Naturally improving insulin resistance with amorfrutins

Syntheses of Amorfrutins and Derivatives via Tandem Diels–Alder and Anionic Cascade Approaches

“…Amorfrutins are plant-derived natural products based on an isoprenoid-substituted β-resorcylic acid core, with a wide range of biological activities. , Amorfrutin A ( 1 ) and B ( 2 ) (Figure a), isolated from Amorpha fruticosa and Glycyrrhiza foetida , increase insulin production in mice by targeting the peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of fat and glucose metabolism, and further decrease inflammation. − A structural variant, amorfrutin 2 ( 3 ), also demonstrates high affinity to PPARγ despite bearing a pentyl group instead of the phenethyl moiety. Amorfrutin C ( 4 ), isolated from the plant Glycyrrhiza foetida , reduces colon cancer progression by disrupting mitochondrial function via an unknown mechanism. , Corresponding resorcinol derivatives of amorfrutin A and B have been isolated from R. complanata and H. umbraculigerum , − and similar resorcinol-based natural products have been described, such as grifolic acid ( 5 ) first identified from the fungus Albatrellus confluens .…”

“…A morfrutins are plant-derived natural products based on an isoprenoid-substituted β-resorcylic acid core, with a wide range of biological activities. 1,2 Amorfrutin A (1) and B (2) (Figure 1a), isolated from Amorpha f ruticosa and Glycyrrhiza foetida, increase insulin production in mice by targeting the peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of fat and glucose metabolism, and further decrease inflammation. 3−5 A structural variant, amorfrutin 2 (3), also demonstrates high affinity to PPARγ despite bearing a pentyl group instead of the phenethyl moiety.…”

“…Nuclear magnetic resonance (NMR) spectra were recorded on Varian INOVA 600 (600 MHz), Varian INOVA 400 (400 MHz), and Bruker AV500 spectrometers at Cornell University's NMR facility. 1 H NMR chemical shifts are reported in ppm (δ) relative to residual solvent peaks (7.26 ppm for chloroform-d, 7.16 ppm for benzene-d 6 , 2.05 for acetone-d 6 ). NMR spectroscopic data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constants (Hz), and integrals.…”

“…Flash column chromatography on alumina using 3% EtOAc in hexanes afforded 10b (1.40 g, 55%, primarily β,γ isomer) as a colorless oil, with up to ∼9% (mol/mol) bis-alkyl impurity. 1 H NMR (500 MHz, benzene-d 6 ): δ 5.27 (t, J = 7.1 Hz, 1H), 5.19 (t, J = 7.0 Hz, 1H), 4.14 (d, J = 2.4 Hz, 1H), 3.92 (d, J = 2.4 Hz, 1H), 3.37 (s, 3H), 3.24 (t, J = 7.7 Hz, 1H), 3.14 (s, 3H), 2.82 (ddd, J = 14.6, 7.4 Hz, 1H), 2.66 (ddd, J = 14.6, 7.4 Hz, 1H), 2.12 (q, J = 7.6 Hz, 2H), 2.03 (t, J = 7.3 Hz, 2H), 1.67 (br s, 3H), 1.58 (s, 3H), 1.54 (s, 3H). 13 (Z)-Ethyl-3-chloro-5-phenylpent-2-enoate (11a).…”

“…Flash column chromatography on silica using a gradient of 0−20% EtOAc in hexanes was performed, affording 11a (4.40 g, 92%) as a yellow oil. 1 H NMR (500 MHz, benzene-d 6 ): δ 7.13−7.05 (m, 2H), 7.06−6.99 (m, 1H), 6.90−6.84 (m, 2H), 5.71 (t, J = 0.9 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 2.59−2.51 (m, 2H), 2.28− 2.20 (m, 2H), 0.94 (t, J = 7.1 Hz, 3H). 13 (Z)-Ethyl-3-chlorooct-2-enoate (11b).…”