Divergent Access to Histone Deacetylase Inhibitory Cyclopeptides via a Late-Stage Cyclopropane Ring Cleavage Strategy. Short Synthesis of Chlamydocin

Abstract

A unified step-economical strategy for accessing histone deacetylase inhibitory peptides is proposed, based on the late-stage installation of multiple zinc-binding functionalities via the cleavage of the strained cyclopropane ring in the common pluripotent cyclopropanol precursor. The efficacy of the proposed diversity-oriented approach has been validated by short stereoselective synthesis of natural product chlamydocin, containing a challenging-to-install fragment of (2S,9S)-2-amino-8-oxo-9,10-epoxydecanoic acid (Aoe) and a range of its analogues, derivatives of 2-amino-8-oxodecanoic and 2-aminosuberic acids.

Generation of Mixed Anhydrides via Oxidative Fragmentation of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates

“…Compound 19 is known as immediate precursor of the corresponding hydroxamic acid Ky-2, a powerful histone deacetylase (HDAC) inhibitor and a potent anticancer agent [40,41,64]. This achievement illustrates the suitability of the developed protocol for the synthesis of bioactive amides and was previously employed by us, along with several other ring-opening reactions, to generate a number of HDAC inhibitors from the single cyclopropanol precursor according to diversity-oriented synthesis paradigm [39].…”

“…Preparation of cyclopropanols 1g and 1h is described in the Supplementary Materials. Peptide cyclopropanol 1e and bicyclic cyclopropanols 1f and 1i have been prepared by following the published protocols [30,39]. Silica gel 40-100 µm was used for column chromatography; silica gel 60F 254 plates were used for TLC.…”

“…Recently, we proposed the use of cyclopropanol moiety as pluripotent functional group for the diversity-oriented synthesis of bioactive compounds, which was validated by the efficient preparation of several histone deacetylase inhibitory cyclopeptides from the single cyclopropane-containing precursor [39]. The last-step ring opening in the latter required an expedient and high yielding protocol to generate a range of different carboxylic acid derivatives.…”

Aerobic Oxidations in Asymmetric Synthesis: Catalytic Strategies and Recent Developments

“…The α-helical structure of PLL catalyst is responsible for the supramolecular binding of prochiral substrate 32 and favors the corresponding transition state (TS ≠ ) leading to the R-enantiomer of 30 (Kelly and Roberts, 2004;Berkessel et al, 2006). The developed transformation was successfully applied in a short and stereodivergent synthesis of chlamydocin, a natural histone deacetylase inhibitor with chiral epoxy ketone warhead (Elek et al, 2019).…”

Stereocontrolled addition of Grignard reagents to oxa-bridged benzazepines: highly efficient synthesis of functionalized benzazepine scaffolds

“…Diversity-oriented synthesis (DOS), dened as a powerful synthetic strategy to the libraries of diverse highly valuable molecules from one parent compound, 26,27 is therefore wellsuited for the timely design and execution of parallel (library) synthesis. 28 In recent years, our group focused on the development of a more facile and efficient diversity-oriented synthesis strategy for the generation of this class of 7-membered heterocyclic compounds.…”