Eastwood et al.
JOCNote
SCHEME 1. Synthesis of Selenide R-Hydroxy Acid 1
requires incorporation of an R-hydroxy acid (rather than an
R-amino acid), but such backbone esters can be efficiently
incorporated into peptides by SPPS16,17 and into proteins by
nonsense suppression.10,18-22 In addition, selenium-contain-
ing natural amino acids such as selenocysteine and seleno-
methionine are well-known to be efficiently incorporated into
proteins. Finally, “caging” the selenide with an o-nitrobenzyl
group allows the process to be initiated photochemically.
The process proposed in Figure 1, however, raises many
questions. Like all SN2 reactions, the selenide-induced ester
displacement is sensitive to steric effects. As such, the reac-
tion is typically applied to methyl esters, although under
optimal conditions and with heating, ethyl, benzyl, and even
isopropyl esters along with many lactones are reactive.
Certainly, the R-carbon of the R-hydroxy acid that is in-
corporated will be sterically crowded. The question is
whether the intramolecularity of the process, perhaps aided
by the inductive effect of the neighboring amide carbonyl,
will overcome the steric burden. Caged selenides are not
common, and so there is the question of the efficiency of
the photochemical step. In addition, selenides are sensitive
to oxidation, more so for aliphatic than aromatic (seleno-
phenol) derivatives. On the other hand, an aliphatic selenide
might be expected to be the stronger nucleophile, but an aryl
selenide has fewer rotatable bonds that need to be restricted
in the cyclization reaction.
Synthesis of enantiopure 1 (Scheme 1) began with conver-
sion of S-(-)-tetrahydro-2-furoic acid to the ring-opened
bromide 4 as previously described.23,24 Conversion to the
diselenide and ester hydrolysis then produced 6.25,26 Acid
diselenide 6 was directly reduced with sodium borohydride,
and the product was alkylated with o-nitrobenzyl bromide to
give the target compound 1.27
The synthesis of 2 (Scheme 2) began with the known
reduction of 2-nitrophenylpyruvic acid by (þ)-B-chlorodii-
sopinocampheylborane (Ipc2BCl) to yield 7 in 94% ee.28 The
selenocyanate was prepared by a modification of the stan-
dard sequence, and the nitrobenzyl group was introduced by
reductive alkylation. The bulky tert-butyl protecting groups
were installed to discourage intramolecular cyclization,
which was seen when 7 was subjected to reducing conditions,
as well as to improve the solubility and ease of purification of
subsequent compounds in the sequence.
To evaluate whether the proposed cleavage mechanism
was viable, studies in model systems were performed. Depsi-
peptides 12 and 14 were chosen for synthetic accessibility and
because they introduce a UV chromophore into the carboxy-
late cleavage product. They were prepared through standard
solution-phase coupling procedures, employing PyBop/
N-methylmorpholine and DCC/DMAP for the hydroxy-
peptide- and depsipeptide-forming reactions, respectively.
Mass spectrometric analysis of initial photolysis studies
indicated the formation of the mechanistically revealing
selenacyclopentane (13, 15) and the appropriate carboxylic
acid but also suggested several complicating side reactions.
Both 12 and 14 produced product m/z ratios consistent
with the dimer of the deprotected selenide, including the
characteristic isotope pattern for a structure with two
selenium atoms. In addition, the aliphatic variant 12
showed m/z ratios consistent with a depsipeptide containing
Given these chemical uncertainties, it seemed prudent to
first evaluate the viability of the chemistry proposed in
Figure 1 before proceeding with chemical biology studies.
In the present work we evaluate two structures that are
meant to provide such a test. We describe the synthesis and
characterization of aliphatic (1) and aromatic (2) variants of
the design, along with mechanistic characterization.
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