Step-wise and pre-organization induced synthesis of a crossed alkene-bridged nisin Z DE-ring mimic by ring-closing metathesis.
This paper describes two approaches for the synthesis of a crossed alkene-bridged mimic of the thioether ring system of the nisin Z DE-fragment. The first approach comprised the stepwise total synthesis featuring a cross metathesis and a macrolactamization on a solid support followed by a ring-closing metathesis in solution. Via this route the title compound was obtained in an overall yield of 7% (85% on average for 16 reaction steps). In the second approach, the linear precursor peptide was subjected to ring-closing metathesis and the bicyclic peptide with the correct side chain connectivity pattern was obtained in yields up to 95%. The preferred formation of the bicyclic crossed alkene-bridged mimic of the DE-ring suggests a favorable pre-organization of the linear precursor peptide.
Ghalit
Nourdin
N
Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
Kemmink
Johan
J
Hilbers
Hans W
HW
Versluis
Cees
C
Rijkers
Dirk T S
DT
Liskamp
Rob M J
RM
D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry; D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry*; D000595:Amino Acid Sequence; D002384:Catalysis; D002625:Chemistry, Organic / Q000379:methods*; D013058:Mass Spectrometry; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009561:Nisin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D013440:Sulfides / Q000737:chemistry
D000475:Alkenes; D010455:Peptides; D013440:Sulfides; D009561:Nisin; C001520:lanthionine; C071364:nisin Z; D000409:Alanine