The diastereoselective addition of organometallic reagents to nitrones bearing carbohydrates as chiral auxiliaries was investigated. The Grignard addition to N-(2,3:5,6-di-O-isopropylidene- scD-gulofuranosyl)benzylidenamine N-oxide (1) at $-$78$\sp\circ$C has shown good to excellent diastereoselectivity. Addition products N-hydroxy-N-(2,3:5,6-di-O-isopropylidene- scD-gulofuranosyl)-(R)-alkylbenzylamine (alkyl = methyl, ethyl and benzyl; 2-4) were hydrolyzed to give corresponding (R)-alkylbenzyl hydroxylamines 5-7 in 85%, 79% and 72% yields for two steps, respectively, and in 93%, 86% and 84% enantiomeric excess, respectively. The chiral auxiliary 2,3:5,6-di-O-isopropylidene- scD-gulofuranose (8) was recovered in 75% yield from the selective hydrolysis procedure. Optically active amines 9-11 could be obtained by hydrogenolysis of 5-7 in quantitative yields. The Grignard addition to mannofuranosyl and glucopyranosyl nitrones was also studied, and low chemical yields (18% and 22%) and moderate stereoselectivities (66% and 77%, respectively) were obtained. / A new method for synthesis of hindered N-sec-alkyl-N-tert-butylamines 12 (alkyl = PhCHCH$\sb3$, 3,4-(MeO)$\sb2$PhCHCH$\sb3$ and cyclohexyl) and N-di-t-butylamine (13) was developed via organometallic addition to ketonitrones. It was found that the addition of ethereal solutions of various Grignard reagents to ketonitrones 14 in benzene solution proceeded smoothly at 0-25$\sp\circ$C, and the addition products were subsequently reduced with CS$\sb2$ to give the hindered secondary amines 12 in good overall yields. This method was also applied to synthesis of optically active hindered (R)-(+)-methyl-3,4-dimethoxybenzylamine (15). / Amine 15 derived from asymmetric synthesis and hindered amine synthesis was employed in enantioselective synthesis of simple tetrahydroisoquinolines (R)-(+)- salsolidine (16), (R)-(+)-carnegine (17) and (R)-(+)-isosalsoline (18) in 63%, 62% and 48% overall yields, respectively, via a short sequence. In the key step of acid-promoted cyclization-rearrangement of 2-diazo-N- ((R)-($-$)-methyl-3,4-dimethoxybenzyl) -N-(1,1-dimethylethyl)acetamide (19), the stereochemistry at the chiral carbon involved in the migration process was proven to be retained. / Syntheses of phosphinate-based peptide analogue inhibitors of matrix metalloproteinases (MMP) were carried out. Eighteen tri- and tetrapeptide analogue phospohinates containing either the (Gly-PO$\sb2$H)-(CH$\sb2$- scDL-Leu) or (Ala-PO$\sb2$H)-(CH$\sb2$- scDL-Leu) dipeptide surrogate functionality were synthesized. It was found from IC$\sb{50}$ measurements that the more-polar diastereomer of 3-BrNpt-(Gly-PO$\sb2$H)-(CH$\sb2$- scDL-Leu)-Trp-NHBn (3-BrNpt = 3-bromo-1,8-naphthoyl) was the most potent inhibitor against the five MMP studied: 1.3 nM for human neutrophil collagenase, 1.6 nM for human fibroblast collagenase, 1.6 nM for human neutrophil gelatinase, 7.6 nM for human fibroblast gelatinase and 100 nM for human fibroblast stromelysin. / Source: Dissertation Abstracts International, Volume: 53-04, Section: B, page: 1850. / Major Professor: Martin A. Schwartz. / Thesis (Ph.D.)--The Florida State University, 1992.
| Identifer | oai:union.ndltd.org:fsu.edu/oai:fsu.digital.flvc.org:fsu_76646 |
| Contributors | Hu, Xiufeng., Florida State University |
| Source Sets | Florida State University |
| Language | English |
| Detected Language | English |
| Type | Text |
| Format | 194 p. |
| Rights | On campus use only. |
| Relation | Dissertation Abstracts International |
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