Enantioselective Total Syntheses of (+)-Castanospermine, (+)-6-Epicastanospermine, (+)-Australine, and (+)-3-Epiaustraline

Abstract

The total syntheses of the potent glycosidase inhibitors castanospermine ((+)-1), 6-epicastanospermine ((+)-2), australine ((+)-3), and 3-epiaustraline ((+)-4) are described. The syntheses of indolizidine alkaloids (+)-1 and (+)-2 were accomplished in eight steps and in 18% and 24% overall yields from 2,5-dihydrofuran while the pyrrolizidine alkaloids (+)-3 and (+)-4 were obtained in a nine-step sequence in 17% and 22% overall yields from the same starting material. These four natural products are derived from a single common intermediate, nitroso acetal (−)-31, which is created in the key step by the asymmetric tandem [4 + 2]/[3 + 2] cycloaddition between silaketal nitro olefin 18 and chiral vinyl ether (+)-23. The ability to access both 5,5- and 5,6-fused bicyclic systems was a result of a successful in situ N-alkylation strategy during the hydrogenolysis of four highly functionalized nitroso acetals. A novel silaketal tether provided exceptional levels of diastereocontrol and the ideal combination of protection and functional-group placement for the tandem nitroalkene cycloaddition process.

Are Oxazolidinones Really Unproductive, Parasitic Species in Proline Catalysis? – Thoughts and Experiments Pointing to an Alternative View

“…1, a); iii) there is only a barely detectable 1 H-NMR multiplet, which could be assigned to CH¼N(O)OR (ca. 6.5 ppm [38]), and which would have to arise from 15. Oxazolidinones derived from proline show two distinct spectroscopic features: i) The H-atom at the bridgehead between the two five-membered rings (HÀC(5)) gives rise to a typical sharp dd NMR signal between 3.8 and 4.4 ppm, depending upon the substituent(s) at C(2) and the solvent used for the measurement [5] [7] [8] [16 -19]; as the reaction of oxazolidinone 8 (HÀC (5) (Fig.…”

“…90 (2007) 436 23 ) Cf. the hetero-Diels -Alder adducts of nitro-olefins and enol-ethers [38]. 24 ) For DFT calculations of such [4 þ 2] cycloadducts (cf.…”

Asymmetric Synthesis of (−)-7-Epiaustraline and (+)-1,7-Diepiaustraline

“…[ 6,4.5 Hz),3.55 (dd,1H,J 4.2,9.6 Hz),3.47 (dd,1H,J 5.7,9.9 Hz),3.29 (ddd,1H,J 6.6,6.9,10.8 Hz),3.04 (ddd,1H,J 4.2,5.7,9.6 Hz),2.89 (ddd,1H,J 6.3,6.6,10.  7.95 (dd,2H,J 1.2,8.4 Hz),1H),2H),5H),7.21 (d,2H,J 8.7 Hz),6.84 (d,2H,J 8.7 Hz),5.16 (dd,1H,J 4.8,7.8 Hz),4.98 (ddd,1H,J 3.9,7.8,11.7 Hz),1H),4.61 (d,1H,J 12.0 Hz), 4.54 (d,1H,J 12.6 Hz),4.42 (d,1H,J 11.4 Hz),4.37 (d,1H,J 11.4 Hz),…”

Asymmetric synthesis of (+)-1-epiaustraline and attempted synthesis of australine

“…This oil was then dissolved in anhydrous pyridine (1mL) and Ac Hz, CH a CH b OAc), 3.87 (dd,1H,J 7.5,3.9 Hz,3.32 (ddd,1H,J 9.6,5.7,4.2 Hz,3.18 (dt,1H,J 11.1,7.8 Hz,2.95 (ddd,1H,J 11.1,7.2,5.4 Hz, H-5b), 2.14- 8,170.4,169.6,169.4 (4x CO),, 73.7 (CH-2), 71.7 (CH-1), 66.7 (CH-3), 65.0 (CH 2 OAc), 64.7 (CH-7a), 52.3 (CH 2 -5), 30.9 (CH 2 -6), 21.0,20.8,20.7,20.4 (4x CH 3 was added Amberlyst A-26 resin (50 mg). The reaction mixture was stirred for 2 h at RT.…”

“…5 These interesting biological properties coupled with the polyfunctional and stereochemically rich nature of these compounds have attracted the attention of synthetic chemists resulting in the total synthesis of alexine, 6 and its epimers, 6,7 australine, 8 and its epimers, [7][8][9][10][11] and casuarine. We demonstrated the viability of this synthestic methodology with the asymmetric synthesis of (-)-7-epiaustaline and (+) -1,7-diepiaustraline.…”