10.1002/ejoc.201800962
European Journal of Organic Chemistry
FULL PAPER
[9]
D. J. Foley, P. G. E. Craven, P. M. Collins, R. G. Doveston, A. Aimon, R.
Talon, I. Churcher, F. von Delft, S. P. Marsden, A. Nelson, Chem. Eur. J.
2017, 23, 15227 ‒ 15232.
in an ice bath, NaOH (2 M in water, 10 mL) was added. Most of
the MeOH was then removed under reduced pressure. Brine (20
mL) was added and the product was extracted with EtOAc (50 mL
+ 25 mL). The combined extracts were dried (Na2SO4) and
concentrated. Flash chromatography (13.2 g silica, 27% to 30%
EtOAc/light petroleum) gave 8i (279.3 mg, 62% [uncorrected for
[10] For recent reviews on the isolation, total synthesis and/or bioactivity of
(bridged) alkaloids, see: a) A. K. Chattopadhyay, S. Hanessian, Chem.
Rev. 2017, 117, 4104 ‒ 4146; b) S. K. Mishra, G. Tripathi, N. Kishore, R.
K. Singh, A. Singh, V. K. Tiwari, Eur. J. Med. Chem. 2017, 137, 504 ‒
544; c) A. Hager, N. Vrielink, D. Hager, J. Lefranc, D. Trauner, Nat. Prod.
Rep. 2016, 33, 491 ‒ 522; d) S. Schläger, B. Dräger, Curr. Opin.
Biotechnol. 2016, 37, 155 ‒ 164; e) H. Ishikawa, S. Shiomi, Org. Biomol.
Chem. 2016, 14, 409 ‒ 424; f) B. M. Trost, M. Osipov, Chem. Eur. J.
2015, 21, 16318 ‒ 16343; g) X.-Y. Liu, Y. Qin, Asian J. Org. Chem. 2015,
4, 1010 ‒ 1019.
impurities in starting material], single diastereomer) as
a
colourless solid; m.p. 177‒180 °C. TLC (50% EtOAc/light
petroleum): RF = 0.46 (UV or phosphomolybdic acid stain). IR: v
1
= 2979, 1748, 1715, 1322, 1131, 1025, 754, 698, 512 cm–1. H
NMR (300 MHz, CDCl3): δ = 7.41–7.31 (m, 4H), 7.29–7.21 (m,
1H), 5.00 (s, 1H), 3.55–3.50 (m, 1H), 3.32–3.12 (m, 3H), 3.00 (s,
3H), 2.74–2.55 (m, 4H), 2.49–2.38 (m, 2H), 2.14–2.06 (m, 1H),
1.92 (s, 3H), 1.49 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 207.9,
169.2, 142.3, 128.3, 127.2, 126.1, 81.5, 68.1, 65.5, 62.2, 56.3,
48.2, 47.0, 41.4, 40.7, 38.9, 38.8, 28.0, 22.4. HRMS (ES+): calcd.
for C23H33N2O5S [M+H]+ 449.2105, found 449.2107.
[11] For examples of alkaloid-inspired synthetic scaffolds and libraries, see:
a) J. Fang, T. Huang, M. Xia, L. Deng, X. Hao, Y. Wang, S. Mu, Org.
Biomol. Chem. 2018, 16, 3026 ‒ 3037; b) D. M. Kuznetsov, A. G.
Kutateladze, J. Am. Chem. Soc. 2017, 139, 16584 ‒ 16590; c) S. G.
Williams, M. Bhadbhade, R. Bishop, A. T. Ung, Tetrahedron 2017, 73,
116 ‒ 128; d) D. Yugandhar, S. Kuriakose, J. B. Nanubolu, A. K.
Srivastava, Org. Lett. 2016, 18, 1040 ‒ 1043; e) H. Kikuchi, T. Nishimura,
E. Kwon, J. Kawai, Y. Oshima, Chem. Eur. J. 2016, 22, 15819 ‒ 15825;
f) M. Spallarossa, L. Banfi, A. Basso, L. Moni, R. Riva, Adv. Synth. Catal.
2016, 358, 2940 ‒ 2948; g) P. Craven, A. Aimon, M. Dow, N. Fleury-
Bregeot, R. Guilleux, R. Morgentin, D. Roche, T. Kalliokoski, R. Foster,
S. P. Marsden, A. Nelson, Bioorg. Med. Chem. 2015, 23, 2629 ‒ 2635;
h) M. C. McLeod, G. Singh, J. N. Plampin III, D. Rane, J. L. Wang, V. W.
Day, J. Aubé, Nat. Chem. 2014, 6, 133 ‒ 140; i) D. A. Goff, Tetrahedron
2013, 69, 242 ‒ 256; j) G. Moura-Letts, C. M. DiBlasi, R. A. Bauer, D. S.
Tan, Proc. Natl. Acad. Sci. USA 2011, 108, 6745 ‒ 6750.
Acknowledgements
The research leading to these results was done within the
European Lead Factory and has received support from the
Innovative Medicines Initiative Joint Undertaking under grant
agreement no. 115489, resources of which are composed of
financial contribution from the European Union’s Seventh
Framework Programme (FP7/2007‒2013) and EFPIA companies’
in-kind contribution.
[12] WHO Model List of Essential Medicines, 20th Edition (March 2017,
amended
August
2017),
World
Health
Organisation,
[13] a) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57,
10257 ‒ 10274; b) R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med.
Chem. 2014, 57, 5845 ‒ 5859.
Conflict of interest
[14] a) G. C. Geary, A. Nortcliffe, C. A. Pearce, D. Hamza, G. Jones, C. J.
Moody, Bioorg. Med. Chem. 2018, 26, 791 ‒ 797; b) S. M. Nicolle, A.
Nortcliffe, H. E. Bartrum, W. Lewis, C. J. Hayes, C. J. Moody, Chem. Eur.
J. 2017, 23, 13623 ‒ 13627; c) A. Nortcliffe, G. D. S. Milne, D. Hamza,
C. J. Moody, Bioorg. Med. Chem. 2017, 25, 2218 ‒ 2225; d) A. T. Murray,
E. Packard, A. Nortcliffe, W. Lewis, D. Hamza, G. Jones, C. J. Moody,
Eur. J. Org. Chem. 2017, 138 ‒ 148.
Two authors (HVA and DH) are employees of Sygnature
Discovery Ltd.
Keywords: aza-Michael addition • bridged compounds • drug
discovery • heterocycles • reductive amination
[15] a) A. Karawajczyk, K. M. Orrling, J. S. B. de Vlieger, T. Rijnders, D. Tzalis,
Front. Med. 2017, 3, 1 ‒ 7; b) A. Karawajczyk, F. Giordanetto, J.
Benningshof, D. Hamza, T. Kalliokoski, K. Pouwer, R. Morgentin, A.
Nelson, G. Müller, A. Piechot, D. Tzalis, Drug Discov. Today 2015, 20,
1310 ‒ 1316.
[1]
[2]
[3]
[4]
D. E. Scott, A. R. Bayly, C. Abell, J. Skidmore, Nat. Rev. Drug. Discov.
2016, 15, 533 – 550.
a) F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752 ‒
6756; b) F. Lovering, Med. Chem. Commun. 2013, 4, 515 ‒ 519.
J. Meyers, M. Carter, N. Y. Mok, N. Brown, Future. Med. Chem. 2016, 8,
1753 ‒ 1767.
[16] M. T. Corbett, J. S. Johnson, Chem. Sci. 2013, 4, 2828 ‒ 2832.
[17] L. Pantaine, V. Coeffard, X. Moreau, C. Greck, Org. Lett. 2015, 17, 3674
‒ 3677.
A. D. Morley, A. Pugliese, K. Birchall, J. Bower, P. Brennan, N. Brown,
T. Chapman, M. Drysdale, I. H. Gilbert, S. Hoelder, A. Jordan, S. V. Ley,
A. Merritt, D. Miller, M. E. Swarbrick, P. G. Wyatt, Drug Discov. Today
2013, 18, 1221 ‒ 1227.
[18] For additional examples of cyclohexadienones (or related compounds)
as precursors to bridged polycyclic molecules, see: a) A. Orue, U. Uria,
D. Roca-López, I. Delso, E. Reyes, L. Carrillo, P. Merino, J. L. Vicario,
Chem. Sci. 2017, 8, 2904 ‒ 2913; b) Z.-T. He, X.-Q. Tang, L.-B. Xie, M.
Cheng, P. Tian, G.-Q. Lin, Angew. Chem. Int. Ed. 2015, 54, 14815 ‒
14818; c) P. Liu, Y. Fukui, P. Tian, Z.-T. He, C.-Y. Sun, N.-Y. Wu, G.-Q.
Lin, J. Am. Chem. Soc. 2013, 135, 11700 ‒ 11703; d) M. Tissot, R. J.
Phipps, C. Lucas, R. M. Leon, R. D. M. Pace, T. Ngouansavanh, M. J.
Gaunt, Angew. Chem. Int. Ed. 2014, 53, 13498 ‒ 13501; e) M. C. Carreño,
C. G. Luzón, M. Ribagorda, Chem. Eur. J., 2002, 8, 208 ‒ 216.
[19] Examples: a) P. Tang, L. Wang, Q.-H. Chen, F.-P. Wang, Tetrahedron
2011, 67, 1076 ‒ 1082; b) Y. Zhang, Y.-T. Di, S.-Z. Mu, C.-S. Li, Q. Zhang,
C.-J. Tan, Z. Zhang, X. Fang, X.-J. Hao, J. Nat. Prod. 2009, 72, 1325 ‒
1327; c) O. E. Edwards, Can. J. Chem. 1981, 59, 3039 ‒ 3043.
[5]
W. H. B. Sauer, M. K. Schwarz, J. Chem. Inf. Comput. Sci. 2003, 43, 987
‒ 1003.
[6]
[7]
D. J. Newman, G. M. Cragg, J. Nat. Prod. 2012, 75, 311 ‒ 335.
a) S. Rizzo, H. Waldmann, Chem. Rev. 2014, 114, 4621 ‒ 4639; b) H.
Lachance, S. Wetzel, K. Kumar, H. Waldmann, J. Med. Chem. 2012, 55,
5989 ‒ 6001; c) S. Wetzel, R. S. Bon, K. Kumar, H. Waldmann, Angew.
Chem. Int. Ed. 2011, 50, 10800 ‒ 10826; d) C. J. Gerry, S. L. Schreiber,
Nat. Rev. Drug. Discov. 2018, 17, 333 – 352.
[8]
P. Ertl, S. Roggo, A. Schuffenhauer, J. Chem. Inf. Model. 2008, 48, 68 ‒
74.
This article is protected by copyright. All rights reserved.