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

Koichi Narita; Noel Sayar; Ken Saijo; Chikashi Ishioka; Tadashi Katoh

doi:10.1055/s-0037-1612059

Synthesis, Table of Contents

Synthesis 2019; 51(06): 1408-1418
DOI: 10.1055/s-0037-1612059

paper

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

Koichi Narita

^aFaculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

,

Noel Sayar

^aFaculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

,

Ken Saijo

^bDepartment of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan Email: katoh@tohoku-mpu.ac.jp

,

Chikashi Ishioka

^bDepartment of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan Email: katoh@tohoku-mpu.ac.jp

,

Tadashi Katoh *

^aFaculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

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Abstract

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Dedicated to Professor Tohru Fukuyama, Nagoya University, Japan on his 70^th birthday

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.

Key words

synthetic intermediate - histone deacetylase inhibitor - natural product - bicyclic depsipeptide - total synthesis

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References

References

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17 We also could not reproduce the Simon’s asymmetric aldol reaction (i.e., Scheme 2, eq. 1, 27 + 28 → 29, 95% yield with 98% ee). Our several follow-up experiments resulted in poor yield (~20%) of 29 with 95–98% ee.

18a Based on the present study, industrial synthesis of FK-A11, which is a novel bicyclic depsipeptide histone deacetylase/phosphatidylinositol 3-kinase dual inhibitor under preclinical trials, has been carried out at Hamari Chemicals, Ltd. (Osaka, Japan).
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19 Sayar N, Narita K, Katoh T. Synthesis 2019; 51 in press,

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