Studies toward Total Synthesis of Divergolides C and D

Abstract

A facile synthesis of the western segment of divergolides C and D has been developed. Exploratory studies with two disconnections, i.e., C4-C5 vs C5-C6, for elaboration of the ansa bridge to the sterically demanding hexasubstituted naphthalenic aromatic core using a chiral synthon assembled from D-glucose via a stereoselective Johnson orthoester rearrangement is described. The studies set the stage for the completion of the total synthesis of the biologically important novel ansamycins, divergolides C and D, and their structural congeners.

Toward the Total Synthesis of Hygrocin B and Divergolide C: Construction of the Naphthoquinone–Azepinone Core

“…This was slightly improved by employing a telescoped procedure, avoiding purification of the somewhat sensitive quinone 26 , giving the Diels–Alder adduct 30 in 33% yield over 2 steps. In both Diels–Alder reactions, there was no sign of the alternative regioisomer, and the regiochemistry of this product was confirmed by HMBC NMR spectroscopy experiments and is in accordance with those previously observed for the reactions of amino­naphtho­quinones. ,, Further functionalization of 30 was also shown to be possible: bromination of the aromatic ring − gave the bromo­amino­naphtho­quinone–azepinone 31 in excellent yield. This allows for lithium–halogen exchange and trapping of the aryllithium with a suitable electrophile.…”

“…In view of these considerations, we decided to eschew the ‘macrocycle-first’ approach recently reported by Rasapalli − and Trauner and, instead, consider two potential synthetic routes: the first employing an ambitious intramolecular Diels–Alder approach from the pendant diene-containing benzoquinone-azepinone 7 , and the second aiming to prepare the tricyclic naphthoquinone–azepinone core 8 , common to both divergolide C 2 and hygrocin B 3 , to which suitable ansa chains could later be attached, either by modifying a pendant ester, nitrile, or allyl group or by introducing a halogen or a formyl group ortho to the naphthol (Scheme ) (cf. Rasapalli). − By focusing initially on the second approach, it was anticipated that the core 8 , bearing a point of attachment for the ansa chain, could be prepared by a Diels–Alder reaction of a suitable diene such as 10 – 13 with a benzoquinone–azepinone 9 . This dienophile could itself be prepared from a suitable tetralone using classic aromatic chemistry.…”

Natural Products from Mangrove Actinomycetes

“…Zhao et al [63] reported a total synthesis of divergolide A by a ring-closing metathesis (RCM) approach in 2012. Then in 2013 Rasapalli et al [64] synthesized the western segment of divergolides C ( 46 ) and D and established the robustness of C4-C5 as a suitable approach to further total synthesis of divergolides C and D; this chemistry was also used for divergolides A and B ( 45 ). A new compound butremycin ( 48 ) was isolated from Micromonospora sp.…”

Quinones as Dienophiles in the Diels–Alder Reaction: History and Applications in Total Synthesis

“…[79] However, the publication of new dienes and methodology for the rapid construction of aminonaphthoquinones through the Diels-Alder reaction of aminobenzoquinones shows that this important field is still actively researched. [80] Although a great number of total syntheses of naphthoquinones have been carried out using this reaction, and this topic could easily form the subject of a separate review, only two very recent, representative examples will be described here.…”