Graduation date: 1994

For years now, opium alkaloids and morphinans have been attractive synthetic targets for numerous organic chemists due to their important biological activity and interesting molecular architecture. Morphine is one of the most potent analgesic drugs used to alleviate severe pain. Our research group maintains a longstanding interest in tandem pericyclic reactions such as the oxy-Cope/Claisen/ene reaction cascade and their application to the total synthesis of complex natural products. Herein we report the ventures towards the formal synthesis of (+/-)-morphine based on the novel tandem oxy- Cope/Claisen/ene reaction developed in our laboratory. These three highly stereoselective pericyclic reactions occurring in a domino fashion generate the morphinan core structure after only 7 steps from commercially available material. The formal synthesis culminated in the production of a formal intermediate after a total of 18 linear steps, with an overall yield of 1.0%, successfully intersecting two previous syntheses of the alkaloids, namely the ones of Taber (2002) and Magnus (2009).

A synthetic approach toward the two major fragments of cathedulin K-19, euonyminol (4) and dimethyl cathate (69), was investigated. Synthesis of dimethyl cathate was accomplished in 3 steps starting from 73. Efforts directed towards the synthesis of euonyminol, a highly oxygenated dihydroagarofuran sesquiterpene, was advanced to a stage in which most of the A ring of 4 was completed. Compound 79 was used as a starting material which was obtained from a Diels-Alder reaction of 80 and 81. Subsequent bromination of 79 and elimination of hydrogen bromide afforded 93 in a one-pot operation. A remarkable chemo- and stereoselective reduction of 93 under Luche conditions gave 94 and the latter was epoxidized stereoselectively by m-chloroperbenzoic acid to yield 91. Introduction of an isopropenyl moiety to 91 was accomplished following Liotta's protocol to provide 145. Vanadium catalyzed epoxidation installed the epoxide moiety of 152a with good stereoselectivity. Two approaches towards 4 from the key intermediate 152a were pursued. The first approach entailed the epoxide cascade reaction of 152a. Treatment of 152a with trifluoro- or trichloroacetic acid afforded 165 and 166, respectively, which possessed most of the functionality required for 4. The second route to 178 proceeded in 5 steps from 152a. Treatment of 152a with titanium tetraisopropoxide afforded 168, which was cyclized to 169 under acid catalysis. The diol moiety of 169 was protected as a benzylidene acetal and subsequent hydroxylation following Davis' procedure afforded 171. Stereoselective reduction of 171 using lithium aluminum hydride in the presence of titanium tetraisopropoxide provided 178. / Graduation date: 1994

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Thesis (M.S.)--University of Florida, 2006. / Title from title page of source document. Document formatted into pages; contains 68 pages. Includes vita. Includes bibliographical references.

Thesis (Ph. D.)--OGI School of Science and Engineering at OHSU, 2001.

Nowadays, both secondary and tertiary amines are playing vital roles in modern chemical industry as well as pharmaceutical industry. Various synthetic methods of amines have also been reported due to their promising applications. In this thesis, a simple and widely applicable one-pot aza-Wittig/reduction method is reported for synthesizing both secondary and tertiary amines. Firstly, we focused on tandem aza-Wittig/reduction reactions for synthesizing secondary amines. We noticed that an aza-Wittig reaction involving an iminophosphrane which is the product from a Staudinger reaction, followed by addition of an aldehyde can be used to construct a C=N double bond in the product. By making use of the PPh3O (byproduct of aza-Wittig reactions) as the catalyst along with trichlorosilane as the reducing agent, the imine products in the aza-Wittig reactions can be converted into amines in one pot. In addition to using PPh3, highly-efficient heterogeneous polystyrene-based rasta resin-supported PPh3 was also examined in our study. Secondly, in order to broaden the utility of this one-pot method, instead of using relatively dangerous organic azides as substrates, in situ azide formation reaction was added to the flow chart. By reacting alkyl bromides with sodium azide or tertabutylammonium azide can give various azides in one-pot. Thirdly, the secondary amines formed using our one-pot procedure can undergo reductive amination reaction with aldehyde to give diverse tertiary amines as the final products in one pot. In this reaction, trichlorosilane reduction was performed twice by utilizing the phosphine oxide byproduct from the aza-Wittig reaction as a catalyst. Finally, chemistry regarding tandem one-pot aza-Wittig reaction by using catalytic amount of phosphine oxide was discussed. Instead of using organic azides, various aryl isocyanates were used as substrates for the reaction, with the help of catalytic amount of a five-membered ring phosphine oxide to give high yields of secondary amines. Chemistry studied in the thesis stands as solid proof for the superiority of our method. Tandem one-pot reactions improved the efficiency of our method by avoiding lengthy workup and purification steps. Our chemistry may serve as a good alternative for both secondary and tertiary amine synthesis in the future. / published_or_final_version / Chemistry / Master / Master of Philosophy

Landmark advances in the field of synthetic protein chemistry have enabled the preparation of complex, homogeneous proteins, including those that carry specific posttranslational modifications (PTMs). In addition, chemical synthesis will allow one to incorporate unnatural elements to generate new biologics with altered properties and functions. Native chemical ligation (NCL) is a milestone in the chemical synthesis of proteins (Kent et al., Science, 1994, 266, 776-779), in which a C-terminal peptide thioester and an N-terminal cysteine (Cys)-containing peptide-both in side-chain unprotected forms-are selectively coupled to generate a natural peptidic linkage at the site of ligation. This method requires a cysteine at the optimal convergent ligation site. However, Cys is one of the least abundant amino acids in natural proteins. Therefore, the development of new ligation methods at other amino acids will be necessary and important in this regard. Along these lines, our laboratory has developed a novel thiol-independent approach-serine/threonine ligation (STL). It uses the N-terminal serine or threonine of a peptide segment to chemoselectively react with another peptide segment with a C-terminal salicylaldehyde ester to form an N,O-benzylidene acetal linked product, followed by acidolysis to afford the final product at the natural Ser/Thr site. To extend the application of STL in chemical protein synthesis, we have developed a robust method for the preparation of peptide salicylaldehyde esters via Fmoc-based solid phase peptide synthesis. Furthermore, we have successfully applied this ligation method in the convergent synthesis of peptide drugs of significant therapeutic importance, including Teriparatide (Forteo), Corticorelin (oCRH), Exenatide (Byetta) and Tesamorelin (hGHRH). Of significance, we have demonstrated the effectiveness of our STL in the assembly of a more complex target of biological interest: human erythrocyte acylphosphatase (~ 11 kDa). In summary, we have developed a new serine/threonine ligation, which can be effectively used to synthesize peptides and proteins. As there are countless serine and threonine residues in natural proteins, particularly those carrying posttranslational modifications, this method is anticipated to offer new opportunities in synthetic protein chemistry and chemical biology. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Head-to-tail cyclic peptides with a wide range of ring sizes have been discovered in various organisms including bacteria, fungi, plants and animals. Many of them exhibit remarkable biological activities with high potency. Daptomycin, a cyclic lipodepsipeptide isolated from soil bacteria Stretomyces roseoporus, is the first natural product antibiotic launched in a generation. Daptomycin has potent bactericidal activity against otherwise antibiotic-resistant Gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and vancomycin-resistant S. aureus. Daptomycin contains a 31-membered ring made up of 10 amino acids and a linear 3-amino acid side chain modified with an n-decanoyl lipid at the N-terminus. The complex structure of daptomycin, the presence of two non-proteinogenic amino acids (kynurenine and 3-methyl glutamic acid) and the macrolactamization of a 31-membered ring render daptomycin a challenging target for total synthesis. We recently developed a chemoselective serine/threonine ligation (STL) allowing peptide ligation at Ser/Thr site using side chain unprotected segments. We have successfully applied STL intramolecularly in the key cyclization step for the synthesis of daptomycin molecule, which allows us to finally achieve the first total synthesis of daptomycin. With this technique in hand, the chemical synthesis of daptomycin analogues, which are difficult to obtain otherwise becomes possible and is now ongoing. This would allow for the search for optimized analogues. We further investigated if STL could be applied for the synthesis of cyclic tetrapeptides, which are extremely difficult to be synthesized in the absence of turninducing components due to their rigid structural framework. To our delight, a series of cyclic tetrapeptides without any turn-inducing component, like Gly, Pro or Damino acids have been successfully synthesized by intramolecular STL. The synthesis of cyclic tetrapeptides with drug-like scaffold would be useful for the therapeutic development. We also applied intramolecular STL to successfully synthesize some natural cyclic peptides with different ring sizes, including anticancer stylopeptide 1, phakellistatin 4 and anti-inflammatory cyclosquamosin D. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy