Catalytic Enantioselective Hetero-[6+4] and-[6+2] Cycloadditions for the Construction of Condensed Polycyclic Pyrroles, Imidazoles, and Pyrazoles

Article abstract of DOI:10.1021/jacs.8b13659

The development of the first chemo-, regio-, and stereoselective hetero-[6+4] and-[6+2] cycloadditions of heteroaromatic compounds via amino aza-and diazafulvenes is presented. Pyrroles, imidazoles, and pyrazoles substituted with a formyl group react with an aminocatalyst to generate an electron-rich hetero-6?€-component that reacts in a chemo-, regio-, and stereoselective manner with electron-deficient dienes and olefins. For the hetero-[6+4] cycloaddition of the pyrrole system with dienes, a wide variation of both reaction partners is possible, providing attractive pyrrolo-azepine products in high yields and excellent enantioselectivities (99% ee). The hetero-[6+4] cycloaddition reaction concept is extended to include imidazoles and pyrazoles, giving imidazolo-and pyrazolo-azepines. The same activation concept is successfully employed to include hetero-[6+2] cycloadditions of the pyrrole system with nitroolefins, giving important pyrrolizidine-alkaloid scaffolds. Experimental NMR and mechanistic studies allowed for the identification of two different types of intermediates in the reaction. The first intermediate is the result of a rapid formation of an iminium ion, which generates a hetero-6?€ aminofulvene intermediate as a mixture of two isomers. Density functional theory calculations were used to determine the mechanism and sources of asymmetric induction in the hetero-[6+4] and-[6+2] cycloadditions. After formation of the reactive hetero-6?€-components, a stepwise addition occurs with the diene or olefin, leading to a zwitterionic intermediate that undergoes cyclization to afford the cycloadduct, followed by eliminative catalyst release. The stereoselectivity is controlled by the second step, and computations elaborate on the various substrate and catalyst effects that alter the experimentally observed enantioselectivities. The computational studies provided a basis for improving the enantioselectivity of the hetero-[6+2] cycloaddition.

Full text of DOI:10.1021/jacs.8b13659

Article
pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Catalytic Enantioselective Hetero-[6+4] and -[6+2] Cycloadditions
for the Construction of Condensed Polycyclic Pyrroles, Imidazoles,
and Pyrazoles
Giulio Bertuzzi,† Mathias Kirk Thøgersen,† Maxime Giardinetti,† Andreu Vidal-Albalat,†
Adam Simon,‡,§ K. N. Houk,*,‡,§ and Karl Anker Jørgensen*,†
†Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
‡Department of Chemistry and Biochemistry and §Department of Chemical and Biomolecular Engineering, University of California,
Los Angeles, California 90095, United States
S
* Supporting Information
ABSTRACT: The development of the first chemo-, regio-, and
stereoselective hetero-[6+4] and -[6+2] cycloadditions of hetero-
aromatic compounds via amino aza- and diazafulvenes is presented.
Pyrroles, imidazoles, and pyrazoles substituted with a formyl group
react with an aminocatalyst to generate an electron-rich hetero-6π-
component that reacts in a chemo-, regio-, and stereoselective
manner with electron-deficient dienes and olefins. For the hetero-
[6+4] cycloaddition of the pyrrole system with dienes, a wide
variation of both reaction partners is possible, providing attractive
pyrrolo-azepine products in high yields and excellent enantioselectiv-
ities (99% ee). The hetero-[6+4] cycloaddition reaction concept is
extended to include imidazoles and pyrazoles, giving imidazolo- and
pyrazolo-azepines. The same activation concept is successfully
employed to include hetero-[6+2] cycloadditions of the pyrrole system with nitroolefins, giving important pyrrolizidine-
alkaloid scaffolds. Experimental NMR and mechanistic studies allowed for the identification of two different types of
intermediates in the reaction. The first intermediate is the result of a rapid formation of an iminium ion, which generates a
hetero-6π aminofulvene intermediate as a mixture of two isomers. Density functional theory calculations were used to
determine the mechanism and sources of asymmetric induction in the hetero-[6+4] and -[6+2] cycloadditions. After formation
of the reactive hetero-6π-components, a stepwise addition occurs with the diene or olefin, leading to a zwitterionic intermediate
that undergoes cyclization to afford the cycloadduct, followed by eliminative catalyst release. The stereoselectivity is controlled
by the second step, and computations elaborate on the various substrate and catalyst effects that alter the experimentally
observed enantioselectivities. The computational studies provided a basis for improving the enantioselectivity of the hetero-
[6+2] cycloaddition.
Heterocyclic compounds, such as pyrroles, imidazoles, and
pyrazoles, are fundamental scaffolds in chemistry. Their
functionalization has been the center of numerous synthetic
efforts, due to their presence in, e.g., biologically relevant
compounds1−5 and materials.6−9 Functionalization of these
heterocyclic compounds is usually carried out through
electrophilic C-functionalizations, for which a large number
of well-established methodologies exist.10 Besides classical
electrophilic aromatic substitution reactions, such as halogen-
ation, nitration, sulfonation, acylation, and Vilsmeier−Haack
formylation, enantioselective functionalization of pyrrole
derivatives has mainly been carried out under Friedel−Crafts
conditions11,12 or following C−H functionalization method-
ologies (Scheme 1, top).13 Only one example of an aldehyde
INTRODUCTION
■
Expanding the borders of reactivity can pave avenues for novel
methodologies in organic synthesis. An important challenge for
such new developments is to provide methodologies where
basic organic molecules are employed in combination with
diverse reaction partners. Furthermore, combining experimen-
tal and computational investigations might provide deeper
mechanistic understandings for expanding reactivity into new
chemical spaces. In the following, we present the unprece-
dented catalytic chemo-, regio-, and enantioselective hetero-
[6+4] and -[6+2] cycloaddition reactions of heteroaromatic
compounds. Mechanistic studies allow for identification of
reactive intermediates in the catalytic cycle. Computational
studies afford important insights into the mechanism and
stereoselectivity of these cycloaddition reactions and allow for
improvement of enantioselectivity.
Received: December 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b13659
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
and only few examples of racemic hetero-[6+2] cycloadditions
have been disclosed.32−34 The nitrogen-containing bicyclic
compounds obtained with the presented methodology
(Scheme 1, bottom) include pyrrolo[1,2-a]azepines 4 or 6
and pyrrolizine derivatives 8. The former is a part of the
scaffold in the family of Stemona alkaloids, like Parvistemonine
A A35 and cephalotaxine alkaloids B.36 Furthermore,
Midazolam C and related imidazobenzodiazepine-based anti-
anxiety drugs,37 present a similar backbone built on a diazole
moiety. Compounds 8 contain a skeleton shared between a
family of recurring natural pyrrolizidine alkaloids D exhibiting
cytotoxicity.38 In addition, this motif is present in Ketorolac, a
non-steroidal anti-inflammatory drug E (Figure 1).39
Scheme 1. N- versus C-Asymmetric Functionalization of
Pyrrole Derivatives
Figure 1. Biologically relevant scaffolds A−E based on products 4, 6,
and 8 in Scheme 1.
(octanal) reacting with N-Boc pyrrole under organocatalytic
oxidative conditions has been reported14 (Scheme 1, top). On
the other hand, the employment of pyrroles and related
heteroaromatic compounds as N-centered nucleophiles is
much less explored, although N-fused bicycles are key
backbones of many important products.15−20
In the present work, we disclose novel direct strategies for
enantioselective functionalization of pyrroles, imidazoles, and
pyrazoles based on unprecedented catalytic enantioselective
hetero-[6+4] and -[6+2] cycloaddition reactions (Scheme 1,
bottom). Mechanistic studies based on NMR and computa-
tional investigations provide valuable information about
catalytic intermediates, reaction courses, and how to improve
the stereoselective performance of the catalyst.
Recently, the first intermolecular organocatalytic enantiose-
lective [6+4],21 [8+2],22,23 and [10+4] cycloadditions24 were
disclosed. In addition, Hayashi reported an intramolecular
[6+2] cycloaddition of a fulvene moiety with a catalytically
generated enamine.25 Hong explored the use of 6-amino-
fulvenes in stoichiometric amounts for intermolecular [6+2],26
[6+3],27 and [6+4] cycloadditions.28 Furthermore, Chen
developed an organocatalyzed enantioselective [6+2] cyclo-
addition where a 4-aminofulvene intermediate is produced in
situ in catalytic quantities.29
Pyrroles, imidazoles, and pyrazoles, substituted with a formyl
group, are stable aromatic species that, upon condensation
with an aminocatalyst, give aminoazafulvenes.30,31 These 6π-
components are expected to be prone to participate in
cycloadditions. Stable 6-aminoazafulvenes were first reported
in 1975 by Kanemasa,32 and later 6-amino-1,4-diazafulvene
was shown to react as a 6π-component in thermal33 and metal-
promoted34 cycloadditions.
RESULTS AND DISCUSSION
■
Screening of Reaction Conditions for Hetero-[6+4]
Cycloadditions. We started our investigation by treating
pyrrole-2-carbaldehyde 1a with secondary aminocatalysts 3 to
provide the desired transient electron-rich 6-aminoazafulvene
which was captured by electron-deficient diene 2a in a hetero-
[6+4] cycloaddition, rendering the tricyclic compound 4aa
after catalyst release. The most commonly employed amino-
catalyst 3a40,41 combined with benzoic acid (BzOH) and
molecular sieves (MS) as additives in dry CDCl3 at room
temperature delivered 4aa in trace amounts, but with an
excellent degree of enantioselectivity (99% ee, Table 1, entry
1). Changing for a less bulky fluorine substituted catalyst
3b42,43 improved the yield to 40% maintaining the
enantioselectivity (entry 2), while catalyst 3c afforded 4aa
with improved yield but slightly diminished enantioselectivity
(entry 3). The most stereoselective catalyst was selected and,
in order to overcome the poor reactivity, other reaction
parameters were evaluated. Notably, to achieve a decent degree
of conversion, both BzOH and molecular sieves (MS) have to
be applied as additives (entries 4 and 5). Performing the
reaction at 40 °C resulted in diminished yield due to rapid
decomposition of 2a (entry 6). However, employing an excess
of 2a improved the yield slightly (entry 7). Finally, after
additional screening (see Supporting Information), we found
that pMeOBzOH, along with a more concentrated reaction
medium and a reaction time of 2 days, afforded 4aa in 73%
yield and 99% ee (entry 8).
Scope of Hetero-[6+4] Cycloadditions for Pyrroles.
First, variations of substituents in the 4-position of the pyrrole
ring were explored. The introduction of heteroatoms such as
bromine (1b), silicon (1c), and sulfur (1d) provided the
products 4ba−da in 68−90% yield and 99% ee (Table 2,
entries 2−4). The absolute configuration of 4da was assigned
To the best of our knowledge, pyrrole, imidazole, and
pyrazole derivatives have never been demonstrated to
participate in enantioselective hetero-[6+4] cycloadditions,
B
DOI: 10.1021/jacs.8b13659
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
(1g,h) and pyrazoles (1i), applying only some minor
modifications of the reaction conditions. The scope of the
cycloadditions of 1g−i was demonstrated by reaction with four
electron-deficient dienes 2 (Scheme 2). Imidazole-2-carbalde-
Table 1. Optimization of the Hetero-[6+4] Cycloaddition
Scheme 2. Scope of the Hetero-[6+4] Cycloadditions of
Imidazoles and Pyrazoles 1g−i with Electron-Deficient
a
Dienes 2
b
c
d
entry
cat. 3
additive
yield (%)
ee (%)
1
2
3
4
5
3a
3b
3c
3b
3b
3b
3b
3b
BzOH, MS
BzOH, MS
BzOH, MS
MS
BzOH
BzOH, MS
BzOH, MS
5
40
65
12
10
20
46
99
99
95
n.d.
n.d.
96
99
99
e
6
f
7
f
g
8
pMeOBzOH, MS
75(73)
a
b
Reaction conditions: see Supporting Information. 20 mol% acid
c
used. Yield measured by NMR on the crude reaction mixture with
Et4Si as internal standard. Determined by chiral stationary phase
UPCC. Reaction at 40 °C. Reaction conditions: 1a (0.1 mmol), 2a
(0.15 mmol), 2 d. Isolated yield.
d
e
f
g
Table 2. Reaction Scope of the Hetero-[6+4] Cycloaddition:
a
Variation of Aldehydes 1 and Electron-Poor Dienes 2
a
Reaction conditions: Supporting Information. Unless otherwise
stated, 10 mol% 3b and 10 mol% pMeOBzOH were employed;
b
c
reaction time: 1 d. Isolated yield. Determined by chiral stationary
d
e
phase UPCC. 3b (20 mol%), pMeOBzOH (20 mol%). Reaction
time: 2 d. Reaction time: 6 d.
f
b
c
hyde 1g, as well as imidazole-4-carbaldehyde 1h, required in
most of the cases milder reaction conditions (10 mol% catalyst
and additive, and higher dilution) due to some instability of
the respective products in the reaction mixtures. The hetero-
[6+4] cycloadducts 4ga, 4gd, and 4ge were obtained in
moderate to good yields (46−69%) and high enantioselectiv-
ities (84−95% ee). In comparison, similar high enantiomeric
excesses, but lower yields were obtained for 4ha, 4hb, and 4he,
probably due to enhanced instability of these products. Finally,
pyrazole-5-carbaldehyde 1i turned out to be the least reactive
heterocycle investigated; however, we were pleased to obtain
4ia and 4ib in 31% and 38% yield, and 87% and 90% ee,
respectively. For the optimization of the reaction conditions
for aldehydes 1g−i see Supporting Information.
entry
1, R
1a, H
1b, Br
1c, Si(iPr)3
1d, SPh
1e, Ph
1f, pMeOC6H4
1a, H
1a, H
1a, H
1a, H
1a, H
2, X
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2b, pBrC6H4
2c, pMeOC6H4
2d, pNO2C6H4
2e, OEt
4, yield (%)
ee (%)
1
2
3
4
5
6
7
8
4aa, 73
4ba, 68
4ca, 90
4da, 70
4ea, 65
4fa, 52
4ab, 87
4ac, 54
4ad, 67
4ae, 60
99
99
99
99
99
99
99
99
99
99
99
9
10
11
2f, OPh
4af, 88
a
b
Reaction conditions: Supporting Information. Isolated yield.
c
Determined by chiral stationary phase UPCC.
Scope of Hetero-[6+4] Cycloadditions for Dienes 5. In
addition, a different class of electron-deficient dienes 5, based
on an acyclic and less conformationally restricted scaffold, was
reacted with pyrrole 1a and imidazole 1g. These examples
required an increased catalyst and additive loading (40 mol%),
and a longer reaction time (4 days; for additional optimization,
see Supporting Information). Both an electron-neutral aryl
substituent (5a) and an electron-poor one (5b) were tolerated
(Scheme 3). Products 6aa and 6ab, displaying a different
decoration of the seven-membered ring with respect to
cycloadducts 4, were obtained in good yields and excellent
enantioselectivities. Furthermore, imidazole 1g reacted with
5a, affording 6ga in moderate yield and slightly diminished
by single-crystal X-ray analysis (see Supporting Information)
and extended by analogy to products 4 and 6 (vide infra). An
aromatic substituent (aldehydes 1e and 1f) gave 4ea and 4fa
with similarly high yields and excellent stereoselectivities
(entries 5 and 6). Modifications on the electron-withdrawing
group of 2 were then explored, finding that different aromatic
ketones (2b−d) and esters (2e,f) allowed the synthesis of
4ab−af in 54−88% yield and 99% ee (entries 7−11).
Scope of Hetero-[6+4] Cycloadditions for Imidazoles
and Pyrazoles. Gratifyingly, the described hetero-[6+4]
cycloaddition strategy could be extended to imidazoles
C
DOI: 10.1021/jacs.8b13659
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
a
Scheme 3. Scope of the Hetero-[6+4] Cycloadditions of
Table 3. Optimization of the Hetero-[6+2] Cycloaddition
Pyrrole 1a and Imidazole 1g with Electron-Deficient Dienes
a
5
yield (conv of 7a,
b c
ratio 8aa/
ee
b
d
,
entry
3
additive
%)
8′aa
(%)
e
1
2
3
ent-3a
ent-3a BzOH
ent-3a BzOH
3b
3d
3d
3d
3d
3d
−
40 (50)
40 (48)
41 (52)
49 (59)
35 (30)
50 (65)
40 (80)
41 (>99)
62 (65)
>20:1
>20:1
>20:1
>20:1
>20:1
18:1
13:1
2.5:1
>20:1
66
76
76
−77
82
82
81
76
82
e f
,
a
b
g
f
f
f
f
i
i
i
Reaction conditions: Supporting Information. Isolated yield.
c
Determined by chiral stationary phase UPCC.
4
5
BzOH
BzOH
BzOH
BzOH
BzOH
BzOH
g
6
enantioselectivity. However, the reaction with ester 5c gave
6gc in only 10% yield and 51% ee. These examples
demonstrate the broad applicability of the methodology for
the construction of structurally diverse hetero-[6+4] cyclo-
adducts.
Transformation of Hetero-[6+4] Cycloadduct 4aa.
Having explored the reactivity of various substrates toward the
hetero-[6+4] cycloaddition reaction, we decided to illustrate
the bicyclic system as a useful intermediate in the synthesis of
more densely functionalized compounds. The reaction of 4aa
with BnSH in the presence of a catalytic amount of Et3N
afforded compound 4′aa, bearing three consecutive stereo-
centers, as a single diastereomer in 57% yield and 99% ee
(Scheme 4).
gh
,
7
8
9
h
a
b
Reaction conditions: Supporting Information. Measured by NMR
on the crude reaction mixture with Et4Si as internal standard.
c
Amount of 7a present in the reaction mixture divided by initial
d
e
amount. Determined by chiral stationary phase UPCC. No MS
added. 20 mol% used. Reaction time: 24 h. In this case, the
reaction was carried out with an inverted stoichiometric ratio: 1.5
f
g
h
i
equiv. 1a employed. 10 mol% used.
mixture, leading to isomer 8’aa. We hypothesized that this shift
was acid promoted, leading us to lower its amount to 10 mol%.
Even so, we found that this side reaction still occurred, but
only when the nitroolefin was consumed (entries 7 and 8).
Therefore, an excess of nitroolefin was employed to disfavor
the isomerization, thus delivering the optimal conditions
(entry 9). Unfortunately, we observed both isomerization and
decomposition of 8aa as isolated compound. At present time,
we have not elucidated the pathway of this double bond shift.
However, we exclude an equilibration between the two
isomers, since recovered 8aa showed only slightly diminished
enantiomeric excess instead of displaying complete racemiza-
tion. Nonetheless, we surmised that exploiting the reactivity of
the electrophilic double bond might circumvent this issue and
at the same time bring diversity to the methodology. We
therefore conceived a two-step one-pot strategy, consisting in
the addition of a nucleophile to the reaction mixture at the end
of the hetero-[6+2] cycloaddition step.
Scope and Transformations of Hetero-[6+2] Cyclo-
adducts of Pyrroles. It was found that aryl groups on the
pyrrole ring lead to stable hetero-[6+2] cycloadducts. Thus,
8ea and 8fa, which were derived from the respective pyrrole-2-
carbaldehydes 1e and 1f reacting with trans-β-nitrostyrene 7a,
were isolated in good yields and enantioselectivities (Scheme
5).
In Scheme 5, we demonstrate the hetero-[6+2] cyclo-
addition of two different pyrrole-2-carbaldehydes with various
nitroolefins coupled with a selective reduction with NaBH4 for
the preparation of dihydropyrrolizines 9. This reaction
afforded 9aa, derived from pyrrole-2-carbaldehyde 1a and
trans-β-nitrostyrene 7a in 45% overall yield and 82% ee. This
protocol was also successfully applied to the hetero-[6+2]
cycloaddition of 1a with 4-bromo- and 4-fluoro-substituted
nitroolefins 7b and 7c affording 9ab and 9ac with similar
results. The 4-bromo-substituted pyrrole-2-carbaldehyde 1b
a
Scheme 4. Transformation of [6+4] Cycloadduct 4aa
a
b
Reaction conditions: Supporting Information. Isolated yield.
c
d
Determined by chiral stationary phase UPCC. Measured by NMR
e
on the crude reaction mixture. 38% recovered starting material (4aa).
Screening of Reaction Conditions for Hetero-[6+2]
Cycloadditions. We then envisioned to extend this strategy
to enantioselective hetero-[6+2] cycloadditions.44,45 We
initially found that pyrrole-2-carbaldehyde 1a reacted with
1.5 equiv of trans-β-nitrostyrene 7a in the presence of catalyst
ent-3a (20 mol%) in CDCl3 at room temperature to produce
cycloadduct 8aa in 40% yield and 66% ee after 48 h (Table 3,
entry 1). The addition of BzOH (20 mol%) increased the
enantioselectivity (entry 2), and performing the reaction in the
presence of MS allowed to reach the same yield in 24 h (entry
3). Employing catalyst 3b, which was a highly stereoselective
catalyst in the hetero-[6+4] cycloaddition, resulted in only a
slightly improved yield and similar enantioselectivity (entry 4).
Bulkier catalyst 3d improved the enantioselectivity to 82% ee,
without significantly lowering the conversion (entries 5 and 6).
See Supporting Information for further screening results. To
ease the purification, we inverted the 1a/7a ratio, affording full
consumption of 7a. During this experiment we noticed that
compound 8aa was prone to double bond shift in the reaction
D
DOI: 10.1021/jacs.8b13659
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 5. Scope of the Hetero-[6+2] Cycloaddition of
Pyrrole-2-carbaldehydes 1 with Nitroolefins 7
Scheme 6. Proposed Mechanism for the Formation of
a
Hetero-[6+4] Cycloadducts 4 via Iminium Ion I and
a
Hetero-6π Component II
a
The crossed double bonds refer to a mixture of cis- and trans-
stereoisomers.
The first step of the mechanistic investigations was to identify the
proposed intermediates I and II shown in Scheme 6. We started by
attempting to detect the reactive intermediate(s) by means of NMR
spectroscopy.47−49 We treated pyrrole-2-carbaldehyde 1b with a
stoichiometric amount of catalyst 3b and BzOH in CDCl3 at room
temperature over MS for 18 h (Scheme 7, Experiment 1). A new
a
Reaction conditions: Supporting Information. Isolated yield.
Scheme 7. Experiments for the Observation of
Intermediates I and II and Their Reaction with Diene 2e
Enantiomeric excess determined by chiral stationary phase UPCC.
Reaction performed on 1 mmol scale.
b
underwent the same reaction sequence, displaying slightly
diminished efficiency. 4-Methoxy- and 3-methoxy-substituted
nitroolefins 7d and 7e also participated successfully in the
hetero-[6+2] cycloaddition with 1a. Further diversity was
demonstrated by addition of 4-methoxythiophenol giving 10ad
and 10ae, displaying three contiguous stereocenters, as single
diastereoisomers, with moderate yields and good enantiose-
lectivities. A neutral nucleophile such as indole was also found
to be a competent reaction partner. This protocol was
employed to prepare 11ab and 11af, obtained as single
diastereoisomers. The absolute stereochemistry of compound
8ea was determined by ECD analysis46 (see Supporting
Information) and extended for analogy to 8, 9, 10, and 11. For
compounds 9, 10, and 11, the stereochemistry of the
stereocenters created during the transformations, relative to
that of the original stereocenter, was assigned by NMR
spectroscopy. The disclosed one-pot hetero-[6+2] cyclo-
addition−nucleophilic addition sequence−was thus demon-
strated to display wide applicability and synthetic utility in the
rapid preparation of complex and biologically relevant
structures from simple and commercially available starting
materials.
species was observed by 1H NMR, assigned to be iminium ion I (see
Supporting Information for detailed NMR spectra). Isolation of I was
impaired by its tendency to rapidly hydrolyze in air.50 When the
electron-deficient diene 2e was added to the NMR tube, product 4be
(EWG = CO2Et, 99% ee) was formed, and in parallel, iminium ion I
disappeared. The absence of MS in the NMR tube considerably
slowed down the regeneration of intermediate I via condensation of
3b with 1b, resulting in increasing catalyst 3b concentration over
time. We thus proved the role of I as a productive intermediate for the
reaction. By treatment of intermediate I with a base, such as
MECHANISTIC INVESTIGATIONS
■
Experimental Investigations. A series of experimental inves-
tigations was initiated to gain insight into possible intermediates and
reaction pathway(s) involved in the mechanism of the hetero-[6+4]
and -[6+2] cycloadditions. A proposed mechanism for the hetero-
[6+4] cycloaddition is outlined in Scheme 6.
1
triethylamine, another species appeared, showing broad signals in H
NMR and two distinctive different signals in 19F NMR, suggesting the
presence of two isomers (see Supporting Information and computa-
tional section). These NMR signals were assigned to intermediate II,
E
DOI: 10.1021/jacs.8b13659
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
which was also unstable and prone to hydrolysis. Further character-
ization of intermediate II was not possible (Scheme 7, Experiment 2).
Then, electron-poor 4π-component 2e was treated with preformed
intermediate II, in the absence of MS, and formation of product 4be
was observed (1H NMR), along with consumption of II and
concomitant catalyst 3b release (monitored by 19F NMR), suggesting
II as a second reactive intermediate in the hetero-[6+4] cycloaddition.
It should be noted that under these latter stoichiometric reaction
conditions and in the presence of triethylamine, performed for the
mechanistic investigations, product 4be was formed in 85% ee, which
is lower than the excellent enantioselectivities obtained in the hetero-
[6+4] cycloaddition under catalytic conditions.
Intermediate Structures. The lowest-energy conformations for
the trans- and cis-iminium ion are shown in Figure 3. The difference in
To better mimic the optimized reaction conditions, we moved to
monitor the actual catalytic reaction proceedings by mean of NMR
spectroscopy (Scheme 7, Experiment 3, and Figure 2). Pyrrole-2-
Figure 3. Optimized ground-state structures for two conformations of
catalyst 3b and lowest-energy conformations for the cis- and trans-
arrangements of intermediates I and II(M06-2X/def2-TZVPP-
SMD//B3LYP/6-31G(d)-SMD, CHCl3).
free energy is 3.2 kcal/mol, in favor of the trans-iminium ion. The cis-
iminium ion acquires a disfavored conformation of the catalyst to
accommodate the pyrrole substituent (the high-energy catalyst is
shown in Figure 3). This corroborates the NMR observation of one
signal for iminium ion I. The cis- and trans-6π-components were also
calculated. We found that their difference in free energy was 1.1 kcal/
mol in favor of the cis-6π-component. This also agrees with the
observation of two signals for intermediate II, where both cis- and
trans-6π-components are observable by NMR spectroscopy.
Figure 2. (A) Consumption of pyrrole-2-carbaldehyde 1b as a
function of time. (B) Amount of catalyst 3b over time. (C)
Development of iminium ion I over time. (D) Cycloadduct 4be
formation as a function of time. Reaction conditions: pyrrole-2-
carbaldehyde 1b (1 equiv), diene 2e (1 equiv), catalyst 3b (20 mol%),
and BzOH (20 mol%) in CDCl3 (0.17 M), in the presence of MS.
Integrations have been normalized toward Et4Si as internal standard.
Calculation of the Enantioselective Hetero-[6+4] Cyclo-
addition Pathway. To probe the mechanism of the hetero-[6+4]
cycloadditions, DFT calculations were performed to locate the
transition states of the reaction of the 6π-components II and a slightly
truncated model of substrate 2. This truncation modified the aryl or
ester group on the terminal carbonyl to a methyl to avoid
conformational flexibility. The concerted cycloaddition transition
structures were exhaustively searched (see Figure S9), but only
revealed stepwise pathways.
We computed the free energy profile for the reaction mechanism
after the hetero-6π-components II are formed (Figure 4). The zero-
energy refers to the separated hetero-6π-components II and substrate
2. The first step involves nucleophilic addition of the pyrrole nitrogen
to the electrophilic β-position of the cyclic enone. The two lowest-
energy transition structures leading to the two stereoisomers are TS-
Ia and TS-Ib (see Figure S10 for the set of the various transition
structure conformations). Transition structure TS-Ia provides the
(R)-zwitterionic intermediate (R)-int-Ia which leads to the observed
stereoisomer with a free energy of activation barrier of 23.4 kcal/mol.
Transition structure TS-Ib yields the corresponding (S)-intermediate
and minor stereoisomer with a free energy of activation barrier of 22.8
kcal/mol. Interestingly, both low-energy TSs are nucleophilic
additions via the pyrrole nitrogen lone pair instead of the π-system.
Both transition structures arise from the trans-II hetero-6π-
component. All transition structures from cis-II were at least 3.0
kcal/mol higher in energy (see Figure S10). We found the difference
in energy between TS-Ia and TS-Ib to be 0.6 kcal/mol, in favor of
TS-Ib. We predict the two zwitterions, (R)-int-Ia and (S)-int-Ib, to
carbaldehyde 1b was continuously consumed during the reaction
(Figure 2, graph A). The concentration of the catalyst quickly
decreased at the beginning of the reaction course, and, since it was
regenerated by product formation, its amount reached a steady state
(graph B). Interestingly, the rapid formation of iminium ion I was
observed at first, and 19F NMR revealed the presence of intermediate
II as well, in about 3:1 ratio in favor of I. Intermediate I reached a
steady state after a rapid build-up (graph C) and remained constant
for several hours, while product 4be was slowly forming (graph D).
During these investigations, intermediate II appeared as two distinct
signals, confirming the presence of two isomers. The importance of
MS was also underlined by this experiment, as they allowed constant
replacement of the reacted intermediates by facilitating the
condensation of catalyst 3b and 1b. Observability of intermediates I
and II in an experiment performed under the real optimized reaction
conditions (i.e., their formation was not forced), indicates compelling
evidence of these species being reactive intermediates in the hetero-
[6+4] cycloaddition.
Computational Investigations. The energies of iminium ion I
and intermediate II, and the details of mechanisms, were investigated
with density functional theory. Computations were performed with
M06-2X51/def2-TZVPP52 corrected energies with the SMD53
(CHCl3) solvation model on B3LYP54−57/6-31G(d) calculated
geometries (see the Supporting Information for details on computa-
tional methods).
F
DOI: 10.1021/jacs.8b13659
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Figure 4. Computed free energy reaction pathway profile for the hetero-[6+4] cycloaddition involving hetero-6-π-intermediate trans-II derived
from catalyst 3b and model of substrate 2 (M06-2X/def2-TZVPP-SMD//B3LYP/6-31G(d)-SMD, CHCl3). The starting point is the computed
free energy of the separated trans-II and substrate, and all following energies are compared to them. All structures are lowest-energy conformations
of transition states or ground states.
Figure 5. Computed free energy reaction pathway profile for the hetero-[6+2] cycloaddition involving hetero-6-π-intermediate trans-II derived
from catalyst 3b and substrate 7a (M06-2X/def2-TZVPP-SMD//B3LYP/6-31G(d)-SMD, CHCl3). The starting point is the computed free energy
of the separated trans-II and substrate, and all following energies are compared to them. All structures are lowest-energy conformations of transition
states or ground states.
form in approximately a 74:26 ratio. The zwitterions are 8.0 and 9.5
kcal/mol higher in energy than the separated (R)- and (S)-
intermediates, respectively.
whereas in (S)-TS-IIb the ketone points directly at the diphenyl
fluoro group, forcing the conformational changes. In summary, the
stereoselectivity is controlled by the C−C bond-forming step - the
second reactive event in the stepwise mechanism. The N−C bond-
forming step yields both (R)- and (S)-intermediates; however, only
(R)-int-Ia cyclizes readily to the adduct. The barrier for cyclization for
(S)-TS-IIb is significantly higher than the reverse reaction back to the
reactants (ΔΔG⧧ = 3.5 kcal/mol), which causes (S)-int-Ib to reverse
until it is completely consumed and converted to the (R)-adduct. This
reaction barrier corresponds with the experimental results, where only
the (R)-product is observed. Calculations using catalyst 3c reveal a
decreased difference in the free energy barriers between forward
cyclization and reverse, for the zwitterionic intermediate leading to
the minor enantiomer (ΔΔG⧧ = 2.8 kcal/mol) in agreement with the
95% ee (Table 1, entry 3). This is due to removing the disfavored
F···O interaction found in (S)-TS-IIb (see Figure S12 for the
transition structure).
From the zwitterionic intermediate, the cyclization via C−C bond
formation occurs by addition of the conjugated enolate to the carbon
of the iminium ion. The lowest-energy transition structures for the
cyclization of the major and minor stereoisomers are shown in Figure
4 (see Figure S11 for full set of transition structures). The lowest-
energy TS, (R)-TS-IIa leads to the observed adduct with a free energy
of activation barrier of 19.5 kcal/mol, which eliminates to the product
(not computed). The lowest-energy TS leading to the minor
stereoisomer, (S)-TS-IIb, has a free energy of activation barrier of
26.3 kcal/mol. Transition structure (S)-TS-IIb is disfavored due to
the s-cis arrangement of the iminium ion and high-energy
conformation of the pyrrolidine catalyst (see high-energy catalyst
conformation in Figure 3). The source of these unstable interactions
arises from the ketone position in the C−C bond TS. In (R)-TS-IIa,
the ketone is on the opposite side of the bulky pyrrolidine substituent,
G
DOI: 10.1021/jacs.8b13659
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Calculation of the Enantioselective Hetero-[6+2] Cyclo-
addition Pathway. While the hetero-[6+4] cycloadditions are
practically stereospecific for the reactions with the electron-deficient
dienes 2, the hetero-[6+2] cycloaddition variant is modest in
enantioselectivity. We examined the example in Table 3, entry 4,
due to its close similarity with the hetero-[6+4] cycloaddition system
(same catalyst used (3b)) to determine the drop in enantioselectivity
to 77% ee. We performed exhaustive computational modeling of the
mechanism (see Figures S13 for full sets of TSs), and the free energy
profile for lowest-energy TSs and intermediates is shown in Figure 5.
The two lowest-energy transition structures for the first N−C bond-
forming step, TS-IIIa and TS-IIIb, are within 0.2 kcal/mol, similar to
the hetero-[6+4] cycloaddition. They have a free energy of activation
barriers of 23.8 and 24.0 kcal/mol for the (R)- and (S)-pathways,
respectively. The two stereoisomeric intermediates, (S)-int-IIIa and
(R)-int-IIIb, are formed. In this case, (S)-int-IIIa cyclizes readily with
a free energy of activation barrier of 14.7 kcal/mol compared to the
separated reactants (2.6 kcal/mol from the intermediate) to form the
(S)-adduct. In contrast, the barrier for cyclization to form the (R)-
adduct is 23.8 kcal/mol via (R)-TS-IVb, equivalent to the N−C
bond-forming barrier for the (R)-pathway. This TS is unfavorable due
to the steric interaction between the nitro group and the phenyl of the
pyrrolidine.
Unlike the [6+4] cycloaddition, the nitro group is small enough not
to force a conformational change in the catalyst in the [6+2]
cycloaddition, and the destabilization of (R)-TS-IVb is not as
pronounced as for (S)-TS-IIb. The free energy barrier for (R)-TS-IVb
is equal to the N−C bond-forming step for the (R)-pathway. To
summarize, the N−C bond formation occurs without stereoselectivity
and yields both zwitterionic intermediates. The (S)-adduct forms
rapidly, whereas the (R)-intermediate (R)-int-IIIb has equal barriers
to form the adduct or reverse to the reactants, leading to a 2:1 ratio of
(R)- to (S)-stereoisomers. In comparison to the hetero-[6+4]
cycloaddition with diene 2, which is stereospecific, the hetero-[6+2]
cycloaddition achieves modest enantioselectivity due to the smaller
size of the nitroolefin 7 in the C−C transition state.
enantioselectivity of 85% ee (Scheme 8), supporting the computa-
tional prediction. The transition structure for the disfavored C−C
bond-forming transition structure TS-3e-a is also shown in Scheme 8
with a free energy barrier of 25.0 kcal/mol, showing the increased
steric repulsion between the nitro group the methyl substituents
introduced in catalyst 3e.
CONCLUSION
■
We have developed a novel catalytic enantioselective activation
of heteroaromatic compounds, such as pyrroles, imidazoles,
and pyrazoles, by organocatalysis. This builds upon the
generation of electron-rich hetero-6π intermediates acting as
nucleophiles. These intermediates react in a highly chemo-,
regio-, and stereoselective manner with various types of
electron-deficient dienes and olefins, in hetero-[6+4] and
-[6+2] cycloaddition reactions, respectively. The reaction of
pyrroles provides bio-attractive pyrrolo-azepine scaffolds by a
[6+4] cycloaddition with dienes, in high yields and excellent
enantioselectivities (99% ee). Imidazolo- and pyrazolo-
azepines are formed in a similar hetero-[6+4] cycloaddition
by reaction of imidazoles and pyrazoles with dienes. The
activation concept for pyrroles has been extended to
enantioselective hetero-[6+2] cycloaddition reactions with
nitroolefins, affording pyrrolizidine alkaloid scaffolds that are
demonstrated to undergo further reactions. By NMR
investigations, we have been able to identify two different
types of intermediates in the catalytic cycle. First, an iminium
ion intermediate is formed; then deprotonation of the
heteroaromatic N−H leads to the reactive electron-rich
hetero-6π intermediate formed in two isomeric forms, of
which only one reacts with the diene or the olefin in the
hetero-[6+4] and -[6+2] cycloadditions, respectively. Mecha-
nistic and computational studies have shown that the hetero-
[6+4] and -[6+2] cycloadditions occur via stepwise mecha-
nisms. The stereocontrol occurs at the second C−C bond-
forming step, rather than the first N−C bond-forming
transition state. The source of stereoselectivity is the difference
in free energy of activation barriers between the C−C and N−
C TSs for the minor stereoisomer, rather than the traditional
comparison between two stereoisomeric transition structures,
because of reversibility of the first step. In the case of the
hetero-[6+4] cycloaddition, high stereoselectivity is achieved
due to the bulky 4π-substrate which interacts strongly with the
substituent of the pyrrolidine catalyst. For the hetero-[6+2]
cycloaddition system, the smaller nitrovinyl substrate does not
cause large steric effects at the pyrrolidine catalyst, which
lowers the C−C bond-forming TS and achieves lower
enantioselectivity compared to the hetero-[6+4] cycloaddition.
Computational investigations predicted a catalyst modification
that could improve the enantioselectivity for the [6+2]
cycloadditions, and experiments showed an increase in the
enantioselectivity from 77% to 85% ee.
Based on these computational results, we anticipated that
destabilizing the minor pathway transition structure for the C−C
bond (R)-TS-IVb would improve the enantioselectivity. We predicted
that substitution at the 3,5-positions of the pyrrolidine phenyl groups
could provide an unfavorable steric environment around the nitro
group in (R)-TS-IVb. This substitution would not interfere with the
other stereoisomeric C−C bond-forming TS (S)-TS-IVa, as well as
both the N−C bond-forming TSs. A 3,5-Me2C6H3-substituted
pyrrolidine catalyst 3e was synthesized to test the prediction (Scheme
8). The reaction of 1a and trans-β-nitrostyrene 7a with catalyst 3e
afforded the corresponding cycloadduct ent-8aa with improved
Scheme 8. Experiments for the Predicted Catalyst 3e and
Calculated Transition Structure
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b13659.
Crystallographic data for 4da (CIF)
Experimental procedures, coordinates of all calculated
structures, and product characterization data (PDF)
a
b
Isolated yield. Enantiomeric excess determined by chiral stationary
phase UPCC.
H
DOI: 10.1021/jacs.8b13659
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(13) Zhang, D.; Qiu, H.; Jiang, L.; Lv, F.; Ma, C.; Hu, W.
Enantioselective Palladium(II) Phosphate Catalyzed Three Compo-
nent Reactions of Pyrrole, Diazoesters, and Imines. Angew. Chem., Int.
Ed. 2013, 52, 13356−13360.
AUTHOR INFORMATION
■
Corresponding Authors
*houk@chem.ucla.edu
*kaj@chem.au.dk
(14) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton, K.;
MacMillan, D. W. C. Enantioselective Organocatalysis Using SOMO
Activation. Science 2007, 316, 582−585.
ORCID
Adam Simon: 0000-0001-6334-3359
K. N. Houk: 0000-0002-8387-5261
Notes
(15) Lee, H.-J.; Cho, C.-W. Cinchona-Based Primary Amine-
Catalyzed Asymmetric Cascade Aza-Michael−Aldol Reactions of
Enones with 2-(1H-Pyrrol-2-yl)-2-oxoacetates: Synthesis of Chiral
Pyrrolizines with Multistereocenters. J. Org. Chem. 2013, 78, 3306−
3312.
The authors declare no competing financial interest.
(16) Bae, J.-Y.; Lee, H.-J.; Youn, S.-H.; Kwon, S.-H.; Cho, C.-W.
Organocatalytic Asymmetric Synthesis of Chiral Pyrrolizines by
Cascade Conjugate Addition−Aldol Reactions. Org. Lett. 2010, 12,
4352−4355.
(17) Lee, H.-J.; Cho, C.-W. Asymmetric Synthesis of Chiral
Pyrrolizine-Based Triheterocycles by Organocatalytic Cascade Aza-
Michael−Aldol Reactions. Eur. J. Org. Chem. 2014, 2014, 387−394.
(18) Li, P.; Fang, F.; Chen, J.; Wang, J. Organocatalytic Asymmetric
Aza-Michael Addition of Pyrazole to Chalcone. Tetrahedron:
Asymmetry 2014, 25, 98−101.
(19) Fu, N.; Zhang, L.; Luo, S.; Cheng, J.-P. Chiral Primary Amine
Catalysed Asymmetric Conjugate Addition of Azoles to α-Substituted
Vinyl Ketones. Org. Chem. Front. 2014, 1, 68−72.
ACKNOWLEDGMENTS
■
This work was made possible by generous support from
Carlsberg Foundation “Semper Ardens”, FNU, Aarhus
University and DNRS. K.N.H. and A.S. thank the National
Science Foundation (CHE-1764328) for financial support.
The authors would like to thank Jeremy D. Erickson for X-ray
analysis as well as Teresa A. Palazzo and Danny K. B.
Jørgensen for ECD analysis. A.S. thanks the NIH Chemistry-
Biology Interface Research Training Grant (T32GM008496)
and the UCLA Dissertation Year Fellowship for funding. This
work used computational and storage resources associated with
the Hoffman2 Shared Cluster provided by the UCLA Institute
of Digital Research and Education (IDRE). This work also
used the Extreme Science and Engineering Discovery Environ-
ment (XSEDE).
(20) Zhang, J.; Zhang, Y.; Liu, X.; Guo, J.; Cao, W.; Lin, L.; Feng, X.
Enantioselective Protonation by Aza-Michael Reaction between
Pyrazoles and α-Substituted Vinyl Ketones. Adv. Synth. Catal. 2014,
356, 3545−3550.
(21) Mose, R.; Preegel, G.; Larsen, J.; Jakobsen, S.; Iversen, E. H.;
Jørgensen, K. A. Organocatalytic Stereoselective [8+2] and [6+4]
Cycloadditions. Nat. Chem. 2016, 9, 487−492.
REFERENCES
■
(1) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P.
Pyrrole: A Resourceful Small Molecule in Key Medicinal Hetero-
aromatics. RSC Adv. 2015, 5, 15233−15266.
́
(22) Donslund, B. S.; Monleon, A.; Palazzo, T. A.; Christensen, M.
L.; Dahlgaard, A.; Erickson, J. D.; Jørgensen, K. A. Organocatalytic
Enantioselective Higher-Order Cycloadditions of In Situ Generated
Amino Isobenzofulvenes. Angew. Chem., Int. Ed. 2018, 57, 1246−
1250.
(2) Baltazzi, E.; Krimen, L. I. Recent Advances in the Chemistry of
Pyrrole. Chem. Rev. 1963, 63, 511−556.
́
́
(3) Estevez, V.; Villacampa, M.; Menendez, J. C. Recent Advances in
the Synthesis of Pyrroles by Multicomponent Reactions. Chem. Soc.
Rev. 2014, 43, 4633−4657.
̀
(23) Wang, S.; Rodríguez-Escrich, C.; Pericas, M. A. Catalytic
Asymmetric [8+2] Annulation Reactions Promoted by a Recyclable
Immobilized Isothiourea. Angew. Chem., Int. Ed. 2017, 56, 15068−
15072.
(4) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R.
Biological Formation of Pyrroles: Nature’s Logic and Enzymatic
Machinery. Nat. Prod. Rep. 2006, 23, 517−531.
(24) Donslund, B.; Jessen, N. I.; Bertuzzi, G.; Giardinetti, M.;
Palazzo, T. A.; Christensen, M. L.; Jørgensen, K. A. Catalytic
Enantioselective [10+4] Cycloadditions. Angew. Chem., Int. Ed. 2018,
57, 13182−13186.
(25) Hayashi, Y.; Gotoh, H.; Honma, M.; Sankar, K.; Kumar, I.;
Ishikawa, H.; Konno, K.; Yui, H.; Tsuzuki, S.; Uchimaru, T.
Organocatalytic, Enantioselective Intramolecular [6+2] Cycloaddition
Reaction for the Formation of Tricyclopentanoids and Insight on Its
Mechanism from a Computational Study. J. Am. Chem. Soc. 2011,
133, 20175−20185.
(5) Mal, D.; Shome, B.; Dinda, B. K. Pyrrole and its Derivatives. In
Heterocycles in Natural Product Synthesis; Majumdar, K. C.,
Chattopadhyay, S. K., Eds.; Wiley-VCH: New York, 2011; pp 313−
544.
(6) McNeill, R.; Siudak, R.; Wardlaw, J. H.; Weiss, D. E. Electronic
Conduction in Polymers. I. The Chemical Structure of Polypyrrole.
Aust. J. Chem. 1963, 16, 1056−1075.
(7) MacDiarmid, A. G. Synthetic Metals”: A Novel Role for Organic
Polymers (Nobel Lecture). Angew. Chem., Int. Ed. 2001, 40, 2581−
2590.
(8) Janata, J.; Josowicz, M. Conducting Polymers in Electronic
Chemical Sensors. Nat. Mater. 2003, 2, 19−24.
(9) Liang, X.; Li, Y.; Li, X.; Jing, L.; Deng, Z.; Yue, X.; Li, C.; Dai, Z.
PEGylated Polypyrrole Nanoparticles Conjugating Gadolinium
Chelates for Dual-Modal MRI/Photoacoustic Imaging Guided
Photothermal Therapy of Cancer. Adv. Funct. Mater. 2015, 25,
1451−1462.
(10) Katritzky, A. R.; Ramsden, C. A.; Joule, J. A.; Zhdankin, V. V.,
Reactivity of Five-Membered Rings with One Heteroatom. Handbook
of Heterocyclic Chemistry; Elsevier, 2010; pp 383−472.
(11) Paras, N. A.; MacMillan, D. W. C. New Strategies in Organic
Catalysis: The First Enantioselective Organocatalytic Friedel−Crafts
Alkylation. J. Am. Chem. Soc. 2001, 123, 4370−4371.
(12) Trost, B. M.; Muller, C. Asymmetric Friedel−Crafts Alkylation
̈
of Pyrroles with Nitroalkenes Using a Dinuclear Zinc Catalyst. J. Am.
Chem. Soc. 2008, 130, 2438−2439.
(26) Hong, B.-C.; Shr, Y.-J.; Wu, J.-L.; Gupta, A. K.; Lin, K.-J. Novel
[6+2] Cycloaddition of Fulvenes with Alkenes: A Facile Synthesis of
the Anislactone and Hirsutane Framework. Org. Lett. 2002, 4, 2249−
2252.
(27) Hong, B.-C.; Sun, H.-I; Chen, Z.-Y. Unprecedented and Novel
Hetero [6+3] Cycloadditions of Fulvene: A Facile Synthesis of the
11-Oxasteroid Framework. Chem. Commun. 1999, 2125−2126.
(28) Hong, B.-C.; Jiang, Y.-F.; Kumar, E. S. Microwave-assisted
[6+4]-Cycloaddition of Fulvenes and α-Pyrones to Azulene−indoles:
Facile Syntheses of Novel Antineoplastic Agents. Bioorg. Med. Chem.
Lett. 2001, 11, 1981−1984.
(29) Zhou, Z.; Wang, Z.-X.; Zhou, Y.-C.; Xiao, W.; Ouyang, Q.; Du,
W.; Chen, Y.-C. Switchable Regioselectivity in Amine-catalysed
Asymmetric Cycloadditions. Nat. Chem. 2017, 9, 590−594.
́
(30) Przydacz, A.; Skrzynska, A.; Albrecht, Ł. Breaking Aromaticity
with Aminocatalysis: A Convenient Strategy for Asymmetric Syn-
thesis. Angew. Chem., Int. Ed. 2019, 58, 63.
I
DOI: 10.1021/jacs.8b13659
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
(31) Xiao, B.-X.; Gao, X.-Y.; Du, W.; Chen, Y.-C. Asymmetric
Reactions Involving Lewis Base Catalyst Tethered Dearomatized
Intermediates. Chem. - Eur. J. 2019, 25, 1607.
(32) Watanabe, M.; Kobayashi, T.; Kajigaeshi, S.; Kanemasa, S.
Azafulvenes 1. A Novel Generative Method of 6-Amino-1-Azafulvene
and its Cycloaddition Reaction with Isothiocyanate. Chem. Lett. 1975,
4, 607−610.
(51) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals
for Main Group Thermochemistry, Thermochemical Kinetics,
Noncovalent Interactions, Excited States, and Transition Elements:
Two New Functionals and Systematic Testing of Four M06-class
Functionals and 12 other Functionals. Theor. Chem. Acc. 2008, 120,
215−241.
(52) Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split Valence,
Triple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn:
Design and Assessment of Accuracy. Phys. Chem. Chem. Phys. 2005, 7,
3297−3305.
(53) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal
Solvation Model Based on Solute Electron Density and on a
Continuum Model of the Solvent Defined by the Bulk Dielectric
Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113,
6378−6396.
(54) Vosko, S. H.; Wilk, L.; Nusair, M. Accurate Spin-dependent
Electron Liquid Correlation Energies for Local Spin Density
Calculations: a Critical Analysis. Can. J. Phys. 1980, 58, 1200−1211.
(55) Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-
Salvetti Correlation-Energy Formula into a Functional of the Electron
Density. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−
789.
(33) Galeazzi, E.; Guzman, A.; Rodriguez, G.; Muchowski, J. M.
Generation and Lithiation of the Dimers of 6-(Dimethylamino)-1,4-
diazafulvene. A Novel Synthesis of 2-Alkanoylimidazoles. J. Org.
Chem. 1993, 58, 974−976.
́
(34) Barluenga, J.; García-Rodríguez, J.; Martínez, S.; Suarez-
́
Sobrino, A. L.; Tomas, M. Facile and Versatile Annulation of the
Imidazole Ring: Single and Sequential Cyclization Reactions of
Fischer Carbene Complexes with 1,4-Diazafulvenes. Chem. - Eur. J.
2006, 12, 3201−3210.
(35) Huang, S.-Z.; Kong, F.-D.; Ma, Q.-Y.; Guo, Z.-K.; Zhou, L.-M.;
Wang, Q.; Dai, H.-F.; Zhao, Y.-X. Nematicidal Stemona Alkaloids
from Stemona Parviflora. J. Nat. Prod. 2016, 79, 2599−2605.
(36) Paudler, W. W.; Kerley, G. I.; McKay, J. The Alkaloids of
Cephalotaxus Drupacea and Cephalotaxus Fortunei. J. Org. Chem.
1963, 28, 2194−2197.
(56) Becke, A. D. Density-functional Thermochemistry. III. The
Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648−5652.
(57) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J.
Ab Initio Calculation of Vibrational Absorption and Circular
Dichroism Spectra using Density Functional Force Fields. J. Phys.
Chem. 1994, 98, 11623−11627.
(37) Walser, A.; Fryer, R. I. Imidazodiazepines and Processes
Therefor. U.S. Patent US4280957 (A), July 28, 1981.
(38) Rizk, A.-F. Naturally Occurring Pyrrolizidine Alkaloids; CRC
Press: Boca Raton, FL, 1990.
(39) Harrington, P. J.; Khatri, H. N.; Schloemer, G. C. Preparation
of Ketorolac. U.S. Patent US6323344 (B1), November 27, 2001.
(40) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Enantioselective Organocatalyzed α-Sulfenylation of Aldehydes.
Angew. Chem., Int. Ed. 2005, 44, 794−797.
(41) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Diphenylprolinol
Silyl Ethers as Efficient Organocatalysts for the Asymmetric Michael
Reaction of Aldehydes and Nitroalkenes. Angew. Chem., Int. Ed. 2005,
44, 4212−4215.
(42) Ho, C.-Y.; Chen, Y.-C.; Wong, M.-K.; Yang, D. Fluorinated
Chiral Secondary Amines as Catalysts for Epoxidation of Olefins with
Oxone. J. Org. Chem. 2005, 70, 898−906.
(43) Sparr, C.; Schweizer, B.; Senn, H. M.; Gilmour, R. The
Fluorine-Iminium Ion Gauche Effect: Proof of Principle and
Application to Asymmetric Organocatalysis. Angew. Chem., Int. Ed.
2009, 48, 3065−3068.
(44) Takaoka, K.; Aoyama, T.; Shioiri, T. Cycloaddition Reactions
of Trimethylsilylketene with 8-Azaheptafulvenes and 6-Amino-1-
azafulvenes. Heterocycles 2001, 54, 209−215.
(45) For a very low enantioselectivity seminal work, see: Yin, G.;
Zhang, R.; Li, L.; Tian, J.; Chen, L. One-Pot Enantioselective
Synthesis of 3-Nitro-2H-chromenes Catalyzed by a Simple 4-
Hydroxyprolinamide with 4-Nitrophenol as Cocatalyst. Eur. J. Org.
Chem. 2013, 2013, 5431−5438.
(46) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J.
Ab Initio Calculation of Vibrational Absorption and Circular
Dichroism Spectra Using Density Functional Force Fields. J. Phys.
Chem. 1994, 98, 11623−11627.
(47) Sonnet, P. E. Synthesis of β-Substituted Pyrroles via 1-(Pyrrol-
2-ylmethylene)pyrrolidinium Salts. J. Org. Chem. 1971, 36, 1005−
1007.
(48) Berthiaume, S. L.; Bray, B. L.; Hess, P.; Liu, Y.; Maddox, M. L.;
Muchowski, J. M.; Scheller, M. E. Synthesis of 5-substituted Pyrrole-2-
carboxaldehydes. Part I. Generation of Formal 5-Lithiopyrrole-2-
carboxaldehyde Equivalents by Bromine-lithium Exchange of 2-
Bromo-6-(diisopropylamino)-1-azafulvene Derivatives. Can. J. Chem.
1995, 73, 675−684.
(49) Sonnet, P. E.; Flippen, J. L.; Gilardi, R. D. Substituted 1-
(Pyrrol-2-ylmethylene)pyrrolidinium Salts a Source of Stable 2-
Azafulvenamines. J. Heterocycl. Chem. 1974, 11, 811−812.
(50) Residual traces of water are responsible for partial hydrolysis of
the iminium ion, explaining why we could never obtain this
intermediate quantitatively.
J
DOI: 10.1021/jacs.8b13659
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX