH. 6 mL
MeOH.
d
e
f
g
Enantioselective addition of arylboronic acids 1 to the
nitrostyrene
2 proceeded efficiently under the optimal
conditions (Scheme 2). To make it more palatable, the two
building blocks for chiral β, β-diaryl nitroalkane 3 were
highlighted in blue (arylboronic acid) and red (nitrostyrenes),
respectively. The decoration of the electron-donating
substituents on the aryboronic acids demonstrated a positive
effect on both the yield and enantioselectivity. Switching the
methoxy group from para position to ortho or meta position
led to dramatic erosion in enantioselectivity (3aa vs 3ba, 3ca).
2 | J. Name., 2012, 00, 1-3
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Sterically more hindered arylboronic acids were observed to synthesis of diclofensine and pharmaceutically important
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produce the desired products in good to excellent selectivity isoquinoline alkaloids.11a
DOI: 10.1039/C9CC01790A
O2N
(3da, 3ga, and 3ha). Aliphatic boronic acids didn’t lead to
detectable products (3ia), which may be due to the incidental
β- Hydride elimination of the palladium complex. It is
noteworthy that compound 3aa can be synthesized
alternatively by the inversion of the two building blocks (3jp).
The (pinacolboryl)benzene can also be subjected to this trans-
formation with good enantioselectivity (3ka).
O2N
5 mol% Pd(TFA)2
MIQOX
7.5 mol%

4
B(OH)2
Ar1
+
Ar2
Ar2
Ar1
MeOH (0.17 M)
40 oC, 24h
1
2
3
Arylboronic Acids Scope
NO2
NO2
NO2
OMe



MeO
Substituents on the phenyl ring of the nitrostyrenes 2 are
also diverse. Both electron-withdrawing groups and electron-
donating groups are tolerant. The steric hindrance and
electronic properties of the substituents on the nitrostyrenes
had a more significant effect on the enantioselectivities.
Interestingly, the enantioselectivity was improved slightly by
adjusting the chlorine from para position (3ad) to meta (3ae)
or ortho (3af) position, while the detrimental effect was
observed when the other chlorine was installed (3ah).
Noteworthily, the ring-fused nitrostyrene is also compatible
and can produce the corresponding product in good yield with
up to 91% ee (3am). Thiophene could be compatible in this
transformation with satisfactory yield and ee value (3an),
representing the first example in Pd catalysed enantioselective
addition of boronic acids to heterocyclic nitroolefins.
Disappointingly, no desired product was isolated when α-
methyl-nitrostyrene was chosen as the substrate (3ao).
MeO
3aa
3ba
3ca
84% yield; 93% ee
74% yield; 76% ee
71% yield; 82% ee
NO2
NO2
NO2
O



O
Cl
F
3da
3ea
3fa
74% yield; 91% ee
NO2
65% yield; 77% ee
NO2
65% yield; 70% ee
NO2



Ph
3ga
3ha
3ia
77% yield; 90% ee
74% yield; 82% ee
< 5% yield; n.d.
NO2
NO2


Alternative Approach to
3aa
OMe MeO
3jp
3ka
Compound
79% yield; 74% ee
70% yield; 86% ee
from p-MeO-PhBpin
Inversion of the blocks
The putative stereochemical model for the asymmetric
addition was depicted in Fig. 2. We envision the Pd-MIQOX
complex recognizes the nitroalkene moiety as a result of the
steric repulsion rather than the π-π stacking effect between
arylboronic acid 1a and nitroalkene 2a (3aa vs ent-3aa). The
poor yield of 3ao can be rationalized by the steric repulsion
between the methyl group of 2o and the tBu group of the
chiral ligand MIQOX4 (Fig. 2, 3ao).
Nitrostyrenes Scope
O2N
O2N
O2N



CF3
MeO
MeO
F
MeO
3aa
3ab
3ac
84% yield; 93% ee
O2N
75% yield; 76% ee
O2N
73% yield; 80% ee
O2N
Cl



Cl
O
O
O
H
H
H
MeO
Cl MeO
MeO
N
N
N
N
N
N
3ad
3ae
3af
Pd
Pd
O2N
Pd
O2N
75% yield; 85% ee
72% yield; 92% ee
68% yield; 91% ee
MeO
MeO
MeO
NO2
steric
steric
repulsion
O2N
O2N
Cl
O2N
-
OMe
stacking
repulsion



Cl
Cl
Disfavored
ent-3aa
Favored
3aa
Disfavored
3ao
MeO
MeO
MeO
MeO
Cl
MeO
Fig. 2 Putative stereochemical model for the asymmetric addition
3ag
67% yield; 82% ee
O2N
3ah
3ai
70% yield; 87% ee
O2N
64% yield; 64% ee
O2N
The chiral β, β-diaryl nitroalkane from the enantioselective
addition of arylboronic acids to nitrostyrenes will allow access
to β-chiral β-arylethylamine, which is embedded in a number
of therapeutically important molecules, including cherylline,15a
diclofensine,17 and protein kinase B (PKB) inhibitor 4.18 To
highlight the synthetic utility of the current methodologies,
scale-up (4 mmol) synthesis of β-aryl nitroalkane 3ag was
realized (Scheme 3). Facile reduction of 3ag with NaBH4/NiCl2-
6H2O led to the chiral β-arylamine 4ag, and subsequent
condensation-reduction cascade afforded the dimethylated
analogue 5ag. These compounds can be regarded as analogues
of PKB inhibitors, which are considered to be potentially
valuable in the treatment of cancers.18 More importantly, the
chiral amine 4ag will serve as a distinct handle for the



OMe
MeO
MeO
3aj
3ak
3al
71% yield; 91% ee
74% yield; 80% ee
68% yield; 89% ee
O2N
O2N
O2N



S
3an
MeO
MeO
3am
3ao
79% yield; 91% ee
57% yield; 84% ee
< 5% yield; n.d.
a all reactions were carried out on a 0.25 mmol of nitrostyrene under the standard
conditions shown in entry 21 of Table 1. Isolated yield. Determined by HPLC
using a Daicel column (OD-H).
b
c
Scheme
nitrostyrenes a,b,c
2 Substrate scope in the asymmetric addition of arylboronic acids to
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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COMMUNICATION
Journal Name
O2N
Fundamental Research Funds for the CentralVieUwnAirvticelersOitnilienes
(KYZ201706).
H2N
N
NaBH4
HCHO

DOI: 10.1039/C9CC01790A

Cl

Cl
Cl
NiCl2-6H2O
HCOOH
Cl
Cl
DCM-MeOH
MeO
Cl
MeO
MeO
3ag
4ag
5ag
63% yield; 82% ee
4 mmol scale
62% yield
Conflicts of interest
over 2 steps
There are no conflicts to declare.
N
H2N
N
Cl
Cl
Notes and references
MeO
OH
Cl
MeO
NH
OH
cherylline
N
1
2
3
4
E. C. Hansen, D. J. Pedro, A. C. Wotal, N. J. Gower, J. D.
Nelson, S. Caron and D. J. Weix, Nat. Chem., 2016, 8, 1126.
S. Li, D. Li, T. Xiao, S. Zhang, Z. Song and H. Ma, J. Agric. Food
Chem., 2016, 64, 8927.
L. Zhang, W. Li, T. Xiao, Z. Song, R. Csuk and S. Li, J. Agric.
Food Chem., 2018, 66, 8957.
H. Guo, C.-G. Dong, D.-S. Kim, D. Urabe, J. Wang, J. T. Kim, X.
Liu, T. Sasaki and Y. Kishi, J. Am. Chem. Soc., 2009, 131,
15387.
diclofensine
antidepressant activity
4
central nervous activity
PKB inhibitor
Scheme 3 Practical Synthesis of PKB inhibitors and Potent Application
Inspired by our previous exploration of novel oxazoline for
the discovery of novel antifungal candidates,2,3 bioactivity of
the readily available isoquinoline-oxalines were investigated
against agriculturally important plant pathogens. To our
delight, the MIQOX ligands demonstrated moderate to good
inhibitory effect against all the pathogens. The molecular
docking with the protein with PDB code of 2FBW was also
conducted for MIQOX2 and its enantiomer (see supplementary
information for more details). The MIQOX7 and MIQOX8 are
most active against R. solani with EC50 values of 0.031 mM
(8.60 mg/L) and 0.028 mM (8.09 mg/L) respectively (Table 2).
MIQOX5 and MIQOX7 demonstrated much better inhibitory
effect against F. graminearum. MIQOX can be elected as
potent antifungal leads for further optimization.
5
6
G. Yang, W. Zhang, Chem. Soc. Rev., 2018, 47, 1783.
(a) M. Chrzanowska, A. Grajewska and M. D. Rozwadowska,
Chem. Rev., 2016, 116, 12369; (b) E. R. Welin, A. Ngamnith-
iporn, M. Klatte, G. Lapointe, G. M. Pototschnig, M. S. J.
McDermott, D. Conklin, C. D. Gilmore, P. M. Tadross, C. K.
Haley, K. Negoro, E. Glibstrup, C. U. Grünanger, K. M. Allan,
S. C. Virgil, D. J. Slamon, B. M. Stoltz, Science, 2019, 363, 270.
(a) Q. He, F. Xie, G. Fu, M. Quan, C. Shen, G. Yang, I. D.
Gridnev and W.Zhang, Org. Lett., 2015, 17, 2250; (b) D. P.
Hickey, C. Sandford, Z. Rhodes, T. Gensch, L. R. Fries, M. S.
Sigman and S. D. Minteer, J. Am. Chem. Soc., 2019, 141,
1382.
7
8
9
C. Zhang, C. B. Santiago, J. M. Crawford, M. S. Sigman, J. Am.
Chem. Soc., 2015, 137, 15668.
(a) S. Li,; K. Huang, B. Cao, J. Zhang, W. Wu, X. Zhang, Angew.
Chem. Int. Ed., 2012, 51, 8573; (b) S. Li, K. Huang, J. Zhang,
W. Wu, X. Zhang, Chem. Eur. J., 2013, 19, 10840; (c) S. Li, T.
Xiao, D. Li, X. Zhang, Org. Lett., 2015, 17, 3782.
Table 2 Antifungal activities of MIQOX ligandsa
Compd.
EC50 Values, mM (mg/L).
B.C. F.G.
0.114(29.01) 0.132(33.68) 0.091(23.18) 0.151(38.51)
R. S.
M.O.
MIQOX5
MIQOX7
MIQOX8
Boscalid
10 A. Duursma, R. Hoen, J. Schuppan, R. Hulst, A. J. Minnaard
and B. L. Feringa, Org. Lett., 2003, 5, 3111.
0.031(8.60)
0.028(8.09)
0.005(1.59)
0.104(28.57) 0.097(26.65) 0.149(41.13)
0.091(26.37) 0.120(34.64) 0.120(34.60)
11 (a) Z.-Q. Wang, C.-G. Feng, S.-S. Zhang, M.-H. Xu and G.-Q.
Lin, Angew. Chem., Int. Ed., 2010, 49, 5780; (b) R. Li, Z. Wen,
N. Wu, Org. Biomol. Chem., 2016, 14, 11080; (c) H.
Miyamura, K. Nishino, T. Yasukawa and S. Kobayashi, Chem.
Sci., 2017, 8, 8362; (d) G. Shen, T. Osako, M. Nagaosa, Y. Uoz-
umi, J. Org. Chem., 2018, 83, 7380; (e) K.-C. Huang, B. Gopu-
la, T.-S. Kuo, C.-W. Chiang, P.-Y. Wu, J. P. Henschke and H.-L.
Wu, Org. Lett., 2013, 15, 5730.
0.016(5.35)
0.165(56.54)
0.003(1.11)
a
The antifungal activity of all the IQOxP ligands was tested against 6
pathogenic fungi using the mycelium growth rate test (see supporting
information for more details). R.S.: Rhizoctonia solani. B. C.: Botrytis cinerea.
F. G.: Fusarium graminearum. M. O.: Magnaporthe oryzae.
In summary, new MIQOX Ligands (except for MIQOX4) were
synthesized from commercially available chiral amino acids.
The first exploration of the MIQOX ligands was accomplished
successfully in highly enantioselective addition and in the
discovery of novel agrochemical candidates. The asymmetric
addition can be scaled up for the practical synthesis of PKB
inhibitors and chiral alkaloids containing chiral β-
arylethylamine subunits. We envisage that the individual
elements of this work will inspire and enable other attempts to
the discovery of multifunctional ligands of both chemical and
biological importance. Probing MIQOX ligands for other
asymmetric transformations and structural optimization for
novel antifungal amides are in progress and will be reported in
due course.
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This work was financially supported by National Key R&D
Program of China (No. 2018YFD0201000), National Natural
Science Foundation of China (No. 21772094) and the
4 | J. Name., 2012, 00, 1-3
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