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Cite this: Chem. Commun., 2012, 48, 8889–8891
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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 dithiocarbamate pendant a-amino acids in high yields. 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 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, dithiocarbamates 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 dithiocarbamate derivatives of a-amino acids may be valid models for the study of the coordination of proteins to metal ions.10 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:
[email protected],
[email protected]; 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.
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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). 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 development of a one-pot multi-component procedure for the synthesis of unnatural a-amino acids containing a modified dithiocarbamates side chain. 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.
Fig. 1
Unnatural a-amino acid with dithiocarbamate side chain.
Chem. Commun., 2012, 48, 8889–8891
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View Article Online Table 1 Standardization of the reaction conditions
Downloaded by US Environmental Protection AG, Cincinnati on 07/04/2013 19:58:49. Published on 29 June 2012 on http://pubs.rsc.org | doi:10.1039/C2CC32894A
Scheme 1 Synthesis of unnatural a-amino acid with dithiocarbamate side chain.
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). 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 sulfamidate. 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 dithiocarbamate 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. Usually an acidic hydrolysis is required after nucleophilic ring opening reaction of sulfamidates for removal of the SO3 group. 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). In conclusion, we have developed a very simple and efficient one-pot methodology for regio- and stereo selective nucleophilic 8890
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Entry
Solvent
Times (h)
Yield (%)
1 2 3 4 5 6
CH3CN THF H2O PEG Toluene DME
24 24 24 24 24 12
45 38 Trace 65 Trace 95
h h h h h h
Table 2 Reactions of dithicarbamate anions with sulfamidatesa Entry Amine
Time Sulfamidatec (h) Product
Yieldb (%)
1
12
93
2
12
95
3
24
69
4
12
88
5
14
92
6
8
87
7
8
91
8
9
89
9
9
94
10
9
95
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 time period. b Yields of the isolated products. c Synthesis of sulfamidates 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 This journal is
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View Article Online Table 3 Ring opening of sulfamidates by dithiocarbamate anions of amino acidsa Time Sulfamidate (h) Product
Downloaded by US Environmental Protection AG, Cincinnati on 07/04/2013 19:58:49. Published on 29 June 2012 on http://pubs.rsc.org | doi:10.1039/C2CC32894A
Entry Amine
Yieldb (%)
1
12
87
2c
12
85
3
12
88
4
12
91
5c
8
84
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 time period. b Yields of the isolated products. c Amines were used as their corresponding hydrochloride salts. 1 mmol of NaHCO3 was used for the in situ neutralization of HCI.
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 this is the first report for ring opening of sulfamidates by dithiocarbamate anions to produce a-amino acids with dithiocarbamate side chain. 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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