Rhodium-Catalysed 1,4-Additions in Water: Synthesis of Succinic Esters and β²-Amino Acid Derivatives

Abstract

The rhodium-catalysed addition of boronic acids to asubstituted activated alkenes proceeds smoothly in water resulting in a unique synthesis of both succinic esters and b 2 -amino acid derivatives.Since the first report by Hayashi and Miyaura in 1998, the rhodium-catalysed addition of aryl and alkenyl organometallic reagents to activated alkenes has emerged as important methodology for organic synthesis. 1 Although both Miyaura and Lautens have reported additions to both activated alkenes and heteroaromatic alkenes that proceed with water as solvent, in the majority of reported examples organic solvents are used either alone or as co-solvents. 2 In a previous study we have revealed an efficient rhodium-catalysed conjugate addition of boronic acids to a,b-dehydroamino acid derivatives using water as the only solvent. 3 In an ongoing programme of research we have sought to broaden the scope of this methodology to other a-substituted activated alkenes. In this paper, we wish to present preliminary results in the synthesis of 2-substituted succinic esters and b 2 -amino acid derivatives. The products from this process are of significant utility as peptidomimetics in the development of pharmaceutical and agrochemical intermediates. 4 The methodology described herein represents a unique alternative to the twostep condensation-hydrogenation approach conventionally employed. 5At the outset of this study we chose to investigate the coupling of arylboronic acid (2b) with dimethyl itaconate (1) using water as the reaction solvent. During preliminary optimisation, the catalyst [Rh(cod)Cl] 2 (cod = cyclocta-1,5-diene) was used with sodium dodecylsulfate (SDS) as a phase transfer agent affording a 55% yield of product 3b. In the absence of SDS the yield fell to less than 10%. The addition of two equivalents of sodium carbonate increased the yield to 81%. Under these optimised conditions a number substituted of substituted aryl and vinylboronic acids (2a-i) was tested and, pleasingly the reaction proceeded in good isolated yield to provide a useful synthetic approach to 2-substituted succinic esters (Scheme 1). 6 The addition of phosphine ligands did not appear to accelerate the conjugate addition under these conditions. It was useful to note that both electron-rich (3h) and electron-deficient aryl boronic acids (3c,g) could be successfully employed as well as different substitution patterns (3d-f). The incorporation of functional groups such as -Cl, -COMe, -NO 2 and -NMe 2 provide pharmacologically interesting products and present opportunities for further modification. Scheme 1Given the importance of b-amino acids and their derivatives the development of new synthetic methodology to prepare such compounds is of significant interest. 7 We were therefore driven to extend the described methodology to include the addition of boronic acids to b-amidoacrylates affording b 2 -amino acid derivatives. The orthogonally protected b-amidoacrylate substrate 4 can be prepared in good yield by the reaction of potassium phthalimide (KNPht) w...