Synthesis of naphtho[2,1-b[pyrano pyrrolothiazole derivatives through 1,3-cycloaddition reaction

Article abstract of DOI:10.1080/00397911.2011.575523

Facile synthesis of a series of naphtho[2,1,b]pyrano pyrrolo thiazoles was accomplished in good yields in a one-pot reaction through intramolecular 1,3-dipolar cycloaddition of cyclic azomethine ylides with Baylis-Hillman adducts as dipolarophiles. The protocol is applicable to a wide variety of photochromic and biologically active napthopyrano products. The regio-and stereochemical outcome of the cycloaddition reaction was ascertained by X-ray crystallographic study of one of the cycloadducts.

Full text of DOI:10.1080/00397911.2011.575523

Synthetic Communications1, 42: 3068–3076, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.575523
SYNTHESIS OF NAPHTHO[2,1-b]PYRANO
PYRROLOTHIAZOLE DERIVATIVES THROUGH
1,3-CYCLOADDITION REACTION
Subban Kathiravan and Raghavachary Raghunathan
Department of Organic Chemistry, University of Madras, Guindy Campus,
Chennai, India
GRAPHICAL ABSTRACT
Abstract Facile synthesis of a series of naphtho[2,1,b]pyrano pyrrolo thiazoles was
accomplished in good yields in a one-pot reaction through intramolecular 1,3-dipolar
cycloaddition of cyclic azomethine ylides with Baylis–Hillman adducts as dipolarophiles.
The protocol is applicable to a wide variety of photochromic and biologically active naptho-
pyrano products. The regio- and stereochemical outcome of the cycloaddition reaction was
ascertained by x-ray crystallographic study of one of the cycloadducts.
Keywords Azomethine ylides; Baylis–Hillman adduct; 1,3-dipolar cycloaddition;
pyrrolothiazoles
INTRODUCTION
The 3H-naphtho[2,1-b]pyran and 3H-naphtho[2,1-b]pyran-7,10-dione ring
systems form the core unit in a number of natural products.[1] Natural products
containing the 3H-naphtho [2,1-b]pyran-7,10-dione, conocurvone (Fig. 1) is a unique
natural product in that it contains three naphthopyrandione units, which are respon-
sible for its remarkable anti-HIV activity.[1a] 3H-Naphtho[2,1-b]pyrans are also
known to exhibit photochromic properties and have wide applications in the
manufacture of ophthalmic lenses, contact lenses, solar protection glasses, filters,
camera optics, transmission devices, agrochem films, glazing decorative objects,
and information storage by optical inscription.[2]
Received January 31, 2011.
Address correspondence to Raghavachary Raghunathan, Department of Organic Chemistry,
University of Madras, Guindy Campus, Chennai 600 025, India. E-mail: ragharaghunathan@yahoo.com
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NAPHTHOPYRANO PYRROLOTHIAZOLE
3069
Figure 1. Biologically active napthopyran natural product.
The family of pyrrolizidine alkaloids continues to provide novel structures with
interesting and potentially valuable biological properties.[3] Pyrrolizidine alkaloids
are known to cause severely toxic effects, primarily to the hepatic system, and are
thought to be the chemical basis of a natural defense mechanism developed by plants
against animal attacks.[4] Pyrrolizidine alkaloids are powerful glucosidase inhibitors.
In addition they also possess antitumor,[5] antispasmolytic,[6] antiviral,[7] and
anti-HIV activity.[8] Pyrrolo[2,1-b]thiazole is an unusual ring system with biological
activity.[9,10] They are involved in neurotransmission in the central nervous system[11]
and are considered as c-lactam analogs of the penems.[12]
Intramolecular [3 þ 2] cycloaddition of azomethine ylide has been widely used
to construct complex cyclic systems from relatively simple precursors. This mode of
cycloaddition simultaneously constructs two carbon–carbon bonds and forms ring
systems with regio- and stereocontrol.[13]
a-Methylene-b-hydroxy esters are easily accessible by Baylis–Hillman reac-
tion,[14] and are well utilized as versatile building blocks for the stereoselective con-
struction of natural products including alkaloids,[15] macrolides,[16] terpenoids,[17]
and haromones.[18]
As part of our ongoing program for the synthesis of novel heterocycles through
cycloaddition reactions,[19] herein we report an expeditious synthesis of napthopyr-
ano pyrrolizidines and indolizidines by intramolecular 1,3-dipolar cycloaddition of
azomethine ylides generated from naphtho-O-alkenyl aldehydes prepared from
Baylis–Hillman adducts in a one-pot reaction.
RESULTS AND DISCUSSION
The required Baylis–Hillman adducts 3a–g were prepared by the direct alkyl-
ation of the hydroxynapthaldehyde 1 with Baylis–Hillman bromides 2a–g in the
presence of K2CO3 and dry acetone (94%) in 3 h (Scheme 1).

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S. KATHIRAVAN AND R. RAGHUNATHAN
Scheme 1. Synthesis of O-alkenyl aldehydes.
The aldehydes 3a–g derived from Baylis–Hillman bromides were condensed
with L-thiaproline 4 to generate azomethine ylides in refluxing toluene under
Dean–Stark conditions. The 1,3-dipole generated underwent intramolecular cyclo-
addition to give naphthopyrano thiapyrrolizidines 5a–g in good yields (Scheme 2,
Table 1, entries 1–7).
The products obtained were thoroughly characterized by spectroscopic data.[16]
For instance, the product 5b showed strong absorption bands at 1708 cmꢀ1 in the
1
infrared (IR) spectrum, characteristic of the carbonyl group. In the H NMR spec-
trum of the compound, the thiapyrrolizine methylene group showed a multiplet in
the regions d 2.97–3.06 and 3.20–3.26. The methyl protons of the ester group showed
a sharp singlet at d 3.50. The benzylic proton resonated as a singlet at d 5.04. The
-OCH2 protons showed two doublets at d 4.40 (d, J ¼ 11.1 Hz, 1H) and 4.48 (d,
J ¼ 10.8 Hz, 1H). The aromatic ring protons appeared as multiplets in the region d
6.95–7.68. The 13C NMR spectrum of the compound showed a peak at 170.9 ppm,
which confirmed the presence of an ester carbonyl group. Finally, the structure of
5b was confirmed by mass spectrometry, which showed a peak at m=z 416 [Mþ].
Further, x-ray structure[20] of 5b confirmed the trans stereochemistry at the ring
junction (Fig. 2).
The structures of all the cycloadducts were confirmed by the spectroscopic
data. The reactions were found to be highly regioselective, leading to the formation
of only one product in which ring junction protons were found to be trans. The
products were formed with good yield irrespective of the nature of the substituent
present in the phenyl ring (Table 1).
Scheme 2. Synthesis of naptho pyrano pyrrolizidine.

NAPHTHOPYRANO PYRROLOTHIAZOLE
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Table 1. Synthesis of naphtho[2,1-b]pyrano thiapyrrolizidine derivatives
Time
(h)
Yieldb
(%)
Entry
Substrate
Producta
1
12
80
2
12
72
3
13
68
4
12
65
5
14
70
aIsolated products were characterized by 1H NMR, 13C NMR, and mass spectral analysis.
bYields refers to pure isolated products after purification by silica-gel column chromatography.

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S. KATHIRAVAN AND R. RAGHUNATHAN
Figure 2. ORTEP diagram of pyrrolo[1,2-c]thiazole 5b. (Figure is provided in color online.)
CONCLUSION
In conclusion, we have developed a new method for the synthesis of a variety of
naphthopyrano indolizidines and pyrrolizidines by intramolecular 1,3-dipolar
cycloaddition using the Baylis–Hillman adducts as internal dipolarophiles.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded on a Shimadzu
Fourier transform (FT)–IR 8300 instrument. Mass spectra were recorded on a Jeol
DX 303 HF spectrometer with Maspec System (msw=9629). 1H and 13C NMR were
recorded in CDCl3 using tetramethylsilane (TMS) as internal standard on a Bruker
spectrometer at 300 and 75 MHz, respectively. Elemental analyses were carried out
on a Perkin-Elmer 2400 B instrument.
Representative Experimental Procedure for the Synthesis of
Cycloadducts (5a–e)
A solution of 3a (1 mmol) and L-thiaproline 4 (1.5 mmol) was heated under
reflux in toluene in a Dean–Stark apparatus. After completion of the reaction as evi-
denced by thin-layer chromatography (TLC), the solvent was removed under
reduced pressure. The crude product was purified by short column chromatography
on silica gel (hexane–ethyl acetate, 95:5) to provide the product in good yield.

NAPHTHOPYRANO PYRROLOTHIAZOLE
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Methyl-6,6a,7,7a8,9,10,11a-octahydro-7-phenylnaphtho[2,1-b]-
pyrano Thiapyrrolizine-6a-carboxylate (5a)
Time 12 h, Rf 0.8 (hexane–ethylacetate 3:1), white powder, yield 81%, mp
94–96 ꢁC. 1H NMR (300 MHz, CDCl3): d 1.41–1.50 (m, 3H), 2.41 (m, 1H),
2.86–2.94 (m, 2H), 3.61 (s, 3H), 3.78 (d, J ¼ 9.0 Hz, 1H), 3.89 (d, J ¼ 10.8 Hz, 1H),
4.49 (d, J ¼ 12.0 Hz, 1H), 4.60 (s, 1H), 7.07–8.20 (m, 11H); 13C NMR (75 MHz,
CDCl3): d 24.69, 25.66, 28.84, 52.37, 53.15, 53.43, 55.59, 60.44, 66.27, 68.41,
113.73, 118.99, 122.52, 123.24, 126.16, 127.23, 127.72, 128.61, 129.25, 129.58,
131.68, 134.20, 136.07, 154.13, 174.43. Mass spectrum m=z: 416 (Mþ). CHN analysis
calculated for C25H23NO3S : C, 79.14; H, 5.27; N, 3.35%. Found: C, 79.25; H, 5.30;
N, 3.42%.
Methyl-6,6a,7,7a8,9,10,11a-octahydro-7-(4-chlorophenyl)-naphtho-
[2,1-b]pyrano Thiapyrrolizine-6a-carboxylate (5b)
Time 12 h, Rf 0.6 (hexane–ethylacetate 3:2), light yellow powder, yield 76%, mp
1
147–148 ꢁC. H NMR (300 MHz, CDCl3): d 2.97–3.06 (m, 1H), 3.20–3.26 (m, 1H),
3.50 (s, 3H), 3.69 (d, J ¼ 5.4 Hz, 1H), 3.86–3.93 (m, 1H), 3.96 (d, J ¼ 4.5 Hz,
1H), 4.02 (s, 1H), 4.40 (d, J ¼ 11.1 Hz, 1H), 4.48 (d, J ¼ 10.8 Hz, 1H), 5.04 (s, 1H),
6.95–7.68 (m, 10H). 13C NMR (75 MHz, CDCl3): d 38.64, 51.47, 51.55, 54.69,
55.62, 57.09, 63.89, 70.81, 110.41, 117.66, 120.84, 122.42, 126.01, 127.72, 127.86,
128.13, 128.91, 129.19, 132.72, 132.82, 133.18, 151.42, 170.87. Mass spectrum m=z:
451 (Mþ). CHN analysis calculated for C25H22NO3SCl: C, 66.51; H, 4.87; N,
3.10%. Found: C, 66.65; H, 4.80; N, 3.23%.
Methyl-6,6a,7,7a8,9,10,11a-octahydro-7-(4-methylphenyl)-naphtho-
[2,1-b]pyrano Thiapyrrolizine-6a-carboxylate (5c)
Time 12 h, Rf 0.6 (hexane–ethylacetate 3:2), light yellow powder, yield 85%, mp
1
143–144 ꢁC. H NMR (300 MHz, CDCl3); d 2.59–2.64 (m, 1H), 2.79–2.85 (m, 1H),
3.48 (s, 3H), 4.16 (s, 2H), 4.22 (d, J ¼ 11.1 hz, 1H), 4.79 (d, J ¼ 10.8 Hz, 1H), 5.19
(s, 1H), 6.99–8.23 (m, 10 H); 13C NMR (75 MHz, CDCl3): d 35.83, 39.89, 52.50,
53.79, 55.24, 55.29, 55.68, 55.84, 56.12, 61.30, 65.49, 70.56, 71.94, 109.96, 114.09,
118.81, 123.44, 123.85, 127.07, 127.36, 127.46, 128.57, 128.80, 129.28, 129.67,
130.25, 131.42, 133.60, 153.14, 158.98, 173.75. Mass spectrum m=z: 431 (Mþ).
CHN analysis calculated for C26H25NO3S: C, 72.38; H, 5.80; N, 3.24%. Found: C,
72.45; H, 5.75; N, 3.32%.
Methyl-6,6a,7,7a8,9,10,11a-octahydro-7-(4-methoxyphenyl)naphtho-
[2,1-b]pyrano Thiapyrrolizine-6a-carboxylate (5d)
Time 12 h, Rf 0.6 (hexane–ethylacetate 3:2), light yellow powder, yield 85%, mp
146–148 ꢁC. 1H NMR (300 MHz, CDCl3): d 1.33 (s, 3H), 1.37–1.47 (m, 1H),
1.99–2.32 (m, 2H), 3.23–3.92 (m, 4H), 3.45 (s, 3H), 4.25 (s, 2H), 4.20 (d, J ¼ 11.1 Hz,
1H), 4.77 (d, J ¼ 10.8 Hz, 1H), 5.24 (s, 1H), 6.81–7.96 (m, 10 H); 13C NMR (75 MHz,
CDCl3): d 37.56, 51.47, 51.55, 54.69, 55.62, 57.09, 63.89, 70.81, 110.41, 117.66,

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S. KATHIRAVAN AND R. RAGHUNATHAN
120.84, 122.42, 126.01, 127.72, 127.86, 128.13, 128.91, 129.19, 132.72, 132.82, 133.18,
151.42, 170.87. Mass spectrum m=z: 447 (Mþ). CHN analysis calculated for
C26H25NO4S: C, 69.79; H, 5.59; N, 3.13%. Found: C, 69.89; H, 5.55; N, 3.21%.
Methyl-6,6a,7,7a8,9,10,11a-octahydro-7-(2-chlorophenyl)-naphtho-
[2,1-b]pyrano Thiapyrrolizine-6a-carboxylate (5e)
Time 12 h, Rf 0.6 (hexane–ethylacetate 3:2), light yellow powder, yield 85%, mp
144–145 ꢁC. 1H NMR (300 MHz, CDCl3): d 1H NMR (300 MHz, CDCl3): d
2.74–2.79 (m, 1H), 2.95–3.01 (m, 1H), 3.07–3.16 (m, 1H), 3.29–3.53 (m, 1H), 3.60
(s, 3H), 3.78–3.80 (m, 1H), 3.97–4.12 (m, 1H), 4.49 (d, J ¼ 11.1 Hz, 1H), 4.62 (d,
J ¼ 11.1 Hz, 1H), 5.13 (s, 1H), 7.04–8.32 (m, 10H); 13C NMR (75 MHz, CDCl3): d
38.4, 51.7, 51.9, 55.7, 55.9, 57.8, 63.8, 70.6, 110.6, 117.8, 120.3, 122.1, 126.0, 127.4,
128.2, 129.0, 132.7, 132.34, 132.9, 133.4, 156.7, 174.3. Mass spectrum m=z: 451
(Mþ). CHN analysis calculated. for C25H22NO3SCl: C, 66.51; H, 4.87; N, 3.10%.
Found: C, 66.60; H, 4.81; N, 3.21%.
ACKNOWLEDGMENTS
S.K. thanks the Council of Scientific and Industrial Research for the award of a
senior research fellowship. R.R. thanks the Department of Science and Technology–
Funding for Infrastructure in Science and Technology, New Delhi, for NMR facility
and financial assistance.
REFERENCES
1. (a) Decosterd, L. A.; Parsons, I. C.; Gustafson, K. R.; Cardellina II, J. H.; McMahon,
J. B.; Cragg, G. M.; Murata, Y.; Pannell, L. K.; Steiner, J. R.; Clardy, J.; Boyd, M. R.
HIV inhibitory natural products, 11: Structure, absolute stereochemistry, and synthesis
of conocurvone, a potent, novel HIV-inhibitory naphthoquinone trimer from a Conosper-
mum sp. J. Am. Chem. Soc. 1993, 115, 6673–6679; (b) Bukuru, J. F.; Van, T. N.; Puyvelde,
L. V.; Mathenge, S. G.; Mudida, F. P.; Kimpe, N. D. A benzochromene from the roots of
Pentas bussei. J. Nat. Prod. 2002, 65, 783–785.
2. Gemert, B. V. Benzo and naphthopyrans (chromenes); In Organic Photochromic and
Thermochromic Compounds; J. C. Crano, R. Guglielmetti (Eds.); Plenum Press:
New York, 1999; vol. 1, chapter 3.
3. Roeder, E. Medicinal plants in Europe containing pyrrolizidine alkaloids. Pharmazie
1995, 50, 83–98.
4. Hartmann, T.; Witte, L.; Ehmke, A.; Theuring, C.; Rowell-Rahier, M.; Pasteels, J. M.
Selective sequestration and metabolism of plant-derived pyrrolizidine alkaloids by
chrysomelid leaf beetles. Phytochemistry 1997, 45, 489–497.
5. (a) Hartmann, T.; Witte, L. In Alkaloids: Chemical and Biological Perspectives; S. W.
Pelletier (Ed.); Pergamon Press: New York, 1995; chapter 4, pp. 155–233; (b) Mattocks,
A. R. Chemistry and Toxicology of Pyrrolizidine Alkaloids; Academic Press: London,
1986; (c) Pereda-Miranda, R. In Phytochemistry of Medicinal Plants; J. T. Arnason, R.
Mata, J. T. Romeo (Eds.); Plennum Press: New York, 1995; chapter 5, pp. 103–108.
6. (a) Gallos, J. K.; Sarli, V. C.; Koftis, T. V.; Coutouli-Argyropoulou, E. A new entry to
hydroxylated pyrrolizidines. Tetrahedron Lett. 2000, 41, 4819; (d) Denmark, S. E.; Hurd,

NAPHTHOPYRANO PYRROLOTHIAZOLE
3075
A. R. Nickel-mediated amination chemistry, part 1: Efficient aminations of (het)aryl
1,3-di- and 1,3,5-trichlorides. J. Org. Chem. 2000, 65, 2875–2879; (e) De Vicente, J.;
Arrayas, R. G.; Carretero, J. C. An efficient and stereoselective synthesis of enantiopure
1,2,7-trihydroxylated pyrrolizidines. Tetrahedron Lett. 1999, 40, 6083–6086; (b) Paolucci,
C.; Venturelli, F.; Fava, A. Chiral building blocks from 1,4:3,6-dianhydrohexitols, III: An
expeditious enantiospecific synthesis of the Geissman–Waiss lactone. Tetrahedron Lett.
1995, 36, 8127–8129.
7. Tang, M.; Pyne, S. G. Asymmetric synthesis of (ꢀ)-7-epiaustraline and (þ)-1,7-
diepiaustraline. J. Org. Chem. 2003, 68, 7818–7824.
8. Romero, A.; Wong, C. H. Chemo-enzymatic total synthesis of 3-epiaustraline, australine,
and 7-epialexine. J. Org. Chem. 2000, 65, 8264–8268.
9. Lalezari, I.; Schwartz, E. L. Synthesis and antineoplastic activity of 5-aryl-2,3-
dihydropyrrolo[2,1-b]thiazole-6,7-dimethanol 6,7-bis(isopropylcarbamates). J. Med. Chem.
1988, 31, 1427–1429.
10. Aicher, T. D.; Balkan, B.; Bell, P. A.; Brand, L. J.; Cheon, S. H.; Deems, R. O.; Fell, J. B.;
Fillers, W. S.; Fraser, J. D.; Gao, J.; Knorr, D. C.; Kahle, G. G.; Leone, C. L.; Nadelson,
J.; Simpson, R.; Smith, H. C. Substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and
tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones as hypoglycemic agents. J. Med. Chem. 1998,
41, 4556–4566.
11. Tverdokhlebov, A. V.; Resnyanska, E. V.; Tolmachev, A. A.; Andrushko, A. P. A novel
approach to pyrrolo[2,1-b]thiazoles. Synthesis 2003, 2632.
12. (a) Baldwin, J. E.; Lowe, C.; Schofield, C. J.; Lee, E. A c-lactam analogue of penems pos-
sessing antibacterial activity. Tetrahedron Lett. 1986, 27, 3461–3464; (b) Boyd, D. B.;
Elzey, T. K.; Hatfield, L. D.; Kinnick, M. D.; Morin Jr., J. M. c-Lactam analogues of
the penems. Tetrahedron Lett. 1986, 27, 3453–3456
13. (a) Coldham, I.; Hufton, R. Intramolecular dipolar cycloaddition reactions of azomethine
ylides. Chem. Rev. 2005, 105, 2765–2810; (b) Pandey, G.; Banerjee, P.; Gadre, S. R. Con-
struction of enantiopure pyrrolidine ring system via asymmetric [3 þ 2]-cycloaddition of
azomethine ylides. Chem. Rev. 2006, 106, 4484–4517; (c) Vedejs, E.; Klapers, A.; Naidu,
B. N.; Piotrowski, D. W.; Tucci, F. C. Enantiocontrolled synthesis of (1S,2S)-6-
desmethyl-(methylaziridino)mitosene. J. Am. Chem. Soc. 2000, 122, 5401–5404.
14. Basaviah, D.; Rao, A. J.; Satyanarayana, T. Recent advances in the Baylis–Hillman
reaction and applications. Chem. Rev. 2003, 103, 811–891; (b) Ciganek, E. In Organic
Reactions; Wiley: New York, 1997; Vol. 51, p. 201–350.
15. Coelho, F.; Diaz, G.; Abella, C. A. M.; Almeida, W. P. The Baylis–Hillman reaction with
chiral a-amino aldehydes under racemization-free conditions. Synlett. 2006, 435–439.
16. Roush, W. R.; Brown, B. B. A highly diastereo- and enantioselective synthesis of the top
half of kijanolide. J. Org. Chem. 1993, 58, 2151–2161.
17. Jenn, T.; Heissler, D. Synthesis of tricyclopolyprenols via a radical addition and a stereo-
selective elimination, part I: Methodology. Tetrahedron 1998, 54, 97–106; (b) Grassi, D.;
Lippuner, V.; Aebi, M.; Brunnerm, J.; Vasella, A. Synthesis and enzymatic phosphoryla-
tion of a photoactivatable dolichol analogue. J. Am. Chem. Soc. 1997, 119, 10992–10999.
18. (a) Mateus, C. R.; Feltrin, M. P.; Costa, A. M.; Coelho, F.; Almeida, W. P. Diastereo-
selectivity in heterogeneous catalytic hydrogenation of Baylis–Hillman adducts: Total syn-
thesis of (ꢂ)-sitophilate. Tetrahedron 2001, 57, 6901–6908; (b) Basavaiah, D.; Hyma, R. S.
Synthetic applications of the baylis-hillman reaction: Simple synthesis of [2E]-2-
butyloct-2-enal and [2E]-2-tridecylheptadec-2-enal. Tetrahedron 1996, 52, 1253–1258.
19. (a) Kathiravan, S.; Raghunathan, R. Synthesis of macrocyclic bis-imidazolidine deriva-
tives through [3 þ 2]cycloaddition reaction. Synlett. 2009, 1126–1129; (b) Suresh Babu,
A. R.; Raghunathan, R.; Satiskumar, B. K. A facile synthesis of ferrocene grafted
N-methyl-spiropyrrolidines through 1,3-dipolar cycloaddition of azomethine ylides.

3076
S. KATHIRAVAN AND R. RAGHUNATHAN
Tetrahedron Lett. 2009, 50, 2818–2821; (c) Poornachandran, M.; Raghunathan, R. Tetra-
hedron 2008, 64, 6461–6474; (d) Poornachandran, M.; Raghunathan, R. Tetrahedron:
Asymmetry 2008, 19, 2177–2183.
20. Selvanayagam, S.; Sridhar, B.; Ravikumar, K.; Kathiravan, S.; Raghunathan, R. Methyl-
6,6a,7,7a8,9,10,11a-octahydro-7-(2-chlorophenyl)naphtho[2,1-b]pyrano thiapyrrolizine-
6a-carboxylate. Acta Cryst. 2010, E66, o2098.

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