Synthesis of Highly Functionalized δ-Lactone-Fused Cyclopentanoids

Abstract

A short and efficient route to d-lactone-fused cyclopentanoids starting from the easily accessible Diels-Alder adducts between homoallylic alcohol acetates and 1,2,3,4-tetrachloro-5,5-dimethoxycyclopenta-1,3-diene is reported. Since homoallyl alcohols were derived from the corresponding aldehydes RCHO (R = alkyl, aryl) through allyl metal addition, the methodology is broad in scope with regard to the choice of R group. The initially formed 1:1 diastereomeric mixture of adducts were subjected to ruthenium-catalyzed oxidation followed by acid-mediated hydrolysis of the acetate groups to obtain the hemiacetals 6a-e. Alkaline H 2 O 2 -mediated cleavage of the hemiacetals led, after esterification with diazomethane, to a chromatographically separable diastereomeric mixture of 7 and 8 in high overall yield (54-68%).The d-lactone structural motif is extremely important due to its occurrence as core structure in innumerable natural products which often display wide ranging biological activity. 1 The versatility of d-lactones as useful building blocks in the syntheses of natural products 2 as well as unnatural target molecules 3 is well documented. Because of their wide ranging biological activities and their ability to serve as building blocks, the synthesis of d-lactones has garnered a lot of attention, which led to development of various synthetic methods. 4 A cyclopentane ring cis-fused to the d-lactone is a basic subunit of nepetalactone insecticides and such subunits are of interest as synthetic intermediates in organic synthesis. 2,3 During the course of our recent studies on the applications of norbornyl a-diketones, 5 prepared efficiently through a methodology developed in our laboratory, 6 it was observed that an endo-hydroxymethyl group directly furnished the hemiacetals, which were cleaved to give glactones (Scheme 1). 5c Encouraged by the applications of d-lactone-fused cyclopentanoids, 2,3 and the availability of umpteen methods for the synthesis of homoallyl alcohols, 7 we became interested in extending the methodology to the synthesis of the title compounds. To this cause, homoallyl alcohols were identified as suitable precursors, as depicted in the retrosynthetic Scheme 2.The desired homoallylic alcohols could be obtained by well-established allylmetal addition to the corresponding aldehydes RCHO, thus providing a broad range of R groups that may be selected for the purpose. Although the diene 3 has been extensively used in reactions with dienophilic partners, 8 to the best of our knowledge aldehydederived a-substituted homoallyl alcohols were not fully explored as dieneophiles. Our initial experiments on Diels-Alder reaction of 1,2,3,4-tetrachloro-5,5-dimethoxycyclopenta-1,3-diene (3) and homoallyl alcohols led to complications. To circumvent this problem, we decided to protect the alcohol group of the homoallyl alcohols as acetates before subjecting them to the Diels-Alder reaction. The required dienophiles 2a-e were prepared by zincmediated allylation of aldehydes 1a-e followed by acetyl protection...

Ruthenium‐Mediated Oxidation under Buffered Conditions: A Simple and Useful Protocol for the Synthesis of Norbornyl α‐Diketones with Acid Sensitive Functionalities

“…Contrary to our expectations based on the previous results, [9] these d-lactones 14 and 15 were chromatographically inseparable.…”

“…[8] While the a-diketones are high yielding in most of the cases, we faced problems while handling substrates that have acid-labile functionalities. Herein, we detail the extension of our recently reported protocol for the synthesis of achiral cyclopenta-annulated d-lactones [9] to the enantiomerically pure d-lactones, which involves the use of buffered ruthenium oxidation conditions.…”

“…[5,6] Adv. Synth methoxycyclopenta-1,3-diene (7) and homoallyl alcohols led to complications, [9] we decided to protect the alcohol group of the homoallyl alcohol 5 as the acetate 6 before subjecting it to the Diels-Alder reaction.…”

“…The diastereomers were chromatographically inseparable. So, based on our previous experience with the synthesis of achiral d-lactones, [9] we decided to continue with our synthetic plan with the mixture of diastereomers 8, 9 and expected that we would be able to separate them at a later stage.…”