An alkylsilyl-tethered, high-capacity solid support amenable to diversity-oriented synthesis for one-bead, one-stock solution chemical genetics.
The synthesis and use of an alkylsilyl-tethered large (500-600 microm) polystyrene resin (1) are disclosed. An optimized Suzuki coupling of bromine-functionalized polystyrene and a silicon-functionalized alkylborane generates the silicon-substituted polystyrene 1 in large scale (>100 g). Resin loading is accomplished by activation as the silyl triflate, which can accommodate even sterically encumbered secondary alcohols and phenols. Treatment with HF/pyridine for linker cleavage is mild, efficient, and amenable to an automated, large-scale distribution system. This platform delivers, minimally, 50 nmol of each small molecule derived from a diversity-oriented, split-pool synthesis on a per bead basis for use in both forward and reverse chemical genetic assays. This technology satisfies many requirements of a one bead-one stock solution approach to chemical genetics.
Tallarico
J A
JA
Harvard Institute of Chemistry and Cell Biology (ICCB), Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts 02115, USA.
Depew
K M
KM
Pelish
H E
HE
Westwood
N J
NJ
Lindsley
C W
CW
Shair
M D
MD
Schreiber
S L
SL
Foley
M A
MA
D000480:Alkynes / Q000737:chemistry; D001966:Bromine / Q000737:chemistry; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods; D015195:Drug Design; D008863:Microspheres; D015394:Molecular Structure; D011137:Polystyrenes / Q000138:chemical synthesis* / Q000737:chemistry; D012116:Resins, Plant / Q000737:chemistry; D012821:Silanes / Q000737:chemistry; D013329:Structure-Activity Relationship
D000480:Alkynes; D011137:Polystyrenes; D012116:Resins, Plant; D012821:Silanes; D001966:Bromine