Organic Letters
Letter
Finally, to demonstrate the broad applicability of our
methodology, we tested a panel of six substituted aromatic
aldehydes bearing different heterocycle moieties (isoxazole,
thiophene, quinoline, and isoquinoline). Complete conversions
were obtained with all of the substrates for the condensation step,
while only isoxazole, thiophene, and quinoline derivatives were
accepted by the enzyme, yielding amino acids L-5a−e. The
synthesis of the isoquinolinylalanine L-5f was unsuccessful due to
the poor acceptance of the corresponding acrylic acid by AvPAL.
The dramatic difference between quinoline and isoquinoline
substrates can be attributed to the different electronic properties
of the two systems, i.e., the position of the nitrogen atom (p- ≫
m-). Amino acids L-5a−e were obtained with >99% ee without
additional deracemization in moderate to good isolated yield
(Scheme 5).
REFERENCES
■
(1) Amino Acids, Peptides and Proteins in Organic Chemistry, Vol. 4,
Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis;
Hughes, A. B., Ed.; Wiley: Chichester, UK, 2011.
(2) Inouye, S.; Shomura, T.; Tsuruoka, T.; Ogawa, Y.; Watanabe, H.;
Yoshida, J.; Niida, T. Chem. Pharm. Bull. 1975, 23, 2669−2677.
(3) Izawa, M.; Takayama, S.; Shindo-Okada, N.; Doi, S.; Kimura, M.;
Katsuki, M.; Nishimura, S. Cancer Res. 1992, 52, 1628−1630.
(4) Huang, S.-X.; Lohman, J. R.; Huang, T.; Shen, B. Proc. Natl. Acad.
Sci. U. S. A. 2013, 110, 8069−8074.
(5) (a) Folkers, K.; Kubiak, T.; Stepinski, J. Int. J. Pept. Protein Res.
1984, 24, 197−200. (b) Cooper, M. S.; Seton, A. W.; Stevens, M. F. G.;
Westwell, A. D. Bioorg. Med. Chem. Lett. 1996, 6, 2613−2616.
(c) Miyazawa, T. Amino Acids 1999, 16, 191−213.
(6) Croce, P. D.; La Rosa, C.; Pizzatti, E. Tetrahedron: Asymmetry 2000,
11, 2635−2642.
(7) Adamczyk, M.; Akireddy, S. R.; Reddy, R. E. Org. Lett. 2001, 3,
3157−3159.
Scheme 5. Examples of Additional Heteroarylalanines
Obtained by One-Pot Condensation−Hydroamination
(8) Tabanella, S.; Valancogne, I.; Jackson, R. W. F. Org. Biomol. Chem.
2003, 1, 4254−4261.
(9) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L. D.;
Weinkauff, J. J. Am. Chem. Soc. 1977, 99, 5946−5952.
(10) Watkins, E. B.; Phillips, R. S. Bioorg. Med. Chem. Lett. 2001, 11,
2099−2100.
(11) (a) Turner, N. J. Curr. Opin. Chem. Biol. 2011, 15, 234−240.
(b) Heberling, M. W.; Wu, B.; Bartsch, S.; Janssen, D. B. Curr. Opin.
Chem. Biol. 2013, 17, 250−260. (c) Poppe, L. Curr. Opin. Chem. Biol.
2001, 5, 512−524.
(12) (a) Yamada, S.; Nabe, K.; Izuo, N.; Nkamichi, K.; Chibata, I. Appl.
Environ. Microbiol. 1981, 42, 773−778. (b) Paizs, C.; Katona, A.; Retey,
J. Chem. - Eur. J. 2006, 12, 2739−2744. (c) Ahmed, S. T.; Parmeggiani,
F.; Weise, N. J.; Flitsch, S. L.; Turner, N. J. ACS Catal. 2015, 5, 5410−
5413.
(13) Gloge, A.; Langer, B.; Poppe, L.; Retey, J. Arch. Biochem. Biophys.
1998, 359, 1−7.
(14) Lovelock, S. L.; Turner, N. J. Bioorg. Med. Chem. 2014, 22, 5555−
2227.
In summary, we have developed a one-pot telescopic route to
afford L-pyridylalanine analogues in high conversions, good
isolated yields, and excellent purity from the corresponding
aldehydes, implementing an additional chemo-enzymatic
cascade to give >99% ee for compounds which gave low
enantiopurity.
(15) (a) Knoevenagel, E. Ber. Dtsch. Chem. Ges. 1898, 31, 2596−2619.
(b) Doebner, O. Ber. Dtsch. Chem. Ges. 1900, 33, 2140−2142.
(c) Kingsbury, C. A.; Max, G. J. Org. Chem. 1978, 43, 3131−3139.
(16) (a) de Lange, B.; Hyett, D. J.; Maas, P. J. D.; Mink, D.; van Assema,
F. B. J.; Sereinig, M.; de Vries, A. H. M.; de Vries, J. G. ChemCatChem
2011, 3, 289−292. (b) Weise, N. J.; Ahmed, S. T.; Parmeggiani, F.;
Siirola, E.; Pushpanath, A.; Schell, U.; Turner, N. J. Catal. Sci. Technol.
2016, 6, 4086−4089.
ASSOCIATED CONTENT
* Supporting Information
■
S
(17) (a) Mjalli, A.; Andrews, R.; Guo, X.-C.; Christen, D. P.;
Gohimmukkula, D. R.; Huang, G.; Rothlein, R.; Tyagi, S.; Yaramasu, T.;
Behme, C. US Patent WO 2004/014844A2, Aug 8 2003. (b) Cage, P.;
Furber, M.; Luckhurst, A. C.; Sanganee, J. H.; Stein, A. L. WO Patent
2009/074829A1, Jun 18, 2009. (c) Konradi, A. W.; Pleiss, M. A.;
Thorsett, E. D.; Ashwell, S.; Welmaker, G. S.; Kreft, A.; Sarantakis, D.;
Dressen, D. B.; Grant, F. S.; Semko, C.; Xu, Y.-Z.; Stappenbeck, F. US
Patent WO 2002/0052375A1, May 2 2002. (d) Hogg, J. H.; Kester, R.
F.; Liang, W.; Yun, W. WO Patent 2014/056871A1, Apr 17 2014.
(e) Chen, Y.; Goldberg, S. L.; Hanson, R. L.; Parker, W. L.; Gill, I.; Tully,
T. P.; Montana, M. A.; Goswami, A.; Patel, R. N. Org. Process Res. Dev.
2011, 15, 241−248.
The Supporting Information is available free of charge on the
Experimental details, characterization data of all com-
1
pounds, and H NMR, 13C NMR, and HRMS spectra
AUTHOR INFORMATION
Corresponding Author
■
*Tel: +44 (161) 306 5173. Fax: +44 (161) 275 1311. E-mail:
(18) Parmeggiani, F.; Ahmed, S. T.; Weise, N. J.; Turner, N. J.
Tetrahedron 2016, 72, 7256−7262.
Notes
(19) No conversion was seen with (E)-3-(6-methoxypyridin-3-yl)
high electron density in the ring and steric clash with active-site residues.
(20) Lovelock, S. L.; Lloyd, R. C.; Turner, N. J. Angew. Chem., Int. Ed.
2014, 53, 4652−4656.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the Biotechnology and Biological
Sciences Research Council (BBSRC) and Glaxo-SmithKline
(GSK) under the Strategic Longer and Larger (sLoLa) grant
initiative ref BB/K00199X/1. N.J.T. acknowledges the Royal
Society for a Wolfson Research Merit Award.
(21) Parmeggiani, F.; Lovelock, S. L.; Weise, N. J.; Ahmed, S. T.;
Turner, N. J. Angew. Chem., Int. Ed. 2015, 54, 4608−4611.
D
Org. Lett. XXXX, XXX, XXX−XXX