Coupling and Introducing Building Block Reagents

Universidad de Alicante, Departamento de Qufmica Orginica and Instituto de Sfntesis Orginica (ISO), Facultad de Ciencias, ctra, San Vicente s/n, 03690 San Vicente del Raspeig, Alicante, Spain 

The Power of functional Resins in Organic Synthesis. Judit Tulla-Puche and Fernando Albericio Copyright 2008 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-31936-7 

Carbodiimides are traditionally one of the most frequently employed dehydrating reagents for the creation of the ester or amide bond, despite known problems related to difficulties in removing the corresponding generated urea or unreactive acylurea by-products [2]. Therefore, the use of polymer-supported carbodiimides is quite appropriate for the easy elimination of these by-products from the reaction medium by simple filtration, as they will remain anchored to the solid phase. In addition, if an ester or amide formation is intended an excess of acid can be used, as the remainder will also stay anchored as the corresponding isourea. 

There are examples of the use of supported carbodiimide 2 (R = Cy) for the formation of N-hydroxybenzotriazole (HOBt)-derived active esters from N-Boc-protected amino acids (see below), which have been subsequently employed in coupling reactions for the synthesis of dipeptide p-nitroanilides and dipeptide diphenyl phosphonates [12, 13]. Such HOBt-active esters have also been generated from pyrazinone-derived acids using 2 (R = Cy) [14], as well as from difluorophenyl acetic acids [15] for further amidation reactions in the parallel synthesis of tissue factor Vila inhibitors. 

However, more frequently employed has been the commercial polystyrene-supported carbodiimide 5 (0.9-1.4mmolg 1), another bound variant of DCC, although showing similar reactivity. In this supported reagent the tether to the polystyrene backbone has greater activity than the N-methylene linkage present in reagent 2 (R = Cy). 

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Our convergent approach to this class of natural products utilizes the iron-mediated arylamine cyclization for construction of the carbazole framework. The retrosynthetic analysis of the antiostatins B (69a-d) leads to cyclohexa-1,3-diene (33) and the arylamines 70 as building blocks (Scheme 18) [134]. The different side chains at C-1 are introduced by a palladium(0)-catalyzed Sonogashira-Hagihara coupling. The amino group at C-4 is attached to the preformed carbazole skeleton. For introduction of the biuret side chain, we have developed 5-isobutyl-1-nitro-biuret (71) as reagent to access the antiostatins of the B-series. 

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