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DOI: 10.1002/tcr.201600030

THE
CHEMICAL
RECORD

Enantioselective Vinylogous
Organocascade Reactions
Hamish B. Hepburn,[a] Luca Dell’Amico,[a] and Paolo Melchiorre*[a,b]

Chem. Rec. 2016, 00, 00–00

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ABSTRACT: Cascade reactions are powerful tools for rapidly assembling complex molecular
architectures from readily available starting materials in a single synthetic operation. Their
marriage with asymmetric organocatalysis has led to the development of novel techniques, which
are now recognized as reliable strategies for the one-pot enantioselective synthesis of
stereochemically dense molecules. In recent years, even more complex synthetic challenges have
been addressed by applying the principle of vinylogy to the realm of organocascade catalysis. The
key to the success of vinylogous organocascade reactions is the unique ability of the chiral
organocatalyst to transfer reactivity to a distal position without losing control on the stereodetermining events. This approach has greatly expanded the synthetic horizons of the field by
providing the possibility of forging multiple stereocenters in remote positions from the catalyst’s
point of action with high selectivity, while simultaneously constructing multiple new bonds. This
article critically describes the developments achieved in the field of enantioselective vinylogous
organocascade reactions, charting the ideas, the conceptual advances, and the milestone reactions
that have been essential for reaching highly practical levels of synthetic efficiency.
Keywords: aminocatalysis, cascade catalysis, enantioselectivity, organocatalysis, vinylogous
reactivity

1. Introduction
Cascade reactions are powerful tools for rapidly achieving
molecular complexity, since multiple chemical bonds are
formed in a single synthetic operation.[1] They fall into the
broader definition of domino processes,[2] where sequences of
chemical transformations take place under the same reaction
conditions (i.e., a single solvent, workup procedure, and purification step is required). Thus, all the reagents and catalysts are
added at (or nearly at) the outset of the process to undergo a
chemical transformation whose product becomes the substrate
for the next step, whose product again becomes the substrate
for the next step, and so on, until a product stable to the reaction conditions is reached. Cascade reactions pose an intellectually stimulating problem, since they require careful
consideration of the compatibility of the transiently formed
intermediates and the substrates, which should not undergo
alternative irreversible reactions to form by-products. Thus,
achieving a high degree of chemoselectivity represents the
greatest obstacle in the design of cascade reactions,[3] but suc[a]

H. B. Hepburn, L. Dell’Amico, P. Melchiorre
ICIQ – Institute of Chemical Research of Catalonia
Barcelona Institute of Science and Technology
Avenida Pa€ Catalans 16
ısos
43007 Tarragona (Spain)
[b]
P. Melchiorre*
ICREA – Catalan Institution for Research and Advanced Studies
Passeig Llu Companys 23
ıs
08010 Barcelona (Spain)
E-mail: pmelchiorre@iciq.es
Homepage: http://www.iciq.org/research/research_group/
prof-paolo-melchiorre/

Chem. Rec. 2016, 00, 00–00

cess results in a big payoff, since cascade reactions reduce timeconsuming and expensive protection/deprotection and isolation procedures of intermediates. In addition, this experimentally simple strategy offers the potential for rapidly increasing
structural and stereochemical complexity. In a single synthetic
step, it converts simple starting materials into complex molecular systems containing multiple stereocenters. Even more
appealing is the development of enantioselective catalytic cascade reactions.[4] By combining multiple asymmetric, catalytic
transformations in a domino sequence, chemists can impart
increased enantiomeric excess to the final product, when compared with the corresponding discrete transformations.[5] This
requires a chiral catalyst that can effectively drive, in a stereocontrolled fashion, consecutive catalytic reactions using different modes of substrate activation.
Given the above, it is easy to understand why the many
synthetic benefits of cascade reactions have attracted the interest of asymmetric organocatalysis[6] researchers. The stability,
versatility, and compatibility with distinct functional groups
make simple chiral organic catalysts perfectly suited for engineering effective asymmetric catalytic methods. The recent
marriage with asymmetric organocatalysis has led to the
emerging field of organocatalytic cascade reactions,[7] which
has provided a way of achieving stereochemical and molecular
complexity from readily available starting materials. The synthetic potential of this bio-inspired approach has been validated by recent applications to the total synthesis of natural
products.[8] Within this context, a key role was played by chiral
primary and secondary amines, which exploit fundamental
and well-established mechanistic patterns, mainly using the
chemistry of simple enamine[9] and iminium ion intermediates,[10] to asymmetrically functionalize carbonyl compounds.[11] Chiral amines were quickly recognized as ideal for

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catalyzing highly efficient cascade processes. This is mainly
because of the ability of a single chiral amine to integrate
orthogonal activation modes of carbonyl compounds into
more elaborate reaction sequences, thus enabling the concomitant construction of two consecutive carbon-carbon bonds in
one simple synthetic operation (Figure 1a).
To fully harness the synthetic power of organocascade
catalysis, it was crucial to identify the iminium ion-enamine
activation sequence as an enabling approach to highly efficient
domino reactions (Figure 1b).[12] The strategy is based on the
1,4-addition of a nucleophile (Nu) to a,b-unsaturated aldehydes or ketones, and subsequent a-functionalization of the
resulting saturated carbonyl with an electrophile (El). In this
well-defined sequence, the chiral amine plays an active role in
both steps. Initially, it lowers the lowest unoccupied molecular
orbitals (LUMO-lowering activation)[13] of chiral iminium
ions, thus facilitating the 1,4-addition of a general nucleophile,
while in the second event, it exerts an energy-raising effect on
the highest occupied molecular orbital (HOMO-raising activation) of the enamine intermediate, promoting the addition
to an electrophilic compound. The strategy has been extensively applied by the synthetic community to access a- and bfunctionalized carbonyl chiral building blocks.[7,12]
Recently, the potential of organocascade catalysis has been
further expanded to target more daunting synthetic objectives.
Key to bringing this chemistry to the next level of efficiency

Hamish B. Hepburn was born in Dundee, Scotland (1988) and completed his
undergraduate studies at the University
of Edinburgh, UK (2006–2011). He
then stayed at the same institution and
completed his Ph.D. in the field of rhodium catalysis under the supervision of
Professor Hon Wai Lam (2011–2014, including one year at
the University of Nottingham, UK). In January 2015, he
joined the group of Paolo Melchiorre at ICIQ, Spain where
he is currently a Marie Curie COFUND – Severo Ochoa
postdoctoral fellow, investigating organocatalytic photochemical reactions.
Luca Dell’Amico was born in Carrara,
Italy. In 2010, he completed his M.Sc. in
medicinal chemistry at the Parma University (I), where in the same year, he
started his Ph.D. In 2013, he spent a
period of research at the Center for Catal˚
ysis at Arhus Univesity (Denmark), working with Prof. Karl Anker Jørgensen. Luca finished his Ph.D.
(Doctor Europaeus degree) at the Parma University in 2014

Chem. Rec. 2016, 00, 00–00

and sophistication was the inclusion of vinylogous reactivity[14] as a new design principle for developing unprecedented
asymmetric organocatalytic domino reactions. This has facilitated the rapid synthesis of complex chiral molecules, while
selectively forging multiple stereocenters at distant positions
from the catalyst’s point of action (Figure 1c).[15]
Central to pursuing this goal is the ability of chiral amine
catalysts to propagate the electronic effects inherent to aminocatalytic reactivity modes (i.e., the HOMO-raising and the
LUMO-lowering activating effects) through the conjugated
p-system of polyunsaturated carbonyls, while transmitting the
stereochemical information at distant positions. The fruitful
combination of asymmetric aminocatalysis with the principle
of vinylogy has expanded chemists’ ability to functionalize a
carbonyl compound at distant positions such as the g-, d-, and
e-carbon atoms (Figure 2).[16]
On the one hand, the propagation of the HOMO-raising
electronic effect (inherent to enamine activation) through the
conjugated p-system of polyunsaturated carbonyls has been
used to induce vinylogous nucleophilicity in extended enamines. Dienamine (E2)[17] and trienamine activations (E3)[18]
have accounted for the direct, stereoselective, and site-selective
functionalization of unsaturated carbonyls at the g- and
e-positions, respectively. On the other hand, the successful
combination of the LUMO-lowering effect (inherent to iminium ion activation) with the vinylogy principle accounts for

under the supervision of Prof. Franca Zanardi. In 2014, he
moved to the ICIQ (Spain), joining the group of Prof. Paolo
Melchiorre. Luca is currently a Marie Curie COFUND postdoctoral fellow, and he is investigating novel organocatalytic
photochemical vinylogous reactivity.
Paolo Melchiorre was born in 1973 in
Camerino (Italy). He earned his M.Sc.
degree (1999) and then his Ph.D. in
chemistry (2003) from Bologna University under the supervision of A. UmaniRonchi and P. G. Cozzi. After a research
period with K. A. Jørgensen at the Center
˚
for Catalysis, Arhus University (Denmark), he joined the
research group of G. Bartoli at Bologna University, where he
became assistant professor in 2007. In 2009, Paolo moved to
Tarragona (Spain) as an ICREA research professor and an
ICIQ senior group leader. His current scientific interests lie
in the discovery and mechanistic elucidation of new enantioselective organocatalytic and photochemical processes.

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Fig. 2. Established activation modes in aminocatalysis and the possibility of
inducing vinylogous nucleophilicity and electrophilicity. The reactive carbon
atoms are highlighted in different colors, depending on their inherent
reactivity: magenta stands for a nucleophilic position, and blue for an
electrophilic center; El: electrophile; Nu: nucleophile.

2. HOMO-Raising Activation-Initiated
Vinylogous Cascade Reactions
2.1. Sequential Dienamine-Iminium Ion
Cascade Pathway

Fig. 1. (a) Combining enamine and iminium ion activations. (b) The
established iminium ion-enamine activation strategy for designing organocascade reactions. (c) Transferring the technique into a vinylogous reactivity pattern to forge multiple stereocenters remote from the catalyst’s point of action;
El: electrophile, Nu: nucleophile; E: Enamine activation; 1,4: iminium ionmediated 1,4-addition.

the direct and stereoselective functionalization with nucleophiles of unmodified carbonyl compounds at the remote dposition (vinylogous iminium ion activation (1,6)).[19]
In this article, we discuss the many opportunities provided
by the vinylogous aminocatalytic activation modes for the
design of novel enantioselective organocascade reactions. The
discussion is organized based on the nature of the initial vinylogous activation mode, which triggers the whole cascade
sequence. After the condensation of polyunsaturated carbonyl
compounds with a chiral amine catalyst, the HOMO-raising
activation strategy brings about the formation of nucleophilic
dienamine and trienamine intermediates, which can start a
domino sequence upon reacting with an electrophile (E2- or
E3-initated cascade, respectively). The LUMO-lowering activation, instead, would provide the electrophilic vinylogous
iminium ion that can initiate a cascade by reacting with a
nucleophile (1,6-initated cascade). We have decided to include
enantioselective vinylogous cycloaddition reactions only when
evidence supporting a stepwise mechanism was provided in the
original studies.

Chem. Rec. 2016, 00, 00–00

The propagation of the HOMO-raising electronic effect
through a conjugated p-system of a polyunsaturated carbonyl
compound (dienamine catalysis, E2) has found extensive use in
vinylogous cascade reactions. Upon the condensation of a chiral aminocatalyst with an a,b-unsaturated carbonyl substrate,
the transiently generated dienamine can attack a suitable electrophile to construct a new bond while leading to an electrophilic iminium ion (Figure 3). If an additional nucleophilic
handle is present in the original substrate, a second intramolecular bond-forming event can occur by means of an iminium
ion-mediated conjugate addition (1,4). This dienamineiminium ion cascade sequence (E2-1,4) allows functionalization of a carbonyl compound at the g- and b-positions, and it
requires the intervention of the aminocatalyst in both bondforming steps.
The first dienamine-iminium ion activation strategy (E21,4 sequence) was reported by Woggon and coworkers in 2008
in the total synthesis of a-tocopherol (Scheme 1), one of the
most significant members of the vitamin E family.[20] The process constructed the core of a-tocopherol through a three-step

Fig. 3. Dienamine (E2)/iminium ion (1,4) cascade sequence; the blue and
grey circles represent the chiral scaffolds of the aminocatalyst.

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Scheme 1. The first example of a dienamine/iminium ion cascade; E2:
dienamine; 1,4: iminium ion; S: spontaneous step. The blue circle represents
the chiral scaffolds of the aminocatalyst 4. The reactive carbon atoms are
highlighted in different colors, depending on their inherent reactivity: magenta
stands for a nucleophilic position, and blue for an electrophilic center.

cascade, two of which were catalyzed by the chiral silyl prolinol
aminocatalyst 4 (TES: triethylsilane).
The reaction was triggered by the vinylogous aldol reaction between the terminal dienamine I, formed upon catalyst
condensation with the b-methyl substituted enal 1, and the
salicylaldehyde derivative 2. The resulting iminium ion intermediate II was then attacked by the phenolic oxygen in an oxaMichael fashion to form a six-membered ring in III. Finally,
following hydrolysis of the aminocatalyst, a third bondforming step, namely a spontaneous (S) intramolecular acetalization, led to the formation of 3 with high stereo-fidelity,
an advanced intermediate en route towards the synthesis of
a-tocopherol. Following this preliminary report, Woggon and
others have since utilized this vinylogous triple cascade process
to synthesize an array of related natural products.[21]
The dienamine-iminium ion cascade pathway has also
served for the rapid construction of six-membered rings
(Scheme 2). Jørgensen and coworkers reported that the reaction of enals 5 with b,g-unsaturated-a-ketoester 6, proceeding
through a vinylogous 1,4-addition/oxa-Michael sequence, provided dihydropyran derivatives 7 in good yields (42–82%) and
enantioselectivities (75–92% ee).[22] Crucial for the successful
development of the chemistry was the design of a bifunctional

Chem. Rec. 2016, 00, 00–00

Scheme 2. Synthesis of dihydropyrans 7 through an E2-1,4 cascade reaction
facilitated by the bifunctional catalyst 8. E2: dienamine; 1,4: iminium ion; the
blue circle in IV and V represents the chiral scaffolds of catalyst 8. The reactive
carbon atoms are highlighted in different colors, depending on their inherent
reactivity: magenta stands for a nucleophilic position, and blue for an
electrophilic center. DEA: diethylamine; TFA: trifluoroacetic acid.

secondary amine-thiourea catalyst that combined hydrogen
(H)-bond directing activation of the electrophile with the
dienamine activation of enals to ensure high levels of enantioand regioselectivity. The bifunctional catalyst 8 was designed
to facilitate the simultaneous activation of both a-ketoester 6
and enal 5, while positioning them in an advantageous threedimensional assembly to ensure control over the trajectory of
the approaching electrophile. This secured high levels of stereoinduction in the addition of the dienamine IV to the conjugate acceptor 6. The resulting intermediate V, which featured
both an iminium ion and an enolate functionality, eventually
underwent a ring closure through an oxa-Michael reaction to
furnish dihydropyrans 7. Although this reaction can be considered as an inverse-electron-demand Diels-Alder reaction, theoretical calculations supported a stepwise process as the more
likely pathway.[22]
As for the atom connectivity, the E2-1,4 cascade sequence
requires the enal substrate to act as a two carbon partner, with
both new carbon-carbon bonds being formed in a 1,2-

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Scheme 3. E2-1,4 cascade reaction: use of a two-carbon electrophile 9 to
access cyclobutanes 10 by means of a vinylogous formal [2 1 2] reaction. E2:
dienamine; 1,4: iminium ion; the blue circle represents the chiral scaffold of
catalyst 8. DEA: diethylamine; TFA: trifluoroacetic acid.

relationship. This means that, as seen in the previously discussed works (Schemes 1 and 2), the use of the four-atom partners 2 and 6 brings about the formation of six-membered ring
products 3 and 7, respectively, through a formal [4 1 2] reaction. However, cyclic products of different ring size can be prepared by purposely modulating the reacting partners. For
example, an E2-1,4 cascade strategy to form a four-membered
ring through a formal [2 1 2] reaction can be envisaged when
using a two carbon partner, such as nitroolefins 9 (Scheme 3).
These compounds can act similarly to a,b-unsaturated carbonyl compounds 6, but the enolate emerging from the
dienamine-triggered Michael addition is unlikely to act as an
oxygen-centered nucleophile. Independently and concurrently,
Jørgensen’s group[23] and Vicario[24] developed vinylogous E21,4 cascade sequences that utilized nitroolefins to facilitate the
formation of enantioenriched cyclobutanes.
In analogy to the cascade depicted in Scheme 2, Jørgensen
used the bifunctional secondary amine-thiourea catalyst 8 to
activate the nitroolefins 9 while ensuring a close proximity
with the dienamine IV (Scheme 3).[23] The simultaneous
activation of the two reacting partners secured a high stereofidelity in the first bond-forming step (dienamine-driven con-

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Scheme 4. E2-1,4 cascade reaction: synthesis of enantioenriched cyclobutanes
using two distinct organocatalysts. E2: dienamine; 1,4: iminium ion; S:
spontaneous step; the blue circle represents the chiral scaffold of catalyst 13.
The reactive carbon atoms are highlighted in different colors, depending on
their inherent reactivity: magenta stands for a nucleophilic position, and blue
for an electrophilic center.

jugate addition), leading to the iminium ion intermediate VII.
The nascent carbon-centered nucleophile then underwent an
iminium ion-mediated conjugate addition to form cyclobutane 10 in good yields (62–93%) and perfect stereoselectivities
(single diastereoisomer and 99% ee or greater).
A related, but different, approach was reported by Vicario
and coworkers,[24] who used two distinct organocatalysts to
mimic the action of the bifunctional catalyst 8. Specifically,
while the secondary amine 13 served to activate enal 5 through
dienamine catalysis, the achiral thiourea catalyst 14 activated
the nitroolefin 11 through H-bonding catalysis (Scheme 4).
Although intermediate VIII does not feature the same level of
three-dimensional organization achieved by a bifunctional
catalyst, impressive levels of regio- and stereoselectivity
(85–95% ee) were achieved. Following the attack of the dienamine IV on the activated nitroolefin in VIII, the iminium ion
intermediate IX was formed, which then drove the conjugate
addition of the enolate in an intramolecular fashion. Finally,
the hydrolysis of the aminocatalyst 13 (TMS: trimethylsilyl),

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Fig. 4. Dienamine (E2)/enamine (E) cascade sequence; the blue and grey
circles represent the chiral scaffolds of the aminocatalyst.

and a spontaneous acetalization (S), furnished the bicyclic product 12.
2.2. Sequential Dienamine-Enamine Cascade Pathway
Vinylogous cascade reactions are not limited to functionalizing
a,b-unsaturated aldehydes in a 1,2-fashion. Unusual functionalizations in a 1,3-relationship, namely at the a- and g- position, have also been achieved. This strategy relies on a dual
HOMO-raising activation pathway which combines a dienamine/enamine sequence (E2-E, Figure 4). First, after condensation of a chiral aminocatalyst with an unsaturated carbonyl
substrate, the resultant dienamine attacks an electrophile to
form a transient iminium ion (not shown). However, gdeprotonation returns a nucleophilic dienamine which can
trap a second electrophile at the a-position. This E2-E cascade
reaction allows the functionalization of a carbonyl substrate at
the g- and a- positions and relies on the aminocatalyst for
both bond-forming steps.
The main issue to address when designing this cascade is
that the reaction partner, reacting with the dienamine, should
feature two distinct electrophilic sites. Thus, it is essential to
discriminate between them to ensure high levels of regioselectivity. Recently, the first E2-E cascade was realized using enal
14 and a 2-acetoxymethyl nitroolefin 15 (Scheme 5).[25]
The substrate 15 avoids the issue of regioselectivity, since
the second electrophilic position is revealed only once the initial dienamine-triggered reaction has happened. Indeed, the
first conjugate addition of the dienamine X to 15, proceeding
through an SN2’ pathway, efficiently generates the required
second electron-poor alkene moiety in XI through the elimination of acetic acid. Deprotonation to form XII favors the subsequent enamine-mediated intramolecular conjugate addition
(a-functionalization) to furnish the cyclohexene structures 16
in good yields (41–61%) and high enantiomeric excess (88–
97% ee). The generally poor diastereomeric ratio of the process
(about 2: 1 dr) is ascribable to the low stereoselectivity of the
protonation step in XII, which sets the stereocenter bearing
the R1 substituent. However, it was found that treating the
products 16 with K2CO3 readily epimerized the stereocenter
to exclusively afford the trans-adduct.

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Scheme 5. Functionalization of the a- and c- position of enals 14 through a
dienamine (E2)/enamine (E) cascade sequence. E2: dienamine; E: enamine; the
blue circle represents the chiral scaffold of the bifunctional catalyst 17. The
reactive carbon atoms are highlighted in different colors, depending on their
inherent reactivity: magenta stands for a nucleophilic position, and blue for an
electrophilic center.

2.3. Sequential Dienamine-Spontaneous Cyclization
Cascade Pathway
An alternative strategy to developing vinylogous cascade reactions is based on the use of a chiral aminocatalyst to only facilitate the formation of the first new bond, while a second
spontaneous bond-forming step sequentially occurs (Figure 5).
After condensation of an aminocatalyst with an unsaturated
carbonyl substrate, the resultant dienamine attacks an electrophile (which can then reveal a nucleophilic moiety) to form
the iminium ion intermediate. However, rather than an additional bond-forming step at this point, hydrolysis of the catalysts creates a tethered carbonyl intermediate, which can then
undergo a range of different spontaneous, non-catalyzed, ringclosing reactions to complete the cascade sequence (E2-S).
Although this strategy does not involve the chiral aminocatalyst for both bond-forming steps, the stereochemical information encoded during the first dienamine step ensures high
stereo-fidelity in the second spontaneous reaction, leading to
products with high levels of stereocontrol. This approach lacks

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Fig. 5. Dienamine (E2)/spontaneous (S) non-catalyzed cyclization cascade
pathway; the blue and grey circles represent the chiral scaffolds of the
aminocatalyst.

the complementary activation seen in the E2-1,4 and E2-E cascades, but it is still a powerful synthetic tool for the construction of multiple bonds in one step.
Given the presence of an aldehyde moiety in the products
of aminocatalytic vinylogous cascades, the most commonly
reported spontaneous step is an intramolecular aldol reaction.
The first vinylogous cascade of this type involved the reaction
of the enal 14 with a diene 18 to form tetracyclic skeletons 19
(Scheme 6).[26] The mechanism is proposed to proceed as follows: the dienamine X participates in an inverse-electrondemand Diels-Alder reaction with 18 (this step can also be
envisaged as an E2-1,4 reaction sequence). After hydrolysis of
the chiral aminocatalyst 13, isomerization and deprotonation
of the newly formed intermediate XIII generates the enolate
XIV, which undergoes an intramolecular aldol reaction to
form product 19 in high yields (36–92%) and enantiomeric
excess (80–98% ee).

Scheme 6. Dienamine-spontaneous cyclization (E2-S) cascade sequence for
the construction of tetracyclic products. The non-catalyzed step is an intramolecular aldol reaction; E2: dienamine; 1,4: iminium ion; S: spontaneous step.
The reactive carbon atoms are highlighted in different colors, depending on
their inherent reactivity: magenta stands for a nucleophilic position, and blue
for an electrophilic center.

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Scheme 7. Dienamine-spontaneous cyclization (E2-S) cascade sequence to
form spirocyclic products. The non-catalyzed step is an intramolecular aldol
reaction; E2: dienamine; S: spontaneous step. The blue circle represents the
chiral scaffolds of the aminocatalyst. The reactive carbon atoms are highlighted
in different colors, depending on their inherent reactivity: magenta stands for a
nucleophilic position, and blue for an electrophilic center. DIPEA: N,Ndiisopropylethylamine.

The strategy of employing an aldol condensation in an
E2-S cascade sequence was also used in conjunction with tetraenamine intermediates XV formed upon condensation of
the aminocatalyst 23 with enal 20 (Scheme 7).[27] Although
these species have the potential to react at very remote positions, they were found to selectively react at the g-position.
The reaction of XV with electrophilic 3-olefinic oxindoles 21
led to the formation of spirocyclic products 22 through an E2S vinylogous cascade.
Mechanistically, the nucleophilic tetraenamine XV attacks
the Michael acceptor 21. After hydrolysis of the aminocatalyst,
the intermediate XVII, which contains both an aldehyde and
an enolate, experiences an intramolecular aldol pathway to
give 22 in good yields (51–93%), diastereomeric ratio (86:14
to > 20:1), and enantiomeric excess (68–95% ee).
E2-S cascade reactions often feature very similar intermediates to E2-1,4 cascade sequences. The reasons why a reaction proceeds through an E2-S pathway instead can be subtle,
and are often ascribable to differences in the substrate’s electronic and steric characteristics. For example, the cascade
sequence illustrated in Scheme 8 appears, at first glance, very
similar to the cascade illustrated in Scheme 3; it is indeed a
reaction between an enal (23 or 5) and nitroolefin 9 in the
presence of the bifunctional amine-thiourea catalyst 8.[28]
However, in the case of Scheme 3, the reaction proceeds
through an E2-1,4 cascade sequence to form the formal
[2 1 2] cyclobutane product 10, while in Scheme 8, the reaction proceeds through an E2-S cascade, affording the sixmembered ring 24. This divergent pathway can be attributed

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Scheme 8. Dienamine-spontaneous cyclization (E2-S) cascade between enal
23 and nitroolefin 9. The non-catalyzed step is an intramolecular Henry condensation; E2: dienamine; S: spontaneous step. The blue circle represents the
chiral scaffolds of the aminocatalyst. The reactive carbon atoms are highlighted
in different colors, depending on their inherent reactivity: magenta stands for a
nucleophilic position, and blue for an electrophilic center. DIPEA: N,N-diisopropylethylamine; TFA: trifluoroacetic acid.

to the nature of the cyclic intermediate XIX. After the nucleophilic attack of dienamine XVIII to nitroolefin 9, the
b-position of the cyclic iminium ion XIX is not sufficiently
electrophilic to permit the conjugate addition of the a-nitro
anion, due to the steric hindrance of the b,b-disubstitution
pattern. This, along with the conformational constraints
enforced by the cyclic structure of XIX, channels the process
through a different pathway. Following hydrolysis of catalyst
8, the a-nitro anion undergoes a spontaneous Henry condensation, forming product 24 in moderate yields (43–73%) and
good enantiomeric excess (84–96% ee).
E2-S cascade reactions can also be utilized to rapidly
construct structurally complex molecules through multiple
bond-forming events. This strategy served for the synthesis
of bridged benzoxazocines 27 by means of a one-pot vinylogous cascade reaction (Scheme 9).[29] A multicomponent
reaction between an aniline 25, a salicylaldehyde 26, and
an enal 5 resulted in the formation of four new bonds and
featured a unique g,d,ipso-functionalization of enal 5. The
reaction is proposed to proceed as follows: condensation of
aniline 25 and salicylaldehyde 26 forms the aromatic imine
XXI, while condensation of the chiral aminocatalyst 28 and
enal 5 forms the dienamine IV. These two intermediates
undergo a stepwise Mannich-initiated formal aza-[4 1 2]
cyclization to form the cyclic six-membered intermediate
XXII. Elimination of the aminocatalyst 28 renders the achiral iminium ion XXIII. Last, an oxa-Michael reaction fur-

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Scheme 9. The formation of structurally complex benzoxazocines 27 through
an E2-S-S reaction sequence. The non-catalyzed step is an intramolecular oxaMichael reaction; E2: dienamine; S: spontaneous step. The blue circle represents the chiral scaffolds of the aminocatalyst. The reactive carbon atoms are
highlighted in different colors, depending on their inherent reactivity: magenta
stands for a nucleophilic position, and blue for an electrophilic center.

nishes the product 27 in good yield (22–91%) and
enantioselectivities (73–91% ee, Scheme 9).
2.4. Extending the HOMO-Raising Activation Strategy
Beyond the c-Position
Condensation of an aminocatalyst with an a,b,g,d-unsaturated aldehyde forms a trienamine intermediate which can
extend the HOMO-raising activation further into the vinylogous reactivity space, well beyond the g-position. Trienamines
feature similar reactivity profiles as the related enamine and
dienamines, and can facilitate functionalization at the ecarbon atom.[16a] Although the field of vinylogous cascade
reactions using trienamine catalysis is far less developed than
the corresponding dienamine field, some examples have been
reported. These cascade sequences are based upon the trienamine/iminium ion (E3-1,4) pathway illustrated in Figure 6.
The earliest example of an E3-1,4 cascade sequence
was detailed in 2013,[30] with the trienamine-catalyzed azaDiels-Alder process between the interrupted 2,5-dienones 28
and a,b-unsaturated imines 29 in the presence of the
cinchona-based primary amine catalyst 31[31] (Scheme 10).
It was found that tethering a Michael donor to the interrupted dienone 28 resulted in an E3-1,4 cascade sequence to

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Fig. 6. Trienamine (E3)/iminium ion (1,4) cascade sequence; initial HOMOraising activation event at the e-position, followed by a complementary
LUMO-lowering event. The blue and grey circles represent the chiral scaffolds
of the aminocatalyst.

generate spirocycle 30 in 92% yield, 99% ee, and as a single
diastereomer. The trienamine intermediate XXIV was formed
through condensation of the cinchona-based primary amine
catalyst 31 with skipped dienone 28 and this intermediate
served as the diene for an inverse-electron-demand aza-DielsAlder reaction with imine 29 to form the intermediate XXV
(this step, if stepwise, can also be seen as an E3-1,6 sequence).
Deprotonation of the acidic proton in the malononitrile moiety resulted in an iminium ion-mediated addition to form the

Scheme 10. The first trienamine-initiated vinylogous cascade reaction: E3-1,4
reaction sequence; E3: trienamine; 1,4: iminium ion. The blue circle represents
the chiral scaffold of the cinchona-based primary amine catalyst 31. The reactive carbon atoms are highlighted in different colors, depending on their inherent reactivity: magenta stands for a nucleophilic position, and blue for an
electrophilic center.

Chem. Rec. 2016, 00, 00–00

intermediate XXVI, which after catalyst hydrolysis, afforded
the product 30.[30]
Very recently, the E3-1,4 cascade strategy was utilized in the
formal [4 1 2] reaction between a nitroindole 33 and an
a,b,g,d-unsaturated aldehyde 32 catalyzed by a bifunctional catalyst 35 to furnish the tricyclic products 34 (Scheme 11).[32]
The condensation of the aminocatalyst 35 with enal 32 leads to
the formation of the trienamine XXVII, while simultaneously,
the urea moiety within 35 activates the nitroolefin 33 through
H-bonding interaction. This double activation manifold promotes the trienamine-driven conjugate addition to form the iminium ion XXVIII. The resultant a-nitro anion attacks the
electrophilic iminium ion to form the intermediate XXIX.
Finally, elimination of the nitro group and re-aromatization of
the indole nucleus leads to the formation of the product 34 in
good yields (51–77%) and enantioselectivities (49–98% ee).
It has also been possible to develop a trienamine-initiated
vinylogous cascade reaction of the E3-S type. The use of the
chiral secondary amine catalyst 13 triggered the formation of

Scheme 11. The formation of cyclic products 34 through E3-1,4 cascade
reaction. E3: trienamine; 1,4: iminium ion. The blue circle represents the
chiral scaffold of the bifunctional amine-thiourea catalyst. The reactive carbon
atoms are highlighted in different colors, depending on their inherent reactivity: magenta stands for a nucleophilic position, and blue for an electrophilic
center.

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Fig. 7. Asymmetric 1,6-additions to cyclic dienones 39 mediated by
vinylogous iminium ion activation (1,6). The blue circle represents the chiral
scaffold of the cinchona-based primary amine catalyst.

Scheme 12. E3-S cascade sequence to generate quinolones; E3: trienamine; S:
spontaneous step. The reactive carbon atoms are highlighted in different
colors, depending on their inherent reactivity: magenta stands for a
nucleophilic position, and blue for an electrophilic center.

tricyclic benzo[de]quinolone products 38 from quinone imine
ketals 36 and 2,4-dienals 37 through an E3-S pathway in
good yields (60–81%) and enantiomeric excess (85–98% ee,
Scheme 12).[33] The cascade sequence is initiated by the condensation of catalyst 13 with enal 37 to form a reactive trienamine, which then participates in a Diels-Alder reaction to
furnish the [4 1 2] adduct XXXI. Aromatization of this intermediate through elimination of an alcohol forms the quinolone core XXXII, which undergoes a final spontaneous
cyclization. The resulting hemi-acetal (not shown in Scheme
12) is reduced in situ to aid isolation of the product 38.

3. Vinylogous Iminium Ion-Initiated
Cascade Reactions
In 2012, our research group became interested in the possibility of transmitting the LUMO-lowering activating effect,
inherent to iminium ion catalysis (1,4), through the conjugated p-system of polyunsaturated carbonyl compounds, in
order to realize a direct nucleophilic 1,6-addition. The difficulty of this goal becomes apparent when considering that the
larger p-orbital LUMO coefficient and the more positive Mulliken atomic charge of extended iminium ions reside at the bcarbon atom, thus explaining the intrinsic preference for a
nucleophilic 1,4-addition manifold.[19b] The requirement for
the chiral catalyst to forge a remote stereocenter with high
fidelity, while inducing exclusive d-site selectivity in the 1,6addition manifold, further complicates matters. We have
found, however, that when a cinchona-based primary amine
catalyst condenses with b-substituted cyclic dienones, it deter-

Chem. Rec. 2016, 00, 00–00

mines the formation of an extended iminium ion intermediate
(Figure 7), with an enhanced electrophilic character at the dcarbon atom. The resulting vinylogous iminium ion activation
(1,6) was used to develop an asymmetric organocatalytic 1,6addition of alkyl thiols to cyclic a,b,g,d-unsaturated dienones
39, proceeding with high stereocontrol and d-site selectivity.[19a] Crucial for the success was: 1) the unique ability of a
cinchona amine of type 40 to stereochemically bias intermediary cyclic species, thus ensuring highly predictable reaction
outcomes; along with 2) the inherent steric bias of the bsubstituent in 39, which provided a useful steric element for
securing d-site selectivity by suppressing the competing 1,4addition manifold. The development of the vinylogous iminium ion activation provided new opportunities for the design
of novel cascade reactions.
3.1. Sequential Vinylogous Iminium Ion/Dienamine
Cascade Pathway
The identification of the vinylogous iminium ion activation
allowed the design of more complex cascade reactions upon
combination with other aminocatalytic activation modes. For
example, the condensation of the chiral aminocatalyst generates an extended iminium ion which can facilitate a nucleophilic attack at the d-position (1,6). After this addition, a
nucleophilic dienamine intermediate is transiently formed. If
an electrophilic position is present in the original substrate, a
second intramolecular bond-forming event can occur under
dienamine activation (E2, Figure 8). The vinylogous iminium
ion-dienamine (1,6-E2) cascade accounts for the functionalization of a a,b,g,d-unsaturated carbonyl compound at the dand g-position, while relying on the chiral aminocatalyst for
both bond-forming steps.
The first example of a 1,6-E2 cascade capitalized upon the
already discussed ability of the cinchona-based primary amine
catalyst of type 40 to condense with b-substituted cyclic dienones 39, while controlling the geometry of the reactive cyclic
iminium ion intermediate XXXIII. We recognized that a well-

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Fig. 8. Vinylogous iminium ion (1,6)/dienamine (E2) cascade pathway; the
blue and grey circles represent the chiral scaffolds of the aminocatalyst.

suited substrate, characterized by a dichotomous reactivity profile, was crucial to realizing a cascade process. On the basis of
the inspiring studies by Carlos Barbas III,[34] the 3-substituted
oxindole 41 seemed well-tailored to first act as a carboncentered nucleophile, and then to develop, after the d-site 1,6addition, electrophilic behavior (Scheme 13). The pendant
carbonyl moiety within the transiently generated nucleophilic
dienamine intermediate XXXIV did drive an intramolecular
aldol reaction, resulting in a fast cyclization. The product of
the vinylogous cascade reaction, which is based on a d-addition/aldolization sequence, is a complex spirocyclopentane

Scheme 14. Synthesis of tricyclic products 45 through a 1,6-E2 cascade
reaction; 1,6: vinylogous iminium ion; E2: dienamine. The blue circle
represents the chiral scaffold of the aminocatalyst 46. PG: protecting group.
The reactive carbon atoms are highlighted in different colors, depending on
their inherent reactivity: magenta stands for a nucleophilic position, and blue
for an electrophilic center.

Scheme 13. The first report of a 1,6-E2 cascade sequence; 1,6: vinylogous
iminium ion; E2: dienamine. The blue circle represents the chiral scaffold of
the cinchona-based primary amine catalyst. The reactive carbon atoms are
highlighted in different colors, depending on their inherent reactivity: magenta
stands for a nucleophilic position, and blue for an electrophilic center.

Chem. Rec. 2016, 00, 00–00

oxindole 42 bearing four contiguous stereocenters and a preserved a,b-unsaturated carbonyl system.[35]
Building upon this precedent, Dixon, Ye and coworkers
developed, in 2015, a vinylogous organocascade reaction
employing five-membered cyclic dienones 43 and N-protected
pyrrolinones 44.[36] The process, promoted by the chiral primary amine catalyst 46, furnished enantioenriched tricyclic
g-lactams 45 in moderate chemical yields (37–67%) and diastereocontrol and a high level of enantiocontrol (92–99% ee,
Scheme 14). A nontrivial reaction mechanism was proposed:
after the vinylogous iminium ion formation and the subsequent 1,6-addition reaction, an isomerization of the transient
dienamine intermediate XXXVII takes place, driven by the
formation of the corresponding iminium ion intermediate

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aziridine 49 in good yields, excellent diastereoselectivity, and
moderate to excellent enantiocontrol (40–95% ee).
Although the 1,6-E2 sequence demonstrated its usefulness
for the implementation of vinylogous cascade strategies, as
highlighted in Schemes 13–15, the synthetic potential of the
approach was limited by the need for a cyclic substrate. Clearly,
the use of a linear a,b,g,d-unsaturated carbonyl compound
would provide a tool for designing more flexible and synthetically relevant vinylogous cascade reactions. However, the successful realization of this plan was far from easy, since
controlling the site and stereoselectivity in the initial 1,6-addition reactions of linear substrates poses more than a conundrum. As a matter of fact, it is easier for a chiral amine catalyst
to stereochemically bias the geometry of a cyclic vinylogous
iminium ion intermediate than a linear counterpart. Such geometrical control is generally essential for securing selectivity.
We found, though, that the presence of a steering group at the
b-position of linear 2,4-dienals accounted for a perfect d-site
selective 1,6-addition reaction. This was critical to the design
of a 1,6-E2 process proceeding by way of an aminocatalyzed
1,6-addition/vinylogous SN2 sequence (Scheme 16). The

Scheme 15. Remote aziridination of cyclic enals by means of a 1,6-E2 cascade
reaction; 1,6: vinylogous iminium ion; E2: dienamine. The blue circle
represents the chiral scaffold of the aminocatalyst 50. The reactive carbon
atoms are highlighted in different colors, depending on their inherent
reactivity: magenta stands for a nucleophilic position, and blue for an
electrophilic center.

(not shown). The newly formed internal dienamine XXXVIII
is now well positioned to undergo an intramolecular Michael
addition, forming the second carbon-carbon bond. Migration
of the C–C double bond in XXXIX to the other side of the carbonyl group (ascribable to an isomerization via the dienamine
of cyclopentenone, presumably driven by the thermodynamic
stability of the product) furnished, after hydrolysis and liberation of the catalyst, the final tricyclic product 45.
The concept of a vinylogous organocascade reaction based
on 1,6-addition/dienamine chemistry was then successfully
extended from cyclic enone to cyclic enals. In 2013, Jørgensen
and coworkers reported an enantioselective remote aziridination reaction, based on the 1,6-E2 sequence.[37] Extended
cyclic 2,4-dienals of type 47 formed the vinylogous iminium
ion in situ, which later underwent 1,6-addition from the
nitrogen-centered nucleophile 48, resulting in the formation
of the dienamine XLI. An intramolecular SN2 process, facilitated by the leaving group (TsO-), led to the aziridinated iminium ion XLII. Hydrolysis of XLII afforded the desired

Chem. Rec. 2016, 00, 00–00

Scheme 16. Synthesis of cyclopropane spiro-oxindoles 53 by means of a 1,6E2 cascade reaction with linear dienals; 1,6: vinylogous iminium ion; E2: dienamine. The blue circle represents the chiral scaffold of the aminocatalyst 23.
The grey circle in XLIII highlights the importance of the tert-butyl moiety as a
steering group.

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notion that a suitable reaction partner for the cascade requires
the ability of the substrate to act as both a nucleophile and an
electrophile suggested 3-chlorooxindole 52 as a potential substrate. The resulting cascade provided straightforward access to
a range of chiral cyclopropane spiro-oxindoles 53.[38]
The reaction relies on the activation of the extended
dienal 51 by means of vinylogous iminium ion formation
XLIII. The presence of a bulky tert-butyl substituent at the bposition was essential to secure high levels of both regio- and
stereoselectivity. Specifically, the tert-butyl group, serving as a
steering group, directed the nucleophilic attack of 52 to the
less congested d-carbon, while controlling the molecular topology of the extended iminium ion XLIII. NMR spectroscopic
studies indicated that the dominant ground-state conformer in
solution had an E,E,E topology, with the same configuration
for the three double bonds in XLIII. The steric prominence of
the tert-butyl group made it a topologically dominant element
that could enforce an uncommon s-cis conformation around
the single C(b)–C(g) bond (highlighted in red in XLIII,
Scheme 16). Collectively, these features contributed to a highly
preorganized, configurationally stable, transient intermediate
XLIII, which was crucial to reaction development. Indeed, the
chiral fragment within the catalyst 23 was positioned close
enough to the reactive d-carbon to determine an effective
shielding of the Re face of the extended iminium ion XLIII,
leaving the opposite Si face available for the approach of the 2chlorooxindole 52. The resulting dienamine intermediate
XLIV then underwent an intramolecular nucleophilic substitution, affording, after hydrolysis, the cyclopropane spirooxindole 53 in good yields and high levels of stereocontrol.
The next step in further expanding the versatility of vinylogous iminium ion-initiated cascades was to overcome the
need for carefully designed substrates. Indeed, the first steps of
the previously developed 1,6-E2 sequences all required the generation of a multifunctional intermediate able to successively
undergo an intramolecular process. The possibility of using linear polyunsaturated carbonyl compounds, though, provided a
more flexible tool for designing more complicated cascade reactions based on intermolecular and stereoselective bond-forming
events. Specifically, a three-component domino process, proceeding by way of an aminocatalyzed Michael addition/1,6addition/vinylogous aldolization sequence, which combines
two intermolecular and one intramolecular bond-forming
event, was developed. The triple vinylogous organocascade
yielded valuable spiro-oxindolic cyclohexane derivatives 57
with six stereogenic centers and very high control over the stereochemistry (from 4:1 to 17:1 dr, 99% ee, Scheme 17).[39,40]
The triple cascade process is based on complicated catalytic machinery, which is largely based on vinylogous reactivity.
An enamine-catalyzed Michael addition of the aldehyde 55 to
the alkylidine oxindole acceptor 54 leads to the transient formation of the nucleophilic intermediate XLVII. The nucleo-

Chem. Rec. 2016, 00, 00–00

Scheme 17. The vinylogous triple cascade proceeds by way of an enamine
(E)/vinylogous iminium ion (1,6)/dienamine activation (E2) sequence; E:
enamine; 1,6: vinylogous iminium ion; E2: dienamine. The blue circle
represents the chiral scaffold of the aminocatalyst 23. The reactive carbon
atoms are highlighted in different colors, depending on their inherent
reactivity: magenta stands for a nucleophilic position, and blue for an
electrophilic center.

phile can then engage in the g-site selective intermolecular
1,6-addition, upon vinylogous iminium ion activation of the
b-substituted 2,4-dienal 56, to forge the spiro-stereocenter.
The transient formation of a nucleophilic dienamine XLVII
drives an intramolecular vinylogous aldolization to provide the
final cyclohexane product 57.
3.2. Sequential Vinylogous Iminium Ion/Iminium Ion
Cascade Pathway
Vinylogous iminium ion-initiated vinylogous cascade processes are not limited to the functionalization of a,b,g,d-unsaturated carbonyl compounds at the adjacent d- and g-carbon
atoms. Stereoselective functionalization of the d- and bcarbons can also be accomplished when using a dual LUMOlowering activation sequence, specifically a vinylogous iminium ion/iminium ion pathway (1,6/1,4 cascade, Figure 9).
After condensation of the carbonyl compound with a chiral

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Fig. 9. Vinylogous iminium ion (1,6)/iminium ion (1,4) cascade pathway; the
blue and grey circles represent the chiral scaffolds of the aminocatalyst.

aminocatalyst, the resultant vinylogous iminium ion is intercepted by a nucleophile, affording, in analogy to the precedent 1,6-E2 sequence, a dienamine intermediate. At this
point, protonation of the dienamine results in the formation
of an iminium ion intermediate that can trap a second nucleophilic species. If the original substrate features a second nucleophilic site, an additional bond formation follows under the
control of the chiral catalyst. This vinylogous iminium ion/
iminium ion (1,6-1,4) cascade reaction allows functionalization of a carbonyl at the d- and b-positions and relies on the
chiral aminocatalyst for both bond-forming steps.
When planning a vinylogous iminium ion-initiated cascade reaction of a linear polyunsaturated carbonyl compound,
the main difficulty is that the chiral catalyst must forge a
remote stereocenter with high fidelity, while inducing exclusive
d-site selectivity in the initial 1,6-addition. This is strictly
dependent on the ability of controlling the molecular topology
of the acyclic intermediate, so as to ensure highly predictable
reaction outcomes. As discussed in the precedent section, the
use of the linear 2,4-dienals 56, bearing a tert-butyl steering
group at the b-position, ensured molecular preorganization of
the catalytically active vinylogous iminium ion intermediate
(Scheme 18). The presence of such steric control element
resulted in only the conformationally stable E,E,E iminium
ion isomer L forming, and this turned out to be key for achieving high selectivity. The use of 3-hydroxyoxindoles 58, which
is characterized by a bidentate nucleophilic profile (both the
C3 carbon and the oxygen atom are nucleophilic sites),
allowed the realization of a 1,6/1,4 cascade with enals 56.[41]
This process, which is based on a highly regio- and stereoselective 1,6-addition/oxa-Michael sequence, directly afforded tetrahydrofuran spirooxindole derivatives 59. Mechanistically,
the reaction proceeds through the formation of the E,E iminium ion isomer L, which drives a selective 1,6-addition of the
nucleophilic carbon within 58 to form the iminium ion intermediate LI. Then, the hydroxyl group participates in an intramolecular oxa-Michael process, leading to the final spirocyclic
adduct 59.
Remarkably, the presence at the b-position of the dienal
substrate 56 of a trimethylsilyl group, characterized by a similar Charton steric parameter[42] of a tert-butyl moiety, directed

Chem. Rec. 2016, 00, 00–00

the process exclusively toward a 1,6-addition manifold, while
preserving the high enantioselectivity. This result further highlights how strongly the steric profile of the b-substituent in 56
is connected with an effective control over the molecular topology of the vinylogous iminium ion intermediate. Synthetically,
it is worth noting that the trimethylsilyl group could be eventually removed upon protiodesilylation under basic conditions, which makes the trimethyl silyl moiety a traceless
directing group to achieve d-site selectivity, providing a formal
1,6-addition of geometrically unbiased, linear dienals.
Recently, Jørgensen and coworkers reported that different
types of naphthols 61 were suitable substrates for the 1,6-1,4
vinylogous cascade process with linear, completely unbiased
enals 60 (Scheme 19).[43] Mechanistically, a Friedel–Crafts
1,6-addition reaction of hydroxyarenes to a vinylogous iminium ion intermediate LIII and subsequent oxa-Michael addition to the iminium ion LIV formed in the first step led to
chromans 62 with high stereo-fidelity. Importantly, no substituents on the 2,4-dienal 60 are required to ensure complete
remote selectivity in the first step. Computational studies

Scheme 18. Synthesis of tetrahydrofuranyl spirooxindoles 59 by means of a
1,6-1,4 cascade reaction with linear dienals; 1,6: vinylogous iminium ion; 1,4:
iminium ion. The blue circle represents the chiral scaffold of the aminocatalyst
23. The grey circle in L highlights the importance of the bulky R2 substituent
as a conformational anchor; TMS: trimethylsilyl; PG: protecting group. The
reactive carbon atoms are highlighted in different colors, depending on their
inherent reactivity: magenta stands for a nucleophilic position, and blue for an
electrophilic center.

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Scheme 19. 1,6-1,4 cascade reaction with linear, completely unbiased dienals;
1,6: vinylogous iminium ion; 1,4: iminium ion. The blue circle represents the
chiral scaffold of the aminocatalyst 63. The reactive carbon atoms are
highlighted in different colors, depending on their inherent reactivity: magenta
stands for a nucleophilic position, and blue for an electrophilic center.

suggested that the d-site selectivity is driven by thermodynamic
control of the Friedel–Crafts reaction step.

two are related and proceed through a common activated ester
intermediate. This intermediate can be formed either through
the addition of an NHC to an enal and the subsequent oxidation of the Breslow intermediate (Strategy 1) or through the
addition of an NHC to an a,b-unsaturated ester to directly
access the activated ester intermediate (Strategy 2). This strategy results in the activation of the remote g-carbon, which in
the presence of a base, undergoes deprotonation to afford a
vinylogous enolate. A third conceptually different strategy has
also been reported, which requires enals that feature a leaving
group at the g-position. Following the addition of the NHC,
intramolecular elimination from the Breslow intermediate
generates the crucial vinylogous enolate species (Strategy 3 in
Figure 10).
Once the vinylogous enolate has been formed, it can
undergo a vinylogous nucleophilic attack to an electrophile. If
this electrophile is tethered to a masked nucleophile, a cascade
reaction occurs where the nucleophilic moiety utilizes the
intrinsic nature of the NHC as a leaving group to attack the
carbonyl moiety and undergo a cyclization (En2-S) (Figure 11).
These En2-S cascade reactions rely on the NHC catalyst for
both new bond-forming steps, and although a cycloaddition
pathway cannot be excluded for these types of transformations,
the current understanding is that they are more likely to proceed through a cascade process.[45]
The first reported use of NHC-catalysis to develop a
En2-S vinylogous cascade reaction was based on Strategy 1 to
activate the g-carbon. This work, shown in Scheme 20, featured the formation of lactones 66 from enals 64 and
electron-deficient ketones 65.[46] In the mechanistic proposal,
the addition of the NHC 67 to enal 64 forms the Breslow
intermediate LVI, which upon oxidation from 68, generates
intermediate LVII. Deprotonation of LVII affords the

4. N-Heterocyclic Carbene-mediated Vinylogous
Cascade Processes
Aminocatalysis is not the only successful organocatalytic
approach for designing vinylogous cascade reactions. Nheterocyclic carbenes (NHC)[44] have also been used as viable
catalytic intermediates for these transformations. Evidence for
the existence of carbenes dates back to the late 19th century,[44a]
and then they have been used extensively as organocatalysts to
functionalize carbonyl compounds at the a- and b-positions.
The activation modes that permit such reactivity can also be
extended into the vinylogous reactivity space to facilitate
remote transformations, including stepwise cascade processes.
Three strategies have been reported to facilitate NHCcatalyzed vinylogous cascade processes (Figure 10). The first

Chem. Rec. 2016, 00, 00–00

Fig. 10. The different strategies utilized to form vinylogous enolates using
NHC catalysis; the blue and grey circles represent the chiral scaffold of the
NHC catalyst.

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Fig. 11. Vinylogous enolate (En2)/spontaneous (S) cyclization cascade
pathway; the initial organocatalytic event is followed by a spontaneous ipsocyclization. The blue and grey circles represent the chiral scaffolds of the NHC
catalyst.

vinylogous enolate LVIII, which undergoes a Lewis acidmediated vinylogous addition to the ketone 65. After this
addition, the resulting anionic intermediate LIX undergoes a
spontaneous intramolecular cyclization to form the lactone

product 66 in good yields (52–82%) and enantioselectivities
(60–94% ee).
Strategy 1 was also used for the formation of bicycle 70
through a formal [3 1 4] cycloaddition between enal 64 and
azomethine 69 in the presence of NHC 67 and the oxidant 68
(Scheme 21).[47] The mechanism is believed to proceed similarly to the one illustrated in Scheme 20: the vinylogous enolate LVIII, upon nucleophilic addition to imine 69, forms the
[3 1 4] adduct 70 after spontaneous intramolecular lactamization in good yields (51–81%) and enantioselectivities (84–
99% ee).
The use of Strategy 2 to form the vinylogous enolate
(Figure 10) has also served for the implementation of a En2-S
cascade sequence. Direct addition of NHC 74 to the a,bunsaturated ester 71 generates the intermediate without the
need for an oxidation step. Besides the different activation
strategy to access the key vinylogous enolate intermediate, the
reaction proceeds in a similar fashion as discussed in Scheme
20: vinyl enolate LVIII attacks the hydrazine 72 and then a
spontaneous cyclization delivered the lactam product 73 in
good yields (31–91%) and enantiomeric excess (90–99% ee,
Scheme 22).[48]

Scheme 21. The formation of the formal [4 1 3] product 70 through a En2-S
cascade sequence; En2/S cyclization pathway; En2: vinylogous enolate; S:
spontaneous cyclization.

Scheme 20. The first reported use of NHC catalysis to develop a vinylogous
cascade; En2/S cyclization pathway. En2: vinylogous enolate; S: spontaneous
cyclization. The blue and grey circles represent the chiral scaffolds of the NHC
catalyst 67. The reactive carbon atoms are highlighted in different colors,
depending on their inherent reactivity: magenta stands for a nucleophilic
position, and blue for an electrophilic center.

Chem. Rec. 2016, 00, 00–00

Scheme 22. NHC-mediated En2-S cascade sequence; En2: vinylogous
enolate; S: spontaneous cyclization. Formation of the vinylogous enolate
achieved via Strategy 2 in Figure 10.

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Curie COFUND action (2014-1-ICIQ-IPMP) and Severo
Ochoa Excellence Accreditation 2014–2018, SEV-2013-0319
for postdoctoral fellowships.

REFERENCES

Scheme 23. NHC-mediated En2-S cascade sequence; En2: vinylogous
enolate; S: spontaneous cyclization. Formation of the vinylogous enolate
achieved via Strategy 3 in Figure 10.

Recently, the vinylogous enolate-generation Strategy 3
(Figure 10) was also applied to realize an En2-S cascade
sequence. Using the enal 75, which bears a suitable carbonate
leaving group at the g-position, it was possible to generate the
intermediate LVIII after elimination of the leaving group following formation of the Breslow intermediate LX. Nucleophilic addition of LVIII to di-tert-butyl azodicarboxylate 76
and subsequent lactamization gave product 77 in good
yields (49–82%) and enantiomeric excess (94–99% ee,
Scheme 23).[49]

5. Summary and Outlook
The intense investigations into organocatalytic cascade reactions have led to the development of highly innovative techniques, which now provide reliable and versatile tools for
modern asymmetric synthesis. Recently, the combination of
organocatalysis and the principle of vinylogy has opened up
new avenues for reaction design, further expanding the synthetic potential of cascade processes. Vinylogous cascade strategies provide effective means to build stereochemically dense,
complex molecules from readily available substrates and using
simple producers while forging stereogenic centers remote
from the catalyst’s point of action. Further interesting development along these lines are foreseen in the near future.[50]

Acknowledgements
Funding for this work was provided by the Institute of Chemical Research of Catalonia (ICIQ) Foundation and the European Research Council (ERC Starting grant agreement no.
278541 – ORGA-NAUT). L.D. and H.B.H. thank the Marie

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Received: February 17, 2016
Published online: ᭿᭿

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