Tandem Organocatalytic Cycloaromatization/Intramolecular Friedel-Crafts Alkylation Sequence for the Synthesis of Indolizinones and Pyrrolo-azepinone Derivatives

Article abstract of DOI:10.1021/acs.joc.9b01314

The organocatalytic synthesis of indolizinones and pyrrolo-azepinones has been accomplished in a tandem fashion through a sequence that comprises initial cycloaromatization followed by intramolecular Friedel-Crafts alkylation. The process takes place under Br?nsted acid catalysis, giving rise to final products in moderate to good yields. Attempts to carry out the tandem protocol in an enantioselective fashion were performed with chiral (R)-BINOL-derived N-triflyl phosphoramides. After initial optimization, the tandem process took place with moderate levels of enantioselectivity.

Full text of DOI:10.1021/acs.joc.9b01314

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Article
Tandem Organocatalytic Cycloaromatization/ Intramolecular
Friedel-Crafts Alkylation Sequence for the Synthesis
of Indolizinones and Pyrrolo-azepinone Derivatives
Fernando Rabasa-Alcañiz, Maria Sanchez-Rosello, Santos Fustero, and Carlos Del Pozo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01314 • Publication Date (Web): 22 Jul 2019
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Tandem Organocatalytic Cycloaromatization/ Intramolecular
Friedel-Crafts Alkylation Sequence for the Synthesis of
Indolizinones and Pyrrolo-azepinone Derivatives
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Fernando Rabasa-Alcañiz,† María Sánchez-Roselló,† Santos Fustero*,†,‡ and Carlos del
Pozo,*,†
† Departamento de Química Orgánica, Universidad de Valencia, 46100 Burjassot, Spain
‡ Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, 46012 Valencia,
Spain.
E-mail: carlos.pozo@uv.es; santos.fustero@uv.es
ABSTRACT:
The organocatalytic synthesis of indolizinones and pyrrolo-azepinones has been accomplished
in a tandem fashion through a sequence that comprises an initial cycloaromatization followed by
an intramolecular Friedel Crafts alkylation. The process takes place under Brønsted acid
catalysis giving rise to final products in moderate to good yields. Attempts to carry out the
tandem protocol in an enantioselective fashion were performed with chiral (R)-BINOL-derived
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N-triflyl phosphoramides. After initial optimization, the tandem process took place with
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moderate levels of enantioselectivity.
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INTRODUCTION
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Pyrrole is the fundamental 5-member ring aromatic N-heterocycle and a prevalent structural
motif in natural and synthetic biologically active compounds, such as natural products, drugs
and agrochemicals, as well as in catalysts and advanced materials.1 Particularly, annulated
pyrroles and pyrrolidines are highly represented moieties in clinically useful pharmaceuticals
and natural products,2 as in the lamellarin, indolizidine, stemona or rhazinilam alkaloid families
(Figure 1).3 Anticancer, antileukemia, anticholinergic and antimicrobial properties are among
the biological activities displayed by those derivatives.4 Therefore, these interesting frameworks
have attracted high interest in synthetic organic chemistry. Cyclization of N-tethered substrates
is by far the most common strategy for the preparation of annulated pyrroles.5 Friedel-Crafts
alkylation and acylation (FCA) of these of compounds give access to indolizines and the
corresponding pyrrolo-azepines, which are also frequently occurring frameworks in natural
products.6 Syntheses based on asymmetric catalysis (metal and organocatalysis) can also be
found in the literature.7
Figure 1. Biologically relevant annulated pyrroles.
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Given the importance of pyrrole-fused derivatives in pharmaceutical and agricultural
development, efficient new methodologies for the construction of the pyrrole core are still
needed. The classical Paal-Knorr reaction, involving a primary amine and a 1,4-dicarbonyl
compound, remains the cornerstone of pyrrole synthesis from acyclic starting materials.
However, olefin metathesis has revealed itself as a powerful alternative of increasing
importance for the construction of functionalized heterocycles from acyclic unsaturated
precursors.8 In this sense, Donohoe9 and Rutjes10 were pioneers in the application of ring closing
metathesis (RCM) to pyrrole synthesis. In their approach, RCM of an appropriate allylamine
renders an intermediate pyrroline, which upon acid-catalyzed elimination or oxidation, evolves
into the corresponding pyrrole. One-pot protocols of this sequence11 or processes involving
enyne cross-metathesis and subsequent aromatization have also been described.12
Donohoe13 and Grela14 independently reported the combination of a cross-metathesis reaction
with an acid-catalyzed cycloaromatization. In the first step of this sequence, a trans-γ-
aminoenone is generated which upon addition of an acid co-catalyst undergoes trans/cis
isomerization and subsequent dehydration towards the final pyrrole (Scheme 1A). In this way,
indolizidine derivatives have been efficiently synthesized by sequences comprising a cross-
metathesis step and a subsequent intramolecular Friedel-Crafts alkylation.15 In this synthetic
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strategy, pyrroles featuring an N-tethered olefin are first converted into the corresponding α,β-
unsaturated carbonyl compounds, which then undergo intramolecular Michael addition (the
intermediate pyrrole being the nucleophile) in a one-pot or sequential fashion. The
intramolecular Friedel-Crafts alkylation has been developed in an organocatalytic asymmetric
fashion employing chiral secondary amines (for iminium activation of enals)15b,e-h or chiral
BINOL-phosphoric acids (for hydrogen-bond activation of enones).15c,d The latter are
compatible with ruthenium metathesis catalysts and they have been combined in a one-pot
tandem protocol (Scheme 1B).
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In comparison to indoles, for which a myriad of asymmetric procedures involving the
FCA have been developed,16 pyrroles have been relatively less used as nucleophilic counterparts
in this reaction. The reasons for the lack of reports on the use of pyrroles in (organocatalytic)
FCA reactions might be found in the high intrinsic nucleophilicity of this heterocyclic ring,
which renders the enantiofacial discrimination more difficult in comparison to its benzannulated
derivative indole.
Scheme 1. Synthetic strategies to access pyrrole-derivatives.
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Previous work
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(A) Cross-metathesis/cycloaromatization approach to pyrroles (Ref. 13 and 14)
NHPG
Brønsted or
Lewis acid
NHPG
R1
HG-II
R2
R2
R1
+
R1
N
PG
O
O
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R2
(B) Cross-metathesis/intramolecular Friedel-Crafts alkylation approach to
indolizidines and pyrrolo[1,2-a]azepines (Ref. 15)
R1
R2
O
N
O
R2
Organocatalyst
*
R1
X
HG-II
R1
N
N
+
O
X
X
R2
This work
(C) Tandem organocatalytic cycloaromatization/intramolecular Friedel-Crafts
alkylation process to indolizidines and pyrrolo[1,2-a]azepines
R1
X
R1
X
X
*
( )n
( )n
( )n
R1
Organocatalyst
O
O
O
O
O
NH
N
O
N
O
R2
n = 1, 2
R2
R2
With these precedents in mind, we envisioned the combination of the cycloaromatization of γ-
amidoenones, accessible by bidirectional cross-metathesis, and an intramolecular Friedel-Crafts
alkylation in a tandem organocatalyzed protocol (Scheme 1C). This intramolecular double
cyclization would generate the bicyclic core of indolizidines and pyrrolo[1,2-a]azepines in just
one step from simple, acyclic substrates.17 Furthermore, efforts towards an enantioselective
approach will be made.
RESULTS AND DISCUSSION
Our study began with the synthesis of the starting amides 3 (Table 1), which was accomplished
in two steps. First, amides 2 were prepared from the corresponding free acid (commercially
available or described in the literature) via the mixed anhydride. In the case of 2d and 2f, a more
reactive acid derivative was necessary and, thus, the appropriate acid chloride was used instead.
Bidirectional olefin cross-metathesis with the corresponding vinyl ketone and Hoveyda-Grubbs
2nd generation catalyst (HG-II) converted 2 into 3. All reactions were carried out at room
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temperature, except in the case of 3e, in which the less reactive phenyl vinyl ketone required a
higher temperature (40 °C), but nevertheless, the reaction was low-yielding and messy.
Compounds 3j, 3k and 3l were obtained along with equimolecular amounts of the
corresponding mono-cross-metathesis products (as a non-separable mixture of the two possible
isomers).
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Table 1. Synthesis of the starting amides 3
Entry
1
X
CH2
2
Yield (%)a
98
R
Me
3
3a
3b
3c
3d
3e
3f
Yield (%)a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2d
2e
2f
60
2
CH2
Et
56
3
CH2
n-Pr
n-Pent
Ph
36
4
CH2
18
12c
5
CH2
6
(CH2)2
(CH2)2
(CH2)2
(CH2)2
CH2O
94
Me
72
7
Et
3g
3h
3i
74
8
n-Pr
n-Pent
Me
51
9
26
10
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14
36
63b
89
3j
39 (+31)d
12 (+19)d
40 (+41)d
39
CH2S
Me
3k
3l
CH2N(Boc)
CH2N(Ts)
CH2C(CO2Et)2
Me
89b
Me
3m
3n
2g
34
Me
59
a
b
Isolated yield after flash column chromatography. A different procedure was used for the
c
d
amide synthesis. See Supporting Information for details. The reaction was run at reflux.
Recovered yields of mono-cross-metathesis products are given in parentheses.
In order to expand the generality of the present methodology, “unsymmetrical” amides 3o and
3p were prepared, in which the substituents of each ketone end were different. A stepwise
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synthesis was required to install each enone sequentially into the structure of the final product
(Scheme 2). Mixed anhydride 6 was prepared and then subjected to cross-metathesis conditions
with the vinyl ketone required in the carbon end of the amide. It should be emphasized that the
metathesis catalyst is perfectly compatible with the relatively reactive mixed anhydride. The
obtained intermediates 7a and 7b were not isolated, but directly treated with allylamine to
afford 8a and 8b, which were then purified by flash chromatography. Finally, a second cross-
metathesis reaction with the second vinyl ketone provided access to 3o and 3p respectively.
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Scheme 2. Synthesis of unsymmetrical substrates 3o,p
With starting amides 3 in hand, their behavior was studied, choosing 3a as a model substrate
(Table 2). Preliminary screening of the reaction conditions revealed that strong Brønsted bases
decomposed the starting material (entries 1-3). DABCO and 9-amino-(9-deoxy)epi-
hydroquinine (HQN-NH2) did not promote any reactivity (entries 4 and 5). To our delight,
Brønsted and Lewis acids catalyzed the formation of dihydroindolizinone 5a via pyrrole 4a
(entries 6 and 7). The sequence can be understood as a cycloaromatization/intramolecular
Friedel-Crafts alkylation process. Aiming at the development of an organocatalytic process,
diphenyl phosphate and the corresponding N-triflyl phosphoramide were tested. The first
catalyst enabled the pyrrole formation, but was insufficiently acidic to efficiently activate the
intermediate enone for the intramolecular Friedel-Crafts alkylation (entry 8). Longer reaction
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times or higher temperatures did not provide better product ratios. Generally, pyrroles are
considered electron-rich heterocycles, but in 3a the free electron pair of the pyrrole nitrogen
belongs at the same time to an amide moiety, which explains the relatively low reactivity in
position 2 of the pyrrole ring. In contrast, the more acidic phosphoramide catalyzes the whole
process and it is able to drive it to completion when the reaction mixture is heated in toluene at
60 ºC (entries 9 and 10).
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Table 2. Preliminary screening of the reaction conditions
Conversion
(%)a
Product(s)
Entry
Catalyst
Solvent
1b
2b
3 b
4 b
5
6 b
7 b
8
NaH
P2Et (phosphazene base)
t-BuOK
THF
THF
decomposition
decomposition
decomposition
THF
DABCO
DCM
DCM
DCM
DCM
DCM
DCM
toluene
0
0
-
HQN-NH2
-
BF3·OEt2
>95
>95
>95
>95
>95
5a
TFA
5a
(PhO)2P(O)OH
(PhO)2P(O)NHTf
(PhO)2P(O)NHTf
4a/5a (8/1)c
4a/5a (1/1)c
5a (84%)e
9
10d
a Conversion was determined from 1H-NMR of the crude mixture. b 100 mol % of
c
1
the corresponding catalyst was used. Product ratio was determined from H-
d
e
NMR of the crude mixture. The reaction was run at 60 °C. Isolated yield after
flash column chromatography.
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Having found suitable conditions for the tandem protocol, these were applied to the rest of
substrates 3. Table 3 summarizes the results obtained in the evaluation of the scope of the
process.
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Table 3. Scope of the tandem cycloaromatization/intramolecular Friedel-Crafts alkylation.
O
O
O
O
O
2( )
4( )
Ph
N
N
N
N
N
2( )
4( )
Ph
O
O
O
O
O
5a
5b
5c
5d
5e
(60%)
(84%)
(80%)
(86%)
(83%)
O
O
O
N
O
N
O
O
4( )
2( )
N
N
N
N
O
S
2( )
4( )
O
O
O
O
O
O
5f
5g
5h
5i
5j
5k
(56%)
(74%)
(72%)
(70%)
(76%)
(70%)
O
N
O
O
O
N
O
EtO2C
EtO2C
N
N
N
Boc
N
Ts N
O
O
O
O
O
5l
5m
5n
5o
5p
(82%)
(64%)
(82%)
(72%)
(80%)
A variety of indolizinone (5a-e) and pyrrolo-azepinone (5f-i) derivatives was obtained in good
yields, either with aliphatic or aromatic substituents at the ketone and at the pyrrole end. This
methodology is also amenable to obtain pyrrolo-oxazepinone 5j, pyrrolo-thiazepinone 5k and
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pyrrolo-diazepinones 5l,m. Finally, unsymmetrical indolizinones 5o,p could also be obtained in
good yields.18
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In the hope of developing an enantioselective process, a variety of (R)-BINOL derived N-triflyl
phosphoramides19 were screened (Table 4). BINOL-derived organocatalysts bearing the most
frequent 3,3’ substitution pattern in the literature were synthesized and tested under the
screening conditions. Among all the catalysts (Table 4, entries 1-8), the one substituted with the
bulky 2,4,6-triisopropylphenyl groups was identified as the best for this transformation in terms
of enantioselectivity (Table 4, entry 5). Non-polar, non-coordinating solvents were the best
choice for this tandem sequence as one would anticipate for the non-covalent interaction (H-
bond) between the catalyst and the substrate in the critical reaction step in which the
stereocenter is formed.
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Table 4. Preliminary screening of the reaction conditions
Ar
O
O
Tf
P
N
O
H
O
Ar
N
O
(10 mol%)
N
H
O
O
solvent, 60 ºC, 4Å MS, 16h
3a
5a
O
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Entry
Ar
Conversion (%)
er
1
2
3
4
5
6
7
8
9a
1-naphthyl
2-naphthyl
9-anthryl
>95
>95
>95
>95
>95
>95
>95
>95
>95
58:42
56:44
58:42
61:39
73:27
70:30
52:48
57:43
69:31
9-phenanthryl
2,4,6-triisopropyl-phenyl
2,4,6-tricyclohexyl-phenyl
4-biphenyl
3,5-bis-trifluoromethyl-phenyl
2,4,6-triisopropyl-phenyl
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DCM
DCE
CHCl3
CCl4
10
11
12
13
14b
2,4,6-triisopropyl-phenyl
2,4,6-triisopropyl-phenyl
2,4,6-triisopropyl-phenyl
2,4,6-triisopropyl-phenyl
2,4,6-triisopropyl-phenyl
>95
>95
70:30
58:42
75:25
78:22
80:20
>95
>95
>95 (76%)c
CCl4
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a No molecular sieves were used. b The reaction was run at 40 °C for 5 days. c Isolated yield after
flash column chromatography.
A solvent screening was also carried out. It is remarkable how apparently subtle changes in the
solvent resulted in dramatic effects on the enantioselectivity, as in the pair DCM/DCE (Table 4,
entries 10, 11). Carbon tetrachloride provided the best result in terms of enantioselectivity, if
only moderate (Table 4, entry 13). The reaction temperature was adjusted to 40 °C, resulting in
a reaction time of 5 days to ensure complete conversion to the final product of the tandem
sequence (5a). Temperatures lower than 40 ºC invariably resulted in mixtures of 4a and 5a, no
matter how long the reaction was run. Thus, it was necessary to sacrifice some
enantioselectivity in favor of conversion in reasonable reaction times. Therefore, optimized
conditions involved the use of (R)-BINOL-derived 2,4,6-triisopropylphenyl-substituted N-triflyl
phosphoramide [(R)-TRIP-NH-Tf] in CCl4 at 40 ºC for five days, in the presence of 4Å MS.
Finally, the best reaction conditions were applied to all amides 3 in order to study the scope of
the reaction (Table 5).
Table 5. Scope of the enantioselective tandem cycloaromatization/intramolecular Friedel-
Crafts alkylation.
Entry
1
3
X
R1
R2
5
Yield (%)a
76 (44)b
er
3a
CH2
Me
Me
5a
80:20 (74:26)b
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2
3
3b
3c
3d
3e
3f
CH2
CH2
Et
n-Pr
n-Pent
Ph
Et
n-Pr
n-Pent
Ph
5b
5c
5d
5e
5f
70
80
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75
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81.5:18.5
83:17
85:15
86:14
73.5:26.5
68:32
69:31
65:35
65:35
73:27
76:24
84:16
65:35
84:16
76:24
4
CH2
5
CH2
6
(CH2)2
(CH2)2
(CH2)2
(CH2)2
CH2O
Me
Me
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7
3g
3h
3i
Et
Et
5g
5h
5i
8
n-Pr
n-Pent
Me
n-Pr
n-Pent
Me
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3j
5j
3k
3l
CH2S
Me
Me
5k
5l
CH2N(Boc)
CH2N(Ts)
CH2C(CO2Et)2
CH2
Me
Me
3m
3n
3o
3p
Me
Me
5m
5n
5o
5p
Me
Me
Et
Me
CH2
Me
Et
a Isolated yield of the tandem sequence run at a 0.09 mmol scale after flash column chromatography.
b Results of the tandem sequence run at a 2.38 mmol scale. See the Experimental Section.
A variety of indolizine and azepine derivatives was obtained with moderate enantioselectivies
(up to 72%) and moderate to good yields for this tandem sequence. Structural variability was
introduced via the ketone substituents (R1 and R2) and the linker chain (X). When the
appropriate heteroatom-bearing linker was used, oxa-azepine, thia-azepine and diazepine ring
systems were obtained.
The reactions giving rise to the indolizine derivatives show slightly higher levels of
enantioselectivity than the reactions producing the pyrrolo-azepinone derivatives, which can be
attributed to a higher stereocontrol as a result of the smaller ring size in the transition state. In
addition, the bulkier the ketone substituents R1 and R2 are in the indolizine derivatives, the
higher is the reaction enantioselectivity, while the opposite is more or less true for the azepines.
In terms of yield, no trends can clearly be inferred.
The absolute configuration of a recrystallyzed sample of 5a was determined to be (S) by
Vibrational Circular Dichroism (VCD) (See Supporting Information for further details).
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SUMMARY
In summary,
we
have
developed
a
novel
tandem
organocatalyzed
7
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cycloaromatization/intramolecular Friedel-Crafts alkylation sequence leading to the synthesis of
a new family of indolizinones and pyrrolo-azepinones in moderate to good yields. The starting
amidodienones are accessible by bidirectional or sequential olefin cross-metathesis. An
asymmetric approach was developed using an (R)-BINOL-derived N-triflyl phosphoramide as
Brønsted acid catalyst for the whole process, obtaining moderate levels of enantioselectivity. In
this sense, further work is currently being carried out in our laboratory.
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EXPERIMENTAL SECTION
General Methods. Reactions were carried out under a nitrogen atmosphere unless otherwise
indicated. Solvents were purified prior to use: THF and toluene were distilled from sodium, and
CH2Cl2 was distilled from calcium hydride. The reactions were monitored with the aid of TLC
on 0.25 mm precoated silica gel plates. Visualization was carried out with UV light and
potassium permanganate stain. Flash column chromatography was performed with the indicated
1
solvents on silica gel 60 (particle size 0.040−0.063 mm). H and 13C NMR spectra were
recorded on a 300 MHz spectrometer. Chemical shifts are given in ppm (δ), referenced to the
residual proton resonances of the solvents. Coupling constants (J) are given in hertz (Hz). The
letters m, s, d, t, and q stand for multiplet, singlet, doublet, triplet, and quartet, respectively. The
designation br indicates that the signal is broad. The abbreviations DCM and THF indicate
dichloromethane and tetrahydrofuran, respectively. A QTOF mass analyzer system has been
used for the HRMS measurements. Enantiomeric excess was determined by means of HPLC
using chiral columns and mixtures of hexane and isopropanol as mobile phase.
General procedure for the synthesis of intermediate amides 3.
To a solution of the corresponding carboxylic acid 1 (5 mmol) in DCM (20 mL, 0.25 M) at 0 ºC,
TEA (1.39 mL, 10 mmol, 2.0 equiv) and ethyl chloroformate (0.48 mL, 5 mmol, 1.0 equiv)
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were sequentially added. After 30 min at the same temperature, allylamine (0.45 mL, 6 mmol,
1.2 equiv) was added dropwise and the resulting mixture was stirred at room temperature for
16h. 20 mL of a saturated NH4Cl solution were added, the organic phase was separated and the
aqueous phase was extracted with DCM (2x20 mL). The combined organic phases were washed
with brine (20 mL) and dried over anhydrous sodium sulfate and the solvent was removed under
vacuum. The crude amide 2 was used as an intermediate in the synthesis of amide 3 without
further purification.
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N-Allyl-4-pentenamide (2a): Starting from commercially available 4-pentenoic acid and
following the procedure described above, 2a was obtained as a colorless oil in 98% (682 mg).
The spectroscopic data matched those from the literature.20
N-Allyl-5-hexenamide (2b): Starting from commercially available 5-hexenoic acid and
following the procedure described above, 2b was obtained as a colorless oil in 94% (720 mg).
The spectroscopic data matched those from the literature.20
N-Allyl-2-(allyloxy)acetamide (2c): Starting from 2-(allyloxy)acetic acid21 and following the
procedure described above, 2c was obtained as a light yellow oil in 36% yield (279 mg). 1H
NMR (300 MHz, CDCl3) δ 6.64 (br s, 1H), 5.96-5.79 (m, 2H), 5.38 – 5.05 (m, 4H), 4.06 (dt, J =
5.7, 1.4 Hz, 2H), 3.97 (s, 2H), 3.94 (tt, J = 5.9, 1.6 Hz, 2H). 13C{1 H} NMR (75 MHz, CDCl3) δ
169.6, 134.1, 133.6, 118.4, 116.6, 72.5, 69.5, 41.3.
N-Allyl-2-(allylthio)acetamide (2d): 2-(Allylthio)acetic acid22 (500 mg, 3.78 mmol) was
dissolved in DCM (15 mL) and cooled down to 0 ºC in an ice bath. To this solution, oxalyl
chloride (0.64 mL, 7.56 mmol, 2.0 equiv) and 2 drops of anhydrous DMF were added. The
resulting solution was allowed to reach room temperature for 3h. Volatiles were then removed
under vacuum and the residue was redissolved in DCM (15 mL) and cooled down to 0 ºC.
Allylamine (0.34 mL, 4.54 mmol, 1.2 equiv) and TEA (1.05 mL, 7.56 mmol, 2.0 equiv) were
added dropwise and the resulting solution was allowed to reach room temperature for 16h. 20
mL of a saturated NH4Cl solution were added, the organic phase was separated and the aqueous
phase was extracted with DCM (2x20 mL). The combined organic phases were washed with
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brine (20 mL) and dried over anhydrous sodium sulfate and the solvent was removed under
vacuum. 2d was obtained as an orange oil in 63% yield (410 mg) and used in the next step
without further purification. 1H NMR (300 MHz, CDCl3) δ 6.87 (br s, 1H), 5.97–5.63 (m, 2H),
5.33 – 5.06 (m, 4H), 3.92 (tt, J = 5.8, 1.5 Hz, 2H), 3.21 (s, 2H), 3.18–3.12 (m, 2H). 13C{1 H}
NMR (75 MHz, CDCl3) δ 168.5, 134.0, 132.7, 119.0, 116.8, 42.2, 35.8, 34.7.
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tert-Butyl allyl(2-(allylamino)-2-oxoethyl)carbamate (2e): Starting from N-allyl-N-(tert-
butoxycarbonyl)glycine23 and following the procedure described above, 2e was obtained as a
1
yellow oil in 89% yield (1.13 g). H NMR (300 MHz, CDCl3) δ 5.92–5.68 (m, 2H), 5.21-5.12
(m, 4H), 3.98–3.75 (m, 6H), 1.46 (s, 9H). 13C{1 H} NMR (75 MHz, CDCl3) δ 169.6, 165.5,
134.1, 132.8, 118.0, 116.5, 81.2, 51.0, 45.9, 41.7, 28.4 (3xCH3).
N-Allyl-2-[(N-allyl-4-methylphenyl)sulfonamide]acetamide (2f): N-Allyl-N-tosylglycinoyl
chloride23 (535mg, 1.86 mmol) dissolved in DCM (5 mL) was added to a solution of allylamine
(0.17 mL, 2.23 mmol, 1.2 equiv) and TEA (0.52 mL, 3.72 mmol, 2.0 equiv) in DCM (10 mL) at
0 ºC. The resulting solution was allowed to reach room temperature for 16h. 20 mL of a
saturated NH4Cl solution were added, the organic phase was separated and the aqueous phase
was extracted with DCM (2x20 mL). The combined organic phases were washed with brine (20
mL) and dried over anhydrous sodium sulfate and the solvent was removed under vacuum. 2f
was obtained as a thick yellow oil in 89% yield (512 mg) and used in the next step without
further purification. 1H NMR (300 MHz, CDCl3) δ 7.74–7.65 (m, 2H), 7.44–7.30 (m, 2H), 6.67
(br s, 1H), 5.83 (ddt, J = 17.2, 10.3, 5.5 Hz, 1H), 5.71–5.53 (m, 1H), 5.29 5.12 (m, 4H), 3.92 (tt,
J = 5.5, 1.6 Hz, 2H), 3.80 (d, J = 6.9 Hz, 2H), 3.66 (s, 2H), 2.45 (s, 3H). 13C{1 H} NMR (75
MHz, CDCl3) δ 168.3, 144.6, 134.8, 133.7, 131.2, 130.2 (2xCH), 127.6 (2xCH), 121.5, 116.8,
53.4, 51.1, 41.9, 21.7.
Diethyl
2-allyl-2-(2-(allylamino)-2-oxoethyl)malonate
(2g):
Starting
from
3,3-
bis(ethoxycarbonyl)hex-5-enoic acid24 and following the procedure described above, 2g was
obtained as a colorless oil in 34% yield (505 mg) after flash column chromatography on silica
1
gel [n-hexane-EtOAc (4:1)]. H NMR (300 MHz, CDCl3) δ 5.93–5.53 (m, 3H), 5.24–5.06 (m,
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4H), 4.21 (q, J = 7.1 Hz, 4H), 3.85 (tt, J = 5.7, 1.5 Hz, 2H), 2.83–2.76 (m, 4H), 1.26 (t, J = 7.1
13
Hz, 6H). C{1 H} NMR (75 MHz, CDCl3) δ 170.6 (2xCO), 169.1, 134.2, 132.7, 119.7, 116.6,
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61.9 (2xCH2), 55.8, 42.0, 39.5, 38.0, 14.2 (2xCH3).
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General procedure for the synthesis of “symmetrical” diketo amides 3a-g
To a solution of amide 2a-g (0.50 mmol) in DCM (5 mL, 0.10 M) under a nitrogen atmosphere,
alkyl vinyl ketone (6 equiv) and Hoveyda-Grubbs 2nd generation catalyst (16 mg, 0.05 mmol, 5
mol%) were added. After stirring for 2h at room temperature, a second equal addition of the
catalyst followed and the reaction mixture was further stirred at room temperature for 16h.
Volatiles were then removed under vacuum and the residue was purified by flash
chromatography on silica gel [n-hexane-EtOAc (1:1) to pure EtOAc].
(E)-6-Oxo-N-[(E)-4-oxopent-2-en-1-yl]-4-heptenamide (3a): Starting from amide 2a and
methyl vinyl ketone, 3a was obtained as a dark brown thick oil in 60% yield (67 mg). 1H NMR
(300 MHz, CDCl3) δ 6.89–6.61 (m, 2H), 6.29 (br s, 1H), 6.18–6.02 (m, 2H), 4.05 (t, J = 4.4 Hz,
2H), 2.62-2.52 (m, 2H), 2.40 (t, J = 7.2 Hz, 2H), 2.24 (s, 3H), 2.22 (s, 3H). 13C{1 H} NMR (75
MHz, CDCl3) δ 198.8, 198.3, 171.5, 146.3, 143.1, 131.8, 130.9, 40.4, 34.3, 27.9, 27.2, 27.2.
HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C12H17NO3 224.1281; found 224.1291.
(E)-6-Oxo-N-[(E)-4-oxohex-2-en-1-yl]-4-octenamide (3b): Starting from amide 2a and ethyl
vinyl ketone, 3b was obtained as a dark brown thick oil in 56% yield (70 mg). 1H NMR (300
MHz, CDCl3) δ 6.89–6.67 (m, 2H), 6.20–6.08 (m, 2H), 5.67 (br s, 1H), 4.07 (td, J = 5.8, 1.7 Hz,
2H), 2.65–2.50 (m, 6H), 2.44–2.33 (m, 2H), 1.15–1.01 (m, 6H). 13C{1 H} NMR (75 MHz,
CDCl3) δ 201.0, 200.6, 171.4, 144.5, 141.2, 130.8, 130.1, 40.5, 34.7, 33.7, 33.7, 28.0, 8.2, 8.1.
HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C14H21NO3 252.1594; found 252.1606.
(E)-6-Oxo-N-[(E)-4-oxohept-2-en-1-yl]-4-nonenamide (3c): Starting from amide 2a and
propyl vinyl ketone, 3c was obtained as a dark brown thick oil in 36% yield (50 mg). 1H NMR
(300 MHz, CDCl3) δ 6.93–6.64 (m, 2H), 6.14 (dq, J = 15.9, 1.6 Hz, 2H), 5.78 (br s, 1H), 4.06
(td, J = 5.7, 1.6 Hz, 2H), 2.67–2.45 (m, 6H), 2.39 (t, J = 7.3 Hz, 2H), 1.75–1.52 (m, 6H), 0.92 (t,
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J = 7.4 Hz, 6H). 13C{1 H} NMR (75 MHz, CDCl3) δ 200.7, 200.2, 171.4, 144.7, 141.4, 131.1,
130.4, 42.4 (2xCH2), 40.5, 34.7, 28.0, 17.7, 17.6, 13.9 (2xCH3). HRMS (ESI/Q-TOF) m/z:
[M+H]+ Calcd for C16H25NO3 280.1907; found 280.1903.
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(E)-6-Oxo-N-[(E)-4-oxonon-2-en-1-yl]-4-undecenamide (3d): Starting from amide 2a and
pentyl vinyl ketone, 3d was obtained as a dark brown thick oil in 18% yield (30 mg). 1H NMR
(300 MHz, CDCl3) δ 6.89–6.66 (m, 2H), 6.13–6.10 (m, 2H), 5.62 (br s, 1H), 4.07 (td, J = 5.7,
1.7 Hz, 1H), 2.64–2.46 (m, 6H), 2.43–2.31 (m, 2H), 1.39–1.19 (m, 12H), 0.92–0.82 (m, 6H).
13C{1 H} NMR (75 MHz, CDCl3) δ 200.8, 200.3, 171.4, 144.5, 141.2, 131.1, 130.4, 40.6, 40.5,
40.5, 36.5, 34.7, 31.6, 31.6, 29.2, 28.0, 24.0, 23.8, 22.6, 14.1. HRMS (ESI/Q-TOF) m/z:
[M+H]+ Calcd for C20H33NO3 336.2533; found 336.2542.
(E)-6-Oxo-N-[(E)-4-oxo-4-phenylbut-2-en-1-yl]-6-phenyl-4-hexenamide (3e): In a variation
of the general procedure, the reaction was run at reflux and phenyl vinyl ketone was used.
Starting from amide 2a, 3e was obtained as a dark brown thick oil in 12% yield (21 mg). 1H
NMR (300 MHz, CDCl3) δ 7.97–7.84 (m, 4H), 7.61–7.51 (m, 2H), 7.51–7.40 (m, 4H), 7.12–
6.82 (m, 4H), 5.78 (br s, 1H), 4.18 (dd, J = 5.8, 3.6 Hz, 2H), 2.77–2.63 (m, 2H), 2.48 (t, J = 7.4
Hz, 1H). 13C{1 H} NMR (75 MHz, CDCl3) δ 190.7, 190.5, 171.4, 147.1, 143.7, 137.8, 137.5,
133.2, 133.0, 128.8 (2xCH), 128.7 (2xCH), 128.7 (2xCH), 128.7 (2xCH), 127.0, 126.5, 40.9,
34.9, 28.5. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C22H21NO3 348.1594; found 348.1600.
(E)-7-Oxo-N-[(E)-4-oxopent-2-en-1-yl]-5-octenamide (3f): Starting from amide 2b and
methyl vinyl ketone, 3f was obtained as a dark brown thick oil in 72% yield (85 mg). 1H NMR
(300 MHz, CDCl3) δ 6.87–6.57 (m, 2H), 6.15-6.06 (m, 2H), 5.71 (br s, 1H), 4.07 (td, J = 5.9,
1.7 Hz, 2H), 2.35-2.19 (m, 10H), 1.86 (p, J = 7.4 Hz, 2H). 13C{1 H} NMR (75 MHz, CDCl3) δ
198.7, 198.1, 172.3, 147.0, 142.8, 132.1, 131.1, 40.4, 35.6, 31.9, 27.3, 27.1, 23.8. HRMS
(ESI/Q-TOF) m/z: [M+H]+ Calcd for C13H19NO3 238.1438; found 238.1447.
(E)-7-Oxo-N-[(E)-4-oxohex-2-en-1-yl]-5-nonenamide (3g): Starting from amide 2b and ethyl
vinyl ketone, 3g was obtained as a dark brown thick oil in 74% yield (98 mg). 1H NMR (300
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MHz, CDCl3) δ 6.87–6.67 (m, 2H), 6.18-6.09 (m, 2H), 5.67 (br s, 1H), 4.06 (td, J = 5.8, 1.7 Hz,
13
1H), 2.61-2.52 (m, 4H), 2.32–2.18 (m, 4H), 1.90-1.81 (m, 2H), 1.09 (t, J = 7.3 Hz, 6H). C{1
7
8
9
H} NMR (75 MHz, CDCl3) δ 201.2, 200.6, 172.3, 145.6, 141.4, 130.8, 130.1, 40.4, 35.6, 33.7,
33.5, 31.9, 23.9, 8.2, 8.1. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C15H23NO3 266.1751;
found 266.1751.
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(E)-7-Oxo-N-[(E)-4-oxohept-2-en-1-yl]-5-decenamide (3h): Starting from amide 2b and
propyl vinyl ketone, 3h was obtained as a dark brown thick oil in 51% yield (75 mg). 1H NMR
(300 MHz, CDCl3) δ 6.87–6.65 (m, 2H), 6.18-6.09 (m, 2H), 5.61 (br s, 1H), 4.06 (td, J = 5.8,
1.7 Hz, 2H), 2.55-2.49 (m. 4H), 2.34–2.18 (m, 4H), 1.91-1.81 (m, 2H), 1.70-1.57 (m, 6H), 0.96-
13
0.90 (m, 6H). C{1 H} NMR (75 MHz, CDCl3) δ 200.8, 200.2, 172.3, 145.7, 141.5, 131.2,
130.4, 42.4, 42.3, 40.4, 35.6, 31.9, 23.9, 17.8, 17.6, 14.0, 13.9. HRMS (ESI/Q-TOF) m/z:
[M+H]+ Calcd for C17H27NO3 294.2064; found 294.2067.
(E)-7-Oxo-N-[(E)-4-oxonon-2-en-1-yl]-5-dodecenamide (3i): Starting from amide 2b and
pentyl vinyl ketone, 3i was obtained as a dark brown thick oil in 26% yield (45 mg). 1H NMR
(300 MHz, CDCl3) δ 6.87–6.67 (m, 2H), 6.18-6.09 (m, 2H), 5.59 (br s, 1H), 4.11–4.01 (m, 2H),
2.56-2.50 (m, 4H), 2.33–2.16 (m, 4H), 1.95–1.78 (m, 2H), 1.68–1.60 (m, 2H), 1.40–1.18 (m,
10H), 0.91-0.87 (m, 6H). 13C{1 H} NMR (75 MHz, CDCl3) δ 200.9, 200.3, 172.3, 145.6, 141.5,
131.1, 130.3, 40.5, 40.4 (2xCH2), 35.7, 31.9, 31.6, 31.6, 24.1, 23.9, 23.9, 22.6, 22.6, 14.1, 14.1.
HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C21H35NO3 350.2690; found 350.2682.
N-[(E)-4-Oxopent-2-en-1-yl]-2-[(E)-4-oxopent-2-en-1-yl]oxyacetamide (3j): Starting from
amide 2c and methyl vinyl ketone, 3j was obtained as a dark brown thick oil in 39% yield (47
mg). A mixture of mono cross-metathesis products was recovered as well in 31% combined
yield. 1H NMR (300 MHz, CDCl3) δ 6.80-6.70 (m, 3H), 6.30 (dt, J = 16.1, 1.9 Hz, 1H), 6.15 (dt,
J = 16.0, 1.8 Hz, 1H), 4.27 (dd, J = 4.6, 1.9 Hz, 2H), 4.17–4.11 (m, 2H), 4.06 (s, 2H), 2.30 (s,
3H), 2.28 (s, 3H). 13C{1 H} NMR (75 MHz, CDCl3) δ 198.1, 197.9, 169.1, 142.3, 141.0, 131.2,
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131.1, 70.2, 70.2, 39.7, 27.5, 27.3. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C12H17NO4
240.1230; found 240.1242.
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N-[(E)-4-Oxopent-2-en-1-yl]-2-[(E)-4-oxopent-2-en-1-yl]thioacetamide (3k): In a variation
of the general procedure, the reaction was run at reflux. Starting from amide 2d and methyl
vinyl ketone, 3k was obtained as a dark brown thick oil in 12% yield (47 mg). A mixture of
mono cross-metathesis products was recovered as well in 19% combined yield. 1H NMR (300
MHz, CDCl3) δ 6.87 (br s, 1H), 6.72-6.58 (m, 2H), 6.19–6.03 (m, 2H), 4.04 (s, 2H), 3.27 (d, J =
6.8 Hz, 2H), 3.15 (s, 2H), 2.23-2.20 (m, 6H). 13C{1 H} NMR (75 MHz, CDCl3) δ 198.1, 197.8,
168.6, 142.4, 140.2, 132.9, 131.2, 40.6, 34.8, 33.9, 27.9, 27.3. HRMS (ESI/Q-TOF) m/z:
[M+H]+ Calcd for C12H17NO3S 256.1002; found 256.1005.
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tert-Butyl
{2-oxo-2-[(E)-4-oxopent-2-en-1-yl]aminoethyl}[(E)-4-oxopent-2-en-1-
yl]carbamate (3l): Starting from amide 2e and methyl vinyl ketone, 3l was obtained as a dark
brown thick oil in 40% yield (68 mg). A mixture of mono cross-metathesis products was
recovered as well in 41% combined yield. 1H NMR (300 MHz, CDCl3) δ 6.76–6.62 (m, 2H),
6.15-6.05 (m, 2H), 4.12–4.03 (m, 4H), 3.85 (s, 2H), 2.26 (s, 3H), 2.25 (s, 3H), 1.46 (s, 9H).
13C{1 H} NMR (75 MHz, CDCl3) δ 198.1 (2xC=O), 169.6, 142.5, 141.5, 131.7, 131.0, 82.1,
51.5, 50.0, 40.3, 28.5 (3xCH3), 27.6, 27.4. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for
C17H26N2O5 339.1914; found 339.1921.
2-{4-Methyl-N-[(E)-4-oxopent-2-en-1-yl]phenylsulfonamido}-N-[(E)-4-oxopent-2-en-1-
yl]acetamide (3m): Starting from amide 2f and methyl vinyl ketone, 3l was obtained as a dark
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brown thick oil in 39% yield (77 mg). H NMR (300 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 1H),
7.36 (d, J = 8.0 Hz, 1H), 6.89 (br s, 1H), 6.71 (dt, J = 16.0, 5.0 Hz, 1H), 6.50 (dt, J = 15.9, 6.3
Hz, 1H), 6.18 (d, J = 16.0 Hz, 1H), 6.08 (d, J = 15.9 Hz, 1H), 4.13–4.04 (m, 2H), 4.00 (dd, J =
6.3, 1.1 Hz, 2H), 2.45 (s, 3H), 2.27 (s, 3H), 2.16 (s, 3H). 13C{1 H} NMR (75 MHz, CDCl3) δ
198.0, 197.2, 168.2, 145.0, 142.0, 138.7, 134.6, 133.8, 131.7, 130.4 (2xCH), 127.6 (2xCH),
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51.7, 51.2, 40.5, 27.7, 27.5, 21.7. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C19H24N2O5S
393.1479, found 393.1478.
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Diethyl
2-{2-oxo-2-[(E)-4-oxopent-2-en-1-yl]aminoethyl}-2-[(E)-4-oxopent-2-en-1-
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yl]malonate (3n): Starting from amide 2g and methyl vinyl ketone, 3n was obtained as a dark
brown thick oil in 59% yield (113 mg). 1H NMR (300 MHz, CDCl3) δ 6.80–6.61 (m, 2H), 6.22
(br s, 1H), 6.11 (d, J = 15.9 Hz, 2H), 4.22 (q, J = 7.1 Hz, 4H), 4.02 (t, J = 4.4 Hz, 2H), 2.95 (d, J
= 7.6 Hz, 2H), 2.86 (s, 2H), 2.24 (s, 3H), 2.22 (s, 3H), 1.25 (t, J = 7.1 Hz, 6H). 13C{1 H} NMR
(75 MHz, CDCl3) δ 198.3, 198.2, 170.1, 169.2, 142.8, 141.9, 134.7, 131.1, 62.3 (2xCH2), 62.0,
55.7, 40.4, 39.6, 36.8, 27.4, 27.4, 14.2 (2xCH3). HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for
C19H27NO7 382.1860, found 382.1863.
General procedure for the synthesis of “unsymmetrical” diketo amides 3o,p
To a solution of 4-pentenoic acid (0.5 mL, 4.90 mmol) and TEA (1.02 mL, 7.35 mmol, 1.5
equiv) in DCM (7mL) at 0 ºC, pivaloyl chloride (0.60 mL, 4.90 mmol, 1.0 equiv) was added
dropwise. After stirring at the same temperature for 1h, the solvent was removed under vacuum
and the residue was redissolved in a mixture of hexane/EtOAc (5/1) and filtered over Celite.
After evaporation of the solvent, 801 mg of the crude mixed anhydride 6 were obtained (89%
yield).
300 mg (1.63 mmol) of the mixed anhydride 6 were dissolved in DCM (8 mL). The
corresponding alkyl vinyl ketone (3 equiv) was added followed by Hoveyda-Grubbs 2nd
generation catalyst (51 mg, 0.08 mmol, 5 mol %). The mixture was stirred for 2h at room
temperature after which additional 5 mol % of the catalyst were added. After stirring for 16h,
volatiles were removed under vacuum. The residue, containing the intermediate functionalized
mixed anhydride 7, was redissolved in DCM (8 mL) and cooled down to 0 ºC. TEA (0.45 mL,
3.26 mmol, 2 equiv) and allylamine (0.13 mL, 1.79 mmol, 1.1 equiv) were added and the
resulting mixture was stirred for 1h at 0 ºC and then for a further 1h at room temperature. At this
time, 8 mL of a saturated NH4Cl solution was added, the organic phase was separated and the
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aqueous phase was extracted with DCM (2x10 mL). The combined organic phases were dried
over anhydrous sodium sulfate and the solvent was removed under vacuum. The crude was
purified by flash chromatography on silica gel [n-hexane-EtOAc (1:1)] to afford the
intermediate amide 8.
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(E)-N-Allyl-6-oxo-4-octenamide (8a): Following the procedure described above and using
ethyl vinyl ketone in the cross-metathesis step, 8a was obtained as a brown oil in 43% yield
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over 2 steps from the mixed anhydride (137 mg). H NMR (400 MHz, CDCl3) δ 6.83 (dt, J =
15.9, 6.8 Hz, 1H), 6.13 (dt, J = 15.9, 1.5 Hz, 1H), 5.83 (ddt, J = 17.1, 10.2, 5.7 Hz, 1H), 5.52 (br
s, 1H), 5.22–5.11 (m, 2H), 3.89 (tt, J = 5.7, 1.5 Hz, 2H), 2.61–2.52 (m, 4H), 2.35 (t, J = 7.4 Hz,
2H), 1.08 (t, J = 7.3 Hz, 3H). 13C{1 H} NMR (75 MHz, CDCl3) δ 201.1, 171.2, 144.8, 134.2,
130.8, 116.8, 42.2, 34.8, 33.6, 28.1, 8.2. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for
C11H18NO2 196.1332, found 196.1332.
(E)-N-Allyl-6-oxo-4-heptenamide (8b): Following the procedure described above and using
methyl vinyl ketone in the cross-metathesis step, 8b was obtained as a brown oil in 41% yield
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over 2 steps from the mixed anhydride (121 mg). H NMR (300 MHz, CDCl3) δ 6.82 (dt, J =
16.0, 6.7 Hz, 1H), 6.10 (dt, J = 16.0, 1.5 Hz, 1H), 5.83 (ddt, J = 17.1, 10.2, 5.7 Hz, 1H), 5.51 (br
s, 1H), 5.22-5.12 (m, 2H), 3.90 (tt, J = 5.7, 1.5 Hz, 2H), 2.67 – 2.52 (m, 2H), 2.36 (t, J = 7.3 Hz,
2H), 2.24 (s, 3H). 13C{1 H} NMR (75 MHz, CDCl3) δ 198.6, 171.1, 146.2, 134.2, 131.9, 116.8,
42.2, 34.7, 28.1, 27.2. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C10H16NO2 182.1176, found
182.1174.
To a solution of amide 8 (0.50 mmol) in DCM (5 mL, 0.10 M) under a nitrogen atmosphere, the
corresponding alkyl vinyl ketone (3 equiv) and Hoveyda-Grubbs 2nd generation catalyst (16
mg, 0.05 mmol, 5 mol%) were added. After stirring for 2h at room temperature, a second equal
addition of the catalyst followed and the reaction mixture was further stirred at room
temperature for 16h. Volatiles were then removed under vacuum and the residue was purified
by flash chromatography on silica gel [n-hexane-EtOAc (1:1) to pure EtOAc].
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(E)-6-Oxo-N-[(E)-4-oxopent-2-en-1-yl]-4-octenamide (3o): Starting from amide 8a and
methyl vinyl ketone, 3o was obtained as a dark brown thick oil in 54% yield (64 mg). 1H NMR
(300 MHz, CDCl3) δ 6.83 (dt, J = 15.9, 6.7 Hz, 1H), 6.71 (dt, J = 16.1, 5.2 Hz, 1H), 6.18-6.09
(m, 2H), 5.66 (br s, 1H), 4.08 (td, J = 6.0, 1.8 Hz, 2H), 2.66–2.51 (m, 4H), 2.40 (t, J = 7.5 Hz,
2H), 2.26 (s, 3H), 1.09 (t, J = 7.3 Hz, 3H). 13C{1 H} NMR (75 MHz, CDCl3) δ 202.9, 201.0,
171.4, 144.4, 142.6, 131.1, 130.9, 40.5, 34.7, 33.7, 28.0, 27.3, 8.2. HRMS (ESI/Q-TOF) m/z:
[M+H]+ Calcd for C13H19NO3 238.1438; found 238.1443.
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(E)-6-Oxo-N-[(E)-4-oxohex-2-en-1-yl]-4-heptenamide (3p): Starting from amide 8b and ethyl
vinyl ketone, 3p was obtained as a dark brown thick oil in 52% yield (62 mg). 1H NMR (300
MHz, CDCl3) δ 5.93–5.88 (m, 1H), 5.80 (dd, J = 3.3, 1.4 Hz, 1H), 3.41-3.32 (m, 1H), 3.02–2.84
(m, 3H), 2.80–2.55 (m, 3H), 2.21 (s, 3H), 2.13 (ddd, J = 13.5, 9.1, 4.6 Hz, 1H), 1.75–1.58 (m,
1H), 1.20 (t, J = 7.3 Hz, 3H). 13C{1 H} NMR (75 MHz, CDCl3) δ 200.6, 198.6, 171.3, 145.9,
141.2, 132.0, 130.1, 40.5, 34.5, 33.7, 27.9, 27.3, 8.1.HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd
for C13H19NO3 238.1438; found 238.1443.
General procedure for the tandem cycloaromatization/intramolecular Friedel-
Crafts process:
To a solution of amide 3 (0.09 mmol) in CCl4 (3 mL, 0.03 M) in a pressure vial, 4 Å MS (300
mg) and (R)-TRIP-N-triflyl phosphoramide (8 mg, 0.009 mmol, 10 mol%) were added. The vial
was sealed and the resulting mixture was stirred at 40 ºC in an oil bath for 5 days. Volatiles
were then removed under vacuum and the residue was purified by flash chromatography on
silica gel. When the starting amide 3 did not show enough solubility in CCl4, it was sonicated in
the solvent until complete dissolution prior to the addition of the catalyst.
For the racemic approach, an analogous protocol was followed using (PhO)2P(O)NHTf as the
achiral organocatalyst and toluene as the solvent at 60 ºC for 16h.
3-Methyl-8-(2-oxopropyl)-7,8-dihydroindolizin-5(6H)-one (5a): Starting from 3a, 5a was
obtained as a light yellow solid (mp = 42-44 ºC) in 84% yield (16 mg) in racemic manner and
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76% yield (14 mg) in enantioenriched manner after flash chromatography [n-hexane-EtOAc
(9:1)]. When the organocatalytic reaction was repeated starting from 532 mg of 3a (2.38 mmol),
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5a was obtained in 44% yield (216 mg) and 74:26 er. [α]D = -20.0° (c 1.0; CHCl3). 1H NMR
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(300 MHz, CDCl3) δ 5.84 (s, 1H), 5.73 (d, J = 2.5 Hz, 1H), 3.50-3.43 (m, 1H), 3.02–2.80 (m,
3H), 2.70 (dd, J = 17.1, 7.8 Hz, 1H), 2.38 (s, 3H), 2.19 (s, 3H), 1.98-1.86 (m, 1H), 1.46–1.34
(m, 1H). 13C{1 H} NMR (75 MHz, CDCl3) δ 206.7, 175.1, 135.4, 132.7, 110.6, 107.7, 47.7,
36.7, 31.6, 30.9, 30.6, 20.4, 16.0. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C12H15NO2
206.1176; found 206.1170. HPLC (Phenomenex Cellulose-4, 70:30 hexane/i-PrOH, 1 mL/min):
tR(major) = 14.88 min, tR(minor) = 17.56 min.
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3-Ethyl-8-(2-oxobutyl)-7,8-dihydroindolizin-5(6H)-one (5b): Starting from 3b, 5b was
obtained as a light yellow solid (mp = 64-66 ºC) in 80% yield (17 mg) in racemic manner and
70% yield (15 mg) in enantioenriched manner after flash chromatography [n-hexane-EtOAc
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(9:1)]. [α]D = -10.3° (c 1.0; CHCl3). H NMR (300 MHz, CDCl3) δ 5.91 (dt, J = 3.2, 1.2 Hz,
1H), 5.79 (dd, J = 3.2, 1.6 Hz, 1H), 3.44-3.35 (m, 1H), 3.01–2.83 (m, 3H), 2.81–2.55 (m, 3H),
2.55–2.40 (m, 2H), 2.12 (dq, J = 12.9, 4.8 Hz, 1H), 1.75–1.61 (m, 1H), 1.20 (t, J = 7.4 Hz, 3H),
1.10 (t, J = 7.3 Hz, 3H). 13C{1 H} NMR (75 MHz, CDCl3) δ 209.5, 169.9, 138.0, 135.9, 109.5,
107.0, 46.3, 36.8, 34.2, 30.1, 27.7, 23.0, 13.1, 7.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for
C14H19NO2 234.1489; found 234.1480. HPLC (Phenomenex Cellulose-4, 70:30 hexane/i-PrOH,
1 mL/min): tR(major) = 8.65 min, tR(minor) = 18.61 min.
8-(2-Oxopentyl)-3-propyl-7,8-dihydroindolizin-5(6H)-one (5c): Starting from 3c, 5c was
obtained as a yellow oil in 86% yield (20 mg) in racemic manner and 80% yield (19 mg) in
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enantioenriched manner after flash chromatography [n-hexane-EtOAc (9:1)]. [α]D = -8.7° (c
1.0; CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.89 (dt, J = 3.3, 1.1 Hz, 1H), 5.77 (dd, J = 3.3, 1.6
Hz, 1H), 3.47–3.29 (m, 1H), 2.98–2.53 (m, 6H), 2.47–2.38 (m, 2H), 2.15-2.06 (m, 1H), 1.78–
1.52 (m, 5H), 0.99-0.91 (m, 6H). 13C{1 H} NMR (75 MHz, CDCl3) δ 209.1, 169.9, 136.2,
135.9, 110.5, 106.9, 46.7, 45.5, 34.2, 31.6, 30.1, 27.7, 22.0, 17.4, 14.1, 13.9. HRMS (ESI/Q-
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obtained as a colorless oil in 83% yield (24 mg) in racemic manner and 63% yield (18 mg) in
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enantioenriched manner after flash chromatography [n-hexane-EtOAc (9:1)]. [α]D = -4.3° (c
1.0; CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.89 (dt, J = 3.2, 1.0 Hz, 1H), 5.77 (dd, J = 3.2, 1.6
Hz, 1H), 3.50–3.30 (m, 1H), 3.04–2.53 (m, 5H), 2.52–2.37 (m, 2H), 2.22–2.01 (m, 1H), 1.77–
1.46 (m, 5H), 1.46–1.16 (m, 9H), 1.00–0.78 (m, 6H). 13C{1 H} NMR (75 MHz, CDCl3) δ 209.,
169.9, 136.5, 135.9), 110.4, 106.9, 46.7, 43.7, 34.2, 31.8, 31.5, 30.1, 29.5, 28.5, 27.7, 23.6, 22.7,
22.6, 14.2, 14.1. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C20H31NO2 318.2428; found
318.2428. HPLC (Phenomenex Cellulose-4, 70:30 hexane/i-PrOH, 1 mL/min): tR(major) = 5.97
min, tR(minor) = 8.00 min.
8-(2-Oxo-2-phenylethyl)-3-phenyl-7,8-dihydroindolizin-5(6H)-one (5e): Starting from 3e, 5e
was obtained as an orange oil in 60% yield (18 mg) in racemic manner and 44% yield (13 mg)
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in enantioenriched manner after flash chromatography [n-hexane-EtOAc (9:1)]. [α]D = -82.0°
(c 1.0; CHCl3).1H NMR (300 MHz, CDCl3) δ 8.07–7.98 (m, 2H), 7.66–7.58 (m, 1H), 7.58–7.46
(m, 2H), 7.39-7.29 (m, 5H), 6.17 (d, J = 3.4 Hz, 1H), 6.02 (dd, J = 3.4, 1.5 Hz, 1H), 3.77–3.64
(m, 1H), 3.56 (dd, J = 17.2, 5.2 Hz, 1H), 3.25 (dd, J = 17.2, 7.9 Hz, 1H), 2.90–2.71 (m, 2H),
2.31-2.22 (m, 1H), 1.98–1.79 (m, 1H). 13C{1 H} NMR (75 MHz, CDCl3) δ 198.1, 168.9, 138.0,
136.9, 134.7, 134.2, 133.7, 129.1 (2xCH), 129.0 (2xCH), 128.3 (2xCH), 127.7 (2xCH), 127.3,
114.9, 108.1, 42.7, 34.1, 30.7, 28.0. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C22H19NO2
330.1489; found 330.1492. HPLC (Phenomenex Cellulose-4, 70:30 hexane/i-PrOH, 1 mL/min):
tR(major) = 28.57 min, tR(minor) = 54.63 min.
3-Methyl-9-(2-oxopropyl)-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepin-5-one (5f): Starting
from 3f, 5f was obtained as a colorless oil in 74% yield (15 mg) in racemic manner and 70%
yield (14 mg) in enantioenriched manner after flash chromatography [n-hexane-EtOAc (9:1)].
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3.3, 1.2 Hz, 1H), 3.45 (td, J = 11.5, 5.6 Hz, 1H), 2.96 (dd, J = 17.1, 6.0 Hz, 1H), 2.91–2.81 (m,
2H), 2.70 (dd, J = 17.1, 7.8 Hz, 1H), 2.40 (s, 3H), 2.20 (s, 3H), 2.01–1.85 (m, 2H), 1.77–1.62
(m, 1H), 1.47–1.33 (m, 1H). 13C{1 H} NMR (75 MHz, CDCl3) δ 206.8, 175.1, 135.4, 132.7,
110.6, 107.7, 47.7, 36.8, 31.6, 30.9, 30.6, 20.4, 16.0. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd
for C13H17NO2 220.1332; found 220.1330. HPLC (Phenomenex Cellulose-4, 70:30 hexane/i-
PrOH, 1 mL/min): tR(major) = 15.36 min, tR(minor) = 9.76 min.
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3-Ethyl-9-(2-oxobutyl)-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepin-5-one (5g): Starting
from 3g, 5g was obtained as a yellow oil in 72% yield (16.5 mg) in racemic manner and 71%
yield (16 mg) in enantioenriched manner after flash chromatography [n-hexane-EtOAc (9:1)].
[α]D25 = +4.6° (c 1.0; CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.90 (dt, J = 3.2, 1.1 Hz, 1H), 5.76
(dd, J = 3.2, 1.2 Hz, 1H), 3.58–3.40 (m, 1H), 3.05–2.62 (m, 6H), 2.60–2.37 (m, 2H), 1.98–1.84
(m, 2H), 1.76–1.60 (m, 1H), 1.45–1.30 (m, 1H), 1.17 (t, J = 7.4 Hz, 3H), 1.07 (t, J = 7.3 Hz,
3H). 13C{1 H} NMR (75 MHz, CDCl3) δ 209.5, 175.3, 139.2, 135.7, 108.6, 107.6, 46.5, 36.9,
36.7, 31.7, 30.9, 22.6, 20.4, 13.2, 7.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C15H21NO2
248.1645; found 248.1648. HPLC (Phenomenex Cellulose-4, 70:30 hexane/i-PrOH, 1 mL/min):
tR(major) = 7.91 min, tR(minor) = 10.12 min.
9-(2-Oxopentyl)-3-propyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepin-5-one (5h): Starting
from 3h, 5h was obtained as a yellow oil in 70% yield (18 mg) in racemic manner and 63%
yield (16 mg) in enantioenriched manner after flash chromatography [n-hexane-EtOAc (9:1)].
[α]D25 = +5.0° (c 1.0; CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.88 (d, J = 3.3 Hz, 1H), 5.75 (dd,
J = 3.3, 1.1 Hz, 1H), 3.55–3.39 (m, 1H), 3.00–2.61 (m, 6H), 2.43 (td, J = 7.2, 2.2 Hz, 2H), 2.01–
1.82 (m, 2H), 1.74–1.51 (m, 4H), 1.46–1.20 (m, 2H), 1.04–0.86 (m, 6H). 13C{1 H} NMR (75
MHz, CDCl3) δ 209.1, 175.3, 137.4, 135.6, 109.6, 107.5, 46.9, 45.4, 36.9, 31.7, 31.2, 30.8, 22.3,
20.5, 17.4, 14.1, 13.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C17H25NO2 276.1958; found
276.1960. HPLC (Phenomenex Cellulose-4, 70:30 hexane/i-PrOH, 1 mL/min): tR(major) =
13.04 min, tR(minor) = 11.60 min.
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9-(2-Oxoheptyl)-3-pentyl-6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]azepin-5-one (5i): Starting
from 3i, 5i was obtained as a yellow oil in 76% yield (23 mg) in racemic manner and 79% yield
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(24 mg) in enantioenriched manner after flash chromatography [n-hexane-EtOAc (9:1)]. [α]D
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= +3.9° (c 1.0; CHCl3). H NMR (300 MHz, CDCl3) δ 5.88 (d, J = 3.3 Hz, 1H), 5.75 (dd, J =
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3.3, 1.1 Hz, 1H), 3.54–3.40 (m, 1H), 2.98–2.61 (m, 6H), 2.43 (td, J = 7.3, 2.4 Hz, 2H), 2.01–
1.80 (m, 2H), 1.76–1.46 (m, 5H), 1.46–1.17 (m, 9H), 0.91-0.86 (m, 6H). 13C{1 H} NMR (75
MHz, CDCl3) δ 209.2, 175.3, 137.6, 135.6, 109.4, 107.5, 46.8, 43.5, 36.9, 31.8, 31.7, 31.5, 30.8,
29.1, 28.8, 23.6, 22.7, 22.6, 20.5, 14.2, 14.1. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for
C21H33NO2 332.2584; found 332.2585. HPLC (Phenomenex Cellulose-4, 70:30 hexane/i-PrOH,
1 mL/min): tR(major) = 17.97 min, tR(minor) = 11.56 min.
7-Methyl-1-(2-oxopropyl)-1,2-dihydropyrrolo[1,2-d][1,4]oxazepin-5(4H)-one (5j): Starting
from 3j, 5j was obtained as a yellow solid (mp = 105-107 ºC) in 70% yield (14 mg) in racemic
manner and 70% yield (14 mg) in enantioenriched manner after flash chromatography [n-
hexane-EtOAc (3:2)]. [α]D = +10.7° (c 1.0; CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.94–5.88
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(m, 1H), 5.80 (dd, J = 3.2, 1.1 Hz, 1H), 4.54 (d, J = 17.9 Hz, 1H), 4.41 (d, J = 17.9 Hz, 1H),
4.00 (dd, J = 10.0, 6.5 Hz, 1H), 3.86-3.75 (m, 1H), 3.41 (dd, J = 11.3, 10.0 Hz, 1H), 2.99 (dd, J
= 17.7, 6.1 Hz, 1H), 2.64 (dd, J = 17.7, 7.3 Hz, 1H), 2.39 (s, 3H), 2.22 (s, 3H). 13C{1 H} NMR
(75 MHz, CDCl3) δ 205.3, 174.5, 132.9, 132.5, 111.3, 108.3, 72.4, 69.6, 43.3, 32.0, 30.4, 15.2.
HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C12H15NO3 222.1125; found 222.1127. HPLC
(Phenomenex Cellulose-4, 70:30 hexane/i-PrOH, 2 mL/min): tR(major) = 7.11 min, tR(minor) =
21.17 min.
7-Methyl-1-(2-oxopropyl)-1,2-dihydropyrrolo[1,2-d][1,4]thiazepin-5(4H)-one (5k): Starting
from 3k, 5k was obtained as a white solid (mp = 78-80 ºC) in 56% yield (12 mg) in racemic
manner and 47% yield (10 mg) in enantioenriched manner after flash chromatography [n-
hexane-EtOAc (9:1)]. [α]D25 = +19.0° (c 1.0; CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.91 (dq, J
= 3.3, 1.1 Hz, 1H), 5.86 (dd, J = 3.3, 0.9 Hz, 1H), 3.95 (d, J = 17.3 Hz, 1H), 3.71-3.61 (m, 1H),
3.47 (d, J = 17.3, 1H), 3.18 (dd, J = 11.4, 4.3 Hz, 1H), 3.08 (dd, J = 17.6, 5.9 Hz, 1H), 2.85 (dd,
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J = 17.6, 7.6 Hz, 1H), 2.46–2.31 (m, 4H), 2.21 (s, 3H). 13C{1 H} NMR (75 MHz, CDCl3) δ
205.5, 172.3, 133.8, 133.7, 111.2, 109.4, 47.4, 34.7, 34.1, 32.6, 30.6, 16.3. HRMS (ESI/Q-TOF)
m/z: [M+H]+ Calcd for C12H15NO2S 238.0896; found 238.0901. HPLC (Phenomenex Cellulose-
4, 70:30 hexane/i-PrOH, 1 mL/min): tR(major) = 21.32 min, tR(minor) = 17.03 min.
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tert-Butyl
7-methyl-5-oxo-1-(2-oxopropyl)-1,2,4,5-tetrahydro-3H-pyrrolo[1,2-d]
[1,4]diazepine-3-carboxylate (5l): Starting 3l, 5l was obtained as a light yellow oil in 64%
yield (18 mg) in racemic manner and 59% yield (17 mg) in enantioenriched manner after flash
chromatography [n-hexane-EtOAc (3:2)]. [α]D25 = +11.6° (c 1.0; CHCl3). Due to the presence of
two major rotamers, two sets of signals are observable. 1H NMR (300 MHz, CDCl3) δ 5.81-5.78
(m, 1H), 5.72-5.70 (m, 1H), 4.67 (d, J = 18.2 Hz, 0.3H), 4.47 (d, J = 18.3 Hz, 0.7H), 3.94-3.81
(m, 1H), 3.68–3.15 (m, 3H), 3.00 (d, J = 5.6 Hz, 0.3H), 2.96– 2.92 (m, 0.7H), 2.78–2.59 (m,
1H), 2.32 (s, 2.1H), 2.30 (s, 0.9H), 2.16 (s, 3H), 1.25 (s, 6.3H), 1.23 (s, 2.7H). 13C{1 H} NMR
(75 MHz, CDCl3) δ 205.6, 173.1, 155.2, 132.6, 132.5, 111.2, 108.9, 81.2, 51.7, 49.8, 44.5, 32.3,
30.6, 28.2, 15.3. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C17H24N2O4 321.1809; found
321.1813. HPLC (Phenomenex Cellulose-4, 70:30 hexane/i-PrOH, 2 mL/min): tR(major) = 9.53
min, tR(minor) = 7.71 min.
7-Methyl-1-(2-oxopropyl)-3-tosyl-1,2,3,4-tetrahydro-5H-pyrrolo[1,2-d][1,4]diazepin-5-one
(5m): Starting from 3m, 5m was obtained as a yellow oil in 82% yield (27 mg) in racemic
manner and 75% yield (25 mg) in enantioenriched manner after flash chromatography [n-
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hexane-EtOAc (3:2)]. [α]D = +6.7° (c 1.0; CHCl3). H NMR (300 MHz, CDCl3) δ 7.49–7.41
(m, 2H), 7.19-7.13 (m, 1H), 5.75–5.69 (m, 2H), 4.65 (d, J = 18.9 Hz, 1H), 4.04 (d, J = 18.9 Hz,
1H), 3.63–3.31 (m, 3H), 3.07–2.97 (m, 1H), 2.80–2.70 (m, 1H), 2.37 (s, 3H), 2.21 (s, 3H), 2.11
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(s, 3H). C{1 H} NMR (75 MHz, CDCl3) δ 205.1, 170.8, 143.7, 136.1, 133.0, 132.0, 129.9
(2xCH), 126.6 (2xCH), 111.2, 109.1, 51.5, 50.7, 44.4, 31.9, 30.5, 21.6, 15.1. HRMS (ESI/Q-
TOF) m/z: [M+H]+ Calcd for C19H22N2O4S 375.1373; found 375.1376. HPLC (Chiralcel AD,
70:30 hexane/i-PrOH, 1 mL/min): tR(major) = 52.12 min, tR(minor) = 59.32 min.
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Diethyl 3-methyl-5-oxo-9-(2-oxopropyl)-5,6,8,9-tetrahydro-7H-pyrrolo[1,2-a]azepine-7,7-
dicarboxylate (5n): Starting from 3n, 5n was obtained as a yellow oil in 72% yield (23 mg) in
racemic manner and 62% yield (20 mg) in enantioenriched manner after flash chromatography
[n-hexane-EtOAc (9:1)]. [α]D25 = -16.4° (c 1.0; CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.81 (dq,
J = 3.2, 1.0 Hz, 1H), 5.73 (dd, J = 3.2, 1.1 Hz, 1H), 4.34–4.13 (m, 2H), 4.11-3.95 (m, 2H), 3.51-
3.35 (m, 3H), 3.01 (dd, J = 17.5, 5.5 Hz, 1H), 2.76 (dd, J = 17.5, 8.2 Hz, 1H), 2.39-2.30 (m,
4H), 2.26-2.17 (m, 4H), 1.28-1.14 (m, 6H). 13C{1 H} NMR (75 MHz, CDCl3) δ 206.0, 170.4,
170.4, 170.4, 134.2, 132.8, 111.0, 108.2, 62.6, 62.3, 54.1, 47.1, 42.0, 38.0, 30.6, 29.9, 15.7,
14.1, 14.0. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C19H25NO6 364.1755; found 364.1759.
HPLC (Phenomenex Cellulose-4, 70:30 hexane/i-PrOH, 1 mL/min): tR(major) = 29.13 min,
tR(minor) = 14.77 min.
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3-Methyl-8-(2-oxobutyl)-7,8-dihydroindolizin-5(6H)-one (5o): Starting from 3o, 5o was
obtained as a whit solid (mp = 44-46 ºC) in 80% yield (16 mg) in racemic manner and 70%
yield (14 mg) in enantioenriched manner after flash chromatography [n-hexane-EtOAc (9:1)].
[α]D25 = -9.2° (c 1.0; CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.86 (dq, J = 3.2, 1.2 Hz, 1H), 5.76
(dd, J = 3.2, 1.5 Hz, 1H), 3.51–3.34 (m, 1H), 2.93 (dd, J = 17.2, 5.4 Hz, 1H), 2.82–2.54 (m,
3H), 2.54–2.40 (m, 5H), 2.13 (dq, J = 13.0, 4.8 Hz, 1H), 1.74-1.61 (m, 1H), 1.10 (t, J = 7.3 Hz,
3H). 13C{1 H} NMR (75 MHz, CDCl3) δ 209.7, 170.2, 135.8, 131.3, 111.6, 106.9, 46.3, 36.8,
34.0, 30.1, 27.8, 16.2, 7.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C13H17NO2 220.1332;
found 220.1338. HPLC (Phenomenex Cellulose-4, 70:30 hexane/i-PrOH, 1 mL/min): tR(major)
= 10.44 min, tR(minor) = 21.24 min.
3-Ethyl-8-(2-oxopropyl)-7,8-dihydroindolizin-5(6H)-one (5p): Starting from 3p, 5p was
obtained as a light brown solid (mp = 55-57 ºC) in 82% yield (16 mg) in racemic manner and
62% yield (12 mg) in enantioenriched manner after flash chromatography [n-hexane-EtOAc
(9:1)]. [α]D = -13.0° (c 1.0; CHCl3). 1H NMR (300 MHz, CDCl3) δ 5.86 (dq, J = 3.2, 1.2 Hz,
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1H), 5.76 (dd, J = 3.2, 1.5 Hz, 1H), 3.51–3.34 (m, 1H), 2.93 (dd, J = 17.2, 5.4 Hz, 1H), 2.82–
2.54 (m, 3H), 2.54–2.40 (m, 5H), 2.13 (dq, J = 13.0, 4.8 Hz, 1H), 1.74-1.61 (m, 1H), 1.10 (t, J =
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7.3 Hz, 3H). 13C{1 H} NMR (75 MHz, CDCl3) δ 209.7, 170.2, 135.8, 131.3, 111.6, 106.9, 46.3,
36.8, 34.0, 30.1, 27.8, 16.2, 7.9. HRMS (ESI/Q-TOF) m/z: [M+H]+ Calcd for C13H17NO2
220.1332; found 220.1337. HPLC (Phenomenex Cellulose-4, 70:30 hexane/i-PrOH, 1 mL/min):
tR(major) = 12.01 min, tR(minor) = 15.04 min.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
xxxxxxxxxxxxx.
HPLC traces of enantioenriched compounds 5, vibrational Circular Dichroism (VCD) of 5a and
NMR spectra of compounds 2a and 2b and all new compounds (1H, 13C) (PDF).
AUTHOR INFORMATION
Corresponding Authors
*E-mail: carlos.pozo@uv.es
*E-mail: santos.fustero@uv.es
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully thank the Spanish Ministerio de Economía y Competitividad (CTQ-2017-85026-
R). F. R. A.. thanks the Spanish Ministerio de Educación, Cultura y Deporte for a predoctoral
fellowship (FPU14/03520). Technical and human support provided by SSTTI (Universidad de
Alicante) is gratefully acknowledged.
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