Solid-phase synthesis of fused 1,4-diazepanone peptidomimetics via tandem N-iminium ion cyclization–nucleophilic addition

Scaffold Diversity from N-Acyliminium Ions

“…Iron chloride, indium trichloride, and indium tribromide were used as Lewis acids to promote the double cyclization process (Scheme 10). 71 Hanessian and co-workers reported the synthesis of enantiopure, 6-substituted octahydroindole (31,33) and hexahydroindole (35) 2-carboxylic acid methyl esters through N-Boc acyliminium ions derived from 4-ω-butenyl and butynyl N-Boc L-pyroglutamic acid esters. 72,73 The terminal alkene tethers of 30 and 32 and the alkyne tether of 34 are potential πnucleophiles that attack the cationic NAIs formed in the presence of Lewis acids including tin(II) halides and BF 3 •OEt 2 .…”

“…It must be mentioned that a plethora of intermolecular NAI reactions, typically deriving from hydroxylactams or other NAI precursors, − have been reported in the past decade. It is also noteworthy that a range of NAI cyclization reactions have been demonstrated on solid supports, especially for the synthesis of peptides and constrained peptidomimetics, but many of these reactions have been reviewed elsewhere. − …”

Solid-Phase Synthesis of Seven-Membered Heterocycles with Two Nitrogen Atoms

“…The diazepanones 270 were obtained in limited yield [105]. When the use of TES was omitted, the cleavage yielded the corresponding unsaturated diazepines [106].…”

Traceless Solid-Phase Synthesis of [6,7,8 + 5,6,7]-Fused Molecular Frameworks

“…Recently, our group reported a synthetic strategy enabling the incorporation of bicyclic scaffolds as peptide constraints during traditional peptide synthesis. The synthesis of bridged 6-oxa-3,8-diazabicyclo[3.2.1]octan-2-ones [ 31 ], fused tetrahydropyrazino[2,1- b ][1,3]oxazine-4,7(6 H ,8 H )-diones X (X = O, n = 1) [ 32 ], hexahydro-4 H -pyrazino[1,2- a ]pyrimidine-4,7(6 H )-diones X (X = NR 3 , n = 1) [ 32 ] and hexahydropyrimido[1,2- d ][ 1 , 4 ]diazepine-4,7(1 H ,6 H )-diones X (X = NR 3 , n = 2) [ 33 ] were performed via westbound direction (towards the amino terminus) N -acyliminium cyclization–nucleophilic addition with Ser, Thr and 2,4-diaminobutyric acid as the sources of oxygen, sulfur and nitrogen nucleophiles, respectively. The solid-phase synthesis of tetrahydro-2 H -oxazolo[3,2-a]pyrazine-5(3 H )-ones IV (R 2 = H) [ 34 ] was carried out via eastbound direction (towards the carboxyl terminus) cyclization, and the scope of this synthetic strategy was expanded recently to yield [7,8,9 + 5]-fused rings from Ser, Cys and C-nucleophiles (structure XI ) [ 13 ].…”