Stereocontrolled solid-phase synthesis of a 90-membered library of indoline-alkaloid-like polycycles from an enantioenriched aminoindoline scaffold.
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Alkaloids↗
Biomedical subjects
Prabhat Arya
Publications and source records attributed to Prabhat Arya.
Natural product-like chemical space: search for chemical dissectors of macromolecular interactions.
Macromolecular interactions (i.e. protein-protein or DNA/RNA-protein interactions) play important cellular roles, including cellular communication and programmed cell death. Small-molecule chemical probes are crucial for dissecting these highly organized interactions, for mapping their function at the molecular level and developing new therapeutics. The lack of ideal chemical probes required to understand macromolecular interactions is the missing link in the next step of dissecting such interactions. Unfortunately, the classical combinatorial-chemistry community has not successfully provided the required probes (i.e. natural product inspired chemical probes that are rich in stereochemical and three-dimensional structural diversity) to achieve these goals. The emerging area of diversity-oriented synthesis (DOS) is beginning to provide natural product-like chemical probes that may be useful in this arena.
Biological Factors↗
Exploring new chemical space by stereocontrolled diversity-oriented synthesis.
Natural products that act as highly specific, small-molecule protein-binding agents and as modulators of protein-protein interactions are highly complex and exhibit functional groups with three-dimensional and stereochemical diversity. The complex three-dimensional display of chiral functional groups appears to be crucial for exhibiting specificity in protein binding and in differentiating between closely related proteins. The development of methods that allow a high-throughput access to three-dimensional, skelatally complex, polycyclic compounds having few asymmetric diversity sites is essential and a highly challenging task. In the postgenomic chemical biology age, in which there is a great desire to understand protein-protein interactions and to dissect protein networking-based signaling pathways by small molecules, the need for developing "stereocontrolled, diversity-oriented synthesis" methods to generate natural product-like libraries is of utmost importance.
Genomics↗
Carbonylation reactions of iodoarenes with PAMAM dendrimer-palladium catalysts immobilized on silica.
Palladium complexes immobilized onto generation 0-3 PAMAM dendrimers supported on silica were used as catalysts for the carbonylation of iodobenzene in methanol to form methyl benzoate. High yields were obtained and the catalyst was recycled 4-5 times without significant loss of activity. The carbonylation reaction was found to be applicable to a variety of iodoarenes regardless of the nature of the substituent.
Journal Article↗
Toward high-throughput synthesis of complex natural product-like compounds in the genomics and proteomics age.
In the age of high-throughput biology, novel genes and proteins are emerging quickly. The need for developing organic synthesis-derived methods that allow rapid access to polyfunctional, complex natural product-like compounds is growing constantly, largely because these small-molecule-based compounds serve as smart, powerful tools both in understanding the roles and functions of emerging biological targets and in validating their biological responses. Developing asymmetric synthesis-derived organic reactions on solid phase allows the synthesis of complex natural product-like compounds in a high-throughput manner. Solid phase organic synthesis is now commonly utilized in the library synthesis of rather simple compounds (i.e., compounds with no multiple stereogenic centers). With few exceptions, the synthesis of complex natural product-like derivatives is still in its infancy. Some recent efforts made in this area indicate opportunities yet to be explored.
Biological Factors↗
High-throughput chemistry toward complex carbohydrates and carbohydrate-like compounds.
In the area of peptide and nucleic acid chemistry and biology, high-throughput synthesis has played an important role in providing useful small-molecule-based chemical probes in understanding the structure and function relationships. The past several years, there has been a constant rise in interest toward understanding the biological roles and functions of another important class of biomolecules, i.e., carbohydrates and carbohydrate conjugates. Although at early stages, in recent years, several groups have developed high-throughput synthetic methods to obtain complex carbohydrates or carbohydrate-like small-molecules. The present review article summarizes some of these developments.
Amino Acids↗
Diversity-Based Organic Synthesis in the Era of Genomics and Proteomics NRC publication no. 43843. David Thomas is a senior colleague and mentor.
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Journal Article↗
Automated high-throughput synthesis of artificial glycopeptides. Small-molecule probes for chemical glycobiology.
A fully automated method for the synthesis of artificial glycopeptides having two (similar or different) carbon-linked glycosyl moieties on a dipeptide scaffold has been developed. By use of this approach that combines the diversity of peptide/pseudopeptide and glycosides, different glycoside moieties can be incorporated onto the peptide/pseudopeptide backbone in a highly controlled manner. The approach utilizes a stepwise reductive amination with glycoside aldehyde derivatives (model 1) or (ii) glycoside reductive amination followed by glycoside amide bond formation (model 2). Further, an automated method has been utilized in the high-throughput library synthesis of 4 x 96 artificial glycopeptides. These libraries were tested as chemical probes/inhibitors of enzyme systems that convert a glucose moiety into rhamnose prior to incorporation of the rhamnose unit and the conversion of UDP-galactopyranose to UDP-galactofuranose via UDP-galactopyranose mutase enzyme during the biosynthesis of the mycobacterium cell wall.
Combinatorial Chemistry Techniques↗
A solid-phase, library synthesis of natural-product-like derivatives from an enantiomerically pure tetrahydroquinoline scaffold.
With the goal of developing a library synthesis of tetrahydroquinoline-derived natural-product-like small molecules, a practical synthesis of enantiomerically pure tetrahydroquinoline scaffold was achieved. An asymmetric aminohydroxylation reaction was the key step in this strategy. This scaffold was further immobilized onto the solid support for the library generation. The library was obtained from three diversity sites: (i) acylation of the hydroxyl group (R(1)), (ii) coupling of the Fmoc-protected amino acid to the amino group (R(2)), and (iii) amidation of the N-terminal amine group (R(3)).
Biological Factors↗
A solid phase library synthesis of hydroxyindoline-derived tricyclic derivatives by Mitsunobu approach.
Hydroxyindoline-derived scaffold, 9, was synthesized with the goal of generating a library of indoline-based natural product-like tricyclic derivatives to be utilized as small-molecule chemical probes. The tricyclic ring was obtained by a Mitsunobu reaction of the N-nosyl amino acid conjugate with the primary hydroxyl group. The solid-phase synthesis was achieved by immobilizing scaffold 9 onto the solid support giving a compound, 15. This was then subjected to a series of reactions on solid phase, including the Mitsunobu reaction, leading to the desired indoline-derived tricyclic derivative. The final product has two diversity sites: (i) amino acid as the first diversity and (ii) amidation of the secondary amine for the second diversity. These two diversity sites were utilized in the library generation by IRORI split-and-mix approach.
Hydroxyl Radical↗
Stereoselective diversity-oriented solution and solid-phase synthesis of tetrahydroquinoline-based polycyclic derivatives.
A diversity-oriented solution and solid-phase synthesis of tetrahydroquinoline-based tricyclic derivatives has been achieved from enantiomerically pure, natural product-like bicyclic scaffold. The solution synthesis of enantiopure bicyclic scaffold was developed by asymmetric hetero Michael reaction. Our approach for the synthesis of polycyclic derivatives utilized regio- and stereoselective hetero Michael reaction and ring-closing metathesis as key steps in solution and on solid phase.
Borohydrides↗
Solution- and solid-phase synthesis of natural product-like tetrahydroquinoline-based polycyclics having a medium size ring.
A solid-phase synthesis of tetrahydroquinoline-derived polycyclic 4, having a medium size ring with an enamide functionality, was achieved from tetrahydroquinoline derivative 3 in five steps with overall 40-45% yield. An enantiopure, tetrahydroquinoline-derived beta-amino ester, 1, was converted into compound 2 that has a free phenolic hydroxyl group as an anchoring site for solid-phase synthesis. The solid-phase worked well for this sequence, in which the synthesis of the unsaturated eight-membered enamide lactam was obtained by a ring-closing metathesis approach. Compound 4 is a novel, natural product-like polycyclic derivative that could further be utilized in library generation for developing small molecule chemical probes.
Biological Products↗
A solution- and solid-phase approach to tetrahydroquinoline-derived polycyclics having a 10-membered ring.
With the goal of library generation using a polycyclic derivative 5 having an enamide functional group, a simple and practical, enantioselective synthesis of tetrahydroquinoline derivative 2 was achieved. The phenolic hydroxyl group in compound 2 was utilized as an anchoring site for solid-phase synthesis. The ring closing metathesis approach yielded the desired polycyclic product 5 on solid phase in five steps (overall 40% yield). Compound 5 is a novel scaffold for the library generation of natural product-like polycyclics having a functionalized medium ring for obtaining a new class of small molecules to be utilized as chemical probes.
Journal Article↗
Part 1. modular approach to obtaining diverse tetrahydroquinoline-derived polycyclic skeletons for use in high-throughput generation of natural-product-like chemical probes.
A practical synthesis of a tetrahydroaminoquinoline scaffold (12) was developed that used a stereocontrolled aza Michael as the key reaction. Three tetrahydroquinoline alkaloid-like, tricyclic derivatives 16, 18, and 19 with different medium to macrocyclic ring skeletons were obtained, using this scaffold as the starting material, in a modular manner. The macrocyclic compounds with an isolated olefin and an electron-deficient olefin were obtained by ring-closing metathesis approaches. Compounds 16 and 18 are unique and contain bridged 10- and 12-membered functionalized rings. The NMR studies of these compounds revealed interesting information on the conformation of the bicyclic scaffolds that was dependent on the nature and the size of the macrocyclic rings. Finally, this modular methodology, using compound 21 anchored onto the solid support, successfully led to the generation of different macrocyclic derivatives, 23, 25, and 27 in solid-phase synthesis. The solid-phase synthesis approach outlined in this article has the potential to generate tetrahydroquinoline-based tricyclic compounds containing different medium to macrocyclic architectures.
Alkaloids↗
Part 2: building diverse natural-product-like architectures from a tetrahydroaminoquinoline scaffold. Modular solution- and solid-phase approaches for use in high-throughput generation of chemical probes.
The solution- and solid-phase synthesis to obtain several natural-product-like, tetrahydroquinoline-based, polycyclic derivatives were developed. In one approach, two derivatives (38 and 41) having an eight-membered unsaturated lactam were successfully obtained both in solution and on solid support.
Alkaloids↗
Solution- and solid-phase, modular approaches for obtaining different natural product-like polycyclic architectures from an aminoindoline scaffold for combinatorial chemistry.
With the goal of developing a modular approach leading to different indoline alkaloid natural-product-like tricyclic derivatives having an unsaturated lactam (see compounds 13, 14, and 16), an aminoindoline-based bicyclic scaffold 10 was obtained from 9. The selective deprotection of the indoline NTeoc or benzylic NHAlloc in compound 10, followed by N-acryloylation and then subjection to a ring-closing metathesis reaction, successfully led to obtaining two different architectures (13/14 and 16) having an unsaturated lactam functionality. This modular solution-phase methodology was then developed on solid phase. To achieve this objective, the aminoindoline bicyclic scaffold having an additional hydroxyl group could be immobilized onto the solid support using alkylsilyl linker-based polystyrene macrobeads, giving 18. By applying a ring-closing metathesis approach, 20 (tricyclic derivative with seven-membered-ring unsaturated lactam) and 23 (tricyclic derivative with eight-membered-ring unsaturated lactam) were then obtained from 18 in a number of steps.
Combinatorial Chemistry Techniques↗
Part 3. a novel stereocontrolled, in situ, solution- and solid-phase, Aza Michael approach for high-throughput generation of tetrahydroaminoquinoline-derived natural-product-like architectures.
With the goal of rapidly accessing tetrahydroquinoline-based natural-product-like polycyclic architectures, herein, we report an unprecedented, in situ, stereocontrolled Aza Michael approach in solution and on the solid phase. The mild reaction conditions required to reach the desired target are highly attractive for the use of this method in library generation. To our knowledge, this approach has not been used before, and it opens a novel route leading to a wide variety of tetrahydroquinoline-derived bridged tricyclic derivatives.
Alkaloids↗