Synthesis of new chromeno-annulated cis-fused pyrano[3,4-c]pyran derivatives via domino Knoevenagel-hetero-Diels-Alder reactions and their biological evaluation towards antiproliferative activity

Article abstract of DOI:10.1039/c2md20023f

A new series of chromeno-annulated cis-fused pyrano[3,4-c]pyran derivatives have been synthesized by intramolecular [4 + 2] domino Knoevenagel-hetero- Diels-Alder reactions of 1-oxa-1,3-butadienes derived in situ from 1,3-dicarbonyls/active methylenes and 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones in the presence of 20 mol% ethylenediamine diacetate (EDDA) in acetonitrile under reflux conditions in good to excellent yields. The structures were established based on spectroscopic data, and were further confirmed by X-ray diffraction analysis. These compounds were evaluated for their anti-proliferative activity using an in vitro MTT cytotoxicity assay. The results clearly demonstrated that compounds 4a, 4b, 4c, 4j, 4k, 4l, 4m and 4n exhibited significant anti-proliferative activity against human A549 lung cancer and non-cancer MRC-5 cell lines along with potent inhibitory activity against human neuroblastoma SK-N-SH cancer cell lines. Among these, compounds 4a, 4b and 4j displayed the most potent anti-proliferative activity against human lung cancer A549 cell lines, while 4a and 4b displayed against neuroblastoma SK-N-SH cancer cell lines when compared to the standard doxorubicin.

Full text of DOI:10.1039/c2md20023f

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CONCISE ARTICLE
Synthesis of new chromeno-annulated cis-fused pyrano[3,4-c]pyran derivatives
via domino Knoevenagel–hetero-Diels–Alder reactions and their biological
evaluation towards antiproliferative activity†
a
a
a
A. Venkatesham, R. Srinivasa Rao, K. Nagaiah, J. S. Yadav,a G. RoopaJones,b S. J. Basha,c B. Sridhard
*
and A. Addlagattab
Received 30th January 2012, Accepted 26th March 2012
DOI: 10.1039/c2md20023f
A new series of chromeno-annulated cis-fused pyrano[3,4-c]pyran derivatives have been synthesized by
intramolecular [4 + 2] domino Knoevenagel–hetero-Diels–Alder reactions of 1-oxa-1,3-butadienes
derived in situ from 1,3-dicarbonyls/active methylenes and 7-O-prenyl derivatives of 8-formyl-
2,3-disubstituted chromenones in the presence of 20 mol% ethylenediamine diacetate (EDDA) in
acetonitrile under reflux conditions in good to excellent yields. The structures were established based on
spectroscopic data, and were further confirmed by X-ray diffraction analysis. These compounds were
evaluated for their anti-proliferative activity using an in vitro MTT cytotoxicity assay. The results
clearly demonstrated that compounds 4a, 4b, 4c, 4j, 4k, 4l, 4m and 4n exhibited significant anti-
proliferative activity against human A549 lung cancer and non-cancer MRC-5 cell lines along with
potent inhibitory activity against human neuroblastoma SK-N-SH cancer cell lines. Among these,
compounds 4a, 4b and 4j displayed the most potent anti-proliferative activity against human lung
cancer A549 cell lines, while 4a and 4b displayed against neuroblastoma SK-N-SH cancer cell lines
when compared to the standard doxorubicin.
years, understanding the biology of cancer has been exception-
Introduction
ally improved and new therapeutic agents have been developed
Cancer is one of the leading causes of death worldwide and
connecting with the mechanisms of cancer cells’ growth-inhibit-
accounted for 7.6 million deaths (nearly 13% of all deaths) in
ing and differentiation-inducing or apoptosis-inducing abili-
2008. More than 70% of all cancer deaths occurred in low- and
ties.3–5 However, many clinically effective anti-cancer drugs used
middle-income countries. Deaths from cancer worldwide are
today have developed resistance in cancer therapy.6 Therefore,
projected to continue to rise to over 11 million in 2030.1 Among
there is still an impetus to identify and develop more potent anti-
all cancers, lung cancer has been recognized to be one of the
cancer therapeutic agents with improved properties such as
leading causes of death with 18.2% of all adulthood cancer
enhanced and specific activity against various cancers in the field
deaths.1 Neuroblastoma (NB), which is an embryonic malig-
of medicinal chemistry.
nancy of the sympathetic nervous system arising from neuro-
In recent years, chromeno fused pyrano/pyranopyran hetero-
blasts, has been identified for 15 percent of all childhood cancer
cyclic natural products have attracted tremendous interest
deaths among children younger than five years of age.2 In recent
among researchers due to their potential applications in medic-
inal chemistry (Fig. 1).7 Among these, chromeno fused pyr-
anopyran derivatives exhibit significant biological activities, such
aDivision of Organic and Biomolecular Chemistry, CSIR-Indian Institute of
as antitumour,8 antimycobacterial9 and antiviral.10 In general
Chemical Technology, Hyderabad-500067, India. E-mail: nagaiah@iict.
these polycyclic heterocycles have been prepared by Lewis/
Brønsted acid or ionic liquid [bmim]BF4 catalysed intra-
molecular domino Knoevenagel–hetero-Diels–Alder (DKHDA)
[4 + 2] cycloaddition of tethered oxadienes with non-activated
olefins tethered to the diene system, and this has become one of
the most powerful methods.11,12 However, many of these
synthetic methods suffer from drawbacks in reaction conditions,
yields, regioselectivity and stereoselectivity. Therefore, the
important biological properties of these chromeno fused pyr-
anopyran derivatives along with our continuous efforts13 in
res.in
bCenter for Chemical Biology, CSIR-Indian Institute of Chemical
Technology, Hyderabad-500067, India
cCenter for Nuclear Magnetic Resonance, CSIR-Indian Institute of
Chemical Technology, Hyderabad-500067, India
dLab of X-ray Crystallography, CSIR-Indian Institute of Chemical
Technology, Hyderabad-500067, India
† Electronic supplementary information (ESI) available: Full
experimental, spectral and biological evaluation details of the
representative compounds. CCDC 848040 and 839724. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c2md20023f
652 | Med. Chem. Commun., 2012, 3, 652–658
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Fig. 1 Chromeno fused pyrano/pyranopyran heterocyclic natural products.
preparing biologically important compounds prompted us to
synthesise a new series of chromeno cis-fused pyrano[3,4-c]
pyrans in high yields with excellent regio- and stereo-selectivity
and to investigate their primary biological activity against three
different (MDA-MB-231, SK-N-SH, and A549) cancer cell lines
and MRC-5 normal cell lines.
7-O-prenyl derivative of 8-formyl-2,3-dimethyl chromenone 2a
with an unsymmetrical 1,3-diketone like 4-hydroxycoumarin 3a
in the presence of 20 mol% ethylenediamine diacetate (EDDA) in
acetonitrile under reflux conditions resulted in the corresponding
cis-major regioisomer 4a, along with cis-minor regioisomer 4a0
(Scheme 2).
The reaction proceeds via a tandem Knoevenagel- and hetero-
Diels–Alder pathway. This reaction is highly stereoselective
affording exclusively chromeno cis-fused pyrano[3,4-c]pyran
derivatives. These results can be explained nicely by assuming
that the reactions are governed firstly by stereoelectronic and
secondly by steric effects.14 Thus more importantly stereospeci-
ficity of the formation of the major product 4a may be explained
by a stereoelectronic effect via an endo-E-syn-transition structure
as shown in Fig. 2. The reaction proceeds via a tandem Knoe-
venagel- and hetero-Diels–Alder pathway. At first instance 7-O-
prenyl-8-formyl-2,3-dimethyl chromenone 2a reacted with
unsymmetrical 1,3-diketone i.e., 4-hydroxycoumarin 3a, in the
presence of EDDA to give Knoevenagel 1-oxa-1,3-butadiene,
which undergoes an intramolecular hetero-Diels–Alder reaction
with the dienophile via endo-E-syn-transition structure I to afford
the cis-adduct 4a exclusively. The endo-E-syn-transition structure
I is more favorable than the exo-Z-syn-transition structure II due
to an sp2-geminal effect according to the phenomenon of 1,3-
allylic strain, which has been already proved by Tietze’s work.15
In addition the regioselectivity of the major product 4a forma-
tion over 4a0 may be explained as shown in Fig. 3. Accordingly,
the Knoevenagel condensate 1-oxa-1,3-butadiene interacts with
the dienophile in two ways as shown in III and IV. Compound 4a
was formed when the a,b-unsaturated ketone moiety in III acted
as the heterodiene and 4a0 was formed when the a,b-unsaturated
ester moiety in IV acted as the heterodiene. The Knoevenagel
adduct III acts as a better heterodiene than IV, which is reflected
in the higher yield of 4a over 4a0.
Results and discussion
Chemistry
According to our synthetic strategy, necessary precursors 2a–c in
synthesizing the anticipated chromeno cis-fused pyrano[3,4-c]
pyrans (4a–o) have been prepared in high yields (89–93%) and
purity by the reaction of substituted 7-hydroxy chromeno alde-
hydes 1a–c and prenyl bromide in the presence of anhydrous
potassium carbonate in dry acetone under reflux conditions
(Scheme 1).
Having prepared the required 7-O-prenyl derivatives of
8-formyl-2,3-disubstituted chromenones (2a–c) in adequate
quantities, we have attempted the synthesis of a new series of
chromeno cis-fused pyrano[3,4-c]pyrans (4a–o) in good to
excellent yields (80–95%) by intramolecular [4 + 2] domino
Knoevenagel–hetero-Diels–Alder reactions of 1-oxa-1,3-butadi-
enes derived in situ from 7-O-prenyl derivatives of 8-formyl-2,3-
disubstituted chromenones (2a–c) and 1,3-dicarbonyl/active
methylene compounds (3a–h). Accordingly, the treatment of the
In addition, the stereochemistry of product 4a was assigned on
the basis of 1H NMR J-coupling constants and NOE studies. In
Scheme 1 7-O-prenyl-8-formyl-2,3-disubstituted chromenones.
This journal is ª The Royal Society of Chemistry 2012
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Scheme 2 Synthesis of chromeno cis-fused pyrano[3,4-c]pyrans.
Fig. 2 Explanation of the observed stereochemistry.
Fig. 3 Explanation of the observed regiochemistry.
1
the H NMR spectrum, the vicinal coupling constant JHa–Hb
¼
7-O-prenyl derivative of 8-formyl-3-methyl chromenone 2b, the
7-O-prenyl derivative of 8-formyl-2-methyl-3-phenyl chrome-
none 2c and various symmetrical cyclic 1,3-diketones such as
4.7 Hz between Ha (d 4.99 ppm) and Hb (d 1.92 ppm) indicates
that both these protons are on the same side, which consequently
confirms that the two six membered tetrahydropyran rings are cis
fused. Also the vicinal coupling constants like JHb–Hc ¼ 4.7 Hz,
JHb–Hd ¼ 11.4 Hz and the presence of u coupling of JHa–Hc ¼ 1.7
Hz further confirmed the positions of Ha, Hb, Hc and Hd as
shown in Fig. 2. The presence of NOE correlation between
Ha/Hb, Hb/Hc, Ha/Me-A and Hb/Me-A further supported the
above observation. The energy-minimized structure of 4a is in
full agreement with the above NMR analysis (Fig. 4).
Encouraged by the above results obtained with 4-hydroxy-
coumarin, next we have focused our attention on tandem
Knoevenagel–hetero-Diels–Alder reactions between the 7-O-
prenyl derivative of 8-formyl-2,3-dimethyl chromenone 2a, the
Fig. 4 Characteristic NOEs and energy-minimized structure of 4a.
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654 | Med. Chem. Commun., 2012, 3, 652–658

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Scheme 3 Synthesis of chromeno cis-fused pyrano[3,4-c]pyrans.
pyrano[3,4-c]pyrans (4j–k) in excellent yields. Accordingly, the
reaction proceeds via the intramolecular [4 + 2] domino Knoe-
venagel–hetero-Diels–Alder/elimination sequence (Scheme 4).
Initially compounds 2a–b reacted with 3e to give Knoevenagel–
hetero-Diels–Alder adducts VIa–b via the condensates Va–b.
Under the same reaction conditions adducts VIa–b undergo retro
Diels–Alder reaction to form ketenes VIIa–b, which trap water to
form b-ketoacid acids VIIIa–b and subsequent in situ decar-
boxylation afforded 4j–k.18
Furthermore, acyclic 1,3-dicarbonyls such as acetyl acetone 3f
and ethylacetoacetate 3g also reacted well with 7-O-prenylated
chromeno aldehyde 2a to afford the corresponding chromeno
cis-fused pyrano[3,4-c]pyrans (4l–m) in good yields under the
similar reaction conditions (Scheme 5). Also the stereospecificity
of the formation of major products 4l–m may be explained by the
endo-E-syn-transition structure as shown in Fig. 2.
Fig. 5 ORTEP diagram for the compound 4e, with displacement
ellipsoids drawn at 30% probability level.
1,3-dimethylbarbituric acid 3b, cyclohexane-1,3-dione 3c, and
dimedone 3d. In all cases, the intramolecular [4 + 2] domino
Knoevenagel–hetero-Diels–Alder reactions proceeded smoothly
and yielded the corresponding novel chromeno pyrano[3,4-c]
pyrans (4b–i) as single diastereomeric derivatives having the cis-
configuration (Scheme 3). The stereospecificity of the formation
of major products 4b–i may be explained by the endo-E-syn-
transition structure as shown in Fig. 2. Further the spatial
stereochemistry of the products 4e and 4g was also confirmed by
single crystal X-ray diffraction analysis (Fig. 5 and 6).16,17
Similarly, 7-O-prenylated chromeno aldehydes 2a and 2b on
treatment with Meldrum’s acid 3e in the presence of 20 mol%
ethylenediamine diacetate (EDDA) in acetonitrile under reflux
conditions furnished the corresponding chromeno cis-fused
Interestingly 3-methyl-1-phenyl-pyrazol-5-one 3h also under-
went smooth coupling with 7-O-prenylated chromeno aldehydes
2a and 2c to yield the corresponding chromeno cis-fused pyrano
[3,4-c]pyrans (4n–o) in excellent yields (Scheme 6). Also the
stereospecificity of the formation of major products 4n–o may be
explained by the endo-E-syn-transition structure as shown
in Fig. 2.
Thus we have synthesized a novel series of chromeno cis-fused
pyrano[3,4-c]pyrans (4a–o) in good to excellent yields.19 All
1
products are new and characterized by H, 13C NMR, IR and
mass spectroscopy. In addition the stereochemistry of these
compounds was established based on the X-ray diffraction
analysis. The purity of these compounds was further evaluated
by high resolution mass spectroscopy.
Biological evaluation
Inhibitory efficiency was tested for some of these cis-fused pyr-
ano[3,4-c]pyrans against three different cancer cell lines (MDA-
MB-231, SK-N-SH and A549) and a normal cell line (MRC-5)
and the results are summarized in Table 1. The MTT assay was
performed following the previously reported protocol in the 96
well plate.13c Compounds 4a, 4b, 4j, 4k and 4m exhibited signif-
icant anti-proliferative activity against human A549 lung cancer
cell lines, while 4a, 4j and 4m were active against human lung
non-cancer MRC-5 cell lines. In addition, compounds 4a, 4b, 4c,
4l, 4m and 4n displayed potent inhibitory activity against human
Fig. 6 ORTEP diagram for the compound 4g, with displacement ellip-
soids drawn at 30% probability level.
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Scheme 4 Synthesis of chromeno cis-fused pyrano[3,4-c]pyrans.
Table 1 In vitro antiproliferative activitya of novel chromeno pyrano
[3,4-c]pyrans against human A549, MDA-MB-231, and SK-N-SH cancer
cell lines and MRC-5 non-cancer cell lines using MTT assay
Breast
Neuroblastoma Lung-cancer Lung-normal
Compound MDA-MB-
(mg mLꢀ1
)
231
SK-N-SH
A549
MRC-5
Scheme 5 Synthesis of chromeno cis-fused pyrano[3,4-c]pyrans.
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
1.05 ꢁ 0.006
1.06 ꢁ 0.02
10.51 ꢁ 0.09
>100
>100
>100
>100
>100
>100
>100
>100
0.1 ꢁ 0.002
0.1 ꢁ 0.004
>100
>100
>100
>100
>100
>100
>100
0.6 ꢁ 0.001
>100
>100
>100
>100
>100
>100
>100
>100
0.09 ꢁ 0.001 0.6 ꢁ 0.001
11.24 ꢁ 0.008 >100
10.7 ꢁ 0.07
10.85 ꢁ 0.03
10.58 ꢁ 0.06
>100
>100
>100
10.94 ꢁ 0.002 0.9 ꢁ 0.001
Scheme 6 Synthesis of chromeno cis-fused pyrano[3,4-c]pyrans.
>100
>100
>100
>100
Doxorubicin 8.14 ꢁ 0.14 0.97 ꢁ 0.03
15.07 ꢁ 0.13 14.84 ꢁ 0.25
(Standard)
neuroblastoma SK-N-SH cancer cell lines. Compounds 4a, 4b
and 4j are most promising leads, suggesting that aromatic
dimethyl substituents and heterocyclic dienophiles have good
activity. On the pyranopyran ring, an ester displays a better
cytotoxicity than the ketone as shown by 4l and 4m. In general,
compounds with 2,3-dimethyl substitution on the chromenone
moiety seem to be a better fit than a phenyl group at the
3-position. Surprisingly, none of the compounds in the current
study displayed any toxicity against the MDA-MB-231 cell line.
Overall, our current cytotoxicity data suggest that some of the
molecules presented in this study have good anti-cancer prop-
erties. Further studies are in progress to understand the molec-
ular target for these molecules which will help in understanding
the structure–activity relationship.
a
Results are expressed as IC50 values in mM concentrations.
MRC-5, human neuroblastoma SK-N-SH and human breast
adenocarcinoma MDA-MB-231 cell lines using an in vitro
cytotoxicity assay. Among these, compounds 4a, 4b and 4j
displayed the most potent anti-proliferative activity against the
human lung cancer A549 cell line, while 4a and 4b exhibited
potent anti-proliferative activity against neuroblastoma SK-N-
SH cancer cell lines when compared to the standard doxorubicin.
Further work is in progress in biotinylation of some of the lead
compounds to identify the molecular targets in the tested
cell lines.
Conclusions
Acknowledgements
In conclusion we have synthesized a series of novel chromeno-
annulated cis-fused pyrano[3,4-c]pyran derivatives and evaluated
their anti-proliferative activity against human lung adenocarci-
noma epithelial A549, human lung non-cancer fibroblast
AV thanks UGC, New Delhi for the award of fellowship and
DST, New Delhi is acknowledged for the SERC research grant
to AA.
656 | Med. Chem. Commun., 2012, 3, 652–658
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S. B. Teraiya, R. A. Patel and N. P. Talpada, Tetrahedron Lett.,
2011, 52, 2853–2856.
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16 The CCDC deposition number for 4e is 848040 Crystal
data: C22H22O5, M ¼ 366.40, monoclinic, space group P21/n,
ꢁ
ꢁ
ꢁ
a ¼ 15.4539(11) A, b ¼ 7.4613(5) A, c ¼ 16.2148(11) A, b ¼
106.214(1) , V ¼ 1795.3(2) A , Z ¼ 4, Dcalcd ¼ 1.356 mg mꢀ3, T ¼
ꢂ
3
ꢁ
294(2) K, m ¼ 0.096 mmꢀ1, F(000) ¼ 776, l ¼ 0.71073 A. Data
ꢁ
collection yielded 16 576 reflections resulting in 3161 unique,
averaged reflections, 2889 with I > 2s(I). Full-matrix least-squares
refinement led to a final R ¼ 0.0462, wR ¼ 0.1298 and GOF ¼
1.043. Intensity data were measured on a Bruker Smart Apex with
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17 The CCDC deposition number for 4g is 839 724. Crystal
data: C25H28O5, M ¼ 408.47, monoclinic, space group P21/c,
ꢁ
ꢁ
ꢁ
a ¼ 11.7974(15) A, b ¼ 13.9420(18) A, c ¼ 13.4238(17) A, b ¼
ꢂ
3
101.254(2) , V ¼ 2165.5(5) A , Z ¼ 4, Dcalcd ¼ 1.253 mg mꢀ3, T ¼
ꢁ
294(2) K, m ¼ 0.086 mmꢀ1, F(000) ¼ 872, l ¼ 0.71073 A. Data
ꢁ
collection yielded 20 554 reflections resulting in 3806 unique,
averaged reflections, 3113 with I > 2s(I). Full-matrix least-squares
refinement led to a final R ¼ 0.0431, wR ¼ 0.1198 and GOF ¼
1.035. Intensity data were measured on a Bruker Smart Apex with
a CCD area detector.
ꢀ
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and T. Tonnaire, Farmaco, 2002, 57, 703–708.
19 General procedure: Chemistry: A mixture of 7-O-prenyl derivatives of
8-formyl-2,3-disubstituted chromenones (2a–c) (1.0 mmol) and 1,3-
diketones (3a–h) (1.0 mmol) in acetonitrile (5 mL) was stirred in the
presence of EDDA (20 mol%) under reflux conditions for an
appropriate time. After completion of the reaction as indicated by
TLC, the excess acetonitrile was distilled off and the residue was
poured into water (20 mL) and extracted with DCM (3 ꢃ 20 mL).
The combined organic layers were dried over anhydrous Na2SO4,
concentrated in vacuo and the residue was purified by column
chromatography over silica gel (100–200 mesh) with eluent hexane–
ethyl acetate to yield the corresponding pure chromeno cis-fused
pyrano[3,4-c]pyrans (4a–o) as solids (yields: 80–95.0%). Data of the
representative compounds are as follows. For full characterization
data, see the ESI†. (1S,14R)-5,6,15,15-Tetramethyl-4,12,16,24-
tetraoxahexacyclo[12.12.0.02,11.03,8.017,26.018,23]hexacosa-2,5,8,10,17(26),
18(23),19,21-octaene-7,25-dione (4a): Yield 79.9%; White solid; mp
220–223 ꢂC; IR (KBr): nmax 3557, 3450, 2923, 1712, 1608, 1437,
1370, 1326, 1294, 1259, 1192, 1131, 1089, 1021, 832, 756, 604, 455
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Domino-Knoevenagel-Hetero-Diels–Alder Reaction and Related
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Bienayme, Wiley-VCH, Weinheim, 2005, pp. 121–167; (i)
M. J. Khoshkholgh, S. Balalaie, R. Gleiter and F. Rominger,
Tetrahedron, 2008, 64, 10924–10929; (j) M. J. Khoshkholgh,
S. Balalaie, H. R. Bijanzadeh and J. H. Gross, Synlett, 2009, 55–58.
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Tetrahedron Lett., 2006, 47, 7571–7574; (b) L. Zhang, J. Sun and
S. A. Kozmin, Adv. Synth. Catal., 2006, 348, 2271–2296; (c)
D. S. Ermolat, V. P. Mehta and E. V. V. Eycken, Synlett, 2007,
3117–3122; (d) M. J. Khoshkholgh, S. Balalaie, H. R. Bijanzadeh,
F. Rominger and J. H. Gross, Tetrahedron Lett., 2008, 49, 6965–
6968; (e) V. S. Matiychuk, R. B. Lesyk, M. D. Obushak, A. Gzella,
D. V. Atamanyuk, Y. V. Ostapiuk and A. P. Kryshchyshyn,
Tetrahedron Lett., 2008, 49, 4648–4651; (f) M. Kiamehr and
F. M. Moghaddam, Tetrahedron Lett., 2009, 50, 6723–6737; (g)
K. C. Majumdar, A. Taher and K. Ray, Tetrahedron Lett., 2009,
50, 3889–3891; (h) Y. R. Lee and Y. M. Kim, Tetrahedron, 2009,
65, 101–108; (i) B. Baruah and P. J. Bhuyan, Tetrahedron, 2009, 65,
7099–7104; (j) J. S. Yadav, B. V. Subba Reddy and A. C. Kunwar,
Tetrahedron Lett., 2010, 51, 2305–2308; (k) N. J. Parmar,
cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.63 (s, 3H), 1.64 (s, 3H),
;
2.06 (s, 3H), 2.29–2.36 (m, 1H), 2.41 (s, 3H), 4.07 (t, J ¼ 11.7 Hz,
1H), 4.53 (ddd, J ¼ 11.7, 5.3, 2.1 Hz, 1H), 4.63 (d, J ¼ 4.2 Hz, 1H),
6.77 (d, J ¼ 8.5 Hz, 1H), 7.14–7.30 (m, 2H), 7.50 (td, J ¼ 7.5, 1.1
Hz, 1H), 7.80 (dd, J ¼ 7.5, 1.1 Hz, 1H), 8.02 (d, J ¼ 8.5 Hz, 1H);
13C NMR (100 MHz, CDCl3): d 177.92, 160.84, 160.24, 158.29,
156.74, 156.56, 152.65, 131.94, 125.88, 123.56, 122.99, 116.25,
116.15, 115.32, 114.03, 108.49, 100.18, 78.34, 63.35, 36.80, 29.67,
27.10, 25.62, 24.24, 18.41, 10.00; MS–ESIMS: m/z 431 [M + H]+;
HRMS calcd for C26H23O6, 431.1494; found, 431.1498; (1S,14R)-
5,6,15,15,18,20-hexamethyl-4,12,16-trioxa-18,20-diazapentacyclo
[12.8.0.02,11.03,8.017,22 ]docosa-2,5,8,10,17(22)-pentaene-7,19,21-trione
(4b): Yield 92%; White solid; mp 169–174 ꢂC; IR (KBr): nmax 3449,
2924, 1707, 1664, 1611, 1439, 1365, 1295, 1258, 1189, 1128, 1079,
This journal is ª The Royal Society of Chemistry 2012
Med. Chem. Commun., 2012, 3, 652–658 | 657

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1024, 825, 788, 742, 652, 604, 470 cmꢀ1; 1H NMR (600 MHz, CDCl3):
d 1.57 (s, 3H), 1.61 (s, 3H), 2.05 (s, 3H), 2.15–2.23 (m, 1H), 2.39 (s,
3H), 3.16 (s, 3H), 3.36 (s, 3H), 4.06 (t, J ¼ 11.2 Hz, 1H), 4.48 (ddd,
J ¼ 11.0, 4.9, 1.1 Hz, 1H), 4.53 (d, J ¼ 3.3 Hz, 1H), 6.77 (d, J ¼ 8.8
Hz, 1H), 8.00 (d, J ¼ 8.8 Hz, 1H); 13C NMR (150 MHz, CDCl3):
d 177.91, 161.27, 160.77, 156.45, 156.40, 154.40, 150.84, 125.67,
116.27, 115.96, 114.05, 109.32, 86.48, 80.50, 62.98, 36.83,
28.87, 28.05, 27.01, 25.53, 23.18, 18.51, 10.10; MS–ESIMS: m/z 425
Violet solid; mp 153–155 ꢂC; IR (KBr): nmax 3428, 2923, 1726, 1644,
1606, 1467, 1437, 1406, 1357, 1326, 1274, 1250, 1190, 1132, 1092,
1
1064, 1021, 956, 831, 784, 668 cmꢀ1; H NMR (300 MHz, CDCl3
+
DMSO-d6): d 1.54 (s, 3H), 1.64 (s, 3H), 2.02 (s, 3H), 2.18–2.24 (m,
1H), 2.43 (s, 3H), 2.49 (dd, J ¼ 18.7, 9.3 Hz, 1H), 3.23 (dd, J ¼
18.7, 8.5 Hz, 1H), 3.80–3.90 (m, 1H), 4.04 (t, J ¼ 11.6 Hz, 1H), 4.54
(ddd, J ¼ 11.6, 3.8, 1.5 Hz, 1H), 6.82 (d, J ¼ 9.3 Hz, 1H), 7.96 (d,
J ¼ 9.3 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 190.59, 177.18,
169.09, 160.61, 156.80, 125.80, 116.98, 116.50, 114.87, 111.56, 81.15,
62.39, 36.82, 32.38, 29.28, 26.27, 24.01, 18.51, 9.95.; MS–ESIMS:
m/z 329 [M + H]+.
[M
+
H]+; HRMS calcd for C23H25N2O6, 425.1712; found,
425.1715; (13R,18S)-4,5,14,14-tetramethyl-3,11,15-trioxatetracyclo
[8.8.0.02,7.013,18]octadeca-1,4,7,9-tetraene-6,16-dione (4j): Yield 85%;
658 | Med. Chem. Commun., 2012, 3, 652–658
This journal is ª The Royal Society of Chemistry 2012