Synthesis of a tricyclic core of rameswaralide

Abstract

A tricyclic core containing a 5,7-fused bicyclic unit of rameswaralide was prepared starting from a 1,6-enyne. The synthetic sequence involved (i) ruthenium-catalyzed [5+2]-cycloaddition of 1,6-enyne, (ii) an acyl radical based approach to construct the lactone, and (iii) a regioselective installation of the conjugated double bond by a concomitant sulfenylation-dehydrosulfenylation sequence. KeywordsRuthenium; Cycloaddition; The fused bicyclic system; Reductive radical cyclization; Total synthesis Rameswaralide (1), a novel diterpene with a tetracyclic ring skeleton, was isolated from the soft coral Sinularia dissecta near the Mandapam coast of India in 1998 (Figure 1). 1 Its relative stereochemistry was determined by analysis of 1 H NMR coupling constants and NOESY correlations. The structure of 1 was further confirmed by selective reduction of the enolic group with NaBH 4 to form the corresponding dihydrorameswaralide (2). It was reported that rameswaralide (1), and its derivatives, could function as effective anti-inflamatory agents for the treatment of a variety of inflammatory disorders, including arthritis, psoriasis and inflammatory bowel disease. 2 Rameswaralide (1) is a highly oxygenated natural product containing a variety of functional groups, including a tertiary hydroxyl group, a carbonyl moiety, a fully enolized β-ketoester, a γ-lactone, and an isopropylidene group (Figure 1). Furthermore, it contains cis-fusions at the AB-and BC-ring junctions. Due to its complex features and biological importance, rameswaralide (1) is a good target for total synthesis. To date, the total synthesis of 1 has not been reported, but several reported approaches have appeared. 3 Herein, we report the synthesis of the tricyclic core 3 containing a 5,7-fused bicyclic (AB-ring) unit of rameswaralide (1) (Figure 2).Retrosynthetically, the tricyclic compound 3 (Figure 2) could be accessed from chemoselective epoxidation of vinylsilane 4. In turn, the five-membered γ-lactone in 4 could be derived from the alkoxycarbonyl radical cyclization of acylselenium 5 onto the exocyclic cis-disubstituted olefin with retention of the alkene functionality. 4 The 5,7-fused bicyclic skeleton 6 could be © 2010 Elsevier Ltd. All rights reserved. * Corresponding author. Tel.: +1-650-723-3385; fax: +1-650-725-0002; bmtrost@stanford.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Supplementary dataSupplementary data associated with this article can be found, in the online version, at doi: 10.1016/j.tetlet. formed by ruthenium-catalyzed [5+2] intramolecular cycloaddition of the 1,6-enyne 7 de...

Ruthenium-Catalyzed Cycloadditions to Form Five-, Six-, and Seven-Membered Rings

“…The collective studies of Trost ultimately enabled total syntheses of the marine norsesquiterpenoid frondosin A (Scheme ) and pseudolaric acid B (Scheme ), which displays activity against multidrug resistant cancer cell lines; in the latter synthesis, however, an analogous rhodium-catalyzed cycloaddition proved to be optimal for the (5+2) cycloaddition to form the core seven-membered ring. Synthetic studies toward the tricyclic core of rameswaralide also were disclosed (not shown) …”

Polycyclic Furanobutenolide-Derived Cembranoid and Norcembranoid Natural Products: Biosynthetic Connections and Synthetic Efforts

“…85 Synthetic access to core tricycle 278 would be accomplished by an acyl radical cyclization and epoxidation of selenide 279 (Scheme 62). Acylselenide 279 would be produced by the acylation of secondary alcohol 280.…”

Pharmacophore-Directed Retrosynthesis Applied to Rameswaralide: Synthesis and Bioactivity of Sinularia Natural Product Tricyclic Cores

“…The potential anti-inflammatory activity and cytotoxicity toward A549 human lung carcinoma epithelial cells (IC 50 67 ± 3.7 μM) of rameswaralide ( 6 ) was also reported. Furthermore, with the exception of rameswaralide, the absolute stereochemistry of these diterpenoids has not yet been confirmed; however, it was indirectly assigned based on the established absolute stereochemistry of a probable biosynthetic precursor. , While several groups have pursued the synthesis of rameswaralide ( 6 ) − and ineleganolide ( 5 ), − which bear the 5,5,7 core (blue, Figure ), to our knowledge, there are no reported total syntheses. Less synthetic work has been directed to members possessing the 5,5,6 core (red) such as that found in yonarolide, scabrolides, dissectolides, and sinulochmodin C ( 1 – 4 ). − …”

“…We decided to set rameswaralide ( 6 ) as our initial target since it displays some of the most compelling bioactivity in this class of tetracyclic diterpenoids (Scheme ). Based on previous work by both Mehta and Trost, who independently synthesized a similar 5,5,7 core of rameswaralide, we anticipated that annulation of the D-ring would be challenging given the lack of further efforts toward this end. With this in mind, we proposed that α-halo enones such as enone 7 could serve as highly versatile intermediates for several D-ring annulation strategies toward rameswaralide ( 6 ).…”

“…We envisioned access to tricycle 8 through our recently described Diels−Alder lactonization (DAL) organocascade process of diene 9 and acryloyl chloride. 29,30 Diene 9 is available through a Stille cross-coupling and 1,2 addition to cyclopentenone 10, in turn available through a known Piancatelli rearrangement 31 of furfuryl alcohol (11).…”