A “Chiral Aldehyde” Equivalent as a Building Block Towards Biologically Active Targets

Abstract

Chiral gamma-aryloxybutenolides, readily accessible through dynamic kinetic asymmetric transformation (DYKAT) of racemic acyloxybutenolides, were utilized as "chiral aldehyde" building blocks for intermolecular cycloadditions and Michael reactions. Unprecedented selectivity in trimethylenemethane cycloadditions with this building block allowed an efficient synthesis of a novel metabotropic glutamate receptor 1 antagonist in development by the Bayer corporation. These studies further inspired work that culminated in the total synthesis of (+)-brefeldin A, a natural product with a range of significant biological properties. All of the stereochemistry in this target molecule was derived from two palladium-catalyzed asymmetric allylic alkylation reactions. The trans-alkenes were synthesized by a Julia olefination and a ruthenium-catalyzed trans-hydrosilylation-protodesilylation protocol. The route to (+)-brefeldin A lends itself to analogue syntheses and was completed in 18 steps in 6 % overall yield.

Acetylides from Alkyl Propiolates as Building Blocks for C3 Homologation

“…[9] In spite of their weak nucleophilicity and the low temperatures required to obtain them, these acetylides add to aldehydes and ketones to give propargylic alcohols 1 in good yields. [10] Other electrophiles, such as nitrones, [11][12][13] acid chlorides, [14] Weinreb amides, [15,16] and acylpyridinium ions [17] are also accessible to these anions (Scheme 1). Less-active electrophiles require the use of coactivators or the replacement (transmetalation) of lithium with magnesium, [18] zinc, [19][20][21][22] cerium [23] or boron [24] ).…”

Enantioselective Allylic Substitutions in Natural Product Synthesis

“…Following the same strategy for the core as in the aflatoxin B lactone synthesis, 2-naphthol was reacted with butenolide 54 in the presence of ligand L2 to afford ether 57 in 87% yield with 97% ee [22,23] Enantioselective Allylic Substitutions in Natural Product Synthesisof note that this was the first of three palladium-catalyzed reactions that generate a p-allyl complex in this total synthesis. The second followed in the next step, whereby a 1,3-dipole fragment 58, which generates trimethylenemethane (TMM) in situ from an initially formed palladium complex.…”

Acetylide aus Alkylpropiolaten als Bausteine zur C3‐Homologisierung

“…[9] Diese Acetylide sind zwar nur schwache Nucleophile und müssen bei tiefen Temperaturen erzeugt werden, doch mit Aldehyden und Ketonen ergeben sie die Propargylalkohole 1 in guten Ausbeuten. [10] Auch andere Elektrophile wie Nitrone, [11][12][13] Säurechloride, [14] Weinreb-Amide [15,16] und Acylpyridinium-Ionen [17] reagieren mit diesen Anionen (Schema 1). Weniger aktive Elektrophile benötigen einen Coaktivator oder den Austausch von Lithium gegen Magnesium, [18] Zink, [19][20][21][22] Cer [23] oder Bor.…”