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Application of a Catalytic Asymmetric Povarov Reaction using Chiral Ureas to the Synthesis of a Tetrahydroquinoline Library
A 2328-membered library of 2,3,4-trisubstituted tetrahydroquinolines was produced using a combination of solution- and solid-phase synthesis techniques. A tetrahydroquinoline (THQ) scaffold was prepared via an asymmetric Povarov reaction using cooperative catalysis to generate three contiguous stereogenic centers. A matrix of 4 stereoisomers of the THQ scaffold was prepared to enable the development of stereo/structure-activity relationships (SSAR) upon biological testing. A sparse matrix design strategy was employed to select library members to be synthesized with the goal of generating a diverse collection of tetrahydroquinolines with physicochemical properties suitable for downstream discovery.Chemistry and Chemical Biolog
Structural Unit Analysis Identifies Lead Series and Facilitates Scaffold Hopping in Combinatorial Chemistry
Application of a Catalytic Asymmetric Povarov Reaction using Chiral Ureas to the Synthesis of a Tetrahydroquinoline Library
A 2328-membered library of 2,3,4-trisubstituted tetrahydroquinolines
was produced using a combination of solution- and solid-phase synthesis
techniques. A tetrahydroquinoline (THQ) scaffold was prepared via
an asymmetric Povarov reaction using cooperative catalysis to generate
three contiguous stereogenic centers. A matrix of 4 stereoisomers
of the THQ scaffold was prepared to enable the development of stereo/structure鈥揳ctivity
relationships (SSAR) upon biological testing. A sparse matrix design
strategy was employed to select library members to be synthesized
with the goal of generating a diverse collection of tetrahydroquinolines
with physicochemical properties suitable for downstream discovery
Application of a Catalytic Asymmetric Povarov Reaction using Chiral Ureas to the Synthesis of a Tetrahydroquinoline Library
A 2328-membered library of 2,3,4-trisubstituted tetrahydroquinolines
was produced using a combination of solution- and solid-phase synthesis
techniques. A tetrahydroquinoline (THQ) scaffold was prepared via
an asymmetric Povarov reaction using cooperative catalysis to generate
three contiguous stereogenic centers. A matrix of 4 stereoisomers
of the THQ scaffold was prepared to enable the development of stereo/structure鈥揳ctivity
relationships (SSAR) upon biological testing. A sparse matrix design
strategy was employed to select library members to be synthesized
with the goal of generating a diverse collection of tetrahydroquinolines
with physicochemical properties suitable for downstream discovery
Build/Couple/Pair Strategy for the Synthesis of Stereochemically Diverse Macrolactams via Head-to-Tail Cyclization
A build/couple/pair (B/C/P) strategy was employed to
generate a
library of 7936 stereochemically diverse 12-membered macrolactams.
All 8 stereoisomers of a common linear amine precursor were elaborated
to form the corresponding 8 stereoisomers of two regioisomeric macrocyclic
scaffolds via head-to-tail cyclization. Subsequently, these 16 scaffolds
were further diversified via capping of two amine functionalities
on SynPhase Lanterns. Reagents used for solid-phase diversification
were selected using a sparse matrix design strategy with the aim of
maximizing coverage of chemical space while adhering to a preset range
of physicochemical properties
Synthesis of Stereochemically and Skeletally Diverse Fused Ring Systems from Functionalized <i>C</i>鈥慓lycosides
A diversity-oriented synthesis (DOS)
strategy was developed for
the synthesis of stereochemically diverse fused-ring systems containing
a pyran moiety. Each scaffold contains an amine and methyl ester for
further diversification via amine capping and amide coupling. Scaffold
diversity was evaluated in comparison to previously prepared scaffolds
by a shape-based principal moments of inertia (PMI) analysis
Synthesis of Stereochemically and Skeletally Diverse Fused Ring Systems from Functionalized <i>C</i>鈥慓lycosides
A diversity-oriented synthesis (DOS)
strategy was developed for
the synthesis of stereochemically diverse fused-ring systems containing
a pyran moiety. Each scaffold contains an amine and methyl ester for
further diversification via amine capping and amide coupling. Scaffold
diversity was evaluated in comparison to previously prepared scaffolds
by a shape-based principal moments of inertia (PMI) analysis
Synthesis of Stereochemically and Skeletally Diverse Fused Ring Systems from Functionalized <i>C</i>鈥慓lycosides
A diversity-oriented synthesis (DOS)
strategy was developed for
the synthesis of stereochemically diverse fused-ring systems containing
a pyran moiety. Each scaffold contains an amine and methyl ester for
further diversification via amine capping and amide coupling. Scaffold
diversity was evaluated in comparison to previously prepared scaffolds
by a shape-based principal moments of inertia (PMI) analysis
Synthesis and Profiling of a Diverse Collection of Azetidine-Based Scaffolds for the Development of CNS-Focused Lead-like Libraries
The synthesis and diversification of a densely functionalized
azetidine
ring system to gain access to a wide variety of fused, bridged, and
spirocyclic ring systems is described. The in vitro physicochemical
and pharmacokinetic properties of representative library members are
measured in order to evaluate the use of these scaffolds for the generation
of lead-like molecules to be used in targeting the central nervous
system. The solid-phase synthesis of a 1976-membered library of spirocyclic
azetidines is also described
Synthesis and Profiling of a Diverse Collection of Azetidine-Based Scaffolds for the Development of CNS-Focused Lead-like Libraries
The synthesis and diversification of a densely functionalized
azetidine
ring system to gain access to a wide variety of fused, bridged, and
spirocyclic ring systems is described. The in vitro physicochemical
and pharmacokinetic properties of representative library members are
measured in order to evaluate the use of these scaffolds for the generation
of lead-like molecules to be used in targeting the central nervous
system. The solid-phase synthesis of a 1976-membered library of spirocyclic
azetidines is also described