Vinyl Grignard-Mediated Stereoselective Carbocyclization of Lactone Acetals

Abstract

A novel Ferrier-type carbocyclization is reported. It involves a carbohydrate-derived lactone acetal synthesized from methyl α-d-glucopyranoside, which upon treatment with excess vinylmagnesium bromide provides a highly substituted carbocyclic product as a single stereoisomer. The yield is greatly increased when N,N,N',N'-tetramethylethylenediamine is added to the reaction mixture. Optimized reaction conditions have been applied to lactone acetals derived from other carbohydrates. Based on the obtained results, a possible reaction mechanism has been proposed. Furthermore, scalability of the reaction up to 15 g scale and derivatization of the carbocyclic product has been demonstrated, including the formation of a rare trans-bicyclo[4.3.0]nonene scaffold via a ring-closing metathesis. The structure of this and all carbocyclic products were confirmed by X-ray crystallographic analysis.

Formal Single Atom Editing of the Glycosylated Natural Product Fidaxomicin Improves Acid Stability and Retains Antibiotic Activity

“…This is of particular interest as the 4- O -isobutyryl moiety of noviose contributes significantly to the biological activity . The key challenge starting from α- d -methoxy mannose is to introduce the gem -dimethyl group at C(5), which we envisioned to perform via a Grignard reaction of the lactone, as reported by Hedberg et al We decided to use an acetonide functionality for orthogonal protection of the 2,3- syn diol, as this can be readily removed under the LA conditions of the substitution reaction at Fdx. We initiated our synthesis with the preparation of the literature known iodide 10 − (Figure b).…”

Single Atom Editing of the Glycosylated Natural Product Fidaxomicin Improves Acid Stability and Retains Antibiotic Activity

“…This is of particular interest as the 4-O-isobutyryl moiety of noviose contributes significantly to the biological activity. 8 The key challenge starting from a-D-methoxy mannose is to introduce the gem-dimethyl group at C( 5), which we envisioned to perform via a Grignard reaction of the lactone as reported by Hedberg et al 41 We decided to use an acetonide functionality for orthogonal protection of the 2,3-syn diol as this can be readily removed under the LA conditions of the substitution reaction at Fdx. We initiated our synthesis with the preparation of the literature known iodide 10 42-45 (Fig.…”

Serendipitous One-Step Synthesis of Cyclopentene Derivatives from 5′-Deoxy-5′-heteroarylsulfonylnucleosides as Nucleoside-Derived Julia–Kocienski Reagents

“…They have also attracted a great deal of attention from a green chemistry viewpoint, as workup and purification procedures for the intermediates can be avoided, and the time, energy, and materials required for the overall process are decreased . There have been many reports of domino reactions consisting of the ring opening of sugars and subsequent carbocyclization. − However, to the best of our knowledge, there are no reports about domino reactions that consist of the tetrahydrofuran ring opening of a nucleoside and carbocyclization to produce a carbocyclic nucleoside. We envisioned that such a domino reaction could be a novel efficient route to carbocyclic nucleosides.…”