Chemoselective Synthesis of N‐Protected Alkoxyprolines under Specific Solvation Conditions

Abstract

N‐Protected hydroxyprolines (Hyp) were transformed chemoselectively into alkoxyproline derivatives by direct O‐alkylation. The starting Hyp was transformed into the corresponding dianion in a mixture of dimethyl sulfoxide and tetrahydrofuran (1:16 v/v) as solvent. Under these conditions, the carboxy‐anion showed reduced nucleophilicity because it was specifically solvated, and the more reactive oxy‐anion was selectively alkylated. N‐Protected trans‐4‐alkoxy‐, cis‐4‐alkoxy‐ and trans‐3‐alkoxyprolines were thus obtained in a single step in very high overall yields and with complete stability of the stereogenic center configuration.

Recyclable Mesoporous Organosilica Nanoparticles Derived from Proline-Valinol Amides for Asymmetric Organocatalysis

“…The subsequent hydrolysis of the ester by using aqueous sodium hydroxide in methanol gave the free acid 3 in 93% yield after acidic workup. A better alternative consists in the direct obtention of acid 3 from 1 in 88% yield by chemoselective O-alkylation . The amide 4 was prepared in 94% yield, through the intermediacy of a mixed anhydride, by reaction with l -valinol in the presence of triethylamine .…”

“…The organic layer was washed with brine (3 × 60 mL) and dried over Na 2 SO 4 , and the solvent was evaporated under vacuum. The acid 3 was isolated by flash column chromatography on silica gel with EtOAc/MeOH = 9:1 to afford colorless oil (8.01 g, 88% yield): [α] D 20 = −66° ( c 0.01, CH 2 Cl 2 ); 1 H NMR (360 MHz, CDCl 3 ) (mixture of rotamers) δ 10.96 (s, 1H), 7.36–7.24 (m, 5H), 5.20–5.07 (m, 2H), 4.52–4.44 (m, 1H), 4.34–4.33 (m, 1H), 4.20–4.08 (m, 2H), 3.79–3.61 (m, 2H), 2.50–2.38 (m, 2H), 2.26–2.14 (m, 1H); 13 C NMR (91 MHz, CDCl 3 ) (mixture of rotamers) δ 177.7, 176.5, 155.6, 154.5, 136.2, 136.1, 128.4, 128.2, 127.99, 127.64, 79.14, 79.12, 76.2, 75.6, 75.2, 67.7, 67.4, 57.99, 57.54, 56.48, 56.45, 51.69, 51.62, 36.6, 35.1.…”

“…A better alternative consists in the direct obtention of acid 3 from 1 in 88 % yield by chemoselective O-alkylation. 77 The amide 4 was prepared in 94% yield, through the intermediacy of a mixed anhydride, by reaction with Lvalinol in the presence of triethylamine. 33 A copper-catalyzed alkyne azide cycloaddition reaction (CuAAC) 78,79 of the alkyne 4 with (3-azidopropyl)-triethoxysilane 5 under anhydrous conditions 80 provided quantitatively the dipeptide 6.…”

DBU Catalysed Enantioselective Degradative Rearrangement: a Way to Tetrasubstituted 2‐Aryl‐2‐Amino Esters

“…In particular, in the experiment conducted in DME in the presence of 1 mol equiv. of DMSO, under “specifically solvation” conditions, [12] the reactivity of 2 a increased, but the process was less enantioselective (entry 4). Operating with catalytic DBU and a stoichiometric amount of either triethylamine (TEA) (entry 5) or solid‐anhydrous Na 2 CO 3 (entry 7), under solid‐liquid (SL) heterogeneous conditions, results analogous to those obtained using excess DBU were reached.…”

“…The characterization of the lower liquid phase was consistent with the formation of a DBU‐onium ionic‐liquid [3aSO 2 ] − [DBUH] + (Scheme 1), in agreements with the literature data regarding the ionic‐liquids formation by DBU trapping of SO 2 [13] . On the basis of these evidences and of the ions‐pairs reactivity under specific solvation conditions, [14] we could assume that at first 2 a forms the DBU‐stabilized enol ‐ 2 a , which rapidly rearranges to the stable ionic‐liquid [3aSO 2 ] − [DBUH] + that, in turn, exchanges its cation with Na 2 CO 3 . Finally, the unstable sodium intermediate forms the product 3 a by loss of SO 2 and protonation.…”