A modular synthesis of dithiocarbamate pendant unnatural α-amino acids

Article abstract of DOI:10.1039/c2cc32894a

Unnatural α-amino acids containing dithiocarbamate side chains were synthesized by a one-pot reaction of in situ generated dithiocarbamate anions with sulfamidates. A wide range of these anions participated in the highly regio- and stereo-selective ring opening of sulfamidates to produce the corresponding dithiocarbamate pendant α-amino acids in high yields.

Full text of DOI:10.1039/c2cc32894a

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COMMUNICATION
A modular synthesis of dithiocarbamate pendant
unnatural a-amino acidsw
Amit Saha,z R. B. Nasir Baig,z John Leazer* and Rajender S. Varma*
Received 23rd April 2012, Accepted 29th June 2012
DOI: 10.1039/c2cc32894a
Unnatural a-amino acids containing dithiocarbamate side chains
were synthesized by a one-pot reaction of in situ generated
dithiocarbamate anions with sulfamidates. A wide range of these
anions participated in the highly regio- and stereo-selective ring
opening of sulfamidates to produce the corresponding dithio-
carbamate pendant a-amino acids in high yields.
amino acids contain the dithiocarbamate functionality at the
N-terminus of the amino acids, where the NH2 group of an
amino acid is involved in forming the dithiocarbamate moiety.
To the best of our knowledge, however, there are only reports for
conjugate addition of cysteine to phenylalkyl isothiocyanates12 for
the synthesis of dithiocarbamate side-chain containing unnatural
amino acids. These methods were only limited to cysteine derived
compounds and there is no report on the synthesis of 3-alkyl
cysteine derivatives, as it is not commercially available and tedious
to synthesize.13 Additionally, existing methods are confined to the
synthesis of dithiocarbamate derivatives of primary amines as it
requires alkyl isothiocyanates as one of the starting materials.
This prompted us to develop a modular methodology with broad
scope for the synthesis of unnatural amino acids containing a
dithiocarbamate side chain (Fig. 1).
Unnatural amino acids are important as building blocks, molecular
scaffolds, conformational constraints, and pharmacologically
active products and represent an array of diverse structural
elements for developing new leads in peptidic and non-peptidic
compounds. Small-molecule combinatorial libraries of unnatural
amino acid residues have immense importance in drug discovery
processes.1 The significance of unnatural amino acids have been
realized and extensively used in peptide research to synthesize
unnatural peptidomimics in order to have control over
conformational flexibility and improve pharmacodynamics,
enzymatic stability and bioavailability.2
We focused our attention on sulfamidates as they are emerging
as important chiral intermediates in many organic synthetic
ventures.14–17 Although they are the synthetic equivalents of
aziridines, sulfamidates have added advantages over aziridines
in terms of reactivity and selectivity.14,17a Thus, sulfamidates
appear to be the ideal choice as intermediates for the develop-
ment of a one-pot multi-component procedure for the synthesis
of unnatural a-amino acids containing a modified dithio-
carbamates side chain.
Organic dithiocarbamates have become the subject of growing
interest for their use as versatile synthetic intermediates,3 and linkers
in solid phase organic synthesis4 and in molecular electronic
devices.5 Moreover, their presence in various biologically active
compounds,6 their vital roles in agriculture,7 and their medicinal
and biological properties,8 have contributed in the development of
convenient synthetic methods for assembly of these compounds.
Among the ligands coordinating through sulfur atoms, dithio-
carbamates have garnered much attention in recent years;
many dithiocarbamate complexes have been synthesized.
These compounds are being investigated to gain insight into
the nature of the sulfur-metal bond in many biomolecules.9 Many
proteins have cysteine and methionine residues and hence dithio-
carbamate derivatives of a-amino acids may be valid models for
the study of the coordination of proteins to metal ions.10
It is envisioned that dithiocarbamate anions generated
in situ by the reaction of amine and carbon disulfide would
participate in the one-pot ring opening of cyclic sulfamidates
at room temperature under open atmospheric conditions to
produce the unnatural a-amino acids with dithiocarbamate side
chains in the absence of any catalyst or additive (Scheme 1).
With this perception the dithiocarbamate anion was prepared
by treating a cooled CH3CN solution of pyrrolidine (0–5 1C)
with carbon disulfide, followed by the addition of sulfamidate.
Dithiocarbamate chemistry has evolved significantly in recent
years.11 Most of the reported dithiocarbamate derivatives of
Sustainable Technology Division, National Risk Management
Research Laboratory, U. S. Environmental Protection Agency,
26 West Martin Luther King Drive, MS 443, Cincinnati, Ohio 45268,
USA. E-mail: Varma.Rajender@epa.gov, Leazer.John@epa.gov;
Fax: +1 513-569-7677; Tel: +1 513-487-2701
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and spectra of all compounds. See
DOI: 10.1039/c2cc32894a
z These authors contributed equally.
Fig. 1 Unnatural a-amino acid with dithiocarbamate side chain.
Chem. Commun., 2012, 48, 8889–8891 8889
c
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Table 1 Standardization of the reaction conditions
Entry
Solvent
Times (h)
Yield (%)
Scheme 1 Synthesis of unnatural a-amino acid with dithiocarbamate
side chain.
1
2
3
4
5
6
CH3CN
THF
H2O
PEG
Toluene
DME
24 h
24 h
24 h
24 h
24 h
12 h
45
38
Trace
65
Trace
95
The reaction mixture was stirred at room temperature under
atmospheric conditions for 24 h leading to stereo and regio selective
ring opening of sulfamidate with the formation of optically pure
product in 45% yield (Table 1, entry 1).17f Optimization of reaction
conditions was performed at room temperature under aerobic
conditions without any special precautions. The best result, in
terms of reaction time and yield, was obtained when DMF was
used as a solvent (Table 1, entry 6).
Table 2 Reactions of dithicarbamate anions with sulfamidatesa
Yieldb
Time
Sulfamidatec (h)
Entry Amine
Product
(%)
To demonstrate the efficacy of the reaction, a variety of
dithiocarbamate anions (generated from various amines) were
allowed to react with an array of sulfamidates to produce
dithiocarbamate a-amino acids in good to high yields (Table 2).
The reaction is presumed to proceed via a pure SN2 mechanism.
Nucleophilic attack of the dithiocarbamate anion leads to an
inversion of configuration at the reaction center of the sulfami-
date. Most of the cyclic and acyclic secondary amines and
primary amines react smoothly with sulfamidates to give the
corresponding unnatural amino acids in high yields, with the
exception of diisopropyl amine (Table 2, entry 3) where a lower
yield (69%) was obtained even after stirring the reaction
mixture for 24 h. The low yield may be due to the steric
hindrance caused by the isopropyl groups of the dithiocarba-
mate anion. The presence of a methyl substituent at the reaction
center in the sulfamidate affects the reaction rate. Serine, phenyl
alanine, and isoleucine derived sulfamidates reacted relatively
faster (Table 2, entries 6–10) as compared to a threonine derived
sulfamidate (Table 2, entries 1–5). Different protecting groups
(Cbz and Boc) present at the nitrogen atom in the sulfamidates
do not appear to have any effect on either reactivity or yield.
The reaction of dithiocarbamate anions from amino acids
(proline, proline methyl ester, 4-hydroxy proline methyl ester
and N-Cbz-Threo-OMe, Table 3, entries 1 to 5) were found to
participate in the ring opening of the sulfamidates to produce
the desired products. It is interesting to note that the hydroxyl
and carboxylic acid groups do not interfere with the reaction to
give the corresponding products in high yields.
1
12
12
93
2
3
95
69
24
12
14
4
5
88
92
6
7
8
9
8
8
9
87
91
89
9
9
94
95
Usually an acidic hydrolysis is required after nucleophilic ring
ꢀ
opening reaction of sulfamidates for removal of the SO3 group.
10
Interestingly, in the case of ring opening of a sulfamidate using a
dithiocarbamate anion, no such acid hydrolysis was required as it
occured during the course of the reaction. The simple aqueous
work-up after the completion of reaction provides the desired
product in very good yield. In order to demonstrate the stability of
a dithiocarbamate under typical peptide coupling conditions, the
product (substrate from Table 2 entry 9) was treated under acidic
conditions for Boc group removal and subsequently coupled with
N-Boc-Phe, under conventional conditions, to give the desired
peptide in 76% isolated yield (Scheme 1, ESIw).
a
Reaction conditions: CS2 (1.5 mmol) was added drop wise to an
amine (1 mmol) solution of DMF (1 mL) at 0–5 1C. Sulfamidate
(1 mmol) solution in DMF (1 mL) was added to the solution of
dithiocarbamate at room temperature and was stirred for the required
b
c
time period. Yields of the isolated products. Synthesis of sulfami-
dates 1–8 is reported in the ref. 14a and 16a.
ring opening of sulfamidates by in situ generated dithiocarbamate
anions to produce a series of unnatural a-amino acids containing
the dithiocarbamate side chain. Operational simplicity, high yield
In conclusion, we have developed a very simple and efficient
one-pot methodology for regio- and stereo selective nucleophilic
c
8890 Chem. Commun., 2012, 48, 8889–8891
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Table 3 Ring opening of sulfamidates by dithiocarbamate anions of
amino acidsa
3 (a) A. K. Mukherjee and R. Ashare, Chem. Rev., 1991, 91, 1;
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Yieldb
(%)
Entry Amine
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2c
3
4
12
8
91
84
5c
a
Reaction conditions: CS2 (1.5 mmol) was added drop wise to an
amine (1 mmol) solution of DMF (1 ml) at 0–5 1C. Sulfamidate
(1 mmol) solution in DMF (1 ml) was added to the solution of
dithiocarbamate at room temperature and was stirred for the required
b
c
time period. Yields of the isolated products. Amines were used as
their corresponding hydrochloride salts. 1 mmol of NaHCO3 was used
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of products, and excellent regio- and stereo selectivity of the
reaction renders the protocol attractive and useful in the field
of synthetic organic chemistry. To the best of our knowledge
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dithiocarbamate anions to produce a-amino acids with dithio-
carbamate side chain.
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Dr Amit Saha and Dr R. B. Nasir Baig are postdoctoral
research participants at the National Risk Management Research
Laboratory, Environmental Protection Agency, administered by
the Oak Ridge Institute for Science and Education (ORISE).
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 8889–8891 8891