Communications
changing the substitution in the oxygen part. Different syn-
thetic routes for this modification have been designed, but by
using our direct synthetic protocol, URB 602 derivatives can be
synthesized in a single step with a good yield of 69%
(Scheme 4). Moreover, with our protocol in hand, a chemical li-
brary of this structure can be obtained easily.
Figure 2. Pharmaceuticals underwent carbamate synthesis using CO2 as
a carbon source. [a] Reaction conditions: substrates (0.5 mmol), Cs2CO3
(1.5 equiv.), DMSO (2.5 mL), EtI (1.2 equiv.), CO2 (balloon), RT, 16 h. [b] All are
isolated yields.
ing hydrogen bonds through the carboxyl group and amine
moiety allow them to enhance biological as well as pharmaco-
kinetic properties.[8,16] For this purpose, we have chosen nor-
tryptyline and cinacalcet (Figure 2) under our optimized reac-
tion conditions. It should be noted that both of the substrates
reacted excellently, up to 86% yield was obtained and again
selective transformation occurred in presence of the double
bond (Figure 2, 20a). Owing to the purification, no special pre-
caution was needed to purify these products by column chro-
matography.
Scheme 4. Synthesis of URB 602 derivative using CO2 as a carbon source.
[a] Reaction conditions: substrates (0.5 mmol), Cs2CO3 (1.5 equiv.), DMSO
(2.5 mL), BnBr (1.2 equiv.), CO2 (balloon), 508C, 48 h. [b] Isolated yield.
Structural diversifications of organic carbamates represent
an important step in pharmaceutical research.[17] This variation
of the carbamate scaffold provides a bigger platform for the
identification of new bioactive compounds with greater effi-
ciency. To attain this, both the nitrogen and oxygen end of the
carbamate structure can be varied. Therefore, parallel to the
amines, different other alkyl partners have also been varied to
generate a chemical library based on this carbamate structures
(Scheme 3). Notably, not only alkyl iodides, but also alkyl bro-
mide can be applied under the optimized reaction conditions.
n-Pentyl bromide and benzyl bromide were investigated as the
alkyl partner along with our model substrate, and a maximum
of 83% yield was achieved after stirring with the n-pentyl bro-
mide for 4 h.
In synthetic organic chemistry, protecting groups play a pivo-
tal role to prevent the formation of undesired side products.[20]
Protection of the a-amino group in amino acids and in pep-
tides is also important to prevent polymerization once they are
activated for forming peptide bond. These protecting groups
should prevent epimerization during peptide bond coupling,
be stable enough for the reaction conditions, and deprotection
methods should be easy and fast. The most common a-amino
protecting groups for the peptide coupling reactions are the
carboxybenzyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), and
tert-butyloxycarbonyl (Boc). Among these Cbz is the most
widely used protecting group for peptide synthesis in solution.
These protecting groups form the carbamate structures after
combing with the a-amino group of amino acids and peptides.
Therefore, using our protocol, CO2 can easily be used as a pro-
tecting reagent for the amine functionality in synthetic organic
chemistry as well as in peptide chemistry (Scheme 5). Different
amino acids, such as phenylalanine, tryptophan, and methio-
nine, reacted well under the optimized conditions. In fact, the
corresponding Cbz protected glycine was obtained in good
yield from glycine salt (28a) using excess of Cs2CO3 (2.5 equiv.).
Extension of using CO2 as the protecting reagent was ach-
ieved by applying on three different peptides that were syn-
thesized by combining corresponding amino acid precursors
(Scheme 5, entries 29a–31a). In all cases, peptides reacted
well, and up to 78% yield of Cbz-protected peptides was ach-
ieved. We did not observe any other by-products. In all cases,
products were recovered after washing with excess dichloro-
methane followed by column purification. We expect that this
protection procedure of peptides can easily be applied to
other higher series of peptides, and thereby can open up new
avenues in peptide-based chemistry and in protecting re-
agents.
URB 602 is a selective inhibitor of monoacylglycerol lipase
(MAGL), which is involved in the hydrolysis of 2-arachidonylgly-
cerol (2-AG) in the brain.[18] This selective inhibition of MAGL
avoids the direct activation of CB1 receptors and leads to less
psychoactive side effects. Whereas the selectivity remains ex-
cellent in vivo, it completely changes in vitro.[19] Therefore,
structural modification of URB 602 is necessary to make it
a powerful inhibitor. This modification can be done through
isosteric replacement, substitution in the aromatic ring, or by
Scheme 3. Different alkyl bromides used for the synthesis of carbamates.
[a] Reaction conditions: substrates (0.5 mmol), Cs2CO3 (1.5 equiv.), DMSO
(2.5 mL), R2Br (1.2 equiv.), CO2 (balloon), RT, 16–36 h. [b] All are isolated
yields.
In summary, we have demonstrated an efficient carbamate
synthesis protocol starting from amines and using CO2 as a C1
source. Notably, our methodology has shown a broad sub-
ChemSusChem 2016, 9, 1 – 6
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