Total Synthesis of Azumamides A and E

Abstract

Azumamide unter der Lupe (2): Im Anschluss an die effiziente Synthese zweier kürzlich entdeckter mariner Naturstoffe – Azumamid A und E – konnte die Stereostruktur der Azumamide aufgeklärt werden.

Methyl Effect in Azumamides Provides Insight Into Histone Deacetylase Inhibition by Macrocycles

“…The conformation of each analogue that best fit the NMR data was obtained from unrestrained MD simulation in explicit water, and these structures show negligible differences in the peptide backbone (Figure 3b−d) in accordance with comparable Jcouplings as well as the relative nuclear Overhauser effect (NOE) and rotating-frame nuclear Overhauser effect (ROE). The structure of compound 5a was essentially the same as the previously reported NMR structure of azumamide E (5e) determined in DMSO, 37 except for rotation of the amide between D-Ala and D-Phe (gray and purple structures in Figure 3b). We therefore determined an NOE/ROE-restrained NMR structure (cyan structure in Figure 3b), which resembled the previously reported structure of azumamde E but exhibited inferior overall fit to our NMR data compared to the unrestrained structure (Supporting Information, Tables S12 and S13).…”

“…(a) Chemical structure of compound 36 with numbering used for NMR assignments. (b) Overlay of azumamide E (5e) from the literature (purple),37 azumamide A (5a) from unrestricted simulation (gray), and azumamide A from NOE-restricted simulation (cyan); RMSD = 0.358 Å for the reported NMR structure and our unrestricted azumamide A structure. (c) Overlay of azumamide A (5a; gray) with desmethyl compound 9b (green), RMSD = 0.318 Å.…”

Natural and Synthetic Macrocyclic Inhibitors of the Histone Deacetylase Enzymes

“… Retrosynthetic analysis of azumamide A–E. The azumamides can be synthesized from three α‐amino acids and a β‐amino acid, which can be prepared from the building blocks in the dashed box (Izzo and De Riccardis, Olsen, Ganesan, Chandrasekhar).…”

“…Brown's asymmetric crotylboration reaction was utilized by De Riccardis and co‐workers as the key step to set the configuration of the β‐amino acid in their total synthesis of azumamides A and E (Scheme ). After oxidation of 3‐benzyloxypropanol ( 208 ) to aldehyde 209 , the crotylboration provided high diastereo‐ and enantioselectivity ( dr >99 %, 98 % ee ) in the formation of intermediate 210 .…”

“… Synthesis of the building block for azumamides A and E by Izzo, De Riccardis, and co‐workers . Reagents and conditions: a) (COCl) 2 , DMSO, Et 3 N, CH 2 Cl 2 , −78 °C; b) (+)‐Ipc 2 BOMe, ( E )‐but‐2‐ene, t BuOK, n BuLi, BF 3 ⋅ Et 2 O, THF, −78 °C, 5 h; c) Ac 2 O, pyridine, CH 2 Cl 2 , overnight; d) O 3 , CH 2 Cl 2 , PPh 3 , NaBH 4 , EtOH, −78 °C to RT, overnight; e) K 2 CO 3 , MeOH, RT, 24 h; f) t BuPh 2 SiCl, DMAP, pyridine, CH 2 Cl 2 , 0 °C to RT, overnight; g) MsCl, Et 3 N, THF, RT, overnight; h) NaN 3 , DMF, 60 °C, 5 h; i) H 2 , Pt 2 O, EtOAc, overnight; j) Boc 2 O, Et 3 N, CH 2 Cl 2 , RT, overnight; k) H 2 , 10 % Pd/C, EtOH, overnight; l) (COCl) 2 , DMSO, Et 3 N, CH 2 Cl 2 , −78 °C; m) KHMDS, THF, BrPPh 3 (CH 2 ) 3 CO 2 Et, −78 °C to RT, overnight; n) HF, pyridine, 0 °C, 3 h; o) TEMPO, phosphate buffer, NaClO 2 , NaClO, MeCN, 35 °C, overnight.…”