One-Pot Knoevenagel and [4 + 2] Cycloaddition as a Platform for Calliviminones

Article abstract of DOI:10.1021/acs.orglett.0c00518

Bioactive compounds featuring an unusual core of spiro[5.5]undecenes and calliviminones were synthesized in very good yield with good regio- and diastereoselectivities through a one-pot Knoevenagel and [4 + 2] cycloaddition from the readily available aldehydes, cyclic-1,3-diones, dienes, and a catalytic amount of (s)-proline.

Full text of DOI:10.1021/acs.orglett.0c00518

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One-Pot Knoevenagel and [4 + 2] Cycloaddition as a Platform for
Calliviminones
Pritam Roy, S. Rehana Anjum, and Dhevalapally B. Ramachary*
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ABSTRACT: Bioactive compounds featuring an unusual core of
spiro[5.5]undecenes and calliviminones were synthesized in very
good yield with good regio- and diastereoselectivities through a
one-pot Knoevenagel and [4 + 2] cycloaddition from the readily
available aldehydes, cyclic-1,3-diones, dienes, and a catalytic
amount of (S)-proline.
Scheme 1. Biological Approach toward the Synthesis of
Calliviminones
ven in these modern times, in organic chemistry, with its
E
myriad of evolved reactions, the eminent Diels−Alder
(DA) reaction has not lost its original vigor and potency.1 Its
dichotomous nature of being elegantly simple and introducing
intricate complexity into products is extremely fascinating.2 Its
integral and frequent association with the synthesis of several
sophisticated organic scaffolds of natural products and
pharmaceutically important molecules and its involvement in
the natural biosynthetic pathways to polyketides, terpenoids,
and alkaloids renders it a stimulating evergreen topic.2
Alkylidene- or arylidene-cyclic-1,3-diones play a crucial role
in [4 + 2] cycloadditions.3 The high-yielding synthesis of
alkylidene- or arylidene-cyclic-1,3-diones and their instanta-
neous utilization as dienophiles in the DA reaction are
extremely demanding tasks. The reason is ascribed to the
fact that they subsequently undergo a side reaction to form bis-
adducts.4 Therefore, it became necessary to trap them a
designed reaction with specific substrates before they could
undergo bis-adduct formation with another molecule of the
cyclic-1,3-dione. This was previously done by the sulfa-Michael
reaction or reduction with Hantzsch ester.5 Sterically more
crowded alkylidene-cyclic-1,3-dione (isobutylidene syncarpic
acid) was observed to form through enzyme catalysis and
underwent both homo- and hetero-DA reactions with myrcene
to produce calliviminones A−D (Scheme 1).6a−d
This evoked us to look for the viable deployment of
alkylidene-cyclic-1,3-diones in [4 + 2] cycloadditions. It is a
highly challenging task to serve the dual-purpose of thwarting
the bis-adduct formation and utilizing the alkylidene-cyclic-1,3-
diones in [4 + 2] cycloaddition. The enterprise mostly rested
on the selection of a suitable reaction partner, whose energy
should be in a comparable spectrum to that of the arylidene-
cyclic-1,3-diones. First of all, it would be fascinating to know if
the reaction would take place. In the case in which it proceeds,
it could be through either a DA or a hetero-Diels−Alder
(HDA) reaction. In either case, the reaction products would be
stimulating because they are known biologically active
compounds, calliviminones A−H (Figure 1).6a−f
For nearly one and a half decades, we have worked
persistently and extensively on the construction of various
alkylidene-cyclic-1,3-diones from different cyclic-1,3-diones
and their utilization in diverse reactions such as transfer
hydrogenation, Michael additions, and [3 + 2] and [4 + 2]
cycloadditions.7 Corollary to this, the present protocol was
designed in a such a way that cyclic-1,3-diones undergo
Knoevenagel condensation (KC) with aldehydes in the
presence of (S)-proline and subsequently participate in the
DA reaction with simple dienes in a one-pot manner (Scheme
2). Initially, we oriented toward the KC of an aldehyde and
N,N-dimethylbarbituric acid because the derivatives of
Received: February 11, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00518
© XXXX American Chemical Society
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A

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Table 1. Reaction Optimization
solvent
(0.3 M)
t
t
yield (%)
[5aaa + 6aaa]
rr
b
c
entry
(h) (°C)
[5aaa/6aaa]
1
2
3
4
5
6
7
8
DCM
DCM
DCE
DCE
CH3CN
CH3CN
C6F6
36
8
24
8
36
6
48
7
8
9
6
12
25
80
25
80
25
80
25
80
80
80
80
80
84
46
83
86
92
90
49
71
81
77
84
86
7.7:1
6.0:1
7.2:1
5.6:1
9.1:1
5.3:1
10.0:1
7.7:1
6.3:1
5.6:1
5.6:1
7.0:1
C6F6
9
10
11
CHCI3
CH3C6H5
CF3C6H6
CH3CN
Figure 1. Natural products based on the syncarpic acid.
d
12
Scheme 2. Reaction Design for the One-Pot Synthesis of
Calliviminones
a
Reactions were carried out in DCM (0.3 M) with 1 equiv of 1a and
1 equiv of 2a (0.3 mmol) in the presence of 5 mol % of proline for 2 h
at 25 °C followed by the removal of DCM and the addition of 1 equiv
of 4a in solvent (0.3 M). Yields refers to the column purified
b
c
products. Ratio of regioisomers determined by NMR spectroscopy.
d
Both reactions was performed in CH3CN in a one-pot manner.
regioselectivity was high, and at 80 °C, this was reversed, with
high reactivity and low regioselectivity, with the exception of
DCM. The DA reactions performed in CHCl3, toluene, and
CF3C6H5 at 80 °C were no better (Table 1, entries 9−11).
These studies illustrated acetonitrile to be an excellent solvent
for the DA reaction (Table 1, entries 5 and 6). On conducting
both the KC and the DA reactions in a one-pot manner in
acetonitrile at 80 °C, opportunely, the KC/DA products 5aaa
and 6aaa were produced in 86% yield with 7.0:1 rr in 12 h
(Table 1, entry 12). Either of the reaction conditions (entries 5
and 6) or even the above one-pot process could be elected, as
per the prerequisite reaction time, yield, and rr.
On arriving at the acceptable reaction conditions for the
proposed reaction sequence, we were obligated to study the
participation of diverse aldehydes 2b−p in the sequence of KC
with 1a and a DA reaction with isoprene 4a (Table 2).
Respective one-pot KC/DA products were engendered in
moderate to good yield in all of the cases. Aromatic aldehydes
2b−m, substituted with either halogens (F, Cl, and Br) or
electron-donating (Me, OMe, NMe2) or electron-withdrawing
(CF3, NO2, and CN) groups mostly at the para position or at
the ortho or meta position, were well compatible under the
reaction conditions and afforded the products in moderate to
good yield (41−88%) with rr 4.0:1 to 8.3:1 (Table 2, entries
1−12). Even the aliphatic aldehyde 2n reacted satisfactorily to
furnish the products 5ana and 6ana in 71% yield with 9.0:1 rr
(Table 2, entry 13). In the case of the heteroaromatic
aldehyde, furfural 2o, the products were obtained in 83% yield
with a relatively high rr of 20.0:1 (Table 2, entry 14).
Astonishingly, for the chiral aliphatic aldehyde (R)-glycer-
aldehyde acetonide 2p, the KC/DA products (+)-5apa and
(+)-7apa obtained in 65% yield were exclusively diastereomers
in the ratio of 11.0:1 (Table 2, entry 15).
pyrimidinetriones (barbiturates) have wide applications in
pharmaceutical and medicinal chemistry.
To test our hypothesis, we initiated the KC of N,N-
dimethylbarbituric acid 1a with benzaldehyde 2a in the
presence of (S)-proline (5 mol %) in DCM. After the
completion of the KC in 2 h at 25 °C, on addition of isoprene
4a in the same DCM solvent at 25 °C, the DA reaction took 36
h to complete, and, delightfully, the expected DA products
5aaa and 6aaa were formed in 84% yield as inseparable 7.7:1
regioisomers (Table 1, entry 1). On raising the DA reaction
temperature to 80 °C, although the reaction completed within
8 h, the yield of the products 5aaa and 6aaa (6.0:1 rr) hugely
plummeted to 46% (Table 1, entry 2). After the KC reaction,
DCM was evaporated under reduced pressure, and, consec-
utively, the DA reaction was conducted in different solvents
such as DCE, CH3CN, C6F6, CHCl3, CH3C6H5, and CF3C6H5
at two different temperatures (25 and 80 °C). The reaction
outcome in DCE at 25 °C was almost identical to that in
DCM, except that it completed faster (within 24 h, Table 1,
entry 3), whereas at 80 °C, the yield improved even more
(86%) with 5.6:1 rr (Table 1, entry 4). To our delight, in
acetonitrile at 25 °C, both the reaction yield and the
regioselectivity were greatly enhanced (Table 1, entry 5).
Providentially, at 80 °C, too, the reaction yield was maintained
at 90%, with beneficial curtailment of reaction time to just 6 h
but with dwindled 5.3:1 rr (Table 1, entry 6). In C6F6, at 25
°C, the yield was only 49%, with a higher rr of 10.0:1 (Table 1,
entry 7), and at 80 °C, the yield ameliorated to 71% with a
diminution in rr to 7.7:1 (Table 1, entry 8). More often than
not, the reactivity and the regioselectivity seemed to be
displaying conflict. At 25 °C, the reactivity was low, but the
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a
Table 2. Reaction Scope with Aldehydes
Table 3. Reaction Scope with Aldehydes and Dienes
b
c
entry
R
t (h)
yield (%) [5 + 6]
rr [5/6]
1
2
3
4
5
6
7
8
4-FC6H4 (2b)
4-ClC6H4 (2c)
6
5
6
5
5
5aba + 6aba (85)
5aca + 6aca (81)
5ada + 6ada (67)
5aea + 6aea (86)
5afa + 6afa (81)
5aga + 6aga (72)
5aha + 6aha (78)
5aia + 6aia (78)
5aja + 6aja (88)
5aka + 6aka (66)
5ala + 6ala (41)
6.3:1
5.3:1
8.3:1
6.7:1
7.1:1
8.0:1
4.0:1
5.0:1
5.3:1
6.0:1
4.5:1
5.3:1
9.0:1
20.0:1
11.0:1
4-BrC6H4 (2d)
4-MeC6H4 (2e)
4-MeOC6H4 (2f)
4-NMe2C6H4 (2g)
4-CF3C6H4 (2h)
4-NO2C6H4 (2i)
4-CNC6H4 (2j)
3-CNC6H4 (2k)
2-CNC6H4 (2l)
2-ClC6H4 (2m)
CH2CH(CH3)2 (2n)
2-furyl (2o)
8
5
5.5
9
12
10
6
12
12
12
9
10
11
12
13
14
5ama + 6ama (70)
5ana + 6ana (71)
5aoa + 6aoa (83)
5apa + 7apa (65)
d
15
chiral aldehyde (2p)
a
Reactions were carried out in DCM (0.3 M) with 1 equiv of 1a and
1 equiv of 2 (0.3 mmol) in the presence of 5 mol % of proline
followed by the removal of DCM and the addition of 1 equiv of 4a in
b
CH3CN (0.3 M). Yields refer to the column purified products.
c
d
Ratio of regioisomers determined by NMR spectroscopy. 2 equiv of
isoprene 4a was used along with (R)-2,2-dimethyl-1,3-dioxolane-4-
carbaldehyde 2p, and an 11:1 ratio of dr values was formed.
After establishing the protocol, we steered to probe the
reaction sequence in depth for the performance of a few
symmetric and asymmetric dienes 4b−f. In all of the cases, the
reaction was studied for three different aldehydes. All dienes
4b−f conducted well and produced the corresponding KC/DA
products in good yield with moderate regioselectivity and
diastereoselectivity (wherever applicable). With the sym-
metrical dienes, unsubstituted 1,3-butadiene 4b and 2,3-
dimethyl-1,3-butadiene 4c, the in situ generated benzylidene
barbiturates 3ad, 3af, and 3aj as dienophiles reacted efficiently
and produced the respective products 5 as the solitary products
in 70−84% yield (Table 3, entries 1−6). On reaction with the
in situ made benzylidene barbiturates 3ab, 3af, and 3aj, 1,3-
cyclohexadiene 4d, being a good DA reactive partner due to its
inherent cisoid confirmation, generated the corresponding
diastereomeric mixture of bridged KC/DA products 5 and 7 in
71−86% yield with 1.3:1 to 3.0:1 dr (Table 3, entries 7−9). In
the case of the unsymmetrical diene, trans-3-methyl-1,3-
pentadiene 4e, the terminal electron-donating methyl on the
double bond regioselectively facilitated the DA reaction with
3ad, 3af, and 3aj powerfully to furnish the relevant
regioselective products 5 and 7 in good 78−85% yield with
a moderate diastereoselectivity of 1.5:1 to 2.1:1 dr, irrespective
of the steric hindrance at the bonding site, indicating that
electronic factors are more domineering than steric factors
(Table 3, entries 10−12). Appreciatively, the monoterpene,
myrcene 4f, upon reaction with the in situ prepared dienophiles
3ab, 3af, and 3aj, gave the respective desired regioisomeric
products 5 and 6 in 70−74% yield with 4.3:1 to 10.0:1 rr
(Table 3, entries 13−15). With the chiral alkylidene
barbiturate 3ap, the dienes 4b, 4d, and 4f reacted fairly to
produce the corresponding diastereomeric mixtures of
products (+)-5 and (+)-7 in moderate 32−52% yield with
1.6:1 to 12.5:1 dr (Table 3, entries 16−18).
To illustrate the versatility of the one-pot reaction, it was
further extended to various other dienophiles generated by
utilizing diverse active methylene compounds such as 1b−d in
the KC with 4-cyanobenzaldehyde 2j (Table 4). Delightfully,
all of the arylidenes 3bj, 3cj, and 3dj generated in situ under
the optimized conditions underwent the DA reaction with
diene 4a to generate the respective regioisomeric mixtures of
products 5 and 6 in moderate to good yield with good
regioselectivity. When the dienophile 3dj was reacted with the
symmetrical diene, 2,3-dimethyl-1,3-butadiene 4c, the DA
product 5djc formed in 56% yield.
The results from 1d prompted us to investigate this reaction
further to get some insights into the mechanics of the reaction
sequence, as it is well known that the cyclic-1,3-diketones have
a predilection to form the Knoevenagel−Michael adduct (bis-
adduct).4,5 When the KC was conducted between 1d and 2j,
the bis-adduct 8dj was generated exclusively in 40.5% yield
C
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a
selective C-methylation, and retro-Friedel−Crafts acylation of
phloroglucinol, with acyl chloride and methyl iodide as starting
materials. With compound 1e in hand, the synthesis
commenced with the KC with isobutyraldehyde 2q, isovaler-
aldehyde 2n, and 2-methylbutanal 2r, followed by the DA
reaction with myrcene 4f to afford mixtures of calliviminones A
and B (35%, 6:1), calliviminones E and F (51%, 8.3:1), and
calliviminones G and H, (35%, 1:1.4), respectively (Scheme
4). The natural product yields were only moderate and did not
Table 4. Reaction Scope with CH Acids
Scheme 4. One-Pot Total Synthesis of Calliviminones
a
Experiments were conducted in an optimized manner, and dienes 4
b
were used in 3.0 equiv. Reaction was performed in one-pot mode in
CH3CN.
(Scheme 3). Amazingly, this isolated bis-adduct 8dj on
subjection to a DA reaction with diene 4a under the optimized
Scheme 3. Controlled Experiments to Prove the Formation
of Olefins 3dj/3dn from Bis-Adducts 8dj/8dn
improve upon either lengthening the reaction time (at 80 °C)
or by performing the reaction at 25 °C for many hours. The
structure and relative stereochemistry of the domino products
5−7 were established by IR, NMR, and mass analysis and were
also finally confirmed by the correlation with the X-ray crystal
structures of 5aaa, (+)-5apa, 5abd, 5ajd, 7ajd, and 7aje
(Figures S1−S6). Structures of synthesized calliviminones A−
H were established by the correlation with naturally isolated
NMR data.6 Furthermore, we are able to apply this
methodology to synthesize functionalized spirooxindoles 10/
11 and explain the observed selectivities through a mechanistic
discussion, as shown in eq S1 and Scheme S1.
In summary, we have developed a common methodology for
the one-pot, two-step total synthesis of a library of important
natural products, calliviminones A−H and an unusual core of
spiro[5.5]undecenes, from readily available simple substrates
through a sequential one-pot combination of domino KC and
DA reactions, respectively. This sequential one-pot protocol is
an ideal method to synthesize the entire family of calliviminone
natural products.
reaction conditions produced the regioisomeric mixture of DA
products 5dja and 6dja in 31% yield with 4.0:1 rr, revealing the
unprecedented existence of an equilibrium between the bis-
adduct 8dj and its constituents 1d and 3dj under the reaction
conditions through retro-Michael addition and thereby
liberating the Knoevenagel product 3dj for reaction with
diene 4a (Scheme 3). A similar type of reaction mechanism
was confirmed by another example with aliphatic aldehyde 2n
and 1d to furnish the DA products 5dna/6dna in 40% yield
with 5.6:1 rr (Scheme 3).
From the illustration of Scheme 1 and Figure 1, we were
elated that this strategy could be conveniently conjectured to
accomplish the total synthesis of calliviminones A, B, E, F, G,
and H under ambient reaction conditions. Calliviminones were
isolated from the fruits of Callistemon viminalis, which is an
herb used to treat gastroenteritis, diarrhea, and skin
infections.6a−d The syncarpic acid 1e and myrcene 4f under
enzyme catalysis undergo [4 + 2] cycloaddition, which follows
either a DA or an HDA reaction, resulting in the formation of
calliviminones A, B, E, F, G, and H or calliviminones C and D,
respectively (Figure 1).6a−d
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00518.
Supporting Information I. Details of experimental
procedures for the catalytic reactions and spectroscopic
data for the products (PDF)
Supporting Information II. NMR spectral data (PDF)
Accession Codes
CCDC 1982749−1982754 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
The total synthesis started with the preparation of syncarpic
acid 1e through a sequence of Friedel−Crafts acylation,
D
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AUTHOR INFORMATION
Corresponding Author
■
Dhevalapally B. Ramachary − Catalysis Laboratory, School of
Chemistry, University of Hyderabad, Hyderabad 500 046,
India; orcid.org/0000-0001-5349-2502; Email: ramsc@
uohyd.ac.in, ramchary.db@gmail.com
Authors
Pritam Roy − Catalysis Laboratory, School of Chemistry,
University of Hyderabad, Hyderabad 500 046, India
S. Rehana Anjum − Catalysis Laboratory, School of Chemistry,
University of Hyderabad, Hyderabad 500 046, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00518
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was made possible by a grant from the Department
of Science and Technology (DST), SERB, New Delhi (grant
no. CRG/2018/000775). P.R. thanks UGC (New Delhi) for
his senior research fellowship. S.R.A. thanks University Grants
Commission (UGC)-Dr. D. S. Kothari Postdoctoral Fellow-
ship (DSKPDF) Scheme, New Delhi for her postdoctoral
research fellowship. We thank Dr. P. Raghavaiah, Dr. Harisingh
Gour University, and M. P. Sagar for X-ray structural analysis.
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