488 J. zyxwvutsr Org. zyxwvutsr Chem. 1994,59, zyxwv 488-490 Synthesis of r-Unsubstituted a-Acyl-8-tetronicAcids from Aldehydes Keiichi Nomura,’ Tetsuya Iida, Kozo Hori, and Eiichi Yoshii’ Faculty zyxwvutsrq of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-01, Japan Received September 22, 1993 As a part of our studies directed toward the total synthesis of tetronasin (1),l an acyltetronic acid polyether antibiotic,2 we needed an efficient method for the prep- aration of y-unmbstituted a-acyl-/3-tetronic acids that can be utilized at a final stage of the synthesis?*‘ Several years ago, we reported a new technique for a-acylation of 8-tetronic acids (y-unsubstituted and -substituted) that involves 0 to C migration of O-acylates which is induced by DMAP in CH2Cl2 solvent at room temperat~re.~ This advanced version of classical Friedel-Crafts acylation6can be carried out under exceptionally mild conditions, but unfortunately it has been found that there is a limitation in which sterically hindered O-acylates (e.g. O-trimeth- ylacetate) strongly resist to the base-induced acyl migra- tion. More recently, Ley and Wadsworth7 introduced a palladium-catalyzed acylation of O-methyl-protected zyxwvu a-(tributylstanny1)tetronic acid in the course of studies aimed at total synthesis of 1, but application of this method to sterically hindered acid chlorides such as 2 has not been recorded. In the meantime, Ley and co-workers8 reported a new three-step entry to y-substituted acyltetronic acids 9: y-alkylation of S-tert-butyl acetothioacetate (5) with primary alkyl halide; transesterification of the homolo- gated acetothioacetate 6 with a-hydroxy ester 7; TBAF- mediated Dieckman cyclization of the resulting diester 8. This methodology, however, is apparently intolerable for the synthesis of 1 which has a bulky a-branched acyl residue, since the keto ester intermediate 4 should not be accessible via a y,y-dialkylation of 5. In this context, we planned to prepare 4 by a Lewis acid catalyzed reaction of aldehyde 3 with (diazoacetoxy)acetic ester 11 according to Roskamp’s 8-keto ester synthesis from aldehyde and (1) Hori, K.; Kazuno, H.; Nomura, K.; Yoshii, E. Tetrahedron Lett. 1993,34, 2183. (2) Davies. D. H.: SnaDe. E. W.: Suteer. P. J.; Kina. T. J.; Falshaw, C. P. J.’Chem. Soc., Chem.*Commun. 1981, 1073. (3) Reviewe on the chemistry and synthesis of tetronic acids: (a) Haynes, L. J.; Plimer, J. R. Quart. Rev. 1960,14,292. (b) Pattenden, G. Fortschr. Chem. Org. Naturst. 1978, 35, 133. (4) A standard, well-established synthesis of y-substituted zyxwvutsr a-a- cyltetronic acids starts with a-lithiation of O-protected tetronic acids, followedby an aldol reaction and subsequent oxidation and deprotection steps. For leading references, see: (a) Clemo, N. G.; Pattenden, G. Tetrahedron Lett. 1982,23,581 and 585. (b) Miyata, 0.; Schmidt, R. R. Ibid. 1982,23, 1793. (c) Takeda, K.; Kubo, H.; Koizumi, T.; Yoshii, E. Ibid. 1982,23,3175. (d) Takeda,K.; Kawaniehi,E. Nakamura,H.;Yoshii, E. Ibid. 1991, 37, 4925. (e) Hori, K.; Hikage, N.; Inagaki, A.; Mori, S.; Nomura, K.; Yoshii, E. J. Org. Chem. 1992, 57, 2888. This acylation method is not useful for y-unsubstituted tetronate as the aldol reaction occurs mainly a t the y-position. (5) Nomura, K.: Hori. K.; Arai, M.: Yoshii, E. Chem. Phorm. Bull. .- 1986; 34, 5188.. . (6) Tanaka, K.; Matauo, K.; Nakazumi, Y.; Morioka, Y.; Takashita, Y.; Tachibana, Y.; Sawamura, Y.; Kohda, S. Chem. Pharm. Bull. 1979,27, 1901; Haynes, L. J.; Jamieson, J. W. M. J. Chem. SOC. 1968, 4132. (7) Ley, S. V.; Wadsworth, D. J. Tetrahedron Lett. 1989, 30, 1001. (8) Booth, P. M.; Fox, C. M. J.; Ley, S. V. J. Chem. Soc.,Perkan Trans. 1 1987, 121. Fox, C. M. J.; Ley, S. V. Org. Synth. 1987, 66, 108. y + x H3C CH3 1 :x. (tetronasin) - ethyl diazoacetate.9 After an extensive model study on the proposed transformation, we were able to obtain 4 in high yield, which was cyclized to 1 (74% overall yield), achieving the first total synthesis of tetronasin sodium.’ This paper describes the results of model studies on the two-step synthesis of y-unsubstituted a-acyltetronic acids from aldehydes. 0 0 8 S Methyl (diaz0acetoxy)acetate (1 1) was prepared from methyl glycolate (10) by two conventional routes as illustrated in Scheme 1.l0 Reaction of 11 with some representative aldehydes was first attempted according to the protocol (SnC12 catalysis) of Holmquist and Rosk- ampf? As shown in Table 1, reactions of primary and secondary aldehydes (14a-d) with 11 in the presence of SnC12 in dichloromethane at room temperature afforded the desired 8-keto esters 15a-d in good to high yields. On the other hand, reactions of tertiary aldehydes (14e-g) proved quite sluggish, resulting in poor yields of the corresponding keto esters even after prolonged reaction and/or with excess amounts of the Sn(I1) catalyst. Toward this end, we have made a brief survey of Lewis acid catalysts and have found that ZrC4 and Tic4 are quite effective in the C-H insertion reaction to sterically hindered aldehydes (Scheme 2). Thus, reactions of 11 in CH2C12 with trimethylacetaldehyde (14e) and l-methyl-l-cyclo- hexanecarboxaldehyde (140 proceeded rapidly at 0 OC and were completed within 0.5 h to give the corresponding keto esters 158 and 15f, respectively, in more than 72% isolated yields (Table 1). 2,2-Diphenylpropanal(14g) also afforded a good yield of 15g, although the reaction proved to be somewhat slower. The heterogeneous reaction with ZrC4 in dichloromethane solvent can be made homoge- (9) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258. (10) Padwa, A.; Kinder, F. R. J. Org. Chem. 1993,58,21. Regitz, M. Rychnovsky, S. D.; Mickus, D. E. J. Org. Chem. 1992,57, 2732. Angew. Chem., Int. Ed. Engl. 1967,6, 733. 0 1994 American Chemical Society