Stereoselective Synthesis of 2,6-trans-Tetrahydropyran via Primary Diamine-Catalyzed Oxa-Conjugate Addition Reaction of α,β-Unsaturated Ketone: Total Synthesis of Psymberin

Abstract

The total synthesis of psymberin was achieved employing a readily available chiral epoxide to prepare two of the three subunits in the natural product. The key reaction was a highly stereoselective organocatalytic oxa-conjugate addition reaction of α,β-unsaturated ketone catalyzed by primary diamine for the synthesis of the 2,6-trans-tetrahydropyran embedded in psymberin.

Asymmetric Intramolecular Oxa‐Michael Reactions of Cyclohexadienones Catalyzed by a Primary Amine Salt

“…The first organocatalytic intramolecular oxa‐conjugate addition of an alcohol to a chiral α,β‐unsaturated ketone was accomplished by Hong et al. in the total synthesis of psymberin 6k. Despite this, only a few organocatalytic asymmetric oxa‐Michael reactions of α,β‐unsaturated ketones have been reported 8…”

Organocatalysis in Total Synthesis

“…Aminocatalysis has been also successfully applied for the activation of ,-unsaturated carbonyl compounds in order to conveniently activate the β-position through a reactive iminium ion, a more electrophile specie that the corresponding conjugated system [ [50], (+)-minfiensine [51], and diazonamide A [52] (Fig XII.4). MacMillan's group has worked intensively in the field of iminium catalysis, establishing a broad scope of applicability using this kind of activation and contributing actively to the development of this area.…”

Psymberin – biologische Eigenschaften und Ansätze zu Total‐ und Analogasynthesen

“…Um die Tetrahydropyran‐Einheit aufzubauen, addierten Byeon und Mitarbeiter zunächst Dithian 69 , das zuvor in drei Stufen ausgehend von ( S )‐Glycidylbenzylether ( 72 ) synthetisiert worden war, an Epoxid 70 , welches in acht Stufen aus 2,2‐Dimethylpropan‐1,2‐diol ( 31 ) erhältlich ist. Sie erhielten Diol 71 in 88 % Ausbeute 54. Anschließende Spaltung des Dithians mit Iod und stereoselektive Reduktion generierte syn ‐Diol 73 .…”

“…Abschließend wird auf die Syntheseroute von Byeon und Mitarbeitern eingegangen (Schema ) 54. Ausgehend von Epoxid 172 erfolgte zunächst die Einführung einer SEM‐Schutzgruppe (→ 173 ).…”