I. Catalysis of Intra- and Intermolecular Schmidt Reactions. II. Copper-Catalyzed Oxaziridine-Mediated C-H Bond Oxidation. III. Synthesis and Cytotoxic Evaluation of Withalongolide A Analogues.

The research presented herein describes four separate projects, focusing on synthetic methodology development, discovery of novel cytotoxic agents, and natural product isolation. Catalysis of Intra- and Intermolecular Schmidt Reactions A method for carrying out the intramolecular Schmidt reaction of alkyl azides and ketones using a substoichiometric amount of catalyst is described. Following extensive screening, the use of the strong hydrogen-bond-donating solvent hexafluoro-2-propanol (HFIP) was found to be consistent with low catalyst loadings, which ranged from 2.5 mol % for favorable substrates to 25 mol % for more difficult cases. Reaction optimization, broad substrate scope, and preliminary mechanistic studies of this improved version of the reaction are discussed. The use of HFIP as the solvent also allowed for the extension of this methodology to intermolecular variants of Schmidt reaction favoring the development of mild, operationally simple, and more efficient protocols, requiring considerably less amounts of acid catalysts for these variants. Copper-Catalyzed Oxaziridine-Mediated C-(&ndash)H Bond Oxidation. The highly regioand chemoselective oxidation of an activated C−(&ndash)H bond via a copper-catalyzed reaction of oxaziridine is described. The oxidation proceeded with a variety of substrates, primarily comprising of allylic and benzylic examples, as well as one example of an otherwise unactivated tertiary C−(&ndash)H bond. The mechanism of the reaction is proposed to involve single-electron transfer (SET) to the oxaziridines to generate a copper-bound radical anion, followed by hydrogen atom abstraction and collapse to products, with regeneration of the catalyst by a final SET event. The involvement of allylic radical intermediates en route to the product was supported by a radical-trapping experiment with TEMPO. Synthesis and Cytotoxic Evaluation of Withalongolide A Analogues. The natural product withaferin A exhibits potent antitumor activity and other diverse pharmacological activities. The recently discovered withalongolide A, a C-19 hydroxylated congener of withaferin A, was reported to possess cytotoxic activity against head and neck squamous cell carcinoma (HNSCC). Interestingly, semisynthetic acetylated analogues of withalongolide A were shown to be considerably more cytotoxic than the parent compound. To further explore the structure-(&ndash)activity relationship (SAR), 20 new semisynthetic analogues of this highly oxygenated withalongolide A were designed, synthesized, and evaluated for cytotoxic activity against four different cancer cell lines. A number of derivatives were found to be more potent than the parent compound and withaferin A. Isolation of Withalongolide O from Physalis longifolia. The SAR analysis of reported bioactive withanolides revealed certain crucial structural requisites for possessing a potent cytotoxic activity. The semisynthesis of a putative unnatural withanolide incorporating all the basic and essential structural features to boost the antiproliferative activity was contemplated. Withaferin A was considered as an appropriate starting material for this purpose. Although the semisynthetic efforts met with failure, it was during the isolation of withaferin A from the crude plant extract that we discovered a novel withanolide, withalongolide O. The structure of withalongolide O was determined using various spectroscopic techniques and subsequently confirmed by X-ray crystallographic analysis. Both withalongolide O and its diacetate exhibited potent cytotoxicity against four different cancer cell lines

Improved Schmidt Conversion of Aldehydes to Nitriles Using Azidotrimethylsilane in 1,1,1,3,3,3-Hexafluoro-2-propanol

This work is licensed under a Creative Commons Attribution 4.0 International License.The Schmidt reaction of aromatic aldehydes using a substoichiometric amount (40 mol %) of triflic acid is described. Low catalyst loading was enabled by a strong hydrogen-bond-donating solvent hexafluoro-2-propanol (HFIP). This improved protocol tolerates a broad scope of aldehydes with diverse functional groups and the corresponding nitriles were obtained in good to high yields without the need for aqueous work up.University of Kansa

Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors

Development of heat shock protein 90 (Hsp90) C‐terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention. Herein, 24 cores were synthesized with varying distances and angles between the sugar and amide moieties. Compounds that exhibited good anti‐proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity, were those that placed the sugar and amide moieties between 7.7 and 12.1 Å apart along with angles of 180°.Angle of attack: The distance and angle between the N‐methylpiperidine and the biaryl side chain was analyzed in an effort to develop more potent Hsp90 C‐terminal inhibitors. Compounds that exhibited good anti‐proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity were those that placed the sugar and amide moieties between 7.7 and 12.1 Å apart along with angles of 180°.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136281/1/chem201504955_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136281/2/chem201504955.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136281/3/chem201504955-sup-0001-misc_information.pd

Improved Schmidt Conversion of Aldehydes to Nitriles Using Azidotrimethylsilane in 1,1,1,3,3,3-Hexafluoro-2-propanol

The Schmidt reaction of aromatic aldehydes using a substoichiometric amount (40 mol %) of triflic acid is described. Low catalyst loading was enabled by a strong hydrogen-bond-donating solvent hexafluoro-2-propanol (HFIP). This improved protocol tolerates a broad scope of aldehydes with diverse functional groups and the corresponding nitriles were obtained in good to high yields without the need for aqueous work up

Microwave-accelerated solvent- and catalyst-free synthesis of 4-aminoaryl/alkyl-7-chloroquinolines and 2-aminoaryl/alkylbenzothiazoles

An efficient synthesis of 4-aminoaryl/alkyl-7-chloroquinolines and 2-aminoaryl/ alkylbenzothiazoles has been developed by microwave-accelerated regioselective aromatic nucleophilic substitution of 4,7-dichloroquinoline and 2-chlorobenzothiazole with aromatic and aliphatic amines under solvent-free conditions in the absence of any added protic or Lewis acid catalyst. Chemoselective reaction with the amino group in preference to the phenolic hydroxy group was observed. Thus, the treatment of 4,7-dichloroquinoline (1 equiv.) with a mixture of aniline (2 equiv.) and phenol (2 equiv.) afforded exclusive formation of 4-aminophenyl-7-chloroquinoline. When 4,7-dichloroquinoline ( 1 equiv.) was separately treated with 2-aminophenol (2 equiv.) and 4-aminophenol (2 equiv.), 4-(2'-hydroxyphenyl)-7-chloroquinoline and 4-(4'-hydroxyphenyl)-7-chloroquinoline, respectively, were formed

Copper-Catalyzed Oxaziridine-Mediated Oxidation of C–H Bonds

The highly regio- and chemoselective oxidation of activated C–H bonds has been observed via copper-catalyzed reactions of oxaziridines. The oxidation proceeded with a variety of substrates, primarily comprising allylic and benzylic examples, as well as one example of an otherwise unactivated tertiary C–H bond. The mechanism of the reaction is proposed to involve single-electron transfer to the oxaziridines to generate a copper-bound radical anion, followed by hydrogen atom abstraction and collapse to products, with regeneration of the catalyst by a final single-electron transfer event. The involvement of allylic radical intermediates was supported by a radical-trapping experiment with TEMPO

Intramolecular Friedel–Crafts Acylation Reaction Promoted by 1,1,1,3,3,3-Hexafluoro-2-propanol

Simple dissolution of an arylalkyl acid chloride in 1,1,1,3,3,3-hexafluoro-2-propanol promotes an intramolecular Friedel–Crafts acylation without additional catalysts or reagents. This reaction is operationally trivial in both execution and product isolation (only requiring concentration followed by purification) and accommodates a broad range of substrates. Preliminary studies that bear upon potential reaction mechanisms are reported

Remodeling and Enhancing Schmidt Reaction Pathways in Hexafluoroisopropanol

The effect of carrying out two variations of the Schmidt reaction with ketone electrophiles in hexafluoroisopropanol (HFIP) solvent has been studied. When TMSN₃ is reacted with ketones in the presence of triflic acid (TfOH) promoter, tetrazoles are obtained as the major products. This observation is in contrast to established methods, which usually lead to amides or lactams arising from formal NH insertion as the major products. The full product profiles of several examples of this reaction are also reported and found to include mechanistically interesting products (e.g., double ring expansion). Application of TfOH promoter in HFIP was also found to promote the reaction of a hydroxyalkyl azide with a ketone, which affords lactams following nucleophilic opening of initially formed iminium ether more efficiently than previously reported methods

Remodeling and Enhancing Schmidt Reaction Pathways in Hexafluoroisopropanol

The effect of carrying out two variations of the Schmidt reaction with ketone electrophiles in hexafluoroisopropanol (HFIP) solvent has been studied. When TMSN₃ is reacted with ketones in the presence of triflic acid (TfOH) promoter, tetrazoles are obtained as the major products. This observation is in contrast to established methods, which usually lead to amides or lactams arising from formal NH insertion as the major products. The full product profiles of several examples of this reaction are also reported and found to include mechanistically interesting products (e.g., double ring expansion). Application of TfOH promoter in HFIP was also found to promote the reaction of a hydroxyalkyl azide with a ketone, which affords lactams following nucleophilic opening of initially formed iminium ether more efficiently than previously reported methods

Remodeling and Enhancing Schmidt Reaction Pathways in Hexafluoroisopropanol

The effect of carrying out two variations of the Schmidt reaction with ketone electrophiles in hexafluoroisopropanol (HFIP) solvent has been studied. When TMSN₃ is reacted with ketones in the presence of triflic acid (TfOH) promoter, tetrazoles are obtained as the major products. This observation is in contrast to established methods, which usually lead to amides or lactams arising from formal NH insertion as the major products. The full product profiles of several examples of this reaction are also reported and found to include mechanistically interesting products (e.g., double ring expansion). Application of TfOH promoter in HFIP was also found to promote the reaction of a hydroxyalkyl azide with a ketone, which affords lactams following nucleophilic opening of initially formed iminium ether more efficiently than previously reported methods