LETTER
Functionalised α- and β3-Amino Acids
2645
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gram scale. Using standard methods, 16 was converted in
two steps into the Fmoc-protected amino acid 3 in good
yield.34 Unlike the synthesis of β3-propargyl glycine 5 for-
mation of the diazoketone starting from 3 proceeded to
give a crude product of reasonable purity that was ex-
posed directly to the Wolff rearrangement. Again the
Wolff rearrangement proved sluggish and required a high-
er catalyst loading and extended reaction time to go to
completion. Moreover, the rearrangement produced nu-
merous side products and consequently an acceptable but
low yield for the three-step process. Derivatisation of 3
and 6 and analysis by NMR spectroscopy revealed that no
significant stereochemical leakage had occurred.
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(23) Kawamoto, S. A.; Coleska, A.; Ran, X.; Yi, H.; Yang, C. Y.;
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In summary, we report concise synthetic procedures for
the synthesis of a new class of bifunctional β3-amino acid
building blocks starting from readily available starting
materials. Importantly, all compounds have been careful-
ly characterised and shown to be of high optical purity.
The ready availability and high purity of the reported ami-
no acids will be of considerable interest to the chemical
community, and we anticipate they will have an impact in
medicinal chemistry and within peptidomimetic research.
Work is ongoing in our laboratory to expand the repertoire
of bifunctional amino acid building blocks and to incorpo-
rate the reported building block in peptides and will be re-
ported in due course.
(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, J. Y.; Nikolovska-Coleska, Z.; Yang, C. Y.; Gomez,
C.; Gao, W.; Krajewski, K.; Jiang, S.; Roller, P.; Wang, S.
M. Bioorg. Med. Chem. Lett. 2007, 17, 3939.
Acknowledgment
The Danish Medical Research Council is thanked for financial sup-
port. Christian Tortzen, Department of Chemistry, University of
Copenhagen is thanked for his assistance with NMR.
(26) Abell, A. D.; Jones, M. A.; Coxon, J. M.; Morton, J. D.;
Aitken, S. G.; McNabb, S. B.; Lee, H. Y. Y.; Mehrtens, J.
M.; Alexander, N. A.; Stuart, B. G.; Neffe, A. T.;
Bickerstaffe, R. Angew. Chem. Int. Ed. 2009, 48, 1455.
(27) Goddard-Borger, E. D.; Stick, R. V. 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, E. D.; Stick, R. V. Org. Lett. 2011, 13,
2514.
Supporting Information for this article is available online at
detailed experimental procedures, 1H and 13C NMR spectra.SunogIoiprfmrntSatnuIpgrfio
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References and Notes
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(31) Despite being a useful reagent diazomethane is underutilised
due to safety concerns. Diazomethane is indeed highly toxic
(8) Pedersen, D. S.; Abell, A. Eur. J. Org. Chem. 2011, 2399.
(9) Seebach, D.; Gardiner, J. Acc. Chem. Res. 2008, 41, 1366.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2643–2646