Trauner’s1 st generation approach

The last approach towards the biomimetic construction of azepinone and pyrrolidinone divergolides to be discussed is the report by Trauner and coworkers published in 2013.³³ The chemistry will be discussed in more detail, as it served as a starting point of the work described in this thesis. The author of this thesis was involved in the preparation of the late-stage intermediates as an undergraduate worker and carried on the work in fulfillment of his Master and PhD studies. In course of the project, the synthesis outlined below was repeated several times before an alternative strategy was chosen.

Following the proposed biosynthesis, the strategy aims towards construction of a macrocyclic naphthoquinone (128) to study the diversification of this macrolactam/macrolactone in subsequent biomimetic ring-contractions. The divergent approach dissects a protected variant of a proto-divergolide into four fragments (Scheme 18). Macrocyclization was to be realized by ring-closing olefin metathesis (RCM).

Scheme 18 Retrosynthesis of proto-divergolide, synthesis of ester 137.

The Western fragment of the proto-divergolide was assembled from diol 132 and carboxylic acid 134. The former was obtained by Brown allylation³⁴of prenal and the latter by Horner-Wadsworth-Emmonds (HWE) olefination,³⁵ followed by protecting group manipulations. The Yamaguchi protocol³⁶ furnished ester 135, while a Jones oxidation after TBAF-mediated

desilation provided carboxylic acid 137, albeit with minimal isomerization of the glutaconic olefin (138).

The synthesis of the aromatic core was slightly improved after publication and robustly produced gram quantities hexa-substituted naphthaldehyde 129. The optimized procedure is detailed below (Scheme 19).

Scheme 19 Construction of naphthaldehyde 129.

The yield of the Diels-Alder reaction of modified Danishefsky diene 139³⁷ and aminoquinone 140,³⁸ followed by methanol elimination and oxygen mediated aromatization was found to be improved by ensuring complete conversion to naphthoquinone 141. Typically, three days of vigorous stirring under air were required, also due to the poor solubility of the product, resulting in suspensions of reaction intermediates. A clean bromination reaction required recrystallized NBS on scale and crystallization furnished material of high purity to enable a higher yielding MOM protection of the phenol. The reduction of 142 and subsequent trapping of the resulting hydroquinone as methyl ethers required strict degassing of all reaction solvents and careful use of Schlenk-technique to ensure that the air-sensitive hydroquinone intermediate is not reoxidized, a process otherwise rapidly outcompeting methylation.

Formylation could be achieved in good yield on 1 g scale, if the carbamate was deprotonated by action of MeLi prior to halogen-metal exchange.

Scheme 20 Koga-auxiliary based synthesis of alkyl bromide 148.

To obtain chiral alkyl bromide 148, we performed a diastereoselective 1,4-addition of a vinyl cuprate to Koga auxiliary (143) based imide 145³⁹that furnished olefin 147 with no detectable amounts of the other diastereomer (Scheme 20). This reaction was performed on a 20 g scale and purified by crystallization in 90% yield but required stoichiometric amounts of costly CuI·SMe2. The subsequent methanolysis/reduction/bromination sequence reproducibly provided bromide 148 in up to 72% yield over two steps, but the volatility of both 147 and 148 called for time consuming distillation of the reaction intermediates after both extractive workup and the necessary chromatography steps. On multigram scale, procuring the material took up to seven days.

Scheme 21 Fragment coupling towards RCM precursor 151.

Halogen-metal exchange of alkyl bromide148 could be achieved using tert-butyl lithium, but 4 to 5 equivalents of the precious olefin was needed to give reasonable yields of the naphthylic alcohol, that was typically immediately oxidized with Dess-Martin periodinane (DMP) (Scheme 21). This can surely be attributed to the acidity of the carbamate proton of 129, a complication that was addressed later on in the project. It has to be noted that the reaction suffered from low reproducibility and more often than not contained by-products that could only be separated by preparative HPLC. Switching the solvent from THF to diethyl ether allowed for a cleaner coupling but could not completely eliminate side reactions to intractable byproducts. Even after careful titration of the tert-butyl lithium solution and determination of alkyl bromide concentration by high field NMR, the stoichiometry of reactants could not be optimized to allow for a robust and scalable reaction. Nevertheless, sufficient amounts of valuable naphthyl ketone 149 could be produced to allow for initial studies towards the construction of a macrocyclization precursor. Boc-deprotection of 149 was achieved with concomitant MOM ether cleavage to yield air sensitive naphthyl amine 150. Carbodiimide-mediated coupling of

carboxylic acid 137 then furnished amide 151, the first published compound to contain the entire carbon skeleton of a divergolide. Initial studies on the competency of 151 to undergo ring-closing metathesis were unsuccessful and attributed to unfavorable amide geometry, as 151 was assumed to reside in the depicted s-trans amide configuration, making it conformationally challenging to make the intramolecular reaction happen.

This concludes the introductory part of this thesis. Chapter 2 will concern the synthetic efforts undertaken to build upon the lessons learned from the 1^st generation approach by Trauner and resolve the challenge of accessing synthetic proto-divergolides and proto-hygrocins.

2 Synthetic studies towards divergolides and hygrocins

The results in this thesis are presented chronologically. In some cases, insights gained at earlier stages of the project were helpful to carry on with the current endeavors, but the final optimization of a particular transformation was realized at a later point. In these cases, a footnote was added that will point the reader to the respective later chapter revealing the optimized conditions.