RNA is an important messenger between DNA and proteins and was long thought to be lacking in structural complexity. However, recent work has shown that small molecules can bind to well-defined RNA-containing structures to provide a strategy for treating diseases ranging from cancer to bacterial infections to malaria. Complex amines, where the nitrogen-bearing carbon is embedded in an array of neighboring chiral centers, readily bind to the ribosome and are found in many therapeutics. However, in addition to their beneficial activities, they often exhibit toxic side effects due to non-selective binding o other biological targets. Tuning reactivity in complex amines is challenging using existing synthetic methodology, hampering efforts to identify molecules that bind only to the ribosome. This proposal focuses on developing a versatile, unified strategy for the stereoselective synthesis of highly functionalized amines. A key feature of allene aziridination is the exquisite control over the type of carbon-heteroatom bond that is installed at each one of the three allene carbons in the synthesis of our complex amines. The axial chirality of the allene substrate is transferred to point chirality in any desired target with excellent fidelity. In addition, selectiv access to any one of eight amine stereotriads can be achieved from a single racemic allene precursor. This unique feature of our chemistry minimizes the use of protecting groups, oxidation state changes and stereochemical inversions that plague current synthetic approaches. The flexibility and versatility of allene aziridination will transform the ways in whic complex amines are synthesized to access novel chemical space for tuning molecular function to address important questions related to human health. To showcase the versatility of allene aziridination as a unified strategy towards the synthesis of diverse bioactive amines, our methodology will first be applied to the synthesis of novel analogues of the aminoglycosides (AGs) to decrease their ototoxicity, a goal having important implications for cystic fibrosis patients. In a second application of our new methods, a systematic study of the hydrogen bonding interactions involved in binding of a potent aminocyclopentitol, jogyamycin, to the 30S subunit of the ribosome, will be carried out. Specific interactions important for the beneficial antimalarial and antitumor activities will be identified. Finally, potent anthraquinone antibiotics that bind to both the major and minor grooves of DNA, in contrast to the minor groove binding exhibited by doxorubicin, will be synthesized. The role of the heteroatom identity and stereochemistry in the unique bicyclic aminosugars present in these compounds will be unraveled through the judicious design and preparation of analogues. This will shed light on how the cardiotoxicity and multi-drug resistance in this class of anthracyclines differs from doxorubicin. The biological testing of our new molecules will carried out in collaboration with the UW Small Molecule Screening and Synthesis Facility, which has resources necessary to undertake the biological assays needed in our work.
The stereoselective and efficient construction of carbon-nitrogen bonds is of paramount importance for the synthesis of numerous molecules related to human health. This project focuses on the development of a unified approach towards the synthesis of complex amines occurring in molecules with antimalarial, antibiotic and antitumor activities. Allene aziridination will be employed as a key step to simplify the preparation of known molecules and provide a springboard for the discovery of more efficacious bioactive molecules to meet public health needs.
|Schmid, Steven C; Guzei, Ilia A; Fernández, Israel et al. (2018) Ring Expansion of Bicyclic Methyleneaziridines via Concerted, Near-Barrierless [2,3]-Stevens Rearrangements of Aziridinium Ylides. ACS Catal 8:7907-7914|
|Schmid, Steven C; Guzei, Ilia A; Schomaker, Jennifer M (2017) A Stereoselective [3+1] Ring Expansion for the Synthesis of Highly Substituted Methylene Azetidines. Angew Chem Int Ed Engl 56:12229-12233|
|Liu, Lu; Gerstner, Nels C; Oxtoby, Lucas J et al. (2017) Fluorinated Amine Stereotriads via Allene Amination. Org Lett 19:3239-3242|
|Burke, Eileen G; Gold, Brian; Hoang, Trish T et al. (2017) Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs. J Am Chem Soc 139:8029-8037|
|Reeves, Ryan D; Phelps, Alicia M; Raimbach, William A T et al. (2017) Diastereoselective Au-Catalyzed Allene Cycloisomerizations to Highly Substituted Cyclopentenes. Org Lett 19:3394-3397|
|Gerstner, Nels C; Adams, Christopher S; Tretbar, Maik et al. (2016) Stereocontrolled Syntheses of Seven-Membered Carbocycles by Tandem Allene Aziridination/[4+3] Reaction. Angew Chem Int Ed Engl 55:13240-13243|
|Gerstner, Nels C; Adams, Christopher S; Grigg, R David et al. (2016) Diastereoselective Synthesis of the Aminocyclitol Core of Jogyamycin via an Allene Aziridination Strategy. Org Lett 18:284-7|
|Burke, Eileen G; Schomaker, Jennifer M (2015) Oxidative allene amination for the synthesis of azetidin-3-ones. Angew Chem Int Ed Engl 54:12097-101|
|Rigoli, Jared W; Weatherly, Cale D; Alderson, Juliet M et al. (2013) Tunable, chemoselective amination via silver catalysis. J Am Chem Soc 135:17238-41|
|Rigoli, Jared W; Boralsky, Luke A; Hershberger, John C et al. (2012) 1,4-Diazaspiro[2.2]pentanes as a flexible platform for the synthesis of diamine-bearing stereotriads. J Org Chem 77:2446-55|