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Efforts Towards The Synthesis Of An Htlv-1 Protease Inhibitor: Synthesis, Spectroscopic Analysis, And Computational Study Of Asymmetric Aldol Products Derived From N3-(p-Methoxyphenoxy)acetyloxazolidine-2-Thione
Date of Award
Thesis and Dissertation-ISU Access Only
Master of Science (MS)
Department of Chemistry
Shawn R. Hitchcock
The Human T-cell leukemia virus (HTLV-1) is indigenous to Japan, Melanesia, South America, the Caribbean, and sub-Saharan Africa.17 The means of transmittance includes sharing syringes, blood transfusions, from mother to child during birth, or sexual transmission. In addition to the acute T-cell leukemia, patients may suffer from inflammation of the eyes, joints, and thyroid along with infective dermatitis.
In the infected patients, the HTLV-1 protease is not produced in large quantities and therefore it makes the retrieval of viral protease difficult. With limited amounts of protease available, the potential for discovery of a protease inhibitor is hindered. A protease inhibitor could possibly alleviate some of the effects of HTLV-1. This became the inspiration for researchers to create a synthetic mimic of the HTLV-1 protease. In 2002, Saiburo Aimoto and co-workers published their work on the synthesis of an enzymatically active HTLV-1 protease via solid-phase polymer chemistry.
Now influenced by Aimoto’s accomplishment, Kenichi Akaji and co-workers were able to synthesize a protease inhibitor that successfully interacted with the Aimoto protease by building upon a titanium catalyzed aldol addition reaction through the use of cis-1-arylsulfonamido-2-indanol as a chiral auxiliary.33 Akaji and associates obtained four diastereomers after nine synthetic steps and tested all four isomers independently to determine the inhibitory activity. Fortunately, one diastereomer displayed nanomolar activity that showed promise.
After nine synthetic steps, the Akaji synthesis had an overall yield of 3.9%. The door was then opened for a novel synthesis for the HTLV-1 protease inhibitor that not only could have the potential for increased selectivity for a single diastereomer, but also have substantially higher yields and fewer synthetic steps with milder conditions. To start this synthesis, a Crimmins’ chiral auxiliary and novel glycolytic side chain needed to be investigated for their potential of high stereoselectivity by performing two series of titanium catalyzed aldol addition reactions with the same alkyl and aryl aldehydes.
The series A reactions were accomplished at -25 °C with an average yield of 73% and the series B reactions were completed at -78 °C with an average yield 73%. The selectivity for a single diastereomer averaged 73:27 for the series A reactions. The selectivity for series B had an average of 89:11 for a single diastereomer. The absolute stereochemistry was confirmed through X-ray crystallographic studies, polarimetry, and the Karplus relationship for vicinal hydrogen coupling (3J). All adducts were characterized through 1H NMR, 13C NMR, infrared spectroscopy, polarimetry, and high resolution mass spectrometry.
Throughout course of the aldol addition reactions, an anomalous hydrogen was appearing in the aromatic region of 1H NMR spectrum (~7.15 ppm) for all aldol adducts. The hydrogen appeared to be coupling with another hydrogen at approximately 5 ppm. This lead to the proposal for the synthesis of two additional aldol adducts and the computational study of select adducts to determine the source of the aromatic deshielding and the conformational arrangement that could allow this anomaly to occur. The results were tabulated and compared to the experimental 1H NMR spectrum chemical shifts.
Haynes, Craig Steven, "Efforts Towards The Synthesis Of An Htlv-1 Protease Inhibitor: Synthesis, Spectroscopic Analysis, And Computational Study Of Asymmetric Aldol Products Derived From N3-(p-Methoxyphenoxy)acetyloxazolidine-2-Thione" (2017). Theses and Dissertations. 678.
Available for download on Saturday, June 22, 2019