Stereoselective synthesis of hexahydro-3-methyl-1-arylchromeno[3,4-b] pyrrole and its annulated heterocycles as potent antimicrobial agents for human pathogens

Article abstract of DOI:10.1016/j.bmcl.2010.10.073

Synthesis of a series of novel hexahydrochromenopyrrole analogues has been accomplished through an intramolecular 1,3-dipolar cycloaddition (1,3-DC reaction) of azomethine ylides, generated by the aldehyde induced decarboxylation of secondary amino acids. These compounds were screened for antibacterial and antifungal activities against six human pathogenic bacteria and three human pathogenic fungi and found to have good antimicrobial properties against most of the microorganisms.

Full text of DOI:10.1016/j.bmcl.2010.10.073

Bioorganic & Medicinal Chemistry Letters 20 (2010) 7288–7291
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Stereoselective synthesis of hexahydro-3-methyl-1-arylchromeno[3,4-b]pyrrole
and its annulated heterocycles as potent antimicrobial agents for human
pathogens
S. Purushothaman a, R. Prasanna a, P. Niranjana a, R. Raghunathan a, , S. Nagaraj b, R. Rengasamy b
⇑
a Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
b Centre for Advanced Studies in Botany, 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:
Synthesis of a series of novel hexahydrochromenopyrrole analogues has been accomplished through an
intramolecular 1,3-dipolar cycloaddition (1,3-DC reaction) of azomethine ylides, generated by the alde-
hyde induced decarboxylation of secondary amino acids. These compounds were screened for antibacte-
rial and antifungal activities against six human pathogenic bacteria and three human pathogenic fungi
and found to have good antimicrobial properties against most of the microorganisms.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 11 August 2010
Revised 24 September 2010
Accepted 15 October 2010
Available online 8 November 2010
Keywords:
Chromenopyrrole
Intramolecular reaction
Azomethine ylide
Heterocycles
1,3-DC reaction
Antimicrobial
The synthesis of fused pyrrolidines, pyrrolizidines, indazoli-
dines, pyranoquinolines and chromenopyrrole ring systems has re-
ceived synthetic chemists attention over the years, since these
heterocycles form the structural subunits of biologically important
alkaloids1 and pharmaceutically important compounds.2 Instruc-
tively, a chromene-derived bisbenzopyran was reported3 as a novel
selective estrogen receptor modulators (SERMa) to alleviate hot
flushes and effectively increase fluidity in rats. Pizzo et al. re-
ported4 the synthesis of chromene derivatives through [4+2] cyclo-
addition in high yields.
The [3+2] cycloaddition reaction is a powerful method for the
synthesis of bicyclic saturated five-membered heterocycles, and
consequently, it has been extensively studied by our research
group.5 The intramolecular version of this reaction generally oc-
curs with high regio- and stereocontrol6 and results in the forma-
tion of fused nitrogen containing bicyclic systems. Majority of
examples reported in the literature pertain to the synthesis of
chromeno[4,3-b]pyrrole fused skeletons and only limited reports
are available for the synthesis of chromeno[3,4-b]pyrroles.
Confalone and co-workers7 first reported the synthesis of
chromeno[4,3-b]pyrrole via deprotonation route. Similarly, Grigg
et al.8 also extensively studied the intramolecular azomethine
ylide cycloaddition reaction for the synthesis of same type of
compounds. Literature is abound with examples for the synthesis
of chromeno[4,3-b]pyrrole fused ring system9 through intramolec-
ular cycloaddition reaction. Although Padwa10 and DeShong et al.11
reported the synthesis of furo/pyrano[3,4-b]pyrrole ring system
through azomethine ylides derived from aziridines, there is no re-
port for the synthesis of chromeno/furano/pyrano[3,4-b]pyrrole
fused ring system via intramolecular [3+2] cycloaddition reaction.
Lamellarins12 a marine natural product (Fig. 1) has a core unit of
chromeno[3,4-b]pyrrole which is cytotoxic to a wide range of can-
cer cell lines13 and selective inhibitor of HIV integrase both in vitro
and in vivo.14 With a need to develop simpler methods for the syn-
thesis of chromeno[3,4-b]pyrrole annulated heterocycles, and in
continuation of our interest in cycloaddition chemistry, herein
we report the synthesis of hexahydro-3-methyl-1-arylchro-
meno[3,4-b]pyrrole and its analogues through intramolecular
1,3-DC reaction of O-alkyl aldehydes with suitably positioned
dipolarophiles.
O
N
O
OMe
OMe
MeO
OMe
MeO
OMe
⇑
Corresponding author. Tel.: +91 44 22202811; fax: +91 44 22300488.
E-mail address: ragharaghunathan@yahoo.com (R. Raghunathan).
Figure 1. Lamellarin G trimethyl ether.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.073

S. Purushothaman et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7288–7291
7289
The required alkenyl aldehyde 2a was prepared from salicylalde-
hyde in three steps in good yield (Scheme 1). Thus, 2-(2-hydroxyeth-
oxy)benzaldehyde15 on treatment with p-chloroacetophenone in
presence of base furnished alkenyl alcohol 1a, which on oxidation
with iodoxybenzoic acid (IBX) in DMSO gave the alkenyl aldehyde
2a in excellent yield. The structures of the alkenyl alcohol 1a and
alkenyl aldehyde 2a were characterized by spectral analysis. The
1H NMR spectrum of 2a exhibited a doublet at d 7.70 (J = 15.9 Hz)
corresponding to one of the olefinic protons. Thus, the geometry of
the olefinic double bond was found to be E isomer. The aldehydic
proton resonated at d 9.82 as a singlet. The carbonyl carbon of
aldehyde was confirmed by the presence of a peak at 196.8 ppm in
the 13C NMR spectrum of 2a.
The intramolecular 1,3-DC reaction was carried out by reacting
the alkenyl aldehyde 2a with sarcosine (3a) in refluxing toluene
under Dean-Stark reaction condition. The azomethine ylide gener-
ated through decarboxylative condensation reaction, underwent
[3+2] cycloaddition smoothly to give hexahydrochromeno[3,4-
b]pyrrole 4 in good yield16a (Scheme 2).
stereochemical outcome of the cycloaddition reaction was con-
firmed by a single crystal X-ray analysis17 of the cycloadduct 4
(Fig. 2).
The same reaction was carried with cyclic amino acids L-proline
(3b), thiazolidine-4-carboxylic acid (3c) and tetrahydroisoquino-
line-3-carboxylic acid (3d) to obtain the polycyclic cis fused cyc-
loadducts 5–7 in good yields16b (Scheme 3). The structures of the
products 5–7 were also confirmed by 1H NMR, 13C NMR, COSY
and mass spectral analysis.
In the 1H NMR of 5 the benzylic proton Ha resonated as a dou-
blet of doublet at d 5.17 (J = 3.0, 12 Hz) which clearly showed the
stereochemistry of the ring junction. The 13C NMR spectrum of 5
showed the benzoyl carbonyl peak at 198.4 ppm. Moreover, the
cycloadduct 5 exhibited a peak at m/z 354.27 (M++1) in the mass
spectrum which confirmed the structure of the cycloadduct 5.
In order to extend the scope of the reaction, the alkenyl alde-
hyde 2b (Scheme 4) was subjected to [3+2] cycloaddition reaction
with various secondary amino acids (3a–3d). The reaction yielded
a novel spirochromenopyrrole 8, spiropyrrolizidine 9, spirothiaz-
olidine 10 and spiroindolizidine 11 (Scheme 5) in good yields.16c,d
The structure of the cycloadducts 8–11 were also established by
spectroscopic data. The 1H NMR spectrum of 8 exhibited singlet
at d 2.45 corresponding to N-methyl group. The benzylic proton
Ha resonated as a doublet at d 4.75 (J = 10.5 Hz). The coupling
constant suggested a cis fusion at the ring junction. The benzylic
–CH– carbon resonated at 41.8 ppm and the carbonyl carbon
exhibited a peak at 199.3 ppm.
The structure of the cycloadduct 4 was confirmed by spectral
analysis. The 1H NMR spectrum of 4 exhibited a singlet at d 2.46
corresponding to N-methyl proton. A distorted doublet of triplet
at d 2.68 was observed for the N-CH (Hb) proton. The benzylic pro-
ton Ha resonated as a doublet of doublet at d 3.92 (J = 2.1, 11.1 Hz).
The coupling constant suggested a cis fusion at the ring junction. A
multiplet in the region d 3.83–3.91 was observed for Hc proton. The
stereochemistry of the cycloadduct 4 was also deduced on the ba-
sis of 2D NOESY experiments. The strong NOESY between Ha and
Hb of 4 clearly proved cis stereochemistry at the ring junction.
The presence of N-methyl and N-methylene group in 4 was con-
Moreover, the cycloadduct 8 exhibited a peak at m/z 320.20
(M++1) in the mass spectrum. Further, the regio- and stereochem-
ical outcome of the cycloaddition reaction was confirmed by a sin-
gle crystal X-ray analysis18 of the cycloadduct 10 (Fig. 3).
In the present study, minimum inhibitory concentration of
newly synthesized arylchromeno[3,4-b]pyrroles were evaluated
against six human bacterial pathogens viz. Staphylococcus aureus,
Bacillus subtilis, Streptococcus pneumoniae, Escherichia coli, Shigella
sp., Salmonella typhi by well diffusion method19 and three human
fungal pathogens viz. Trichoderma sp., Aspergillus sp. and Candida
albicans, by poison food technique.20 The compounds at the con-
firmed by the two signals at 39.7 and 55.2 ppm respectively in 13
C
NMR spectrum. The O-methylene carbon exhibited a peak at
65.7 ppm. The N-CH carbon of 4 resonated at 64.6 ppm and was
confirmed by DEPT 135 spectrum. The carbonyl carbon exhibited
a peak at 198.7 ppm. Moreover, the cycloadduct 4 exhibited a peak
at m/z 328.33 (M++1) in the mass spectrum. Finally, the regio and
centration range 5–150 lg/mL in 0.25% DMSO was used in this
study with tetracycline and carbendazim, respectively, for bacteria
Cl
Cl
and fungi being used as control.
Effect of tested compounds on the growth of human bacterial
pathogens: Antibacterial activity for the above cycloadducts 4–11
was evaluated against both positive and negative human patho-
genic bacterial strains and was compared with the reference anti-
biotic tetracyclin as minimum inhibitory concentration (MIC).
All the eight compounds exhibited different levels of antibacte-
rial activity. Further, the antibacterial activity of the tested com-
pounds was found to be dose dependent and remarkable at
higher concentrations. The minimum inhibitory concentration
(MIC) of the compounds 4–11 against human pathogens
determined by well diffusion method ranged between 10 and
O
O
CHO
OH
(i)
(iii)
OH
(ii)
O
O
CHO
1a
2a
Scheme 1. Synthesis of alkenyl aldehyde 2a. Reagents and conditions: (i) Chloro-
ethanol, NaOH/H2O, reflux, 16 h, 78%, (ii) p-chloroacetophenone, rt, 10% NaOH in
EtOH, 6 h, 80% (1a), (iii) IBX, DMSO, rt, 8 h, 85% (2a).
Cl
Cl
toluene/reflux
O
O
Hc
Ha
4h, 70%
H
N
N
CO2H
Hb
3a
O
CHO
2a
O
4
Scheme 2. Synthesis of hexahydrochromeno[3,4-b]pyrrole 4.
Figure 2. ORTEP diagram of 4.

7290
S. Purushothaman et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7288–7291
Cl
Cl
X
O
Hc
O
Hc
H
H
Ha
toluene/reflux
6h, 72%
toluene/reflux
4-6h
Ha
N
2a
N
X
Hb
CO2H
Hb
CO2H
O
O
N
H
NH
7
3d
5) X = -CH2 (74%)
6) X = S (78%)
3b) X = -CH2
3c) X = S
Scheme 3. Synthesis of spirochromenopyrrole annulated heterocycles 5–7.
CHO
OH
(iii)
(i)
O
O
(ii)
OH
H
O
O
O
1b
2b
Scheme 4. Synthesis of alkenyl aldehyde 2b. Reagents and conditions: (i) Chloro-
ethanol, NaOH/H2O, reflux, 16 h, 78%. (ii) -tetralone, 0 °C to rt, 10% NaOH in EtOH,
a
5 h, 72% (1b). (iii) IBX, DMSO, rt, 10 h, 88% (2b).
Figure 3. ORTEP diagram of 10.
Hc
O
Ha
S
N
of 7–25
l
g/mL against all the tested pathogenic bacteria. Further
Hb
the compounds 5 and 11 were found to be more active than the
standard antibiotic tetracyclin. The high activity of the compounds
5, 7 and 8 against all the bacterial pathogens than the standard
drug tetracycline indicated, that there is a possibility that these
compounds might be developed as a drug. The compounds 4 and
6 were found to have moderate activity against all the pathogens
O
10
S
toluene,
reflux,
CO2H
N
6h, 78%.
H
3c
with MIC ranging from 15 to 30 lg/mL while compounds 8–10
exhibited low anti bacterial activity against the tested pathogens
with high MIC values (Table 1).
Hc
toluene,
reflux,
toluene,
reflux,
O
O
Ha
Ha
4h, 72%.
4h, 74%
Effect of tested compounds on the growth of human fungal
pathogens: All the eight compounds exhibited different levels of
antifungal activity against the three tested fungal pathogens, Trich-
oderma sp., Aspergillus sp. andC. albicans with 10% DMSO as control.
The antifungal activity of the test compounds was dose dependent
and remarkable at higher concentrations. The minimum inhibitory
concentrations (MICs) of all the compounds 4–11 against the
N
2b
N
Hb
H
Hb
N
CO2H
O
O
CO2H
N
H
3a
3b
9
8
CO2H
toluene,
reflux,
6h, 78%.
NH
pathogens ranged between 15 and 105 lg/mL and showed moder-
3d
ate activity against all the microorganisms compared to standard
drug carbendazim. Among all the eight compounds tested, the
compounds 4, 5, and 7 inhibited moderately all the three human
fungal pathogens at low concentrations (20–45
pared to compounds 6 and 8–10 which showed antifungal activity
only at higher concentrations (70–110 g/mL) (Table 2).
lg/mL) as com-
Hc
O
Ha
l
N
In conclusion, we have achieved the synthesis of a variety of no-
vel chromeno[3,4-b]pyrrole and its analogues through intramolec-
ular 1,3-DC reaction. All the synthesized compounds showed good
antimicrobial activity against all the selected human bacterial and
fungal pathogens. In particularly cycloadducts 5, 7 and 11 exhib-
ited the best antibacterial activity even better than the antibiotic
tetracycline against all the bacterial pathogens. The synthetic com-
pounds also exhibited moderate activity against all the fungal
pathogens.
Hb
O
11
Scheme 5. Synthesis of spirochromenopyrrole annulated heterocycles 7–11.
70
lg/mL. Significantly the compounds 5, 7 and 11 showed good
antibacterial activity even at the lower concentration in the range

S. Purushothaman et al. / Bioorg. Med. Chem. Lett. 20 (2010) 7288–7291
7291
Table 1
In vitro antibacterial activity against human pathogens
Cycloadducts
MIC of +Ve bacteriaa
MIC of ÀVe bacteriaa
S. aureus
B. subtilis
S. pneumoniae
E. coli
Shigella sp.
S. typhi
4
5
6
7
8
9
10
20
5
25
5
20
65
45
5
15
5
20
5
35
70
55
5
25
10
30
15
60
55
40
10
20
10
10
15
10
25
50
65
5
25
5
10
15
25
15
55
60
60
5
30
20
45
75
70
5
11
Tetracyclin
15
10
10
15
25
a
Minimum inhibitory concentration (MIC) in lg/mL.
10. Padwa, A.; Ku, H. J. Org. Chem. 1979, 44, 255.
11. DeShong, P.; Kell, D. A.; Sidler, D. R. J. Org. Chem. 1985, 50, 2309.
12. Andersen, R. J.; Faulkner, D. J.; Cun-Heng, H.; Van Duyne, G. D.; Clardy, J. J. Am.
Chem. Soc. 1985, 107, 5492.
Table 2
In vitro antifungal activity against human pathogens
Cycloadducts
MIC of fungus pathogensa
13. Quesada, A. R.; Gravalos, M. D. G.; Puentes, J. L. F. Br. J. Cancer 1996, 74, 677.
14. Reddy, M. V. R.; Rao, M. R.; Rhodes, D.; Hansen, M. S. T.; Rubins, K.; Bushman, F.
D.; Venkateswarlu, Y.; Faulkner, D. J. J. Med. Chem. 1999, 42, 1901.
15. He, J.; Zheng, J.; Liu, J.; She, X.; Pan, X. Org. Lett. 2006, 8, 4637.
16. General procedure for synthesis of cycloadducts: The solution containing
1.0 mmol of alkenyl aldehyde (2) and 2.5 mmol of secondary amino acid was
refluxed in dry toluene for 4–6 h at 110 °C using Dean-Stark apparatus. After
completion of the reaction as indicated by TLC, toluene was evaporated under
reduced pressure. The crude product was then purified by column
chromatography using hexane/EtOAc (8:2) as eluent.
Trichoderma sp.
Aspergillus sp.
C. albicans
4
5
6
7
8
9
10
11
40
30
75
35
25
70
25
85
75
75
25
15
45
25
65
20
75
95
90
35
10
45
105
110
105
50
(a) Synthesis of hexahydrochromeno[3,4-b]pyrrole (4): Isolated yield: 70%. White
solid. Mp 128 °C. 1H NMR (300 MHz, CDCl3): d = 2.36 (t, J = 9.3 Hz, 3H); 2.46 (s,
3H); 2.68 (dt, J = 6.6, 2.1 Hz, 1Hb); 3.51 (t, J = 8.4 Hz, 1H); 3.83–3.91 (m, 1Hc);
3.92 (dd, J = 2.1, 11.1 Hz, 1Ha); 4.19–4.25 (m, 2H); 6.80–6.91 (m 3H); 7.04–7.10
(m, 1H); 7.40 (d, J = 8.4 Hz, 1H); 7.86 (d, J = 8.4, 1H). 13C NMR (75 MHz, CDCl3):
d = 39.2, 39.7, 55.2, 61.1, 64.6, 65.7, 117.7, 122.0, 127.1, 127.2, 128.7, 129.1,
130.0, 134.9, 140.1, 154.8, 198.7. ESI Mass m/z 328.33 (M++1). Anal. Calcd. for
Carbendazim
15
a
Minimum inhibitory concentration (MIC) in lg/mL.
Acknowledgments
C19H18ClNO2: C, 69.62; H, 5.53; N, 4.27. Found: C, 69.74; H, 5.62; N, 4.38.
(b) Synthesis of octahydrochromeno[4,3-b]pyrrolizine (5): Isolated yield: 74%.
White solid. Mp 152–54 °C. 1H NMR (300 MHz, CDCl3): d = 1.68–1.75 (m, 2H);
1.95–2.03 (m, 1H); 2.11–2.15 (m, 2H); 2.34–2.42 (m, 1H); 2.65–2.73 (m, 1H);
3.02–3.09 (m, 1H); 3.76–3.85 (m, 1H); 4.20–4.25 (m, 2H); 5.17 (dd, J = 3.0,
12 Hz, 1H); 6.82–6.81 (m, 2H); 7.11–7.15 (m, 2H); 7.18–7.22 (m, 2H); 7.32–
7.34 (m, 2H). 13C NMR (75 MHz, CDCl3): d = 31.9, 46.7, 50.8, 54.1, 82.1, 93.8,
97.0, 99.3, 109.9, 120.9, 124.1, 126.2, 128.2, 128.4, 132.1, 132.3, 143.7, 158.6,
198.4. ESI Mass m/z 354.27 (M++1). Anal. Calcd. for C21H20ClNO2: C, 71.28; H,
5.70; N, 3.96. Found: C, 71.42; H, 5.90; N, 3.86.
The authors S.P. and R.R. thank DST, New Delhi for assistance
under the DST-FIST program for the NMR facility. The authors wish
to thank Professor D. Velmurugan and S. Sundaramoorthy for sin-
gle crystal X-ray data. S.P. thanks CSIR New Delhi for the award
of SRF. R.P. thanks UGC New Delhi for the award of JRF.
References and notes
(c) Synthesis of spiro hexahydrochromeno[3,4-b]pyrrole (8): Yield: 72%. White
soild. Mp 162–64 °C. 1H NMR (300 MHz, CDCl3): d = 2.29 (d, J = 9 Hz, 1H); 2.40
(m, 2H); 2.45 (s, 3H); 2.69–2.76 (m, 1H); 2.98–3.09 (m, 2H); 3.21 (d, J = 9 Hz,
1H); 3.85 (dd, J = 12, 3.6 Hz, 1H); 4.05 (dd, J = 12,3.6 Hz, 1H); 4.75 (d,
J = 10.5 Hz,1H); 6.75–6.76 (m, 1H); 6.79–6.83 (m, 2H); 6.88–6.92 (m, 1H);
7.04–7.10 (m, 1H); 7.15–7.31 (m, 1H); 7.33–7.48 (m,1H); 8.08 (d, J = 7.8 Hz,
1H). 13C NMR (75 MHz, CDCl3): 26.0, 27.5, 40.5, 41.8, 57.2, 61.4, 65.4, 68.2,
117.4, 121.8, 124.7, 126.5, 127.2, 128.0, 129.7, 132.5, 133.6, 143.6, 157.3, 199.3.
ESI Mass m/z 320.20 (M+ +1). Anal. Calcd. for C21H21NO2: C, 78.97; H, 6.63; N,
4.39. Found: C, 79.07; H, 6.72; N, 4.41.
(d) Synthesis of spiro octahydrochromeno[4,3-b]pyrrolizine (9): Yield: 74%. White
solid. Mp 170–72 °C. 1H NMR (300 MHz, CDCl3): d = 1.42–1.62 (m, 2H); 1.79–
1.93 (m, 3H); 2.03–2.14 (m, 3H); 2.19–2.26 (m, 1H); 2.83–2.89 (m, 1H); 3.01–
3.07 (m, 1H); 3.16–3.18 (m, 1H); 4.04 (dd, J = 10.2, 7.5 Hz, 1H); 5.05 (d,
J = 7.5 Hz, 1H); 5.09 (dd, J = 10.2,7.5 Hz, 1H); 6.58 (d, J = 8.1 Hz, 1H); 6.79 (t,
J = 7.1 Hz, 1H); 6.84–6.81 (m, 1H); 7.00–7.15 (m, 4H); 7.48 (d, J = 7.8 Hz, 1H).
13C NMR (75 MHz, CDCl3): d = 24.4, 27.2, 29.7, 31.5, 46.8, 50.0, 55.0, 82.0, 95.9,
97.6, 109.4, 120.5, 125.8, 126.2, 126.5, 126.9, 127.7, 128.5, 129.3, 138.2, 139.1,
160.0, 198.5. ESI Mass m/z 346.22 (M++1). Anal. Calcd. for C23H23NO2: C, 79.97;
H, 6.71; N, 4.05. Found: C, 80.12; H, 6.91; N, 4.02.
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17. The detailed X-ray crystallographic data for 4 (CCDC numbers: 752538) is
available from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK.
18. The detailed X-ray crystallographic data for 10 (CCDC numbers: 770455) is
available from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK.
19. Parekh, J.; Chanda, V. S. Turk. J. Biol. 2007, 31, 53.
20. Eloff, J. N. Planta Med. 1998, 64, 711.