Total synthesis and cytotoxic activity of dechlorogreensporones A and D

Abstract

The first and convergent total syntheses of polyketide natural products dechlorogreensporones A and D have been accomplished in 17 longest linear steps with 2.8% and 5.4% overall yields, respectively, starting from known methyl 2-(2-formyl-3,5-dihydroxyphenyl)acetate and commercially available R-(+)-propylene oxide and 1,2-epoxy-5-hexene. Our synthesis exploited key Mitsunobu esterification and (E)-selective ring-closing metathesis (RCM) to assemble the macrocycles as well as a Jacobsen hydrolytic kinetic resolution to install the stereogenic centers. Both synthetic compounds were found to display significant cytotoxic activity against seven human cancer cell lines with the IC₅₀ ranges of 6.66–17.25 μM.

Introduction

The well-known 14-membered β-resorcylic acid lactones (RALs) are a group of fungal polyketide metabolites that possess a multitude of biological and pharmacological activities [1]. A subclass of RALs are those containing an α,β-unsaturated ketone at the 8–10 positions, which are derivatives of radicicol [2]. The major examples of this subclass of RALs are the pochonins [3] and the monocillins [4] (Fig. 1). This group of metabolites has been shown to exhibit various interesting biological activities e.g. antiviral activity against Herpes Simplex Virus 1 (HSV 1) [3a], antifungal activity (against Mucorflavas IFO 9560) [5], HSP-90 inhibitory activity [6], and latent HIV-1 reactivation activity [3c]. In consequence of their diverse and promising biological properties and structural features, this class of macrolides has been synthetic targets for many synthetic organic research groups worldwide [7]. Precedented strategies to construct the macrocyclic cores of RALs possessing similar core skeleton mainly relied on esterification reaction [7] and ring-closing metathesis [7](c), [7](f), [7](g), [7](h), [7](i), [7](j), [7](k) (Fig. 2). Other key bond formations included Pd-catalyzed cross coupling/elimination [7](a), [7](b), [7](d), [7](e), substitution by dithiane anion [7c] and nucleophilic addition to Weinreb amide (acylation) [[7](f), [7](g), [7](h), [7](i)].

Dechlorogreensporones A (5) and D (6) are new 14-membered β-RALs, which were isolated, along with other 12 new RALs from a culture of a freshwater fungus Halenospora sp. by Oberlies and co-workers in 2014 (Fig. 3) [8]. Compounds 5 and 6 are radicicol analogues possessing a methoxy group at the 16-position, which represent rare examples of RALs containing β-resorcylic acid monomethyl ethers. Dechlorogreensporones A and D have the same planar structure which includes a stereogenic center at the 2-position. However, the minor structural difference is that 5 contains a keto group at the 5-position, whereas 6 bears an alcohol stereogenic center. In addition, dechlorogreensporone A (5) is structurally very similar to the previously reported natural product cryptosporiopsin A [9]. The absolute configuration of the C-2 asymmetric carbon in macrolactones 5 and 6 and other co-metabolites was proposed by the isolation group to be S by the evidence of X-ray diffraction analysis of the bromobenzoyl derivative of one of the metabolites in the series. The absolute configuration of the C-5 in 6 and co-metabolites containing C-5 alcohol stereogenic center was assigned to be S via a Mosher's ester method. Interestingly, the assigned C-2 absolute configuration of 5 and 6 and other analogues in the series is opposite to that of cryptosporiopsin A, which was assigned by analogy to the known RAL pochonin D. Dechlorogreensporones A and D were tested for cytotoxic activities against two human cancer cell lines and were found to exhibit cytotoxicity against the MDA-MB-435 (melanoma) cancer cell line with IC₅₀ values of 14.1 and 11.2 μM, respectively. They also exhibited cytotoxicity against the HT-29 (colon) cancer cell line with IC₅₀ values of >20 and 25.4 μM, respectively. Due to promising biological activities of this subclass of RALs and our ongoing program for anticancer drug discovery, our research group has been focusing on a synthetic program of selected compounds of this class. Herein, we report the first total synthesis of both 5 and 6 as well as evaluation of their cytotoxic activity against seven human cancer cell lines.