Intramolecular Diels-Alder reactions. 5 [1] Facile synthesis of an octahydrobenzocycloheptenone derivative utilising intramolecular Diels-Alder reaction

Abstract

173Carbocyclic molecules containing fused six-and seven-membered rings are found in a number of natural products [3], e.g. in himachalane and perforene sesquiterpenes such as α-himachalene [4] and perforenone A and B [5]. Of particular medicinal interest are the daphnane and tigliane derivatives, some of which can act as tumor promoters [6]. A number of syntheses of such fused 6/7 bicyclic ring systems [7] involved an IMDA reaction as the key step. Abstract. Undecatrienone 4 was prepared in a short sequence via siloxycyclopropanes 1 and 3. Intramolecular Diels-Alder reaction (IMDA) of 4 under various conditions afforded octahydrobenzocycloheptenone derivative 5 as a mixture of three or four diastereomers. High diastereoselectivities in favour of the endo-product cis-5a could be obbe achieved by choice of the appropriate Lewis acid promoter [8c]. The use of strong Lewis acids with two free coordination sites led to the formation of the otherwise unfavoured trans-fused cycloadducts via a novel chelate-controlled cycloaddition reaction. The transfused octalone products, that were now available in good yields for the first time, were elaborated to the sesquiterpene α-eudesmol [8c], and, in a formal total synthesis, to the pharmaceutically important compound dihydromevinolin [1]. Here, we report the extension of the siloxycyclopropane route developed in our laboratory to undecatrienone substrates, and an IMDA reaction to furnish a fused 6/7 ring system. Since these syntheses were performed with racemates, all chiral compounds are provided as mixtures of both enantiomers; for clarity, only one enantiomer is depicted in the schemes. IntramolecularOur approach to the undecatrienone substrate starts with the literature-known siloxycyclopropane 1 [9]. Deprotonation of 1 with LDA and subsequent reaction with E-1-iodo-3,5-hexadiene (2) [10] in presence of the lithium complexing agent 1,3-dimethylimidazolidin-2-one (DMEU) furnished the tetrasubstituted cyclopropane 3 in 44% yield with recovery of some starting material 1. The modest yield of this reaction could not be explained in terms of low reactivity of the iodide 2 since analogous alkylation reactions with saturated iodides [11] generally proceed very smoothly (70-90% yield). It was found, however, that the yield was considerably lower (61%) when 1-iodo-3-butene was employed [12]. We therefore attribute the lower yields of the alkylation reactions with homoallylic iodides to the competing elimination reaction with either excess of LDA or the ester enolate acting as base. Due to the volatility and tendentained with TiCl 4 as promoter. This selectivities were attributed to the formation of a seven-membered ring chelate as intermediate. The configurational assignment of all four diastereomers of 5 was based on isomerisation reactions and NMR analysis.We recently described syntheses and IMDA reactions of variably substituted 1,7,9-decatrien-3-ones to octahydronaphthalenones [1, 8]. The trienone substrates were assembled in fast and efficient sequences from simple precursors ...

Donor−Acceptor-Substituted Cyclopropane Derivatives and Their Application in Organic Synthesis

“…Ring opening of 173 furnished enones 174 , which in part immediately underwent the intramolecular [4 + 2] cycloaddition to bicyclic compounds 175 . In other cases, heating or treatment with Lewis acid was required to promote the Diels−Alder reaction to 175 49 …”

“…The resulting compounds are very useful starting materials for intramolecular Diels−Alder reactions. In case of compound 173a , ring cleavage to 174a was immediately followed by stereoselective intramolecular cycloaddition, leading to bicyclic compound 175a in moderate yield and diastereoselectivity (Scheme ) 72 …”