Synthesis of Orthogonally Protected Lanthionines

Abstract

Synthetic approaches to the lantibiotics, a family of thioether-bridged antimicrobial peptides, require flexible synthetic routes to a variety of orthogonally protected derivatives of lanthionine 1. The most direct approaches to lanthionine involve the reaction of cysteine with an alanyl beta-cation equivalent. Several possibilities exist for the alanyl beta-cation equivalent, including direct activation of serine under Mitsunobu conditions: however, the low reactivity of sulfur nucleophiles in the Mitsunobu reaction has previously precluded its use in the synthesis of the lantibiotics. We report here a new approach to the synthesis of protected lanthionine, using a novel variant of the Mitsunobu reaction in which catalytic zinc tartrate is used to enhance the nucleophilicity of the thiol. In the course of these studies, we have also demonstrated that the synthesis of lanthionine from trityl-protected beta-iodoalanines is prone to rearrangement, via an aziridine, to give predominantly trityl-protected alpha-iodo-beta-alanines, and hence norlanthionines, as the major products.

Progress in Lanthionine and Protected Lanthionine Synthesis

“…demonstrated that the interpretations made by Dugave and Ménez and by Swali et al. of the reactions of ( R )‐ 103 with ( R )‐ 105 or ( S )‐ 109 had to be reassessed (Scheme and Scheme ) . Indeed, when the synthesis of β‐iodoalanine 109 is done through the mesylate with the Dugave's iodination method, 2D‐NMR shows a mixture with an isomeric form …”

“…Moreover, Mohd Mustapa et al. described that the HSQC spectrum of the β‐iodoalanine prepared from the mesylate ( R )‐ 118 corresponds to a mixture of enantiomers of α‐iodo‐β‐alanine ( R / S )‐ 119 , contaminated by the desired β‐iodo‐α‐alanine ( S )‐ 109 as the minor product (Scheme ) …”

“…Moreover, the HMBC‐NMR correlations between the methylene protons of the Fmoc part of Lan and the CH next to the allyl carboxylate (trityl part) confirmed that nor ‐Lan 115 (major product) was obtained instead of the two rotamers of 104 . Noteworthy, Lan 104 (minor product) was a pure diastereomer while nor ‐Lan 115 was a mixture of diastereomers . In the next step, the substitution of Alloc for trityl on the crude mixture of 104 and 115 was followed by HPLC separation of the isomers 113 and 116 .…”

A New Ligation Strategy for Peptide and Protein Glycosylation: Photoinduced Thiol–Ene Coupling

“…In order to overcome the troublesome operation required for product isolation due to the presence of cysteine and cystine [24] and evaluate the efficiency of the reaction on the basis of isolated product yield, the photoinduced reaction of allyl a-C-galactoside 1 a with N-Fmoc cysteine tert-butyl ester (4) [25] was performed under the optimized conditions of run 4 in Table 1. From this reaction, the galactosyl amino ester 5 a was readily isolated by chromatography in excellent yield (92 %) ( Table 2).…”

Optically Active (Peptido‐carbene)palladium Complexes: Towards True Solid‐Phase Combinatorial Libraries of Transition Metal Catalysts

“…The amino groups were protected as azides, and the alcohols were subsequently converted into the iodides via the mesylates with sodium iodide in acceptable yields and in agreement with previous synthesis of analogues. [24,25] The imidazoles and alkyl iodides were employed in the synthesis of four different imidazolium salts as shown in Scheme 3. S N 2 iodide displacements in compounds 2 by the imidazoles 1 generated the imidazolium iodides in moderate yields (40-42 %) after purification on silica gel.…”