Unlocking Access to Enantiopure Fused Uracils by Chemodivergent [4+2] Cross-Cycloadditions: DFT-Supported Homo-Synergistic Organocatalytic Approach

Article abstract of DOI:10.1002/anie.202007509

The discovery of chemical methods enabling the construction of carbocycle-fused uracils which embody a three-dimensional and functional-group-rich architecture is a useful tool in medicinal chemistry oriented synthesis. In this work, an unprecedented amine-catalyzed [4+2] cross-cycloaddition is documented; it involves remotely enolizable 6-methyluracil-5-carbaldehydes and β-aryl enals, and chemoselectively produces two novel bicyclic and tricyclic fused uracil chemotypes in good yields with a maximum level of enantiocontrol. In-depth mechanistic investigations and control experiments support an intriguing homo-synergistic organocatalytic approach, where the same amine organocatalyst concomitantly engages both aldehyde partners in a stepwise eliminative [4+2] cycloaddition, whose vinylogous iminium ion intermediate product may diverge—depending upon conditions—to either bicyclic targets by hydrolysis or tricyclic products by a second homo-synergistic trienamine-mediated stepwise [4+2] cycloaddition.

Full text of DOI:10.1002/anie.202007509

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Unlocking Access to Enantiopure Fused Uracils via
Chemodivergent [4 + 2] Cross Cycloadditions: a DFT-Supported
Homo-Synergistic Organocatalytic Approach
Authors: Claudio Curti, Gloria Rassu, Marco Lombardo, Vincenzo
Zambrano, Luigi Pinna, Lucia Battistini, Andrea Sartori,
Giorgio Pelosi, and Franca Zanardi
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10.1002/anie.202007509
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RESEARCH ARTICLE
Unlocking Access to Enantiopure Fused Uracils via
Chemodivergent [4 + 2] Cross Cycloadditions: a DFT-Supported
Homo-Synergistic Organocatalytic Approach
Claudio Curti,*[a] Gloria Rassu,[b] Marco Lombardo,*[c] Vincenzo Zambrano,[b] Luigi Pinna[d] Lucia
Battistini,[a] Andrea Sartori,[a] Giorgio Pelosi,[e] and Franca Zanardi*[a]
[a]
Prof. Dr. C. Curti, Prof. Dr. L. Battistini, Prof. Dr. A. Sartori, Prof. Dr. F. Zanardi
Dipartimento di Scienze degli Alimenti e del Farmaco
Università di Parma
Parco Area delle Scienze 27A, 43124 Parma, Italy
E-mail: claudio.curti@unipr.it (C.C.), franca.zanardi@unipr.it (F.Z.)
Dr. G. Rassu, Dr. V. Zambrano
Istituto di Chimica Biomolecolare
Consiglio Nazionale delle Ricerche
[b]
[c]
Traversa La Crucca 3, 07100 Li Punti Sassari, Italy
Prof. Dr. M. Lombardo
Dipartimento di Chimica “Giacomo Ciamician”
Università di Bologna
Via Selmi 2, 40126 Bologna, Italy
E-mail: marco.lombardo@unibo.it
[d]
[e]
Prof. Dr. L. Pinna
Dipartimento di Chimica e Farmacia
Università di Sassari
Via Vienna 2, 07100 Sassari, Italy
Prof. Dr. G. Pelosi
Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale
Università di Parma
Parco Area delle Scienze 17A, 43124 Parma, Italy
Supporting information for this article is given via a link at the end of the document.
Abstract: The discovery of chemical methods enabling the
construction of carbocycle-fused uracils which embody a three-
dimensional and functional group-rich architecture is a useful tool in
medchem synthesis. In this work, an unprecedented amine-catalyzed
[4 + 2] cross cycloaddition is documented, which involved remotely
enolizable 6-methyluracil-5-carbaldehydes and -aryl enals, and
chemoselectively produced two novel bicyclic and tricyclic fused uracil
chemotypes in good yields and maximum level of enantiocontrol. In-
depth mechanistic investigations and control experiments support an
intriguing homo-synergistic organocatalytic approach, where the
same amine organocatalyst concomitantly engages both aldehyde
partners in a first stepwise eliminative [4 + 2] cycloaddition, whose
vinylogous iminium ion intermediate product may diverge – depending
upon conditions – to either bicyclic targets via hydrolysis, or tricyclic
products via a further homo-synergistic trienamine-mediated stepwise
[4 + 2] cycloaddition.
discovery field, an ever-growing demand for innovative synthesis
methods is profiling, enabling the rapid construction of high-
quality lead structures that merge the drug-like properties of
functionalized core scaffolds with an increased three-dimensional
shape, thereby expanding the uncharted chemical space around
the putative biological targets.[2]
Introduction
Over the past two decades, the development of breakthrough
synthetic methods, such as organocatalyzed processes and direct
activation modalities of nonactivated C-H bonds, have
revolutionized the way molecules are imagined and made, with
enormous impact on neighboring disciplines including
pharmaceutical research and chemical biology.[1] In the drug
Figure 1. Uracil and examples of uracil-based drugs. NNRT = Non-Nucleoside
Reverse Transcriptase.
1
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Scheme 1. Previous vinylogous C(sp3)-H functionalization strategies for the asymmetric construction of fused (hetero)cycles.
Among the privileged core motifs, the naturally occurring
heterocycle uracil (compound 1, Figure 1) occupies a preeminent
position, due to its innate chemical structure – a stable six-
membered 2,4-pyrimidindione ring with a prevalence of the
lactam tautomeric form – responsible for it to establish key gene-
related H-bond connections.[3] In addition, uracil has proven to be
extremely inclined toward chemical modification, especially at the
N1, N3, C5, and C6 positions.[4] Accordingly, a wide array of uracil-
based molecules has been accessed so far, exhibiting as many
diverse biological activities ranging from antiviral and anti-tumor
to herbicidal, bactericidal, and anti-malarial action, as testified by
the outstanding number of uracil-founded drugs approved
worldwide (Figure 1).[5] Chemical modifications of the uracil ring
often maintain the pyrimidindione core, which is enriched with
atoms and/or flexible aromatic/aliphatic chains (e.g. compounds
2, 3, and 4), while it is possibly fused with flanking heterocycles,
as in the pyridopyrimidine structure 5, which generally are
flattened and C(sp2)-rich rings.[6] Rare examples of chiral uracil-
fused cycles have been reported so far, which have been mainly
accessed in racemic format via nonasymmetric syntheses.[5b]
Asymmetric chemical methods enabling the rapid elaboration of
commercially available uracil-based materials toward chiral
enantio- and functional group-enriched fused uracils are still on
demand, and our aim here is to address this goal.
opportunity in organic synthesis for the predictable and selective
functionalization of remote C(sp3)-H bonds.[7] In particular, the
benzylic site of ortho-methyl (hetero)aromatic carbaldehydes IV
and VIII or extended polyenals of type I (Scheme 1) may be
envisaged as a remotely enolizable position of the vinylogous
aldehyde system, so that useful functionalization chemistry with
suitable acceptor components may be fostered. However,
deprotonation of these benzylic vinylogous sites is not simple,
since it generates highly reactive ortho-quinodimethane species
(oQDMs) – indeed truly polyenolate donors – where the aromatic
character of the original ring is temporarily lost.[8] To enhance the
acidity of such benzylic protons, clever solutions were devised, as
exemplified in Scheme 1. In a first example (Scheme 1, eq. 1),[9]
upon condensation of aldehyde I with the amine catalyst, the
activated oQDM-trienamine donor Iʹ is formed in situ, which
closes with the electron-poor olefin II to consign the -locked
fused cyclohexane product III. When a similar organocatalyzed
reaction was performed using methylindole carbaldehyde IV (eq.
2), featuring a formyl function directly attached to the aromatic ring,
the cross-coupling with enal acceptor VI failed to produce any
cyclized products, probably due to insufficient capability of the
reaction system to generate the dearomatized oQDM donor. In
that instance, a strategic escamotage was devised, to temporarily
activate the donor carbaldehyde chemoselectively as
a
The application of the principle of vinylogy – which states that the
electronic properties of a functional group within a molecule are
possibly transmitted to a remote position through interposed
methylenemalonate derivative V, to trigger the intended [4 + 2]
coupling between the in situ-activated components Vʹ and VIʹ.
The spontaneous malononitrile elimination finally provided the
conjugated multiple bonds
– has become an appealing
2
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RESEARCH ARTICLE
,ipso-locked cyclohexene aldehyde products VII in a global
eliminative [4 + 2] cycloaddition reaction.[10]
Scheme 2. Projected plan for the asymmetric construction of fused uracils in this work.
In the third example (Scheme 1, eq. 3), the cross-coupling
between ortho-tolualdehyde VIII and enals VI could be feasible by
Our efforts in this work were directed to put this plan into practice,
to demonstrate its viability with diversely substituted substrates,
installing electron-withdrawing groups in the donor component (i.e. and to get insights into the reaction mechanism via in-depth DFT
nitro groups); in the event, an eliminative [4 + 2] cyclization took
place between VIIIʹ and the iminium ion-activated enal partner
VIʹ.[11]
computational investigation backed up by sound experimental
evidence.
In this work, we focus on a novel uracil scaffold, namely
compound 7 (Scheme 2), which is easily equipped with an
exocyclic carbaldehyde handle at C5 starting from the cheap,
commercially available 6-methyluracil precursor 6. Concomitant
vinylogation of the C6-methyl with both the aldehyde and the
endocyclic lactam moieties would render the C-H deprotonation
at C6 feasible under mild conditions. Remote -deprotonation
would lead to electron-rich diene 7ʹ, which is anticipated to
undergo either one single or double [4 + 2] cycloadditions with
iminium ion-activated dienophile 8ʹ, to ultimately provide access
to diversely shaped chiral carbocyclic uracils of type 9 and/or 10
(vide infra).
Distinguishing features of this strategy are: (1) the exploitation of
the unique structural motif of methyluracil carbaldehyde 7, whose
scarce aromatic character would in principle facilitate the
formation of the putative active oQDM-type species 7ʹ;[3] (2) the
perspective of generating, for the first time, new chiral, 3D space-
filling fused uracils in one pot from available uracil-based
Results and Discussion
Synthesis. As a proof of concept of the feasibility of the proposed
plan (Scheme 2), we initially evaluated the reaction between N,N-
dimethyl-substituted methyluracil carbaldehyde 7a and
cinnamaldehyde (8a) under amine organocatalysis (Table 1).
Compound 7a, in turn, was accessed via a two-step procedure by
starting from cheap and commercially available 6-methyluracil (6)
via bis-N-methylation (Me2SO4, K2CO3) followed by Vilsmeier
formylation. Thus, treating 7a and 8a in an equimolar ratio in the
presence of popular TMS-protected prolinol C1 (20 mol%) and
catalytic DIPEA in CH2Cl2, led to the formation of carbaldehyde
9aa in 36% yield, accompanied by not negligible amounts of the
tricyclic product 10aa (9% yield; Table 1, entry 1). While
compound 9aa coincided exactly with our expectations according
to a plausible eliminative [4 + 2] cross cycloaddition between the
two substrates, compound 10aa came as a surprise, likely as the
result of a double cycloadditive process involving two mol equiv
of the cinnamaldehyde component (for mechanistic details, see
infra). Since the very first experiment, hence, we became aware
of three facts: the reaction was feasible, it could lead to two new
uracil-fused chemotypes, and the enantiocontrol by secondary
amine organocatalysis was excellent for both types. Accordingly,
we proceeded to the systematic screening of the reaction
conditions, to maximize both yield and chemoselectivity for either
target, while maintaining enantiocontrol.
precursors, representing
a step forward with respect to
established methods of functionalization of uracils; and (3) the
possibility of introducing variable substituents at the N1/N3 atoms,
thus allowing modulation of the physico-chemical properties of
substrates and targets.
From
a mechanistic point of view, additional interesting
perspectives would open, as to define the actual role of the amine
catalyst in activating either or both the aldehyde carbonyl groups
of the reacting partners 7 and 8, to unveil the concerted vs
stepwise nature of the cyclization reactions, as well as to unravel
the intimate reasons responsible for chemodivergency toward
either class of uracil-fused products.
3
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RESEARCH ARTICLE
impacted the overall efficiency (Table 1, entry 12, and Table S2
in Supporting Information), clearly suggesting clues on the
reaction mechanism (see infra).
Table 1. Proof of concept of the plan and selected optimization of reaction
conditions.[a]
Overall, the optimized reaction protocol toward bicyclic product
9aa entailed the use of a 2:1 ratio of N,N-dimethyl-substituted 7a
and cinnamaldehyde 8a, catalyst C1 with a 20 mol% loading, in
the absence of any additives, in dichloromethane at room
temperature for 24 h, leading to 9aa in 68% isolated yield, >10:1
chemoselectivity and >99% ee (Table 1, entry 14).
The optimized procedure to tricyclic product 10aa called for the
use of uracil 7a and enal 8a in a 1:3 ratio, using the same catalyst
C1 in 20 mol% loading, with the addition of catalytic benzoic acid
(20 mol%) in dichloromethane at room temperature, giving 10aa
in 68% isolated yield, 6:1 chemoselectivity, and >99% ee (Table
1, entry 16).
We next investigated a battery of diversely functionalized
substrates 7 and 8 to evaluate the functional group compatibility
of the two procedures. Table 2 and Table 3 illustrate the results
of this investigation toward bicyclic uracils 9 and tricyclic
compounds 10, respectively. As for the eliminative [4 + 2]
cyclization to products 9, substituted cinnamaldehydes 8 bearing
either electron-withdrawing or electron-donating groups proved
competent enal substrates in couple with N,N-dimethyl uracil 7a,
giving the corresponding bicycles 9ab, 9ac, 9ae, 9af, and 9ah in
Entry
Cat.
C
7a:8a
Additive
Yield[b]
9aa:10aa[c]
ee
[%]
9aa/10aa[d]
1
C1
C2
C3
-
1:1
DIPEA
45
30
15
-
4:1
99/>99
99/n.d.
n.d./n.d.
-
2
1:1
DIPEA
>10:1
n.d.
-
3
1:1
DIPEA
4
1:1
-
5
6[e]
-
1:1
DIPEA
-
-
-
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
C1
1:1
DIPEA
35
40
55
65
35
15
30
55
74
45
79
1:1
99/>99
99/>99
99/>99
99/n.d.
99/n.d.
n.d./n.d.
99/>99
99/>99
>99/n.d.
99/>99
n.d./>99
7
1:1
Et3N
2:1
8
1:1
-
5:1
9
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
2:1
-
10:1
10:1
n.d.
>10:1
1:1
10[f]
11[g]
12[h]
13
14
15
16
-
reasonable-to-good
enantioselectivities in all cases. The reaction toward 9ab was
repeated on 5× scale proving equally efficient and
isolated
yields
and
excellent
-
-
a
BA
-
enantioselective. Good results were also obtained with naphthyl
derivative 9ad and furyl-equipped compound 9ag. Inferior
performance was instead witnessed using a polyconjugated
dienal substrate (namely, 5-phenyl-2,4-pentadienal 8i), which
reacted with 7a giving bicycle 9ai in a poor 20% yield,
accompanied by preponderant formation (50% yield) of the
corresponding aromatized compound (see Supporting
Information). In this case, extended double bond conjugation
could be responsible for facile oxidation of 9ai in air during the
workup procedure. Variation of the uracil component 7 entailed
the use of methoxymethyl- (MOM), methoxyethoxymethyl- (MEM),
and benzyloxymethyl- (BOM) substituted uracils 7b, 7c, and 7d,
respectively, which were prepared from commercial methyluracil
carbaldehyde 6 in three steps (see Supporting Information).
These substrates reacted with cinnamaldehyde according to the
standard procedure, providing the corresponding products 9ba,
9ca, and 9da in good isolated yields and, again, notable
enantiomeric excesses.[12]
As a limitation of the procedure, the reactions failed with N,N-
unsubstituted uracil substrate (Table 2), mainly due to its very
poor solubility in dichloromethane. Also, -alkyl-substituted enals
(e.g. R2 = cyclohexyl) proved recalcitrant substrates under the
reported reaction conditions, even with prolonged reaction times
and higher temperatures. In all cases reported in Table 2,
chemoselectivity between the expected products 9 and the
corresponding tricycles 10 remained at high levels (9:10, >10:1),
as determined by NMR analysis of the crude reaction mixtures.
By simply adjusting the substrate ratio and adding benzoic acid
co-catalyst (optimized conditions of Table 1, entry 16), access to
variously adorned products 10 was at hand, which remarkably
feature a tricyclic skeleton with six contiguous stereocenters. The
representative compounds in Table 3 were obtained in good
isolated yields, moderate-to-good chemoselectivity (10:9, 6:1),
complete diastereoselectivity, and excellent levels of
>10:1
3:1
1:1.5
1:3
-
BA
1:6
[a]All reactions were run under inert atmosphere on a 0.2 mmol scale (0.1 M).
[b]Combined yield of isolated products 9aa and 10aa. [c]Determined by 1H NMR
analysis of the crude reaction mixture. [d]Determined by HPLC analysis on a
chiral stationary phase. [e]Toluene was used. [f]0 °C and 48 h reaction time.
[g]50 °C and 12 h reaction time. [h]10 mol% catalyst loading. DIPEA = N,N-
diisopropylethylamine. BA = benzoic acid. n.d. = not determined. For complete
optimization survey, see Tables S1-S2 in the Supporting Information.
As for the organocatalysts screened, the first catalyst used, C1,
revealed to be the best one, since reactions performed with other
secondary amine catalysts or tertiary amine bifunctional catalysts
either gave inferior results in terms of product yield (entries 2 and
3), or proved completely non-productive (Table S1, Supporting
Information). No reaction took place in the absence of any amine
catalyst, both in the presence or absence of the DIPEA additive,
emphasizing the key role of the catalyst in triggering the
transformation (entries 4 and 5). The role of solvent, additive,
molar ratio between substrates, catalyst loading, and reaction
temperature was next investigated (Table 1, entries 7-16 and
Table S2 in the Supporting Information), ultimately leading to the
following conclusions. First, chemodivergency, i.e. 9aa:10aa ratio,
was strictly dependent by the 7a:8a substrate ratio, with bicycle
9aa prevailing with excess of 7a over 8a, and tricycle 10aa
predominating with excess 8a over 7a. Second, the role of the
additive crucially impacted both yield and chemoselectivity; in fact,
the absence of any added Brønsted base or acid improved the
overall efficiency of the reaction toward the formation of bicycle
9aa, while catalytic addition of benzoic acid as an additive
enhanced the efficiency of the transformation in favor of tricyclic
product 10aa. Lastly, the catalyst loading had to be maintained at
20 mol% level, since lowering the quantity of catalyst heavily
4
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10.1002/anie.202007509
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RESEARCH ARTICLE
enantioselectivity, as detected by chiral HPLC analysis of the
corresponding bis-carbinols.
Table 3. Substrate scope for the chemo-, regio-, diastereo-, and
enantioselective synthesis of tricyclic uracils 10.[a]
Table 2. Substrate scope for the chemo-, regio-, and enantioselective synthesis
of bicyclic uracils 9.[a]
[a] All reactions were run under an inert atmosphere in 0.1 M solutions of dry
CH2Cl2. Yields refer to isolated products 10. Diastereomeric ratios (dr) were
determined by 1H NMR analysis of the crude reaction mixtures. Enantiomeric
excesses (ee) were determined by HPLC analysis of the corresponding bis-
alcohols of type 12 (see infra, Scheme 3) using a chiral stationary phase. [b]
Relative configuration corroborated by 2D NMR NOESY analysis (CDCl3, 400
MHz). For further details, see the Supporting Information.
[a] All reactions were run under an inert atmosphere in 0.1 M solutions of dry
CH2Cl2. Yields refer to isolated products 9. Enantiomeric excesses (ee) were
determined by HPLC analysis on a chiral stationary phase. [b] Isolated yield on
a 5 × scale. [c] The corresponding aromatized achiral product was isolated in
50% yield. For further details, see the Supporting Information.
The varied functional group pattern of compounds 9 and 10
served for further chemical transformations. Derivatization of
aldehyde ent-9ae into crystalline benzoyl carbinol 11 (Scheme 3,
eq. 1), allowed us to determine the absolute configuration of the
products indirectly, by single crystal X-ray analysis (see the
Supporting Information for details).[13] Further elaborations
included carbonyl reduction of products 10 into the corresponding
bis-alcohols 12 (Scheme 3, eq. 2), and reductive removal of BOM
protections from bis-carbinol 12da to afford N,N-unsubstituted
tricycle 13da (eq. 3).
Scheme 3. Chemical elaboration of the fused uracil products. MOM
=
methoxymethyl, MEM = methoxyethoxymethyl, BOM = benzyloxymethyl. For
5
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experimental details, see the Supporting Information. [a] Obtained from 7a and
p-methoxycinnamaldehyde (8e) according to the conditions reported in Table 2,
using ent-C1 instead of C1.
and Chart S2 in Supporting Information), now the second C5-C6
bond-forming reaction determines the overall cyclization barrier.
Mechanistic Insights. The chemistry herein disclosed posed
questions about the actual mechanism of these transformations,
and a special investigation was deserved to unravel three central
points: i) role played by the amine catalyst in orchestrating the
coupling between the substrates; ii) nature of the eliminative [4 +
2] cross cycloaddition to bicycles 9 (i.e. concerted vs stepwise,
catalyst recycling via elimination); iii) nature of the double [4 + 2]
cycloaddition sequence to tricycles 10 and possible linking
between the bicycle/tricycle catalytic cycles.
i) About the role played by the amine catalyst. From the observed
experimental results, we learned that C1 was an indispensable
ingredient for the reaction to occur, enantiocontrol was almost
excellent in all cases, and decreasing catalyst loading to less than
20 mol% dramatically lowered the efficiency of the process, giving
clues about a double participation of the catalyst in activating both
substrates. Given the poorly differentiated nature of the starting
reactants 7 and 8 (both -unsaturated aldehydes), it was
reasonable to assume a concomitant covalent activation of both
7 and 8 by the aminocatalyst. Organocatalyzed cross- or self-
condensations of aldehydes are known in the literature, but in-
depth studies supported by calculations and/or experimental
evidence about their mechanism are quite rare and could hardly
help us in this endeavor.[14] To test the hypothesis that a double
activation of reactants by C1 was operative, a couple of control
experiments was carried out, where either of the two reactants
was replaced by a non-aldehyde non-activatable congener
(Scheme 4, eqs. 1 and 2). Thus, when 7a was reacted with E-
nitrostyrene (14) in the presence of C1 (20 mol%), the
corresponding bicyclic compound 15 was isolated in 18% yield as
a single diastereoisomer (Scheme 4, eq. 1). Incorporation of the
catalyst moiety within the framework of the final product clearly
established the role of dienamine intermediate 7a-EN in the
addition reaction, thus confirming the hypothesis that uracil-based
aldehyde 7a may be activated by C1 via dienamine formation.
More detailed investigation of this control reaction via DFT
calculations[15] showed that this cycloaddition reaction proceeds
via a two-step mechanism entailing a first rate- and stereo-
determining dienamine-mediated vinylogous Michael reaction to
fix the C7-C8 bond, followed by closure of the nitronate
intermediate to the evolving iminium ion to install the C5-C6 bond
(see Chart S2 in the Supporting Information).
In the second control experiment (Scheme 4, eq. 2), uracil
aldehyde 7a was converted into alkenylidene malononitrile 16a,
which was reacted with cinnamaldehyde 8a under the usual
optimized conditions. In the event, bicyclic product 9aa was
mainly recovered in excellent enantiocontrol (99% ee), thus
corroborating the hypothesis of an active participation of catalyst
C1 in this reaction, via iminium ion 8a-IM (in this instance, a [4 +
2] cycloaddition followed by elimination of malononitrile is
operative).[10b] Further confirmation of this hypothesis came from
DFT calculations, as described in the next paragraph.
ii) About the nature of the eliminative [4 + 2] cross cycloaddition
toward bicycles 9. Given the reasonable existence of both 7a-EN
and 8a-IM in the reaction context, we initially modeled the addition
reaction of 7a-EN to the iminium ion 8a-IM (Chart 1). DFT
calculations[15] revealed a two-step reaction mechanism but,
contrary to the previously calculated pathway (Scheme 4, eq. 1
Scheme 4. Control experiments supporting the mechanistic investigation.
In this case, both the dienamine 7a-EN and the Michael acceptor
8a-IM possess a single unhindered diastereotopic face available
for the addition. As a result, a single approach of the two reagents
becomes energetically feasible, determining the (S)-absolute
configuration of the C7 stereocenter of the target. The reaction
profile for the complete cyclization deriving from the most
favorable synclinal approach of 7a-EN and 8a-IM and leading to
the iminium ion of the final product 9aa is reported in Chart 1. The
structures of transition states relative to C7-C8 (TS-I) and C5-C6
(TS-II) bond-forming reactions, as well as the transition state for
the elimination reaction (TS-III) are also depicted in Chart 1. While
the iminium ion moiety within intermediate I-2a could be in
principle hydrolyzed releasing half of the bound catalyst C1, the
part directly bound to C5 cannot readily re-enter the catalytic cycle.
In order to establish whether the final eliminated product 9aa
could be formed from this intermediate, we tried to model the
elimination reaction from the enamine I-2a-EN deriving from I-2a,
but no feasible reaction pathway could be found. Indeed, a
possible elimination pathway was found from enamine I-2a-EN-
H+ bearing a protonated pyrrolidine ring at C5 (Chart 1). A
possible explanation could be that, even in the absence of acidic
additives, catalytic amounts of protic acids are still present in
solution, due to easy oxidation of the commercially available
starting aldehydes.
A
second explanation for the different behavior of
cinnamaldehyde 8a with respect to nitrostyrene 14 could be found
in the different energetic requirement for the final cyclization step.
While the nitronate ion cyclizes almost with no barrier (I-7 in Chart
S2), ring closure of intermediate I-1a is considerably more
energetically demanding (Chart 1), rendering iminium ion
hydrolysis before the cyclization step possible.
6
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10.1002/anie.202007509
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RESEARCH ARTICLE
Chart 1. Reaction scheme (above) and reaction profile (below) for the addition of 7a-EN to 8a-IM. Free energy profiles (kcal∙mol−1) in the gas-phase at the M06-
2X/6-31G(d) level of theory. Energies in parentheses are relative to single point calculations at the M06-2X/6-311++G(d,p) level of theory in CH2Cl2. SM-1: separated
reactants at infinite distance (7a-EN + 8a-IM); RC: reactant complex; TS: transition state; I: intermediate; PC-1a: product complex (9aa-IM + C1). Structures of
transition states TS-I (synclinal approach), TS-II (cyclization step) and TS-III (elimination reaction); distances in Angstrom. Silylated diphenylmethanol group is
represented as a green sphere.
To establish whether this last reaction pathway is possible, we
modeled the corresponding cyclization/elimination steps on the
aldehyde deriving from intermediate I-1 (I-3a-ALD, see Chart S1,
Supporting Information). The calculated reaction profiles for the
cyclization reactions are in complete accordance with those
reported by Houk for the aldol reaction between acetaldehyde and
N,N-dimethylvinylamine.[16] In particular, in the absence of acidic
additives, the reaction proceeds to give an oxetane intermediate
with a large activation barrier (40.0 kcal∙mol−1 in the gas phase
and 31.6 kcal∙mol−1 in CH2Cl2); on the contrary, in the presence
of a protic acid, the cyclization step proceeds promptly without any
barrier. Similar to what observed for I-2a (Chart 1), no further
elimination reaction could be found in the absence of a proton
source. Upon protonation of the cyclized alcohol intermediate, a
transition state leading to the iminium ion of the final product was
easily identified, by starting from either E- or Z-configured
enamine (Chart S1, Supporting Information). Differently from
amine elimination, where the iminium ion/enamine conversion
was almost an isoergonic transformation (I-2a/I-2a-EN, Chart 1,
ΔG298 = −1.4 kcal∙mol−1 in the gas phase and 0.12 kcal∙mol−1 in
CH2Cl2), in this latter case the same conversion was highly
endergonic (ΔG298 = 22.9/23.3 kcal∙mol−1 in the gas phase and
20.8/24.7 kcal∙mol−1 in CH2Cl2, for E- and the Z-enamines,
respectively), suggesting a quite large activation barrier.
Finally, to confirm the involvement of 8a-IM in the reaction course,
the addition of 7a-EN to 8a was also modeled (Chart 2). In this
case,
a single-step asynchronous cyclization was found,
characterized by a transition state (TS-IV) in which the C7-C8
7
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10.1002/anie.202007509
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RESEARCH ARTICLE
bond is almost formed (2.09 Å), while the C5-C6 bond is
considerably longer (2.89 Å). Moreover, the corresponding
activation barrier (15.8 kcal∙mol−1 in the gas phase and 13.6
kcal∙mol−1 in CH2Cl2) resulted more than doubled than that
relative to the addition to 8a-IM (see Chart 1 vs Chart 2).
iii) About the nature of the double [4 + 2] cycloaddition sequence
to tricycles 10 and possible linking between the bicycle/tricycle
catalytic cycles. As described in the synthesis paragraph, when
the reaction was carried out in the absence of additives and with
a slight excess of uracil 7a (1.5 equiv), product 9aa was isolated
in good overall yield, together with trace amounts of tricyclic
adduct 10aa (Table 2, entry 9, non-optimized conditions). Indeed,
when the reaction was carried out in the same conditions in the
presence of 20 mol% benzoic acid as an acidic additive (Table 2,
entry 13), 9aa and 10aa were isolated in comparable yields.
These results suggested that 10aa derives directly from an
intermediate involved in the formation of 9aa. Thus, under
optimized conditions (Table 2, entry 16), 10aa could be isolated
as the main reaction product if the catalytic cycle is fostered by an
acidic additive and a larger excess of cinnamaldehyde 8a is used
(3 equiv). Considering the mechanistic rationale so far obtained,
it seems reasonable to postulate that the trienamine 9aa-EN -
directly deriving by isomerization of the iminium ion 9aa-IM (the
final product in Chart 1) - is involved in a further coupling to the
iminium ion of cinnamaldehyde (8a-IM), leading to the formation
of 10aa (Chart 3). DFT calculations showed, once more, that this
reaction follows a two-step mechanism, where the second step,
namely the cyclization reaction, determines the overall reaction
barrier. Again, both trienamine 9aa-EN and the Michael acceptor
8a-IM have only one unhindered diastereotopic face available for
the addition, completely determining the (8R,9S)-absolute
configuration of the newly forged C8 and C9 stereocenters.
Accordingly, the second cyclization step fixes the absolute
(5S,10S)-configuration at the C5 and C10 stereocenters in an
unequivocal manner. The overall [4 + 2] cycloaddition entails a
first trienamine-mediated bisvinylogous Michael reaction,
followed by an intramolecular enamine-mediated Michael
reaction; in the event, four new contiguous stereocenters are
nicely formed with complete absolute stereocontrol. The
configuration of the last new stereocenter at the C6 position is
determined later, during enamine/iminium ion equilibration to
consign the final target 10aa; the aldehyde substituent at C6
assumes the most thermodynamically stable pseudo-equatorial
disposition, thus accounting for the observed 6S-absolute
configuration for this stereocenter.
So far, the calculation results suggested that 1) the addition
reaction involves both the enamine of 7a and the iminium ion of
8a derived from condensation with catalyst C1, constituting a
perfect yet rare example of a very efficient enantioselective homo-
synergistic organocatalytic transformation. Indeed, amine-
catalyzed eliminative [4 + 2] cycloadditions were previously
reported by Watanabe[14a] and Jorgensen groups,[14c] dealing with
self- or cross condensation of linear enals; in those instances,
double activation of both substrates via enamine and iminium ion
formation with the organocatalyst was postulated, but only a
partial investigation of the actual reaction mechanism was
documented. 2) The presence of traces of a protic acid is required
to foster the final elimination reaction, and 3) even if the acid-
catalyzed cyclization step involving the aldehyde acceptor is
considerably faster than the addition to the corresponding iminium
ion (Chart S1 vs Chart 1), the subsequent iminium/enamine
isomerization, required for the final elimination step, appears
much more energetically favorable in the case of the iminium ion
pathway (Chart 1).
Given the above considerations, chemodivergence toward either
bicyclic product 9aa or tricyclic congener 10aa is established by
the presence of the key oQDM-like trienamine intermediate 9aa-
EN directly deriving from 9aa-IM. If conditions are present which
favor this isomerization (e.g. protic conditions), the reaction
proceeds to tricycle 10aa, especially when excess of dienophile
8a-IM is present. On the other hand, if 9aa-IM is not given the
possibility to isomerize to trienamine 9aa-EN, for instance
because it is hydrolyzed to the corresponding aldehyde, then the
reaction path stops at this stage consigning bicycles 9. As a
confirmation of this sentence, one further control experiments was
carried out (Scheme 4, eq. 3), where bicyclic compound 17,
bearing
a
quaternary C6 carbon, was reacted with
Chart 2. Reaction scheme (above), reaction profile (below, left) for the addition
of 7a-EN to 8a and structure of transition state TS-IV (below, right, distances in
Angstrom). Free energy profiles (kcal∙mol−1) in the gas-phase at the M06-2X/6-
31G(d) level of theory. Energies in parentheses are relative to single point
calculations at the M06-2X/6-311++G(d,p) level of theory in CH2Cl2. SM-4:
separated reactants at infinite distance; RC: reactant complex; TS: transition
state. Silylated diphenylmethanol group is represented as a green sphere.
cinnamaldehyde 8a in the presence of catalyst C1 and benzoic
acid (20 mol% each). In the event, no even minimal conversion of
17 to the corresponding tricyclic compound was witnessed in 24
h. In this case, transformation of 17 to the corresponding oQDM
would be in principle possible via 5,8-conjugate water elimination,
but no isomerization to the trienamine would be feasible due to
interruption of conjugation by the quaternary C6 center, with
consequent inhibition of the [4 + 2] cyclization to any tricyclic
8
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10.1002/anie.202007509
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RESEARCH ARTICLE
product. That is to say, only hypervinylogous enamines of type
9aa-EN may succeed to forge such complex tricyclic structures,
providing chemodivergence.[17]
An overall depiction of the intertwined catalytic cycles accounting
for the transformations outlined in this work is given in Scheme 5.
Chart 3. Reaction scheme (above) and reaction profile (below) for the addition of 9aa-EN to 8a-IM. Free energy profiles (kcal∙mol−1) in the gas-phase at the M06-
2X/6-31G(d) level of theory. Energies in parentheses are relative to single point calculations at the M06-2X/6-311++G(d,p) level of theory in CH2Cl2. SM-2: separated
reactants at infinite distance (9aa-EN + 8a-IM); RC: reactant complex; TS: transition state; I: intermediate. Transition state TS-V (addition reaction) and TS-VI
(cyclization reaction); distances in Angstrom. Silylated diphenylmethanol group is represented as a green sphere.
Scheme 5. Organocatalytic homo-synergistic cycles 1 (black arrows) and 2 (red arrows) accounting for the chemodivergent synthesis of bicycles 9 and tricycles 10
in this study.
9
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10.1002/anie.202007509
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RESEARCH ARTICLE
[6]
M. I. Lin, B. H. Su, C. H. Lee, S. T. Wang, W. C. Wu, P. Dangate, S. Y.
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A novel method has been developed, which allowed the rapid
transformation of easily accessible and low-cost uracil substrates
of type 7 to new three-dimensional carbocycle-fused uracils. The
rationale behind this endeavor was simple: installation of a
carbaldehyde functional group at the C5 site of 6-methyluracil (as
in uracils 7) would enhance the remote enolization at the
vinylogous C6-methyl site, favor the formation of a reactive oQDM
species (an activated diene) for [4 + 2] coupling to an enal
acceptor (dienophile), while providing a possible appendage for
the covalent activation by the amine catalyst. The hypothesis was
confirmed by real-world chemistry and, upon optimized mild
reaction conditions, the route proved practical and
chemodivergent, providing access to two distinct small collections
of products in good yields and almost complete
enantioselectivities namely, bicyclic compounds 9 and tricyclic
products 10, remarkably featuring six contiguous stereocenters.
Detailed DFT calculations and control experiments clarified the
role of the silylprolinol catalyst, which solely and concomitantly
activates both enal substrates and orchestrates the overall
transformation. Mechanistically, a first organocatalyzed stepwise
eliminative [4 + 2] cross cycloaddition between the carbaldehyde
substrates leads to a bicyclic iminium ion intermediate (PC-9aa-
IM), which divergently turns into bicyclic targets 9 by hydrolysis,
or converts to tricyclic targets 10 via a further trienamine-mediated
stepwise [4 + 2] cycloaddition, depending upon the reaction
conditions.
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[12] Interestingly, the presence of lipophilic MOM, MEM, and BOM groups at
N1/N3 uracil moiety highly impacted the physical properties of both the
starting substrates 7 and products 9, which in fact proved much more
soluble in organic solvents as compared to the dimethyl-protected
counterparts.
[13] Deposition Number CCDC 1995936 contains the supplementary
crystallographic data for this paper. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre and
Fachinformationszentrum Karlsruhe Access Structures service
www.ccdc.cam.ac.uk/structures.
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[15] DFT computational investigation of the relevant reactions involved in this
work was carried out at the M06-2X/6-311++g(d,p) IEFPCM
(CH2Cl2)//M06-2X/6-31G(d) level of theory. For details, see Supporting
Information.
We anticipate that this robust and simple chemical transformation
will serve to widen sampling of three-dimensional chemical space
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[17] Water content in commercial benzoic acid used in this work, either as a
solid or in CH2Cl2 solution, was determined via Karl Fischer titration (KF)
and resulted 0.53% and 0.02%, respectively. Also, reaction of 7a and 8a
with H2O (7.0 equiv) and in the absence of benzoic acid led to the almost
exclusive formation of 9aa; these experiments allowed us to exclude an
active role of water in controlling chemoselectivity. Interestingly, KF
titration of a control reaction between 7a and 8a (under the optimized
conditions in Table 1, entry 14) revealed the formation of water (0.5
equiv) after 12 hours (ca 50% conversion), thus confirming the proposed
catalytic cycle shown in Scheme 5, where 1 equiv of water is formed in
either catalytic cycle. We thank a reviewer for drawing this point to our
attention.
Acknowledgements
This work was supported by Regione Autonoma della Sardegna
(RASSR81788, 2017, “Green Chemistry in Drug Discovery -
sintesi sostenibili di nuovi inibitori di telomerase”) and by
Università di Parma (ZNRFNC_RICERCA_IST). G.P. wishes to
thank Chiesi Farmaceutici S.p.A. for the use of D8Venture
diffractometer. Thanks are due to Centro Interdipartimentale
Misure “G. Casnati” (Università di Parma, Italy) for instrumental
facilities. We thank M. Cito (Department of Food and Drug,
University of Parma) for Karl Fischer titration measurements.
Keywords: asymmetric synthesis • fused-ring systems •
heterocycles • organocatalysis • vinylogy
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10
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Entry for the Table of Contents
In synergy to diverge. Cross [4 + 2] cycloadditions between uracil-based aldehydes and -aryl enals were carried out under mild
conditions in the presence of the popular diphenylsilyl-protected prolinol organocatalyst, which provided homo-synergistic activation
of both substrates. Bicyclic and tricyclic fused uracils were chemodivergently forged in good yields and maximum levels of
enantioselectivity.
Università di Parma Twitter username: @unipr
11
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