Chemoselective modification of natural products: The use of aluminum-amides complexes as reagents for the transient in situ masking of reactive carbonyl groups

Francis Javier Barrios, Purdue University

Abstract

The development of new anticancer agents represents an exciting and new strategy toward the inhibition of the activation of the transcription factor nuclear factor κB (NF κB). The activation pathway of NF κB in malignant and highly drug-resistant cancers is well-recognized and can also occur from treatment with existing cancer chemotherapeutics. As a result, NF κB has become a focus of intense drug improvement efforts. The upregulation of the NF κB pathway has been recently implicated in highly drug-resistant leukemia cell populations, also known as leukemia stem cells. It has been demonstrated that parthenolide, a known inhibitor of NF κB activation, can target leukemia stem cells with high selectivity without affecting normal stem cell and progenitor hematopoietic cells. Parthenolide was promising for its use as an antileukemia agent, but its direct use in clinical trial has failed due to low potency. Parthenolide contains the &agr;-methylidene-γ-lactone that is the biologically active site that acts as a Michael acceptor for some amino acids and this site was modified to address the issues of potency. In our effort to discover novel cytotoxic compounds, several derivatives of &agr;-santonin were also prepared. It was found that the sesquiterpene lactone, &agr;-santonin, can be manipulated to install the &agr;-methylidene-γ-lactone moiety making it suitable for structure-activity relationship studies. Many pharmaceuticals have been developed by the structural modification of natural products. Direct modification of complex organic molecules can be a challenging task because multiple reactive functional groups are commonly displayed. The chemoselective addition of nucleophiles to molecules that have two different carbonyl groups is a challenging goal in organic synthesis. Common multi-step strategies to achieve this goal require the use of protecting groups and/or reduction/oxidation sequences. The drawback of this multi-step strategy is low synthetic efficiency. In order to address this problem a new method to selectively modify complex structures, such as natural products for drug discovery, has been developed using aluminum-amides complexes. This method consists in converting a reactive carbonyl group into a stable aminal. This aminal is the intermediate that forms when nucleophiles are added to Weinreb amides and is resistant to nucleophilic attack. Aluminum complexes of N,O-dimethylhydroxylamine are useful to mask reactive carbonyl groups in situ from nucleophiles such as organolithiums, Grignards reagents, hydrides, Wittig reagents and enolates. The effectiveness of this method by adding nucleophiles into substrates with multiple carbonyl groups is demonstrated. Also, a protocol that allows the in situ unmasking of the trapped carbonyl group, so additional synthetic manipulation can be done, has been developed. 1H NMR and 19F NMR analysis supports the in situ masking and unmasking of the more reactive carbonyl group.

Degree

Ph.D.

Advisors

Colby, Purdue University.

Subject Area

Chemistry|Organic chemistry

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