Enantioselective one-pot synthesis of dihydroquinolones via BINOL-derived Lewis acid catalysis

Article abstract of DOI:10.1039/c4ob00627e

A high-yielding and diastereoselective route to biologically significant 2-aryl- and 2-alkyl-3-amido dihydroquinolones has been developed in up to 90 : 10 e.r. by employing a novel Lewis acidic BINOL-derived copper(ii) catalyst.

Full text of DOI:10.1039/c4ob00627e

Organic &
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Enantioselective one-pot synthesis of
dihydroquinolones via BINOL-derived Lewis acid
catalysis†
Cite this: Org. Biomol. Chem., 2014,
12, 5094
Received 24th March 2014,
Accepted 3rd June 2014
Peter C. Knipe and Martin D. Smith*
DOI: 10.1039/c4ob00627e
www.rsc.org/obc
A high-yielding and diastereoselective route to biologically signifi-
cant 2-aryl- and 2-alkyl-3-amido dihydroquinolones has been
developed in up to 90 : 10 e.r. by employing a novel Lewis acidic
BINOL-derived copper(II) catalyst.
The synthesis of 2-substituted dihydroquinolones (1-azaflava-
nones) has been the subject of increased synthetic effort fol-
lowing the discovery that these molecules exhibit potent
cytotoxic activity against a large number of human cancer cell
lines.1,2 In particular there has been growing interest in gener-
ating these structures in an enantioselective fashion.3 In
addition to their notable biological profile, dihydroquinolones
are competent intermediates for the synthesis of the core of
the Martinella family of naturally-occurring alkaloids.4 Strat-
egies to control asymmetry in the synthesis of dihydroquino-
lones have included Rh(BINAP)-catalyzed intermolecular
conjugate addition,5 kinetic resolution of racemic dihydroqui-
nolones by Pd(SiocPhox)-catalyzed allylation,4 enamine cataly-
sis with amino-sulfonamides6 and hydrogen bond-catalyzed
intramolecular conjugate addition of anilines.7–9
Our ongoing studies into catalytic asymmetric electrocyclic
reactions have been focused on benzylic deprotonation fol-
lowed by [1,5]-azaelectrocyclization onto a pre-formed imine,
under the control of a chiral counter-cation.10 This has been
achieved through the use of phase-transfer catalysis, employ-
ing chiral cinchona-derived quaternary ammonium salts to
mediate asymmetry, and has been used as the key step in the
cascade synthesis of pyrrolizidines and indolizidines.11 We
reasoned that a similar strategy could be employed in the cata-
lysis of [1,6]-electrocyclic reactions by different positioning of
anion-stabilizing groups (Fig. 1). Our investigations began with
the synthesis of aniline 1, formed in two steps from 2-nitro-
benzoic acid. We planned to condense the aniline with various
aldehydes to allow access to the requisite imines for our study,
Fig. 1 Concept for asymmetric [1,6]-electrocyclization.
but the poor nucleophilicity of the electron-poor aniline ren-
dered it ineffective in this regard. Imine formation reactions
under conditions previously employed10 were low-yielding and
the imines were prone to hydrolysis (Scheme 1).
To circumvent the problems associated with synthesis and
isolation of sensitive imines we carried out both the imine for-
mation and cyclization reactions under acidic conditions.
There is precedent for such reactivity in three-component
coupling reactions under both Lewis- and Brønsted-acid cataly-
sis, as well as in intramolecular cyclization reactions.6,12–14
A
screen of acids indicated that ScIII, CuII and ZnII trifluoro-
methanesulfonates gave excellent conversion of amine 1 and
benzaldehyde to the corresponding dihydroquinolone 2.
However, chiral ligands were ineffective in achieving signifi-
cant levels of enantioselectivity (Table 1, entries 5–9). A range
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
12 Mansfield Road, Oxford, OX1 3TA, UK. E-mail: martin.smith@chem.ox.ac.uk
†Electronic supplementary information (ESI) available. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4ob00627e
Scheme 1 Attempted imine formation.
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Table 1 Acidic conditions screena,b
Entry
Catalyst (eq.)
Ligand
Solvent
T/°C
Conv./%c
e.r.d
1
2
3
4
5
6
7
8
Sc(OTf)3 (0.1)
Zn(OTf)2 (0.1)
Cu(OTf)2 (0.1)
(PhO)2PO2H (0.2)
Sc(OTf)3 (0.01)
Sc(OTf)3 (0.01)
Sc(OTf)3 (0.1)
Cu(OTf)2 (0.1)
Cu(OTf)2 (0.1)
(R)-TRIP (0.05)
(R)-TRIP (0.02)
7 (0.01)
—
—
—
—
3
4
4
3
5
—
—
—
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1 : 1 THF–PhMe
1 : 1 THF–PhMe
1 : 1 THF–PhMe
PhMe
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
−30
−30
100 (30 min)
100 (1 h)
100 (1 h)
80 (1 h)
100 (3 h)
100 (3 h)
100 (2 h)
56 (16 h)
49 (16 h)
100 (4 h)
50 (4 d)
—
—
—
—
50 : 50
52 : 48
50 : 50
50 : 50
50 : 50
70 : 30
76 : 24
83 : 17
9
10
11
12
PhMe
1 : 1 THF–PhMe
100 (2 d)
a All reactions were carried out employing 2 eq. benzaldehyde under the conditions indicated. b For full catalyst screening conditions, please refer
to the ESI. c Determined by 1H NMR analysis of the crude reaction mixture. d Determined by HPLC analysis.
of chiral phosphoric acids were also examined (see ESI† for and 13, yields were generally excellent, and all products were
full details); (R)-TRIP gave the best enantioselectivity, but low obtained as
a single diastereoisomer. The trans-stereo-
reaction rates made its use at cryogenic temperatures impracti- chemistry of 12 was verified by single crystal X-ray diffraction,
cal (entries 10 & 11). Inspired by the emerging field of chiral with other products assumed to be trans- by analogy.‡ Enantio-
counter-anion directed asymmetric catalysis,15–20 CuII N-triflyl- selectivities were modest, with meta-substitution generally
phosphoramide (NTPA)-derived Lewis acid 7 was synthesized – affording the highest enantiomeric ratios within each
with 3,3′-(diisopropyl)phenyl substituents chosen to reflect the isomeric series (e.g. 11 and 18). Electron-poor aldehydes gave
most successful chiral phosphoric acid – and effectively cata- better enantioselectivities than those with electron-donating
lysed the asymmetric process, affording the dihydroquinolone substituents (10–15 vs. 16–18), yet all substituted examples
2 in 83 : 17 e.r. when the reaction was carried out at −30 °C gave lower selectivity than the parent benzaldehyde derivative.
(entry 12). The catalyst gave both higher conversion and We attribute this to a sterically-congested substrate-catalyst
enantioselectivity than (R)-TRIP at the same temperature, and complex, leading to high sensitivity to the presence of
with lower catalyst loading.
substituents.
Copper(II) NTPA catalyst 7 was prepared in three steps from
In general, previous synthetic efforts towards the synthesis
(R)-(3,3′)-bis[(triisopropyl)phenyl] BINOL.21,22 Sequential treat- of dihydroquinolones have focused primarily on products with
ment of the diol with POCl3 and trifluoromethanesulfonamide aromatic substituents, and generally aliphatic substrates have
provided the phosphoramide in 86% yield, and subsequent garnered lower enantioselectivities.6–8 We were pleased to find
exposure to Ag2CO3 afforded the corresponding AgI salt, which that in the case of our CuII salt 7 catalysed process, alkyl alde-
underwent salt metathesis with CuCl2·2H2O to generate CuII hydes typically gave superior yields and enantioselectivities to
salt 7 in 75% over two steps.23,24
the aromatic examples outlined above (Table 3).
The optimized asymmetric reaction was then employed in
All dihydroquinolones were obtained in close to quantitat-
the synthesis of a variety of 2-aryl dihydroquinolones (Table 2). ive yields and as a single diastereoisomer. Primary aliphatic
Nitrile and ester electron-withdrawing groups at the 3-position aldehydes (19–22) gave generally good enantioselectivities,
were found to be inferior in both yield and enantioselectivity with the exception of 4-pentenal derivative 22, where com-
to N,N-dimethylacetamide (2, 8 and 9). With the exception of 9 plexation of the alkene to the copper(II) catalyst may be a
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Table 2 Scope of the reaction I: aromatic aldehydesa,b,c
Table 3 Scope of the reaction II: aliphatic aldehydesa,b,c
a All reactions were carried out with 2.0 eq. aldehyde and 1 mol%
catalyst 7 in the presence of 4 Å MS, and were analysed after 48 h. b All
yields are for isolated pure product. c Enantioselectivities determined
by chiral HPLC.
a All reactions were carried out with 2.0 eq. aldehyde and 1 mol%
catalyst 7 in the presence of 4 Å MS, and were analysed after 48 h. b All
yields are for isolated products. c Enantioselectivities determined by
chiral HPLC; diastereoselectivities determined by examination of
crude 1H NMR spectra.
factor. Amongst the secondary aldehyde-derived dihydroquino-
lones (23–26) there was a clear correlation between size and
enantioselectivity: smaller substituents (23 and 26) gave poor
e.r. (59 : 41 and 65 : 35 respectively) whilst bulkier groups (24
and 25) led to much higher selectivities (90 : 10 and 88 : 12 e.r.
respectively). The high enantioselectivity achieved when
pivaldehyde was employed (27, 90 : 10 e.r.) is also consistent
with this trend.
It is plausible that the formation of dihydroquinolones
could result either from intramolecular attack of an enolate
onto an aniline-derived imine, or alternatively from an initial
Knoevenagel condensation followed by intramolecular 1,4-
addition of the aniline. Treatment of α-benzyl substrate 28
with scandium triflate successfully generated product 29,§
suggesting that the imine pathway is operational, since Knoe-
venagel condensation is not possible in this case (Fig. 2A). The
same product was observed to form slowly when catalyst 7 was
employed, with the poor conversion (ca. 6% after 24 h) likely
due to the lower catalytic activity of 7 relative to scandium tri-
flate. A mechanism for the overall transformation is therefore
proposed in Fig. 2B. Coordination of copper to the 1,3-dicarbo-
nyl acidifies the α-proton; deprotonation of I (either inter- or
intramolecular) generates copper(II) enolate–iminium species II,
Fig. 2 Mechanistic proposal for dihydroquinolone formation.
which upon cyclization and epimerization affords the dihydro-
quinolone and regenerates the catalyst.25 Whether the process
constitutes an electrocyclic ring-closure or
a 6-endo-trig
Mannich reaction is unclear, since the expected stereochemical
markers are lost in the facile epimerization of the product.26
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The precise interactions that lead to asymmetric induction,
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Acknowledgements
The European Research Council has provided financial
support under the European Community’s Seventh Framework
Programme (FP7/2007–2013)/ERC grant agreement no. 259056.
Thanks to Dr Barbara Odell and Dr Russell W. Driver for assist-
ance with NMR and X-ray crystallography respectively.
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