Aluminum Chloride-Mediated Dieckmann Cyclization for the Synthesis of Cyclic 2-Alkyl-1,3-alkanediones: One-Step Synthesis of the Chiloglottones

Abstract

Cyclic 2-alkyl-1,3-alkanediones are ubiquitous structural motifs in many natural products of biological importance. Reported herein is an AlCl·MeNO-mediated Dieckmann cyclization reaction of general synthetic utility that enables direct access to complex 2-alkyl-1,3-dione building blocks from readily available dicarboxylic acid and acid chloride substrates. This new strategy enables direct synthetic access to the chiloglottone plant pheromones from commercial material in a single synthetic transformation.

Acid Chlorides as Formal Carbon Dianion Linchpin Reagents in the Aluminum Chloride-Mediated Dieckmann Cyclization of Dicarboxylic Acids

“…During our investigations of the aluminum­(III)-mediated Dieckmann cyclization of dicarboxylic acids with acid chlorides, we observed distinct reactivity with β-branched acid chlorides, such as 3,3-dimethylbutyryl chloride 7 . These substrates were poorly tolerated under the reaction conditions, resulting primarily in acid chloride self-condensation byproducts . While these substrates did not provide the desired Dieckmann product 6 , we were able to isolate 2-acyl-1,3-dione 11 as a cross-condensation product in 12% yield (Scheme ).…”

“…Specifically, strategies have been developed that use three possible synthons as linchpin reagents , the carbonyl dianion, , dication, and carbene (Figure A). We recently reported an efficient protocol for the formation of complex cyclic-1,3-diones 6 in a one-step Dieckmann cyclization reaction of dicarboxylic acids in the presence of acid chlorides (Figure B) . Despite these advances, highly functionalized substrates were not tolerated under the reaction conditions.…”

“…Altogether, these results corroborate the role of acid chlorides as a formal carbon dianion linchpin reagent for simple acid chlorides such as acetyl chloride as well as complex β-substituted acid chlorides. Lastly, we extended this one-step Dieckmann cyclization method for dicarboxylic acids to the synthesis of the related cyclic 2-acetyl-1,3-alkanediones relying on our previously reported reaction protocol . Similar to their alkyl counterparts, the structurally related cyclic 2-acyl-1,3-alkanediones represent common motifs in many complex molecules of biological importance. , Currently available literature procedures for the construction of these building blocks require harsh reaction conditions relying on reducing metals or the preformation of the 1,3-diketone moiety .…”

“…We recently reported an efficient protocol for the formation of complex cyclic-1,3-diones 6 in a one-step Dieckmann cyclization reaction of dicarboxylic acids in the presence of acid chlorides (Figure 1B). 8 Despite these advances, highly functionalized substrates were not tolerated under the reaction conditions. As such, we initiated mechanistic studies to enhance the synthetic utility of this method.…”

“…These substrates were poorly tolerated under the reaction conditions, resulting primarily in acid chloride self-condensation byproducts. 8 While these substrates did not provide the desired Dieckmann product 6, we were able to isolate 2-acyl-1,3-dione 11 as a cross-condensation product in 12% yield (Scheme 1). Similarly, acetyl chloride 9 formed the corresponding 2-acyl-1,3-dione 12, which had previously been observed by Matoba et al, 9 albeit in low yield.…”