A stereoselective approach to polyhydroxylated L-Choi derivatives has been developed. The oxidative cyclization of L-tyrosine was optimized to avoid partial racemization and to allow a more efficient scale-up.Aeruginosin 298-A (1, Figure 1) is a serine protease inhibitor that was isolated from a fresh water blue green algae in 1994. 1 Approximately sixteen members of the aeruginosin family have been identified, and fourteen share the unusual bicyclic amino acid L-Choi [(2S,3aS,6R, 7aS)-2-carboxy-6-hydroxyoctahydroindole] or a close derivative as a common motif. 2 L-Choi is an example of the growing class of sterically encumbered proline analogues that exert a profound influence on the secondary structure when embedded in oligopeptide sequences. Several synthetic approaches to Choi and aeruginosin natural products have been reported. 3 Many other natural and synthetic compounds contain fused bicyclic scaffolds that closely resemble Choi. 4 The naturally occurring di-, tri-and tetrahydroxylated indolizidine alkaloids, lentiginosine (an amyloglucosidase inhibitor), swainsonine (an α-mannosidase inhibitor), and castanospermine (2, an α -glucosidase inhibitor; analog 3 4f ) are particularly noteworthy ( Figure 1). Parkacine (4) is an alkaloid from Amaryllis belladonna var blanda Brunsvigia josephinae. The significance of these fused bicyclic scaffolds for biologically active natural products has inspired the development of novel chemical libraries. 5 Our initial studies toward L-Choi derivatives centered around the oxidative cyclization of Ltyrosine previously developed in our laboratory. 3n,6 Although this oxidation was originally performed in methanol and subsequently nitromethane, a 3:1 mixture of acetonitrile:isopropanol has proven more successful upon scale-up (Scheme 1). This optimized procedure led to spirocycle 6 in 42% yield and >99% ee. Subsequent methanolysis of the pwipf@pitt.edu. Supporting Information Available: Experimental procedures for compounds 9, 10, 12, 14, 15, 17-20, copies of 1 H and 13 C NMR spectra for 6, 7, 9, 10, 12, 14-21, and CIF files for 14 and 18. This material is available free of charge via the Internet at http://pubs.acs.org. spirocycle was performed according to a literature procedure. 6 While at first not immediately apparent, we came to realize that the conversion of the spirocycle 6 to hydroxyhydroindole 7 ocurred in a mediocre 53% ee (Table 1, entry 1). This partial racemization is likely to occur at the lactone stage prior to methanolysis. We screened a variety of bases and measured product ratios and enantiomeric excess by chiral HPLC analysis. Stronger bases and/or extended reaction times gave products with further deteriorated enantiomeric purity, while weak bases promoted only spirocycle opening to generate hydroxydienone 8. Gratifyingly, lowering the reaction temperature and using NaOMe had a beneficial effect, providing 7 in 87% ee (Table 1, entry 11). Addition of water and switching the base to KOH not only improved the ee further to 97%, but also decrea...
The synthesis of a discovery library of 80 3,4-dehydroproline amides was achieved in a four-step reaction sequence from easily accessible 3-aminoallene-3-carboxylate methyl esters. Diversification of these proline mimics was introduced at five different sites: the substituents at the 3-pyrroline unit (R1, R2, R3), at the nitrogen (R4), and the C-terminus (R5). The 3-pyrroline scaffold was synthesized in excellent yields by a silver-catalyzed intramolecular cyclization of aminoallenes, followed by N-functionalization reactions. Maximum diversity was introduced in the final step of the reaction sequence by taking advantage of the carboxylic acid handle of the 3-pyrroline subunit. Amide coupling reactions using polystyrene-carbodiimide (PS-carbodiimide) and 1-hydroxybenzotriazole (HOBt) under microwave irradiation led to 3,4-dehydroproline amides that were obtained in purities greater than 85% by LC/MS/ESLD after scavenging the excess HOBt on a silica-bound carbonate SPE cartridge.
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