Development of a Protocol for Eight- and Nine-Membered Ring Synthesis in the Annulation of sp²,sp³-Hybridized Organic Dihalides with Keto Esters

Abstract

A protocol has been developed in which annulation reactions of various dihalides with keto esters can be carried out to provide entry to eight- and nine-membered carbocycles. In this process wherein one alkenyl- or aryl bromide and a tethered alkyl chloride comprise the organic dihalide, a selective metal-halogen exchange reaction between the sp(2)-hybridized bromide and an organolithium initiates the process. Transmetalation to an organoytterbium reagent generates a species that undergoes selective carbonyl addition to the ketone of the keto ester, creating a lactone intermediate. Subjection of the resulting chloroalkyl lactone to intramolecular reductive coupling with samarium(II) iodide completes the desired annulation.

Enantiospecific Strategy Towards Oxygen‐Bridged Terpenoids: Tandem Transannular‐Cyclization and Ring‐Contraction Processes

“…We subsequently approached the second part of our hypothesis, that is, a tandem reaction combining transannular‐cyclization and ring‐contraction processes that we hoped would lead to 1,4‐epoxycyclononanes. Owing to both entropy and enthalpy factors, the synthesis of nine‐membered carbocycles by ring‐closing procedures is rendered quite difficult 8a. 17 Nine‐ and ten‐membered rings, however, have similar total strain levels,18 and therefore ring‐contraction processes from cyclodecanes to cyclononanes should not be seriously hindered by thermodynamic phenomena.…”

The Alkylation of Carbanions

“…Highly reactive carbanions can lead to the formation of strained rings, for example cyclopropanes [272,292,471], benzocyclopropenes [472], or benzocyclobutenes [469,473,474]. Particularly stable are x-chloroalkyl derivatives [475][476][477] whereas, not surprisingly, the x-bromoor x-iodoalkyl carbanions are usually more difficult to prepare and handle (see below). For the organic chemist it is particularly important to know how readily such cyclizations/oligomerizations will occur, and under which conditions it will be possible to trap the intermediate carbanion intermolecularly with an added electrophile.…”

Versatile Methodology to Synthesize Oxygen‐Bridged Nine‐ and Ten‐Membered Cycloalkanes by the Hypoiodite Reaction

“…For these reasons it is necessary to consider all possible synthetic solutions to face the synthetic and structural challenges represented by the aforementioned target molecules. Among these synthetic methodologies are worth noting the following: (a) 1,4-elimination reactions mediated by a base in the presence of a good leaving group [8] (this is a kind of Grob fragmentation [9] that affords good results if the disposition of the hydrogen atom to be abstracted and the leaving group are adequate), (b) retroaldol reactions, [10] (c) cyclobutane thermolysis by a [2+2] cycloreversion reaction, [11] (d) transannular ring expansion induced by electrophiles, [12] (e) transannular cyclization in acidic media, [13] (f) ring expansion mediated by hydrogen peroxide, [14] (g) intramolecular reductive coupling mediated by SmI 2 , [15] (h) anionic oxy-Cope rearrangement [16] (this reaction is less reversible than the conventional Cope re- arrangement because the initially formed enol tautomerises to afford the corresponding ketone), and (i) the hypoiodite reaction. [17] In the present work, a new methodology to synthesize 1,7-epoxycyclononane and 1,8-epoxycyclodecane systems is reported.…”