Tetrahedron Letters
Computational and experimental evaluation of a-(N-2-quinolonyl)
ketones: a new class of nonbiaryl atropisomers
⇑
Andrea N. Bootsma, Carolyn E. Anderson
Calvin College, Department of Chemistry and Biochemistry, 1726 Knollcrest Circle SE, Grand Rapids, MI 49546, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Given the usefulness of atropisomers within both asymmetric catalysis and pharmaceuticals, a thorough
Received 26 August 2016
Revised 8 September 2016
Accepted 15 September 2016
Available online 16 September 2016
computational study of substituted a-(N-2-quinolonyl)ketones has been conducted. This class of tertiary
amides is unique, as the amide is embedded within an aromatic construct, and the nitrogen bears an
aliphatic substituent. Using a computational approach, 80-substituted quinolones were identified as
potential class 2 and 3 atropisomeric targets with calculated C–N rotational barriers of greater than
20 kcal/mol. These results, along with experimental efforts toward the synthesis of these targets, are
reported.
Keywords:
Quinolone
Microwave-assisted synthesis
Atropisomerism
Gold-catalysis
Ó 2016 Elsevier Ltd. All rights reserved.
Introduction
important group of compounds, biaryl structures (e.g. BINOL,
BINAP, and NOBIN) have garnered the most attention; however,
Atropisomerism is a steroechemical property that arises as a
result of hindered rotation around a central bond. Depending on
the barrier to rotation, atropisomers can be grouped into three
unique classes.1 The most configurationally stable, denoted as class
3 isomers, possess rotational barriers that exceed 30 kcal/mol,
leading to a t1/2 for racemization on the order of years. Compounds
in this class exist as chiral structures that can be isolated as single
enantiomers or diastereomers, depending on the presence or
absence of secondary chiral centers (e.g. BINOL).2 Compounds
whose rotational barriers are more moderate (20–30 kcal/mol)
are known as class 2 atropisomers and exhibit rotational half-lives
of hours to days. Class 1 atropisomers, with barriers less than
20 kcal/mol, can sometimes be observed by spectroscopic means
(e.g. NMR or chiral HPLC) but can only be isolated as equilibrating
mixtures under normal laboratory conditions.3
The presence of atropisomerism in pharmaceutical targets has
become a concern in recent years.4 While class 3 atropisomers
can be treated as other stereoisomeric leads, many compounds of
interest exhibit rotational restriction but are not configurationally
stable.5 The issues associated with the characterization and regula-
tory registration of such class 2 atropisomeric drug candidates are
significant.
nonbiaryl species can also exist as stable pairs of atropisomers,
including: amides, macrocycles, and molecules whose characteris-
tic ring flips are restricted.4,7 Exploration and application of mole-
cules from these classes to current problems in asymmetric
catalysis remains an important synthetic goal.8
In the course of our work developing new methods for the syn-
thesis of
a-(N-2-pyridonyl)ketones and a-(N-2-quinolonyl)ke-
tones, we noted irregularities in the 1H NMR of quinolone 2,
indicative of slowed rotation around the central C–N bond
(Scheme 1).9 Computational studies supported this observation,
suggesting that compound 2 is a class 1 atropisomeric structure
with a barrier to rotation of 14.0 kcal/mol.9 Further examination
of quinolone 2, suggests that additional substitution at the posi-
tions adjacent to the hindered C–N bond might slow rotation fur-
ther, enabling the formation of more configurationally stable
class 2 or even class 3 atropisomeric compounds, rendering them
potentially useful as ligands for asymmetric catalysis or as tem-
plates suitable for elaboration into inhibitors of various biological
targets.
While the rotational barriers of tertiary amides have been well
studied,8,10
a-(N-2-quinolonyl)ketones represent a new class of
nonbiaryl atropisomers, in which the amide functionality is imbed-
ded within an aromatic construct. Further, although N-acyl
indoles,11 N-aryl quinazolinones,12 and N-aryl bicyclic lactams13
provide some insights into the restriction to C–N bond rotation
in systems related to that discussed here, the aromatic system
and aliphatic nitrogen substitution present in the current study
In addition, many privileged asymmetric catalyst and ligand
structures rely on non-C2 symmetric axial chirality.6 Within this
⇑
Corresponding author. Tel.: +1 616 526 6343; fax: +1 616 526 6501.
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.