Amdt/Eistert homologation

Hales and Paquette have observed that sequential reduction and hydrolysis of 805 can lead efficiently to endo,endo diacid 811 Amdt-Eistert homologation, conventional elaboration of bisfthioether) 813, and exhaustive oxidation was utilized to arrive at 813. The plan was to deploy the dianion of 813 in a manner which would lead to 814. However, the principal product proved to be the unwanted 815. 

The equivalence of sulfur and oxygen in this ring system carries over to NSAIDs as well. Preparation of the sulfur analogue of isoxepac (6-4) starts with the alkylation of thiophenol (27-1) with benzyl chloride (26-1). Cyclization of the intermediate thioether (27-2) then affords the homothioxanthone (27-3). The carboxyl side chain is then extended by means of the Amdt-Eistert homologation reaction. The acid is thus hrst converted to its acid chloride by means of thionyl chloride. Reaction with excess diazomethane leads to the diazoketone (27-4). Treatment of that intermediate with silver benzoate and triethylamine leads the ketone to rearrange to an acetic acid. There is thus obtained tiopinac (27-5) [28]. 

Disadvantages of the silver-promoted method for Amdt-Eistert homologation are the large excess of nucleophile required and also the requirement for the use of the free amine during peptide formation procedures. 13 Activation of the diazo ketone by UV light has been shown to be suitable for this type of procedure and good yields are obtained using only 1.2 equivalents of a hydrochloride salt of an amino ester in the presence of triethylamine (Scheme 5). 14 ... 

The key step of the Amdt-Eistert Homologation is the Wolff-Rearrangement of the diazoketones to ketenes, which can be accomplished thermally (over the range between r.t. and 750°C, photochemically or by silver(I) catalysis. The reaction is conducted in the presence of nucleophiles such as water (to yield carboxylic acids), alcohols (to give alcohols) or amines (to give amides), to capture the ketene intermediate and avoid the competing formation of diketenes. 

Since ketene is probably the intermediate of the Wolff rearrangement, the choice of solvents dictates the nature of the product. Indeed, water gave carboxylic acids, whereas alcohols or amines led to esters and amides, respectively. These combinations have been applied to the synthesis of more complex molecules. For example, the total synthesis of carbonolide B, a 16-membered macrolide antibiotic, relied on Amdt-Eistert homologation. In this sequence, a protected furanuronic acid was transformed to the corresponding a-diazoketone, which was then converted to its homologous carboxylic ester. The reaction was achieved using catalytic amounts of silver benzoate and excess of triethylamine in methanol (Scheme 3.4).11... 

The Wolff rearrangement is the third step of the Amdt-Eistert homologation of carboxylic acids. Figure 14.27 picks up an example that was discussed in connection with Figure 8.13, that is, the homologation of trifluoroacetic acid to trifluoropropionic acid. The first step of the Amdt-Eistert synthesis consists of the activation of the carboxylic acid via the acid chloride. The Cj elongation to an a-diazoketone occurs in the second step. 

D. Seebach, M. Overhand, F. N. M. Kllhnle, B, Martinoni, L. Oberer, U. Hommel, H. Widmer, (3-Peptides Synthesis by Amdt-Eistert Homologation with Concomitant Peptide Coupling. Structure Determination by NMR and CD Spectroscopy and by X-Ray Crystallography. Helical Secondary Structure of a P-Hexapeptide in Solution and its Stability towards Pepsin , Helv. Chim. Acta 1996,79, 913-941. 

J. L. Matthews, C. Braun, C. Guibourdenche, M. Overhand, D. Seebach, Preparation of Enantiopure P-Amino Acids from a-Amino Acids Using the Amdt-Eistert Homologation , in Enantioselective Synthesis of P-Amino Acids , Chapter 5, (Ed. E. Juaristi), Wiley-VCH, New York, 1997, 105- 126. 

The oligomers of 3-amino acids, as opposed to a-peptides, show a remarkable ability to fold into well-defined secondary structures in solution as well as in the solid state. The 3-amino acid building blocks were synthesized from a-amino acids using the Amdt-Eistert homologation reaction in the laboratory of D. Seebach... 

A.T. Russell and co-workers synthesized (R)-(-)-homocitric acid-y-lactone in multigram quantities starting from a citric acid derivative and using the Amdt-Eistert homologation as the key step. ... 

In the usual Amdt-Eistert homologation strategy, (9) (14) (15), the nonmigrating group R is a... 

The tetrahydopyrrole moiety was constructed from amino ester 1, available by an Amdt-Eistert homologation of a protected L-phenylalanine. Conversion by previously described chemistry then provided 2, which was transformed to 3 by acylation, decarboalkoxylation, and reprotection. 

Amdt-Eistert homologation Baylis-Hillman reaction Benzoin condensation Corey-Fuchs reaction Henry reaction (Nitroaldol reaction)... 

Amdt, F. Eistert, B. Ber. 1935, 68, 200-208. Fritz Arndt (1885—1969) was bom in Hamburg, Germany. He discovered the Amdt—Eistert homologation at the University of Breslau where he extensively investigated the synthesis of diazomethane and its reactions with aldehydes, ketones, and acid chlorides. Fritz Arndt s chain-smoking of cigars ensured that his presence in the laboratories was always well advertised. Bemd Eistert (1902—1978), bom in Ohlau, Silesia, was Arndt s Ph.D. student. Eistert later joined 1. G. Farhenindustrie, which became BASF after the Allies broke up the conglomerate after WWII. 

Fuchter, M. J. Amdt-Eistert Homologation. In Name Reactions for Homologations-Part 1 Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 336-349. (Review). 

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