Stereostructure Clarifying Total Synthesis of the (Polyenoyl)tetramic Acid Militarinone B. A Highly Acid-Labile N-Protecting Group for Amides

Abstract

The 5S, 8′R, and 10′R configurations of militarinone B (3), which is a natural product from Paecilomyces militaris, should equal those in its biosynthetic precursor, militarinone C. The configuration at C-1′ emerged from syntheses of the militarinone B candidates 1′′S- and 1′′R-(5S,8′R,10′R)-3 from the building blocks 9, 11, 14, and 15a while introducing TMB as a more acid-labile N-protecting group for β-ketoamides than DMB. Comparisons of 1′′S- and 1′′R-(5S,8′R,10′R)-3 with natural militarinone B (3; reisolated from Nature) revealed identity versus distinctness.

Structure‐Proving Syntheses of the Polyenoyltetramic Acids Pyranonigrin J and I

“…(4) The “Eastern building block” 13 was traced back to oct‐2‐en‐1‐al ( 16 ). (5) The “Western building blocks” ( S )‐ 15 and ( S )‐ 17 should emerge by aminolyses [21] of our previously used [15,16,17] β‐ketothioester 18 . The latter results from propiolic acid in 3 steps [15] .…”

“…The total synthesis of polyenoyltetramic acids [12] -natural, "near-natural" or unnatural -is a research topic of ongoing interest. [14] We have been active in this field by contributing structure-revealing total syntheses of αand β-lipomycin [15] and of the militarinones B [16] and C. [17] In the following, we describe structure-confirming total syntheses of the polyenoyltetramic acids pyranonigrin J (3) and pyranonigrin I (4). We synthesized these compounds with the suggested [7,13] (S)-configuration (Scheme 3-Scheme 5).…”

“…Our retrosynthetic analyses (Scheme 2) relied on disconnection principles which we had found useful in our lipomycin [15] and militarinone [16,17] syntheses or which others had used in synthetic endeavors in the field: (1) The C-3À C-4 bond in the heterocycles of our targets 3 and 4 should result from Lacey-Dieckmann cyclizations. [19] The substrates of this step were the β-ketoamides (S)-11 and (S)-12, respectively.…”

“…The (key) role of acting as a "conjunctive reagent" therein was assigned to the β-ketothioester 18. [15] This compound was developed and applied in our group a while ago and re-applied twice [16,17] hence. Employing 18 made our respective syntheses (ref.…”

Multiply Unsaturated and ω‐Brominated β‐Ketothioesters for Synthesizing β‐Ketolactams and the Scaffolds of Fully Enolized N‐Hydroxy‐3‐(polyenoyl)pyridine‐2,4‐dione Natural Products

“…Respective pairs of reactants should Stille‐couple and thus complete the respective polyenoyl side chain and the adjacent stereocenter. The just‐mentioned “ N‐ (TMB‐oxy)‐ω‐bromo‐β‐ketoamides” should originate from an unprecedented hydroxylaminolysis [21] which, however, would be akin to the well‐known Ley‐type aminolyses; [13] such hydroxylaminolyses would hopefully be undertaken by the β‐(hydroxylamino)propionic acid derivative 23 as our so‐called “western building block” in the following “ω‐bromo‐β‐ketothioesters” serving as our “eastern building blocks”: in the mono‐unsaturated and almost completely enolized ω‐bromo‐β‐ketothioester 11 from our tetramic acid works [2a–d] (Scheme 1), in its di‐unsaturated vinylog 24 , and in its tri‐unsaturated bis‐vinylog 25 , respectively.…”