Syntheses of dechlorogreensporones A and D

Abstract

Dechlorogreensporones A (1) and D (2) are new 14-membered ẞ-resorcylic acid lactones (RALs), which were isolated, along with other 12 new RALS from a culture of a fresh water fungus Halenospora sp. originating from a stream in North Carolina, USA by Oberlies and co-workers in 2014. The structures of compounds 1 and 2 contain a 14-membered ẞ-resorcylic acid lactone with an (E)-enone at C8-C10 and a stereogenic center at the 2-position. The only structural difference is that 1 consists of a keto group at the 5-position, while 2 bears an alcohol stereogenic center. These isolated natural products 1 and 2 displayed cytotoxicity against the MDA-MB- 435 melanoma cancer cell line with IC50 values of 14.1 and 11.2 μM, respectively. They also displayed cytotoxicity against the HT-29 colon cancer cell line with IC50 values of >20 and 25.4 μM, respectively. This work involves the syntheses of 1 and 2 in order to confirm the assigned absolute configuration of these natural products and to further evaluate cytotoxic activity against other cancer cell lines. The key strategies include ring-closing metathesis of diene precursor 9 or 10 to assemble the 14- membered macrolactone and to also construct the E-double bond at C8-C9, and Mitsunobu esterification between alcohol intermediate 4 or 6 and benzoic acid derivative 8 to form the ester bond of diene 9 or 10. Alcohol intermediate 4 was prepared in 6 steps via allylation of R-(+)-propylene oxide (3), while alcohol intermediate 6 was synthesized from 1,2-epoxy-5-hexene (5) in 9 steps using Jacobsen hydrolytic kinetic resolution (HKR) to generate the stereogenic center at the 5-position. The synthesis of benzoic acid 8 was accomplished in 12 steps from methyl 2-(2-formyl-3,5-dihydroxyphenyl)acetate (7). The syntheses of dechlorogreen- sporones A (1) and D (2) have been completed via a longest linear 17 steps from known phenol 7. The synthesis of 1 has been accomplished in 23 total steps in 2.8% overall yield, while the synthesis of 2 has been achieved in 26 total steps in 5.4% overall yield. The 'H and 13C NMR spectroscopic data, HRMS data and specific rotation of synthetic compounds 1 and 2 were in excellent agreement with those reported for the natural products, which confirmed the assigned absolute configurations of the natural products. Synthetic compounds 1 and 2 were found to exhibit the cytotoxic activity against seven cancer cell lines with the IC50 range of 6.66-17.25 μM. Moreover, dechlorogreensporone D (2) displayed more potent antiproliferative activity against these seven cancer cell lines compared to dechloro- greensporone A (1). Nevertheless, 1 was approximately 5-fold less cytotoxic to Vero cells compared to 2.