Download PDF
Synlett 2012(4): 607-610  
DOI: 10.1055/s-0031-1290352
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

First Syntheses of Lorneic Acids A and B with Potential PDE5 Inhibition Activity

Xiang Maa, Yuting Songa, Hao Liua, Ruijiao Chena, Xiaochuan Chen*a,b
a Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, P. R. of China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax: +86(28)85413712; e-Mail: chenxc@scu.edu.cn;
Further Information

Publication History

Received 23 November 2011
Publication Date:
13 February 2012 (online)

   Permissions and Reprints All articles of this category
Preview

Abstract

Two natural products with potential PDE5 inhibition activity, lorneic acids A and B, have been synthesized for the first time in high yield using a chiral amide stereocontrolled addition of aryl lithium to aldehyde as the key step, and the configuration of the chiral benzylic alcohol in lorneic acid B was determined to be S.

Key words

lorneic acid A/B - PDE5 inhibitor - asymmetric synthesis - chiral auxiliary - ortho-lithiation

    References and Notes

  • 1 Iwata F. Sato S. Mukai T. Yamada S. Takeo J. Abe A. Okita T. Kawahara H. J. Nat. Prod.  2009,  72:  2046 
    Search in Google Scholar
  • 2a Bhatnagar I. Kim SK. Mar. Drugs  2010,  8:  2673 
    Search in Google Scholar
  • 2b Yasuhara SE. Drugs Future  2011,  36:  321 
    Search in Google Scholar
  • 2c Speakman MJ. Curr. Pharm. Des.  2009,  15:  3502 
    Search in Google Scholar
  • 3 Capon RJ. Skene C. Lacey E. Gill JH. Wicker J. Heiland K. Friede T. J. Nat. Prod.  2000,  63:  1682 
    Search in Google Scholar
  • 4 Saksena AK. Jao E. Murphy B. Schumacher D. Chan TM. Puar MS. Jenkins JK. Maloney D. Cordero M. Pramanik BN. Bartner P. Das PR. McPhail AT. Girijavallabhan VM. Ganguly AK. Tetrahedron Lett.  1998,  39:  8441 
    Search in Google Scholar
  • 5a Puterbaugh WH. Hauser CR. J. Org. Chem.  1964,  29:  853 
    Search in Google Scholar
  • 5b Baldwin JE. Bair KW. Vaulx RL. Puterbaugh WH. Hauser CR. J. Org. Chem.  1964,  29:  3514 
    Search in Google Scholar
  • 5c Marxer A. Rodriguez HR. J. Org. Chem.  1975,  40:  1427 
    Search in Google Scholar
  • 6a Beak P. Brown RA. J. Org. Chem.  1977,  42:  1823 
    Search in Google Scholar
  • 6b Beak P. Brown RA. J. Org. Chem.  1982,  47:  34 
    Search in Google Scholar
  • 6c Watanabe M. Snieckus V. J. Am. Chem. Soc.  1980,  102:  1457 
    Search in Google Scholar
  • 6d Beak P. Tse A. Hawkins J. Chen C.-W. Mills S. Tetrahedron  1983,  39:  1983 
    Search in Google Scholar
  • 7a Poolsak S. Nopporn T. Somsak R. Synthesis  2005,  2934 
  • 7b Anstiss M. Clayden J. Grube A. Youssef LH. Synlett  2002,  290 
  • 7c Gonnot V. Antheaume C. Nicolas M. Mioskowski C. Baati R. Eur. J. Org. Chem.  2009,  6205 
  • 7d Hart DJ. Mannino A. Tetrahedron  1996,  52:  3841 
    Search in Google Scholar
  • 7e Shankaran K. Snieckus V. J. Org. Chem.  1984,  49:  5022 
    Search in Google Scholar
  • 8 Matsui S. Uejima A. Suzuki Y. Tanaka K. J. Chem. Soc., Perkin Trans. 1  1993,  701 
  • 11 Trost BM. Belletire JL. Godleski S. McDougal PG. Balkovec JM. J. Org. Chem.  1986,  51:  2370 
    Search in Google Scholar
  • 12a Narayanan KS. Berlin KD. J. Org. Chem.  1980,  45:  2240 
    Search in Google Scholar
  • 12b Beugelmans R. Chastanet J. Ginsburg H. Quintero-Cortes L. Roussi G. J. Org. Chem.  1985,  50:  4933 
    Search in Google Scholar
  • 13a Nateuda F. Terashima S. Tetrahedron  1988,  44:  4721 
    Search in Google Scholar
  • 13b Kozikowski AP. Lee J. J. Org. Chem.  1990,  55:  863 
    Search in Google Scholar
  • 14 Trost BM. Rudd MT. Org. Lett.  2003,  5:  4599 
    Search in Google Scholar
  • 15 Fujioka H. Kitagawa H. Nagatomi Y. Kita Y. J. Org. Chem.  1996,  61:  7309 
    Search in Google Scholar
  • 16 Sugai T. Katoh O. Ohta H. Tetrahedron  1995,  51:  11987 
    Search in Google Scholar
9

A solution of 10 (0.13 g, 0.45 mmol) in THF (6 mL) was added to a stirred mixture of t-BuLi (0.65 mL, 1.03 mmol) and TMEDA (0.15 mL, 0.99 mmol) in THF (2 mL) at -78 ˚C. The mixture was warmed to 0 ˚C and stirred for 5 min, then cooled to -78 ˚C again. To the mixture a solution of hexanal (0.12 mL, 0.99 mmol) in THF (1 mL) was added and stirred at -78 ˚C for 30 min. Then the mixture was warmed to r.t. and stirred overnight, quenched with sat. NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography to afford a mixture of 13a and 13b (0.13g, 76%). The mixture of 13a and 13b (0.13 g, 0.34 mmol) was dissolved in MeCN (9 mL), then DMAP (12 mg, 0.10 mmol) and Boc2O (0.26 mL, 1.22 mmol) were added, stirred overnight at r.t. After concentration the residue was purified by column chromatography to afford 14a (0.13 g, 80%) and 14b (28 mg, 17%). Compound 14a: [α]D ²5 -69 (c = 1.2, MeOH). IR (neat): 3326, 2929, 2859, 1739, 1655, 1529, 1370, 1280, 1163, 1089, 1026 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.20-7.28 (m, 8 H), 7.09 (d, J = 7.9 Hz, 1 H), 5.88 (dd, J = 5.8, 8.0 Hz, 1 H), 4.49-4.53 (m, 1 H), 3.49 (dd, J = 4.0, 9.5 Hz, 1 H), 3.39 (dd, J = 4.8, 9.5 Hz, 1 H), 3.34 (s, 3 H), 2.97 (dd, J = 6.9, 13.6 Hz, 1 H), 2.93 (dd, J = 7.5, 13.3 Hz, 1 H), 2.35 (s, 3 H), 1.82-1.88 (m, 1 H), 1.68-1.74 (m, 1 H), 1.42 (s, 9 H), 1.23-1.25 (m, 6 H), 0.84 (t, J = 6.6, 13.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 168.7, 153.6, 140.2, 138.7, 138.2, 133.2, 129.4, 128.6, 128.4, 127.6, 126.4, 126.3, 82.3, 76.4, 72.7, 58.8, 50.7, 37.6, 37.3, 31.5, 27.8, 25.3, 22.4, 21.4, 14.0. HRMS (ESI+): m/z [M + Na]+ calcd for C29H41NO5Na: 506.2882; found: 506.2880. Compound 14b: [α]D ²5 -18 (c = 0.4, MeOH).
IR (neat): 3328, 2928, 2854, 1739, 1657, 1523, 1370, 1278, 1160, 1089, 1025 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.20-7.33 (m, 8 H), 7.09 (d, J = 7.6 Hz, 1 H), 5.43 (t, J = 7.0, 14.0 Hz, 1 H), 4.53-4.59 (m, 1 H), 3.46 (dd, J = 4.0, 9.6 Hz, 1 H), 3.43 (dd, J = 5.9, 10.6 Hz, 1 H), 3.37 (s, 3 H), 3.05 (dd, J = 6.9, 13.9 Hz, 1 H), 2.95 (dd, J = 8.1, 13.8 Hz, 1 H), 2.33 (s, 3 H), 1.55-1.72 (m, 2 H), 1.46 (s, 9 H), 1.10-1.26 (m, 6 H), 0.82 (t, J = 6.9, 14.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 168.7, 153.5, 140.2, 138.4, 138.3, 133.2, 129.3, 128.6, 128.4, 127.9, 126.4, 126.1, 82.4, 76.4, 73.3, 59.0, 50.7, 37.3, 37.1, 31.6, 27.8, 24.8, 22.4, 21.4, 14.1. HRMS (ESI+): m/z [M + Na]+ calcd for C29H41NO5Na: 506.2882; found: 506.2877.

10

Compound 17: ¹H NMR (400 MHz, CDCl3): δ = 7.28-7.35 (m, 5 H), 7.13 (d, J = 7.7 Hz, 1 H), 6.94 (d, J = 7.5 Hz, 1 H), 6.62 (s, 1 H), 5.88 (dd, J = 4.2, 9.2 Hz, 1 H), 4.85 (d, J = 12.4 Hz, 1 H), 4.78 (s, 1 H), 4.63 (d, J = 12.4 Hz, 1 H), 3.39 (s, 3 H), 2.08 (s, 3 H), 1.66-1.85 (m, 2 H), 1.15-1.45 (m, 6 H), 0.90 (s, 9 H), 0.86 (t, J = 6.8, 13.4 Hz, 3 H), 0.09 (s, 3 H), 0.05 (s, 3 H). Compound 18: ¹H NMR (400 MHz, CDCl3):
δ = 7.43-7.48 (m, 2 H), 7.30-7.38 (m, 3 H), 7.22 (d, J = 7.7 Hz, 1 H), 7.08 (s, 1 H), 7.03 (d, J = 7.8 Hz, 1 H), 5.92 (dd,
J = 4.2, 9.3 Hz, 1 H), 4.90 (d, J = 12.4 Hz, 1 H), 4.75 (s, 1 H), 4.67 (d, J = 12.4 Hz, 1 H), 3.37 (s, 3 H), 2.29 (s, 3 H), 1.61-1.77 (m, 2 H), 1.01-1.08 (m, 6 H), 0.91 (s, 9 H), 0.78 (t, J = 6.5, 13.4 Hz, 3 H), 0.10 (s, 3 H), 0.06 (s, 3 H).

17

Synthesis of (-)-2: A solution of 25 (35.3 mg, 0.11 mmol) in t-BuOH (3 mL) containing concd HCl (0.3 mL) was stirred at 40 ˚C for 6 h. After cooling, the mixture was extracted with EtOAc. The extract was dried over Na2SO4 and concentrated. The residue was purified by column chroma-tography to afford (-)-2 as a colorless oil (27.7 mg, 91%); [α]D ²¹ -20 (c = 0.3, MeOH). IR (neat): 3405, 2928, 2861, 1710, 1613, 1458, 1398, 1206, 1061, 958 cm-¹. ¹H NMR (400 MHz, CD3OD): δ = 7.32 (d, J = 8.0 Hz, 1 H), 7.26 (s, 1 H), 7.01 (d, J = 7.7 Hz, 1 H), 6.81 (d, J = 15.6 Hz, 1 H), 6.12 (dt, J = 7.1, 15.6 Hz, 1 H), 4.94 (t, J = 6.5, 13.2 Hz, 1 H), 3.22 (d, J = 7.1 Hz, 2 H), 2.32 (s, 3 H), 1.64-1.67 (m, 2 H), 1.30-1.42 (m, 6 H), 0.90 (t, J = 6.8, 11.4 Hz, 3 H). ¹³C NMR (100 MHz, CD3OD): δ = 175.6, 143.4, 138.4, 133.5, 131.8, 128.8, 127.4, 127.3, 124.8, 71.3, 39.7, 39.2, 32.9, 26.7, 23.7, 21.4, 14.4. HRMS (ESI+): m/z [M + NH4]+ calcd for C17H28NO3: 294.2064; found: 294.2057.

18

It is noteworthy that slight concentration-dependent changes in the chemical shifts of the signals of the unsaturated carboxyl acid chain were observed in NMR spectra of 2, owing to variable aggregation extent via carboxyl group (see Supporting Information).

19

Synthesis of 1: A solution of 28 (91 mg, 0.38 mmol) and KOH (0.31 g) in 30% EtOH-H2O (5 mL) was stirred for 8 h at 100 ˚C. After cooling to r.t., the mixture was acidified with 3 M HCl acid to pH 3, and was extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to afford 1 (70 mg, 72%) as a pale yellow oil. IR (neat): 2958, 2928, 2855, 1709, 1605, 1460, 1222, 1163, 1094, 965 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 7.9 Hz, 1 H), 7.18 (s, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.74 (d, J = 15.7 Hz, 1 H), 6.59 (d, J = 15.6 Hz, 1 H), 6.09 (dt, J = 6.9, 15.6 Hz, 1 H), 6.04 (dt, J = 7.0, 15.6 Hz, 1 H), 3.28 (d, J = 6.9 Hz, 2 H) 2.31 (s, 3 H), 2.23 (q, J = 6.8 Hz, 2 H), 1.33-1.48 (m, 4 H), 0.93 (t, J = 7.2, 14.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 177.5, 137.2, 136.0, 133.6, 131.9, 131.5, 127.8, 127.5, 127.0, 126.4, 122.4, 38.8, 33.0, 31.6, 22.3, 21.2, 14.0. HRMS (ESI+): m/z [M + H]+ calcd for C17H23O2: 259.1693; found: 259.1687.