An easy access to novel steroidal dispiropyrrolidines through 1,3-dipolar cycloaddition of azomethine ylides

Article abstract of DOI:10.1016/j.tetlet.2008.05.089

A facile one-pot synthesis of novel steroidal dispiropyrrolidines has been accomplished by 1,3-dipolar cycloaddition reaction of various azomethine ylides derived from isatin/acenaphthenequinone/ninhydrin and sarcosine with various estrone derivatives as dipolarophiles, in good yield. The effect of various solvents on the 1,3-dipolar cycloaddition reaction are also studied.

Full text of DOI:10.1016/j.tetlet.2008.05.089

Tetrahedron Letters 49 (2008) 4618–4620
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An easy access to novel steroidal dispiropyrrolidines through 1,3-dipolar
cycloaddition of azomethine ylides
*
A. R. Suresh Babu, R. Raghunathan
Department of 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:
A facile one-pot synthesis of novel steroidal dispiropyrrolidines has been accomplished by 1,3-dipolar
cycloaddition reaction of various azomethine ylides derived from isatin/acenaphthenequinone/ninhydrin
and sarcosine with various estrone derivatives as dipolarophiles, in good yield. The effect of various
solvents on the 1,3-dipolar cycloaddition reaction are also studied.
Received 18 March 2008
Revised 13 May 2008
Accepted 19 May 2008
Available online 23 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Cycloaddition
Azomethine ylide
Dispiroheterocycles
Steroidal pyrrolidines
The formation of active steroids by aromatase enzymes has
been considered to play an important role in the development of
human breast carcinoma.1,2 It has been documented that increased
aromatase activity in the breast cancer tissue is greater compared
to the non-malingnant parenchyma.3–5 The enzyme is the rational
target for the development of drugs to treat hormonal-dependent
breast cancer.6–9 In recent years, clinical research on aromatase
inhibitors has increased significantly and several oral aromatase
inhibitors have been demonstrated to be highly potent and specific
inhibitors of estrogen synthesis.10–12 Our efforts were focused on
designing estrogen derivatives that might inhibit or that may pos-
sess antiestrogenic activity.
the reaction of (Z)-16-arylidene estrone derivatives37 1a–d as 2
p
components in 1,3-dipolar cycloaddition reactions with various
azomethine ylides for the facile synthesis of hitherto unknown
steroidal pyrrolidines. Thus the dipoles generated from sarcosine
2 and various 1,2-diketones, namely (a) isatin 3, (b) acenaphthen-
equinone 6 and (c) ninhydrin 9 were reacted with the steroidal
dipolarophiles 1a–d to afford a series of novel dispirosteroidal pyr-
rolidines 4a–d, 7a–d and 10a–d. The structures of the cycloadducts
were confirmed through spectral and elemental analysis.38 The
reactions were carried out using three different sets of conditions
and the results are shown in Table 1.
The intermolecular [3+2]-cycloaddition reaction of azomethine
ylides with various alkenes and alkynes represents an efficient and
convergent method for the construction of pyrrolidine and pyrro-
lizidine units.13–15 Functionalised pyrrolidine alkaloids constitute
classes of compounds with significant biological activities.16,17
Spiro compounds represent an important class of naturally occur-
ring substances characterised by highly pronounced biological
properties.18–26 Oxindole derivatives are found to be potent aldose
reductase inhibitors (ARIs), which help to treat and prevent
diabetic complications arising from elevated levels of sorbitol.27
Spirooxindoles have been reported to behave as poliovirus and
rhinovirus 3C-proteinase inhibitors.28
Table 1
Effect of solvent on the cycloaddition reactions
Entry
R1
R2
R3
Method A
T (h) Y (%)
Method B
T (h) Y (%)
Method C
T (h) Y (%)
4a
4b
4c
4d
7a
7b
7c
7d
10a
10b
10c
10d
H
H
H
OMe
H
H
H
OMe
H
H
H
Cl
Me
OMe
H
H
H
H
OMe
H
H
H
OMe
H
H
8.1
8.4
8.6
8.8
8.2
7.8
8.8
8.9
8.2
8.6
8.4
8.7
39
43
36
33
40
36
38
35
38
35
34
32
5.6
6.0
6.8
7.0
5.5
6.8
5.8
5.7
6.0
6.5
6.7
6.9
63
62
60
61
65
64
62
60
62
61
63
63
6.0
5.8
7.0
7.3
5.2
6.6
6.0
5.9
5.8
6.3
6.5
6.4
70
68
67
68
70
72
68
66
70
69
70
68
Cl
Me
OMe
H
Cl
Me
OMe
In continuation of our studies in the area of cycloaddition reac-
tions29–36 and with a view to synthesise a rare class of novel
dispiroheterocyclic derivatives, we herein report for the first time,
H
OMe
H
OMe
T (h): time in hours; Y (%): yield in %; Method A: toluene/reflux; Method B: ace-
* Corresponding author. Tel.: +91-44-22202811.
tonitrile/reflux; Method C: methanol/reflux.
E-mail address: ragharaghunathan@yahoo.com (R. Raghunathan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.089

A. R. Suresh Babu, R. Raghunathan / Tetrahedron Letters 49 (2008) 4618–4620
4619
Schemes 1–3 suggest one-pot three component reactions
involving sarcosine and isatin/acenaphthenequinone/ninhydrin
with various p-substituted (Z)-16-arylidene estrones for the
synthesis of novel dispirosteroidal pyrrolidines 4a–d, 7a–d and
10a–d.
pyrrolidine –NCH3 carbon resonated at d 14.92 and d 25.30 ppm.
The amide and cyclopentanone carbonyl carbons resonated at d
178.79 and d 221.72, respectively. The structure of the product
4a was further confirmed through mass spectroscopy, which
showed a molecular ion peak at 532.6 (M+) (Scheme 1).
The IR spectrum of the steroidal dispirooxindolopyrrolidine 4a
showed peaks at 1616.9 cmꢀ1 and 1702.6 cmꢀ1 due to the oxindole
and cyclopentanone ring carbonyl groups. The 1H NMR spectrum of
4a exhibited singlets at d 0.50 and d 2.20 for the C-18 methyl of the
estrone and –NCH3 protons of the pyrrolidine moiety. The Hb and
Hc protons of the pyrrolidine moiety resonated as two triplets at
d 3.55 (J = 8.0 Hz) and d 3.96 (J = 9.2 Hz). The benzylic proton Ha
occurred as a triplet at d 4.03 (J = 8.5 Hz), which proved the regio-
chemistry of the cycloaddition reaction. If the other regioisomer 5a
had been formed, proton Ha would have appeared as a singlet in
the 1H NMR spectrum. On decoupling the –NCH2 proton at d
3.55, Hb and Ha protons appeared as two doublets at d 3.98
(J = 8.8 Hz) and d 4.06 (J = 8.8 Hz). The –NH proton of the oxindole
moiety appeared as a singlet at d 8.01. The 13C NMR spectrum of 4a
showed two peaks at d 68.18 and d 78.33 ppm due to the two-spiro
carbons. The C-18 methyl carbon of the estrone moiety and the
The IR spectrum of the steroidal dispiro-acenaphthenenopyr-
rolidine 7d showed peaks at 1705.6 cmꢀ1 and 1735 cmꢀ1 due to
cyclopentanone and acenaphthenenone carbonyl group. The 1H
NMR spectrum of 7d exhibited singlets at d 0.56 and d 2.19 for
the C-18 methyl of the estrone and –NCH3 protons of the pyrrol-
idine moiety. The Hb and Hc protons of the pyrrolidine moiety res-
onated as two triplets at d 3.68 (t, 1H, J = 8.0 Hz) and d 4.01 (t, 1H,
J = 8.5 Hz). The benzylic proton Ha occurred as a triplet at d 4.09 (t,
1H, J = 9.2 Hz). The 13C NMR spectrum of 7d showed two peaks at d
69.09 and d 80.06 ppm due to the two-spiro carbons. The C-18
methyl carbon of the estrone moiety and the pyrrolidine –NCH3
carbon resonated at d 14.85 and d 25.05 ppm. The acenaphthene-
none and cyclopentanone carbonyl carbons resonated at d 209.24
and 222.33 ppm. The structure of the product 7d was further
confirmed through mass spectroscopy of 7d, which showed a
molecular ion peak at 657.8 (M+) (Scheme 2).
The IR spectrum of steroidal dispiroindanedione-pyrrolidine
10d showed peaks at 1704.5 cmꢀ1and 1732 cmꢀ1 due to the cyclo-
pentanone and indanedione carbonyl groups. The 1H NMR spec-
trum of 10d showed singlets at d 0.16 and d 2.19 for the C-18
R1 R2
R3
O
O
O
N
H
R1 R2
CH3NHCH2COOH
H
R3
HO
HO
O
O
3
2
1a-d
OH
various
conditions
CH3NHCH2COOH
H
OH
HO
O
2
9
1a-d
R1
R2 HO
R3
various
conditions
R1
R2
R3
O
O
Ha
Hb
Hc
CH3
R1
R2
R3
HO
R1
N
R2
R3
N
O
HO
O
N
H3C
N
H
4a-d
O
O
H
Ha
Hb
Hc
CH3
5a-d
O
O
N
N
O
Scheme 1.
H3C
O
10a-d
11a-d
R1 R2
Scheme 3.
O
O
R3
CH3NHCH2COOH
O
H
CH3
N
HO
6
2
1a-d
various
conditions
HN
O
O
R1
R2
R3
HO
R1
Ph
R2
R3
HO
O
O
H
Ha
Hb
Hc
CH3
N
N
O
N
H3C
O
HO
CH3
HN
7a-d
O
8a-d
Scheme 2.
Figure 1. Mode of approach of the azomethine ylide.

4620
A. R. Suresh Babu, R. Raghunathan / Tetrahedron Letters 49 (2008) 4618–4620
14. Tsuge, O.; Kanemasa, S.. In Advances in Heterocyclic Chemistry; Katritzky, A. R.,
Ed.; Academic Press: San Diego, 1989; Vol. 45, p 231.
15. Grigg, R.; Sridharan, V.. In Advances in Cycloaddition; Curran, D. P., Ed.; Jai Press:
London, 1993; Vol. 3, p 161.
16. Monlineux, R. J. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S.
W., Ed.; Wiley: New York, 1987; Chapter 1.
17. Fujimori, S. Jpn. Patent Appl. 88-2912.; . Chem. Abstr. 1990, 112, 98409.
18. Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410.
19. Howe, R. K.; Shelton, B. R. J. Org. Chem. 1990, 55, 4603.
20. De Amici, M.; De Michelli, C.; Sani, V. M. Tetrahedron 1990, 46, 1975.
21. Cohen, V. L.; Kleinmann, E. E., PCT. Int. Appl. W.O. 1995, 24, 398.
22. Caroll, W. A.; Grieco, P. A. J. Am. Chem. Soc. 1993, 115, 1164.
23. Early, W. G.; Oh, T.; Overman, L. E. Tetrahedron Lett. 1988, 29, 3785.
24. Ban, Y.; Taga, N.; Oishi, T. Chem. Pharm. Bull. 1976, 24, 736.
25. Ban, Y.; Seto, M.; Oishi, T. Chem. Pharm. Bull. 1975, 23, 2605.
26. Ban, Y.; Taga, N.; Oishi, T. Tetrahedron Lett. 1974, 2, 187.
27. Kabat, H. J. Pharmacol. 1994, 80, 160.
28. Rajeswaran, W. G.; Labroo, R. B.; Cohen, E. A. J. Org. Chem. 1999, 64, 1369.
29. Jayashankaran, J.; Rathnadurga, R.; Venketesan, R.; Raghunathan, R.
Tetrahedron 2005, 61, 5595.
30. Arumugam, N.; Jayashankaran, J.; Rathnadurga, R.; Raghunathan, R.
Tetrahedron 2005, 61, 8512.
31. Poornachandran, M.; Raghunathan, R. Tetrahedron 2005, 46, 7197.
32. Jayashankaran, J.; Rathnadurga, R.; Raghunathan, R. Tetrahedron Lett. 2004, 45,
7303.
33. Amalraj, A.; Raghunathan, R.; Sridevikumari, M. R.; Raman, N. Bioorg. Med.
Chem. 2003, 11, 407.
34. Subramaniyan, G.; Raghunathan, R. Tetrahedron 2001, 57, 2909.
35. Amalraj, A.; Raghuanthan, R. Tetrahedron 2001, 57, 10293.
36. Subramaniyan, G.; Raghunathan, R.; Martin Castro, A. M. Synthesis 2002, 2440.
37. Minu, M.; Jindal, D. P. Ind. J. Chem. 2003, 42B, 166.
methyl of the estrone and –NCH3 protons of the pyrrolidine moi-
ety. The Hb and Hc protons of the pyrrolidine moiety resonated
as two triplets at d 3.67 (t, 1H, J = 9.2 Hz) and d 3.86 (t, 1H,
J = 10.5 Hz). The benzylic proton Ha occurred as a triplet at d 4.44
(t, 1H, J = 9.5 Hz). The 13C NMR spectrum of 10d showed two peaks
at d 69.89 and d 83.16 ppm due to the two-spiro carbons. The C-18
methyl carbon of the estrone moiety and the pyrrolidine –NCH3
carbon resonated at d 13.02 and d 25.27 ppm. The indanedione
and cyclopentanone carbonyl carbons resonated at d 199.22, d
199.96 and d 218.89 ppm. The structure of the product was further
confirmed through mass spectroscopy of 10d, which showed a
molecular ion peak at 635.7 (M+) (Scheme 3).
The preferred mode of approach of the azomethine ylide is
shown in Figure 1. The azomethine ylide approaches the prochiral
carbon from the least hindered side of the steroidal dipolarophile,
accounting for the high selectivity in the mode of approach in
accordance with literature reports.39–41
From Table 1, it is evident that the rate of the reaction and the
yields of the cycloadducts are good in polar solvents (60–72%).
In conclusion, we have synthesised successfully a series of hith-
erto unknown steroidal pyrrolidines by 1,3-dipolar cycloaddition
reactions. We anticipate that these steroidal dipolarophiles can
be further exploited for the synthesis of a variety of complex
steroidal heterocycles through cycloaddition reactions. Further
work in this direction is in progress.
38. Representative procedure for the synthesis of steroidal dispiropyrrolidines
derivatives 4a. A solution of (Z)-16-benzylidene estrone 1 (1 mmol), sarcosine
2 (1 mmol), isatin 3 (1 mmol) in methanol (30 mL) was refluxed for 6 h. The
progress of the reaction was evidenced by the TLC analysis. The solvent was
removed under reduced pressure and the crude product was subjected to
column chromatography using petroleum ether/ethylacetate (4:1) as eluent.
Spectral data for 4a: 1-N-Methyl-spiro[2.30]-oxindole spiro[3.200]estrone-4-
Acknowledgements
A.R.S. thanks the Council of Scientific and Industrial Research
(CSIR) for the award of Senior Research Fellowship (SRF). R.R.
thanks DST and DST-FIST, New Delhi for financial support.
phenyl pyrrolidine. [a]
D +120, (c 1, CH2Cl2), 1H NMR (400 MHz, CDCl3): d 0.48–
2.16 (m, 13H), 0.50 (s, 3H, ꢀ18 CH3), 2.20 (s, 3H), 3.55 (t, 1H, J = 8.0 Hz), 3.96 (t,
1H, J = 9.2 Hz), 4.03 (t, 1H, J = 8.5 Hz), 5.35 (br s, 1H), 6.47–7.45 (m, 12H),
8.01(s, –NH, 1H); 13C NMR (100 MHz, CDCl3): d 14.92, 25.30, 26.73, 29.09,
31.01, 34.92, 36.91, 44.12, 46.84, 47.46, 51.50, 60.47, 68.18, 78.33, 109.18,
112.75, 115.28, 122.89, 126.16, 127.01, 127.45, 128.50, 128.77, 129.52, 130.26,
131.63, 137.75, 139.54, 141.86, 153.49, 178.79, 221.72; IR (KBr): 1616.9,
1702.6 cmꢀ1; EIMS m/z: 532.6 (M+); Anal. Calcd for C35H36N2O3: C, 78.91; H,
6.81; N, 5.25. Found: C, 79.07; H, 6.65; N, 5.25.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.089.
Spectral data for 7d: 1-N-Methyl-spiro [2.20]-acenapthenene-10-one-spiro
[3.200] estrone-4-(3,4,5-trimethoxyphenyl)-pyrrolidine.
[
a
]
D
+182, (c 1,
CH2Cl2), 1H NMR (400 MHz, CDCl3):
d 0.02–2.43 (m, 13H), 0.56 (s, 3H,
ꢀ18CH3), 2.19 (s, 3H), 3.68 (t, 1H, J = 8.0 Hz), 3.87 (s, 6H), 3.90 (s, 3H), 4.01 (t,
1H, J = 8.5 Hz), 4.09 (t, 1H, J = 9.2 Hz), 5.50 (br s, 1H), 6.42–8.08 (m, 9H); 13C
NMR (100 MHz, CDCl3): d 14.85, 25.05, 26.01, 28.83, 31.14, 31.93, 34.83, 36.33,
43.75, 47.44, 52.18, 56.15, 60.86, 69.09, 80.96, 112.59, 115.14, 120.15, 125.13,
125.87, 127.95, 128.71, 130.29, 131.12, 132.14, 135.54, 137.01, 137.01, 137.58,
143.02, 153.63, 209.24, 222.33; IR (KBr): 1705.6, 1735 cmꢀ1; EIMS m/z: 657.8
(M+); Anal. Calcd for C42H43NO6: C, 76.68; H, 6.58; N, 2.12. Found: C, 76.47; H,
6.76; N, 2.34.
References and notes
1. Miller, W. R.; Forrest, A. P. M. Cancer Res. 1982, 42, 3365.
2. Miller, W. R. J. Steroid Biochem. Mol. Biol. 1991, 39, 783.
3. Brodie, A. M.; Njar, V. C. O. J. Steroid Biochem. Mol. Biol. 1998, 66, 1.
4. Miller, W. R.; Forrest, A. P. M. Lancet 1974, 2, 866.
5. Van Landegham, A. A.; Portman, J.; Nabauurs, M.; Thijssen, J. Cancer Res. 1985,
45, 2900.
6. Bulun, S. E.; Price, T. M.; Aitken, J.; Mahendroo, M. S.; Simpson, E. R. J. Clin.
Endocrinol. Metabol. 1993, 77, 1662.
7. Dowsett, M.; Lee, K.; Macaulay, V. M.; Detre, S.; Rowlands, M.; Grimshaw, R. J.
Steroid Biochem. Mol. Biol. 1996, 56, 145.
8. Lu, Q.; Nakamura, J.; Savinov, A.; Yue, W.; Weisz, J.; Dabbs, D. J.; Wolz, G.;
Brodie, A. M. Endocrinology 1996, 137, 3061.
9. Miller, W. R.; Mullen, P.; Watson, C.; Dixon, J. M.; Telford, J. J. Steroid Biochem.
Mol. Biol. 1997, 61, 193.
10. Brodie, A. M.; Schwarzel, W. C.; Shaikh, A. A.; Brodie, H. J. Endocrinol. 1977, 100,
1684.
11. Bhatnagar, A. S.; Hausler, A.; Schieweek, K.; Lang, M.; Bowman, R. J. Steroid
Biochem. Mol. Biol. 1990, 37, 1021.
Spectral data for 10d: 1-N-Methyl-spiro-[2.20]- indane-10,30-dione-spiro [3.200]
estrone-4-(3,4,5-trimethoxyphenyl)-pyrrolidine. [
a
]
D
+147, (c 1, CH2Cl2), 1H
NMR (400 MHz, CDCl3): d 0.71–2.75 (m, 13H), 0.16 (s, 3H, ꢀ18CH3), 2.39 (s,
3H), 3.67 (t, 1H, J = 9.2 Hz), 3.77 (s, 9H), 3.86 (t, 1H, J = 10.5 Hz), 4.44 (t, 1H,
J = 9.5 Hz), 6.40–7.95 (m, 9H); 13C NMR (100 MHz, CDCl3): d 13.02, 25.27,
26.36, 27.04, 29.09, 31.76, 35.89, 37.24, 44.24, 47.53, 49.40, 51.83, 56.17, 58.17,
60.91, 69.89, 83.16, 107.07, 112.67, 115.31, 122.46, 123.25, 125.90, 131.18,
132.51, 135.69, 136.92, 137.85, 140.81, 141.05, 152.88, 153.73, 199.22, 199.96,
218.89; IR (KBr): 1704.5, 1732 cmꢀ1; EIMS m/z: 635.7 (M+); Anal. Calcd for
C
39H41NO7: C, 73.68; H, 6.49; N, 2.20. Found: C, 73.48; H, 6.34; N, 2.33.
39. Ius, A.; Parini, C.; Sportoletti, G.; Vecchio, G.; Ferrara, G. J. Org. Chem. 1971, 36,
3470.
40. Green, B.; Liu, D. Tetrahedron Lett. 1975, 33, 2807.
41. Ahmed, S.; Boruah, R. C. Ind. J. Chem. 1998, 37B, 838.
12. Lonning, P. E.; Paridaen, R.; Thurlimann, B.; Piscitelli, G.; Di Salle, E. J. Steroid
Biochem. Mol. Biol. 1997, 61, 151.
13. Padwa, A., Ed.1,3-Dipolar Cycloaddition Chemistry; Wiley: New York, 1984;
Vols. 1 and 2,.