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

Xiang Ma; Yuting Song; Hao Liu; Ruijiao Chen; Xiaochuan Chen

doi:10.1055/s-0031-1290352

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Synlett 2012(4): 607-610
DOI: 10.1055/s-0031-1290352

LETTER

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

Xiang Ma^a, Yuting Song^a, Hao Liu^a, Ruijiao Chen^a, 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)

Abstract
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Supplementary Material

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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

Supporting Information

References and Notes

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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.

Supplementary Material

Supporting Information