Azide- and Alkyne-Functionalised α- and β3-Amino Acids

Tjerk Jacco Sminia; Daniel Sejer Pedersen

doi:10.1055/s-0032-1317445

Synlett, Table of Contents

Synlett 2012; 23(18): 2643-2646
DOI: 10.1055/s-0032-1317445

letter

Azide- and Alkyne-Functionalised α- and β³-Amino Acids

Tjerk Jacco Sminia

Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark Fax: +45(35)336040 Email: dsp@farma.ku.dk

,

Daniel Sejer Pedersen*

Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark Fax: +45(35)336040 Email: dsp@farma.ku.dk

› Author Affiliations

Abstract

All articles of this category

Abstract

The synthesis and full characterisation of bifunctional β³-amino acids that have side chains functionalised with terminal azides (S)-4 and (R)-4 or acetylenes 5 and 6 is reported for the first time. The building blocks incorporate a turn-inducing β³-segment and a side chain that can be functionalised further, for example, through copper-catalysed Huisgen cycloaddition. Moreover, the corresponding α-amino acids 1 and 3 have been synthesised and characterised. All amino acid building blocks were of high optical purity as demonstrated by derivatisation and subsequent NMR analysis.

Key words

alkynes - azides - amino acids - diazotransfer - Arndt–Eistert homologation - peptidomimetics

Full Text

References

References and Notes
1 Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. 2002; 41: 2596
2 Tornoe CW, Christensen C, Meldal M. J. Org. Chem. 2002; 67: 3057
3 Tornoe CW, Meldal M In Peptides 2001 . American Peptide Society and Kluwer Academic Publishers; San Diego: 2001: 263
4 Johansson H, Pedersen DS. Eur. J. Org. Chem. 2012; 4267
5 Soares da Costa TP, Tieu W, Yap MY, Pendini NR, Polyak SW, Sejer Pedersen D, Morona R, Turnidge JD, Wallace JC, Wilce MC. J, Booker GW, Abell AD. J. Biol. Chem. 2012; 287: 17823
6 Stanley NJ, Pedersen DS, Nielsen B, Kvist T, Mathiesen JM, Bräuner-Osborne H, Taylor DK, Abell AD. Bioorg. Med. Chem. Lett. 2010; 20: 7512
7 Buysse K, Farard J, Nikolaou A, Vanderheyden P, Vauquelin G, Pedersen DS, Tourwè D, Ballet S. Org. Lett. 2011; 13: 6468
8 Pedersen DS, Abell A. Eur. J. Org. Chem. 2011; 2399
9 Seebach D, Gardiner J. Acc. Chem. Res. 2008; 41: 1366
10 Horne WS, Gellman SH. Acc. Chem. Res. 2008; 41: 1399
11 Horne WS, Boersma MD, Windsor MA, Gellman SH. Angew. Chem. Int. Ed. 2008; 47: 2853
12 Horne WS, Johnson LM, Ketas TJ, Klasse PJ, Lu M, Moore JP, Gellman SH. Proc. Natl. Acad. Sci. U.S.A 2009; 106: 14751
13 Gloriam D, Wellendorph P, Johansen L, Thomsen A, Phonekeo K, Pedersen DS, Bräuner-Osborne H. Chem. Biol. 2011; 18: 1489
14 Tomboly C, Ballet S, Feytens D, Kover KE, Borics A, Lovas S, Al-Khrasani M, Furst Z, Toth G, Benyhe S, Tourwe D. J. Med. Chem. 2008; 51: 173
15 Holland-Nell K, Meldal M. Angew. Chem. Int. Ed. 2011; 50: 5204
16 Pinsker A, Einsiedel J, Harterich S, Waibel R, Gmeiner P. Org. Lett. 2011; 13: 3502
17 Larregola M, Lequin O, Karoyan P, Guinvarc’h D, Lavielle S. J. Pept. Sci. 2011; 17: 632
18 Garner J, Harding MM. Org. Biomol. Chem. 2007; 5: 3577
19 Cantel S, Isaad AL. C, Scrima M, Levy JJ, DiMarchi RD, Rovero P, Halperin JA, D’Ursi AM, Papini AM, Chorev M. J. Org. Chem. 2008; 73: 5663
20 Schafmeister CE, Po J, Verdine GL. J. Am. Chem. Soc. 2000; 122: 5891
21 Ebert M.-O, Gardiner J, Ballet S, Abell AD, Seebach D. Helv. Chim. Acta 2009; 92: 2643
22 Ingale S, Dawson PE. Org. Lett. 2011; 13: 2822
23 Kawamoto SA, Coleska A, Ran X, Yi H, Yang CY, Wang S. J. Med. Chem. 2011; 55: 1137
24 Pehere, A. D.; Pietsch, M.; Gütschow, M.; Neilsen, P. M.; Callen, D. F.; Pedersen, D. S.; Nguyen, S.; Sykes, M.; Morton, J. D.; Abell, A. D.; manuscript submitted for publication.
25 Chen JY, Nikolovska-Coleska Z, Yang CY, Gomez C, Gao W, Krajewski K, Jiang S, Roller P, Wang SM. Bioorg. Med. Chem. Lett. 2007; 17: 3939
26 Abell AD, Jones MA, Coxon JM, Morton JD, Aitken SG, McNabb SB, Lee HY. Y, Mehrtens JM, Alexander NA, Stuart BG, Neffe AT, Bickerstaffe R. Angew. Chem. Int. Ed. 2009; 48: 1455
27 Goddard-Borger ED, Stick RV. Org. Lett. 2007; 9: 3797
28 We discovered that imidazole-1-sulfonyl azide hydrochloride (8) when stored in a desiccator at r.t. decomposed over the course of 1–2 months to form a viscous black tar. Later Goddard-Borger and Stick published a safety update addressing this and other reagent related issues, attributing the decomposition to slow water hydrolysis of 8 and formation of hydrazoic acid.²⁹ More recently, Goddard-Borger and co-workers evaluated the stability of a wide range of imidazole sulfonyl azide salts and found that the hydrogensulfate and tetrafluoroborate salts are safe alternatives to the hydrochloride salt 8.³⁰ Herein we report the use of the hydrochloride salt 8 that we have found to be perfectly stable (>10 months) when dried rigorously in a vacuum desiccator over KOH and stored at –20 °C. However, based on the reports by Goddard-Borger and co-workers we recommend that the hydrogensulfate salt be used for reproducing the experiments reported herein.
29 Goddard-Borger ED, Stick RV. Org. Lett. 2011; 13: 2514
30 Fischer N, Goddard-Borger ED, Greiner R, Klapötke TM, Skelton BW, Stierstorfer J. J. Org. Chem. 2012; 77: 1760
31 Despite being a useful reagent diazomethane is underutilised due to safety concerns. Diazomethane is indeed highly toxic and explosive. However, with careful use of a modern diazomethane distillation kit the synthesis of diazomethane in Et₂O is simple, safe, and fast. Diazomethane distillation kits with clear-seal joints are available from many glassware manufacturers. We commonly employ a mini-Diazald apparatus available from Sigma-Aldrich that produces up to 1 mmol of diazomethane.
32 Many azido-functionalised α-amino acids are commercially available. However, to the best of our knowledge no optically active azido-functionalised β³-amino acids are available.

Both enantiomers of amino acid 5 are commercially available from a number of vendors and according to Chemical Abstract (CAS) have been reported in two Chinese papers:

33a Zhan J.-R, Chen T.-Y, Liu B. Huaxue Shiji 2004; 26: 137
33b Liao B.-R, Hong Y.-Y, Xu J, Liu B. Youji Huaxue 2004; 24: 63

34 Attempting the reaction on the methyl ester derivative of 15 under the same reaction conditions led to the formation of several side products, reduced yields, and significant racemisation.

Supplementary Material

Supporting Information