Ion-pairing catalysis in the enantioselective addition of hydrazones to N-acyldihydropyrrole derivatives

Article abstract of DOI:10.1039/c8cc05311a

We have demonstrated that dihydropyrrole-based enamide derivatives can act as efficient precursors of chiral quaternary N-acyliminium salts under Br?nsted acid catalysis that undergo reactions with hydrazones, the latter participating as masked nucleophilic carbonyl group equivalents. The optimized methodology provides a variety of enantiopure α-substituted proline derivatives in excellent yields, being even compatible with disubstituted β-enamides that generate two contiguous stereocentres.

Full text of DOI:10.1039/c8cc05311a

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Ion-Pairing Catalysis in the Enantioselective Addition of
Hydrazones to N-Acyldihydropyrrole Derivatives
Nagore Zabaleta, a Uxue Uria,*a Efraim Reyes, a Luisa Carrillo a and Jose L. Vicario *a
+Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We have demonstrated that dihydropyrrole-based enamide generation of the starting enamide through condensation from
derivatives can act as efficient precursors of chiral quaternary N- the corresponding precursors5 or using allenamides as starting
acyliminium salts under Brønsted acid catalysis that undergo materials6 (Scheme 1).
reaction with hydrazones, the latter participating as masked
Previous work
nucleophilic carbonyl group equivalents. The optimized
O
R2
methodology provides a variety of enantiopure α-substituted
proline derivatives in excellent yields, being even compatible with
disubstituted β-enamides that generate two contiguous
stereocentres.
N
R3
O
O
O
O
O
O
O
O
∗
R1
X
P
∗
O
P
R2
OH
(cat.)
O
O
N
R3
R1 Nu
Nu
R2
+ HN
R3
R3
R1
N
H
R2
Asymmetric counteranion-directed catalysis has emerged as a
new strategy to achieve stereocontrol in organic reactions.1
This approach relies on the generation of a cationic reactive
intermediate that remains closely bounded to the
enantiomerically pure anionic catalyst through contact ion-
pair, that allows transfer of stereochemical information to the
new stereogenic centres. In this context, BINOL-based chiral
phosphoric acids and related derivatives have demonstrated
their proficiency as a privileged family of catalysts.2 These
strong Brønsted acids are able to promote the formation of an
activated cationic intermediate from the starting material
through protonation/elimination and, in this sense, a variety of
reactions have been reported under this type of catalytic
activation, being N-acyliminium ion chemistry particularly
suited for the application of this concept.3 In fact, several
reports exist in which enantioselective 1,2-addition reactions
to N-acyliminium ions have been carried out catalysed by a
chiral phosphoric acid or derivative, in all cases relying on the
use of hemiaminals or related substrates as starting materials.4
Alternatively, quaternary N-acyliminium ions have been
generated under chiral Bronsted acid-catalysis via the in situ
R1
One stereocenter
can be formed
O
Counteranion-directed
catalysis
•
N
R3
R2
This work
∗
O
O
O
P
∗
O
O
O
Hydrazone
as umpoled
OH
O
P
O
N
R2
R3
R2
(cat.)
O
O
N
C-Nucleophile
N
R2
protonation
R3
N
R1
N
N
(enantioselective
when R1
N
R1
N
R1
≠ H)
Enamide
(nucleophilic)
R3
N
Two stereocenters
can be formed
N-Acyliminium ion
(electrophilic)
Scheme 1 Methods for the generation of quaternary N-acyliminium ions in reactions
under counterion-directed catalysis and the enantioselective addition of hydrazones to
enamides reported in this work.
In this report we wish to present the use of N-
acyldihydropyrrole derivatives as precursors of quaternary N-
acyliminium ion electrophiles through activation with a BINOL-
based chiral phosphoric acid catalyst and their subsequent
reaction with donor-acceptor hydrazones as umpoled
nucleophiles.7 This implies the reversal of the natural
nucleophilic reactivity of the starting enamide substrate in the
presence of the Brønsted acid catalyst8 and also involves
inversion of the natural polarity of the hydrazone moiety from
its natural electrophilic behavior to the less conventional
character as an acyl anion equivalent (Scheme 1). In addition,
there are only two examples where hydrazones have been
employed as umpoled reagents undergoing addition to an
imine under chiral phosphoric acid catalysis but in both cases
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the reaction involves activation of the azomethine electrophile We next evaluated the role played by the N-protecting group
via H-bonding (or protonation).9
at the dihydropyrrole derivative, observing that other
We started using hydrazone 1a as a model system due to its carbamate substituents like Fmoc could be successfully used in
proven ability to act as glyoxyl anion equivalent in previous combination with hydrazone 1c (entry 7). However, the use of
research.7c In
a series of preliminary experiments, this N-phenyldihydropyrrole 2c led to the formation of a complex
hydrazone was reacted with N-Boc dihydropyrrole 2a, which mixture of unknown products (entry 8). Remarkably,
serves as aliphatic N-acyliminium ion precursor, in the dihydropyrroles 2d and 2e reacted efficiently in terms of both
presence of a catalytic amount of different chiral phosphoric yield and enantiocontrol (entries 9 and 10). These results were
acids (see Supporting Information for details). In all cases, the interpreted in terms of the beneficial effect of this acidic NH
formation of product 4a in moderate to good yields and with a moiety which can engage in additional H-bonding interactions
variable e.e. was observed. From all these preliminary with the phosphoryl moiety of the phosphate counteranion, In
experiments, TRIP phosphoric acid 3a was identified as the fact, dihydropyrrole 2e with a more acidic NH group performs
best catalyst in terms of enantiocontrol, working in toluene at - better than 2d with respect to enantiocontrol, being possible
5°C and in the presence of 4
Å
MS as water scavenger (entry 1 to reduce the catalyst loading to 1 mol%10 or to carry out the
in Table 1). The enantioselectivity could be improved by reaction at higher scale.11 Moreover, 2e also performed well in
modifying the N-substituent of the hydrazone to the more the reaction with hydrazones 1a and 1e, in both cases
donating 4-MeSC6H4 at the expense of a lower yield (entry 2 vs affording the desired products with excellent e.e. (entries 11
1) while the simpler N-phenyl hydrazone 1c performed and 12).
efficiently (entry 4). Remarkably, when hydrazone 1d Subsequently, the scope of the reaction towards the use of
containing an electron-withdrawing substituent at this position hydrazones with different substituents at the azomethine
was tested, the starting material was recovered (entry 5). This position was evaluated (Table 2). In general, the reaction
is pointing towards the necessity of an electron-donating performed excellently when strongly electron-withdrawing
substituent at this position of the hydrazone to become substituents such as alkoxycarbonyl, acetyl or CF3 were
reactive as C-nucleophile. In this sense, N-tert-butyl incorporated (entries 1-3). Remarkably, the simple
substituted hydrazone 1e was also found to be reactive, benzaldehyde-derived hydrazone 1i, which had been found to
although providing a lower e.e. (entry 6).
be unreactive as C-nucleophile in other literature examples,
was also found to undergo smooth reaction with 2e, furnishing
adduct 4o in high yield and enantioselectivity (entry 4).
Table 1 Role of the N-substituents at the hydrazone and enamide reagents.a
Ar
Table 2 Scope of the reaction.a
Ar=2,4,6-(iPr)3C6H2
O
O
O
P
OH
NHR1
R2
N
R2
N
N
NHR1
H
Ar
N
3a
(10 mol%)
CO2Et
+
4Å MS, Toluene, -5ºC
EtO2C
1a-e
2a-e
R1
4a-k
Entry
1d
2d
3d
4
R
Prod.
4l
Yield (%)b
87
e.e. (%)c
>99
98
Entry Prod.
R2
Yield (%)c e.e. (%)d
i
CO2 Pr (1f)
1a
2a
3a
4b
5a
6a
7b,e
8b
4a
4b
4c
4c
4d
4e
4f
4-MeOC6H4 (1a)
4-MeSC6H4 (1b)
Ph (1c)
Boc (2a)
60
53
63
96
<5
87
93
<5
95
98
85
80
86
92
90
93
<5
72
92
<5
92
>99
98
91
Ac (1g)
4m
4n
4o
4p
4q
4r
87
Boc (2a)
CF3 (1h)
73
99
Boc (2a)
Ph (1i)
94
90
Ph (1c)
Boc (2a)
5
C6F5 (1j)
78
97
4-NO2C6H4 (1d)
tBu (1e)
Boc (2a)
6
4-CNC6H4 (1k)
4-CF3C6H4 (1l)
4-(MeO2C)C6H4 (1m)
4-BrC6H4 (1n)
4-ClC6H4 (1o)
4-FC6H4 (1p)
3-FC6H4 (1q)
2-FC6H4 (1r)
4-MeC6H4 (1s)
4-MeOC6H4 (1t)
90
88
Boc (2a)
7
90
86
Ph (1c)
Fmoc (2b)
Ph (2c)
8
4s
65
83
4g
4h
4i
Ph (1c)
9
4t
79
92
9b
Ph (1c)
C(S)NHBn (2d)
C(S)NHArf (2e)
C(S)NHArf (2e)
C(S)NHArf (2e)
10
11
12
13
14
15
4u
4v
4w
4x
4y
4z
82
90
10b
11b
12b
Ph (1c)
95
94
4j
4-MeOC6H4 (1a)
tBu (1e)
80
84
4k
94
82
a
b
83
91
Reaction carried out in a 0.13 mmol scale of 2, 1.2 eq. of 1. Reaction carried
out in a 0.09 mmol scale of 1, 1.5 eq. of 2 and 10 mol% of 3a in 0.18 mL of
60
83
c
toluene. Yield of pure product after flash column chromatography. Hydrazones
a Reaction carried out in a 0.09 mmol scale of 1, 1.5 eq. of 2e and 10 mol% of 3a
in 0.18 mL of toluene. b Yield of pure product after flash column chromatography.
Hydrazones 4l-z were isolated as thermodynamic mixtures of Z/E
diastereoisomers (see Supporting Information). c Determined by HPLC analysis on
4h-j were isolated as thermodynamic mixtures of Z/E diastereoisomers in ratios
d
varying from 5:1 to 6.7:1. Determined by HPLC analysis on a chiral stationary
phase (see Supporting Information). e The reaction was carried out at 10ºC. Ar:
f
3,5-(CF3)2C6H3.
d
a chiral stationary phase (see Supporting Information). 5 mol% of 3a was
employed.
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Other hydrazones with aryl substituents that incorporate we observed a considerable erosion of the enantiomeric
electron-withdrawing groups performed excellently (entries 5- excess of the adducts or recovered starting materials because
11), regardless the position of this substituent at the aryl of poor configurational stability.
moiety (entries 11-13). More interestingly, the less reactive
hydrazones 1s and 1t provided the corresponding adducts in
high yields and e.e. The absolute stereostructure of the
cycloadducts obtained by this protocol was established by
single-crystal X-ray analysis of enantiopure samples of
compound 4m 12
.
In addition, we also evaluated the possibility of using 3-
substituted dihydropyrroles as potential N-acyliminium ion
precursors that would result in the formation of two
contiguous stereocentres (Scheme 2). Remarkably, enamides
5a and 5b provided adducts 6a and 6b respectively in good
yields and moderate d.r., being the cis-diastereoisomers the
major one. This is indicating that phosphoric acid catalyst 3a is
Scheme 3 Synthesis of PEP inhibitor analogues.
promoting a highly enantioselective
β-protonation of the
enamide moiety, which is followed by the addition of the
hydrazone to the formed acyliminium cation, presumably
under catalyst control, in view of the cis relative arrangement
that implies the reaction of the hydrazone through the most
hindered face of the acyl iminium intermediate. We also
verified the excellent performance of the more sterically
Finally, we surveyed different chemical manipulations of the
thiourea moiety present in adducts
4 in order to illustrate the
synthetic applicability of the reaction (Scheme 4). For example,
the oxidation of the hydrazone moiety together with the
intramolecular S-addition of the thiourea could be carried out
by the use of PIFA providing bicyclic adducts 9a-b in good
yields, as a single diastereoisomer and without erosion of the
enantiopurity of the starting material. Moreover, compound
9a could be easily decarboxylated under mild basic conditions
leading to the formation of 10 in very good yield. Furthermore,
closely related enantioenriched bicyclic compound 12 could be
obtained in good yields if compound 4o is methylated prior to
the oxidative process employing NBS.
hindered substrate 5c
.
Scheme 2 Reaction using substituted dihydropyrroles.
Having succeeded in the development of a general method for
the addition of hydrazones to dihydropyrrole derivatives, its
synthetic potential as a tool in synthesis was demonstrated by
preparing the scaffold of anti-amnesic pyrrolidine derivatives
which inhibit or decrease the enzymatic activity of prolyl
endopeptidase.13 For this propose, we set up an effective
procedure to transform the hydrazone moiety of glyoxylate
Scheme 4 Chemical manipulation of adducts 4.
In conclusion, we have demonstrated that previously prepared
dihydropyrrole derivatives are efficient substrates to generate
chiral cuaternary N-acyliminium salt intermediates in the
hydrazones
corresponding ketones (Scheme 3). Firstly bicyclic
intermediate was quantitatively formed under basic
(1a, 1c and 1e) derived adducts to the
presence of a strong chiral Br
reaction with N-monosubstituted hydrazones 1a-t provide a
wide range of enantiopure -hydrazono proline derivatives in
excellent yields, being even possible to generate two
contiguous stereocentres starting from -disubstituted
ønsted acid catalyst. Their
7
α
conditions and next, [bis(trifluoroacetoxy)iodo]benzene (PIFA)
mediated oxidative hydrolysis provided the desired α-
β
ketoamide 8 14
These conditions were successfully employed
.
enamides. Moreover, an efficient protocol to cleavage the
glyoxylate derived hydrazone has been developed proving the
potential synthetic applicability of the present methodology.
on a set of representative compounds.15 We also attempted
the direct deprotection of the dihydropyrrole scaffold by
hydrolysis of the thiourea moiety on adduct 4j but in all cases
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6
7
For an enantioselective protonation of allenamides, see: (a)
E. Manoni, A. Gualandi, L. Mengozzi, M. Bandini and P. G
The authors thank the Spanish MINECO (FEDER-CTQ2017-
83633-P), the Basque Government (IT908-16) and UPV/EHU
(EHUA15/24 and fellowship to N. Z.) for financial support.
Cozzi,. RSC Adv., 2015,
addition reactions: (b) C. Romano, M. Jia, M. Monari, E.
Manoni and M. Bandini, Angew. Chem., Int. Ed., 2014, 53
13854; (c) T. Yang and F. D. Toste, Chem. Sci., 2016, , 2653.
5, 10546; For enantioselective 1,4-
,
7
Conflicts of interest
For a review on hydrazones as umpoled nucleophiles, see:
(a) R. Brehme, D. Enders, R. Fernández and J. M. Lassaletta,
Eur. J. Org. Chem. 2007, 5629; (b) M. G. Retamosa, E.
Matador, D. Monge, J. M. Lassaletta and R. Fernandez,
Chem. Eur. J., 2016, 22, 13430. For some selected examples
see: (c) M. Fernández, U. Uria, J. L. Vicario, E. Reyes and L.
Carrillo, J. Am. Chem. Soc., 2012, 134, 11872; (d) D. Monge,
S. Daza, P. Bernal, R. Fernández and J. M. Lassaletta, Org.
Biomol. Chem., 2013, 11, 326; (e) A. Crespo-Peña, D. Monge,
E. Martín-Zamora, E. Álvarez, R. Fernández and J. M.
Lassaletta, J. Am. Chem. Soc., 2012, 134, 12912; (f) T.
Hashimoto, H. Kimura and K. Maruoka, Tetrahedron:
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Zamora, R. Fernández and J. M. Lassaletta, Org. Lett., 2007,
There are no conflicts to declare.
Notes and references
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2
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8
The electrophilicity of enamides in the presence of chiral
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Information for details).
11 When the reaction was carried out with 0.4 mmol of
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12 CCDC 1841491-1841492 contains the supplementary
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