Synthesis of orthogonally protected lanthionines.
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.
Mohd Mustapa
M Firouz
MF
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London, WC1H OAJ UK.
Harris
Richard
R
Bulic-Subanovic
Nives
N
Elliott
Susan L
SL
Bregant
Sarah
S
Groussier
Marianne F A
MF
Mould
Jessica
J
Schultz
Darren
D
Chubb
Nathan A L
NA
Gaffney
Piers R J
PR
Driscoll
Paul C
PC
Tabor
Alethea B
AB
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D010455:Peptides; D013237:Stereoisomerism; D013440:Sulfides
D000900:Anti-Bacterial Agents; D010455:Peptides; D013440:Sulfides; C001520:lanthionine; D000409:Alanine