Expeditious Syntheses of Conjugated Allenyl Esters and Oxazoles through a Cascade Reaction of .ALPHA.-Alkynyl Malonates under Alkaline Conditions

Abstract

Since the development of various synthetic methods for the achiral and chiral allenes, extensive studies on the structure and reactivity of the characteristic allenes have been performed. [1][2][3][4][5][6][7][8][9] Allenylic compounds have been efficiently utilized as a key intermediate to synthesize biologically active natural products. [10][11][12] The specific reactivities of allenylic compounds have been widely applied to carbon-carbon and carbon-hetero atom cyclizations, aldol reactions, DielsAlder reactions, [2ϩ2] and [4ϩ2] cycloadditions, etc. [13][14][15][16][17][18][19] Because of this usefulness of allenes, there have been many reports on methods for constructing the allenylic moieties. [1][2][3][4][5][6][7][8][9][20][21][22][23][24][25][26] Previously, we communicated a characteristic synthetic method for conjugated allenyl esters and trisubstituted oxazoles via alkaline hydrolysis of diethyl a-alkynyla-methoxy(or acetylamino)malonates followed by decarboxylation of the corresponding resultant monocarboxylates in a cascade reaction manner. 27)We now describe, in detail, expeditious syntheses of conjugated allenyl esters and trisubstituted oxazoles and the related reactions based on the following concept and background.28) Cysteine proteases of the papain family have been implicated in the pathogenesis of a various of serious diseases. Hence, the development of cysteine protease inhibitors has been extensively studied worldwide. 29) We thus designed diethyl a -alkynyl-a -methoxy(or acetylamino)malonates (DAM, A) as new lead compounds for developing cysteine protease inhibitors, as shown in Chart 1.27) Chart 1 illustrates our idea of the enzyme inhibition and latent function of DAM (A), readily obtained from the reaction of diethyl keto(or acetylimino)malonate with alkynyl anionic species, against cysteine proteases. Namely, enzymatic and/or nonenzymatic hydrolysis of an ethoxycarbonyl group (a "trigger" moiety leading compounds A to the conjugated allenyl ester) of the DAM (A) followed by enzymatic and/or non-enzymatic decarboxylation of the corresponding resultant monocarboxylic acids B may generate the conjugated allenyl esters C. The conjugated allenyl esters C must be capable of trapping an active-site nucleophile (SH group of the cysteine residue) 30) of the target enzyme, which may cause inhibition of the SH enzymes. In the molecule of DAM (A), the R group would be designed as the specific enzyme-recognition moiety bearing a di-or tripeptide substituent.Diethyl a-alkynyl-a-methoxymalonates 2a-e, employed for syntheses of conjugated allenyl esters (vide infra), were readily prepared from diethyl ketomalonate by its treatment with various ethynyl lithiums derived from 1a-e, as shown Sho-machi, Tokushima 770-8505, Japan: and b Rigaku Corporation; 3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666, Japan. Received September 3, 2005; accepted November 4, 2005; published online November 11, 2005 Diethyl a a-alkynyl-a a-methoxymalonates (2a-e) were smoothly hydrolyzed and then decarboxylated under a...

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