A Concise Approach for Producing Optically Pure Carboxylic Acid Segments for the Synthesis of Bicyclic Depsipeptide Histone Deacetylase Inhibitors

Abstract

Optically pure carboxylic acid segments, which are common key intermediates for the synthesis of naturally occurring bicyclic depsipeptide histone deacetylase inhibitors, have been produced efficiently. The method features the chromatographic separation of two diastereomers, which were formed by direct amide condensation of racemic (3RS,4E)-3-hydroxy-7-mercaptohept-4-enoic acid (rac-Hmh) with chiral amino acids. This approach offers a reliable and practical method for producing optically pure carboxylic acid segments, which can facilitate easier access to important anticancer agents derived from them.

Facile Total Synthesis of Thailandepsins D–F: Novel Bicyclic Depsipeptide Histone Deacetylase Inhibitors Isolated from a Microorganism

“…The spectroscopic properties (IR, 1 H and 13 C NMR, and MS) of the synthetic form of 4 were identical to those reported for the natural form of 4. 2 12 and carboxylic acid segment 13 10 as starting materials, the second target compound, thailandepsin E (5) was then synthesized in a manner similar to that of the synthesis of thailandepsin D (4) (cf. Scheme 2).…”

“…9 However, to the best of our knowledge, the total synthesis of thailandepsins D-F (4-6) has not been reported to date. In our preceding paper, 10 we developed a concise approach to study the optically pure carboxylic acid segments for the synthesis of naturally occurring bicyclic depsipeptide HDAC inhibitors. This study describes the first total syntheses of thailandepsins D-F (4-6), utilizing the carboxylic acid segments (cf.…”

“…Scheme 1, compounds 12 and 13) that our group previously prepared and described. 10 The method described in this study will offer easier access to this class of pharmaceutically important natural products by providing a reliable and practical source of the substances. The retrosynthetic analysis of thailandepsins D-F (4-6) is illustrated in Scheme 1.…”

“…The amine segments 10 and 11 were obtained from N-Boc-D-valinal (14), N-Boc-D-isoleucinal (15), ethyl acetate (16), and the D-cysteine derivative 17, as previously described in our work on the total syntheses of spiruchostatins A 11 and C. 12 The carboxylic acid segments 12 and 13 were prepared from racemic (3RS,4E)-3-hydroxy-7thiohept-4-enoic acid 18 (rac-Hmh) and D-amino acid methyl esters 19 (D-norleucine methyl ester) and 20 (D-methionine methyl ester), as described in our previous work. 10 We initially pursued the synthesis of thailandepsin D (4), as shown in Scheme 2. The crucial condensation of amine segment 10 11 with carboxylic acid segment 12 10 pro-ceeded well under the mild conditions [O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (1.3 equiv), 1-hydroxy-7-azabenzotriazole (HOAt) (1.3 equiv), i-Pr 2 NEt (2.6 equiv), CH 2 Cl 2 , -30 °C, 5 h], which were employed in our previous research.…”

“…10 We initially pursued the synthesis of thailandepsin D (4), as shown in Scheme 2. The crucial condensation of amine segment 10 11 with carboxylic acid segment 12 10 pro-ceeded well under the mild conditions [O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (1.3 equiv), 1-hydroxy-7-azabenzotriazole (HOAt) (1.3 equiv), i-Pr 2 NEt (2.6 equiv), CH 2 Cl 2 , -30 °C, 5 h], which were employed in our previous research. 11a The target condensation product 21 was obtained in a relatively high yield (85%) without appreciable epimerization at the C2 stereogenic center.…”