Lanthanide and asymmetric catalyzed syntheses of sterically hindered 4-isoxazolyl-1,4-dihydropyridines and 4-isoxazolyl-quinolones

Article abstract of DOI:10.1016/j.tetlet.2015.12.038

The Ytterbium (III) triflate catalyzed Hantzsch synthesis allows for the preparation of sterically hindered 4-isoxazolyl-1,4-dihydropyridines in moderate to good yields. Asymmetric organocatalysis with (R)-4-Oxo-2,6-bis-(2,4,6-triisopropyl-phenyl)-3,5-dioxa-4l5-phospha-cyclohepta[2,1-a;3,4-a']dinaphthalen-4-ol (R-TRIP) produces moderate yields of chiral 4-isoxazolyl-quinolones with high enantioselectivity.

Full text of DOI:10.1016/j.tetlet.2015.12.038

Accepted Manuscript
Lanthanide and asymmetric catalyzed syntheses of sterically hindered 4-isoxa-
zolyl-1,4-dihydropyridines and 4-isoxazolyl-quinolones
Scott A. Steiger, Chun Li, Charles F. Campana, Nicholas R. Natale
PII:
S0040-4039(15)30452-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.038
TETL 47085
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Accepted Date:
23 November 2015
8 December 2015
Please cite this article as: Steiger, S.A., Li, C., Campana, C.F., Natale, N.R., Lanthanide and asymmetric catalyzed
syntheses of sterically hindered 4-isoxazolyl-1,4-dihydropyridines and 4-isoxazolyl-quinolones, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.12.038
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Lanthanide and asymmetric catalyzed syntheses of sterically hindered 4-isoxazolyl-1,4-
dihydropyridines and 4-isoxazolyl-quinolones
a,d
b
c
a
Scott A. Steiger, Chun Li, Charles F. Campana, Nicholas R. Natale*
a
Medicinal Chemistry Graduate Program, University of Montana, Missoula MT 59812, USA
b
Department of Chemistry Ithaca College, Ithaca NY, USA
c
Bruker AXS Inc., 5465 East Cheryl Parkway, Madison, WI 53711, USA
d
Present address: Office of Commercialization, Washington State University P.O. Box 641802,
Pullman, WA 99164-1802, USA
_
*
_________
Corresponding author. Tel 406-243-4132; fax 406-243-5228.
E-mail address: nicholas.natale@umontana.edu (N.R. Natale)
1
Multi-component organic cyclizations, exemplified by the Hantzsch pyridine synthesis have
2
been know for over a century. The concept of scaffolds and scaffold hopping in medicinal
chemistry is much more recent, however, the number of potentially useful applications of
scaffolds is arithmetically increased by their judicious combination, and especially valuable are
those combinations which are attainable by efficient stereoselective methodology.
Interest in the usefulness of Hantzsch esters was exponentially enhanced by the discovery that
specific 4-aryldihydropyridines (DHPs) possessed robust biological activity as calcium channel
3
antagonists, and thus are useful as antihypertensive medicines. In many cases, there is a
4
pronounced enantioselectivity of action, yet as often observed the agents in general medical
practice have been obtained by chromatographic or classical resolution. The corresponding 4-
5
,6
aryl quinolones have been found to have useful activity as inhibitors of TGFβ Signaling, and as
agents which reduce cellular tau levels which represents an important target in Alzheimer's
7
,8
disease, and are the current subject of intensive pre-clinical development. Early advances in
stoichiometric adjuvant asymmetric synthesis of chiral DHPs were accomplished first by Meyers

9
10
11
and Natale, and later by Enders, and Dondoni. The critical breakthrough to catalytic multi-
1
2
component asymmetric DHP synthesis was achieved initially by Gong, and extended to
7
quinolones by Gestwicki. We herein report, to the best of our knowledge, the first facile
preparation of the most sterically hindered 4-isoxazolyl-1,4-dihydropyridines to date, the first
examples of 4-isoxazolyl-quinolones, as well as their highly stereoselective organocatalytic
asymmetric synthesis.
O
N
O
N
H C
3
Ar
O
N
O
Ar
H C
3
H
CO Et
2
EtO C
CO Et
2
2
Ar
H C
3
(
R)-TRIP
CHO
Yb(OTf)3
phosphate
N
H
CH3
H C
3
N
H
CH3
1
3
2
Scheme 1. Lanthanide catalyzed synthesis of sterically hindered 3-aryl-Isoxazolyl-
Dihydropyridines 2, and asymmetric organocatalysis of dihydroquinolones 3.
1
3
The Isoxazolyl-dihydropyridines are characterized by their complex conformational dynamics,
which we have demonstrated can lead to divergent structure activity relationships (SAR) for
1
4,15
different biomolecular targets.
In previous studies we observed that increasing the size of
1
6
substituents on the isoxazole lead to vanishingly low yields, even under forcing conditions. As
an example, naphthyl groups appended to isoxazoles, even separated by an ethylene spacer,
produced typical single digit yields in the Hantzsch synthesis, even under elevated pressure.
Previous reports on the use of lanthanide catalysts are noteworthy for their relatively mild
reaction conditions, and we sought to test the scope and limitations of this promising
methodology.

1
6
The Ytterbium catalyzed method produced moderate to good yields of IDHPs unavailable
using standard methods. The single crystal x-ray diffractometry (sc-xrd) of 2a and 2b illustrates
the steric crowding of the C-3 isoxazole substituent. Characteristic of IDHPs, in the unit cell,
intermolecular hydrogen bonding is observed between the isoxazole ring N and the DHP N-H. In
1
the anthryl example, 2c, significant anisotropy is observed in the H NMR for both the C-2 and
C-6 methyl groups of the DHP moiety, consistent with an analogous conformation in solution.
Single crystal x-ray diffractometery and solid state conformation.
The Isoxazolyl-quinolone was crystallized and its structure determined by x-ray diffractometry.
The heterocyclic axis at the quinolone C-4 is oriented O-endo, that is, with the isoxazolyl oxygen
towards the dihydropyridine moiety, and the 3'-aryl exo to the quinolone. The Quinolone 3-ester
adopts a synperiplanar conformation, the quinolone locks the C-5 ketone in the antiperiplanar
conformer. In the unit cell, there is an intermolecular hydrogen bond between the quinolone N-1
hydrogen, and the quinolone ring carbonyl oxygen.
Table 1. Lanthanide catalyzed synthesis of sterically hindered IDHPs 2a-i.
Entry
Ar
% yield HRMS calc'd Found
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
g
h
i
1'-Naphthyl
64.04
501.2026
491.2182
511.2233
469.1975
501.2026
441.2026
623.2757
623.2757
487.2233
501.2019
491.2205
511.2228
469.1990
501.2019
441.2057
623.2709
623.2807
487.2256
1'-(2'-methoxy-Naphthyl) 50.21
9'-Anthryl 41.98
3,4-Bis-benzyloxy-phenyl 67.95
3-Phenoxy- phenyl
4-Methoxy- phenyl
2,4-Dimethoxy- phenyl
3,4-Dimethoxy- phenyl
4-Biphenyl
60.98
60.96
63.98
53.19
46.23

A
B
C
Figure 1. 50% probability ellipsoids ORTEPs of (A) Naphthyl-2a. R = 5.1%. (B) Methoxy-
Naphthyl-2b. R= 9%. (C) IQ (+)-3a, R = 5.2%.

6
The asymmetric synthesis was performed according to Gestwicki, from the isoxazole aldehydes
using the organocatalysis of BINOL phosphates as pioneered by Gong. Chemical yields were
moderate to good, and optical purities as established by HPLC-CSP were excellent (>90% e.e.).
7
Absolute configurations were assigned by analogy to the work of Schade, who established the
absolute configuration of the (+) enantiomer as (R)- by single crystal x-ray diffractometry. The
quinolone absolute configuration is probably driven by the relative reactivity rates of ketoester
verses cyclic 1,3-diketone, and therefore arises from initial Knovenagel condensation by the
ketoester, followed by Michael addition of the diketone. In contrast, the IDHP in Entry 2j, the
Knovenagel product was preformed with the triazole, followed by condensation with the
ketoester. Therefore, that the absolute configuration of the entries in Table 2 are all (-), (S)- is
fortuitous. We would not expect the corresponding multi-component synthesis of IDHPs
analogous to 2j to proceed with significant stereoselectivity, unless the initial Knovenagel adduct
was similarly preformed.
Table 2. Asymmetric organocatalytic synthesis of IDHP 2j and 4-isoxazolyl-Quinolones, 3. All
examples gave optical purities of >90% e.e by HPLC-CSP (Supporting data).
Entry
RS-3a
Ar
-Ph
R
-CH
Catalyst
Yb(OTf)
Yield
30.25
25.92
71.60
64.35
62.07
60.40
67.19
65.34
31.56
21.32
[]D
-11.2
-13.5
-2.36
-0.032
-2.68
2
2
2
2
CH
CH
CH
CH
3
3
(
-)-3a
RS-3b
-)-3b
RS-3c
-)-3c
RS-3d
-)-3d
RS-2j
-)-2j
(R)-TRIP
Yb(OTf)
(R)-TRIP
Yb(OTf)
(R)-TRIP
Yb(OTf)
(R)-TRIP
Yb(OTf)
(R)-TRIP
-o-Br-Ph
-m-Br-Ph
-p-Br-Ph
-p-Br-Ph
-CH
-CH
-CH
3
3
(
3
3
(
3
3
(
-4-CH
2
(N-phenethyl)triazole
3
(

We are intrigued by the potential of the hindered 4-isoxazole dihydropyridines and 4-isoxazolyl-
1
8
quinolones for theranostic applications, and look forward to detailed study of their
conformational dynamics and bioactivity. We will report on our progress in due course.
Supplementary Material
Full experimental details and characterization for all new compounds. Crystal structure
determination, atomic coordinates and hydrogen-bond geometry for 2a, 2b, and RS-3a,
including unit cells. SYBYL transition state modeling of the organocatalytic asymmetric
synthesis.
Acknowledgement
The authors are grateful to the Center for Structural and Functional Neuroscience for NIH NCRR
P20RR015583 and NINDS R15 NS038444 for support of this work.

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O
O
O
N
N
O
CO Et H C
2
3
CO Et
CH3
2
Ar
H C
O
3
CH3
Ar
O
N
NH OAc
4
H
2
Eq
CO Et
EtO C
CO Et
2
2
2
O
Ar
NH OAc H C
4
3
CHO
N
CH3
H C
N
CH3
3
O
Yb(OTf)3
1
H
H
(
R)-TRIP
3
2
phosphate