Doctor of Philosophy (PhD)



Document Type



This dissertation describes the first total synthesis of alloviroidin in trace amounts, along with that of three analogs containing L-proline (Pro), trans-3-hydroxyproline (3-Hyp) or cis-4-hydroxyproline (4-hyp) residue substituting for 2,3-trans-3,4-trans-dihydroxyproline in the natural product. We report herein an efficient strategy that provides a dipeptide containing a (2S,4S)-4,5-dihydroxyleucine (dihyLeu) residue, including a diastereoselective dihydroxylation. Nα-Carbobenzyloxy-(2S)-4,5-dehydroleucine was coupled with valine ethyl ester to give a dipeptide that was subjected to a Sharpless asymmetric dihydroxylation to introduce the diol. The relative configuration at C4 was assigned as S by X-ray crystallography after derivatization as an α-amino-γ-lactone hydrochloride salt. The preparation of the 2-(methylsulfonyl)tryptophan residue is described followed by incorporation into a tetrapeptide, Fmoc-Ala-[2-MeSO2]-Trp-diHyLeu(OTBS)-Val-OEt. An efficient synthesis of four tripeptide fragments is also described: Fmoc-D-Thr(OTBS)-D-Ser(OTBS)-Pro*-OBn, where Pro* represents Pro, 3-Hyp, 4-hyp and DHP. These tripeptides were assembled via a [2+1] coupling between Fmoc-D-Thr(OtBu)-D-Ser(OtBu)-OH and the appropriate proline benzyl ester. The acid labile side-chain protecting groups were swapped out for fluoride-labile silyl ethers. Linear heptapeptides were prepared via [3+4] fragment condensations between the series of four tripeptide acids Fmoc-D-Thr(OTBS)-D-Ser(OTBS)-Pro*-OH and the tetrapeptide amine H-Ala-[2-MeSO2-Trp]-diHyLeu(OTBS)-Val-OEt. Deprotection of the N- and C-terminii, followed by cyclization and global side chain deprotection generated our target cyclopeptides. Removal of excess TBAF reagent and salts formed as byproducts during ethyl ester and silyl ether deprotections was achieved by treatment with DOWEX 50WX8-400 H+ resin and calcium carbonate. This procedure led to reasonable yields of the three analogs but afforded only trace amounts of the natural product after HPLC purification. We examined the conformational preferences of dipeptide fragments Ac-D-Ser-Pro*-NHMe (in both free and TBS protected side chains of D-Ser and Pro* residues) using computational studies. The computational analyses confirm that the ratio of trans:cis conformers varies with the degree, regio- and stereochemistry of proline hydroxylation. These equilibrium constant about the prolyl amide bond calculated for these dipeptides are in qualitative agreement with those determined by NMR for tripeptides Fmoc-D-Thr-D-Ser-Pro*-OBn (in both free and TBS protected side chains).



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Committee Chair

Taylor, Carol

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Chemistry Commons