A Consecutive Ring-Expansion Strategy towards the Macrocyclic Core of the Solomonamide Natural Products

Abstract

A synthetic strategy based on the application of three consecutive ring expansion reactions has been used in the synthesis of analogues of the macrocyclic core of the solomonamide natural products. Starting from a simple, readily available tetrahydrocarbazole, oxidative ring expansion is followed by two further 3- and 4-atom ring expansion reactions, enabling the insertion of amino acid- and hydroxyacid-derived linear fragments into 15–17-membered ring-enlarged macrocyclic products.

Comprehensive Study on Solomonamides: Total Synthesis, Stereochemical Revision, and SAR Studies toward Identification of Simplified Lead

“…The stereochemistry of crotylated product 160 was confirmed by a synthesis of five-membered cyclic carbamate derivative 169 , using coupling constant based on literature precedences . Later, compound 160 was converted to key nonamino acid 163 through the intermediacy of 161 and 162 . Having nonamino acid 163 and dipeptide 99 in hand, we synthesized ketone 167 in 7 steps with overall good yield.…”

“…The unique macrocyclic scaffold and interesting biological properties of the solomonamides have generated intense synthetic efforts from our group during the past decade . Ever since the disclosure of its structure, several synthetic attempts toward the total synthesis of target natural products have been published, mainly from the Chandrasekhar group, the Butler group, the Sarabia group, and a very recent report from the Unsworth group . In our initial attempts, we have utilized photo-Fries rearrangement for the synthesis of AHMOA fragment.…”

Modern Macrolactonization Techniques

“…In a subsequent step, a simple rearrangement can lead to a larger ring-expanded cycle. [71][72][73][74][75] In most cases, none of these transformations necessitate highly diluted conditions. Following seminal strategies by Shemyakin and co-workers, 76 the Unsworth group has pioneered the development of a specific class of ring expansion strategy that they have coined as successive ring expansions of lactams and -ketoesters (Scheme 18).…”

“…In a subsequent step, a simple rearrangement can lead to a larger ring-expanded cycle. [70][71][72][73][74] In most cases, none of these transformations necessitate highly dilute conditions.…”

Ring expansion reactions of PO-containing molecules

“…We therefore set out to explore whether strategies similar to those able to promote the ring expansion of lactam derivatives ( e.g. 4a → 4b → 4c , Scheme 1B) 9,10 can be applied to phosphonamidate derivatives of the type 5 . By testing amine ( 5a ) and alcohol ( 5b ) tethered substrates, a reactivity trend was revealed that contrasts that seen in the established lactam ring expansions; the more nucleophilic amine derivatives 5a rearrange less easily (or not at all), while less nucleophilic alcohol derivatives 5b rearrange well to form cyclic phosphonate esters 7b .…”