Synthesis of the orthogonally protected amino alcohol Phaol and analogs

Abstract

The development of a multigram synthesis of the orthogonally protected amino acid-derived Phaol [2-{[(2S)-2-amino-3-phenylpropyl]amino}ethanol] is described. The goal of this work is to synthesize an orthogonally protected Phaol in a multigram scale up to 10 g (Cbz-Phaol), so it can be used in solution-based peptide synthesis of peptaibols. Two synthetic schemes were proposed and examined. Between the reduction-coupling and the coupling-reduction scheme, the latter gave the best results. A two-step synthesis affords easily purifiable products. Several analogs were synthesized using this methodology. All the molecules were orthogonally protected, so that they can be used in peptide synthesis. Deprotection posed no problems.

Tetrahydro-4H-(pyrrolo[3,4-d]isoxazol-3-yl)methanamine: A Bicyclic Diamino Scaffold Stabilizing Parallel Turn Conformations

“…The solvent was removed under reduced pressure, and the crude product was crystallized from hexane/AcOEt (12:1), affording compound 5 (1.5 g, 5.85 mmol, 97% yield) as a white solid: TLC hexane/AcOEt, 7:3; R f 0.18; mp 92 °C; [α] D 20 −28.5° ( c 0.6, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) δ 7.32–7.20 (m, 5H), 4.80 (br s, 1H), 3.86 (br s, 1H), 3.66–3.63 (m, 1H), 3.55–3.52 (m, 1H), 2.83 (d, J = 7 Hz, 2H), 2.08 (br s, 1H), 1.41 (s, 9H) ppm; MS (ESI) m / z calcd for C 14 H 21 NO 3 251.15, found 274.40 [M + Na] + . The analytical and spectroscopic data are in agreement with the literature data …”

Total Synthesis of Septocylindrin B and C-Terminus Modified Analogues

“…In this case, the Lewis acid ZnBr 2 was used [9]. The secondary amine and the alcohol of the Phaol residue were both protected with a Boc group, as described by Nelissen et al [6], and deprotected using BiCl 3 [10]. The glutamic acid residues were used as γ-methyl esters (residue Q* in Figure 2) and subsequently converted to glutamine by treatment with NH 3 .…”

“…After the successful synthesis of Septocylindrin B, several analogues were synthesized, characterized by the modified Phaol moieties described by Nelissen et al [6] (Figure 4). Crisma et al [11] investigated the influence of the replacement of Gln by Glu(OMe) in Alamethicin.…”

“…In view of a total synthesis of these peptides, orthogonally protected Phaol is needed in large amounts. In 2011, Nelissen et al [6] presented a procedure for the large scale synthesis of orthogonally protected Phaol and analogues thereof. The goal of the present work is to exploit these newly synthesized amino alcohol moieties to accomplish the total synthesis of Septocylindrin B and analogues via a segment condensation approach.…”