pubs.acs.org/joc
include intramolecular nucleophilic substitutions,1a,4 intramo-
Two-Step Hantzsch Based Macrocyclization
Approach for the Synthesis of Thiazole-Containing
Cyclopeptides§
lecular amide formations,1c,5 disulfide formations,6 intramolec-
ular Suzuki reactions,7 ring-closing metathesis reactions,8 and
SNAr displacement reactions.9 Of particular interest, thioalkyl-
ation reactions offer a facile and versatile approach to the
synthesis of cyclic peptides.4,10 Examples of described macro-
cyclizations via thioalkylation include the reaction of the thiol
group of a C-terminal cysteine with N-terminal acetyl bromide
or N-terminal benzyl bromide.4,10 A conceptually different
approach, wherein thioalkylation proceeds via Michael addi-
tion of a thiolate anion to an R,β-unsaturated ester, has been
reported for the synthesis of cyclic thioether dipeptides.11
Herein, we describe an innovative thioalkylation ap-
proach toward the generation of macrocyclic peptides fol-
lowing the intramolecular nucleophilic substitution (SN2) of
N-terminus 4-chloro methyl thiazole peptides with the thiol
group of cysteine. The final products are not entirely pep-
tidic, and the described newly generated macrocyclic com-
pounds contain the thiazole ring, a pharmacophore present
in many natural and synthetic products with a wide range of
pharmacological activities that can be well illustrated by the
large numbers of naturally occurring thiazole-containing
macrocyclic compounds12 and drugs in the market contain-
ing this function group.13
Adel Nefzi,* Sergey Arutyunyan, and Jason E. Fenwick
Torrey Pines Institute for Molecular Studies,
11350 SW Village Parkway, Port Saint Lucie,
Florida 34987, United States
Received August 27, 2010
Macrocyclization via an efficient high-yielding solid-phase
intramolecular thioalkylation reaction is described. The
reaction of S-nucleophiles with newly generated N-terminal
4-chloromethyl thiazoles led to the desired macrocyclization
products 5 in high purities and good overall yields.
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Conformational constraint by cyclization is a common ap-
proach used to restrict the flexibility of peptides and there-
fore is a valuable approach to study topographical require-
ments of receptors.1 Cyclization of peptides can provide
potent and selective ligands for receptors when appropriate
conformational constraints are incorporated.1 Furthermore
cyclic peptides are often more stable to peptidases, and
therefore they can have improved pharmacokinetic profiles and
serve as promising lead compounds for further development.2
Macrocycles are known for their broad range of activities
including antitumor activities and antibiotic activities such as
the structurally complex vancomycin family.3 Reported ap-
proaches on the solid-phase synthesis of macrocyclic compounds
§ Dedicated to Dr. Richard Houghten for his 65th birthday.
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DOI: 10.1021/jo1016822
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Published on Web 10/29/2010
J. Org. Chem. 2010, 75, 7939–7941 7939
2010 American Chemical Society