First Total Synthesis of N-Oxido-3-aza-1,3,5(10)-trieno Steroids

Abstract

An efficient synthesis of 3-aza-steroids bearing a pyridine as an A ring was achieved via intramolecular cycloaddition of orthoquinodimethanes, which were generated from a 3-azabicy­clo[4.2.0]octa-1,3,5-trien-7-one ketal.

aza-steroid - pyridine - intramolecular Diels-Alder reaction - Wacker oxidation

References

<A NAME="RG09705ST-1">1</A> Zeelen FJ. Medicinal Chemistry of Steroids   Elsevier; Amsterdam: 1990. 

<A NAME="RG09705ST-2">2</A> Singh H. Kapoor VK. Paul D. Prog. Med. Chem.  1979,  16:  35 

<A NAME="RG09705ST-3A">3a</A> Crabb TA. Mitchell JS. J. Chem. Soc., Perkin Trans. 2  1977,  1592 

<A NAME="RG09705ST-3B">3b</A> Crabb TA. Mitchell JS. J. Chem. Soc., Perkin Trans. 2  1979,  581 

<A NAME="RG09705ST-4">4</A> Bernath G. Fülop F. Argay G. Kalman A. Sohar P. Tetrahedron Lett.  1981,  22:  3797 

<A NAME="RG09705ST-5A">5a</A> Dolle RE. Allaudeen HS. Kruse LI. J. Med. Chem.  1990,  33:  877 

<A NAME="RG09705ST-5B">5b</A> Brandt M. Levy MA. Biochemistry  1989,  28:  140 

<A NAME="RG09705ST-5C">5c</A> Gandiha A. Marshall G. Paul D. Singh H. J. Pharm. Pharmacol.  1974,  26:  871 

<A NAME="RG09705ST-6A">6a</A> Chesnut RW. Durham NN. Mawsdsley EA. Berlin RA. Steroids  1976,  525 

<A NAME="RG09705ST-6B">6b</A> Lange C. Holzhey N. Schönecker B. Beckert R. Möllmann U. Dahse H.-M. Bioorg. Med. Chem.  2004,  12:  3357 

<A NAME="RG09705ST-7A">7a</A> Singh H. Paul D. Parashar VV. J. Chem. Soc., Perkin Trans. 1  1973,  1204 

<A NAME="RG09705ST-7B">7b</A> Singh H. Paul D. J. Chem. Soc., Perkin Trans. 1  1974,  1475 

<A NAME="RG09705ST-7C">7c</A> Singh H. Bhardwaj TR. Ahuju NK. Paul D. Parashar VV. J. Chem. Soc., Perkin Trans. 1  1979,  305 

<A NAME="RG09705ST-8">8</A> Morgan LR. Chem. Ind. (London)  1963,  293 

<A NAME="RG09705ST-9A">9a</A> Anderson KM. Liao S. Nature (London)  1968,  219:  277 

<A NAME="RG09705ST-9B">9b</A> Wilson JD. J. Biol. Chem.  1968,  243:  2012 

<A NAME="RG09705ST-10">10</A> Cachoux F. Ibrahim-Ouali M. Santelli M. Synlett  2000,  418 

<A NAME="RG09705ST-11">11</A> Cachoux F. Ibrahim-Ouali M. Santelli M. Tetrahedron Lett.  2000,  41:  1767 

<A NAME="RG09705ST-12">12</A> Cachoux F. Ibrahim-Ouali M. Santelli M. Tetrahedron Lett.  2001,  42:  843 

<A NAME="RG09705ST-13A">13a</A> Tubul A. Ouvrard P. Santelli M. Synthesis  1991,  173 

<A NAME="RG09705ST-13B">13b</A> Ouvrard P. Tubul A. Santelli M. Bull. Soc. Chim. Fr.  1993,  130:  772 

<A NAME="RG09705ST-13C">13c</A> Pellissier H. Santelli M. Tetrahedron  1996,  52:  9093 

<A NAME="RG09705ST-13D">13d</A> Pellissier H. Wilmouth S. Santelli M. Tetrahedron Lett.  1996,  37:  5107 

<A NAME="RG09705ST-14A">14a</A> Oppolzer W. J. Am. Chem. Soc.  1971,  93:  3833 

<A NAME="RG09705ST-14B">14b</A> Oppolzer W. J. Am. Chem. Soc.  1971,  93:  3834 

<A NAME="RG09705ST-14C">14c</A> Oppolzer W. Keller KJ. J. Am. Chem. Soc.  1971,  93:  3836 

<A NAME="RG09705ST-14D">14d</A> Oppolzer W. Angew. Chem., Int. Ed. Engl.  1977,  16:  10 

<A NAME="RG09705ST-14E">14e</A> Oppolzer W. Synthesis  1978,  793 

<A NAME="RG09705ST-15A">15a</A> Kametani T. Nemoto H. Ishikawa H. Shiroyama K. Fukumoto K. J. Am. Chem. Soc.  1976,  98:  3378 

<A NAME="RG09705ST-15B">15b</A> Kametani T. Nemoto H. Ishikawa H. Shiroyama K. Matsumoto H. Fukumoto K. J. Am. Chem. Soc.  1977,  99:  3461 

<A NAME="RG09705ST-15C">15c</A> Kametani T. Nemoto H. Tetrahedron  1981,  37:  3 

<A NAME="RG09705ST-15D">15d</A> Nemoto H. Fukumoto K. Tetrahedron  1998,  54:  5425 

<A NAME="RG09705ST-16">16</A> Mariet N. Ibrahim-Ouali M. Santelli M. Tetrahedron Lett.  2002,  42:  5789 

<A NAME="RG09705ST-17A">17a</A> Mash EA. Math SK. Flann CJ. Tetrahedron Lett.  1988,  29:  2147 

<A NAME="RG09705ST-17B">17b</A> Grieco PA. Nishizawa M. Oguri T. Burke SD. Marinovic N. J. Am. Chem. Soc.  1977,  99:  5773 

<A NAME="RG09705ST-17C">17c</A> Colvin EW. Raphael RA. Roberts JS. J. Chem. Soc., Chem. Commun.  1971,  858 

<A NAME="RG09705ST-17D">17d</A> Bauduin G. Bondon D. Pietrasantra Y. Pucci B. Tetrahedron  1978,  34:  3269 

<A NAME="RG09705ST-17E">17e</A> Ates A. Gautier A. Leroy B. Plancher JM. Quesnel Y. Marko IE. Tetrahedron Lett.  1999,  40:  1799 

<A NAME="RG09705ST-18">18</A> Khim SK. Nuss JM. Tetrahedron Lett.  1999,  40:  1827 

<A NAME="RG09705ST-19">19</A> Pellissier H. Wilmouth S. Santelli M. Bull. Soc. Chim. Fr.  1995,  132:  627 

<A NAME="RG09705ST-20A">20a</A> Barco A. Benetti S. Pollini GP. Synthesis  1973,  316 

<A NAME="RG09705ST-20B">20b</A> Kataoka H. Yamada T. Goto K. Tsuji J. Tetrahedron  1987,  43:  4107 

<A NAME="RG09705ST-21A">21a</A> Krapcho AP. Glynn GA. Grenon BJ. Tetrahedron Lett.  1967,  215 

<A NAME="RG09705ST-21B">21b</A> Krapcho AP. Synthesis  1982,  805 

<A NAME="RG09705ST-21C">21c</A> Krapcho AP. Synthesis  1982,  893 

<A NAME="RG09705ST-22">22</A>

The crystallographic data (CCDC 272301) can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; e-mail: [e-mail].

<A NAME="RG09705ST-23">23</A> Iwama T. Matsumoto H. Shimizu H. Kataoka T. Muraoka O. Tanabe G. J. Chem. Soc., Perkin Trans. 1  1998,  1569 

<A NAME="RG09705ST-24">24</A> Tsuji J. Shimizu I. Yamamoto K. Tetrahedron Lett.  1976,  2975 

<A NAME="RG09705ST-25">25</A> Miller DG. Wayner DDM. J. Org. Chem.  1990,  55:  2924 

<A NAME="RG09705ST-26">26</A> Pellissier H. Michellys P.-Y. Santelli M. Tetrahedron  1997,  53:  7577 

<A NAME="RG09705ST-27">27</A>

All compounds showed satisfactory spectroscopic data as well as microanalytical data. Diastereomeric ratios were established from the ¹H NMR spectrum of the crude product.
Experimental procedure for the preparation of 11: A solution of 10 (0.75 g, 2.53 mmol) in 1,2,4-trichlorobenzene (50 mL) was stirred under argon at 200 °C for 24 h. After cooling, the solvent was removed under reduced pressure (0.2 Torr). The resulting oil was purified by flash chromatography on silica gel (EtOAc-Et₂O, 2:8 to 5:5) to afford compounds 11a (0.336 g; 41%), 11b (0.232 g; 29%), and 11c (0.12 g; 15%) in 85% overall yield.
11a: White solid; mp 146-147 °C. IR (film): 3083, 2932, 1773, 1610 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.30 (d, J = 11.9 Hz, 1 H), 1.52 (m, 3 H), 1.92 (m, 3 H), 2.14 (m, 3 H), 2.73 (d, J = 3.8 Hz, 1 H), 2.76 (m, 1 H), 2.84 (dt, J = 8.5 Hz, J = 12.4 Hz, 1 H), 3.23 (m, 1 H), 3.34 (m, 1 H), 4.98 (m, 2 H), 5.42 (m, 1 H), 7.06 (d, J = 5.3 Hz, 1 H), 8.35 (m, 2 H). ¹³C NMR (250 MHz, CDCl₃): δ = 21.6, 23.8, 27.5; 28.9, 34.2, 35.1, 37.0, 43.2, 44.8, 49.1, 96.7, 116.6, 121.3, 132.7, 137.2, 144.1, 147.5, 151.0, 177.2. Anal. Calcd for C₁₉H₂₁NO₂: C, 77.26; H, 7.17. Found: C, 77.48; H, 7.26.
11b: Oil. IR (film): 2930, 2880, 1762, 1550 cm^-1. ¹H NMR (500 MHz, CDCl₃) : δ = 1.49 (m, 1 H), 1.62 (m, 1 H), 1.64 (m, 1 H), 1.69 (m, 1 H), 1.71 (m, 1 H), 1.80 (d, J = 11.8 Hz, 1 H), 2.03 (m, 1 H), 2.12 (m, 1 H), 2.26 (m, 1 H), 2.52 (dd, J = 5.4, 11.8 Hz, 1 H), 2.65 (d, J = 10.5 Hz, 1 H), 2.89 (m, 1 H), 3.44 (d, J = 5.4 Hz, 1 H), 5.11 (d, J = 9.5 Hz, 1 H), 5.14 (d, J = 17.0 Hz, 1 H), 5.64 (dt, J = 9.9, 17.2 Hz, 1 H), 7.32 (d, J = 5.0 Hz, 1 H), 8.34 (s, 1 H), 8.39 (d, J = 5.0 Hz, 1 H). ¹³C NMR (250 MHz, CDCl₃): δ = 25.8, 27.0, 27.1, 29.5, 38.9, 40.4, 41.7, 43.8, 49.1, 49.4, 96.3, 116.7, 119.8, 132.0, 137.2, 144.4, 147.1, 150.4, 175.5. HRMS (EI): m/z calcd for C₁₉H₂₁NO₂ [M⁺]: 295.1572; found: 295.1571.
11c: Oil. IR (film): 2928, 1771, 1609 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.09 (qd, J = 5.7, 12.2 Hz, 1 H), 1.49 (qd, J = 2.7, 11.1 Hz, 1 H), 1.59 (m, 1 H), 1.91 (m, 2 H), 2.01 (d, J = 12.2 Hz, 1 H), 2.07 (dd, J = 4.2, 12.2 Hz, 1 H), 2.08 (m, 1 H), 2.12 (qd, J = 5.4, 11.9 Hz, 1 H), 2.12 (m, 1 H), 2.45 (td, J = 7.6, 11.3 Hz, 1 H), 2.90 (m, 1 H), 5.09 (m, 1 H), 5.88 (m, 1 H), 7.18 (d, J = 5.1 Hz, 1 H), 8.32 (s, 1 H), 8.37 (d, J = 5.1 Hz, 1 H). ¹³C NMR (250 MHz, CDCl₃): δ = 25.7, 26.7, 29.8, 31.6, 32.9, 39.5, 39.8, 41.0, 51.4, 51.9, 94.3, 116.7, 119.0, 132.4, 135.4, 147.2, 147.5, 150.3, 179.7. HRMS (EI): m/z calcd for C₁₉H₂₁NO₂ [M⁺]: 295.1572; found: 295.1569.