An Improved Synthetic Route to Angularly Functionalized Hydrofluorene Derivatives through Pd(0)-Catalyzed Heck Reaction

Abstract

4a-Substituted 1,1-dimethyl or 1-carbomethoxy-1-methyl hydrofluorenes carrying various substituents in the aromatic ring could be conveniently synthesized by Pd(0)-catalyzed Heck reaction. The required bromobenzyl-substituted ethylidene cyclohexane substrates were derived from Hagemann's ester (methyl analogue) via condensation with appropriate benzyl bromide, hydrolytic decarboxylation of the ester, 1,4-addition of methyl or cyano group followed by necessary functional group manipulation, and Wittig olefination. Simple organic transformations converted the vinyl group to carboxy, formyl or hydroxymethyl. The ring juncture stereochemistry of the products could be ascertained by correlation approach.Hydrofluorenes constitute the basic skeleton of a large number of highly functionalized diterpenoids of the gibberellin and rearranged abietane groups, but synthetic methodologies for these important and apparently simple molecules have been scant. Though there are few reports on the syntheses of 4a-substituted hydrofluorenes, 1,2 only a single methodology established by Ghatak and coworkers 2 is available, to our knowledge, for the synthesis of 4a-(carboxyl)-substituted hydrofluorenes carrying substituents at C-1 position; the corresponding position in gibberellins usually carry a methyl and a carboxyl group. As these products are expected to serve as putative intermediates to C-10 functionalized gibberellins, we became interested to develop an improved synthetic methodology for 1,1-disubstituted hydrofluorenes with diverse functional groups at the 4a-position.Inserting a vinyl group at the angular position of hydrofluorenes appeared to us as particularly promising, as it can be easily transformed to other functional groups. Trost et al. first reported 3 the synthesis of hydrofluorenes with a 4a-vinyl substituent by palladium-catalyzed reductive cyclization. Although the yields achieved were moderate to good, the methodology involves a complex reagent system and only C-1 unsubstituted hydrofluorenes were synthesized. We have recently reported the results of our fruitful venture in harnessing the Pd(0)-catalyzed Heck reaction for the synthesis of several complex diterpenoids. 4 In continuation of that exercise we now describe a simple, generalized and high-yielding method using Pd(0)-catalyzed intramolecular cyclization to produce a series of functionalized hydrofluorenes with substituents at C-1, C-4a and the aromatic ring. Easy transformations of the vinyl group to many other functionalities are also demonstrated.The retrosynthetic plan is described in Scheme 1. The required 2-(2-bromobenzyl)-1-ethylidenecyclohexane intermediates were obtainable from the respective cyclohexanones. The latter could in turn be prepared through alkylation of suitably substituted benzyl bromides with the methyl analogue of Hagemann's ester, easy decarboxylation to the cyclohexenones, and subsequent introduction of a methyl or carbomethoxy group at the b-position of the conjugated carbonyl system. Scheme 1 Retrosynthetic plan R 3 R 2 M e...