Endo-Oxacyclizations of Polyepoxides:  Biomimetic Synthesis of Fused Polycyclic Ethers

Abstract

Boron trifluoride-etherate promotes the endo-selective oxacyclization of polyepoxides derived from various acyclic terpenoid polyalkenes, including geraniol, farnesol, and geranylgeraniol, providing an efficient and stereoselective synthesis of substituted oxepanes and fused polyoxepanes. The mechanism of the oxacyclization reaction probably involves intramolecular nucleophilic addition of epoxide oxygen to open another epoxide that is activated as an electrophile by the Lewis acid. These oxacyclizations proceed stereospecifically with inversion of configuration upon opening of each epoxide to provide trans-fused polycyclic products. The oxacyclization cascade is terminated by a tethered nucleophile, which may be the carbonyl oxygen of a ketone, ester, or carbonate, or a trisubstituted alkene. The best oxacyclization yields are generally observed with tert-butyl carbonate as the terminating nucleophile, although in some cases the oxacyclization products include formation of tert-butyl ethers as a minor product. The oxacyclization transformations described herein may mimic ring-forming steps in the biosynthesis of trans-syn-trans-fused polycyclic ether marine natural products.

Stereochemical Uniformity in Marine Polyether Ladders—Implications for the Biosynthesis and Structure of Maitotoxin

“…However, the synthetic methodology has serious limitations in terms of the number of rings that may be assembled as well as the substituents and ring sizes, perhaps making it less appealing as a general biosynthetic proposal for the polyether ladders. [26] The third approach, developed by Giner, involves the rearrangement of an epoxy ester and is a very different mode of cyclization from the other two bio- Angewandte Chemie mimetic models (Scheme 7). [27] Extrapolating this synthetic strategy to the biosynthesis of polyethers would require an all-cis polyene precursor, noted as advantageous in explaining the cis bonds in the brevetoxins and ciguatoxins.…”

Stereochemische Uniformität bei marinen Polyetherleitern: Folgerungen für Biosynthese und Struktur des Maitotoxins

“…Allerdings unterliegt die Methode gravierenden Einschränkungen bezüglich der Zahl der Ringe sowie der Substituenten und der Ringgrößen, was eher dagegen spricht, diesen Weg als allgemeinen Biosynthesemechanismus für die Polyetherleitern zu formulieren. [26] Der dritte Ansatz, der sich stark von den beiden anderen biomimetischen Modellen unterscheidet, beruht auf der Umlagerung eines Epoxyesters (Schema 7). [27] [28] Die Enzyme sind homolog zur Limonenepoxid-Hydrolase, deren Wirkung auf einfachen Säure-Base-Reaktionen beruht [29] und die, anders als klassische Epoxid-Hydrolasen, keine enzymgebundenen Intermediate bildet (Schema 8).…”

Biomimetic Synthesis of Polyether Natural Products via Polyepoxide Opening

“…McDonald reported the first cascade reactions that produce oxepane and trans-fused bisoxepane motifs via endo-selective epoxide opening [30,192]. A range of terminating nucleophiles such as ketones, esters, carbonates, and acetals were examined and demonstrated to be a factor in determining regioselectivity in these Lewis acid-promoted polyepoxide cyclizations (Scheme 15.16a).…”

“…A range of terminating nucleophiles such as ketones, esters, carbonates, and acetals were examined and demonstrated to be a factor in determining regioselectivity in these Lewis acid-promoted polyepoxide cyclizations (Scheme 15.16a). McDonald and coworkers extended these reactions to polyepoxides 202-205 for the synthesis of polyoxepane systems [30,192]. The efficiency of these reactions tends to drop as the number of epoxides in the polyepoxide precursor increases (Scheme 15.16b).…”