Organic Letters
Letter
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(1, 3, 4, 21, 25, 30, 49−52, 55−57, and 60), while the other 52
compounds are novel (full characterization data for all new
the 28 compounds shown in the paper, another 37 compounds
were synthesized from sinomenine. For these compounds (32−
Most of the 65 compounds were produced on a scale of 25 mg
or greater. Chemoinformatic diversity analysis was used to
compare this collection to a commercially available screening
collection. The set of 66 compounds (including sinomenine)
contains the following complexity parameters (average): Fsp3 =
0.48, number of stereogenic centers = 3.1, ring fusion density39
= 0.37, ring complexity index39 = 1.40, and Glob40 = 0.36,
which are markedly higher in value compared to Chembridge
compounds (combined Diverset-CL and Diverset-EXP) Fsp3 =
0.38, number of stereogenic centers = 0.55, ring fusion density
= 0.06, ring complexity index = 1.06, and Glob = 0.08. See
Figure S3 for graphs comparing diversity parameters.
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Complex molecules are different from and complementary to
compounds in standard screening collections. As we have
demonstrated previously with gibberellic acid,24 adrenoster-
one,24 quinine,24 abietic acid,25 pleuromutilin,26 and now here
with sinomenine, natural products are an outstanding starting
point for the construction of complex and diverse small
molecules.
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(32) Lou, Y.-T.; Ma, L.-Y.; Wang, M.; Yin, D.; Zhou, T.-T.; Chen, A.-
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Tetrahedron 2012, 68, 2172.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
■
S
Experimental procedures, NMR spectra, and graphs
comparing complexity parameters (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Notes
(33) Yang, T.; Zhao, K.-m.; Zhang, L.; Fang, P.-h.; Jiang, W.-w.
Agrochem. 2012, 647.
(34) O’Brien, C. Chem. Rev. 1964, 64, 81.
The authors declare no competing financial interest.
(35) Csutoraa
26, 2251.
́ ́
s, C.; BereAnyi, S.; Makleit, S. Synth. Commun. 1996,
ACKNOWLEDGMENTS
■
(36) Compound 30 is known and can be accessed in two steps from
1 in an overall 6% yield.32
(37) He, L.; Zhang, Y.-H.; Guan, H.-Y.; Zhang, J.-X.; Sun, Q.-Y.; Hao,
X.-J. J. Nat. Prod. 2011, 74, 181.
We are grateful to the University of Illinois for support of this
work. A.G. is a recipient of the NIH Chemistry−Biology
Interface Training Grant (NRSA 1-T32-GM070421).
(38) Chuang, K. V.; Navarro, R.; Reisman, S. E. Angew. Chem., Int.
Ed. 2011, 50, 9447.
(39) Todeschini, R.; Consonni, V. Handbook of Molecular Descriptors;
John Wiley & Sons: Hoboken, 2009; Vol. 41.
(40) Kuenemann, M. A.; Bourbon, L. M. L.; Labbe, C. M.;
́
Villoutreix, B. O.; Sperandio, O. J. Chem. Inf. Model. 2014, 54, 3067.
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