Development of the Synthesis of Desepoxy-Tedanolide C.

We are presenting the development of our route for the total synthesis of desepoxy-tedanolide C. Through the obtained analytical data, the proposed structure of tedanolide C is questioned and a different configuration for this natural product is proposed. Key steps of the synthesis are a Kiyooka aldol reaction that builds up the tertiary alcohol flanked by three oxygenated carbon atoms and two aldol reactions used for fragment couplings. A Julia-Kocienski olefination was used for installation of the side chain. Besides the successful synthesis, the development for the protecting group setup of the southwestern hemisphere is described in detail as well as another retrosynthetic attempt for building up the target molecule.

Stereoselective Synthesis of Allylic Alcohols via Substrate Control on Asymmetric Lithiation.

Allylic alcohols are a privileged motif in natural product synthesis and new methods that access them in a stereoselective fashion are highly sought after. Toward this goal, we found that chiral acetonide-protected polyketide fragments performing the Hoppe-Matteson-Aggarwal rearrangement in the absence of sparteine with high yields and diastereoselectivities rendering this protocol a highly valuable alternative to the Nozaki-Hiyama-Takai-Kishi reaction. Various stereodyads and -triads were investigated to determine their substrate induction. The mostly strong inherent stereoinduction was attributed to a combination of steric and electronic effects.

Access to Naphthoic Acid Derivatives through an Oxabenzonorbornadiene Rearrangement.

Herein, the synthesis of 1-hydroxy-2-naphthoic acid esters through an unexpected Lewis-acid-mediated 1,2-acyl shift of oxabenzonorbornadienes is reported. Using this methodology, novel substitution patterns for 1-hydroxy-2-naphtoic acid esters can be obtained. A mechanistic proposal and rationale for this transformation, the products of which had been previously incorrectly characterized, is given.

Sparteine-Free, Highly Stereoselective Construction of Complex Allylic Alcohols Using 1,2-Metallate Rearrangements.

Stereotriads bearing allylic alcohols are privileged structures in natural products, and new methods accessing these in a stereoselective fashion are highly sought after. Toward this goal, we found that the use of chiral polyketide fragments allows for performing the Hoppe-Matteson-Aggarwal rearrangement in the absence of sparteine with high yields and diastereoselectivities, rendering this protocol a highly valuable alternative to the Nozaki-Hiyama-Takai-Kishi reaction. The switch of directing groups in most cases resulted in the reversed stereochemical outcome, which could be explained by conformational analysis on density functional theory level and a Felkin-like model.

Synthesis of Desepoxy-Tedanolide C.

The synthesis of desepoxy-tedanolide C was accomplished and provided experimental evidence on the configuration of tedanolide C. The reported chemical shifts and coupling constants point to a configuration different from the published structure and analogous to the structures of the other members of this family of natural products. The key step is a Kiyooka aldol protocol for the stereoselective synthesis of the tertiary alcohol flanked by three additional oxygenated carbon atoms. Furthermore, two additional aldol reactions and a Julia-Kocienski olefination were used to assemble the carbon framework.

Polyoxygenated Tertiary Alcohols: A Kiyooka Approach.

A Kiyooka aldol approach for the stereoselective synthesis of tertiary alcohols is presented. This approach allows for the incorporation of different substituents at all three remaining positions at the chiral center bearing the tertiary alcohol. To demonstrate the validity of this approach different chiral alcohols were depicted and the relationship of double bond geometry of the ketene acetal and the diastereoselectivity was established.

Total Synthesis of Pericoannosin A.

The first total synthesis of pericoannosin A (1) containing 15 steps in the longest linear sequence with an overall yield of 5.5% is reported. The hybrid peptide-polyketide was isolated from the endophytic fungus Periconia sp. F-31 and bears a unique tricyclic core structure. The key steps are a glycolate aldol reaction and a Diels-Alder reaction utilizing an Evans auxiliary for controlling the stereochemistry. Furthermore, a late-stage equilibration was employed.

Synthesis of Natural and Unnatural Cyclooligomeric Depsipeptides Enabled by Flow Chemistry.

Flow chemistry has been successfully integrated into the synthesis of a series of cyclooligomeric depsipeptides of three different ring sizes including the natural products beauvericin (1 a), bassianolide (2 b) and enniatin C (1 b). A reliable flow chemistry protocol was established for the coupling and macrocyclisation to form challenging N-methylated amides. This flexible approach has allowed the rapid synthesis of both natural and unnatural depsipeptides in high yields, enabling further exploration of their promising biological activity.