Total Synthesis of (−)‐Reidispongiolide A, an Actin‐Targeting Marine Macrolide

Abstract

Reidispongiolide A (1), isolated by D Auria et al. from the sponge Reidispongia coerulea, which was collected off the coast of New Caledonia, [1] and sphinxolide B (2) [2] are representative members of a structurally unique family of cytotoxic marine macrolides.[3] Their interaction with actin in the cell cytoskeleton leads to microfilament destabilization, and they show potent antiproliferative activity (for example, IC 50 = 0.04 and 0.01 mg mL À1 against human colon carcinoma HT29) and the ability to circumvent multidrug resistance. This profile makes these macrolides valuable molecular probes in cell biology and promising lead compounds for the development of novel chemotherapeutic agents that target actin. [4,5] Their structures comprise a highly oxygenated 26-membered macrolactone, containing a d-lactone ring, and appended with an elaborate side chain at C25 which terminates in an N-vinylformamide group. Through the combination of degradation fragment [2d, 6, 7] synthesis and detailed NMR analysis, we determined the stereochemistry of the entire reidispongiolide macrolide to be that shown in 1 (Scheme 1).[8] Subsequently, Rayment and co-workers [9] reported the X-ray crystal structure of actin-bound reidispongiolide A, assigning the complete configuration and revealing its intriguing mechanism of microfilament destabilization. The sparse natural supply of the reidispongiolides [1] and sphinxolides [2] makes total synthesis of paramount importance, not only to support further biological applications but also to enable structure-activity relationship (SAR) studies. Herein, we report the first total synthesis of reidispongiolide A based on a highly convergent modular assembly process that evolved from our stereochemical analysis groundwork. [7a, 8] As outlined in Scheme 1, our synthetic strategy for reidispongiolide A involves a late-stage introduction of the C30-C36 side-chain segment 3, which incorporates the sensitive N-vinylformamide functionality, through a suitable aldol coupling with the macrolactone aldehyde 4. We elected to disassemble the macrolide 4 into key subunits 5 (C14-C29) and 6 (C4-C13) based on an envisaged second aldol coupling to introduce the stereocenter at C13. The remaining subunit 7 Scheme 1. Synthetic strategy for reidispongiolide A (1) that involves the key building blocks 3, 5, and 6.

Assembly of the Entire Carbon Backbone of a Stereoisomer of the Antitumor Marine Natural Product Hemicalide

“…>95:5; d.r.=diastereomeric ratio), according to the well documented 1,5‐ anti (C31–C27) and 1,3‐ syn (C27–C29) stereocontrol in the aldol and reduction processes, respectively. After dimethylation of 1,3‐diol 14 (Me 3 OBF 4 , Proton sponge ® , CH 2 Cl 2 , RT), cleavage of the PMB group of the alcohol at C31 was performed with DDQ at this stage to avoid potential interference with the conjugated triene later on and the corresponding alcohol was converted into a TES ether to afford the C16–C46 subunit 15 (64 %, three steps from 14 ). The stage was set for the assembly of the entire carbon framework by the key Suzuki–Miyaura coupling with alkenyl iodide 17 , which in turn had been prepared previously from ( S )‐Roche ester .…”

The Stereocontrolled Total Synthesis of Polyketide Natural Products: A Thirty-Year Journey

“…An aldol coupling with 139 was envisaged to install the pendant side chain, while the macrocyclic core would be constructed from a substrate-controlled aldol reaction between C14-C29 ketone 137 and C1-C13 aldehyde 138, which was posited to give the Felkin-Anh product. [70] These three fragments would then be assembled through the four highlighted aldol disconnections. Initial synthetic studies for the C1-C13 fragment found that any extended manipulations involving lower C1 oxidation states resulted in unavoidable alkene isomerisation.…”

Direct Methods for Stereoselective Polypropionate Synthesis: A Survey

“…They display high levels of stereocontrol in boron-mediated anti-aldol reactions 5e,25 and have been widely used in propionate total syntheses. 26 The origin of the high levels of p-face selectivity in these reactions can be traced to the relative steric and electronic contributions of the substituents (H, Me, OBz) of the derived E-enolate 43. For such (E)-enol borinates, there is a strong preference for the proton to reside in an ecliptic conformation with regard to the double bond in order to minimize 1,3-allylic strain.…”