Direct, Asymmetric Synthesis of Carbocycle-Fused Uracils via [4+2] Cycloadditions: a Noncovalent Organocatalysis Approach

Article abstract of DOI:10.1002/adsc.202100082

The peculiar versatility of remotely enolizable 6-methyluracil-5-carbaldehydes as useful vinylogous pronucleophiles in direct, asymmetric [4+2] cyclizations with suitable nitroolefins has been demonstrated. Under the strategic exploitation of noncovalent bifunctional organocatalysis, a dearomative remote enolization strategy was implemented, to generate oQDM-type dienolate intermediates that were efficiently and stereoselectively trapped by either aromatic or aliphatic nitroolefins. A series of functionalized, chiral carbocycle-fused uracils embedding three contiguous stereocenters were thus collected in one step in good yields, with generally good levels of enantioselectivity, and complete diastereocontrol. Furthermore, the ability to provide enantiopure products via simple one-cycle recrystallizations and the possibility to further functionalize these scaffolds without losing their chiral integrity were demonstrated. (Figure presented.).

Full text of DOI:10.1002/adsc.202100082

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DOI: 10.1002/adsc.202100082
Direct, Asymmetric Synthesis of Carbocycle-Fused Uracils via
[4+2] Cycloadditions: a Noncovalent Organocatalysis Approach
Enrico Marcantonio,a Claudio Curti,a,* Lucia Battistini,a Andrea Sartori,a
Luana Cardinale,b Giorgio Pelosi,c and Franca Zanardia,*
a
Dipartimento di Scienze degli Alimenti e del Farmaco
Università di Parma
Parco Area delle Scienze 27A, 43124 Parma, Italy
Fax: (+39)-0521-905006
phone: (+39)-0521-905080
phone: (+39)-0521-905067
E-mail: claudio.curti@unipr.it; franca.zanardi@unipr.it
Department of Chemistry
b
University of Hamburg
Martin Luther King Platz 6, 20146 Hamburg, Germany
Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale
c
Università di Parma
Parco Area delle Scienze 17A, 43124 Parma, Italy
Manuscript received: January 20, 2021; Revised manuscript received: March 13, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100082
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
Abstract: The peculiar versatility of remotely enolizable 6-methyluracil-5-carbaldehydes as useful vinylogous
pronucleophiles in direct, asymmetric [4+2] cyclizations with suitable nitroolefins has been demonstrated.
Under the strategic exploitation of noncovalent bifunctional organocatalysis, a dearomative remote enolization
strategy was implemented, to generate oQDM-type dienolate intermediates that were efficiently and
stereoselectively trapped by either aromatic or aliphatic nitroolefins. A series of functionalized, chiral
carbocycle-fused uracils embedding three contiguous stereocenters were thus collected in one step in good
yields, with generally good levels of enantioselectivity, and complete diastereocontrol. Furthermore, the ability
to provide enantiopure products via simple one-cycle recrystallizations and the possibility to further
functionalize these scaffolds without losing their chiral integrity were demonstrated.
Keywords: asymmetric synthesis; fused-ring systems; heterocycles; noncovalent organocatalysis; vinylogy
Introduction
found in many bioactive natural products and pharma-
ceuticals, when transforming them into novel, hetero-
The ability of small chiral organic molecules – i.e. cycle-containing chiral variants.[2] In tackling this
organocatalysts – to turn flat, achiral scaffolds into issue, one obvious problem emerges related to the
sophisticated 3D-shaped and enantioenriched deriva- inherent thermodynamic stability of (hetero)aromatic
tives makes these molecules powerful resources in the molecules, whose functionalization often requires
toolbox of contemporary organic synthesis.[1] In partic- harsh reaction conditions hardly compatible with
ular, organocatalysis may prove strategic in the crucial, sophisticated transformations. In this context, the
yet challenging endeavour of desymmetrizing “flat” benzylic C(sp3) sites of ortho-alkyl substituted aro-
(hetero)aromatic cycles, ubiquitous structural motifs matic carbaldehydes of type I (Figure 1A) may be
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versatile, poorly aromatic pronucleophiles namely, 6-
methyluracil-5-carbaldehydes 1, remotely enolizable
uracil derivatives, which could be employed in amino-
catalytic [4+2] cross cycloaddition reactions with β-
aryl enals 2 (Figure 1C).[5d] In such cases, in exploiting
homo-synergistic covalent organocatalysis (Hayashi-
Jørgensen prolinol catalyst C1 was used), both
aldehyde partners were concomitantly activated into
the corresponding dienamine and iminium ion species,
to furnish, depending on the conditions, either bicyclic
targets 3 or tricyclic derivatives 4 in good yields and
maximum levels of enantiopurity via single or double
[4+2] cycloadditions, respectively. Interestingly, soon
after our publication, Albrecht and coworkers reported
a similar aminocatalytic strategy, affording a series of
N-methyl enantioenriched tricyclic uracil derivatives
similar to 4 (not shown).[5e]
Uracil and its derivatives are considered precious
structures in drug discovery as they display a wide
array of outstanding biological activities ranging from
the most renowned antiviral and anti-tumour activities,
to herbicidal, insecticidal, and bactericidal properties.[9]
Quite surprisingly, so far, apart from the above
mentioned contributions, only few examples of chiral,
carbocycle-fused uracils have been developed, which
have been mainly accessed in racemic format via
nonasymmetric syntheses.[10]
In contrast to these reasonably-well assessed,
covalent activation modalities, the parallel develop-
ment of noncovalent activation strategies, in which
chiral, bifunctional amine/H-bond donor catalysts
trigger similar organocatalytic, stereoselective trans-
Figure 1. (A) General strategy for the construction of chiral
fused (hetero)cycles IV via dearomative, vinylogous enolization
of ortho-alkyl-substituted aromatic carbaldehydes of type I and
subsequent [4+2] cyclization with suitable dienophiles III. (B)
Known covalent strategies for enhancing the acidity of the
benzylic C(sp3)À H protons of aromatic carbaldehydes. (C)
Homo-synergistic, aminocatalytic [4+2] cross cycloaddition
reactions between 6-methyluracil-5-carbaldehydes 1 and β-aryl
enals 2 promoted by prolinol C1.
envisaged as remotely enolizable sites of vinylogous formations, remains immature.[11] This is probably due
aldehyde systems,[3] which can engage in remote to the inherent difficulties of the bifunctional organo-
benzylic functionalization with suitable electrophiles catalyst in establishing a constructive and highly
III, leading to functionally rich, fused (hetero)cycles organized network of weak noncovalent interactions
of type IV via [4+2] cyclization.
between these specific reacting partners, efficient in
Such vinylogous enolizations are challenging since overcoming the high barrier of the initial dearomative
the resulting, highly reactive ortho-quinodimethane vinylogous enolization, and subsequently in bringing
intermediates of type II (oQDM) imply the unfavoura- the high reactivity of the oQDM species under strict
ble loss of the aromatic character of the original ring.[4] control.
In the last decade, clever solutions were found to
In 2017, the Li’s group employed chiral amino-
promote vinylogous enolizations by enhancing the thiourea C2 as the noncovalent organocatalyst to
acidity of the remote C(sp3)À H benzylic protons, promote the [4+2] aldol-hemiacetalization sequence
mostly by covalent derivatization of the aldehyde from nitrotolualdehydes and highly activated
moiety to chiral iminium ions of type V;[5] N- trifluoromethyl ketones (Scheme 1, eq. 1a).[12]
acylazolium intermediates VI,[6] alkylidene malononi-
The rather unstable cyclic hemiacetal adducts were
trile derivatives VII[7] or nitroalkene compounds finally secured, by oxidation, to the corresponding
VIII[8] (Figure 1B).
lactone derivatives. In 2018, Xu and colleagues
The mild, vinylogous deprotonation of these acti- developed another two-step methodology for the
vated species, usually by an amine base, unveils the asymmetric [4+2] cycloaddition between 2-benzyl-
corresponding oQDM dienes, resulting in the develop- benzofuran(thiophene) carbaldehydes and nitroalkene
ment of several stereoselective [4+2] cyclizations, dienophiles under bifunctional quinine-squaramide
whereby the chiral information is transmitted by the catalysis (Scheme 1, eq. 1b).[13] Tricyclic products with
organocatalyst to products via covalent HOMO-raising four contiguous stereocenters were obtained as epimer-
(as in V and VI) and/or LUMO-lowering strategies. ic mixtures, which were subjected to carbinol reduction
Along these lines, we recently introduced new and to yield the corresponding deoxy-derivatives. The
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products 6 via simple functionalization reactions are
documented.
Results and Discussion
As a starting point of our work, we treated the readily
available N1,N3-dibenzyloxymethyl-substituted- (di-
BOM) 6-methyluracil-5-carbaldehyde 1a with trans-β-
nitrostyrene (5a), in the presence of the quinine-
derived squaramide organocatalyst C3 (10 mol%) in
toluene, at ambient temperature (Table 1).
It was satisfying to find that the envisaged [4+2]
cycloaddition was viable, even though an almost
racemic adduct ent-6aa (55:45 er) was isolated in a
low 35% yield, after 24 hours. Of note, complete
diastereocontrol was operative, so that product ent-6aa
was accessed as a single diastereoisomer (>20:1 dr).
Although this first result was rewarding insofar as the
dr value was concerned, screening was necessary to
improve enantioselectivity.
Thus, we moved to alternative cinchona-thiourea
catalysts C5 and C6, derived from pseudoenantiomeric
hydroquinine and quinidine, respectively (Table 1).
Both catalysts proved viable, providing more
efficient and stereoselective transformations yielding
ent-6aa and 6aa, respectively, in good 65% and 60%
Scheme 1. (1) Previously reported noncovalent activation strat-
egies, and (2) general plan for the present transformation. HD =
H-bond donor.
application of this chemistry to restricted categories of
reactants (e.g. trifluoromethyl ketones or aromatic
aldehydes bearing additional aryl substituents at the
benzylic vinylogous site) and the lack of direct
procedures are major limitations of these
approaches.[14]
Table 1. Catalyst screening for the direct, vinylogous [4+2]
cycloaddition of uracil aldehyde 1a to nitroolefin 5a.[a]
Inspired by these precedents and given our success
in managing the reactivity of uracil-based aldehydes as
pro-diene components in covalent organocatalyzed [4
+2] cycloadditions, we now wondered whether we
could transfer this knowledge to a more challenging
noncovalent organocatalysis context. By exploiting the
low aromatic profile of uracil and its derivatives,[15] the
right choice of a bifunctional amine/H-bond donor
organocatalyst could enable the dearomative vinyl-
ogous enolization of 6-methyluracil-5-carbaldheydes 1
to give the corresponding oQDM-type dienolates 1’
(Scheme 1, eq. 2). Subsequent stereoselective [4+2]
connection between 1’ and nitroalkenes 5 would be
feasible under the guidance of the catalyst, directly
producing a new class of highly functionalized,
enantioenriched carbocycle-fused uracils 6 embedding
three contiguous stereocenters.
[a] Unless otherwise noted, all reactions were run under an inert
atmosphere of nitrogen or argon using 1a (0.05 mmol), 5a
(2.0 equiv.), and the indicated catalyst C (10 mol%) in
toluene (0.07 M) at rt for 24 h. Yields refer to isolated yields
after flash chromatographic purification on silica gel;
enantiomeric ratios (er) were determined by HPLC analysis
on a chiral stationary phase. Products 6aa and ent-6aa were
obtained as single isomers and no other diastereoisomers
Herein we report how this plan was successfully
put into practice and demonstrate its versatility and
general application with diversely substituted sub-
strates. Furthermore, the possibility of obtaining
enantiopure products via one-cycle recrystallizations
and the demonstration of the synthetic utility of uracil
1
could be detected in the crude by H NMR analysis. For
further details, see the Supporting Information. BOM=
benzyloxymethyl.
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isolated yields and with improved enantiocontrol in
both cases (84:16 er using C5 and 83:17 er with C6).
Again, the reactions proved completely diastereoselec-
tive so that no other diastereoisomers could be detected
in the reaction crudes. Continuing catalyst screening,
axially chiral amine-thiourea catalyst C7 (Wang’s
catalyst) failed to promote any reaction, while optimal
results were achieved with Takemoto’s amine-thiourea
C4, providing cycloadduct 6aa in a 70% isolated yield
as a single diastereoisomer and with 84:16 er. To verify
the direct involvement of both amine and thiourea
components in triggering the reaction and imparting
enantioselectivity, control experiments were performed
using either achiral thiourea C8 or thiourea-free
dihydroquinine C9 as catalysts (10 mol%) under
otherwise identical reaction conditions. As expected,
both reactions provided unsuccessful results, with the
former being completely inert and the latter affording
an almost racemic product 6aa in a poor 30% yield.
Quite surprisingly, even Et3N alone promoted an
efficient and diastereoselective reaction, affording
racemic 6aa in a 71% isolated yield as a single isomer.
Overall, these preliminary results proved the feasibility
of our proposal, paving the way for a highly
diastereoselective [4+2] cyclization and proving, once
again, the versatility of 6-methyluracil carbaldehyde
1a as a powerful vinylogous pronucleophile. Nonethe-
less, as expected, the relatively low enantiomeric ratios
registered thus far highlighted our initial perception of
how difficult it would be to find the conditions for
effective enantiodiscrimination between transition
Table 2. Optimization survey for the direct, vinylogous [4+2]
cycloaddition of uracil aldehyde 1a to nitroolefin 5a (selected
entries).[a]
Entry 5a
T
Solvent Yield [%][b] er[c]
°
[×equiv.] [ C]
1[d]
2
3
4
5
2
2
2
2
2
2
2
2
2
1
23
23
23
23
23
23
23
60
0
toluene 70
toluene 78
CH2Cl2 75
84:16
85:15
76:24
55:45
71:29
87:13
87:13
85:15
84:16
91:9
EtOH
THF
90
78
84
20
63
71
85
6
xylene
xylene
xylene
xylene
xylene
7[e]
8
9
10
23
[a] Unless otherwise noted, all reactions were run under an inert
atmosphere of nitrogen or argon on a 0.05 mmol scale, in the
indicated solvent (0.07 M) for 72 h. For the complete
optimization survey, see Tables S1–S7 in the Supporting
Information. BOM=benzyloxymethyl.
[b] Isolated yields.
[c] Determined by HPLC analysis on a chiral stationary phase.
[d] 24 h reaction time.
[e] C4 (1 mol%).
states through weak noncovalent interactions coordi- with a portion of the product partially precipitating as
nated by a proficient catalyst. Eager to improve both a solid (vide infra, recrystallization experiments).
yields and enantiocontrol, we elected catalyst C4 as
With the optimized conditions in hand, the applica-
the best chiral candidate to be used in additional tions and limitations of the reaction were next
optimization studies, with carbaldehyde 1a and nitro- examined.
styrene 5a employed again as model substrates
(Table 2).
As reported in Table 3, the reaction between
protected uracil carbaldehyde 1a and several aromatic
After having surveyed several reaction parameters and aliphatic nitroalkenes 5 promoted by 10 mol% of
(reaction time, work-up procedure, solvent, catalyst catalyst C4 were examined at first. Both electron-rich
loading, temperature, stoichiometry, dilution, and and electron-poor para-substituted nitrostyrenes 5b–e
additives), optimal conditions were found by treating performed well, affording the corresponding bicyclic
1a and 5a (1:1 stoichiometric ratio) with 10 mol% products 6ab–6ae in good isolated yields and high
°
catalyst C4 in 0.07 M xylene, at 23 C for 72 h, enantioselectivities (75–90% yields, 91:9-94:6 enantio-
affording 6aa in a 85% isolated yield as a single meric ratios). With ortho- and meta-substituted nitro-
diastereoisomer with a rewarding 91:9 er (Table 2, styrene acceptors 5f–i, a certain drop in the overall
entry 10; for the detailed optimization survey, see efficiency and/or enantioselectivity was observed. For
Tables S1–S7 and the Representative Procedure 1 in example, with the 2-fluoro derivative 5f, a relatively
the Supp. Info). Some observations deserve comment: efficient reaction was witnessed at the expense of
i. when run in EtOH, the reaction went almost to enantioselectivity (6af, 75% yield, 78:22 er); with
completion, albeit with complete loss of enantioselec- bulky 3-benzyloxynitrostyrene 5h, the corresponding
tivity (Table 2, entry 4); ii. catalyst loading as low as adduct 6ah was isolated in a 50% yield with an
1 mol% was sufficient to raise er of 6aa to 87:13 acceptable 88:12 er. In line with these results, both
albeit at the expense of efficiency (20% yield, entry 7); heterocyclic acceptors 5j and 5k proved to be suitable
and iii. all tested reactions, except for the one driven in substrates for the reaction, affording the corresponding
CH2Cl2 (entry 3), ended up as heterogeneous mixtures products 6aj and 6ak in 73% and 68% yields and high
enantiomeric ratios (92:8 and 95:5 er, respectively).
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Table 3. Scope and limitations of nitroalkenes 5.[a]
Table 4. Scope and limitations of substrates 1.[a]
[a] Unless otherwise noted, all reactions were run under inert
atmosphere using 1 (0.09 mmol), 5 (1.0 equiv.), and C4
(10 mol%) in xylene (0.07 M) at rt for 72 h. Yields refer to
isolated yields after flash chromatographic purification;
enantiomeric ratios (er) were determined by HPLC analysis
on a chiral stationary phase. All compounds 6 were isolated
as single isomers and no other diastereoisomers could be
detected in the crude by 1H NMR analysis. For further details,
see Representative Procedure 1 and the Supp. Info.
[a] Unless otherwise noted, all reactions were run under inert
atmosphere using 1a (0.09 mmol), 5 (1.0 equiv.), and C4
(10 mol%) in xylene (0.07 M) at rt for 72 h. Yield refers to
isolated yields after flash chromatographic purification on
silica gel; enantiomeric ratios (er) were determined by HPLC
analysis on a chiral stationary phase. All compounds 6 were
isolated as single isomers and no other diastereoisomers
1
could be detected in the crude by H NMR analysis. For
further details, see Representative Procedure 1 and the Supp.
Info. BOM=benzyloxymethyl.
[b]
°
Reactions run at 60 C.
BOM) uracil 1a, several N1,N3 homoprotected uracil
derivatives featuring either the methoxymethyl-
The reaction also proved viable with notoriously inert (MOM, 1b), methoxyethoxymethyl- (MEM, 1c), or
aliphatic substrates such as (E)-4-phenyl-1-nitrobutene trimethylsilylethoxymethyl (SEM, 1d) groups were
(5l) and (E)-(2-nitrovinyl)cyclohexane (5m), which prepared and tested. Both pronucleophiles 1b and 1c
performed very similarly under slightly modified resulted viable substrates for the reaction, yielding the
°
reaction conditions (60 C), to afford the corresponding corresponding cycloadducts 6ba, 6bb, 6be and 6cb in
[4+2] cycloadducts 6al and 6am in 38–40% isolated good isolated yields and enantioselectivities as single
yields and comparable enantiomeric ratios of ca. diastereoisomers (up to 88% yield and up to 94:6 er).
90:10.
Of note, similarly to its diBOM congener, uracil 1b
It is important to note that throughout the study, all also proved viable when reacted with aliphatic nitro-
products were isolated as single diastereoisomers, olefin 5m, so that adduct 6bm could be obtained in
confirming the complete diastereocontrol of the proc- 38% yield and 88:12 er. To complete the alkoxy-
ess anticipated in the previous screening.
substituted series of uracil pronucleophile, 1,3-diSEM
We next switched to the uracil carbaldehyde derivative 1d was tested with brominated nitrostyrene,
component, taking differently protected pronucleo- giving 6db in 50% yield and 85:15 er. Alkyl
philes 1b-i into consideration, as described in Table 4. substituents at the uracil nitrogen atoms were also
In line with the dibenzyloxymethyl-substituted (di- considered, with dimethyl-substituted aldehyde 1e
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performing better than the dibenzyl derivative 1f in
terms of efficiency (65% vs 35%, 6eb vs 6fb), albeit
dibenzylated product 6fb could be obtained in higher
enantiopurity (88:12 vs 68:32 er). The crucial role
played by the protecting group R1 in modulating the
reactivity of pronucleophilic uracil carbaldehydes of
type 1 was also confirmed by observing the complete
inertia of N-unprotected 6-methyluracil-5-carbaldehyde
1g (R1 =H) which failed to react with 4-bromo-
substituted nitrostyrene 5b under the optimized reac-
tion conditions.
Similarly, prostereogenic 6-ethyl- and 6-phenyl-
ethyl carbaldehydes 1h and 1i failed to provide the
corresponding cycloadducts in reactions with 5b, even
at higher temperature.
To showcase the practicality of the process, we
performed the reaction between 1a and nitrostyrene 5a
on a 7×-scale (Scheme 2).
Table 5. Recrystallization procedures and production of enan-
tiopure products 6.
Entry
6
Original Method[b] Yield [%][c] er[d]
er[a]
1
2
3
4
5
6
7
6aa 91:9
6aa 91:9
6ab 93:7
6af 78:22
6aj 92:8
6bb 91:9
A
B
A
A
A
B
C
75
78
66
20
78
55
65
>99:1
>99:1
>99:1
>99:1
99:1
>99:1[e]
>99:1
6aa
–
[a] Enantiomeric ratios of the indicated compounds 6 obtained as
reported in Tables 2–4.
[b] Method A: dissolution of isolated, pure 6 in a mixture of
hexane/CH2Cl2 at reflux, then slow cooling to rt. Method B:
dissolution of isolated, pure 6 in anhydrous EtOH at reflux,
then slow cooling to rt. Method C: dissolution of the reaction
crude in EtOH at reflux, then slow cooling to rt.
[c] Isolated yields.
Pleasingly, these conditions did not impact the
outcome of the reaction, and 6aa was obtained with
comparable efficiency and enantioselectivity (78%
yield, 90:10 er, complete diastereoselectivity).
The absolute configuration of all products 6 was
assigned by analogy with the brominated derivative
6bb (Table 4), whose (5S,6R,7R) chiral arrangement
[d] Enantiomeric ratio determined by HPLC analysis on a chiral
stationary phase.
[e] er of the precipitate fraction.
For further details, see paragraph 6 in the Supp. Info.
was unambiguously ascertained by X-ray crystallo- almost enantiopure in a good 75% yield (Table 5,
graphic analysis of a suitable crystal (see the Supp. entry 1). Similar results were obtained also from
Info for details).[16,17]
anhydrous ethanol (entry 2, method B), and for several
As previously noted, one of the main downsides other adducts such as 6ab, 6af, and 6aj (entries 3–5).
encountered in handling uracil derivatives of type 6 Interestingly, we observed a similar resolution also for
resided in their poor and quite unpredictable solubility the diMOM-protected adduct 6bb: in this case though,
in the most common solvents. Furthermore, the the enantiopure fraction was the solid rather than the
observation that the majority of the previously reported filtrate (entry 6). In all instances, virtually enantiopure
reactions ended in heterogeneous mixtures, with the compounds could be isolated after one-cycle crystal-
solid fraction usually resulting in a near racemic mix lization (>99:1 enantiomeric ratios). Of note, we also
of the pure product, led us to investigate the possible performed the enantiomeric enrichment directly from
chiral resolution of the enantioenriched products of the crude reaction mixtures; as a prototypical example,
type 6 by recrystallization.
the crude reaction mixture containing 6aa was con-
As reported in Table 5, we performed a small centrated and then dissolved in anhydrous ethanol at
survey starting from diBOM-protected adduct 6aa, reflux (Table 5, entry 7, method C), allowing the
which was obtained in a good 91:9 er via the reported formation of a precipitate consisting of pure racemic
organocatalytic [4+2] cyclization (Table 2, entry 10). 6aa, and a filtrate, which consigned enantiopure 6aa
In a proof of concept, recrystallization of pure 6aa in a 65% isolated yield.
from a mixture of hexane and CH2Cl2 at reflux
A plausible mechanistic scenario for this [4+2]
(method A) allowed the separation of two fractions of cycloaddition is shown in Scheme 3A. Though a
product (the solid and the filtrate), the filtrate resulting concerted, Diels Alder-like mechanism between the
diene intermediate 1’ and dienophile 5 cannot be ruled
out, based on the above results and several precedents
with these catalysts,[18] we envisage, for the present
transformation, a one-pot, two-step catalytic cycle
involving a vinylogous Michael addition reaction
(VMcR)/intramolecular Henry organocascade, by
means of the dual activation and transfer of chirality
operated by catalyst C4.
According to the Takemoto’s activation model,[18a]
the thiourea unit of catalyst C4 activates nitroalkene 5
by double hydrogen bonding, while the tertiary amine
Scheme 2. Synthesis of carbocycle-fused uracil 6aa on a 7×-
scale.
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To endorse the proposed VMcR-initiated mecha-
nism, we confronted the present transformation with a
previously reported and strictly related reaction be-
tween uracil carbaldehyde 1e and nitrostyrene 5a in
the presence of prolinol catalyst C1 (covalent activa-
tion, Scheme 3B).[5d] In that occasion, the prolinol
moiety of the catalyst remained “entrapped” in the
bicyclic product 12ea, without possibility of catalyst
recycling. DFT calculations clearly evidenced that the
reaction proceeded through a concerted “asynchro-
nous” [4+2] mechanism where a first, rate-limiting
Michael addition step was followed by an almost
barrierless Mannich-type ring closure.[19]
In the present transformation, a similar reaction
profile could be operative, also considering that the
vinylogous Michael adduct 11 has never been isolated
nor detected in the reaction mixture, even in the
presence of protic solvents.
More interestingly, the fact that covalent organo-
catalysis failed to produce the expected carbocycle-
fused uracils by lack of catalyst recycling (Scheme 3B)
emphasizes the key and indispensable role of non-
covalent organocatalysis in this reaction. To further
support this point, we carried out the reaction of uracil
carbaldehyde 1a and nitrostyrene 5a in the presence of
pyrrolidine-thiourea catalyst C10 (mixed covalent/non-
covalent activation, Scheme 3C).[20] No reaction was
observed, even when a protic source like benzoic acid
(20 mol%) was added, which could have facilitated
elimination and recycling of the amine catalyst.
Another interesting point is related to the stereo-
chemical outcome of products 6: whichever the
catalyst used, a relative 5,6-cis-6,7-trans configuration
was obtained in the products. Based on this observa-
tion and the above proposed mechanism (Scheme 3A),
we may conclude that while the absolute configuration
at the newly formed C7 stereocenter is clearly dictated
by the chiral organocatalyst, the stereochemistry of the
remaining C5 and C6 stereocenters could be the result
of a double stereoinduction by both the just-installed
C7 and the catalyst.
Scheme 3. (A) Proposed reaction mechanism for the stepwise
[4+2] cycloaddition between uracil carbaldehydes 1 and nitro-
alkenes 5. (B) Previously reported cycloaddition between
carbaldehyde 1e and nitrostyrene 5a promoted by prolinol
catalyst C1, whose mechanism was demonstrated to be stepwise
by DFT-analysis. (C) Control reaction between 1a and 5a
promoted by pyrrolidine-thiourea catalyst C10 under the
optimized reaction conditions. The reaction failed even when
run in the presence of benzoic acid (BA, 20 mol%).
Finally, to prove the synthetic utility of the accessed
chiral, enantioenriched fused uracil derivatives 6,
base deprotonates the benzylic C(sp3)À H site of uracil several transformations were performed, as described
carbaldehyde 1 to afford the active oQDM species 1’. in Scheme 4.
Here, an extra hydrogen bond between the C4-carbonyl
First, we reduced the nitro functionality embedded
of the uracil ring and the protonated base of the in position 6: indeed, the task proved quite challenging,
catalyst might contribute to stabilize the dienolate but after several attempts, we found that treatment of
intermediate (as a 1,3-dicarbonyl-like pronucleophile), diMOM- and diBOM-protected uracil scaffolds 6bb
thus ensuring the preferential approach to the Re face and 6aa with zinc, ammonium formate and parafor-
of the alkene delivering a non-isolable nitronate maldehyde, in methanol at reflux gave the correspond-
intermediate IX. Considering this VMnR as the rate- ing tricyclic N,O-acetals 8bb and 8aa in good isolated
limiting step of the process, a second, faster intra- yields (72% and 68% respectively). Of note, in the
molecular Henry-type cyclization step would proceed, absence of paraformaldehyde as the amino alcohol
involving the nitronate and the aldehyde moieties (Si- “trapping” agent, the reduction procedure within 6 was
Re approach), thus delivering bicycle 6 as the sole still viable, albeit much less efficient, as exemplified
product.
by the reduction of 6bb to amino alcohol 7bb which
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and further probe experimentations supporting the
hypothesized reaction mechanism are currently under-
way in our laboratories and will be reported in due
course.
Experimental Section
Representative Procedure 1. Synthesis of (+)-6aa
In a round-bottomed flask equipped with a magnetic steer bar
and kept under nitrogen atmosphere, uracil-carbaldehyde 1a
(35.0 mg, 0.089 mmol, 1 equiv.) and trans-β-nitrostyrene (5a)
(13.3 mg, 0.089 mmol, 1 equiv.) were dissolved in xylene
°
(1.25 mL) at 23 C. Takemoto’s catalyst C4 (3.7 mg,
0.009 mmol, 0.1 equiv.) was then added and the resulting
°
reaction was stirred at 23 C and monitored by TLC. After 72 h,
the heterogeneous mixture was directly subjected to flash
chromatography on silica gel (petroleum ether/ethyl acetate 7:3)
to afford (+)-6aa (41 mg, 85% yield) as a pale-yellow
amorphous solid.
Scheme 4. Functionalization of enantioenriched carbocycle-
fused uracil derivatives 6.
was isolated in a modest 42% yield. In addition,
selective removal of the benzyloxymethyl groups with-
in 8aa with BBr3,[21] gave access to the corresponding
N1,N3-H uracil derivate 9aa in a 78% isolated yield.
Also, despite uracil derivatives 6 resulted stable to
air oxidation at room temperature,[22] treatment of 6aa
with Et3N in CH2Cl2 at reflux for 24 h promoted clean
aromatization of the system, with the corresponding
aromatic bicycle 10aa obtained in a 75% isolated
yield.
Representative Procedure 2. Recrystallization of
(+)-6aa
Compound (+)-6aa (41 mg, 0.075 mmol, er 91:9) was dis-
solved in n-hexane (9 mL) and CH2Cl2 (3.9 mL) under reflux
until full dissolution. The resulting solution was subjected to
crystallization over a period of 12 h at rt and then filtered over a
Buckner funnel. The filtrate was evaporated under reduced
pressure to afford enantiopure (+)-6aa (31.0 mg, 75% yield,
er>99:1) as an amorphous solid.
Conclusion
Representative Procedure 3. Synthesis of oxazoli-
dine (+)-8aa
In summary, to complement our previous study which
introduced novel 6-methyluracil-5-carbaldehydes of
type 1 as useful pronucleophiles under covalent
To a solution of nitro-derivative (+)-6aa (40 mg, 0.073 mmol,
°
91:9 er) in dry MeOH (4.3 mL) cooled to 0 C (ice bath),
organocatalysis, we have, herein, demonstrated the ammonium formate (30 mg, 0.47 mmol, 6.4 equiv.), Zn (12 mg,
0.18 mmol, 2.5 equiv.) and paraformaldehyde (33 mg,
1.10 mmol, 15.0 equiv.) were added. The suspension was then
vigorously stirred under reflux for 5 h. The resulting mixture
was then filtered and concentrated under reduced pressure. The
resulting solid was extracted with CH2Cl2 (3×10 mL), the
combined organic layers were washed with brine (10 mL), dried
(Na2SO4), and evaporated under reduced pressure. The crude
was purified by silica gel flash chromatography (petroleum
ether/AcOEt 3.5:6.5) to provide oxazolidine (+)-8aa (27 mg,
68%) as a pale-yellow amorphous solid.
versatility of these compounds as easily enolizable
aromatic carbaldehydes to be engaged in direct,
asymmetric [4+2] cyclizations with suitable nitro-
olefins, under the guidance of noncovalent bifunctional
organocatalysis. The in situ-generated oQDM-type
dienolates were efficiently and stereoselectively
trapped by either aromatic or aliphatic nitroolefins
through an asymmetric vinylogous Michael/Henry
reaction cascade, affording a collection of highly
functionalized, chiral, carbocycle-fused uracils embed-
ding three contiguous stereocenters, in good yields,
generally good levels of enantioselectivity, and com-
plete diastereoselectivity. The strategic, indispensable
role of noncovalent organocatalysis in promoting the
transformation vis-à-vis the covalent activation coun-
terpart has been highlighted.
Acknowledgements
This work was supported 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 Dr. L.
Marzocchi for proofreading the text and Prof. Dr. M. Lombardo
(University of Bologna, Italy) for helpful discussion on the
reaction mechanism.
Furthermore, the ability to provide enantiopure
products 6 by simple one-cycle recrystallization
procedures and the possibility to functionalize these
scaffolds further, without losing their chiral integrity,
were demonstrated. Studies involving DFT calculations
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Direct, Asymmetric Synthesis of Carbocycle-Fused Uracils
via [4+2] Cycloadditions: a Noncovalent Organocatalysis
Approach
Adv. Synth. Catal. 2021, 363, 1–10
E. Marcantonio, C. Curti*, L. Battistini, A. Sartori, L.
Cardinale, G. Pelosi, F. Zanardi*