- Email: [email protected]
Construction of novel steroidal isoxazolidinone derivatives under Vilsmeier–Haack conditions
Tetrahedron Letters 54 (2013) 874–877
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Construction of novel steroidal isoxazolidinone derivatives under Vilsmeier–Haack conditions Shamsuzzaman a,⇑, Hena Khanam a, Ashraf Mashrai a, Nazish Siddiqui b a b
Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India Department of Illmul, Advia Ajmal Khan Tibbiya College, Aligarh Muslim University, Aligarh 202002, India
a r t i c l e
i n f o
Article history: Received 11 September 2012 Revised 22 November 2012 Accepted 24 November 2012 Available online 1 December 2012 Keywords: 6-Hydroxyiminocholestane Isoxazolidinone Vilsmeier reagent Steroid
a b s t r a c t A novel expeditious and convenient synthesis of 5a-cholestano-[5,6-c]-isoxazolidin-50 -ones based on the reaction of 5a-6-hydroxyiminocholestanes with Vilsmeier–Haack reagent (DMF/POCl3) is described. The systems presented here, are novel scaffolds and have not been described before. Structural assignment of newly synthesized compounds was performed by IR, 1H NMR, 13C NMR, 2D 1H–1H COSY, MS and analytical data. Ó 2012 Elsevier Ltd. All rights reserved.
Isoxazolidinones are well-established building blocks in synthetic organic chemistry. One of the reasons the isoxazolidinones, particularly 5-isoxazolidinones, are of considerable interest to organic chemists is that they are good precursors to unnatural b-amino acids: these are, indeed, unmasked forms of 5-isoxazolidinones. These structures exhibit a wide range of biological activities.1,2 These type of compounds are an important class of heterocyclic structures, that can be applied in drug and pharmaceutical fields. These compounds have attracted scientific interest because of their potential cytotoxic, pro-apoptotic and antimicrobial capabilities.3 Furthermore, they can be used for the preparation of nucleoside analogues.4 Nucleoside analogues have emerged in recent years as highly promising candidates for the development of new efficient drugs against cancer and viral infections, particularly that of the HIV.5 Moreover, Parnafungins, natural products containing an isoxazolidinone ring, have been isolated from Fusarium larvarum and have been shown to be potent inhibitors of the fungal polyadenosine polymerase.6 Because of the importance of these scaffolds in synthetic organic chemistry and their usefulness as pharmacological molecules, much attention has been focused on their synthesis. Synthetic routes to them are numerous, including the enantioselective conjugate addition of hydroxylamines to pyrazolidinone acrylamides,7 propenoates,8 crotonic acid esters9 and a,b-unsaturated-d-lactones.10 The 1,3-dipolar cycloaddition of nitrones with ynolates to give isoxazolidinones has been developed quite re⇑ Corresponding author. Tel.: +91 9411003465. E-mail address: [email protected] ( Shamsuzzaman). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.11.105
cently.11 Significant effort continues to be directed into the development of efficient methodologies to new isoxazolidinone-based structures. The Vilsmeier–Haack reagent (halomethyleniminium salt) formed from the interaction of dialkyl formamide such as DMF with POCl3 has attracted the attention of synthetic organic chemists since its discovery in 1927.12 It is one of the most commonly used reagents for the introduction of an aldehydic (CHO) group into electron rich aromatic systems.13 However, the scope of the Vilsmeier reagent is not confined to the aromatic formylation reaction alone. A wide variety of alkene14 derivatives, carbonyl15 compounds, activated methyl and methylene16 groups exhibit reactivity towards the Vilsmeier reagent. In addition to the carbon nucleophiles, some oxygen17 and nitrogen18 nucleophiles are also reactive towards Vilsmeier reagent. Numerous transformations of the iminium salts into products other than aldehydes have been achieved19,20 and these transformations enhance the scope and versatility of the Vilsmeier–Haack reaction. Following our interest on the synthesis of new steroidal derivatives21 we herein report a prompt and novel strategy for the synthesis of 5a-cholestano-[5,6-c]-isoxazolidin-50 -ones (7–9) based on the reaction of 5a-6-hydroxyiminocholestanes (4–6) with Vilsmeier reagent. Interestingly, the reaction proceeded smoothly and the desired steroidal 50 -isoxazolidinone derivatives (7–9) were obtained in good yield (80–87%). With the best of our knowledge there are no reports, however, describing the synthesis of steroidal 50 -isoxazolidinones via Vilsmeier–Haack reaction. The 5a-6-hydroxyiminocholestanes22 (4–6) employed for the present investigation, were conveniently obtained from the corre-
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Shamsuzzaman et al. / Tetrahedron Letters 54 (2013) 874–877
sponding steroidal ketones23 (1–3) by the known literature method. Treatment of compounds (4–6) with DMF/POCl3 at room temperature furnished corresponding steroidal isoxazolidinone derivatives (7–9) (Scheme 1). To search for optimum reaction conditions and establish a reproducible procedure, the temperature of reaction was increased. Reaction time was interestingly reduced when it was carried out at 60–65 °C (Table 1). Moreover, to examine the solvent effects, we applied the same conditions with solvents of different polarity. DMF with medium polarity was found to be the best solvent among acetonitrile, chloroform, dichloromethane and toluene in terms of yield and rate (Table 2). With acetonitrile (most polar) and toluene (least polar) even at refluxing temperature did not improve rate and yield significantly. With solvents other than DMF poor yield of products was observed (<40%). Thus most appropriate conditions for this important conversion were found to be (a) 60–65 °C temperature and (b) solvent: DMF. Detailed experimental procedure and spectral data (Figs. S1–S15) can be found in Supplementary data. Elucidation of the proposed structures (7–9) was based on their correct elemental analyses and compatible IR, 1H NMR, 13C NMR, 2D 1H–1H COSY and MS spectral data. The mass spectrum of compound 7 displayed the molecular ion [M+] peak at m/z 487. The IR absorption showed peaks at 3310 cm1 for stretching of the N–H group and at 1759 cm1 for stretching of the C@O group. The 1H NMR spectrum (400 MHz, CDCl3) of compound 7 featured a signal as singlet at d 8.70 integrating for one hydrogen, which is the characteristic signal of the N–H proton, while another downfield signal as doublet of doublets at d 3.22 (J = 4.24, 13.52 Hz) was assigned to the C-6 methine proton. The 13C NMR spectra (100 MHz, CDCl3) showed distinct signals. Resonance at d 167.26 was diagnostic signals for the carbonyl carbon of heterocyclic ring. Based on these spectral data, the formation of isoxazolidinone ring attached to steroidal skeleton was confirmed. However, the position of the ring was still undecided, and this was determined with the help of 2D-NMR experiments. The signal at d 8.70 in the 1H NMR spectrum of compound 7 was unambiguously assigned to the spin system containing the N–H function. It did not show any cross peak with any of the protons in the 2D spectrum, clearly suggesting that there are no adjacent protons which are coupled to N–H proton. The signal at d 4.67 was assigned to H-3a, which further showed cross-peaks at d 1.66, 1.57 (H-2b, H-2a) and at d 2.00, 1.88 (H-4b, H-4a). Neither H2-4 proton showed any cross peaks, indicating that there is an
Table 1 Effect of temperature on rate of reaction
H
O
1-3 OAc Cl H
Time (min): 60–65 °C
7 8 9
6 4 3
50 45 30
Compound
Solvent
Time (h)
Yield (%)
7
CH3CN DMF CHCl3 CH2Cl2 C7H8 CH3CN DMF CHCl3 CH2Cl2 C7H8 CH3CN DMF CHCl3 CH2Cl2 C7H8
16 50 (min) 12 14 20 12 45 (min) 11 10 17 10 30 (min) 9 8 16
22 87 35 30 25 20 84 32 26 20 18 84 30 24 18
8
9
interruption at C-5. Thus N–H is attached to this carbon. A doublet of doublet at d 3.20–3.25 was attributed to H-6 which showed cross peaks with the signals at d 1.59 and 1.40 due to H-7b and H-7a. All these data clearly suggest the fusion of heterocyclic moiety to the 5, 6 position of steroid. The other compounds 8 and 9 were characterized in the same way. Mechanistically, we assume that aminooxymethylene-dimethyl-ammonium derivative of cholestane is formed from cholesteryl oxime and chloromethyleniminium intermediate (formed in situ from DMF/POCl3) followed by intramolecular cyclization to form a four membered spiro intermediate which undergoes 1,2-hydride shift and simultaneous intramolecular rearrangement to give corresponding products (7–9) as depicted in Scheme 2. The stereochemistry at C-6 can be established on the basis of the mechanism as well as on the coupling constant (J) value of C6-proton. The proposed reaction mechanism gives rise to a chiral centre at C6 with C6–CO bond being equatorially (a) oriented,
H H NH2OH.HCl/CH3COONa C2H5OH/reflux, 4 h
X
Time (h): rt
Table 2 Effect of solvent on rate and yield of reaction at 60–65 °C temperature
H H
Compound
H
X
H
N
H H
OH
DMF/POCl3 stirring at 0 °C for 15 min, X then at 60-65 °C
4-6 (1) (2) (3)
OAc Cl H
H HN O
H
C
O
7-9 (4) (5) (6)
Scheme 1. Synthesis of steroidal isoxazolidinone derivatives.
OAc (7) Cl (8) H (9)
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Shamsuzzaman et al. / Tetrahedron Letters 54 (2013) 874–877
O O
O
H3C N
P
C
H
+
Cl
H3C
P
Cl
O
Cl Cl
H3C N
Cl
CH3
H
Cl
C
H
N
Cl
CH3
CH3
Reactive species
H H
H H X
+ OH
CH3
Cl C H
X
H
N
O C H
NH
N O
C H
H H2O
H
N
H
H X
X
N
HN
H
X
N
1,2 hydride shift &rearangement
H
O
H
H H
HN
N
CH3
H
X
H
H
H N
H
H
-HCl
HN O
O
H
C
O
Scheme 2. A tentative mechanism for the synthesis of steroidal isoxazolidinones 7–9.
resulting in cis geometry of isoxazolidinone ring which might be due to the fact that during the rearrangement hydride ion approaches from the axial (b) side to push the bulky group already present at C-6 to the less hindered equatorial (a) side to avoid 1,3-diaxial interaction due to C-10 methyl group. It is further supported by coupling constant (J) values of C6–H that appeared as a doublet of doublet due to C7–H (axial) and C7–H (equatorial) protons with J = 13.52 and 4.24 Hz, respectively, strongly supporting the dihedral angle between C6–H and neighbouring two C7-protons which should be 180°(anti, axial–axial relationship) and 60° (gauche, axial–equatorial relationship)24,25 As anticipated, the above results are in excellent agreement with the cis geometry of isoxazolidinone ring (C6–bH) and S configuration at C6.21a In conclusion, we have developed an efficient synthetic approach for the synthesis of a novel class of steroidal isoxazolidinones via Vilsmeier reagent (DMF/POCl3). This is a simple, mild and straightforward reaction, which completes in a short span of time. The novelty of the entire process lies in the Vilsmeier cyclization of 6-hydroxyiminocholestanes into steroidal isoxazo-
lidinones, which, to the best of our knowledge, is unprecedented. Further studies to broaden the scope towards the synthesis of the novel steroidal derivatives are under investigation in our laboratory. Acknowledgments We are very grateful to the Department of Chemistry, A.M.U., Aligarh, for providing necessary research facilities. Facilities provided by SAP (DRS-I) for their generous research support are also gratefully acknowledged. We also thank SAIF Punjab University Chandigarh for providing spectral data. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012. 11.105. These data include MOL files and InChiKeys of the most important compounds described in this article.
Shamsuzzaman et al. / Tetrahedron Letters 54 (2013) 874–877
References and notes 1. (a) Nozaki, Y.; Katayama, N.; Ono, H.; Tsubotani, S.; Harada, S.; Okazaki, H.; Nakao, Y. Nature 1987, 325, 179–180; (b) Baldwin, J. E.; Ng, S. C.; Pratt, A. J. Tetrahedron Lett. 1987, 28, 4319–4320; (c) Harada, S.; Tsubotani, S.; Hida, T.; Kogama, K.; Kondo, M.; Ono, H. Tetrahedron 1988, 44, 6589–6606. 2. Janecki, T.; Wasek, T.; Rozalski, M.; Krajewska, U.; Studzian, K.; Janecka, A. Bioorg. Med. Chem. Lett. 2006, 16, 1430–1433. 3. Rozalski, M.; Krajewska, U.; Panczyk, M.; Mirowski, M.; Rozalska, B.; Wasek, T.; Janecki, T. Eur. J. Med. Chem. 2007, 42, 248–255. 4. Merino, P.; Franco, S.; Mates, J. A.; Merchan, F. L.; Romero, P.; Tejero, T.; Uriel, S.; Matute, R. ARKIVOC 2004, 48–58. 5. Merino, P. Curr. Med. Chem. AIA 2002, 1, 389. and references cited therein. 6. Overy, D.; Calati, K.; Kahn, J. N.; Hsu, M.-Jo.; Martín, J.; Collado, J.; Roemer, T.; Harris, G.; Parish, C. A. Bioorg. Med. Chem. Lett. 2009, 19, 1224–1227. 7. Sibi, M. P.; Liu, M. Org. Lett. 2001, 3, 4181–4184. 8. Baldwin, J. E.; Harwood, L. M.; Lombard, M. J. Tetrahedron 1984, 40, 4363– 4370. 9. Ishikawa, T.; Nagai, K.; Senzaki, M.; Tatsukawa, A.; Saito, S. Tetrahedron 1998, 54, 2433–2448. 10. Panfil, I.; Maciejewski, S.; Belzecki, C.; Chmielewski, M. Tetrahedron Lett. 1989, 30, 1527–1528. 11. Shindo, M.; Itoh, K.; Tsuchiya, C.; Shishido, K. Org. Lett. 2002, 4, 3119–3121. 12. Vilsmeier, A.; Haack, A. Chem. Ber. 1927, 60, 119–122. 13. (a) Jackson, W. G.; Sargeson, A. M.; Tucker, P. A.; Watson, A. D. J. Am. Chem. Soc. 1981, 103, 533–540; (b) Pedras, M. S. C.; Jha, M. J. Org. Chem. 2005, 70, 1828– 1834.
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14. (a) Meth-Cohn, O.; Westwood, K. T. J. Chem. Soc., Perkin Trans. 1 1984, 1173– 1182; (b) Reddy, M. P.; Rao, G. S. K. J. Org. Chem. 1981, 46, 5371–5373. 15. (a) Marson, C. M. Tetrahedron 1992, 48, 3659–3726; (b) Katritzky, A. R.; Marson, C. M. J. Am. Chem. Soc. 1983, 105, 3279–3283. 16. Mittelbach, M.; Junek, H. J. Heterocycl. Chem. 1982, 19, 1021–1024. 17. (a) Nohara, A.; Umetani, T.; Sanno, Y. Tetrahedron 1974, 30, 3553–3561; (b) Venugopal, M.; Umarani, R.; Perumal, P. T.; Rajadurai, S. Tetrahedron Lett. 1991, 32, 3235–3238. 18. (a) Barton, D. H. R.; Elliot, J. D.; Gero, S. D. J. Chem. Soc., Perkin Trans. 1 1982, 2085–2090; (b) Brehme, R.; Nikolajewski, H. E. Tetrahedron Lett. 1982, 23, 1131–1134. 19. Meth-Cohn, O.; Westwood, K. T. J. Chem. Soc., Perkin Trans. 1 1983, 2089–2092. 20. (a) Meth-Cohn, O.; Narine, B.; Tarnowski, B. Tetrahedron Lett. 1979, 20, 3111– 3114; (b) Meth-Cohn, O.; Narine, B.; Tarnowski, B. J. Chem. Soc., Perkin Trans.1 1981, 1520–1530; (c) Meth-Cohn, O.; Rhouati, S.; Tarnowski, B. Tetrahedron Lett. 1979, 20, 4885–4886; (d) Meth-Cohn, O.; Rhouati, S.; Tarnowski, B.; Robinson, A. J. Chem. Soc., Perkin Trans.1 1981, 1537–1543. 21. (a) Shamsuzzaman; Salim, A. Tetrahedron Lett. 1997, 38, 5705–5708; (b) Shamsuzzaman, ; Khan, M. S.; Alam, M.; Tabassum, Z.; Ahmad, A.; Khan, A. U. Eur. J. Med. Chem. 2010, 45, 1094–1097. 22. (a) Shopee, C. W.; Lack, R. E.; Roy, S. K. J. Chem. Soc. 1963, 3767–3774; (b) Ford, E. G.; Chakravorty, P.; Wallis, E. S. J. Am. Chem. Soc. 1938, 60, 413–415. 23. (a) Anagnostopoulos, C. E.; Fieser, L. F. J. Am. Chem. Soc. 1954, 76, 532–536; (b) Backer, R. H.; Squire, E. N. J. Am. Chem. Soc. 1948, 70, 1487–1490. 24. Karplus, M. J. Phys. Chem. 1961, 64, 1793–1798. 25. Silverstein, R. M.; Webster, F. X. In Spectrometric Identification of Organic Compounds, 6th Ed.; Wiley: India, 2007, pp 185–186.
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Construction of novel steroidal isoxazolidinone derivatives under Vilsmeier–Haack conditions Shamsuzzaman a,⇑, Hena Khanam a, Ashraf Mashrai a, Nazish Siddiqui b a b
Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India Department of Illmul, Advia Ajmal Khan Tibbiya College, Aligarh Muslim University, Aligarh 202002, India
a r t i c l e
i n f o
Article history: Received 11 September 2012 Revised 22 November 2012 Accepted 24 November 2012 Available online 1 December 2012 Keywords: 6-Hydroxyiminocholestane Isoxazolidinone Vilsmeier reagent Steroid
a b s t r a c t A novel expeditious and convenient synthesis of 5a-cholestano-[5,6-c]-isoxazolidin-50 -ones based on the reaction of 5a-6-hydroxyiminocholestanes with Vilsmeier–Haack reagent (DMF/POCl3) is described. The systems presented here, are novel scaffolds and have not been described before. Structural assignment of newly synthesized compounds was performed by IR, 1H NMR, 13C NMR, 2D 1H–1H COSY, MS and analytical data. Ó 2012 Elsevier Ltd. All rights reserved.
Isoxazolidinones are well-established building blocks in synthetic organic chemistry. One of the reasons the isoxazolidinones, particularly 5-isoxazolidinones, are of considerable interest to organic chemists is that they are good precursors to unnatural b-amino acids: these are, indeed, unmasked forms of 5-isoxazolidinones. These structures exhibit a wide range of biological activities.1,2 These type of compounds are an important class of heterocyclic structures, that can be applied in drug and pharmaceutical fields. These compounds have attracted scientific interest because of their potential cytotoxic, pro-apoptotic and antimicrobial capabilities.3 Furthermore, they can be used for the preparation of nucleoside analogues.4 Nucleoside analogues have emerged in recent years as highly promising candidates for the development of new efficient drugs against cancer and viral infections, particularly that of the HIV.5 Moreover, Parnafungins, natural products containing an isoxazolidinone ring, have been isolated from Fusarium larvarum and have been shown to be potent inhibitors of the fungal polyadenosine polymerase.6 Because of the importance of these scaffolds in synthetic organic chemistry and their usefulness as pharmacological molecules, much attention has been focused on their synthesis. Synthetic routes to them are numerous, including the enantioselective conjugate addition of hydroxylamines to pyrazolidinone acrylamides,7 propenoates,8 crotonic acid esters9 and a,b-unsaturated-d-lactones.10 The 1,3-dipolar cycloaddition of nitrones with ynolates to give isoxazolidinones has been developed quite re⇑ Corresponding author. Tel.: +91 9411003465. E-mail address: [email protected] ( Shamsuzzaman). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.11.105
cently.11 Significant effort continues to be directed into the development of efficient methodologies to new isoxazolidinone-based structures. The Vilsmeier–Haack reagent (halomethyleniminium salt) formed from the interaction of dialkyl formamide such as DMF with POCl3 has attracted the attention of synthetic organic chemists since its discovery in 1927.12 It is one of the most commonly used reagents for the introduction of an aldehydic (CHO) group into electron rich aromatic systems.13 However, the scope of the Vilsmeier reagent is not confined to the aromatic formylation reaction alone. A wide variety of alkene14 derivatives, carbonyl15 compounds, activated methyl and methylene16 groups exhibit reactivity towards the Vilsmeier reagent. In addition to the carbon nucleophiles, some oxygen17 and nitrogen18 nucleophiles are also reactive towards Vilsmeier reagent. Numerous transformations of the iminium salts into products other than aldehydes have been achieved19,20 and these transformations enhance the scope and versatility of the Vilsmeier–Haack reaction. Following our interest on the synthesis of new steroidal derivatives21 we herein report a prompt and novel strategy for the synthesis of 5a-cholestano-[5,6-c]-isoxazolidin-50 -ones (7–9) based on the reaction of 5a-6-hydroxyiminocholestanes (4–6) with Vilsmeier reagent. Interestingly, the reaction proceeded smoothly and the desired steroidal 50 -isoxazolidinone derivatives (7–9) were obtained in good yield (80–87%). With the best of our knowledge there are no reports, however, describing the synthesis of steroidal 50 -isoxazolidinones via Vilsmeier–Haack reaction. The 5a-6-hydroxyiminocholestanes22 (4–6) employed for the present investigation, were conveniently obtained from the corre-
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Shamsuzzaman et al. / Tetrahedron Letters 54 (2013) 874–877
sponding steroidal ketones23 (1–3) by the known literature method. Treatment of compounds (4–6) with DMF/POCl3 at room temperature furnished corresponding steroidal isoxazolidinone derivatives (7–9) (Scheme 1). To search for optimum reaction conditions and establish a reproducible procedure, the temperature of reaction was increased. Reaction time was interestingly reduced when it was carried out at 60–65 °C (Table 1). Moreover, to examine the solvent effects, we applied the same conditions with solvents of different polarity. DMF with medium polarity was found to be the best solvent among acetonitrile, chloroform, dichloromethane and toluene in terms of yield and rate (Table 2). With acetonitrile (most polar) and toluene (least polar) even at refluxing temperature did not improve rate and yield significantly. With solvents other than DMF poor yield of products was observed (<40%). Thus most appropriate conditions for this important conversion were found to be (a) 60–65 °C temperature and (b) solvent: DMF. Detailed experimental procedure and spectral data (Figs. S1–S15) can be found in Supplementary data. Elucidation of the proposed structures (7–9) was based on their correct elemental analyses and compatible IR, 1H NMR, 13C NMR, 2D 1H–1H COSY and MS spectral data. The mass spectrum of compound 7 displayed the molecular ion [M+] peak at m/z 487. The IR absorption showed peaks at 3310 cm1 for stretching of the N–H group and at 1759 cm1 for stretching of the C@O group. The 1H NMR spectrum (400 MHz, CDCl3) of compound 7 featured a signal as singlet at d 8.70 integrating for one hydrogen, which is the characteristic signal of the N–H proton, while another downfield signal as doublet of doublets at d 3.22 (J = 4.24, 13.52 Hz) was assigned to the C-6 methine proton. The 13C NMR spectra (100 MHz, CDCl3) showed distinct signals. Resonance at d 167.26 was diagnostic signals for the carbonyl carbon of heterocyclic ring. Based on these spectral data, the formation of isoxazolidinone ring attached to steroidal skeleton was confirmed. However, the position of the ring was still undecided, and this was determined with the help of 2D-NMR experiments. The signal at d 8.70 in the 1H NMR spectrum of compound 7 was unambiguously assigned to the spin system containing the N–H function. It did not show any cross peak with any of the protons in the 2D spectrum, clearly suggesting that there are no adjacent protons which are coupled to N–H proton. The signal at d 4.67 was assigned to H-3a, which further showed cross-peaks at d 1.66, 1.57 (H-2b, H-2a) and at d 2.00, 1.88 (H-4b, H-4a). Neither H2-4 proton showed any cross peaks, indicating that there is an
Table 1 Effect of temperature on rate of reaction
H
O
1-3 OAc Cl H
Time (min): 60–65 °C
7 8 9
6 4 3
50 45 30
Compound
Solvent
Time (h)
Yield (%)
7
CH3CN DMF CHCl3 CH2Cl2 C7H8 CH3CN DMF CHCl3 CH2Cl2 C7H8 CH3CN DMF CHCl3 CH2Cl2 C7H8
16 50 (min) 12 14 20 12 45 (min) 11 10 17 10 30 (min) 9 8 16
22 87 35 30 25 20 84 32 26 20 18 84 30 24 18
8
9
interruption at C-5. Thus N–H is attached to this carbon. A doublet of doublet at d 3.20–3.25 was attributed to H-6 which showed cross peaks with the signals at d 1.59 and 1.40 due to H-7b and H-7a. All these data clearly suggest the fusion of heterocyclic moiety to the 5, 6 position of steroid. The other compounds 8 and 9 were characterized in the same way. Mechanistically, we assume that aminooxymethylene-dimethyl-ammonium derivative of cholestane is formed from cholesteryl oxime and chloromethyleniminium intermediate (formed in situ from DMF/POCl3) followed by intramolecular cyclization to form a four membered spiro intermediate which undergoes 1,2-hydride shift and simultaneous intramolecular rearrangement to give corresponding products (7–9) as depicted in Scheme 2. The stereochemistry at C-6 can be established on the basis of the mechanism as well as on the coupling constant (J) value of C6-proton. The proposed reaction mechanism gives rise to a chiral centre at C6 with C6–CO bond being equatorially (a) oriented,
H H NH2OH.HCl/CH3COONa C2H5OH/reflux, 4 h
X
Time (h): rt
Table 2 Effect of solvent on rate and yield of reaction at 60–65 °C temperature
H H
Compound
H
X
H
N
H H
OH
DMF/POCl3 stirring at 0 °C for 15 min, X then at 60-65 °C
4-6 (1) (2) (3)
OAc Cl H
H HN O
H
C
O
7-9 (4) (5) (6)
Scheme 1. Synthesis of steroidal isoxazolidinone derivatives.
OAc (7) Cl (8) H (9)
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Shamsuzzaman et al. / Tetrahedron Letters 54 (2013) 874–877
O O
O
H3C N
P
C
H
+
Cl
H3C
P
Cl
O
Cl Cl
H3C N
Cl
CH3
H
Cl
C
H
N
Cl
CH3
CH3
Reactive species
H H
H H X
+ OH
CH3
Cl C H
X
H
N
O C H
NH
N O
C H
H H2O
H
N
H
H X
X
N
HN
H
X
N
1,2 hydride shift &rearangement
H
O
H
H H
HN
N
CH3
H
X
H
H
H N
H
H
-HCl
HN O
O
H
C
O
Scheme 2. A tentative mechanism for the synthesis of steroidal isoxazolidinones 7–9.
resulting in cis geometry of isoxazolidinone ring which might be due to the fact that during the rearrangement hydride ion approaches from the axial (b) side to push the bulky group already present at C-6 to the less hindered equatorial (a) side to avoid 1,3-diaxial interaction due to C-10 methyl group. It is further supported by coupling constant (J) values of C6–H that appeared as a doublet of doublet due to C7–H (axial) and C7–H (equatorial) protons with J = 13.52 and 4.24 Hz, respectively, strongly supporting the dihedral angle between C6–H and neighbouring two C7-protons which should be 180°(anti, axial–axial relationship) and 60° (gauche, axial–equatorial relationship)24,25 As anticipated, the above results are in excellent agreement with the cis geometry of isoxazolidinone ring (C6–bH) and S configuration at C6.21a In conclusion, we have developed an efficient synthetic approach for the synthesis of a novel class of steroidal isoxazolidinones via Vilsmeier reagent (DMF/POCl3). This is a simple, mild and straightforward reaction, which completes in a short span of time. The novelty of the entire process lies in the Vilsmeier cyclization of 6-hydroxyiminocholestanes into steroidal isoxazo-
lidinones, which, to the best of our knowledge, is unprecedented. Further studies to broaden the scope towards the synthesis of the novel steroidal derivatives are under investigation in our laboratory. Acknowledgments We are very grateful to the Department of Chemistry, A.M.U., Aligarh, for providing necessary research facilities. Facilities provided by SAP (DRS-I) for their generous research support are also gratefully acknowledged. We also thank SAIF Punjab University Chandigarh for providing spectral data. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012. 11.105. These data include MOL files and InChiKeys of the most important compounds described in this article.
Shamsuzzaman et al. / Tetrahedron Letters 54 (2013) 874–877
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