Parallel Synthesis and Biological Evaluation of Destruxin E Analogs Modified with a Side Chain in the α‐Hydroxycarboxylic Acid Moiety

Abstract

This study demonstrates the synthesis and biological evaluation of destruxin E analogs possessing various functional groups in the α‐hydroxycarboxylic acid moiety. Parallel synthesis of eleven analogs was successfully achieved through solution‐phase peptide synthesis and macrolactonization. Biological evaluation of the synthetic analogs using osteoclast‐like multi nuclear cells (OCLs) revealed that the epoxide group in the side chain of α‐hydroxycarboxylic acid and the orientation of the oxygen atom are essential factors in the desired potent activity that induces morphological changes in OCLs for the inhibition of bone‐resorbing activity.

Structure Revision of Trichomide D by Total Synthesis

“…Having the desired acylproline derivative 5 in hand, we next synthesized the macrolactone 18 (Scheme ). Acylation of the β-alanine 2-trimethylsilylethyl ester (H-β-Ala-OTMSE, 13 ) with Boc- l -MeAla-OH was performed using EDCI/HOBt to afford the dipeptide 14 in 84% yield. After removal of the Boc group under acidic conditions, introduction of an l -MeIle residue was smoothly conducted using Fmoc- l -MeIle-Cl under weakly basic conditions, leading to the desired tripeptide 15 in 91% yield.…”

“…Therefore, we investigated the synthesis of (1γ S )-trichomide D to confirm the correct structure of trichomide D as shown in Scheme . Acylation of the proline derivative 6 with the 2-hydroxy-4-pentenoic acid derivative 21 was performed using PyBroP/DIEA, leading to the dipeptide 22 in 75% yield. Asymmetric dihydroxylation of the alkene moiety in 22 smoothly proceeded in the presence of K 2 OsO 2 (OH) 4 /(DHQD) 2 PHAL, and the desired diol 23 with the S configuration at the secondary alcohol stereogenic center was obtained in 78% yield after the separation of diastereomers.…”