Synthesis of (±)-mispyric acid, a triterpene inhibitor of DNA polymerase β isolated from Mischocarpus pyriformis

Inhibitory Effect of Mispyric Acid on Mammalian DNA Polymerases

“…Both natural mispyric acid (compound 1) and unnatural (the enantiomer) mispyric acid (entmispyric acid, compound 2), as well as derivatives of the two which have hydroxyl groups instead of carboxyl groups (i.e., compounds 3 and 4, respectively) were synthesized chemically as described previously. 2,3) The chemical structures of compounds 1-4 are shown in Fig. 1.…”

“…We synthesized both enantiomers of mispyric acid and derivatives of the two starting with isoprene, geraniol and 1,5-dimethoxy-1.4-cyclohexadiene. 2,3) We then investigated the inhibitory effects on major mammalian pols (i.e., pol to ") of these compounds. We discuss the relationship between the structure of mispyric acid and the inhibition of mammalian pols.…”

Triterpenoid total synthesis. Synthesis and absolute configuration of mispyric acidTriterpenoid total synthesis. Part 8. For part 7 see ref. 1

“…After having been stirred at this temperature for 30 min, the mixture was cooled to −90 °C, and the solution of 13 (543 mg, 1.01 mmol) in THF (1 cm 3 ) was quickly added. The mixture was allowed to warm to room temperature and stirred for 1 h. 5.02 (1 H, t, J 6.9, CHC), 5.12 (1 H, t, J 6.8, CHC), 5.17 (1 H, m, CHC), 5.24 (1 H, t, J 6.4, 4′-H), 7.35-7.44 (6 H, m, m-, p-Ar), 7.68 (4 H, dd, J 8.0 and 1.7, o-Ar);  C (100 MHz; CDCl 3 ) −5. 1, 16.0, 16.1, 17.7, 18.4, 19.2, 20.7, 23.7, 25.2, 25.7, 25.9, 26.0, 26.7, 27.0, 28.0, 34.7, 38.3, 39.9, 44.8, 54.7, 60.3, 61.2, 118.5, 122.3, 124.0, 124.5, 126.2, 127.6, 129.5, 131.1, 133.7, 135.5, 136.3, 137.5, 138.1, 170.8, 199.5.…”

“…2 In continuation of our works on synthesis of DNA polymerase inhibitors 3 and biosynthetically unique triterpenoids, 4 we initiated the synthesis of mispyric acid (1). While we have already reported the first synthesis of (±)-1 as a preliminary communication, 5 the enantioselective synthesis of 1 has never been disclosed and the absolute configuration of natural 1 has remained unknown. Herein, we report the first synthesis and determination of the absolute configuration of 1 in detail.…”

“…Our synthetic plan for 1 is shown in Scheme 1, which is based on our racemate synthesis. 5 The target compound 1 was readily obtainable from A, which was prepared from B by installation of a methyl group to the enone and subsequent methylenation of the carbonyl group. For the construction of the key intermediate B, two alkylations (C with D, and E with F) were chosen as the key steps.…”