Organic Letters
Letter
6
as lipophilic nucleotides and peptides. The anodic substitution
reaction of compound 8 using 1-dodecanethiol or allylTMS as
the nucleophile afforded the desired product 9 or 10, in 68%
and 82% yield, respectively (Scheme 5). The anodic oxidation
and the C−C bond cleavage, we conducted anodic oxidation of
compound 12 in the absence of allylTMS, which was added
into the reaction mixture after the completion of oxidation.
When 3.0 F/mol, 6.0 F/mol electricity were passed, the desired
product was obtained in 22%, 40% yield, respectively. It was
found with increasing electricity the approach improved the
yield albeit with low current efficiency. Although further
examination is needed, the present results reveal the usefulness
of this methodology for the modification of proline peptide
derivatives.
Scheme 5. Anodic Oxidation Reactions of Compounds 8 and
1
1
In conclusion, we have demonstrated that 1,3,5-trimethox-
ybenzene can be used as a 5-substituted leaving group for
proline moieties under LPC/NM conditions. This leaving
group is tolerant of deprotection conditions for N- and C-
terminal modification of 5-substituted proline derivatives. TMP
can also be activated by anodic oxidation to form the N-acyl
iminium cation via C−C bond cleavage to effectively provide
the corresponding proline analogue.
ASSOCIATED CONTENT
Supporting Information
■
*
S
Experimental procedures, compound characterization data, and
1
13
of compound 11 did not give product 10 due to the higher
oxidation potential of carbamate (E = +1.86 V) compared to
ox
the hexenyl moiety (Eox = +1.77 V). The allylated product
could be constructed by another route, i.e., N-functionalization
using an allylated synthetic intermediate containing a stable C−
C bond. In contrast, the electrochemical thiol-substitution
reaction of 8 is extremely effective, considering the oxidation
potential and the instability of the N−C−S linkage. This
approach might allow effective assembly of proline-based lipid-
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
7
bilayer motifs using various alkyl thiols.
To apply the method for the functionalization of peptide
derivatives containing the 5-TMP proline residue at C-terminal,
tripeptide 12 was prepared as shown in Scheme 6. The
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Scheme 6. Anodic Modification of Tripeptide 12
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dx.doi.org/10.1021/ol503198p | Org. Lett. XXXX, XXX, XXX−XXX