Studies towards the synthesis of tedanolide C. Construction of the C13-epi C1–C15 fragment

Abstract

The preparation of an advanced intermediate on route towards the synthesis of tedanolide C is reported here. It is based on the coupling of two fragments of similar size and complexity, which in turn are prepared by highly stereoselective substrate-controlled titanium-mediated aldol reactions from chiral ketones.

Synthesis of Desepoxy‐Tedanolide C

“…Due to the fact that the configuration would significantly deviate from tedanolide even though a biosynthetic relationship is likely and the computationally proposed structure involves an eclipsed orientation of the protons H‐9 and H‐10, we used instead 5 as our target molecule for the synthesis of tedanolide C as the configurations resemble those of the other members of this family. Smith and his group targeted the putative structure of tedanolide C ( 4 ), [5] whereas the groups of Roush, [6] Romea and Urpi [7] used the enantiomer ( ent ‐ 4 ) as their synthetic target.…”

“…Due to the fact that the configuration would significantly deviate from tedanolide even though a biosynthetic relationship is likely and the computationally proposed structure involves an eclipsed orientation of the protons H-9 and H-10, we used instead 5 as our target molecule for the synthesis of tedanolide C as the configurations resemble those of the other members of this family. Smith and his group targeted the putative structure of tedanolide C (4), [5] whereas the groups of Roush, [6] Romea and Urpi [7] used the enantiomer (ent-4) as their synthetic target. Our interest in this family of natural products was initiated by their extraordinary biological activity, the challenge of constructing a polyketidal natural product with a wide variety of sites which could hamper its synthesis due to retro-aldol processes and/or eliminations and finally because this group of natural products features a rare macrolactone comprising a primary alcohol.…”

Development of the Synthesis of Desepoxy-Tedanolide C

“…The groups of Romea and Urpi reported the synthesis of the largest fragment of tedanolide C ( 8 ) so far. In their synthesis of the 13- epi C1–C15 fragment the key disconnection is again between C7 and C8, building up this bond by the addition of a vinyl nucleophile (13- epi C8–C15) to an aldehyde (C1–C7) . As already mentioned, all these synthetic approaches aim for the synthesis of the proposed isomer of tedanolide C ( 8 ).…”

“…Considering that the coupling constant of the same protons in tedanolide ( 1 ) are in a similar range (Schmitz: 10.8 Hz, Kalesse: 8.5 Hz, Smith: 10.1 Hz, Roush: 9.6 Hz) and that a common biosynthetic pathway of all tedanolides is quite likely, we decided to aim for 9 as the synthetic target of this work which is in better accordance with the other tedanolides. The absolute stereochemistry of 9 was chosen based on tedanolide ( 1 ) and 13-deoxytedanolide ( 2 ) as their structures were already confirmed by successful total syntheses. , Previous synthetic attempts toward tedanolide C ( 8 ) were conducted by the groups of Roush, Smith, and Romea and Urpi targeting different enantiomers of the proposed structure. The syntheses of two fragments of tedanolide C ( 8 ) were reported by the Roush group so far.…”

“…The absolute stereochemistry of 9 was chosen based on tedanolide ( 1 ) and 13-deoxytedanolide ( 2 ) as their structures were already confirmed by successful total syntheses. 7 , 8 Previous synthetic attempts toward tedanolide C ( 8 ) were conducted by the groups of Roush, 9 Smith, 10 and Romea and Urpi 11 targeting different enantiomers of the proposed structure. The syntheses of two fragments of tedanolide C ( 8 ) were reported by the Roush group so far.…”