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Novel polycyclic benzannulated indol...

Maina, Lincoln Wamae.

Novel polycyclic benzannulated indole scaffolds via indole aryne cycloaddition, Pd (0)-catalyzed cross-coupling and ROM/RCM methodologies. Their applications to library development and drug discovery.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Novel polycyclic benzannulated indole scaffolds via indole aryne cycloaddition, Pd (0)-catalyzed cross-coupling and ROM/RCM methodologies. Their applications to library development and drug discovery.
Author:	Maina, Lincoln Wamae.
Description:	221 p.
Notes:	Source: Dissertation Abstracts International, Volume: 76-07(E), Section: B.
Notes:	Adviser: Keith R. Buszek.
Contained By:	Dissertation Abstracts International76-07B(E).
Subject:	Organic chemistry.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3685066
ISBN:	9781321606508

Novel polycyclic benzannulated indole scaffolds via indole aryne cycloaddition, Pd (0)-catalyzed cross-coupling and ROM/RCM methodologies. Their applications to library development and drug discovery.
Maina, Lincoln Wamae.

Novel polycyclic benzannulated indole scaffolds via indole aryne cycloaddition, Pd (0)-catalyzed cross-coupling and ROM/RCM methodologies. Their applications to library development and drug discovery. - 221 p.

Source: Dissertation Abstracts International, Volume: 76-07(E), Section: B.

Thesis (Ph.D.)--University of Missouri - Kansas City, 2015.

Heterocyclic chemistry is one of the most valuable sources of novel compounds with diverse biological activity. The indole nucleus for instance, is an important element of many natural and synthetic molecules with significant biological activity. Drug discovery and development processes highly value the utility of the ability to synthesize a diverse library based on one core scaffold which can be screened against a variety of different receptors and cell lines, yielding several active compounds. Privileged structures offer an ideal source of lead compounds for drug discovery due to their inherent affinity for diverse biological targets. Indole motifs represent one of the most prominent privileged structures and are ubiquitous in natural products and pharmaceutical compounds. A variety of fused heterocyclic structures will be designed, resulting in novel polycyclic frameworks with virtually no representation in the National Institutes of Health PubChem and Molecular Library of Small Molecule Repository (MLSMR) databases.

ISBN: 9781321606508Subjects--Topical Terms:

708640
Organic chemistry.

Novel polycyclic benzannulated indole scaffolds via indole aryne cycloaddition, Pd (0)-catalyzed cross-coupling and ROM/RCM methodologies. Their applications to library development and drug discovery.
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245 1 0 $a Novel polycyclic benzannulated indole scaffolds via indole aryne cycloaddition, Pd (0)-catalyzed cross-coupling and ROM/RCM methodologies. Their applications to library development and drug discovery.
300 $a 221 p.
500 $a Source: Dissertation Abstracts International, Volume: 76-07(E), Section: B.
500 $a Adviser: Keith R. Buszek.
502 $a Thesis (Ph.D.)--University of Missouri - Kansas City, 2015.
520 $a Heterocyclic chemistry is one of the most valuable sources of novel compounds with diverse biological activity. The indole nucleus for instance, is an important element of many natural and synthetic molecules with significant biological activity. Drug discovery and development processes highly value the utility of the ability to synthesize a diverse library based on one core scaffold which can be screened against a variety of different receptors and cell lines, yielding several active compounds. Privileged structures offer an ideal source of lead compounds for drug discovery due to their inherent affinity for diverse biological targets. Indole motifs represent one of the most prominent privileged structures and are ubiquitous in natural products and pharmaceutical compounds. A variety of fused heterocyclic structures will be designed, resulting in novel polycyclic frameworks with virtually no representation in the National Institutes of Health PubChem and Molecular Library of Small Molecule Repository (MLSMR) databases.
520 $a These molecular frameworks would be predicted to occupy unoccupied or sparsely occupied regions of the chemical property space which increase their chances of finding applications as new drug leads with different modes of actions. Consequently, efficient methodologies resulting in polycyclic structures from biologically active heterocyclic templates are highly desired in the drug discovery and development programs. The synthesis of such a unique class of polycyclic benzannulated indole scaffolds is described.
520 $a The 4,6,7-tribromoindole and the 5,6,7-tribromoindole were synthesized via the Bartoli and Leimgruber-Batcho and indole synthesis protocols respectively. Both indoles underwent selective metal-halogen exchange at C-7 and subsequent elimination to give the 6,7-indole aryne which underwent Diels-Alder cycloadditions with cyclopentadiene, furan and 2,5-dimethyl furan. These cycloadducts were N-alkylated and then subjected to Grubb's catalyst ring opening metathesis/ring closing metathesis to afford 12 unique 6,7-benzannulated with an additional 7 or 8-membered rings fused from the benzenoid ring to the pyrrole ring of the indole nucleus.
520 $a Library development is facilitated by the extra bromine at the 4 or 5 position of the indole nucleus which serves as a diversity handle which can be subjected to several palladium catalyzed cross-couplings including but not limited to Suzuki-Miyaura, Negishi and Buchwald-Hartwig. These scaffolds can even be further diversified via olefin functionalization: cross metathesis, hydroamination and epoxidation among others to afford pharmaceutically useful functional groups like carbamates, ureas, secondary and tertiary amines as well as sulfonamides.
590 $a School code: 0134.
650 4 $a Organic chemistry. $3 708640
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710 2 $a University of Missouri - Kansas City. $b Chemistry. $3 730302
773 0 $t Dissertation Abstracts International $g 76-07B(E).
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791 $a Ph.D.
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