Beilstein J. Org. Chem. 2020, 16, 1617–1626.
1
,2-dibromoethane, formation of dimer 32 increased (17% iso- ORCID® iDs
lated yield). This supports the previously reported proposals
that dimerisation occurs via single-electron oxidation of the
recombination of the resulting picolyl radical [28-30]. Whilst
trace oxygen may be involved, as indicated by the presence of
alcohol 31, no dimerisation or alcohol formation was seen in the
absence of a halide/pseudohalide-based oxidant, during C-phos- References
phorylation or deuteration.
1. Hatley, R. J. D.; Macdonald, S. J. F.; Slack, R. J.; Le, J.;
Conclusion
In conclusion, a novel method for the assembly of 7-alkyl-
2.
Anderson, N. A.; Campbell-Crawford, M. H. J.; Hancock, A. P.;
Pritchard, J. M.; Redmond, J. M. Novel compounds. WO Patent
WO2016046226, March 31, 2016.
1
,2,3,4-tetrahydro-1,8-naphthyridine-based arginine mimetics
was developed. The synthesis of phosphonate 7 was optimised, 3. Procopiou, P. A.; Barrett, T. N.; Copley, R. C. B.; Tame, C. J.
with a sequential diphosphorylation process using commercial-
ly available starting materials affording the desired compound
in 64% overall yield. A Horner–Wadsworth–Emmons/reduc-
tion/deprotection procedure was used to synthesise amines in
good yield requiring no chromatography, although racemisa-
tion was observed where chiral aldehydes possessed an
α-proton. This methodology utilised the underused base-stable
phosphoramidate protecting group, which was superior to the
more commonly applied Boc protecting group which was
unstable to the lithiation. This synthetic route replaces tradi-
tional Wittig and tandem alkylation/reduction methodologies,
which suffer from complications arising from troublesome by-
products and reaction selectivity. The new procedure proceeds
in a higher yield than previously obtained and may potentially
offer benefits in large-scale manufacture of integrin inhibitors
and other arginine peptidomimetics.
4
.
Procopiou, P. A.; Anderson, N. A.; Barrett, J.; Barrett, T. N.;
Crawford, M. H. J.; Fallon, B. J.; Hancock, A. P.; Le, J.; Lemma, S.;
Marshall, R. P.; Morrell, J.; Pritchard, J. M.; Rowedder, J. E.;
Saklatvala, P.; Slack, R. J.; Sollis, S. L.; Suckling, C. J.; Thorp, L. R.;
5.
Hutchinson, J. H.; Halczenko, W.; Brashear, K. M.; Breslin, M. J.;
Coleman, P. J.; Duong, L. T.; Fernandez-Metzler, C.; Gentile, M. A.;
Fisher, J. E.; Hartman, G. D.; Huff, J. R.; Kimmel, D. B.; Leu, C.-T.;
Meissner, R. S.; Merkle, K.; Nagy, R.; Pennypacker, B.; Perkins, J. J.;
Prueksaritanont, T.; Rodan, G. A.; Varga, S. L.; Wesolowski, G. A.;
6.
7.
8.
Cox, J. M.; Ma, L.; Zhou, X.; Haimbach, R. E.; Coleman, P. J.;
Zhou, H.; Kelley, D. E.; Stoch, S. A.; Duong, L. T.; Hoek, M.
Composition and methods for treating chronic kidney disease. WO
Patent WO2016154369, Sept 29, 2016.
Devasthale, P.; Moore, F.; Zhao, G.; Pieniazek, S. N.; Selvakumar, K.;
Dhanusu, S.; Panda, M.; Marcin, L. R. Cyclobutane- and
azetidine-containing mono and spriocyclic compounds as alpha V
integrin inhibitors. WO Patent WO2018089355, May 17, 2018.
Yasuda, N.; Hsiao, Y.; Jensen, M. S.; Rivera, N. R.; Yang, C.;
Wells, K. M.; Yau, J.; Palucki, M.; Tan, L.; Dormer, P. G.;
Supporting Information
Supporting Information File 1
Detailed experimental procedures, and product
9. Anderson, N. A.; Campbell, I. B.; Fallon, B. J.; Lynn, S. M.;
Macdonald, S. J. F.; Pritchard, J. M.; Procopiou, P. A.; Sollis, S. L.;
1
0.Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.;
Acknowledgements
Thanks to Sean M. Lynn for assistance with NMR spectrosco-
py analysis and the GSK UK Discovery Analytical team for
acquiring HRMS data.
1
1
Funding
13.Chackalamannil, S.; Xia, Y.; Greenlee, W. J.; Clasby, M.; Doller, D.;
Tsai, H.; Asberom, T.; Czarniecki, M.; Ahn, H.-S.; Boykow, G.;
Financial support for this work was provided by GSK via the
GSK/University of Strathclyde Centre for Doctoral Training in
Synthetic and Medicinal Chemistry. We thank EPSRC for
further funding via Prosperity Partnership EP/S035990/1.
1625