Stereoselective synthesis of hydroxylated 3-aminoazepanes using a multi-bond forming, three-step tandem process

Abstract

Stereoselective synthesis of hydroxylated 3-aminoazepanes using a multi-bond forming, three-step tandem process. Organic & Biomolecular Chemistry , 10 (41 A multi-bond forming, three-step tandem process involving a palladium(II)-catalysed Overman rearrangement and a ring closing metathesis reaction has been utilised for the efficient synthesis of a 2,3,6,7-tetrahydro-3-amidoazepine. Substrate directed epoxidation or dihydroxylation of this synthetic intermediate has allowed the diastereoselective synthesis of hydroxylated 3-aminoazepanes including the syn-diastereomer of the balanol core. Asymmetric synthesis of the 2,3,6,7-tetrahydro-3-amidoazepine 10 motif was also achieved using a chiral palladium(II)-catalyst during the Overman rearrangement.

Pyrrole‐Based Macrocyclic Small‐Molecule Inhibitors That Target Oocyte Maturation

“…Then, tert ‐butyloxycarbonyl (Boc) group protection of the secondary amine was performed using (Boc) 2 O in the presence of triethylamine and 4‐dimethylaminopyridine (DMAP). To recover the hydroxy functional group, deprotection of the primary alcohol was effected in the presence of tetra‐ n ‐butylammonium fluoride (TBAF) in tetrahydrofuran (THF) to yield alcohol 21 …”

“…To recover the hydroxy functional group, deprotection of the primary alcohol was effectedi nt he presenceo ft etra-n-butylammoniumf luoride (TBAF) in tetrahydrofuran (THF) to yield alcohol 21. [14] Alcohol 21 was then phosphorylated with dibenzyl-N,N-diisopropylphosphoramidite in the presence of 1H-tetrazole, and subsequento xidation in the presenceo fmeta-chloroperoxybenzoica cid (mCPBA) resulted in the benzyl-protected phosphoryl ester 22. [11] Finally,t rifluoroacetic acid (TFA)-mediated Boc deprotection of the secondary amine resulted in formation of the desired precursor 11.A fter the successful synthesis of precursors 10 and 11,o ur next objectivew as to enablet he amide coupling reactionu sing 2-(1H-benzotriazol-1-yl)-1,1,3,3tetramethyluronium hexafluorophosphate (HBTU) and N,N-diisopropylethylamine( DIEA) in DMF to afford diene 23 in good yield (Scheme 4).…”

One-Pot Multi-Reaction Processes: Synthesis of Natural Products and Drug-Like Scaffolds

“…Directed epoxidation and regioselective reduction of azepane 28 followed by deprotection gave amino alcohol 29, the syn-stereoisomer of the core of balanol, a fungal metabolite and a potent inhibitor of human protein kinase C. 31 4 and TMEDA gave the all-syn-3-amidoazepane-4,5-diol as a single stereoisomer. Deprotection then gave 30 in high overall yield.…”

“…For example, hydroxylated 3-aminoazepanes, motifs found in natural products and medicinal agents, were prepared by using a combination of the one-pot multi-reaction process and directed oxidations. 31 Initially, 2-aminoethanol (26) was converted into the allylic alcohol 27 in seven steps and 53% overall yield by using a strategy involving alkylation of the amine with 4-bromobut-1-ene, followed by extension of the carbon chain using a one-pot Swern oxidation and a Wittig reaction (Scheme 11). Conversion of alcohol 27 into the allylic trichloroacetimidate, followed by the one-pot Overman rearrangement and RCM reaction with Grubbs' second-generation catalyst gave azepane 28 in 79% yield over the three steps.…”

Chemoenzymatic Synthesis of Substituted Azepanes by Sequential Biocatalytic Reduction and Organolithium-Mediated Rearrangement

“…Molecules incorporating 7-membered heterocyclic rings, particularly azepanes and benzazepines, find many applications in medicinal and pesticidal chemistry . Azepanes display activity as glycosidase inhibitors, − norepinephrine and dopamine transporters or protein kinase C inhibitors, and are promising candidates for the treatment of viral infections, diabetes or cancer. ,, Natural products and medicinal agents incorporating the azepane ring (Scheme a) include balanol, zilpaterol, azelastine, capuramycin , and Stemona alkaloids . Azepane 1 is a potential therapeutic agent against cancer, and 2 is an inhibitor of NET/DAT .…”