Regioselective synthesis of spiropyrrolidine/spiropyrrolizidine/ spirothiazolidine-grafted macrocycles through 1,3-dipolar cycloaddition methodology

Article abstract of DOI:10.1016/j.tet.2013.09.015

Synthesis of 13- and 16-membered macrocyclic enone with alkyl ether and triazole as a linker was achieved using intramolecular aldol condensation. The newly synthesized macrocyclic enone was successfully utilized as a dipolarophile in 1,3-dipolar cycloadd

Full text of DOI:10.1016/j.tet.2013.09.015

Tetrahedron 69 (2013) 9742e9750
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Regioselective synthesis of spiropyrrolidine/spiropyrrolizidine/
spirothiazolidine-grafted macrocycles through 1,3-dipolar
cycloaddition methodology
*
S. Purushothaman, R. Prasanna, R. Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 May 2013
Received in revised form 3 September 2013
Accepted 5 September 2013
Available online 24 September 2013
Synthesis of 13- and 16-membered macrocyclic enone with alkyl ether and triazole as a linker was
achieved using intramolecular aldol condensation. The newly synthesized macrocyclic enone was suc-
cessfully utilized as a dipolarophile in 1,3-dipolar cycloaddition (1,3-DC). The dipole generated from
isatin/acenaphthenequinone with various secondary amino acids (sarcosine, L-proline, and thiazolidine-
4-carboxylic acid) were reacted with macrocyclic enone to give a new class of spiropyrrolidine-grafted
macrocycles in good yield (>85%). The structures were assigned by 2D NMR spectra and the regio-
and stereochemical outcome of the cycloadducts were established by a single crystal X-ray analysis.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Macrocycles
Azomethine ylide
1,3-DC reaction
Spiropyrrolidine
Pyrrolizidine
1. Introduction
of natural products and pharmacologically active compounds, since
it offers high regio- and stereoselective products.13 Pyrrolidine,
Macrocyclic compounds with large cavities are found to have
potential application in chemistry, biology and nanotechnology.1,2
Heteroatom containing macrocylic compounds are present in nat-
ural products with potent biological activites.3 The structural
complexity, conformational bias and flexible nature are the unique
properties of the macrocyclic compounds.4 Heterocyclic com-
pounds are known to interact with various proteins and, hence,
macrocycles with heterocyclic units are found to be excellent mo-
lecular ligand.5 Such compounds can also act as sensor for chiral
molecule and used for selective metal ion and anion recognition.6,7
The Cu(I)-catalyzed alkyneeazide cycloaddition is the most useful
methodology for the construction of a variety of 1,2,3-triazole-
grafted macrocycles.8 In recent years, 1,2,3-triazoles are much
attracted in supramolecular chemistry because of its dual nature to
act as both hydrogen bond donor and acceptor.9 Due to its stability
and lipophilicity, these triazoles are more significantly utilized as
a nonpeptidic inhibitor.10
pyrrolizidine, and thiazolidine moieties are found in many natu-
rally occurring alkaloids.14 Broussonetine C together with several
structurally related compounds isolated from the branch of
Broussonetia kazinoki SIEB containing pyrrolidine moiety exhibit
unique b-galactosidase and b
-mannosidase inhibitory activities.15
Spiroheterocyclic compounds are of great synthetic importance in
organic chemistry. Particularly, spiropyrrolidines and spi-
ropyrrolizidines have received considerable attention as a result of
their biological activity.16 They display interesting antimicrobial,
antitumor, and antibiotic properties. In addition, they also act as
inhibitors of human NK-I receptor activity.17
The wide range of biological importance of spiropyrrolidine
heterocycles and diverse applications of macrocycles prompted us
to devise
spiropyrrolidine-grafted heterocycles. The azomethine ylides gen-
erated from isatin and cyclic and acyclic -amino acids are con-
a synthetic methodology for the construction of
a
sidered to be important since their cycloaddition to alkenes leads to
the formation of spirooxindolo pyrrolidines, which form the basic
building units of several natural products.
In considering possible synthetic schemes based on the chem-
istry discussed earlier, we decided that an intramolecular aldol
condensation reaction of a strategically positioned aldehyde and
ketone will be able to produce a macrocyclic dipolarophile. The
macrocyclic dipolarophile can be reacted with various azomethine
1,3-Dipolar cycloaddition reaction of azomethine ylides with
olefins represents an efficient route for the construction of the
pyrrolidine structure.11,12 This method is widely used for synthesis
* Corresponding author. Tel.: þ91 44 22202811; fax: þ91 44 22300488; e-mail
address: ragharaghunathan@yahoo.com (R. Raghunathan).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.015

S. Purushothaman et al. / Tetrahedron 69 (2013) 9742e9750
9743
ylide generated from secondary amino acids and diketones to give
spiropyrrolidine-grafted macrocycles through intermolecular 1,3-
DC reaction.
2. Results and discussions
Synthesis of macrocyclic dipolarophile 3 was accomplished in
two steps as shown below. The controlled O-alkylation of salicy-
laldehyde with 1,4-dibromobutane gave 2-(4-bromobutoxy)benz-
aldehyde (1),18a which was further subjected to second O-alkylation
with o-hydroxy acetophenone to give ketoaldehyde 2 (Scheme 1).
The structure of ketoaldehyde 2 was fully characterized by spec-
troscopic methods.
Scheme 3. Synthesis of macrocycle (6a).
Table 1
Reaction of enone with various dipolesa
Adduct
Structureb
Timec
Yield in
mg (%)d
Mpe
6a
4.0
430(90)
220e222
Scheme 1. Synthesis of ketoaldehyde (2).
The ketoaldehyde 2 was subjected to intramolecular aldol con-
densation to give the macrocyclic enone 3 in good yield. The for-
mation of macrocyclic enone 3 was thoroughly characterized by
spectroscopic techniques (Scheme 2).
6b
6c
4.0
5.0
430(86)
480(92)
200e204
197e199
Scheme 2. Synthesis of macrocyclic enone (3).
The 1H NMR spectrum of macrocyclic enone 3 exhibited two
distinct multiplets in the range
d 2.14e2.15 and 4.09e4.10 for
7a
6.0
470(92)
248e252
methylene protons of butane chain. The geometry of the olefinic
double bond was found to be E as evidenced by 1H NMR spectra
wherein the olefinic proton of 3 appeared as doublets at
d 7.63
and 8.95 (J¼15.6 Hz). Finally, the structure of the macrocyclic
enone was confirmed by a single crystal X-ray analysis 3 (Fig. 1).
In solid state, the macrocyclic enone 3 exists as trimer as shown
below.18b
7b
7c
5.0
6.0
485(90)
500(89)
208e212
222e224
15a
15b
6.0
6.0
520(95)
530(92)
212e216
210e214
Fig. 1. ORTEP diagram of 3.
The enone 3 was successfully utilized as a new class of dipo-
larophile in 1,3-DC reaction of azomethine ylides. Thus, the reaction
of sarcosine 5a with isatin 4a under DeaneStark reaction condition
led to the generation of azomethine ylide, which readily underwent
regioselective 1,3-dipolar cycloaddition reactions with 3 to furnish
spirooxindolopyrrolidine-grafted macrocyclic pyrrolidine 6a in
good yield as a single isomer as evidenced by thin layer chroma-
tography and crude NMR (Scheme 3). The results are summarized
in Table 1.
(continued on next page)

9744
S. Purushothaman et al. / Tetrahedron 69 (2013) 9742e9750
Table 1 (continued )
Adduct
Structureb
Timec
Yield in
mg (%)d
Mpe
15c
16a
6.0
533(90)
537(92)
248e252
Scheme 5. Synthesis of macrocycle (7a).
In the 13C NMR spectrum of 6a, the N-methyl carbon resonated
at 35.4 ppm. From DEPT 135, the presence of N-methylene and O-
methylene carbons were confirmed by the signals at 58.2, 68.0, and
69.5 ppm, respectively. The spiro carbon, oxindole, and benzoyl
carbonyl carbon exhibited peaks at 73.2, 179.3, and 200.6 ppm,
respectively.
7.0
244e246
The H,HeCOSY spectrum of 6a showed that the N-methylene
proton at
more, these N-methylene protons has an H,HeCOSY relationship
with the Ha hydrogen at 4.17e4.24. The Hb proton at 6.29 has
a contour with Ha proton at 4.17e4.24 as well as N-methylene
d 3.17 has contour with the hydrogen at d 3.82. Further-
16b
6.0
535(88)
210e212
d
d
d
protons. This unambiguously confirmed the observed regiochem-
istry of the cycloaddition. The N-methylene carbon of 6a at
58.2 ppm has a C,HeCOSY relationship with protons at
The methine carbon of 6a at 45.7 and 68.0 ppm has a C,HeCOSY
relationship with protons at 4.17e4.240 (Ha) and 6.29 (Hb).
The doublet at
d 3.17 & 3.82.
d
d
d
6.29 (J¼11.4 Hz, Hb) have an equal and strong
gradient HMBC contour with the benzoyl carbonyl carbon and spiro
16c
6.0
565(90)
224e226
carbon at 200.6 and 73.2 ppm, which again confirmed the observed
regioselectivity and d values of the Ha and Hb protons. Furthermore,
the observed regiochemistry was confirmed by HMBC contour of Hb
with oxindole carbonyl carbon at 179.3 ppm. If the other possible
regioisomer 2 had formed (Scheme 5), then the above HMBC con-
tour may be observed for Ha instead Hb. Moreover, the cycloadduct
6a exhibited a peak at m/z 469 (Mþþ1) in the mass spectrum.
Finally, the regio- and stereochemical outcome of the cycload-
dition reaction was confirmed by a single crystal X-ray analysis
(Triclinic, P-1 with 0.049 R value) of the cycloadduct 6a (Fig. 2).19
a
Reaction carried out with 1 mmol of macrocyclic enones (3 and 14).
b
Isolated products were characterized by 1H NMR, 13C NMR, mass, and X-ray
diffraction analysis of cycloadducts 6a, 6b, and 7a.
c
Time in hours.
Isolated yield.
Uncorrected melting point in ꢁC.
d
e
The structure and regiochemistry of the cycloadduct 6a was
established by IR, 1H/13C NMR and mass spectral analysis. In the IR
spectrum of 6a, the absorption bands at 1720 and 1682 cmꢀ1 cor-
respond to amide carbonyl and keto carbonyl groups, respectively.
The 1H NMR spectrum of 6a showed a sharp singlet at
d
2.24 ppm
for N-methyl protons. The N-methylene protons of pyrrolidine ring
resonated as a triplet and multiplet at
d
3.17 (J¼7.5 Hz) and
d
3.80e3.83, respectively, and the O-methylene protons of butane
chain exhibited a multiplet in the range d 4.28e4.32. The Hb proton
exhibited a downfield doublet at
due to anisotropic effect of the macrocyclic phenyl ring and amide
carbonyl group. The benzylic Ha proton was exhibited a multiplet in
d
6.29 (J¼11.4 Hz), which may be
the region of
d 4.17e4.24, which clearly proved the regiochemistry
of the cycloaddition reaction. If the other possible regioisomer 2
had formed (Scheme 5), then the benzylic Ha proton would have
shown a doublet instead of multiplet. The assigned chemical shift
values of the protons were also confirmed by 2D NMR techniques.
Fig. 2. ORTEP diagram of 6a.
From the above observation, it can be observed that the cyclo-
addition reaction occurred in a highly regio- and stereoselective
manner. This is because, the formation of isomer I via endo tran-
sition state (TS I) is more favorable than isomer II formed via exo
approaches (TS II). The strong repulsion between amide and enone
carbonyl groups in exo approach for the formation isomer II is less
favorable. Hence, the formation of isomer I through endo TS 1 is
anticipated (Fig. 3).
Scheme 4. Synthesis of macrocycle (6bec).

S. Purushothaman et al. / Tetrahedron 69 (2013) 9742e9750
9745
Fig. 3. Stereoselectivity.
The regioselectivity of the cycloaddition is as expected for re-
action of similar enones with azomethine ylides.20 The formation of
regioisomer I via TS III (Path a) is stabilized by secondary orbital
interaction between amide and enone carbonyl, while the forma-
tion of regioisomer II via TS IV (Path b) has a strong steric repulsion
between oxindole and phenyl moieties, which clearly shows that
the formation of regioisomer I is more favorable than regioisomer II
(Fig. 4). This is in conformity with 2D NMR values.
Fig. 5. ORTEP diagram of 6b.
We have further extended the scope of the 1,3-dipolar cycload-
dition reaction for the synthesis of spiroacenaphthenone
pyrrolidine-grafted macrocycles 7a. The dipole generated from
sarcosine (5a) and acenaphthoquinone (4b) under DeaneStark re-
action condition reacted with macrocyclic enone 3 as dipolarophile
in a regio- and stereoselective manner. The structures of the cyclo-
adduct 7a was confirmed by spectroscopic methods (Scheme 5).
Finally, the regio- and stereochemical outcome of the cycloaddi-
tion reaction was confirmed by a single crystal X-ray analysis
(Monoclinic, P21/c with0.045 R value) of the cycloadduct 7a(Fig. 6).22
Fig. 4. Regioselectivity.
In order to establish the generality of this cycloaddition reaction,
we extended the methodology for the synthesis of spirooxi
ndolopyrrolizidine/spirooxindolopyrrolothiazole-grafted
cycles (6bec). The azomethine ylides generated from -proline (5b)
and thiazolidine-4-carboxylic acid (5c) with isatin (4a) were reac-
ted with macrocyclic enone as dipolarophile to give the
macro
L
a
spirooxindole-grafted macrocycles 6bec in good yield (Scheme 4)
(88e92%).
Fig. 6. ORTEP diagram of 7a.
The structure of the cycloadduct was established by spectro-
As a logical extension of our methodology, the azomethine
scopic data. The 1H NMR spectrum of the cycloadduct 6b exhibited
ylides generated from
L-proline (5b) and thiazolidine-4-carboxylic
a multiplet in the range
chain methylene protons. The benzoyl proton Hb was resonated as
a doublet at
6.58 (J¼10.8 Hz). The benzylic proton appeared as
a multiplet in the range 4.20e4.22. These observations clearly
d 1.56e1.94 for the pyrrolizidine and butane
acid (5c) were reacted with macrocyclic dipolarophile
3
in
a highly regio- and stereoselective manner to produce a macrocy-
clic-grafted spiroacenaphthenone pyrrolizidine/pyrrolothiazole
(7bec) in good yield (Scheme 6) (88e92%). The structure and
d
d
proved the regio- and stereochemistry of the cycloaddition re-
action. The presence of N-methyl and O-methylene groups were
confirmed by signals at 47.3, 67.3 and 68.5 ppm, respectively, in the
13C NMR and DEPT 135 spectrum of 6b; the benzoyl and amide
carbonyl carbons exhibited peaks at 199.7 and 179.6 ppm. The rest
of the carbons of 6b were resonated at the expected ppm values.
Moreover, the cycloadduct 6b exhibited a peak at m/z 495 (Mþþ1)
in the mass spectrum. Finally, the regio- and stereochemical out-
come of the cycloaddition reaction was confirmed by a single
crystal X-ray analysis of the cycloadduct 6b (Fig. 5).21
Scheme 6. Synthesis of macrocycle (7bec).

9746
S. Purushothaman et al. / Tetrahedron 69 (2013) 9742e9750
regiochemistry of the cycloadducts (7bec) were established by IR,
1H/13C NMR and mass spectral analysis.
After successful synthesis of spiropyrrolidine-grafted macro-
cycles with alkyl chain as spacer group, we have extended the
methodology for the synthesis of spiroheterocycles-grafted mac-
rocycles with triazole as a spacer unit.
The triazole-linked macrocyclic dipolarophile can be obtained
through a click reaction of alkyne fragment of 12 and N-alkyl azide
9. The synthesis of alkynyl ketone 12 and N-alkyl azide 9 can be
achieved from easily available stating materials, such as 2-hydroxy
acetophenone 10 and salicylaldehyde, respectively, as described in
Scheme 7.
attached butane chain C) and 49.9 ppm (N-methylene of triazole
core). These values were further confirmed by DEPT 135 NMR
spectrum of 13. The aldehyde and keto carbons exhibited a peak at
189.5 and 199.8 ppm.
The ketoaldehyde 13, was subjected to intramolecular aldol
condensation to give the macrocyclic enone as reported earlier
(Scheme 11). The structure of the macrocyclic enone 14 was un-
ambiguously determined by spectroscopic methods.
Scheme 11. Synthesis of triazole-linked macrocyclic enone (14).
The 1H NMR spectrum of the macrocyclic triazole 14 exhibited
Scheme 7. Synthetic plan for triazole-linked macrocycles.
a sharp singlet at d 7.55 for triazole eCHe proton. The geometry of
the olefinic double bond was found to be E as evidenced by 1H NMR
spectra wherein one of the olefinic protons of 14 appeared as
The preparation of azide fragment 9from salicylaldehyde was easily
achieved from O-bromoaldehyde 8 by treatment with NaN3 in DMSO
at room temperature. The structure of N-alkyl azide 9 was confirmed
on the basis of FTIR and NMR spectroscopic data (Scheme 8).
a doublet at
d
7.48 (J¼15.9 Hz). The newly formed enone carbonyl
carbon was resonated at 196.9 ppm in the 13C NMR spectrum of 14.
Finally, the structure of the macrocyclic enone 14 (Fig. 7) was
confirmed by a single crystal X-ray analysis.23
Scheme 8. Synthesis of azide fragment (9).
The required alkyne unit 12 was synthesized from 2-hydroxy
acetophenone 10 via O-alkylation with propargyl bromide 11 in
the presence of K2CO3 in good yield as shown in Scheme 9. The
structure of alkyne fragment 12 was confirmed on the basis of FTIR
and NMR spectroscopic data.
Scheme 9. Synthesis of alkyne fragment (12).
Fig. 7. ORTEP diagram of 14.
The azide fragment 9 and alkyne fragment 12 was then sub-
jected to click reaction in the presence of sodium ascorbate and
CuSO4 at room temperature to give the triazole-linked ketoalde-
hyde 13 in good yield (Scheme 10).
The synthesized macrocyclic enone was successfully utilized as
an efficient dipolarophile in intermolecular 1,3-DC reaction of
azomethine ylide generated via decarboxylation route. The azo-
methine ylide (dipole) generated from sarcosine (5a) and isatin (4a)
under DeaneStark reflux condition reacted with macrocyclic enone
14 (dipolarophile) resulting in the formation of triazole-linked
spirooxindolopyrrolidine macrocycle as a single cycloadduct 15a.
The product was formed in good yield (95%), in a one pot three
component process, as evidenced by thin layer chromatography
and NMR (Scheme 12).
Scheme 10. Synthesis of triazole-linked ketoaldehyde (13).
The structure of the ketoaldehyde 13 was established by spec-
troscopic data. The 1H NMR spectrum of the ketoaldehyde 13
exhibited two distinct sharp singlets at
and aldehyde protons, respectively. O-methylene protons exhibited
a singlet at 5.31 and multiplet in the region 4.48e4.52, re-
spectively. A neat singlet at 7.70 corresponding to triazole eCHe
d 2.57 and 10.45 for acetyl
d
d
d
proton proved the presence of triazole unit. In the 13C NMR spec-
trum of 13, presence of O and N-methylene carbons were confirmed
by the signals at 67.3 (O-methylene of triazole core), 62.5 (O-
Scheme 12. Synthesis of macrocycle (15a).

S. Purushothaman et al. / Tetrahedron 69 (2013) 9742e9750
9747
The structure and regiochemistry of the cycloadduct 15a was
established by IR, 1H/13C NMR spectroscopic and mass spectro-
metric studies. The IR spectrum of 15a showed strong absorption
bands at 1620 and 1697 cmꢀ1, which confirmed the presence of
keto carbonyl and amide carbonyl groups, respectively. The 1H NMR
spectrum of 15a showed a sharp singlet at
protons. The N-methylene protons of pyrrolidine ring resonated as
triplets at 3.22 and 3.67, respectively. The Hb proton exhibited
a doublet at
4.86 (J¼12.9 Hz) and the benzylic Ha proton exhibited
a multiplet in the region of 4.40e4.44, which clearly proved the
regiochemistry of the cycloaddition reaction. If the other possible
regioisomer had formed, then the benzylic Ha proton would have
shown a doublet instead of multiplet. The methine proton of the
triazole ring was confirmed by the presence of sharp singlet at
d 2.09 ppm for N-methyl
d
d
Scheme 14. Synthesis of macrocycle (16a).
d
d
The structure and the regiochemistry of the cycloadduct 16a was
unambiguously established by their spectroscopic data.
Following the same reaction condition as explained for that of
acyclic amino acid, sarcosine, the reaction between macrocyclic
enone 14 and the azomethine ylide generated in situ by the
decarboxylative condensation with acenaphthequinone (4b) and
proline (5b)/thiazolidine-4-carboxylic acid (5c) was studied. The
reaction afforded spiroacenaphthenone pyrrolizidine/
pyrrolothiazole-grafted macrocycle with triazole spacer unit
(16bec) in good yield (Scheme 15) (88e90%). The structure and the
regiochemistry of both cycloadducts (16bec) were unambiguously
established by their spectroscopic and elemental analysis data.
d
7.83. The NH proton of the oxindole ring was showed a singlet at
7.70. These protons were also confirmed by 2D NMR techniques.
In the 13C NMR spectrum of 15a, the N-methyl carbon of pyr-
L-
d
rolidine showed a peak at 38.8 ppm. From DEPT 135, the presence
of N-methylene and O-methylene carbons were confirmed by the
signals at 67.1 and 68.5 ppm, respectively. The spiro carbon, oxin-
dole and benzoyl carbonyl carbon exhibited peaks at 75.2,178.3 and
200.6 ppm, respectively.
The H,HeCOSY spectrum of 15a showed that the N-methylene
proton at
more, these N-methylene protons has an H,HeCOSY relationship
with the Ha hydrogen at 4.40e4.42. The Hb proton at 4.86 has
a contour with Ha proton at 4.40e4.42 as well as N-methylene
d 3.22 has contour with the hydrogen at d 3.67. Further-
d
d
d
protons. This unambiguously confirmed the observed regiochem-
istry of the cycloaddition. The N-methylene carbon of 15a at
58.2 ppm has a C,HeCOSY relationship with protons at
d
3.22 and
d
3.67. The methine carbon of 15a at 47.6 and 68.1 ppm has
Scheme 15. Synthesis of macrocycle (16bec).
a C,HeCOSY relationship with protons at
d 4.40e4.42 (Ha) and
d
4.86 (Hb).
The doublet at
3. Conclusion
d
4.86 (J¼5.4 Hz, Hb) have strong gradient HMBC
contour with the benzoyl carbonyl carbon and spiro carbon at 203.2
and 75.2 ppm, which again confirmed the observed regioselectivity
and
To conclude, the present study provides the first insight into
the synthesis of
a variety of spiropyrrolidine/pyrrolizidine/
d values of the Ha and Hb protons. Furthermore, the observed
pyrrolothiazole-grafted macrocycles with alkyl chain or triazole
as spacer unit by the regioselective intermolecular 1,3-dipolar
cycloaddition reaction of macrocyclic enone with azomethine
ylide generated from various diketones and sarcosine/proline/
thiazolidine-4-carboxylic acid. The dipole addition was found to be
highly regioselective in all the cases that have been studied and
the 1,3 dipolar cycloaddition reaction would be of interest since it
paves the way for the synthesis of a variety of spiroheterocycles-
grafted macrocycle in high yield using easily available starting
materials.
regiochemistry was confirmed by HMBC contour of Hb with oxin-
dole carbonyl carbon at 178.3 ppm. If the other possible
regioisomer had formed, then the above HMBC contour may be
observed for Ha instead of Hb. Moreover, the cycloadduct 15a
exhibited a peak at m/z 550 (Mþþ1) in the mass spectrum.
With a view to extend the application of the cycloaddition re-
action for the synthesis of spirooxindolopyrrolizidine/pyrrolothia-
zole 15bec, we have carried out the reaction of the azomethine
ylide generated from isatin (4a) with cyclic secondary amino acids,
L-proline (5b)/thiazolidine-4-carboxylic acid (5c) with triazole-
linked macrocyclic enone 14 (Scheme 13).
4. Experimental section
4.1. General
All melting points are uncorrected. IR spectra were recorded on
ABB IR-MB3000 series FTIR spectrophotometer. One- and two-
dimensional NMR spectra were recorded on BRUKER 300 MHz in-
struments in CDCl3 solvent with tetramethylsilane (TMS) as in-
ternal standard. Chemical shifts are given in parts per million (
d
scale), and coupling constants are given in Hertz. Elemental anal-
ysis was carried out using PerkineElmer 2400 instrument. Single
crystal X-ray diffraction analysis was performed using Bruker
APEXII area-detector diffractometer. Column chromatography was
performed on silica gel (ACME, 100e200 mesh). Routine monitor-
ing of the reaction was done using thin layer chromatography de-
veloped on glass plates coated with silica gel-G (ACME) of 25 mm
thickness and visualized with iodine. Mass spectra were obtained
from high resolution ESI mass spectrometer Q-TOF analyzer.
Scheme 13. Synthesis of macrocycle (15bec).
We considered worthwhile to investigate the reaction of mac-
rocyclic enone 14 with the azomethine ylide generated from acyclic
secondary amino acid, sarcosine (5a) with reactive 1,2-diketone,
acenaphthequinone (4b) (Scheme 14).

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S. Purushothaman et al. / Tetrahedron 69 (2013) 9742e9750
4.2. Syntheses
1684, 1230, and 738 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 1.79e1.97
(m, 2H); 2.23e2.32 (m, 1H); 2.47e2.63 (m, 1H); 2.92e2.93 (m, 2H);
3.40 (d, J¼11.1 Hz, 1H); 3.49e3.61 (m, 1H); 3.85 (d, J¼11.1 Hz, 1H);
3.91e3.99 (m, 1H); 4.00e4.06 (m, 1H); 4.21e4.24 (m, 2H);
4.60e4.66 (m, 1H); 5.88 (dd, J¼1.8, 7.5 Hz, 1H); 6.41e6.45 (m, 3H);
6.60 (d, J¼8.4 Hz, 1H); 6.86e6.92 (m, 2H); 6.98e7.00 (m, 2H);
7.12e7.17 (m, 3H); 7.36 (dd, J¼1.5, 7.2 Hz, 1H); 7.66 (d, J¼7.5 Hz, 1H).
13C NMR (75 MHz, CDCl3): 26.5, 27.1, 29.6, 36.6, 52.0, 55.9, 59.8,
68.2, 69.5, 71.0, 74.7, 76.5,109.6,111.8,112.7,119.9,121.0,122.1,123.7,
126.4,128.4,128.7,128.8,129.3,129.6,132.7,134.0,141.1,157.3,157.9,
179.5, 200.1 ppm. HRMS (ESI): MHþ, found 513.1849. C30H29N2O4S
requires 513.1848.
General procedure for the synthesis of macrocycles 6, 7, 15, and
16: To a solution of macrocyclic enone 3 or 14 (1 mmol), amino acid
5aec (1.5 mmol) and diketone 4aeb (1 mmol) were refluxed in dry
toluene (50 mL) under N2 atmosphere for 4e8 h at 110 ꢁC using
DeaneStark apparatus. After the completion of reaction as in-
dicated by TLC, toluene was evaporated under reduced pressure.
The crude product was washed with water and extracted with
dichloromethane (4ꢂ20 mL). The combined organic layers were
dried (MgSO4) and filtered, concentrated in vacuum. The crude
product was purified by column chromatography (60% hexane/
EtOAc) to give the macrocycle (86e95%) as a crystalline solid.
Macrocycle 7a: A mixture of macrocyclic enone 3 (300.0 mg,
1 mmol), sarcosine 5a (135.0 mg, 1.5 mmol), and acenaph-
thenequinone 4b (182.0 mg, 1 mmol) were refluxed in dry toluene
(50 mL) under N2 atmosphere for 6 h at 110 ꢁC using DeaneStark
apparatus. The crude product was purified by column chromatog-
raphy (60% ethyl acetate/hexane) to give the macrocycle 7a
(470.0 mg, 92%) as a yellow solid. Mp 248e252 ꢁC. [Found: C, 78.79;
H, 5.60; N, 2.88. C33H29NO4 requires C, 78.71; H, 5.80; N, 2.78%].
Rf¼0.26 (ethyl acetate/hexane, 7:3). IR (Neat): 2932, 1720, 1674,
4.3. Experimental data
Macrocycle 6a: A mixture of macrocyclic enone 3 (300.0 mg,
1 mmol), sarcosine 5a (135.0 mg, 1.5 mmol), and isatin 4a
(150.0 mg, 1 mmol) were refluxed in dry toluene (50 mL) under N2
atmosphere for 4 h at 110 ꢁC using DeaneStark apparatus. The
crude product was purified by column chromatography (60% ethyl
acetate/hexane) to give the macrocycle 6a (430.0 mg, 90%) as
a crystalline yellow solid. Mp 220e222 ꢁC. [Found: C, 74.24; H, 6.14;
N, 5.88. C29H28N2O4 requires C, 74.34; H, 6.02; N, 5.98%]. Rf¼0.24
(ethyl acetate/hexane, 7:3). IR (Neat): 2361, 1720, 1682, 1250 and
1242, 995, and 748 cmꢀ1 1H NMR (300 MHz, CDCl3):
. d 1.75e1.84
(m, 1H); 1.87e1.94 (m, 1H); 2.10 (s, 3H); 2.25e2.38 (m, 2H); 3.19 (t,
J¼7.8 Hz, 1H); 3.69e3.75 (m, 1H); 3.79e3.88 (m, 2H); 4.16e4.25 (m,
2H); 4.27e4.34 (m, 1H); 5.72 (dd, J¼1.5, 7.5 Hz, 1H); 5.90 (t,
J¼7.5 Hz, 1H); 6.21 (d, J¼48.1 Hz, 1H); 6.36 (d, J¼11.1 Hz, 1H);
6.63e6.89 (m, 1H); 6.81e6.88 (m, 2H); 7.07e7.13 (m, 1H); 7.35 (t,
J¼8.1 Hz, 1H); 7.44e7.49 (m, 3H); 7.54 (t, J¼8.1 Hz, 1H); 7.60e7.68
(m, 1H); 7.74 (d, J¼7.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): 26.1, 27.3,
35.7, 45.9, 59.1, 61.2, 68.4, 69.3, 76.6, 111.7, 112.6, 119.7, 119.9, 120.7,
122.6, 124.4, 127.4, 127.8, 127.9, 128.6, 128.7, 128.8, 129.9, 130.9,
131.8,131.9,133.5,138.5,142.1,156.8,157.5, 200.8, 206.8 ppm. HRMS
(ESI): MHþ, found 504.2175. C33H30NO4 requires 504.2175.
748 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 1.86e197 (m, 2H); 2.24 (s,
3H); 2.28e2.40 (m, 2H); 3.17 (t, J¼7.5 Hz, 1H); 3.80e3.83 (m, 1H);
3.85e3.95 (m, 2H); 4.17e4.24 (m, 1H); 4.28e4.32 (m, 2H);
6.24e6.27 (m, 1H); 6.29 (d, J¼11.4 Hz, 1H); 6.40 (d, J¼7.5 Hz, 1H);
6.48 (t, J¼7.5 Hz, 1H); 6.63 (d, J¼8.1 Hz, 1H); 6.88e6.93 (m, 2H);
6.99e7.08 (m, 2H); 7.10e7.20 (m, 2H); 7.24e726 (m, 1H); 7.50 (dd,
J¼1.5, 6.0 Hz, 1H); 7.86 (s, 1H). 13C NMR (75 MHz, CDCl3): 25.9, 27.4,
35.4, 45.7, 58.2 60.7 68.0, 69.5, 73.2, 108.9, 112.2, 112.3, 120.2, 120.6,
122.7, 126.5, 127.4, 127.9, 128.7, 128.8, 129.1, 129.7, 132.4, 133.5,
140.8, 157.4, 157.5, 179.3, 200.6 ppm. HRMS (ESI): MHþ, found
469.2124. C29H29N2O4 requires 469.2127.
Macrocycle 7b: A mixture of macrocyclic enone 3 (300.0 mg,
1 mmol),
L-proline 5b (175.0 mg, 1.5 mmol), and acenaph-
thenequinone 4b (182.0 mg, 1 mmol) were refluxed in dry toluene
(50 mL) under N2 atmosphere for 5 h at 110 ꢁC using DeaneStark
apparatus. The crude product was purified by column chromatog-
raphy (60% ethyl acetate/hexane) to give the macrocycle 7b
(485.0 mg, 90%) as a yellow solid. Mp 208e212 ꢁC. [Found: C, 79.55;
H, 5.84; N, 2.66. C35H31NO4 requires C, 79.37; H, 5.90; N, 2.64%].
Rf¼0.25 (ethyl acetate/hexane, 7:3). IR (Neat): 2360, 1728, 1680,
Macrocycle 6b: A mixture of macrocyclic enone 3 (300.0 mg,
1 mmol), -proline 5b (175.0 mg,1.5 mmol), and isatin 4a (150.0 mg,
L
1 mmol) were refluxed in dry toluene (50 mL) under N2 atmo-
sphere for 4 h at 110 ꢁC using DeaneStark apparatus. The crude
product was purified by column chromatography (60% ethyl ace-
tate/hexane) to give the macrocycle 6b (430.0 mg, 86%) as a pale
yellow solid. Mp 200e204 ꢁC. [Found: C, 75.14; H, 6.01; N, 5.70.
1248, and 747 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 1.71e1.80 (m, 2H);
C
31H30N2O4 requires: C, 75.28; H, 6.11; N, 5.66%]. Rf¼0.25 (ethyl
acetate/hexane, 7:3). IR (Neat): 2365, 1718, 1684, 1050, and
750 cmꢀ1 1H NMR (300 MHz, CDCl3):
1.56e1.63 (m, 1H);
1.82e2.07 (m, 4H); 2.46e2.58 (m, 3H); 2.70e2.75 (m, 1H);
3.70e3.77 (m, 1H); 3.96e4.02 (m, 1H); 4.12e4.18 (m, 1H);
4.24e4.36 (m, 2H); 4.49e4.56 (m, 1H); 5.24 (dd, J¼1.5, 7.5 Hz, 1H);
5.80 (t, J¼7.5 Hz, 1H); 6.51 (d, J¼8.1 Hz, 1H); 6.76 (d, J¼12.0 Hz, 1H);
6.79e6.85 (m, 1H); 6.93 (t, J¼7.2 Hz, 1H); 6.98 (d, J¼8.1 Hz, 1H);
7.17e7.22 (m, 1H); 7.38e7.42 (m, 2H); 7.46 (dd, J¼1.2, 7.8 Hz, 1H);
7.60e7.70 (m, 2H); 7.83 (d, J¼7.8 Hz,1H); 7.91 (dd, J¼1.5, 7.2 Hz, 1H).
13C NMR (75 MHz, CDCl3): 26.7, 27.2, 27.4, 31.0, 48.4, 54.2, 63.2, 68.4,
68.8, 69.6, 76.6, 78.1, 111.7, 112.9, 119.6, 120.8, 120.9, 123.3, 124.9,
127.6, 127.7, 127.9, 128.0, 128.2, 128.6, 130.4, 130.9, 131.3, 132.0,
133.5, 135.8,142.0, 157.3, 157.4, 201.2, 206.8 ppm. HRMS (ESI): MHþ,
found 530.2328. C35H32NO4 requires 530.2331.
.
d
1.71e1.94 (m, 5H); 2.26e2.33 (m, 1H); 2.44e2.47 (m, 1H);
2.50e2.58 (m, 2H); 3.52 (t, J¼10.2 Hz, 1H); 3.88e4.00 (m, 2H);
4.20e4.22 (m, 2H); 4.33e4.41 (m, 1H); 5.90 (dd, J¼1.2, 9.0 Hz, 1H);
6.39e6.47 (m, 2H); 6.53e6.56 (m, 1H); 6.58 (d, J¼10.8 Hz, 1H);
6.81e6.86 (m, 1H); 6.87e6.90 (m, 1H); 6.98 (t, J¼7.5 Hz, 1H);
7.08e7.14 (m, 3H); 7.22 (d, J¼7.2 Hz, 1H); 7.34 (dd, J¼0.9, 6.3 Hz,
1H); 7.71 (s, 1H). 13C NMR (75 MHz, CDCl3): 25.6, 26.0, 26.3, 29.9,
47.3, 52.8, 61.5, 67.2, 67.3, 68.5, 72.9, 75.6, 109.0, 110.7, 111.8, 118.8,
119.8,121.0,124.9,125.9,126.2,127.0,127.8,128.1,128.2,131.6,132.6,
140.2, 156.2, 156.9, 179.6, 199.7 ppm. HRMS (ESI): MHþ, found
495.2283. C31H31N2O4 requires 495.2284.
Macrocycle 6c: A mixture of macrocyclic enone 3 (300.0 mg,
1 mmol), thiazolidine-4-carboxylic acid 5c (203.0 mg, 1.5 mmol),
and isatin 4a (150.0 mg, 1 mmol) were refluxed in dry toluene
(50 mL) under N2 atmosphere for 5 h at 110 ꢁC using DeaneStark
apparatus. The crude product was purified by column chromatog-
raphy (60% ethyl acetate/hexane) to give the macrocycle 6c
(480.0 mg, 92%) as a colorless solid. Mp 197e199 ꢁC. [Found: C,
70.32; H, 5.58; N, 4.56. C30H28N2O4S requires C, 70.29; H, 5.51; N,
4.46]. Rf¼0.25 (ethyl acetate/hexane, 7:3). IR (Neat): 2360, 1720,
Macrocycle 7c: A mixture of macrocyclic enone 3 (300.0 mg,
1 mmol), thiazolidine-4-carboxylic acid 5c (203.0 mg, 1.5 mmol),
and acenaphthenequinone 4b (182.0 mg, 1 mmol) were refluxed in
dry toluene (50 mL) under N2 atmosphere for 6 h at 110 ꢁC using
DeaneStark apparatus. The crude product was purified by column
chromatography (60% ethyl acetate/hexane) to give the macrocycle
7c (500.0 mg, 89%) as a pale yellow solid. Mp 222e224 ꢁC. [Found:
C, 74.69; H, 5.42; N, 2.66. C34H29NO4S requires C, 74.56; H, 5.34; N,
2.56%.]. Rf¼0.25 (ethyl acetate/hexane, 7:3). IR (Neat): 2360, 1720,
1684, 1250, and 748 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
1.94e2.07
(m, 2H); 2.44e2.50 (m, 1H); 2.71e2.73 (m, 1H); 3.07e3.08 (m, 2H);

S. Purushothaman et al. / Tetrahedron 69 (2013) 9742e9750
9749
3.36 (d, J¼10.8 Hz, 1H); 3.74e3.82 (m, 1H); 3.91 (d, J¼10.8 Hz, 1H);
3.97e4.03 (m,1H); 4.11e4.17 (m,1H); 4.29e4.37 (m, 2H); 4.76e4.82
(m, 1H); 5.23 (dd, J¼1.8, 7.8 Hz, 1H); 5.81 (t, J¼7.5 Hz, 1H); 6.50 (d,
J¼8.4 Hz, 1H); 6.61 (d, J¼12.3 Hz, 1H); 6.79e6.85 (m, 1H); 6.93e7.01
(m, 2H); 7.20e7.23 (m, 1H); 7.42e7.43 (m, 2H); 7.48 (dd, J¼1.5,
7.2 Hz, 1H); 7.66e7.71 (m, 1H); 7.69 (d, J¼8.4 Hz, 1H); 7.91e7.94 (m,
1H); 8.08 (d, J¼6.9 Hz, 1H). 13C NMR (75 MHz, CDCl3): 26.7, 27.2,
36.9, 52.5, 56.1, 60.4, 68.4, 69.4, 71.6, 76.5, 78.7, 111.6, 112.8, 119.7,
121.1, 121.2, 125.3, 126.7, 127.5, 128.1, 128.2, 128.4, 130.2, 130.7, 131.2,
132.2, 133.9, 134.0, 142.5, 157.2, 157.5, 200.7, 200.9 ppm. HRMS
(ESI): MHþ, found 548.1829. C34H30NO4S requires 548.1896.
Macrocycle 15a: A mixture of macrocyclic enone 14 (375.0 mg,
1 mmol), sarcosine 5a (133.0 mg,1.5 mmol), and isatin 4a (147.0 mg,
1 mmol) were refluxed in dry toluene (50 mL) under N2 atmo-
sphere for 6 h at 110 ꢁC using DeaneStark apparatus. The crude
product was purified by column chromatography (60% ethyl ace-
tate/hexane) to give the macrocycle 15a (520.0 mg, 95%) as a col-
orless solid. Mp 212e216 ꢁC. [Found: C, 69.99; H, 5.77; N, 12.72.
8.10 Hz, 2H); 6.90e6.98 (m, 3H); 7.10e7.22 (m, 3H); 7.47 (d, J¼7.5 Hz,
1H); 7.59 (d, J¼7.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): 28.8, 30.3, 41.1,
54.0, 59.7, 66.4, 66.7, 70.4, 78.1, 82.4, 114.2, 115.2, 116.3, 124.6, 124.8,
125.4, 128.3, 130.7, 131.7, 132.4, 132.5, 133.7, 134.2, 136.8, 146.7, 147.9,
160.2, 161.4, 183.9, 203.7 ppm. HRMS (ESI): MNaþ, found 616.1992.
C33H31N5O4SNa requires 616.1994.
Macrocycle 16a: A mixture of macrocyclic enone 14 (375.0 mg,
1 mmol), sarcosine 5a (133.0 mg, 1.5 mmol), and acenaph-
thenequinone 4b (182.0 mg, 1 mmol) were refluxed in dry toluene
(50 mL) under N2 atmosphere for 7 h at 110 ꢁC using DeaneStark
apparatus. The crude product was purified by column chromatog-
raphy (60% ethyl acetate/hexane) to give the macrocycle 16a
(537.0 mg, 92%) as a yellow solid. Mp 244e246 ꢁC. [Found: C, 74.08;
H, 5.62; N, 9.68. C36H32N4O4 requires C, 73.95; H, 5.52; N, 9.58%].
Rf¼0.24 (ethyl acetate/hexane, 7:3). IR (Neat): 2924, 2854, 2361,
1720, 1666, 1450, and 1242 cmꢀ1 1H NMR (300 MHz, CDCl3):
.
d
1.93e1.97 (m, 1H); 2.01 (s, 3H); 2.04e2.26 (m, 2H); 2.31e2.37 (m,
1H); 3.22 (t, J¼8.1 Hz, 1H); 3.50e3.57 (m, 1H); 3.83e3.91 (m, 2H);
4.46e4.55 (m, 3H); 4.59e4.68 (m, 2H); 4.80 (d, J¼10.2 Hz, 1H);
6.18e6.27 (m, 2H); 6.32 (dd, J¼1.8, 7.8 Hz, 1H); 6.69e6.72 (m, 1H);
6.73e6.79 (m,1H); 6.85e6.92 (m, 1H); 7.05e7.12 (m,1H); 7.39e7.50
(m, 2H); 7.53e7.55 (m, 1H); 7.56e7.59 (m, 2H); 7.75 (d, J¼6.9 Hz,
1H); 7.83 (d, J¼7.8 Hz, 1H); 8.03 (s, 1H). 13C NMR (75 MHz, CDCl3):
23.4, 23.7, 33.2, 41.9, 47.5, 61.0, 65.6, 74.8, 109.6, 11.3, 118.5, 119.3,
122.3, 122.8, 125.8, 126.0, 126.7, 127.5, 128.2, 129.4, 130.0, 140.2,
153.1, 155.3, 195.0, 198.9 ppm. HRMS (ESI): MHþ, found 585.2502.
C
32H31N5O4 requires C, 69.93; H, 5.69; N, 12.74%.]. Rf¼0.25 (ethyl
acetate/hexane, 7:3). IR (Neat): 2361, 1697, 1620, 1597, 1242, and
748 cmꢀ1. 1H NMR (300 MHz, CDCl3):
1.84e1.90 (m, 2H); 2.09 (s,
d
3H); 2.16e2.20 (m, 2H); 3.22 (t, J¼8.1 Hz, 1H); 3.47e3.50 (m, 1H);
3.52e3.61 (m, 1H); 3.67 (t, J¼8.7 Hz, 1H); 4.40e4.44 (m, 2H);
4.50e4.59 (m, 1H); 4.69 (d, J¼9.6 Hz, 2H); 4.86 (d, J¼12.9 Hz, 1H);
6.42 (dd, J¼1.5, 7.5 Hz, 1H); 6.52e6.59 (m, 3H); 6.68 (d, J¼8.4 Hz,
1H); 6.83 (t, J¼7.5 Hz, 1H); 6.94 (t, J¼7.5 Hz, 1H); 7.03e7.19 (m, 3H);
7.16e7.19 (m, 1H); 7.50 (dd, J¼1.2, 7.5 Hz, 1H); 7.70 (s, 1H); 7.83 (s,
1H). 13C NMR (125 MHz, CDCl3): 24.8, 26.3, 34.9, 49.8, 58.9, 63.5,
65.3, 66.3, 73.3, 109.2, 112.0, 113.1, 120.9, 121.1, 122.7, 123.4, 127.1,
127.4, 127.7, 128.7, 128.9, 129.0, 131.0, 131.3, 132.2, 140.9, 144.4,
155.6, 156.6, 179.2, 202.3 ppm. HRMS (ESI): MHþ, found 550.2456.
C36H33N4O4 requires 585.2502.
Macrocycle 16b: A mixture of macrocyclic enone 14 (375.0 mg,
1 mmol), -proline 5b (172.0 mg, 1.5 mmol) acenaphthenequinone
L
4b (182.0 mg, 1 mmol) were refluxed in dry toluene (50 mL) under
N2 atmosphere for 6 h at 110 ꢁC using DeaneStark apparatus. The
crude product was purified by column chromatography (60% ethyl
acetate/hexane) to give the macrocycle 16b (535.0 mg, 88%) as
a yellow solid. Mp 210e212 ꢁC. [Found: C, 74.79; H, 5.69; N, 9.30.
C
32H32N5O4 requires 550.2454.
Macrocycle 15b: A mixture of macrocyclic enone 14 (375.0 mg,
1 mmol), -proline 5b (172.0 mg, 1.5 mmol), and isatin 4a (147.0 mg,
L
1 mmol) were refluxed in dry toluene (50 mL) under N2 atmo-
sphere for 6 h at 110 ꢁC using DeaneStark apparatus. The crude
product was purified by column chromatography (60% ethyl ace-
tate/hexane) to give the macrocycle 15b (530.0 mg, 92%) as a pale
yellow solid. Mp 210e214 ꢁC. Rf¼0.22 (ethyl acetate/hexane, 7:3).
[Found: C, 70.90; H, 5.68; N, 12.22. C34H33N5O4 requires C, 70.94; H,
C
38H34N4O4 requires C, 74.73; H, 5.61; N, 9.17%]. Rf¼0.23 (ethyl
acetate/hexane, 7:3). IR (Neat): 2922, 2850, 2360, 1716, 1668, 1440,
and 1240 cmꢀ1 1H NMR (300 MHz, CDCl3):
1.77e1.87 (m, 3H);
.
d
1.90e1.95 (m, 2H); 2.12e2.21 (m, 2H); 2.24e2.29 (m, 1H);
2.46e2.50 (m, 2H); 3.18e3.19 (m, 1H); 3.92e4.07 (m, 2H);
4.40e4.47 (m, 1H); 4.53e4.60 (m, 1H); 4.68e4.72 (m, 1H);
4.75e4.85 (m, 2H); 5.37 (d, J¼11.4 Hz, 1H); 6.16e6.19 (m, 2H); 6.31
(d, J¼8.4 Hz, 1H); 6.74e6.82 (m, 2H); 6.94 (t, J¼7.5 Hz, 1H); 7.16 (t,
J¼7.5 Hz, 1H); 7.48e7.53 (m, 4H); 7.67 (d, J¼6.9 Hz, 1H); 7.75e7.78
(m, 1H); 7.88 (d, J¼8.1 Hz, 1H); 8.65 (s, 1H). 13C NMR (75 MHz,
CDCl3): 24.8, 26.2, 27.0, 30.6, 48.3, 49.7, 62.3, 65.9, 66.8, 66.8, 68.9,
76.9, 77.2, 111.0, 112.6, 119.9, 120.9, 121.1, 123.3, 125.1, 125.6, 127.6,
127.8, 127.9, 128.5,129.1, 130.5,131.2, 131.8, 131.9, 136.0, 142.0, 144.2,
155.1, 157.2, 199.9, 206.8 ppm. HRMS (ESI): MHþ, found 611.2660.
5.78; N, 12.17%]. IR (Neat): 2360, 1699, 1618, 1596, and 1240 cmꢀ1
1H NMR (300 MHz, CDCl3):
1.75e1.91 (m, 5H); 2.05e2.11 (m, 2H);
.
d
2.21e2.25 (m, 1H); 2.50e2.60 (m, 2H); 2.95e3.03 (m, 1H); 3.79 (t,
J¼10.2 Hz, 1H); 3.92e3.99 (m, 1H); 4.33e4.40 (m, 1H); 4.47e4.54
(m, 1H); 4.65e4.73 (m, 1H); 4.91e4.99 (m, 2H); 5.30 (d, J¼11.7 Hz,
1H); 6.42 (d, J¼7.8 Hz,1H); 6.46e6.48 (m,1H); 6.57 (t, J¼7.5 Hz,1H);
6.72e6.77 (m, 2H); 6.88e6.96 (m, 2H); 7.09e7.14 (m, 2H); 7.17e7.23
(3, H); 7.46 (dd, J¼1.2, 7.5 Hz, 1H); 8.56 (s, 1H). 13C NMR (75 MHz,
CDCl3): 22.6, 24.3, 25.0, 28.6, 46.2, 47.9, 60.5, 63.5, 64.3, 71.1, 107.7,
109.0, 110.2, 118.2, 118.8, 120.2, 123.6, 124.1, 124.7, 125.8, 126.7, 127.1,
127.8, 1303, 138.7, 142.4, 154.1, 155.1, 178.2, 197.5 ppm. HRMS (ESI):
MHþ, found 576.2615. C34H34N5O4 requires 576.2611.
Macrocycle 15c: A mixture of macrocyclic enone 14 (375.0 mg,
1 mmol), thiazolidine-4-carboxylic acid 5c (200.0 mg,1.5 mmol), and
isatin 4a (147.0 mg, 1 mmol) were refluxed in dry toluene (50 mL)
under N2 atmosphere for 6 h at 110 ꢁC using DeaneStark apparatus.
The crude product was purified by column chromatography (60%
ethyl acetate/hexane) to give the macrocycle 15c (533.0 mg, 90%) as
a colorless solid. Mp 248e252 ꢁC. [Found: C, 66.88; H, 5.46; N, 11.88.
C38H35N4O4 requires 611.2658.
Macrocycle 16c: A mixture of macrocyclic enone 14 (375.0 mg,
1 mmol), thiazolidine-4-carboxylic acid 5c (200.0 mg, 1.5 mmol),
and acenaphthenequinone 4b (182.0 mg, 1 mmol) were refluxed in
dry toluene (50 mL) under N2 atmosphere for 6 h at 110 ꢁC using
DeaneStark apparatus. The crude product was purified by column
chromatography (60% ethyl acetate/hexane) to give the macrocycle
16c (565.0 mg, 90%) as a pale yellow solid. Mp 224e226 ꢁC. [Found:
C, 70.58; H, 5.03; N, 8.99. C37H32N4O4S requires C, 70.68; H, 5.13; N,
8.91%]. Rf¼0.22 (ethyl acetate/hexane, 7:3). IR (Neat): 2923, 2854,
2360, 1718, 1668, 1454, and 1242 cmꢀ1. 1H NMR (300 MHz, CDCl3):
C
33H31N5O4S requires C, 66.76; H, 5.26; N, 11.80%]. Rf¼0.22 (ethyl
d 1.99e2.02 (m, 1H); 2.08e2.17 (m, 2H); 2.30e2.33 (m, 1H);
acetate/hexane, 7:3). IR (Neat): 1698, 1628, 1594, and 1243 cmꢀ1. 1H
NMR (300 MHz, CDCl3): 1.94e1.96 (m, 1H); 2.04e2.08 (m, 3H);
2.24e2.31 (m, 1H); 2.96e2.98 (m, 2H); 3.42e3.46 (d, J¼10.8 Hz, 1H);
3.76e3.83 (m, 1H); 3.89 (d, J¼10.8 Hz, 1H); 3.94e4.00 (m, 1H);
4.47e4.53 (m,1H); 4.69e4.75 (m, 2H); 5.00 (s, 2H); 5.20 (d, J¼12.3 Hz,
1H); 6.38 (d, J¼7.5 Hz, 2H); 6.55 (t, J¼6.9 Hz, 1H); 6.76 (dd, J¼3.0,
3.02e3.04 (m, 3H); 3.27 (d, J¼11.1 Hz, 1H); 3.83 (d, J¼11.1 Hz, 1H);
3.88e3.95 (m, 1H); 4.01e4.13 (m, 1H); 4.54e4.64 (m, 1H);
4.73e4.79 (m, 2H); 4.81e4.86 (m, 2H); 5.26 (d, J¼11.1 Hz, 1H);
6.08e6.09 (m, 2H); 6.30 (d, J¼8.1 Hz, 1H); 6.70e6.76 (m, 1H); 6.81
(d, J¼8.1 Hz,1H); 6.95 (t, J¼7.5 Hz,1H); 7.17e7.22 (m,1H); 7.48e7.58
(m, 3H); 7.71e7.77 (m, 2H); 7.86e7.90 (m, 2H); 8.70 (s,1H). 13C NMR

9750
S. Purushothaman et al. / Tetrahedron 69 (2013) 9742e9750
7. (a) Camiolo, S.; Gale, P. A.; Hursthouse, M. B.; Light, M. E. Org. Biomol. Chem.
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(75 MHz, CDCl3): 24.2, 25.5, 36.7, 49.2, 55.0, 61.6, 62.7, 66.0, 70.5,
76.0, 110.0, 111.8, 119.3, 120.6, 124.3, 124.9, 125.4, 126.9, 127.5, 128.6,
129.8, 130.8, 130.9, 131.4, 132.8, 141.9, 143.2, 154.4, 156.7, 198.7,
205.5 ppm. HRMS (ESI): MNaþ, found 651.2045. C37H32N4O4SNa
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Acknowledgements
The author S.P. thanks DST, New Delhi for fellowship and DST-
FIST program for the NMR facility. The authors wish to thank Pro-
fessor D. Velmurugan and T. Srinivasan for single crystal X-ray data.
S.P. and R.P. thank CSIR, New Delhi for the award of SRF. R.R. thanks
DST for financial support and UGC for BSR Faculty Fellowship.
12. (a) Poornachandran, M.; Raghunathan, R. Tetrahedron 2008, 64, 6461e6474; (b)
Arumugam, N.; Periyasami, G.; Raghunathan, R.; Kamalraj, S.; Muthumary, J.
Eur. J. Med. Chem. 2011, 46, 600e607.
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1515e1518.
Supplementary data
14. (a) Nyerges, M.; Gajdics, L.; Szollosy, A.; Toke, L. Synlett 1999, 111e113; (b) Dietz,
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dx.doi.org/10.1016/j.tet.2013.09.015.
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