Enantioselective organocatalytic partial transfer hydrogenation of lactone-fused quinolines

Article abstract of DOI:10.1021/ol5011196

The first enantioselective synthesis of 4-aza-podophyllotoxin derivatives by partial transfer hydrogenation of lactone-fused quinolines was achieved using a chiral Bronsted acid catalyst. This reaction was extended to a large scope of substrates with good yields and enantioselectivities.

Full text of DOI:10.1021/ol5011196

Letter
pubs.acs.org/OrgLett
Enantioselective Organocatalytic Partial Transfer Hydrogenation of
Lactone-Fused Quinolines
Alexandre Aillerie,†,‡ Vincent Lemau de Talance,†,‡ Aurelien Moncomble,†,§ Till Bousquet,*,†,‡
́
́
and Lydie Pelinski*,†,‡
́
†Universite
́
́
Lille Nord de France, F-59000 Lille, France
de Lille 1, Unite de Catalyse et de Chimie du Solide, UMR CNRS 8181, ENSCL, B.P. 108, 59652 Villeneuve d’Ascq,
‡Universite
France
́
§Universite
́
de Lille 1, Laboratoire de Spectrochimie IR & Raman, UMR CNRS 8516, F-59655 Villeneuve d’Ascq, France
S
* Supporting Information
ABSTRACT: The first enantioselective synthesis of 4-aza-
podophyllotoxin derivatives by partial transfer hydrogenation of
lactone-fused quinolines was achieved using a chiral Brønsted
acid catalyst. This reaction was extended to a large scope of
substrates with good yields and enantioselectivities.
atalytic asymmetric transformations have become an
Cessential part of contemporary organic synthesis. Over
the past decades, the field of organocatalysis has emerged and
grown dramatically with many new applications.1 In an
international context oriented toward the development of
eco-friendly processes, the use of nonmetallic catalysts has
proven to be a good alternative in organic synthesis.
In this wide area, chiral Brønsted acids are frequently utilized
to catalyze asymmetric reactions.2 In particular, the use of chiral
phosphoric acids in the presence of organic hydrides was
successfully applied to the enantioselective reduction of
nitrogen-containing substrates3 such as imines,4 enamines,5
benzoxazines,6 benzodiazepines,7 pyridines8 and quinolines.9
To our knowledge, when this biomimetic approach was carried
out with substituted quinolines, only the tetrahydro adducts,
resulting from a double addition of hydride, were isolated.
More recently, this complete reduction was also observed in an
Figure 1. Podophyllotoxin derivatives.
other,12e,14 none of the reported syntheses controlled the
stereogenic center at the C1 position.
In this context, we describe in this paper the first
enantioselective synthesis of aza-podophyllotoxins by partial
transfer hydrogenation of lactone-fused quinolines.12h
Hence, our initial investigations were focused on finding the
appropriate chiral phosphoric acid catalyst 7 for the reduction
of quinoline 4a in the presence of Hantzsch ester 6 (Table 1,
entries 1−9). Among the commercially available chiral
phosphoric acids, we focused our attention on the phosphoric
acid derivatives of BINOL (7a−e), H8-BINOL (7f−g), and
VAPOL (7h) (Figure 2).
Following this survey, we were pleased to find that, as
suspected, the lactone moiety prevents the second reduction
step from occurring, allowing thus the isolation of the
dihydroquinoline 5a. Interestingly, partial hydrogenations
were already reported on pyridine and benzopyrylium ions.8,15
Among the catalysts used, the phosphoric acid 7a was found
to be the best for this transformation with respect to reactivity
and enantioselectivity with a 92% yield and 92% ee (Table 1,
entry 1).16 The treatment of 4a with the catalyst antipode
asymmetric relay catalysis Friedlander condensation/transfer
̈
hydrogenation.10
The mechanism reported by Rueping for the exclusive
formation of tetrahydroquinolines describes the formation of
the highly reactive dihydro intermediate which undergoes the
second reduction step via an enamine protonation.9a
Besides this, since the synthesis of the first 4-aza-2,3-
didehydro-4-deoxypodophyllotoxin 1 and the report of its
potent anticancer activity,11 many researchers have studied with
interest these dihydroquinoline derivatives.12 From a pharma-
ceutical point of view, these molecules belong to the lignan
family and are structurally close to podophyllotoxin 2 and the
commercially available topoisomerase II inhibitors, etoposide
3a and teniposide 3b, widely used in medicine as anticancer
agents (Figure 1).13
Despite the substantial medical application of the 4-aza-
podophyllotoxins and given that it was proven that one
enantiomer is much more biologically active than the
Received: April 18, 2014
Published: May 22, 2014
© 2014 American Chemical Society
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Letter
reactivity or selectivity (Table 1, entry 19). When 0.1 mol % of
catalyst 7a was used, the product yield dramatically dropped to
28% (Table 1, entry 20). Additionally, when 2 mol % of catalyst
was used, it was determined that 50 °C was the optimal
temperature for the activity (Table 1, entry 18 vs entries 21 and
22).
Table 1. Optimization of the Reaction Conditions
These preliminary studies revealed that the best conditions
for the transfer hydrogenation of quinoline 4a were 2 equiv of
dihydropyridine 6 and 2 mol % of catalyst 7a at 50 °C in
toluene for 24 h.
Under these optimized conditions, we explored the scope of
the Brønsted acid catalyzed monohydrogenation for the
formation of various aza-podophyllotoxin derivatives (Table 2).
a
b
cd
,
entry
catalyst (mol %)
solvent
toluene
yield (%)
ee (%)
92
1
7a (10)
7a (10)
7b (10)
7c (10)
7d (10)
7e (10)
7f (10)
7g (10)
7h (10)
7a (10)
7a (10)
7a (10)
7a (10)
7a (10)
7a (10)
7a (10)
7a (5)
92
88
86
93
95
87
98
93
97
99
62
42
71
77
79
82
92
91
87
28
65
85
e
2
toluene
−84
88
1
3
toluene
4
toluene
5
toluene
3
6
toluene
1
7
toluene
25
91
35
91
95
90
90
95
95
93
93
93
93
88
93
93
Table 2. Scope of the Transfer Hydrogenation Reaction
8
toluene
9
toluene
10
11
12
13
14
15
16
17
18
19
20
21
22
benzene
CH2Cl2
CHCl3
acetonitrile
tetrahydrofuran
f
MTBE
g
DMC
toluene
toluene
toluene
toluene
toluene
toluene
7a (2)
7a (1)
7a (0.1)
h
7a (2)
i
7a (2)
a
General conditions: 1 equiv of quinoline and 2 equiv of Hantzsch
b
c
ester. Isolated yields. Determined by chiral-phase HPLC analysis.
d
e
f
See ref 16. Opposite catalyst enantiomer was employed. Methyl tert-
g
h
butyl ether. Dimethyl carbonate. Reaction conducted at 30 °C.
i
Reaction conducted at 70 °C.
Figure 2. Chiral phosphoric acid catalysts.
resulted in the formation of the opposite dihydroquinoline
enantiomer (Table 1, entry 2).
After observing that the nature of the organic hydride had no
significant effect on the reactivity or the enantioselectivity,17
further studies using catalyst 7a were oriented toward the
solvent employed.
It is worth noting that the nature of the solvent had a major
effect on the product yield but not on the enantioselectivity.
The best reactivity was observed in aromatic nonpolar solvents
(Table 1, entries 1 and 10). Chlorinated solvents resulted in
decreased product yields (Table 1, entries 11 and 12).
Interestingly, dimethyl carbonate, considered as a green solvent,
gave a rather good yield and selectivity (82% yield, 93% ee)
(Table 1, entry 16).
a
General conditions: 1 equiv of quinoline and 2 equiv of Hantzsch
b
c
ester. Isolated yields. Determined by chiral-phase HPLC analysis.
In this survey, we considerably changed the nature of the
substituent R2. In order to fit the biological requirements, we
have tested the dimethoxy and the methylene dioxy groups for
R1.18 To our satisfaction, high enantioselectivities and good
yields were generally observed. Surprisingly, the replacement of
the dimethoxy substituents R1 on the quinoline ring by a
methylene dioxy moiety generally induced a significant decrease
of the enantioselectivity (Table 2, entries 1 vs 8, 4 vs 9, and 5 vs
10). Arising from a relatively minor structural change in these
substrates, this difference in enantioselectivity is intriguing and
Further experimentations revealed that the catalyst loading
could be lowered to 1 mol % without significant loss of
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Letter
a
still remains to be clarified. Although it has to be emphasized
that the best enantioselectivity was observed when such a
dioxolane R1 group was combined with a methoxy dioxolane
aryl subunit as R2 (product 4k, 96% ee) (Table 2, entry 11),
only a moderate yield of 57% was obtained.
Scheme 3. Proton Exchange between 10 and 11
Based on the literature precedent,9a the mechanism
suggested for the transfer hydrogenation of lactone-fused
quinolines involves an initial protonation of the quinoline.
Subsequent hydride transfer results in the formation of the
stable 1,4-dihydroquinoline (Scheme 1).
a
In toluene.
decided to go further with the structural analysis of both
dihydroquinolines.
The optimization of the structures 10 and 11 revealed a
significant difference of geometry (Figure 3). Indeed, while the
Scheme 1. Proposed Mechanism for the Brønsted Acid
Catalyzed Transfer Hydrogenation of Lactone-Fused
Quinolines
Figure 3. Optimized structures for 10 and 11.
dihydroquinoline ring system 10 is nearly planar, a curved
shape is adapted by 11.23 Related to this, the out-of-plane angle
of the N−H bond is higher in the molecule 11 than in the
lactone-fused derivative. These structural differences are in
correlation with a higher nitrogen lone-pair delocalization and
consequently a higher double bond character in the N−C and
C−C bonds of the enamine moiety in the lactone-fused
dihydroquinoline 10.24 Thus, by increasing the strength of the
enamine double bond, the reactivity of 10 toward a proton is
considerably affected in comparison to the molecule 11. This is
also supported by the fact that the carbon in the β-position of
the nitrogen in the lactone-fused dihydroquinoline 10 has a
lower electron density than in dihydroquinoline 11.25
This study revealed the crucial role played by the five-
membered ring lactone moiety in the particular reactivity of the
starting quinolines 4 and 8 in the transfer hydrogenation
reaction.
After the optimization and the extension of the reaction
scope, we focused our interest on the particular reactivity of the
lactone-fused dihydroquinolines.
In order to explain their nonreactivity toward a Brønsted acid
in the presence of 6, we have initially assumed that the
mesomeric electron-withdrawing group in the β-position of the
nitrogen could stabilize the enamine. For this purpose, we
performed the transfer hydrogenation on both quinolines 8 and
9 bearing in position 3 a similar electron-withdrawing
substituent (Scheme 2)
Scheme 2. Transfer Hydrogenation of Quinolines 8 and 9
In summary, we have developed the first organocatalytic
enantioselective transfer hydrogenation of lactone-fused quino-
lines to obtain various aza-podophyllotoxin derivatives. The
exclusive formation of stable 1,4-dihydroquinolines was
rationalized by computational studies highlighting the higher
stability of the enamino-lactone toward protonation.
ASSOCIATED CONTENT
* Supporting Information
■
S
Whereas the formation of the dihydroadducts 10 and 11 was
expected in both the cases, ester derivative 9 underwent a
complete reduction furnishing the tetrahydroquinoline 12 in
70% yield.
Therefore, a DFT-based study was conducted on dihy-
droquinolines 10 and 11 using the ωB97X-D functional19 and a
PCM model20 for the solvent.21
First, in order to evaluate their difference of reactivity toward
a proton, a proton exchange between 10 and 11 was studied
(Scheme 3).
Highlighting the much easier protonation of dihydroquino-
line 11, an equilibrium constant K of 3.5 × 1015 was calculated
for this transformation.22 This result is in good agreement with
the experimental observation, as 11 leads to the tetrahy-
droadduct after protonation. In order to understand such a
difference of reactivity between 10 and 11 toward a proton, we
Full experimental details and analytical data including NMR
spectra and chiral HPLC analyses. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: till.bousquet@univ-lille1.fr.
*E-mail: lydie.pelinski@univ-lille1.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are thankful to the Centre National de la
Recherche Scientifique, Universite
de Ressources Informatiques of the University de Lille 1. Cel
■
́
de Lille 1, and the Centre
ine
́
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Letter
(16) As no single crystals have been obtained, assignment of the
absolute configuration was based and extrapolated from the chiral
HPLC of the compound 5k described in ref 14.
(17) Results not reported here. Hantzsch esters with various esters
groups (methyl, isopropyl, benzyl, allyl) gave the same yield and
enantioselectivity for the reaction reported in Table 1. Benzothiazo-
lines were also tested but did not allow any conversion: Zhu, C.;
Akiyama, T. Org. Lett. 2009, 11, 4180.
(18) Additionnally, the synthesis of quinolines 4 bearing an electron-
withdrawing group in R1 position can not be realized.
(19) Chai, J.-D.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2008, 10,
6615.
(20) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105,
2999.
(21) See Supporting Information for more details.
(22) Determined from the calculated Gibbs energy variation of ΔrG°
= −19.4 kcal/mol.
(23) Maximum dihedral angles of the nitrogen-containing ring is 3°
for 10 and 28° for 11.
(24) N−C bond lengths: 1.352 Å for 10 and 1.377 Å for 11. C−C
bond lengths: 1.342 Å for 10 and 1.360 Å for 11.
(25) APT charges: −0.65 and −0.74 in 10 and 11 respectively.
Delabre is thanked for assistance in HPLC analysis. This
research was supported by the “Conseil Reg
Calais” (program PRIM) and the “Comite
contre le Cancer”.
́
ional Nord-Pas de
Nord de la Ligue
́
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