Synthesis of the ABC tricyclic fragment of the pectenotoxins via stereocontrolled cyclization of a γ-hydroxyepoxide appended to the AB spiroacetal unit

Abstract

The stereocontrolled synthesis of the C1-C16 ABC spiroacetal-containing tricyclic fragment of pectenotoxin-7 6 has been accomplished. The key AB spiroacetal aldehyde 9 was successfully synthesized via acid catalyzed cyclization of protected ketone precursor 28 that was readily prepared from aldehyde 12 and sulfone 13. The syn stereochemistry in aldehyde 12 was installed using an asymmetric aldol reaction proceeding via a titanium enolate. The stereogenic centre in sulfone 13 was derived from (R)-(+)-glycidol. The absolute stereochemistry of the final spiroacetal aldehyde 9 was confirmed by NOE studies establishing the (S)-stereochemistry of the spiroacetal centre. Construction of the tetrahydrofuran C ring system began with Wittig olefination of the AB spiroacetal aldehyde 9 with (carbethoxyethylidene)triphenylphosphorane 10 affording the desired (E)-olefin 32. Appendage of a three carbon chain to the AB spiroacetal fragment was achieved via addition of acetylene 11 to the unstable allylic iodide 39. Epoxidation of (E)-enyne 8 via in situ formation of L-fructose derived dioxirane generated the desired syn-epoxide 36. Semi-hydrogenation of the resulting epoxide 36 followed by dihydroxylation of the alkene effected concomitant cyclization, thus completing the synthesis of the ABC spiroacetal ring fragment 6.

TiCl4‐Promoted Asymmetric Aldol Reaction of Oxazolidinones and its Sulphur‐Congeners for Natural Product Synthesis

“…Because of the diastereoselectivity, observed as a 4.6: 2 : 1 mixture of Evans syn isomer: non‐ Evans syn isomer: anti ‐isomer. Halim et al [166] . installed the syn stereochemistry in aldehyde 152.2 through Enolization of 152.1 with TiCl 4 in the presence of (−)‐sparteine at 0 °C.…”

Titanium Enolate Chemistry at the Beginning of the 21st Century

“…Stereoselective syn aldol formation based on titanium(IV) enolates has been utilized in the preparation of natural products such as pectenotoxin‐730a and of macrolides belonging to the latrunculin group,30b as well as, more recently, in a diastereoselective synthesis of syn ‐β‐hydroxyacylsilanes 31…”

Synthetic studies towards the pectenotoxins: a review

“…Shortly after Paquette and co-workers published their synthesis of the C1-C26 fragment of PTX2 in 2005, 37 we disclosed our approach towards the C1-C16 ABC spiroacetal containing subunit 105. 47,48 Our strategy hinged on initial formation of the C1-C11 AB spiroacetal fragment 100. In a similar manner to that observed by Paquette, we also formed the 7S-spiroacetal centre as opposed to the required 7R in natural PTX2 (Scheme 12).…”