Synthesis of Complex Druglike Molecules by the Use of Highly Functionalized Bench-Stable Organozinc Reagents.
The reactivity of a representative set of 17 organozinc pivalates with 18 polyfunctional druglike electrophiles (informers) in Negishi cross-coupling reactions was evaluated by high-throughput experimentation protocols. The high-fidelity scaleup of successful reactions in parallel enabled the isolation of sufficient material for biological testing, thus demonstrating the high value of these new solid zinc reagents in a drug-discovery setting and potentially for many other applications in chemistry. Principal component analysis (PCA) clearly defined the independent roles of the zincates and the informers toward druggable-space coverage.
Discovery Chemistry, Process Chemistry, and Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA. thomas_greshock@merck.com.
Thomas J
0000-0002-3313-9733
TJ
Greshock
Discovery Chemistry, Process Chemistry, and Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
Keith P
KP
Moore
Discovery Chemistry, Process Chemistry, and Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
Ray T
RT
McClain
Discovery Chemistry, Process Chemistry, and Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
Ana
A
Bellomo
Discovery Chemistry, Process Chemistry, and Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
Cheol K
CK
Chung
Discovery Chemistry, Process Chemistry, and Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
Spencer D
SD
Dreher
Discovery Chemistry, Process Chemistry, and Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
Peter S
PS
Kutchukian
Discovery Chemistry, Process Chemistry, and Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
Zhengwei
Z
Peng
Discovery Chemistry, Process Chemistry, and Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
Ian W
IW
Davies
Discovery Chemistry, Process Chemistry, and Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
Petr
P
Vachal
Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5-13, Haus F, 81377, München, Germany.
Mario
M
Ellwart
Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5-13, Haus F, 81377, München, Germany.
Sophia M
SM
Manolikakes
Ludwig-Maximilians-Universität München, Department Chemie, Butenandtstrasse 5-13, Haus F, 81377, München, Germany. paul.knochel@cup.uni-muenchen.de.
Paul
P
Knochel
Discovery Chemistry, Process Chemistry, and Structural Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA.
Philippe G
PG
Nantermet
D057166:High-Throughput Screening Assays; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D025341:Principal Component Analysis; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D015032:Zinc / Q000737:chemistry*
D009942:Organometallic Compounds; D011725:Pyridines; D015032:Zinc
druglike molecules; high-throughput screening; late-stage functionalization; medicinal chemistry; organozinc reagents