Enantioselective Desymmetrization of para-Quinamines through an Aminocatalyzed Aza-Michael/Cyclization Cascade Reaction

Article abstract of DOI:10.1021/acs.orglett.5b01595

An unprecedented organocatalytic asymmetric desymmetrization of para-quinamines leading to functionalized hydroindoles, a common motif in many alkaloids, has been reported. The ability of diarylprolinol silyl ethers to promote iminium and enamine activation of α,β-unsaturated aldehydes in one catalytic cycle is the centerpiece of the strategy involving a challenging aza-Michael/intramolecular cyclization cascade reaction. A range of prochiral para-quinamines and α,β-unsaturated aldehydes were investigated to afford 16 examples of hydroindoles possessing four contiguous stereocenters including one quaternary carbon. The hydroindole structures include multiple orthogonal functionalities, which underwent various transformations.

Full text of DOI:10.1021/acs.orglett.5b01595

Letter
pubs.acs.org/OrgLett
Enantioselective Desymmetrization of para-Quinamines through an
Aminocatalyzed Aza-Michael/Cyclization Cascade Reaction
Loïc Pantaine, Vincent Coeffard,* Xavier Moreau, and Christine Greck*
́
́
de Versailles-St-Quentin-en-Yvelines, 45 Avenue des Etats-Unis, 78035
Institut Lavoisier Versailles, UMR CNRS 8180, Universite
Versailles cedex, France
S
* Supporting Information
ABSTRACT: An unprecedented organocatalytic asymmetric
desymmetrization of para-quinamines leading to functionalized
hydroindoles, a common motif in many alkaloids, has been
reported. The ability of diarylprolinol silyl ethers to promote
iminium and enamine activation of α,β-unsaturated aldehydes
in one catalytic cycle is the centerpiece of the strategy involving
a challenging aza-Michael/intramolecular cyclization cascade reaction. A range of prochiral para-quinamines and α,β-unsaturated
aldehydes were investigated to afford 16 examples of hydroindoles possessing four contiguous stereocenters including one
quaternary carbon. The hydroindole structures include multiple orthogonal functionalities, which underwent various
transformations.
esymmetrization processes are powerful means of trans-
Scheme 1. Desymmetrization Towards Hydroindoles
D
forming prochiral or meso-molecules into functionalized
enantioenriched compounds.1 Among the vast array of substrates
available for such transformations, cyclohexadienone systems
contain a rigid six-membered ring and functionalities, which are
attributes that make dienones attractive starting materials to
reach complex cyclic architectures via a desymmetrization
process.2 The chief challenge facing the organic chemists within
this field lies in the use of a catalyst enabling the discrimination
between two enantiotopic atoms or groups during the symmetry-
breaking transformation. Despite the hurdles, significant achieve-
ments have emerged in the asymmetric desymmetrization of
cyclohexadienone substrates.2 Besides transition metal catalysis,
the ability of asymmetric organocatalysis to promote a wide
range of synthetic transformations has been successfully
exploited to promote the desymmetrization of dienone systems.
For instance, prolinol silyl ethers,3 N-heterocyclic carbenes,4
cinchona-derived thiourea,5 phase transfer catalysts,6 or phos-
phoric acids7 turned out to be suitable catalytic systems. While
several reports have described desymmetrization processes for
which the nucleophile that attacks the dienone is already attached
to the cyclohexadienone motif, bimolecular transformations have
received less attention. In an important contribution to this field,
the group of Rovis reported an asymmetric desymmetrization of
peroxyquinols in the presence of aliphatic and aryl aldehydes
using a Brønsted acid-catalyzed acetalization and intramolecular
oxa-Michael cascade reaction.7b Other contributions by the
groups of Johnson,3c Wang,8 and Fan9 have outlined the ability of
cyclohexadienone motifs to give complex cyclic architectures via
bimolecular transformations. Despite these recent advances, to
the best of our knowledge a bimolecular asymmetric organo-
catalyzed desymmetrization strategy starting from para-quin-
amines 1 (4-amino-4-alkyl-2,5-cyclohexadienones) has never
been reported, while new advances in this area could pave the
way to new nitrogen-containing heterocycles (Scheme 1).
As part of our ongoing research into the development of
organocatalytic methodologies,10 we wish to report herein the
implementation of a novel dissymmetrical construction of
functionalized nitrogen-containing polycycles via an aza-
Michael/cyclization cascade reaction. The ability of chiral
secondary amines to promote iminium and enamine activation
of α,β-unsaturated aldehydes 2 in one catalytic cycle will be the
centerpiece of the desymmetrization strategy toward hydro-
indole structures. This is a common motif in natural substances
and biorelevant compounds such as the alkaloids thelepogine,11
eburenine,12 and dihydro-β-erythroidine (DHβE).13 Central to
the implementation of the desymmetrization is the addition of
para-quinamines 1 to α,β-unsaturated aldehydes 2. Amino-
catalyzed aza-Michael additions have been extensively studied in
Received: June 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01595
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the literature, but some challenges still require additional efforts
to extend this reaction in synthetically interesting new
directions.14 In particular, the use of hindered amines in
intermolecular aza-Michael reactions remains scarce in the
literature thus limiting the substrate scope to more reactive
amines such as hydroxylamine derivatives or nitrogen-containing
heterocycles. In addition, the reversibility inherent to the
addition of an amine onto iminium species, the amine
nucleophile/aminocatalyst competition toward addition and
the intermolecular nature of the strategy are potential difficulties
to embark on the reaction of para-quinamines 1 with α,β-
unsaturated aldehydes 2. Nevertheless, recent breakthroughs in
aza-Michael reactions with amines catalyzed by diarylprolinol
silyl ethers 3 and AcONa were a driving force to investigate the
desymmetrization depicted in Scheme 1.15
gave rise to 4aa in 80% yield and 96% ee (entry 3). Experiments
carried out under acidic conditions (entry 4) or neutral
conditions (entry 5) gave lower yields of 4aa. The influence of
the reaction medium was then investigated by screening various
solvents (entries 6−8). While toluene turned out to be a suitable
solvent for the desymmetrization process (4aa, 50% yield),
switching to DMF or MeCN was detrimental to the formation of
4aa. With the optimized conditions in hand (Table 1, entry 3),
the scope and limitations with respect to the nature of R1 and R2
were assessed (Table 2). A reaction time of 7 days was required
to ensure maximum conversion rates and optimal yields. Initially,
changes to the R2 group on the α,β-unsaturated aldehydes 2 were
investigated (2a−m). We first focused our attention on the
influence of the position of the aromatic substituent on the
efficiency and stereoselectivities of the reaction. Starting from
aldehydes 2b and 2e bearing a methyl or a methoxy group in
para-position, similar results as for 4aa were obtained even if a
slight decrease of ee was observed for 4ae (entries 1, 2, and 5).
For the methyl and methoxy series, the reaction rate starting
from 1a is in the order para > meta > ortho with similar levels of
stereoselectivities within each series (entries 2−7). This
reactivity order could be explained by an increased steric
hindrance at the β position of the enal thus hampering the
nucleophilic addition of the para-quinamine 1a. Substrates 2h
and 2i possessing a halogen group also reacted to afford the
desired hydroindoles 4ah and 4ai in 61% and 51% yield,
respectively, with good diastereoselectivities and high enantio-
selectivities (entries 8 and 9). Surprisingly, a slight decrease of
reactivity (27−30% yield) was observed starting from α,β-
a
Table 1. Reaction Optimization
b
c
d
entry
3
solvent
% yield
dr
% ee
1
2
3
3a
3b
3c
3c
3c
3c
3c
3c
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
DMF
60
4:1
n.d.
3:1
4:1
2:1
2:1
n.d.
3:1
92
n.r.
80
n.d.
96
e
a
4
57
95
Table 2. Substrate Scope
f
5
65
95
6
7
8
50
92
<10
20
n.d.
97
MeCN
a
Reactions were performed on 0.15 mmol scale using 1 equiv of 1a,
1.5 equiv of 2a, 20 mol % of 3, and 1 equiv of AcONa at 55 °C for 3
days unless otherwise noted. n.r. = no reaction. n.d. = not determined.
b
c
d
b
c
entry
R1
R2
Ph (2a)
4
% yield
dr
% ee
Isolated yield for the major diastereomer. Diastereomeric ratios were
1
e
determined by H NMR analysis of the crude. The structure of each
diastereomer has been determined by full analyses; see Supporting
1
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Et (1b)
4aa
4ab
4ac
4ad
4ae
4af
80
76
65
50
71
61
43
61
51
30
27
63
42
24
13
61
3:1
5:1
5:1
4:1
5:1
5:1
5:1
4:1
5:1
2:1
4:1
5:1
4:1
2.5:1
2:1
5:1
96
93
93
92
81
n.d.
88
92
93
97
90
86
69
88
90
93
2
4-MeC6H4 (2b)
3-MeC6H4 (2c)
2-MeC6H4 (2d)
4-MeOC6H4 (2e)
3-MeOC6H4 (2f)
2-MeOC6H4 (2g)
4-ClC6H4 (2h)
4-FC6H4 (2i)
4-NO2C6H4 (2j)
2-NO2C6H4 (2k)
2-thienyl (2l)
Me (2m)
d
Information for further studies. Enantiomeric excesses were
3
determined by chiral HPLC on the Wittig products prepared from
4
e
major diastereomers. See Supporting Information. One equivalent of
5
f
AcOH was used instead of AcONa. No AcONa was added to the
6
reaction mixture.
7
4ag
4ah
4ai
8
9
We began our investigation by studying the reaction of the
readily available para-quinamine 1a with trans-cinnamaldehyde
2a in the presence of diarylprolinol silyl ether catalysts 3 and
AcONa (Table 1).16 The tosyl nitrogen protecting group of 1a is
essential to the success of the reaction.17 For instance, acetyl or
tert-butoxycarbonyl groups shut down the reactivity of the para-
quinamines because these groups rendered the NH less acidic for
a subsequent deprotonation under basic conditions.15b Starting
from 1a, various diarylprolinol silyl ether catalysts 3 were
investigated (entries 1−3).18 The catalyst 3a provided the
desired product 4aa in 60% isolated yield and 92% ee for the
major diastereomer, while no reaction occurred by using the 3,5-
(CF3)2C6H3-derived catalyst 3b (entries 1 and 2). In order to
improve the yield, we surmised that the presence of a bulkier silyl
group (e.g., TBS) could improve the stability and lifetime of the
catalyst.10b Therefore, the best result was obtained with 3c, which
10
11
12
13
14
15
16
4aj
4ak
4al
4am
4ba
4ca
4da
Ph (2a)
Bu (1c)
Ph (1d)
Ph (2a)
Ph (2a)
a
Reactions were performed on 0.15 mmol scale using 1 equiv of 1, 1.5
equiv of 2, 20 mol % of 3c, and 1 equiv of AcONa at 55 °C for 7 days
unless otherwise noted. n.d. = not determined. Isolated yield for the
major diastereomer. Diastereomeric ratios were determined by H
NMR analysis of the crude. Enantiomeric excesses were determined
by chiral HPLC on the Wittig products prepared from major
diastereomers 4. See Supporting Information for details. In this
b
c
1
d
e
case, the reaction mixture was stirred for 3 days.
B
DOI: 10.1021/acs.orglett.5b01595
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Organic Letters
Letter
unsaturated aldehydes 2j and 2k bearing a nitro substituent on
the aromatic ring (entries 10 and 11). The thiophene-derived
enal 2l was found to undergo a clean reaction with para-
quinamine 1a to provide the product 4al in 63% yield and 86% ee
(entry 12). Crotonaldehyde 2m was also amenable to the
desymmetrization reaction providing access to 4am in 42% yield
with 69% ee (entry 13). Variations to the prochiral scaffold were
next investigated (entries 14 and 15). The rate decreased rapidly
with the increase of the chain R1 length for similar reasons as
described above. While the reaction of 1b bearing an ethyl group
afforded 4ba in 24% yield and 88% ee, the butyl-derived product
4ca was prepared in a modest yield of 13% with high
enantiocontrol (90% ee). An increase of the yield was observed
by reacting 2a with 1d bearing a phenyl group. The product 4da
was obtained in 61% yield and 93% ee (entry 16).
challenging aminocatalyzed aza-Michael reaction and an
iminium/enamine cascade process mediated by a diphenylpro-
linol TBS ether catalyst in the presence of sodium acetate.
Sixteen examples of hydroindoles were prepared (13−80%) with
enantiomeric excesses ranging from 69% to 97%. A noteworthy
feature of this transformation lies in the formation of four
contiguous stereocenters including one quaternary carbon. The
original desymmetrization process was combined with a Ru-
catalyzed oxidative process to outline the synthetic potential of
the strategy leading to hydroindole motifs, which can undergo
various transformations.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and compound characterization data
including NMR spectra and relevant HPLC traces. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01595.
From a synthetic standpoint, the in situ preparation of
aldehydes is particularly interesting due to their sensitivity to
storage and possible degradation over time. To this aim, the
desymmetrization strategy has then been combined with a Ru-
catalyzed aerobic oxidation of allylic alcohols through a
multicatalytic sequential approach (Scheme 2).
AUTHOR INFORMATION
■
Corresponding Authors
Scheme 2. Multicatalytic Oxidation and Organocatalytic
Desymmetrization Sequence
*E-mail: vincent.coeffard@uvsq.fr.
*E-mail: christine.greck@uvsq.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Fondation de Cooper
́
ation Scientifique Campus
Paris Saclay for a Ph.D. grant to L.P. This work was supported by
the French National Research Agency under the Program
Investing in the Future Grant no. ANR-10-IDEX-0003-02. We
acknowledge financial support from CNRS and Universite de
́
Versailles-St-Quentin-en-Yvelines.
The oxidation of cinnamyl alcohol 5 in the presence of
tetrapropylammonium perruthenate (TPAP)19 and O2 pro-
duced the corresponding trans-cinnamaldehyde 2a, which was in
situ converted to 4aa in 46% yield and 93% ee after subsequent
addition of para-quinamine 1a, catalyst 3c, and AcONa. To
illustrate the synthetic potential of bicyclic structures 4, selective
transformations were carried out (Scheme 3). Hydrogenation of
4aa furnished the perhydroindole 6 in a 79% yield and
functionalization of the aldehyde via a Wittig reaction gave rise
to 7 in 83% yield.
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