Enantioselective [4 + 2]-Annulation of Azlactones with Copper-Allenylidenes under Cooperative Catalysis: Synthesis of α-Quaternary α-Acylaminoamides

Article abstract of DOI:10.1021/acs.orglett.9b01103

The first enantioselective decarboxylative [4 + 2]-annulation of ethynyl benzoxazinanones with azlactones has been developed under cooperative copper and bifunctional tertiary aminourea catalysis. This direct and modular approach combines dipolar copper-a

Full text of DOI:10.1021/acs.orglett.9b01103

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective [4 + 2]-Annulation of Azlactones with Copper-
Allenylidenes under Cooperative Catalysis: Synthesis of
α‑Quaternary α‑Acylaminoamides
Amit Kumar Simlandy,⊥ Biki Ghosh,⊥ and Santanu Mukherjee*
Department of Organic Chemistry, Indian Institute of Science, Bangalore - 560012, India
S
* Supporting Information
ABSTRACT: The first enantioselective decarboxylative [4 +
2]-annulation of ethynyl benzoxazinanones with azlactones
has been developed under cooperative copper and bifunctional
tertiary aminourea catalysis. This direct and modular approach
combines dipolar copper-allenylidene intermediates with
azlactone enolates and allows for the synthesis of α-quaternary
α-acylaminoamides as a single diastereomer generally in high
yields with good to excellent enantioselectivities (up to 99:1
er).
derivatives (Scheme 1A).5 Despite this long-awaited break-
α-Amino acids and their derivatives, owing to their
omnipresence in molecules of biological importance, have
captivated the attention of synthetic organic chemists for
decades and led to the development of numerous strategies for
their synthesis.1 α-Acylaminoamides are one such class of
amino acid derivative which is present in a plethora of natural
products and bioactive targets (Figure 1A).2 Due to the
dependence of biological activities of such compounds on their
absolute configuration, enantioselective synthesis of α-
acylaminoamides is of paramount importance.3
through, the scope of carbonyl partner is restricted to
aldehydes and therefore cannot be applied to the enantiose-
lective synthesis of α-acylaminoamides bearing a quaternary
Scheme 1. Catalytic Enantioselective Approaches to α-
Acylaminoamides
The four-component Ugi reaction (Ugi-4CR) undeniably
provides the most straightforward and modular access to α-
acylaminoamide derivatives.4 The Tan group has very recently
developed a phosphoric acid catalyzed highly enantioselective
four-component Ugi reaction for assembling aldehyde, amine,
carboxylic acid, and isocyanide into α-acylaminoamide
Figure 1. (A) Bioactive molecules and (B) synthetic intermediate
having α-acylaminoamide moiety.
Received: March 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01103
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
stereogenic center (α-quaternary α-acylaminoamides).
Although they are found in several bioactive molecules and
often serve as a synthetic intermediate for proteasome
inhibitors such as omuralide (Figure 1B),6 a direct catalytic
enantioselective synthesis of α-quaternary α-acylaminoamides
is yet to be developed.
enantioselective C−C bond formation. The intermediate H,
thus formed, would undergo an annulation (lactamization)
reaction with concomitant opening of the azlactone ring to
produce cyclic α-acylaminoamide, bearing contiguous tertiary
and quaternary stereogenic centers (3).
To put our hypothesis into practice, the reaction between N-
tosyl ethynyl benzoxazinanone 1a and phenylalanine-derived
azlactone 2a was chosen for optimizing catalyst(s) and reaction
conditions (Table 1).13 When the reaction was carried out
with 10 mol % of a preformed copper complex derived from
We disclose herein a catalytic, modular, and highly
enantioselective approach to α-quaternary α-acylaminoamides.
Our strategy is based on the use of azlactone as the central
building block of α-quaternary α-acylaminoamides. Azlactones
(A), owing to their acidic α-proton, are known to react with a
wide variety of electrophiles through their enolate form to
generate α-quaternary azlactones (B) (Scheme 1A).7 Ring
opening of α-quaternary azlactones with amines can generate
α-quaternary α-acylaminoamides (C).8 Notwithstanding the
modularity of this two-step approach, we preferred a direct
access to α-quaternary α-acylaminoamides from azlactones. A
prerequisite to this approach is a reagent bearing both an
electrophilic carbon center and a nucleophilic nitrogen center.
We realized that tethering these two reactive ends in a single
entity in the form of a dipole (D) would prevent their internal
recombination and at the same time generate cyclic α-
quaternary α-acylaminoamides (E) (Scheme 1B).
Cu(OTf)2 and Ph-Pybox (L1) in the presence of Hunig’s base
̈
(25 mol %) in THF at −10 °C, the desired cyclic α-
a
Table 1. Optimization of the Reaction Conditions
While searching for the precursor of such a dipole, we
became interested in ethynyl benzoxazinanones, a reagent
introduced by Lu and Xiao in 20169 based on the initial
development of vinyl benzoxazinanones by Tunge et al.10
Ethynyl benzoxazinanones (1) under catalytic Cu(I) readily
decarboxylate to generate a 1,4-dipole containing electrophilic
Cu-allenylidene and a nucleophilic nitrogen center (F) under
mildly basic conditions (Scheme 2). Because of the covalent
Scheme 2. Catalytic Hypothesis of the Proposed [4 + 2]-
Annulation
b
c
Cu-salt
L
base
solvent
yield (%)
er
1
2
3
4
5
6
7
8
Cu(OTf)2
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
L4
L4
L4
L7
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
DBU
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
−
I
II
III
III
III
ent-III
III
THF
THF
THF
28
16
29
37
37
52
75
50
21
80
<2
20
<2
30
47
87:13
88:12
92:8
88:12
92:8
90:10
92:8
77:23
70:30
88:12
n.d.
11:89
n.d.
91:9
84:16
96:4
97:3
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12
13
14
15
16
17
18
19
20
d
75
d
90
e
e
e
d
CuI
CuI
CuI
99
d
97:3
71:29
67:33
78
attachment with copper, enantioselective addition of nucleo-
philes to Cu-allenylidenes is possible with the help of chiral
ligands (L*) on copper. Consequently, a number of
enantioselective annulation reactions involving ethynyl benzox-
azinanones have appeared during the past couple of years.11
Our catalytic hypothesis relied on the cooperative
combination12 of the copper and a Brønsted base catalyst
(Scheme 2). Reactive azlactone enolate G, whose generation
can be aided by a Brønsted base, was expected to attack the
electrophilic Cu-allenylidene end of F for a diastereo- and
40
a
Reactions were performed using 1.0 equiv of 1a and 1.2 equiv of 2a
on a 0.05 mmol scale. Diastereomeric ratio (dr) was found to be
b
1
>20:1 by H NMR analysis of the crude reaction mixture. Unless
stated otherwise, yields correspond to the NMR yield using
trimethoxy benzene as the standard. Enantiomeric ratio (er) as
c
determined by HPLC analysis using a stationary phase chiral column.
d
Yields correspond to the isolated yield after column chromatog-
e
raphy. Initial concentration 0.05 M. n.d. = not determined.
B
DOI: 10.1021/acs.orglett.9b01103
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
acylaminoamide 3aa was obtained as a single diastereomer
with promising enantioselectivity (87:13 er) albeit with only a
moderate yield (entry 1). A quick evaluation of copper
precatalysts identified inexpensive CuI as optimal in terms of
enantioselectivity (entry 3). Toluene proved to be a superior
solvent for this reaction, and 3aa was formed in slightly higher
yield maintaining the same level of enantioselectivity (entry 5).
The yield of the reaction was further increased to 75% without
compromising the er when triethylamine was used as the base
(entry 7). With the optimum base and solvent in hand,
combinations of CuI with other ligands (L2−L6) were
screened: Although the enantioselectivity of the reaction
could not be improved, the t-Bu-Pybox (L4)-CuI complex
furnished the product in 80% yield (entry 10). It must be
noted that the reaction failed to proceed in the absence of any
base under otherwise identical reaction conditions (entry 13).
While a Brønsted base is necessary for the generation of Cu-
allenylidene from 1a, its role in the enolization of azlactone
and subsequent bond formation steps cannot be under-
estimated.
Table 2. Substrate Scope
This speculation led us to explore the possibility of utilizing
enantiopure chiral amines as a Brønsted base with the objective
of obtaining the product with higher er. We were further
inspired by the recent work of Song et al.11d on the cooperative
combination of copper and bifunctional tertiary aminourea
derivatives.14 Accordingly, combinations of a number of such
bifunctional catalysts (I−III)15 with CuI-L1 were tested.
The initial experiments with bifunctional tertiary aminoureas
derived from Cinchona alkaloids (I and II) did not lead to
encouraging results (entries 14−15). However, the bifunc-
tional urea derived from (R,R)-1,2-diaminocyclohexane (Take-
moto urea, III)16 furnished the product in 75% isolated yield
with 96:4 er (entry 16). Considering the superior efficacy of L4
in promoting the reaction, the combination of CuI-L4 and III
was tested, which not only led to the isolation of 3aa in 90%
yield but also improved the enantioselectivity marginally (entry
17). Finally, lowering the initial concentration to 0.05 M
resulted in the formation of 3aa in near-quantitative yield with
97:3 er (entry 18). The significantly lower yield and er of 3aa
obtained for the reaction performed under the combination of
(S,S)-1,2-diaminocyclohexane-derived urea (ent-III) and CuI-
L4 (entry 19) clearly highlights the importance of identifying
the matched-catalyst combination for reactions under cooper-
ative catalysis. Interestingly, both these conditions (entries
18−19) resulted in the same enantiomer as the major product.
A control experiment with the combination of achiral Pybox
(L7)-CuI complex and III furnished the 3aa with 67:33 er in
favor of the same product enantiomer (entry 20). These
observations indicate that the ligand (Pybox) attached to
copper is the key stereocontrolling element in this reaction and
the bifunctional tertiary aminourea only reinforces the
enantioinduction offered by Cu-Pybox.
a
Yields correspond to the isolated yield after column chromatography.
1
Diastereomeric ratios (dr) were determined by H NMR analysis of
the crude reaction mixture. Enantiomeric ratio (er) as determined by
HPLC analysis using stationary phase chiral columns.
ities (Table 2A). Similar levels of yield and er were also
observed for ethynyl benzoxazinanones bearing other N-
protecting groups (Table 2B). Products with good enantiose-
lectivities were generally formed in the reactions between N-
tosyl ethynyl benzoxazinanone (1a) and azlactones derived
from other α-amino acids. These examples include substitution
on the aryl ring of phenylalanine (Table 2C) as well as α-
amino acids such as alanine, valine, leucine, and phenylglycine
(Table 2D). Only in the case of alanine-derived azlactone (2e),
the product (3ae) was formed with moderate er, and for
valine-derived azlactone (2f), the product (3af) was formed in
moderate yield. The applicability of our protocol for the
With the matched-catalyst combination identified and the
reaction conditions established (Table 1, entry 18), we turned
our attention to substantiate the suitability of our protocol for
other ethynyl benzoxazinanone and azlactone derivatives. As
detailed in Table 2, our protocol is suitable for both these
reaction partners bearing substituents at various positions (R,
PG, R1, and R2). For example, investigation of substituents on
the aromatic ring of N-tosyl ethynyl benzoxazinanone (1)
showed that both electron-donating and electron-withdrawing
groups at different positions were tolerated to give products
generally in high yields with good to excellent enantioselectiv-
C
DOI: 10.1021/acs.orglett.9b01103
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Organic Letters
Letter
synthesis of cyclic α-acylaminoamides containing electronically
contrasting N-acyl substituents was also tested (Table 2E).
While the p-methoxybenzoyl group was well tolerated, the N-
(p-trifluoromethylbenzoyl) product was formed with relatively
low enantioselectivity. Finally, reactions between leucine-
derived azlactone (2g) and substituted N-tosyl ethynyl
benzoxazinanones (1e and 1i) demonstrated the modular
nature of our protocol and its potential for the generation of a
library of cyclic α-acylaminoamides. It is worth mentioning
that, in all cases, the products were formed as a single
formation of 1,2,3-triazole 5 in high yield. Regioselective
Markovnikoff hydroalkoxylation of alkyne was possible with
Mg/MeOH under sonication, although the product methyl
enol ether 6 was formed in moderate yield. Considering the cis-
disposition of alkyne and benzoyl amide moieties, 3aa was
subjected to iodocyclization conditions using N-iodosuccini-
mide (NIS) as the electrophilic iodine source in the presence
of a catalytic amount of an achiral tertiary aminothiourea
derivative. As expected, the desired tricyclic 1,3-oxazine 7 was
formed through a 6-exo-dig cyclization as a single diastereomer
(with respect to olefin geometry) in 97% yield.
1
diastereomer, as indicated by the H NMR analyses of the
The relative and absolute configuration of 7 was determined
to be (R,R) by single crystal X-ray diffraction analysis (CCDC
1893569; Scheme 3B). The stereochemistry of 3aa was in
retrospect established from 7. The same configuration was
assigned to the other products shown in Table 2 by analogy.
In a related outcome, an attempted synthesis of
bromoalkyne with N-bromosuccinimide (NBS) in the presence
of AgNO3 unexpectedly gave rise to geminal dibromo-
substituted tricyclic 1,3-oxazine 8 in 87% yield. It must be
noted that all these transformations proceeded without any
erosion of enantiomeric purity.
crude reaction mixtures.
The scalability of our [4 + 2]-annulation protocol was
verified by carrying out a reaction between 1a and 2a on a 1.0
mmol scale (Scheme 3A). Using only 5 mol % of CuI-L4
complex and 20 mol % of III, 3aa was isolated as a single
diastereomer in 98% yield with 96.5:3.5 er.
Scheme 3. (A) Larger Scale Preparation and (B) Synthetic
Elaborations of Cyclic α-Acylaminoamide
a
In conclusion, we have developed the first decarboxylative [4
+ 2]-annulation of ethynyl benzoxazinanones with azlactones
for the enantioselective synthesis of α-quaternary α-acylami-
noamides. This direct and modular approach combines dipolar
copper-allenylidene intermediates and enolates generated from
azlactones under tertiary aminourea catalysis in a cooperative
fashion. The resulting 3,4-dihydroquinolin-2-ones, bearing
vicinal tertiary and quaternary stereogenic centers, are formed
as a single diastereomer with good to excellent enantiose-
lectivity. The products are densely functionalized, and the
versatility of the terminal alkyne group is demonstrated
through a number of synthetic elaborations. This reaction
represents the first direct catalytic enantioselective approach to
cyclic α-quaternary α-acylaminoamides.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01103.
Experimental details and characterization data (PDF)
NMR spectra (PDF)
Accession Codes
CCDC 1893569 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
a
Reaction conditions: (a) PhI, Pd(PPh3)2Cl2, CuI, Et3N, DMF, 25
°C, 5 h; (b) TsN3, CuTc, toluene, 0−25 °C, 2 h; (c) Mg, MeOH,
sonication, 25 °C, 8 h; (d) NIS, 1-(3,5-bis(trifluoromethyl)phenyl)-3-
(2-(dimethylamino)ethyl)thiourea, CHCl3, 0−25 °C, 48 h; (e) NBS,
AgNO3, acetone, 25 °C, 3 h.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sm@iisc.ac.in.
ORCID
In order to demonstrate the utility of this [4 + 2]-
annulation, we performed a number of synthetic elaborations
of the densely functionalized product, cyclic α-acylaminoamide
3aa (Scheme 3B). For example, Sonogashira coupling with
iodobenzene afforded a disubstituted alkyne 4 in 67% yield.
Copper catalyzed click reaction with tosyl azide resulted in the
Amit Kumar Simlandy: 0000-0002-8792-4825
Biki Ghosh: 0000-0002-1140-0347
Santanu Mukherjee: 0000-0001-9651-6228
D
DOI: 10.1021/acs.orglett.9b01103
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Organic Letters
Letter
Czabaniuk, L. C. Benzylic Phosphates as Electrophiles in the
Palladium-Catalyzed Asymmetric Benzylation of Azlactones. J. Am.
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Lin, L.; Feng, X. Asymmetric Synthesis of 3,4-Diaminochroman-2-
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Author Contributions
⊥These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is funded by the Science and Engineering Research
Board (SERB), New Delhi [Grant No. EMR/2016/005045].
A.K.S. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, and B.G. thanks IISc Bangalore for their
respective doctoral fellowships. We are grateful to Mr. Rupak
Saha (Department of Inorganic and Physical Chemistry, IISc,
Bangalore) for his help with the X-ray diffraction analysis.
́
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