Flow Reactions
FULL PAPER
(0.25%); in contrast, analogous searches for compounds containing
13-membered and 18-membered lactams yielded 127 (1.86ꢁ10À4 %)
and 9 hits (1.3ꢁ10À5 %), respectively.
ing our aspiration of “druglike” with regard to functionality
and physicochemical properties (for example, the Lipinski
descriptors).[24]
Future work will extend this methodology to the construc-
tion of more densely functionalized systems and, in particu-
lar, the construction of macrocyclic libraries for use in
screening against protein–protein interaction targets.
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revealed that the median concentration employed was 0.002m and
that the most common concentration employed was 0.0005m. The
two most common macrocyclization reactions were macrolactamiza-
tion and macrolactonization.
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Experimental Section
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Representative preparative-scale flow macrocyclization: Azidoalkyne 3a
(0.10m in EtOH, 100 mL, 0.010 mmol, 1.0 equiv), TTTA (0.01m in EtOH,
100 mL, 0.001 mmol, 0.10 equiv), DIPEA (0.1m in EtOH, 200 mL,
0.020 mmol, 2.0 equiv), and EtOH (200 mL) were aspirated from their re-
spective source vials, mixed through a PFA mixing tube (0.2 mm inner di-
ameter), and loaded into an injection loop. The reaction segment was in-
jected into the flow reactor, set at 1508C, passed through the reactor at
300 mLminÀ1 (5 min residence time). A total of 20 reaction segments pre-
pared in this manner were collected in a round bottom flask. Upon com-
pletion, the reaction mixture was concentrated and dried in vacuo. The
crude reaction mixture was purified by using a Biotage Horizon automat-
ed flash column chromatography system (silica gel, EtOAc, Rf =0.27) to
yield 6a as a white solid (45.6 mg, 73%). 1H NMR (600 MHz, CDCl3):
d=7.60 (s, 1H), 7.45 (d, J=7.5 Hz, 2H), 7.35 (t, J=7.5 Hz, 2H), 7.22–
7.28 (m, 1H), 4.94 (d, J=13.2 Hz, 1H), 4.77 (brs, 1H), 4.48–4.69 (m,
2H), 4.22–4.30 (m, 1H), 4.10–4.18 (m, 1H), 2.99 (brs, 1H), 2.53 (brs,
3H), 2.34 (brs, 1H), 2.07–2.21 (m, 2H), 0.81 ppm (d, J=7.0 Hz, 3H);
13C NMR (150 MHz, CDCl3): d=172.4, 145.6, 139.6, 128.2, 127.0, 126.0,
123.1, 78.0, 62.8, 55.8, 49.5, 31.8, 29.6, 24.1, 9.9 ppm; HRMS (ESI-TOF):
m/z: calcd for C17H22N4O2: 315.1815 [M+H]+; found: 315.1819.
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Acknowledgements
This work was funded by Pfizer Worldwide R&D, where K.J. is em-
ployed. The authors would like to thank Neal Sach and John Kath for in-
valuable advice, Jason Hein and Valery Fokin for helpful discussions and
gifts of trisACHTUNGTRENNUNG(triazole) catalysts, Khanh Tran and Kevin Freeman-Cook for
generous supply of intermediates, Jeff Elleraas for chiral chromatography
support, and Curtis Moore and Raj Chadha for crystallographic data.
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