Organic Letters
Letter
(2) Ramanathan, S. K.; Keeler, J.; Lee, H. L.; Reddy, D. S.; Lushington,
G.; Aube, J. Org. Lett. 2005, 7, 1059−1062.
similar dihedral angles of benzodiazepinone 1a and ideal γ-turns
(ϕ = 75° 3, and ψ = −65° 3), benzotriazepinones 5 and 19g
deviated more significantly about the ψ torsion angle (ϕ = 75°
1, and ψ = −65° 9). Pyrrolobenzotriazepinone 7c exhibited a ϕ
torsion angle (−75° 3) that was more similar to that of an ideal
inverse γ-turn than the value in pyrrolobenzodiazepinone R-20a
(−75° 14); however, the ψ-torsion angle of 7c differed by 40°
away from that of an ideal inverse γ-turn, significantly more than
that of its pyrrolobenzodiazepinone counterpart 20a (65° 8).
The dihedral angle values of the aza-amino acid residue in 7c
appear to be more closely related to that of the i + 2 residue of a
type II′ β-turn (ϕ = −80° 8, and ψ = 0° 27). The aza-amino
acid residue nitrogen in the triazepinones adopted nonplanar
configurations existing out of the plane formed by its three
neighboring atoms by 0.361(1) Å for benzotriazepinone 19g
and 0.015(2) Å for pyrrolobenzotriazepinone 7c. For
comparison, the deviation from planarity of the corresponding
α-carbons of (R)-1a, (S)-1a, and 20a were, respectively,
+0.497(2), −0.500(3), and 0.441 Å and illustrate that
triazepinones 19g and 7c are chiral albeit flatter than their
diazepinone counterparts.
In conclusion, chemoselective alkylation was key for
conception of efficient diversity oriented strategies to make
1,3,4-benzotriazepin-2-one and pyrrolo[1,2][1,3,4]-
benzotriazepin-6-one analogues. Without nitrogen protection
under relatively mild conditions, benzotriazepinones were made
in four to seven steps and 4−60% yields from methyl
anthranilate. Using groups suitable for further functionalization,
a set of scaffolds was synthesized and shown by X-ray analysis to
have potential for γ-turn mimicry. Biological activity of
triazepinone library members is under investigation and will be
reported in due course.
(3) Dufour-Gallant, J.; Chatenet, D.; Lubell, W. D. J. Med. Chem. 2015,
58, 4624−4637.
(4) Sulkowski, T. S.; Childress, S. J. J. Med. Chem. 1964, 7, 386.
(5) Dorr, A. A.; Lubell, W. D. Org. Lett. 2015, 17, 3592−3595.
̈
(6) McDonald, I. M.; Austin, C.; Buck, I. M.; Dunstone, D. J.; Gaffen,
J.; Griffin, E.; Harper, E. A.; Hull, R. A. D.; Kalindjian, S. B.; Linney, I. D.;
Low, C. M. R.; Patel, D.; Pether, M. J.; Raynor, M.; Roberts, S. P.;
Shaxted, M. E.; Spencer, J.; Steel, K. I. M.; Sykes, D. A.; Wright, P. T.;
Xun, W. J. Med. Chem. 2007, 50, 4789−4792.
(7) (a) McDonald, I. M.; Austin, C.; Buck, I. M.; Dunstone, D. J.;
Griffin, E.; Harper, E. A.; Hull, R. A. D.; Kalindjian, S. B.; Linney, I. D.;
Low, C. M. R.; Pether, M. J.; Spencer, J.; Wright, P. T.; Adatia, T.;
Bashall, A. J. Med. Chem. 2006, 49, 2253−2261. (b) McDonald, I. M.;
Black, J. W.; Buck, I. M.; Dunstone, D. J.; Griffin, E. P.; Harper, E. A.;
Hull, R. A. D.; Kalindjian, S. B.; Lilley, E. J.; Linney, I. D.; Pether, M. J.;
Roberts, S. P.; Shaxted, M. E.; Spencer, J.; Steel, K. I. M.; Sykes, D. A.;
Walker, M. K.; Watt, G. F.; Wright, L.; Wright, P. T.; Xun, W. J. Med.
Chem. 2007, 50, 3101−3112.
(8) Alizadeh, A.; Mokhtari, J. Helv. Chim. Acta 2014, 97, 398−403.
(9) (a) Rosenstrom, U.; Skold, C.; Lindeberg, G.; Botros, M.; Nyberg,
̈
̈
F.; Karlen
́
, A.; Hallberg, A. J. Med. Chem. 2004, 47, 859−870.
(b) Rosenstrom, U.; Skold, C.; Plouffe, B.; Beaudry, H.; Lindeberg,
G.; Botros, M.; Nyberg, F.; Wolf, G.; Karlen
Hallberg, A. J. Med. Chem. 2005, 48, 4009−4024.
̈
̈
́
, A.; Gallo-Payet, N.;
(10) Vlasiuk, S. V.; Pavlosky, V. I.; Andronati, S. A.; Gdaniec, M.;
Simonov, Y. A. Chem. Heterocycl. Compd. 2000, 36, 1077−1085.
(11) Dong, C.; Xie, L.; Mou, X.; Zhong, Y.; Su, W. Org. Biomol. Chem.
2010, 8, 4827−4830.
(12) Yotphan, S.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2009, 11,
1511−1514.
(13) Bartels, J.; Lu, P.; Maurer, K.; Walker, A. V.; Moeller, K. D.
Langmuir 2011, 27, 11199−11205.
(14) Dorr, A. A.; Lubell, W. D. Heterocycles 2014, 88, 1149−1161.
̈
(15) Crifar, C.; Dorr, A. A.; Lubell, W. D. Tetrahedron Lett. 2015, 56,
̈
3451−3453.
ASSOCIATED CONTENT
* Supporting Information
■
(16) Bourguet, C. B.; Proulx, C.; Klocek, S.; Sabatino, D.; Lubell, W. D.
J. Pept. Sci. 2010, 16, 284−296.
S
(17) Sabatino, D.; Proulx, C.; Klocek, S.; Bourguet, C.; Boeglin, D.;
Ong, H.; Lubell, W. D. Org. Lett. 2009, 11, 3650−3653.
(18) Garcia-Ramos, Y.; Proulx, C.; Lubell, W. D. Can. J. Chem. 2012,
90, 985−993.
The Supporting Information is available free of charge on the
X-ray crystallographic data for 19g and 7c (CIF)
Experimental details and spectroscopic characterization
(19) Tan, S. J.; Xi, H. W.; Bedoura, S.; Lim, K. H. Inorg. Chim. Acta
2012, 384, 29−36.
(20) Burgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973, 95,
5065−5067.
AUTHOR INFORMATION
Corresponding Author
■
(21) (a) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302−1315.
(b) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952−3015.
(22) Johansson Seechurn, C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062−5085.
Notes
(23) Traore,
3591.
́
M.; Doan, N.; Lubell, W. D. Org. Lett. 2014, 16, 3588−
The authors declare no competing financial interest.
(24) De Lucca, G. V.; Otto, M. Bioorg. Med. Chem. Lett. 1992, 2, 1639−
1644.
ACKNOWLEDGMENTS
We thank the Canadian Institutes of Health Research (CIHR)
for funding and members of the Universite
Dr. Alexandra Furtos-Matei, Marie-Christine Tang, Louiza
■
(25) (a) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J.
Org. Chem. 1956, 21, 478−479. (b) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.;
Jin, Z. Org. Lett. 2004, 6, 3217−3219.
́
de Montrea
́
l facilities:
(26) Bouayad-Gervais, S. H.; Lubell, W. D. Molecules 2013, 18, 14739−
Mahrouche, Karine Gilbert for high-resolution mass spectrom-
14746.
(27) Rose, G. D.; Gierasch, L. M.; Smith, J. D. Adv. Protein Chem. 1985,
37, 1−109.
etry analyses and Dr. Francine Belanger-Gariep
analyses.
́
y for X-ray
REFERENCES
■
(1) (a) Sternbach, L. H. J. Med. Chem. 1979, 22, 1−7. (b) Horton, D.
A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893−930.
(c) Costantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13, 65−85.
(d) Spencer, J.; Rathnam, R. P.; Chowdhry, B. Z. Future Med. Chem.
2010, 2, 1441−1449.
D
Org. Lett. XXXX, XXX, XXX−XXX