A Three-Component Enantioselective Cyclization Reaction Catalyzed by an Unnatural Amino Acid Derivative

Article abstract of DOI:10.1002/anie.201708952

A new diastereo- and enantioselective three-component cyclization reaction is described. The reaction takes place between a ketone, a carboxylic acid, and a nitroalkene to yield a bicyclic octahydro-2H-indol-2-one scaffold possessing three chiral centers. This reaction involves a rearrangement of the nitro group under simple thermal conditions. A plausible mechanism is proposed for this new reaction based on DFT calculations and isotope-labeling experiments. A new concise enantioselective synthesis of the alkaloid (+)-pancracine is presented as an example of the potential of this novel organocatalytic cyclization reaction in the synthesis of natural products.

Full text of DOI:10.1002/anie.201708952

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Accepted Article
Title: New Three-Component Enantioselective Cyclization Reaction
Catalyzed by an Unnatural Amino Acid Derivative
Authors: Fernando P. Cossío, Andrea Ruiz-Olalla, Maria de Gracia
Retamosa, Abel de Cózar, and Tamara Bello
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708952
Angew. Chem. 10.1002/ange.201708952
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Angewandte Chemie International Edition
10.1002/anie.201708952
COMMUNICATION
New Three-Component Enantioselective Cyclization Reaction
Catalyzed by an Unnatural Amino Acid Derivative
[
a]
[a]
[a]
[a,b]
María de Gracia Retamosa, Andrea Ruiz-Olalla, Tamara Bello, Abel de Cózar,
and Fernando
[
a]
P. Cossío*
Abstract: A new three-component diastereo- and enantioselective
cyclization reaction is described. The reaction takes place between a
ketone, a carboxylic acid and a nitroalkene to yield a bicyclic
octahydro-2H-indol-2-one scaffold possessing three chiral centers.
This reaction involves a rearrangement of the nitro group under
simple thermal conditions. A plausible mechanism is proposed for
this new reaction based on DFT calculations and isotope labeling
experiments. A new concise enantioselective synthesis of alkaloid
O2N
Ph
Ph
R1
N
H
CO2Me
NO2
O
OH
O
R1
O
X (n mol %)
N
L
+
+
O
X
HO
O
45 ºC., 24-100 h
R2
X
H
H
R2
1
2
3
4
2
1
2
(
+)-pancracine is presented as an example of the potential of this
1a: X=CH2
3a: R =Ph
4a: X=CH2; R =R =Ph
4b: X=O; R =R =Ph
2
1
1
1
1
1
b: X=O
c: X=S
d: X=O
3b: R =4-Me-C H
6
4
novel organocatalytic cyclization reaction in the synthesis of natural
products.
2
1
1
3
3
3
c: R =4-MeO-C H 4c: X=S; R =R =Ph
6
4
2
1
2
d: R =4-F-C H
4d: X= O
; R =R =Ph
C
6
4
C
O
2
e: R =2-thienyl
O
1
1
2
Natural amino acids and some conveniently functionalized
derivatives behave as minimalistic analogues of enzymes.
2a: R =Ph
2
4e: X=CH2: R =n-Pr; R =Ph
1
1
2
b: R =n-Pr
4f: X=CH ; R =4-MeO-C H ; R =Ph
2 6 4
1
1
2
[
1]
2c: R =4-MeO-C6H4
4g: X=CH2; R =4-F-C6H4; R =Ph
These so-called organocatalysts promote well-known chemical
transformations such as aldol and conjugate addition reactions,
as well as cycloadditions and domino multicomponent reactions
leading to cyclic or polycyclic compounds. However, the
question whether small amino acid derivatives can lead to the
discovery of novel chemical reactions remains open.
1
1
2
2
2
d: R =4-F-C H
4h: X=CH ; R =4-NO -C H ; R =Ph
2 2 6 4
6
4
1
1
2
e: R =4-NO -C H
4i: X=CH ; R =(CH ) NHBoc; R =Ph
2
6
4
2
2 5
2
1
1
2f: R =(CH ) NHBoc
4j: X=CH ; R =Ph; R =4-Me-C H
2
5
2
6
4
1
2
4k: X=CH2; R =Ph; R =4-MeO-C6H4
1
2
4
4
l: X=CH ; R =Ph; R =4-F-C H
2 6 4
1
2
m: X=CH ; R =Ph; R =2-thienyl
2
Conjugate
(Michael)
addition
between
carbonyl
compounds and nitroalkenes takes place efficiently to yield γ-
[
2]
[3]
nitrocarbonyl compounds.
Previous careful studies
have
4a
4i
shown that the nitro group participates in the catalytic cycle and
in many domino/cascade multicomponent reactions leading to
[
4]
polycyclic systems. However, these domino reactions can be
[
6]
reduced to consecutive known transformations .
Scheme 1. Synthesis of γ−lactams 4a-m via three-component
reaction between ketones 1a-d, carboxylic acids 2a-f and
L
nitroalkenes 3a-e catalyzed by densely substituted proline X .
The structures of 4a and 4i (X-ray diffraction analysis, 50%
probability ellipsoids) are also given.
Previous work in our group has described the synthesis of
[
7]
unnatural densely substituted proline esters
Scheme 1). We have found that these unnatural amino esters
such as XL
(
[
8]
are efficient catalysts for the aldol reaction. Furthermore, their
amino derivatives constitute suitable organocatalysts for the
[a]
Dr. M. de G. Retamosa, Dr. A. Ruiz-Olalla, Dr. T. Bello, Dr. A. de
Cózar, Prof.Dr. F. P. Cossío
[
9]
conjugate addition between ketones and nitroalkenes.
In
Departamento de Química Orgánica I and Centro de Innovación en
Química Avanzada (ORFEO-CINQA), University of the Basque
Country (UPV/EHU) and Donostia International Physics Center
contrast, nitro derivative X was found to be inefficient in the
L
catalysis of this latter reaction. Analysis of the crude reaction
mixtures obtained in the presence of a catalytic amount of acid
(
DIPC)
additive showed the formation of
a minor product that
Pº Manuel Lardizabal 3, 20018 Donostia/San Sebastián, Spain
E-mail: fp.cossio@ehu.es
Dr. A. de Cózar
incorporated the carboxylic acid used to promote the reaction.
Therefore, we repeated the reaction in the presence of an
[b]
Ikerbasque, Basque Foundation for Science
E-48011 Bilbao, Spain
equimolar quantity of the three components, namely
1
cyclohexanone 1a (X = CH
2
, Scheme 1), benzoic acid 2a (R =
Supporting information for this article is given via a link at the end of
the document.
2
phenyl) and (E)-nitrostyrene 3a (R = phenyl). After one day of
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Angewandte Chemie International Edition
10.1002/anie.201708952
COMMUNICATION
reaction at 45ºC in the presence of 20% catalytic loading we
obtained cycloadduct 4a (Scheme 1, Table 1) with excellent
yield and enantiomeric excess. The catalytic loading could be
lowered to 10 mol % but the reaction required 60 h to achieve a
similar chemical yield. Cycloadduct 4a was stable under these
thermal conditions. However, stronger acidic (TFA, 10 eq., 72h)
or basic (TEA, 10 eq. 72h) conditions resulted in decomposition
7
8
20
20
24
24
1a 2c 3a 4f
1a 2d 3a 4g
86
81
97
96
[g]
9
20
20
20
20
20
20
24
36
24
24
24
24
1a 2e 3a 4h
78
58
65
76
86
67
97
96
95
98
96
96
[
d]
10
1a 2e 3a 4i
[
10]
of the reaction product. X-ray diffraction analysis
cycloadduct 4a showed an unexpected bicyclic structure
Scheme 1) in which three new chiral centers were generated in
of
1
1
1
1
1
2
3
4
1a 2a 3b 4j
1a 2a 3c 4k
1a 2a 3d 4l
1a 2a 3e 4m
1
(
one single preparative step with virtually complete diastereo-
and enantiocontrol. We also tested this protocol in the presence
of organocatalysts for which the usual Michael addition reaction
[
9,11]
[11a]
has been reported,
such as L-proline,
an O-silylprolinol derivative
amino derivative of X
,
a
[11c]
cinchona
and the
[
11b]
alkaloid derivative,
[
a] Reactions were monitored by TLC or H-NMR until consumption of the
[
9]
L
. In all these cases, reaction with
starting acid and nitroalkene (conversion
≥ 99 %). [b] See Scheme 1 for
stoichiometric amounts of acid did not yield 4a, with the only
exception of the latter case, in which a mixture of 4a and the
Michael adduct 5a (vide infra) was obtained in a 33:67 ratio, with
an isolated yield of only 20% for 4a. Therefore, the steric and
the substitution patterns of reactants and products. [c] Yields of isolated
pure products [d] Enantiomeric excesses (ee, in %) were determined by
high-performance liquid chromatography (HPLC) using chiral stationary
phases (see the Supporting Information). [e] Only 60 % conversion was
observed under these conditions. [f] Reaction carried out in
dichloromethane as solvent and with 4 eq. of ketone. [g] A small amount of
Michael adduct was detected (See the Supporting Information).
L
electronic features of X are especially adequate for this novel
reaction (see the Supporting Information).
When we repeated the reaction between 1a, 2a and 3a in
the absence of visible light or in the presence of radical traps,
the reaction proceed normally, thus allowing us to discard
photocatalytic processes and the presence of radical or biradical
The reaction also worked with other ketones such as 1b-d.
Similarly, the new reaction was found to be compatible with
aromatic and alkyl acids, although in the case of 2b another
isomer was observed (see the Supporting Information). The
structure of the adduct 4i formed from δ−amino acid 2f was also
[
9]
intermediates. In addition, when the previously reported
Michael cycloadduct 5a was allowed to react in the presence of
a and X , no noticeable formation of 4a was observed.
Likewise, when the N-methylated derivative of X
[
10]
confirmed by X-ray diffraction analysis . 4-Nitrobenzoic acid 2e
was satisfactorily incorporated into adduct 4h (Table 1, entry 9),
but a small amount of the Michael product 5a was observed.
However, when TFA was used, no adduct 4 was formed and
only 5a was observed, with a conversion of 43 % after 24 h of
reaction:
2
L
[
9]
L
was tested,
no reaction took place, thus demonstrating that the NH moiety
leading to the enamine intermediate is required for this reaction.
L
In addition, catalyst X was recovered intact after completion of
the reaction, thus proving that the nitro group of the catalyst
survives along the catalytic cycles.
O
Ph
NO2
XL (20 mol%)
1
a + TFA + 3a
After analyzing different possible routes, including (2+4)
mechanisms, the catalytic cycle shown in Figure 1A emerged as
the most plausible proposal. First, ketone 1 forms the enamine
intermediate INT1, which leads to protonated nitronate INT2
after reaction with nitroalkene 3, whose electrophilicity is
enhanced by protonation in the presence of acid 2 (see the
Supporting Information). Transition structure TS1 shows an
efficient chiral discrimination induced by XL and the assistance
of the nitro group present in the organocatalyst, thus leading to a
quite rigid saddle point, in which the conformation of the
enamine moiety is restricted and addition on one of the prochiral
faces of the nitroalkene is favored (Figure 1B). This
stereocontrol results in a computed enantiomeric ratio of 90:10,
in qualitative agreement with the experimentally observed ee
value (see entry 3 of Table 1 and the Supporting Information).
Acid 2 adds to protonated nitronate INT2 to form acyl derivative
INT3 via saddle point TS2 (Figure 1C). The calculated activation
neat, 45 ºC, 24h
5
a
Therefore, we concluded that, beyond a certain acidity of
reactant 2, the standard conjugate addition competes with the
novel reaction.
Table 1.Three-component cyclization reaction between ketones 1a-d,
carboxilic acids 2a-e and nitroalkenes 3a-d catalyzed by unnatural amino
L
ester X .
[
a]
[b]
[c]
[d]
Entry
Time
(h)
1+2+3->4
Yield
(%)
ee
X
L
mol %
(%)
1
2
3
4
5
6
20
10
20
20
20
20
24
60
100
24
48
24
1a 2a 3a 4a
1a 2a 3a 4a
1b 2a 3a 4b
1c 2a 3a 4c
1d 2a 3a 4d
1a 2b 3a 4e
91
88
97
97
95
97
95
96
[
[
[
e]
f]
56
71
62
38
[
12]
barrier associated with this step is ca. 23 kcal/mol.
elimination and subsequent tautomerization
Water
lead to
f]
intermediates INT4 and INT4’. This latter zwitterionic
intermediate generates the amide moiety of INT5 via transition
structure TS3, with activation energy of ca. 17 kcal/mol.
According to this mechanism, the relatively long reaction times
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Angewandte Chemie International Edition
10.1002/anie.201708952
COMMUNICATION
[
13]
required to complete the catalytic cycle at 45 ºC are associated
(trichloromethyl)benzene 6 (Scheme 2). This labeled acid was
allowed to react with 1a and 3a in the presence of X to yield
]4a. The high-resolution mass spectrum (HR-MS) of
with INT2→INT3 and, into
a
lesser extent, INT4→INT5
L
1
6
18
elementary steps, since from this latter intermediate the
formation of the γ-lactam ring requires an activation energy of
only 8.6 kcal/mol. Finally, from INT6 the catalyst is released and
compound 4 is formed via hydration of cation INT7 (Figure 1A).
Numerical simulations of the kinetic equations resulting from the
catalytic cycle gathered in Figure 1A showed that these
activation energies result in reaction times of ca. 48 h for ca.
[ O
this latter compound showed a (M+1) signal associated with the
2 2
, O
+
1
8
presence of two O atoms (Scheme 2).
1
8
Cl
Cl
Cl
18
O
OH2
Ph
Ph
microwaves, 100 W,
bar, 140 ºC, 30 min.
(93 %)
18O H
6
9
5 % conversion of 1b, 2a and 3a into INT7b, in qualitative
[18O ]2a
2
6
agreement with the observed reaction time.
O N
2
Ph
A
3a (0.9 eq.)
a
d
(91 %)
O
N
-
H2O
XL (20 mol %)
1a (8.0 eq.)
45 ºC, 24 h
N
N
O
H
XL
R
O
Ar
O
3
X-ray
O
X
INT1
TS1
O
18
H+
O
N
N
*
*
Ar
R
O
1
ΔG298‡ = 2.7 kcal/mol
O
b
H
HO
*
H
N
a
Ph
INT6
O
X
N
a
O
18
O
H2, Pd-C
18
X
c
O
O
N
TS4
MeOH, 50 ºC,
30 bar, 1 mL/min
(76 %)
*
N
N
d
d
ΔG298‡ = 8.6 kcal/mol
Ar
OH
*
*
Ph
Ph
INT7
*
R
R
O
Ar
X
[18O]7 (M+1) =218.1431
+
O
INT2
[16O , O ]4a (M+1) =338.1533
18
+
X
2
2
+
HN
O
HO
2
+
N
X
7 (M+1) =216.1396
4a (M+1) =334.1449
O
H O
-H+
2
*
R
O
INT5
*
Ar
O
TS2
ΔG298‡ = 22.9 kcal/mol
16
18
18
O
TS3
2 2
Scheme 2. Synthesis of isotope labelled compounds [ O , O ]4a and [ O]7
ΔG298‡ = 17.3 kcal/mol
N
18
+
HO
*
R
O
O
from acid [
spectrometry (HR-MS) for [
The structure and absolute configuration of 7, as determined by X-ray
O ]2a. The (M+1) molecular ion obtained by high-resolution mass
2
*
Ar
16 18 16 18
2 2 2 2
O , O ]4a, 4a, [ O , O ]7 and 7 are reported.
*
OH
OH
X
4
N
O
R
N
diffraction analysis (thermal ellipsoids of non-hydrogen atoms at 50
probability) are provided.
%
HN
*
N
X
O
*
Ar
INT3
O
*
R
X
*
Ar
INT4'
O
N
O
OH
13
16
18
N
X
2 2
The C-NMR spectrum of mixed 4a and [ O , O ]4a
2
-H O
*
18
18
showed that the two O atoms of [ O
2
]2a were incorporated
*
Ar
into the carboxy and the amide groups (Figure 2). In both cases
INT4
2
a
13
18
the frequencies of the C= O resonances decrease slightly with
1
.12
13
16
B
C
respect to the corresponding C= O signals, with an observed
1
.82
1
.32
2
.00
13
18
[14]
Δδ( C= O) value of ca. –0.03 ppm As a control signal we
3
a
1.90
2
.31
compared these changes in chemical shifts with the invariance
3
a
1
b
of the signal corresponding to
C
c
(Scheme 2, Figure 2).
]4a and 4a yielded compounds
O]7 and 7, respectively (Scheme 2). The structure of this latter
1
8
16
2 2
Hydrogenolysis of [ O , O
1
b
1
8
[
TS1b
XL
TS2b
XL
[10]
compound was confirmed by X-ray diffraction analysis
+
18
(
Scheme 2). Also in this case, the (M+1) MS peak of [ O]7 was
two units higher than that measured for 7. This result agrees
Figure 1. (A) Proposed catalytic cycle for the new reaction described in
13
with the C-NMR spectra of both compounds, with a similar
Scheme 2. Free activation energies calculated for the key steps of the
1
3
18
13
18
13
16
Δδ( C= O )value for the C= O and C= O peaks, whereas
the resonance associated with the C carbon atom was the
same in both compounds (Scheme 2, Figure 2). Therefore, one
1
b+2a+3a
→
4b
reaction,
computed
at
the
B3LYP-
D3(PCM=cyclohexanone)/6-311+G*//B3LYP-D3/6-31G(d) level of theory, are
also given. See the Supporting Information for additional details. (B, C)
Optimized structures for TS1b (B) and TS2b (C). Bond distances are given in
d
18
18
2
of the O atoms of [ O ]2a is present in the carboxamide group
L
Å. Carbon atoms of X , 1b, 3a and 2a are highlighted in gray, orange, light
of the γ-lactam, thus confirming the prediction made on the basis
blue and green, respectively.
of the proposed computational mechanism.
According to this mechanistic proposal, the oxygen atom of
the amide bond present in adduct 4 stems from the acid 2 and
not from the nitro group of electrophile 3. To test this prediction
1
8
18
2 2
we synthesized doubly labeled acid [ O ]2a from OH and
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Angewandte Chemie International Edition
10.1002/anie.201708952
COMMUNICATION
Ph
O
NO2
OH
O
O
N
A
XL (30 mol %), 2a
O
+
O
O
PhCH , 45 ºC, 3 days
3
H
O
(64 %, ee=99 %)
O
H
13C=18
O
c
13C=16
13C=18
13C=16
O
O
O
1
d
3f
4n
H2 (40 bar), Pd/C,
O
O
O
O
MeOH, 1,4-dioxane, (72 %)
1mL/min, 50 ºC
a
b
H H
N
H H
LiAlH , reflux,
overnight
a + [16O , O ]4a
18
4
4
N
2
2
O
O
O
(>95 %)
H
H
O
H
a
O
H
b
1
70
168
166
164
δ (13C) / ppm
92
90
88
O
8
O
9
O
O
H C=O (37 %), MeOH
Et N, room temp., 15 min.
3
B
d
2
H
H
H
H
HCl, MeOH,
room temp., 10 h
N
N
13C=16
O
13C=18
a
O
O
a
(58 %, two steps)
O
O
O
O
b
1
0
O
11
DDQ, 1,4-dioxane
microwaves (150 W), (62 %)
O
+ [18O]7
7
1
25 ºC, 10 min.
H
H
trwo steps
ref. 17)
N
HO
HO
N
(
1
80
176
172
168
164
144
140
136
δ (13C) / ppm
O
O
O
O
+)-Pancracine
O
(
1
3
16
18
13
12
Figure 2. (A) C NMR spectrum of a mixture of [
O
2
,
O
2
]4a and 4a. (B)
C
1
8
NMR spectrum of a mixture of [ O]7 and 7. Invariant resonances c and d are
Scheme 3. Synthesis of (+)-pancracine from three-component reaction
included as internal references.
catalyzed by unnatural amino ester X . Numbers in parentheses correspond to
L
chemical yields of isolated pure products.
[
15]
We selected alkaloid pancracine as a suitable example of
the applicability of this novel reaction to the synthesis of
polycyclic chiral natural compounds. Our synthesis started with
the three-component reaction between ketone 1d, nitroalkene 3f
In summary, in this work we describe a three-component
reaction that yields N-acyloxy 7a-hydroxyoctahydro-2H-indol-2-
ones possessing three chiral centers and we demonstrate the
potential of this reaction in synthetic chemistry. We anticipate
that unnatural readily available amino acids and their oligomers
can lead to the discovery of new catalytic stereocontrolled
chemical transformations.
(
Scheme 3) and benzoic acid 2a. In the presence of 30 mol% of
, these reactants yielded chiral γ-lactam 4n in 64% yield and
X
L
with complete diastereo- and enatiocontrol (Scheme 3).
Hydrogenolysis of this latter compound yielded compound 8 in
7
2% yield, together with small amounts of two diastereomers
8
a,b (4% and 2%, respectively) and a racemic α,β-unsaturated
γ-lactam 8c (4%, see the Supporting Information). The Acknowledgements
structures of 8a-c were confirmed by X-ray diffraction
[
10]
analysis
. Intermediate 8 was reduced to pyrrolidine 9 in
Financial support for this work was provided by the Spanish
MINECO (CTQ2016-80375-P and CTQ2016-81797-REDC) and
the Gobierno Vasco/Eusko Jaurlaritza (GV/EJ, Grant IT673-13).
A.R.-O. thanks the MINECO for her Ph.D. grant. M.d.G.R and
T.B. thank the DIPC and UPV/EHU for their respective
postdoctoral contracts.
quantitative yield. This latter compound reacted with
formaldehyde to form the 1-azabicyclo[3.2.1]octane scaffold of
(
+)-pancracine. In situ deprotection of the dioxolane moiety and
[
16]
oxidation of compound 11 yielded late precursor
12, from
which (+)-pancracine can be obtained according to the
[
17]
procedure described by Overman et al.
Thus, our novel
reaction reduced the synthetic route to 7 steps and permits a
concise synthesis of the unnatural (+)-enantiomer.
Conflicts of interest
The authors declare no conflict of interest.
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Angewandte Chemie International Edition
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COMMUNICATION
[
[
9]
A. Ruiz-Olalla, M. de G. Retamosa, F. P. Cossío, J. Org. Chem. 2015,
Keywords: multicomponent reactions • DFT calculations •
8
0, 5588-5599.
10] CCDC 1451831 (4a), 1451832 (4i), 1451834 (7), 1451835 (8a),
451836 (8b) and 1451837 (8c) contain the supplementary
asymmetric catalysis • organocatalysis • synthetic methods
1
[
1]
a) B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000, 122,
395-2396; b) K. Sakthivel, W. Notz, T. Bui, C. F. Barbas III,J. Am.
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
2
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Angewandte Chemie International Edition
10.1002/anie.201708952
COMMUNICATION
Entry for the Table of Contents
Layout 2:
COMMUNICATION
Dr. M. de G. Retamosa, Dr. A. Ruiz-
Olalla, Dr. T. Bello, Dr. A. de Cózar and
Prof. Dr. F. P. Cossío*
Page No. – Page No.
New Three-Component
Enantioselective Cyclization Reaction
Catalyzed by an Unnatural Amino
Acid Derivative
Text for Table of Contents
Brand new cycle. Unnatural densely substituted proline ester X
L
catalyzes the formation of bicyclic γ−lactams possessing three new
chiral centers. This new reaction has no equivalent in organocatalytic, enzymatic or organometallic chemistry and can be used in the
synthesis of complex natural products.
This article is protected by copyright. All rights reserved.