Chiral squaramide-catalyzed asymmetric synthesis of pyranones and pyranonaphthoquinones via cascade reactions of 1,3-dicarbonyls with Morita-Baylis-Hillman acetates of nitroalkenes

Article abstract of DOI:10.1039/c4cc02279c

Cascade reactions of 1,3-dicarbonyls with Morita-Baylis-Hillman acetates of nitroalkenes using a quinine derived chiral squaramide organocatalyst led to the formation of pyranones and pyranonaphthoquinones in good to excellent yields and high diastereo- and enantioselectivities. Representative examples of the reaction scale-up with a much lower catalyst loading without an appreciable loss of selectivities and synthetic transformations of the products are also reported here. The compounds described herein for the first time were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease, since the structures are related to bioactive α-lapachones. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02279c

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Chiral squaramide-catalyzed asymmetric synthesis
of pyranones and pyranonaphthoquinones via
cascade reactions of 1,3-dicarbonyls with
Cite this:DOI: 10.1039/c4cc02279c
Received 27th March 2014,
Accepted 29th April 2014
Morita–Baylis–Hillman acetates of nitroalkenes†‡
Divya K. Nair,a Rubem F. S. Menna-Barreto,b Eufranio N. da Silva Junior,*c
ˆ
´
DOI: 10.1039/c4cc02279c
Shaikh M. Mobind and Irishi N. N. Namboothiri*a
www.rsc.org/chemcomm
Cascade reactions of 1,3-dicarbonyls with Morita–Baylis–Hillman
acetates of nitroalkenes using a quinine derived chiral squaramide
organocatalyst led to the formation of pyranones and pyrano-
naphthoquinones in good to excellent yields and high diastereo-
and enantioselectivities. Representative examples of the reaction
scale-up with a much lower catalyst loading without an appreciable
loss of selectivities and synthetic transformations of the products
are also reported here. The compounds described herein for the
first time were evaluated against the infective bloodstream form of
Trypanosoma cruzi, the etiological agent of Chagas disease, since
the structures are related to bioactive a-lapachones.
Fig. 1 Selected biologically active a-lapachones.
to name a few. Recently, an asymmetric total synthesis of an
a-lapachone natural product rhinacanthin A (Fig. 1) has been
reported.8
The diverse biological profiles of a-lapachones inspired us
to pursue their synthesis, especially in an asymmetric fashion.
Although enantioselective conjugate addition of hydroxynaphtho-
quinone to different electron deficient alkenes, such as nitro-
alkenes,9 enones,10 unsaturated esters11 and phosphonates,12
in the presence of various chiral catalysts has been reported,
there are only two such reactions, to our knowledge, that lead to
a-lapachones13 and neither uses Morita–Baylis–Hillman adducts
of activated alkenes as the key substrates.
Naturally occurring naphthoquinones are widely distributed in
the plant kingdom, exhibit redox properties and are involved in
processes such as photosynthesis and electron transfer reactions.1
These compounds exhibit several activities against various diseases,
e.g. Chagas disease, caused by the protozoan Trypanosoma cruzi,
which affects approximately eight million individuals in Latin
America.1,2 Pyranonaphthoquinones, in particular, display anti-
cancer properties, besides being active against bacteria, fungi
and mycoplasmas.3
Recently, we reported the synthesis of furans, pyrans,14 and
imidazopyridines15 as well as arenofurans16 via cascade SN20-
intramolecular Michael addition of binucleophiles such as
1,3-dicarbonyl compounds, 2-aminopyridines and arenols, respec-
tively, to Morita–Baylis–Hillman (MBH) acetates of nitroalkenes
(e.g. 2, E = CO2Et, Scheme 1). Chen et al. also cleverly exploited the
bielectrophilic nature of MBH acetates of nitroalkenes 2 (E = CO2Et)
for the synthesis of various carbocycles and heterocycles.17 The
primary MBH acetate 2 (E = H), on the other hand, received less
attention in such cascade reactions.18,19
Although a-lapachones (e.g. Fig. 1) inherently possess weaker
trypanocidal activity,1 structural modifications could lead to
enhanced activity.4 Moreover, a-lapachones exhibit a variety of other
biological activities such as anti-tumor,5 anti-parasite (Leishmania),6
and mosquito cytochrome P450 enzyme inhibitory properties,7
a Department of Chemistry, Indian Institute of Technology Bombay,
Mumbai 400 076, India. E-mail: irishi@iitb.ac.in
b Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, 21045-900, Brazil
c Institute of Exact Sciences, Department of Chemistry,
Federal University of Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
E-mail: eufranio@ufmg.br
d National Single-Crystal X-Ray Diffraction Facility,
Indian Institute of Technology Bombay, Mumbai 400 076, India
† Dedicated to Professor H. Ila on the occasion of her 70th birthday.
‡ Electronic supplementary information (ESI) available: Also complete experi-
mental procedures, characterization data and copies of NMR spectra for all the
new compounds. CCDC 993968. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4cc02279c
Scheme 1 SN20-intramolecular Michael addition.
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Table 1 Optimization of catalysts and solventsa
In the above scenario, we decided to employ 1,3-dicarbonyl
compounds 1, including 2-hydroxy-1,4-naphthoquinone (lawsone),
as binucleophiles in the reaction with primary MBH-acetates of
nitroalkenes 2 (E = H) in anticipation that the exclusive products
would be pyrans 4 (Scheme 1). It appeared that such a cascade
reaction in the presence of a suitable chiral catalyst would lead
to enantioenriched pyrans and dihydropyranonaphthoquinones
(lapachones). Therefore, we realized that the reaction sequence
should begin with an enantioselective Michael addition of 1,3-
dicarbonyls 1 to MBH acetate 2 (E = H) in an SN20 manner to give
intermediate 3, followed by a diastereoselective intramolecular
oxa-Michael addition of 3 to afford the desired pyrans 4. We
hypothesized that this cascade reaction can be efficiently trig-
gered by a chiral bifunctional catalyst which can simultaneously
activate MBH-acetate 2 and deprotonate diketone 1.
In order to identify suitable reaction conditions for the
asymmetric SN20-intramolecular Michael addition cascade, we
have chosen dimedone 1a and MBH-acetate 2a as the model
substrates and 10 mol% of C1–C10 as the catalysts (Fig. 2 and
Table 1). When the reaction was carried out in THF using
(ꢀ)-sparteine C1 as the catalyst, complete conversion was
observed in 1 h to give the product in 80% yield, but, unfortu-
nately, there was no selectivity at all (entry 1). This prompted us to
switch to bifunctional catalysts with a Lewis basic moiety which
can deprotonate 1,3-dicarbonyl 1 and a Bronsted acid moiety
which can activate MBH acetate 2. Thus cinchona-derived thiourea
catalysts C2–C820 were screened (entries 2–10). Although product
4a was isolated in good to excellent yield (78–94%), to our dismay,
the selectivity remained low to moderate (24–69% ee).
Entry
Cat.
Solvent
Time
Yieldb (%)
eec (%)
1
2
3
4
5
6
C1
C2
C3
C3
C4
C5
C6
C6
C7
C8
C9
C10
C9
C9
C9
C9
C9
C9
C9
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CHCl3
CH2Cl2
DCE
Dioxane
CH3CN
EtOAc
Toluene
1 h
2 h
4 h
7 h
5 h
5 h
3 h
48 h
80
78
89
90
88
85
94
88
87
85
90
92
83
86
83
92
86
90
76
0
24
50
57
51
65
69
60
52
54
92
86
91
92
90
95
90
91
50
7
8d
9
5 h
10
11
12
13
14
15
16
17
18
19
5.5 h
15 min
15 min
20 min
20 min
20 min
15 min
30 min
25 min
3 h
a
Optimizations were done with 0.11 mmol of 1a, 0.1 mmol of 2a and
b
0.01 mmol of catalyst C in 0.5 mL solvent under N2. After silica gel
c
column chromatography. Determined by chiral HPLC using an AD-H
column for the major diastereomer (dr, determined by 1H NMR spectro-
d
scopy, were in the range of 88 : 12 to 91 : 09). ꢀ40 1C.
but dropped in toluene (50%, entry 19) while maintaining the
yields in the range of 76–90%. However, a considerable improve-
ment in the ee (to 95%) was observed in 1,4-dioxane (92% yield,
15 min, entry 16). Finally, 10 mol% of catalyst C9 in 1,4-dioxane at
rt was identified as the best condition for our further reactions.
Initially, the scope of 1,3-dicarbonyls was investigated under
the above optimized conditions using MBH acetate 2a as the
representative substrate (Table 2). The results with cyclohexane-
1,3-dione 1b were inferior to what we obtained with dimedone
1a (4b: 81% yield, 88 : 12 dr, 92% ee). Cyclic b-keto ester hydroxy
At this juncture, we turned to quinine-squaramide catalysts
C9–C10,21 in anticipation that their stronger H-bonding cap-
`
ability vis-a-vis their thiourea counterparts C2–C8 would enhance
the selectivities. Accordingly, we were pleased to note a dramatic
rate acceleration and an equally dramatic rise in the enantio-
selectivity when squaramide C9 was employed (90% yield, 92% ee,
15 min, entry 11). A slight improvement in the yield with a
marginal drop in the selectivity was observed in the presence of
squaramide C10 (92% yield, 86% ee, 15 min, entry 12). After
zeroing in on the catalyst, several solvents were screened at room
temperature with the aim of further improving the selectivity
(entries 13–19). Thus the ee remained Z90% in solvents such as
CHCl3, CH2Cl2, DCE, CH3CN and EtOAc (entries 13–15, 17 and 18),
Table 2 Screening of 1,3-dicarbonyls 1a–c
a
b
Yields after silica gel column chromatography. dr was determined
by 1H NMR spectroscopy of the crude product and ee (for the major
diastereomer) by chiral HPLC using an AD-H column. All the reac-
c
tions were carried out with 0.55 mmol of 1a, 0.5 mmol of 2a and
0.05 mmol of C9 in 2.5 mL 1,4-dioxane under N2.
Fig. 2 Catalysts screened.
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Table 3 Scope of MBH acetates 2a–d
Fig. 3 X-ray structure of 5j and the proposed mechanistic model.
a representative compound 5j (Fig. 3, also see the ESI‡).
Furthermore, the absolute configuration of 5j was also assigned
(3R, 4S) based on X-ray data and that of the analogs 4 and 5 by
analogy. A plausible mechanism, using lawsone 1d and MBH
acetate 2c as the representative substrates, is outlined in Fig. 3.
The first step is initiated by deprotonation of 1d by the tertiary
amine of the quinuclidine moiety resulting in an enolate. The
enolate then adds to MBH acetate 2c from the Si face in a
Michael fashion, which is facilitated by activation of the nitro
group by double H-bonding with the squaramide moiety of the
chiral catalyst, leading to elimination of the acetate in the overall
SN20 reaction. In the second step, the enolate generated by
H-bonding of the carbonyl group with the protonated quinuclidine
moiety adds to the nitroalkene activated by the squaramide moiety
from the Re face in a 6-endo-trig intramolecular oxa-Michael
fashion, giving rise to the desired dihydropyran. Our solvent
screening (Table 1, entries 11, 13–19) suggests that polar
aprotic solvents (e.g. dioxane) that do not interfere with the
catalyst are suitable for this transformation.
a
b
Yields after silica gel column chromatography. dr was determined
by 1H NMR spectroscopy of the crude product and ee (for the major
diastereomer) by chiral HPLC using an AD-H column. All the reac-
tions were carried out with 0.55 mmol of 1a, 0.5 mmol of 3 and
0.05 mmol of C9 in 2.5 mL 1,4-dioxane under N2. 5a = 4e.
c
d
Our methodology was applicable to the gram scale reaction
as well with a catalyst loading as low as 1 mol% (Scheme 2, see
also the ESI‡). Addition of 696 mg (4 mmol) of lawsone 1d to
0.884 g of MBH acetate 2c or 1.004 g of 2f (4 mmol) in the
presence of 30 mg (0.04 mmol, 1 mol%) of catalyst C9 afforded
1.110 g (3.64 mmol, 83%) of nitroquinone 5c or 1.168 g
(3.20 mmol, 80%) of 5f without any appreciable change in the
diastereo- and enantioselectivities. The nitro group of quinones 5c
and 5f could be transformed to the amino group using NiCl2ꢁ6H2O/
NaBH4 to afford aminoquinones 6c and 6f. While 6f was isolated in
chromenone 1c also reacted with MBH acetate 2a to afford
product 4c in excellent yield (93%). However, while the diastereo-
selectivity was high (99 : 1), the enantioselectivity was moderate
(49% ee). Finally, to our delight, lawsone 1d turned out to be an
excellent binucleophile, providing product 5a in high yield (81%)
and with impressive selectivities (98 : 2 dr, 499% ee).
Having achieved nearly absolute selectivities using lawsone
1d as the binucleophile, we proceeded to investigate the scope
of MBH acetates 2 under the optimized conditions (Table 3). As
in the case of 2-furyl MBH acetate 2a, the thienyl analog 2b also
reacted well with lawsone 1d to afford pyranonaphthoquinone
5b in high (80%) yield and enantioselectivity (97% ee), though
with moderate diastereoselectivity (71 : 29 dr). The MBH acetates
2d, 2j, and 2k, with fused or chloro-substituted aromatic rings,
reacted with lawsone 1d to give products 5d, 5j, and 5k with high
diastereo-(Z92: 8) and enantioselectivities (Z99). The yields
(80–90%) and enantioselectivities (97 to 499%) were excellent
for dihydropyranonaphthoquinones 5c, 5e, 5f, 5h, and 5i, with
unsubstituted or para-substituted aromatic rings, though there
was a marginal drop in the diastereoselectivities (89 : 11 to 93: 7).
High yield (88%) and absolute diastereoselectivity (499: 1) with
marginally lower enantioselectivity (89% ee) for product 5g were
observed in the case of MBH acetate 2g with multiple electron
donating substituents.
The structure and relative configuration of the products
were determined by detailed spectral analysis (see the ESI‡)
which were further confirmed by single crystal X-ray analysis of Scheme 2 Synthetic applications of a-lapachones 5.
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˜
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Due to the potential trypanocidal activity of the lapachone
derivatives (vide supra), we evaluated compounds 5a–5g and
5i–5l against the infective bloodstream form of Trypanosoma
cruzi, the etiological agent of Chagas disease. Benznidazole
(IC50/24 h = 103.6 ꢂ 0.6 mM),23 the standard anti-T. cruzi drug,
was used as the positive control. Preliminary experiments showed
that our compounds at concentrations of up to 0.5% in DMSO had
no deleterious effects on the parasites. The compounds evaluated
were not active against T. cruzi with IC50 values 41000.0 mM (see
the ESI‡). Possible enhancement of trypanocidal activity via
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In conclusion, a chiral squaramide-catalysed cascade reaction
of 1,3-dicarbonyl compounds, including 2-hydroxy-1,4-naphtho-
quinone (lawsone), with Morita–Baylis–Hillman acetates of
nitroalkenes affords pyrans and pyranonaphthoquinones
(a-lapachones) in high yields and excellent diastereo- and
enantioselectivities. The transformation which involves an
SN20-intramolecular oxa-Michael addition sequence is amen-
able for scale-up even with a very low catalyst loading (1 mol%)
without an appreciable loss in yield or selectivity. The multi-step
transformation of a representative product to a naphthoquinone-
based 1,2,3-triazole via nitro group reduction, conversion to azide
and click reactions as well as preliminary evaluation of the
a-lapachones for trypanocidal activity have been carried out.
INNN thanks DST India for financial assistance. DKN thanks
CSIR India for a senior research fellowship. RFSMB and ENSJ
thank CNPq and CAPES Brazil.
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