Total Synthesis of Cyclosporin O by Convergent Approach Employing Fmoc-Amino Acid Chlorides Mediated by Zinc Dust

Abstract

An epimerization free and efficient total synthesis of immunosuppressant cyclosporin O (CsO) by step-by-step assembly of amino acids in solution phase is reported. The couplings were performed by employing Fmoc-amino acid chlorides and were mediated by zinc dust under neutral conditions. The yield and purity of the coupling of sterically hindered N-methylamino acids to N-methylamino acids at positions 8, 9, 10, and 11 were enhanced by repeating the coupling thrice at these particular junctures. All the 10 intermediate peptides pertaining to CsO and the final CsO were isolated and completely characterized through IR, 1H NMR, mass spectrometry, and HPLC techniques.

Macrocyclic N-Methylated Cyclic Peptides and Depsipeptides

“…inflatum GAMS, CsB 52, CsD 54, and CsE 55 as minor derivatives were also isolated from the culture after extensive application of separation techniques [36]. Traber et al [38] successfully isolated other minor components, Cs K-Z (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76). Using more extensive chromatography protocols, other minor compounds, Cs E-I (55-59) from the culture of To.…”

“…The following synthesis attempts were reported by three authors synthesizing the same Cs derivative, CsO 65 [69][70][71]. CsO 65 is one of the Cs derivatives that has no MeBmt as one of the constituent residues.…”

The diketopiperazine-fused tetrahydro-β-carboline scaffold as a model peptidomimetic with an unusual α-turn secondary structure

“…At the end, acceptable yields could be obtained via formation of the chloride intermediate [48], by reaction of acid 4 with thionyl chloride, and subsequent coupling with 2 in CH 2 Cl 2 and 2,6-lutidine to give 5 . The formation of the fused, tetracyclic THBC-DKP ring system was then easily achieved by removal of the N -Fmoc protecting group [49] and spontaneous lactamization to give the diketopiperazine ring of 6 .…”

Protection Reactions

“…Formation of DKPs can be minimized by adopting methods like fragment condensation with Fmoc-dipeptide acids or using esters such as benzyl or tert-butyl esters that have lower reactivity to aminolysis for protection of the carboxy terminus of peptides. The latter approach has been employed for the successful solution-phase synthesis of cyclosporine O -a peptide with several NMAs using Fmoc chemistry [76]. Employing fluoride reagents for deblocking Fmoc can also prevent DKP formation.…”