Download PDF
Synlett 2010(8): 1205-1208  
DOI: 10.1055/s-0029-1219810
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Stereoselective Synthesis of (-)-Pironetin by an Iterative Prins Cyclisation and Reductive Cleavage Strategy

J. S. Yadav*, Hissana Ather, N. Venkateswar Rao, M. Sridhar Reddy, A. R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax: +91(40)27160512; e-Mail: yadavpub@iict.res.in;
Further Information

Publication History

Received 17 December 2009
Publication Date:
09 April 2010 (online)

    Permissions and Reprints All articles of this category

Abstract

A stereoselective synthesis of pironetin, a natural product which is highly immunosuppressive and shows remarkable plant growth regulatory and antitumoral activities, is described. The approach avails successfully the high stereoselection of Prins cyclisation. The route relies, in addition, on the reductive opening of cyclic ethers, olefin metathesis, and lithium acetylide displacement of tosylate.

Key words

natural products - Prins cyclisation - stereoselective synthesis - reductive cleavage - olefin metathesis

    References and Notes

  • 1a Kobayashi S. Tsuchiya K. Harada T. Nishide M. Kurokawa T. Nakagawa T. Shimada N. Kobayashi K.
    J. Antibiot.  1994,  47:  697 
    Google Scholar
  • 1b Kobayashi S. Tsuchiya K. Kurokawa T. Nakagawa T. Shimada N. Iitaka Y.
    J. Antibiot.  1994,  47:  703 
    Google Scholar
  • 1c Tsuchiya K. Kobayashi S. Harada T. Nishikiori T. Nakagawa T. Tatsuta K.
    J. Antibiot.  1997,  50:  259 
    Google Scholar
  • 2 Konodoh M. Usui T. Kobayashi S. Tsuchiya K. Nishikawa K. Nishikiori T. Mayumi T. Osada H. Cancer Lett.  1998,  126:  29 
    CrossrefGoogle Scholar
  • 3 For a paper about chemical modifications of pironetin to reduce its toxicity, see: Yasui K. Tamura Y. Nakatani T. Horibe I. Kawada K. Koizumi K. Suzuki R. Ohtani M. J. Antibiot.  1996,  49:  173 
    Google Scholar
  • For examples of the Prins cyclisation, see:
  • 4a Barry CStJ. Crosby SR. Harding JR. Hughes RA. King CD. Parker GD. Willis CL. Org. Lett.  2003,  5:  2429 
    Google Scholar
  • 4b Yang X.-F. Mague JT. Li C.-J. J. Org. Chem.  2001,  66:  739 
    Google Scholar
  • 4c Aubele DL. Wan S. Floreancig PE. Angew. Chem. Int. Ed.  2005,  44:  3485 
    Google Scholar
  • 4d Barry CS. Bushby N. Harding JR. Willis CS. Org. Lett.  2005,  7:  2683 
    Google Scholar
  • 4e Cossey KN. Funk RL. J. Am. Chem. Soc.  2004,  126:  12216 
    Google Scholar
  • 4f Crosby SR. Harding JR. King CD. Parker GD. Willis CL. Org. Lett.  2002,  4:  3407 
    Google Scholar
  • 4g Marumoto S. Jaber JJ. Vitale JP. Rychnovsky SD. Org. Lett.  2002,  4:  3919 
    Google Scholar
  • 4h Kozmin SA. Org. Lett.  2001,  3:  755 
    Google Scholar
  • 4i Jaber JJ. Mitsui K. Rychnovsky SD. J. Org. Chem.  2001,  66:  4679 
    Google Scholar
  • 4j Kopecky DJ. Rychnovsky SD.
    J. Am. Chem. Soc.  2001,  123:  8420 
    Google Scholar
  • 4k Rychnovsky SD. Thomas CR. Org. Lett.  2000,  2:  1217 
    Google Scholar
  • 4l Rychnovsky SD. Yang G. Hu Y. Khire UR. J. Org. Chem.  1997,  62:  3022 
    Google Scholar
  • 4m Su Q. Panek JS. J. Am. Chem. Soc.  2004,  126:  2425 
    Google Scholar
  • 4n Yadav JS. Reddy BVS. Sekhar KC. Gunasekar D. Synthesis  2001,  885 
    Google Scholar
  • 4o Yadav JS. Reddy BVS. Reddy MS. Niranjan N. J. Mol. Catal. A: Chem.  2004,  210:  99 
    Google Scholar
  • 4p Yadav JS. Reddy BVS. Reddy MS. Niranjan N. Prasad AR. Eur. J. Org. Chem.  2003,  1779 
    Google Scholar
  • For our previous applications of Prins cyclisation, see:
  • 5a Yadav JS. Reddy MS. Rao PP. Prasad AR. Tetrahedron Lett.  2006,  47:  4397 
    Google Scholar
  • 5b Yadav JS. Reddy MS. Prasad AR. Tetrahedron Lett.  2006,  47:  4937 
    Google Scholar
  • 5c Yadav JS. Reddy MS. Prasad AR. Tetrahedron Lett.  2005,  46:  2133 
    Google Scholar
  • 5d Yadav JS. Reddy MS. Prasad AR. Tetrahedron Lett.  2006,  47:  4995 
    Google Scholar
  • 5e Yadav JS. Reddy MS. Rao PP. Prasad AR. Synlett  2007,  2049 
    Google Scholar
  • 5f Yadav JS. Rao PP. Reddy MS. Rao NV. Prasad AR. Tetrahedron Lett.  2007,  48:  1469 
    Google Scholar
  • 5g Yadav JS. Kumar NN. Reddy MS. Prasad AR. Tetrahedron  2006,  63:  2689 
    Google Scholar
  • 5h Yadav JS. Kumar Rao PP. Reddy MS. Prasad AR. Tetrahedron Lett.  2008,  49:  5427 
    Google Scholar
  • As shown below, compound 10 was subjected to TBS ether cleavage and then transformed to the corresponding acetonide to confirm the anti relationship of hydroxyl groups by examination of the ¹³C NMR spectrum. See:
  • 6a Rychnovsky SD. Skalitzky DJ. Tetrahedron Lett.  1990,  31:  945 
    Google Scholar
  • 6b Evans DA. Rieger DL. Gage JR. Tetrahedron Lett.  1990,  39:  7099 ; One broad coupling (J = 9.0 Hz) of 3-H of the acetonide in Scheme 3 in its ¹H NMR supported the stereochemistry of the 4-α-methyl group
    Google Scholar
  • 7 Nicolaou KC. Koftis TV. Vyskocil S. Petrovic G. Ling T. Yamada YMA. Tang W. Frederick MO. Angew. Chem. Int. Ed.  2004,  43:  4318 
    CrossrefGoogle Scholar
  • 8a Toshima K. Jyojima T. Miyamoto N. Katohno M. Nakata M. Mastumura S. J. Org. Chem.  2001,  66:  1708 
    Google Scholar
  • 8b Moune S. Niel G. Busquet M. Eggleston I. Jouin P. J. Org. Chem.  1997,  62:  3332 
    Google Scholar
  • 9 Imoto H. Matsumoto M. Odaka H. Sakamoto J. Kimura H. Nonaka M. Kiyota Y. Momose Y. Chem. Pharm. Bull.  2004,  52:  120 
    CrossrefGoogle Scholar
  • 10a Scholl S. Ding S. Lee CW. Grubbs RH. Org. Lett.  1999,  1:  953 
    Google Scholar
  • 10b Sanford MS. Love JA. Grubbs RH. J. Am. Chem. Soc.  2001,  123:  6543 
    Google Scholar
  • 10c Shibahara S. Fujino M. Tashiro Y. Takahashi K. Ishihara J. Hatakeyama S. Org. Lett.  2008,  10:  2139 
    Google Scholar
  • 10d Schwab P. France MB. Ziller JW. Grubbs RH. Angew. Chem., Int. Ed. Engl.  1995,  34:  2039 ; Angew. Chem. 1995, 107, 2179
    Google Scholar
11

Spectroscopic and Physical Data of Selected Compounds(2 R ,3 S ,4 R ,6 R )-2-[( S )-1-(Benzyloxy)propan-2-yl]-tetra-hydro-6-hydroxymethyl)-3-methyl-2 H -pyran-4-ol (5)
[α]D ²5 +18.5 (c 1.0, CHCl3); R f  = 0.3 (SiO2, 60% EtOAc in hexane). IR (neat): 3390, 2926, 2859, 1359, 1158, cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.23-7.30 (m, 5 H), 4.39-4.55 (m, 2 H), 3.21-3.56 (m, 7 H), 2.02-2.11 (m, 1 H), 1.77-1.86 (m, 1 H), 1.22-1.44 (m, 2 H), 0.96 (d, 3 H, J = 6.64 Hz), 0.85 (d, 3 H, J = 6.64 Hz). ¹³C NMR (75 MHz, CDCl3): δ = 138.53, 128.30, 127.48, 79.47, 75.50, 73.33, 73.12, 72.97, 65.83, 40.40, 36.77, 34.10, 12.04, 9.54. ESI-HRMS: m/z
[M + Na]+ calcd for C17H26NaO4: 317.1728; found: 317.1719.
(2 S ,3 R ,4 R ,5 R )-1-(Benzyloxy)-5-( tert -butyldimethyl-silyloxy)-2,4-dimethyloct-7-en-3-ol (10) [α]D ²5 +13.9 (c 0.65, CHCl3); R f  = 0.6 (SiO2, 10% EtOAc in hexane). IR (neat): 3500, 2930, 2855, 1461, 1063, 911 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.30-7.27 (m, 5 H), 5.81-5.67 (m, 1 H), 5.08-4.49 (m, 2 H), 4.45-4.56 (m, 2 H), 3.97-3.92 (m, 1 H), 3.75 (d, 1 H, J = 9.82 Hz), 3.53-3.39 (m, 2 H), 2.37-2.20 (m, 2 H), 1.85-1.70 (m, 2 H), 1.46 (br, OH), 0.89-0.87 (m, 12 H), 0.75 (d, 3 H, J = 6.8 Hz), 0.06 (s, 3 H), 0.09 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 138.60, 135.13, 128.24, 127.47, 127.36, 116.90, 116.67, 81.09, 73.86, 72.82, 71.15, 60.70, 40.55, 39.38, 35.30, 26.02, 18.2, 9.7, 9.1,
-3.17, -4.37. ESI-HRMS: m/z [M + Na]+calcd for C23H40NaO3Si: 415.2644; found: 415.4635.
(3 E ,6 R ,7 S ,8 R ,9 S ,11 E )-8-Methoxy-7,9-dimethyltridec-3,11-dien-6-ol (4)
[α]D ²5 +4.0 (c 1.3, CHCl3); R f  = 0.5 (SiO2, 20% EtOAc in hexane); IR (neat): 3420, 2966, 2931, 1715, 1457, 1083, 971 cm-¹; ¹H NMR (300 MHz, CDCl3): δ = 5.62-5.29 (m, 4 H), 3.90-3.83 (m, 1 H), 3.48 (s, 3 H), 2.98 (m, 1 H), 2.57 (br, 1 H, OH), 2.27-1.75 (m, 8 H), 1.67 (d, 3 H, J = 6.40 Hz), 0.98 (t, 3 H, J = 7.34 Hz), 0.92 (d, 3 H, J = 7.9 Hz), 0.89 (d, 3 H, J = 7.8 Hz). ¹³C NMR (75 MHz, CDCl3): δ = 134.69, 129.18, 126.58, 125.63, 89.80, 70.6, 61.63, 38.10, 37.8, 37.2, 36.05, 25.63, 17.93, 14.57, 13.8, 10.91. ESI-HRMS: m/z [M + Na]+calcd for C16H30NaO2: 277.1987; found: 277.1977.
(2 R ,3 S ,4 R ,6 R )-3-Ethyl-tetrahydro-6-[( E ,2 S ,3 R ,4 S )-3-methoxy-4-methyloct-6-en-2-yl]-2-vinyl-2 H -pyran-4-ol (3a)
[α]D ²5 -27.6 (c 0.65, CHCl3). IR (neat): 3427, 2967, 2929, 1718, 1457, 1089, 759 cm-¹. ¹H NMR (300 MHz, CDCl3):
δ = 5.88-5.71 (m, 1 H), 5.49-5.36 (m, 2 H), 5.26-5.11 (m, 2 H), 3.69-3.45 (m, 3 H), 3.33 (s, 3 H), 3.05 (dd, 1 H, J = 9.55, 2.94 Hz), 2.32-2.27 (m, 1 H), 2.08-1.95 (m, 2 H), 1.76-1.41 (m, 7 H), 1.25-1.14 (m, 1 H), 1.02-0.75 (m, 11 H). ¹³C NMR (75 MHz, CDCl3): δ = 130.65, 130.44, 128.71, 126.13, 84.8, 80.25, 74.34, 73.43, 70.67, 50.97, 49.21, 40.54, 38.99, 38.25, 35.49, 19.41, 17.96, 11.86, 10.18. ESI-HRMS: m/z [M + Na]+ calcd for C19H34NaO3: 333.2405; found: 333.2409.
(4 R ,5 R ,7 R ,8 S ,9 R ,10 S ,12 E )-4-Ethyl-9-methoxy-5-(methoxymethoxy)-8,10-dimethyltetradeca-2,12-dien-7-yl acetate (17)
IR (neat): 2929, 2855, 1740, 1244, 1097, 966 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 5.51-5.03 (m, 5 H), 4.63-4.59 (m, 2 H), 3.56-3.41 (m, 1 H), 3.39 (s, 3 H), 3.37 (s, 3 H), 2.84-2.77 (m, 1 H), 2.03 (s, 3 H), 2.17-1.91 (m, 3 H), 1.66 (d, 6 H, J = 5.28 Hz), 1.75-1.50 (m, 4 H), 1.45-1.28 (m, 2 H), 0.92-0.79 (m, 9 H). ¹³C NMR (75 MHz, CDCl3): δ = 170.40, 134.51, 132.50, 125.50, 125.5, 96.30, 88.51, 66.99, 68.30, 58.0, 55.62, 49.06, 39.52, 36.42, 35.50, 33.75, 23.65, 21.20, 19.53, 19.35, 15.30, 12.42, 10.25. ESI-HRMS: m/z [M + Na]+ calcd for C23H24NaO5: 421.2929; found: 421.2923.
(5 R ,6 R )-5-Ethyl-5,6-dihydro-6-[( E ,2 R ,3 S ,4 R ,5 S )-2-hydroxy-4-methoxy-3,5-dimethylnon-7-enyl]pyran-2-one (1)
[α]D ²5 -139.5 (c 0.35, CHCl3); R f  = 0.3 (SiO2, 50% EtOAc in hexane); IR (neat): 3479, 2965, 2931, 1718, 1459, 1384, 1088 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.04 (dd, 1 H, J = 9.82, 6.04 Hz), 6.04 (d, 1 H, J = 9.82 Hz), 5.50-5.32 (m, 2 H), 4.76 (m, 1 H), 4.23 (br d, 1 H), 3.47 (s, 3 H), 3.39 (br, OH), 2.36-2.27 (m, 1 H), 3.00-2.97 (m, 1 H), 2.13-2.06 (m, 1 H), 1.97-1.63 (m, 6 H), 1.67 (d, 3 H, J = 5.27 Hz), 1.56-1.45 (m, 1 H), 1.01 (t, 3 H, J = 7.18 Hz), 0.97 (d, 3 H, J = 7.18 Hz), 0.95 (d, 3 H, J = 6.70 Hz). ¹³C NMR (75 MHz, CDCl3): δ = 164.1, 144.8, 121.5, 96.1, 75.2, 69.7, 55.4, 41.8, 29.4, 20.1.164.75, 150.77, 130.08, 126.91, 120.72, 90.2, 77.73, 67.17, 61.55, 39.16, 39.05, 37.32, 36.73, 35.96, 20.76, 17.91, 15.1, 11.88, 10.96. ESI-HRMS: m/z [M + Na]+ calcd for C19H32NaO4 347.2198; found: 347.2205.