The resorcylic macrolide is an important family of natural products featuring a 6-alkyl-2,4-dihydroxybenzoic acid (the β-resorcylate moiety) fused with a macrocyclic lactone ring. These resorcylic macrolides have demonstrated a wide range of important biological activities. For example, trans-resorcylide (1, Fig. 1) and cis-resorcylide (2) are plant growth inhibitors [1, 2]. Radicicol (3) was originally isolated from Monicillium nordinii in 1953 [3] and has shown antibiotic anticancer activity. It was later discovered as a potent and selective heat shock protein 90 (Hsp90) inhibitor with IC50 of 20 nM [4]. Hsp90 is a chaperon protein and has been an important therapeutic target for developing new cancer treatment. Monocillin VI (4) was recently isolated from the cultures of Paecilomyces sp. SC0924. It exhibited potent growth inhibition activity against quite a few cancer cell lines including MCF-7, A549, and Hela cells as well as antifungal activity against Peronophythora litchi [5].

Fig. 1
figure 1

Selected resorcylic macrolides and our synthetic plan via macrocyclic Stille carbonylation

These resorcylic macrolides, due to their diverse structures and remarkable biological activities, have garnered a significant amount of synthetic attention. For example, Couladouros et al. reported the first total synthesis of trans-resorcylide (1) and cis-resorcylide (2) in 2004 [6]. Miller and Mennen reported a formal synthesis of trans-resorcylide (1) in 2007 [7]. Tsuji et al. synthesized dehydroxy-trans-resorcylide by an intramolecular alkylation [8]. Radicicol (3) has been synthesized by the groups of Lett [9, 10], Danishefsky [11,12,13], and Winssinger [14]. The Danishefsky group also synthesized cycloproparadicicol to improve the corresponding pharmacokinetics and reduce nonspecific toxicities [15]. The key for synthesizing these resorcylic macrolides is to construct the β-resorcylate moiety and the macrolactone moiety. While most of the syntheses relied on starting materials already equipped with the resorcylate core, Danishefsky and co-workers reported a remarkable Diels-Alder reaction of strained ynolides to build the β-resorcylate moiety. For the macrolactone moiety, macrolactonization and ring closing metathesis are the two common strategies to form the desired macrolactones. Notably, in Miller’s formal synthesis of trans-resorcylide (1), an acyl-anion equivalent macrocyclization was used to build the corresponding macrocycle.

Our group has been developing novel palladium-catalyzed carbonylation reactions to facilitate the total synthesis of complex natural product [16, 17]. For example, we have developed a palladium-catalyzed alkoxycarbonylative macrolactonization to streamline the synthesis of tetrahydropyran/tetrahydrofuran-containing bridged macrolactones including 9-demethylneopeltolide [18]. This effective method was also used as the key step in Harran’s total synthesis of callyspongiolide [19]. An intramolecular carbonylative Heck macrolactonization has been realized and utilized by us to streamline the total synthesis of spinosyn A [20]. We also developed a novel palladium-catalyzed carbonylative spirolactonization of hydroxycyclopropanols to synthesize oxaspirolactone-containing C12-oxygenated labdanolic diterpenes α-levantanolide and α-levantenolide [21] and stemona alkaloids bisdehydroneostemoninine and bisdehydrostemoninine [22]. Very recently, we have used a palladium-catalyzed hydrocarbonylative lactonization to synthesize three rare abies sesquiterpenoids, which in turn enabled the identification of novel selective covalent inhibitors of oncogenic protein tyrosine phosphatase SHP2 and elucidation of DNA polymerase epsilon subunit 3 (POLE3) as one of their potential cellular targets [23]. In this context, we considered the possibility of developing a palladium-catalyzed macrocyclic Stille carbonylation to build the desired macrocyclic enone moiety of these resorcylic macrolides (cf. 1-4) by converting vinylstannane-containing benzyl chloride 6 to macrocyclic enone 5. Macrocyclic Stille carbonylation has been rarely used in total synthesis [24, 25] and no macrocyclic Stille carbonylation of benzyl chloride has been reported so far. Therefore, we hope to develop a new strategy to access these important resorcylic macrolides and generalize the macrocyclic Stille carbonylation for macrocyclic enone synthesis.

We chose cis-resorcylide (2) as the initial target molecule to test the hypothesis of using the macrocyclic Stille carbonylation to build the corresponding macrocycle. For this purpose, benzyl chloride 20 (Scheme 1b) with an intramolecularly tethered vinylstannane need to be prepared. We planned to use an esterification of acyl chloride 19 and secondary alcohol 14 to synthesize the macrocyclic Stille carbonylation precursor 20. Our synthesis of 14 started from known bromide 9 [26], which was treated with Mg metal and 1,2-dibromoethane followed by transmetalation with CuI. The resulting cuprate reagent underwent regioselective epoxide ring opening with epoxide 10 to afford alcohol 11 in 74% yield. After removal of the TMS group with Cs2CO3 in MeOH, the terminal alkyne was subsequently converted to alkynyl stannane via deprotonation with nBuLi followed by trapping the acetylide with nBu3SnCl. Stereoselective reduction of the internal alkyne with the Schwartz’s reagent gave cis-vinylstannane 14 in good yield. We then synthesized known benzoic acid 18 from commercially available starting material 15. Vilsmeier-Haack formylation accompanied by in situ chlorodehydration gave aldehyde 16 in quantitative yield. Due to the difficulties we encountered in removing the methyl groups at a late stage, the two methyl ethers were switched to benzyl ethers via a sequence of BBr3 deprotection and benzylation with BnBr in presence of Cs2CO3 in acetone. The resulting benzyl protected aldehyde 17 was then oxidized to benzoic acid 18, which was subsequently converted to acyl chloride 19 with the treatment of oxalyl chloride and DMF in DCM. Acyl chloride 19, without further purification was reacted with alcohol 14 to deliver the Stille carbonylation precursor 20 in modest yield.

Scheme 1
scheme 1

Total synthesis of trans-resorcylide (1)

With 20 in hand, we investigated various reaction conditions for the macrocyclic Stille carbonylation and were surprised to discover that, under the reaction conditions of 10 mol% of Pd(PPh3)4 and 20 mol% of P(2-furyl)3 under balloon pressure of carbon monoxide in p-dioxane at 80 °C, macrocyclic product 21 with a trans-enone was obtained in 36% yield while compound 20 contains a cis-vinylstannane moiety. The expected macrocyclic cis-enone was not isolated. We didn’t observe the direct intramolecular Stille cross coupling product too. The detailed reaction mechanism for the formation of the macrocyclic trans-enone was not fully understood at this stage. One hypothesis is that the macrocyclic cis-enone was initially formed, but then quickly isomerized to the trans one under the carbonylation reaction conditions via either a reversible Michael-type addition with PPh3 and/or P(2-furyl)3 as the nucleophile at the relative high reaction temperature or a Pd-catalyzed isomerization probably involving in situ formed Pd-H species. Removal of the two benzyl groups with the treatment of BCl3 at −78 °C in DCM [27] completed the total synthesis of trans-resorcylide (1). Notably, removal of these two benzyl groups was nontrivial at all. Couladouros and co-workers had experienced difficulties in converting 21 to trans-resorcylide (1) directly and developed a three-step detour. In our case, the use of solid NaHCO3 and methanol to quench the final benzyl deprotection at low temperature is important and the use of aqueous NaHCO3 solution led to decomposition of the final product. The 1H NMR, 13C NMR, and other spectroscopic data of our synthetic trans-resorcylide (1) match well with the reported ones.

In summary, we have developed a total synthesis of trans-resorcylide (1). The synthesis features a palladium-catalyzed macrocyclic Stille carbonylation to build the 12-membered macrocycle. Notably, while intermediate 20 contains a cis-vinylstannane, the palladium-catalyzed macrocyclic Stille carbonylation delivered product 21 with a trans-enone moiety. We are currently using the macrocyclic Stille carbonylation strategy to synthesize other family members of the resorcylic macrolides as well as probe molecules to understand their mode of actions.