Hydroarylation of Substituted Norbornene Amino Acids: Studies on Long-Range Stereo-Electronic Effects on the Regioselectivity of the Addition

2-Amino-3-(phenylsulfanyl)norbornane-2-carboxylate: An Appealing Scaffold for the Design of Rac1–Tiam1 Protein–Protein Interaction Inhibitors

“…According to the retrosynthetic scheme and operating on the diastereoisomeric mixture of 4 and 5 , we functionalized the C5–C6 double bond by means of a Pd-catalyzed hydroarylation with 3-iodoaniline in the presence of Pd(OAc) 2 /Ph 3 P/TEA/HCOOH in MeCN at reflux (Scheme ). Only compounds 8 and 9 were obtained in satisfactory yields (75%) and were identified as the two regioisomers deriving from the hydroarylation of 4 at C5 or C6, respectively, with the coupling at C5 being favorite . The stereo- and regiochemistry were assigned by NMR (Figure S4, Supporting Information) and by comparison with similar compounds previously reported .…”

“…Exploiting our synthetic experience in the field of cycloaddition reactions − and Pd-catalyzed reactions, , we planned to build the norbornane ring by a Diels–Alder reaction between cyclopentadiene and the opportune dienophile. Then functionalization of norbornene at C5 or C6 through a Pd-catalyzed hydroarylation, followed by a Buchwald amination, could afford the nitro precursor which could be easily reduced to the desired products.…”

Identification of the first enantiopure Rac1–Tiam1 protein–protein interaction inhibitor and its optimized synthesis via phosphine free remote group directed hydroarylation

“…Fig. 3 Umpolung conversion of nitro-to amino group to modulate the long range effect on the hydroarylation reaction, (*data for regioselectivity in NBoc protected norbornene have been previously reported 12,14 ).…”

“…Our previous studies 14,25 disclosed that the regioselectivity is mainly driven by a long range effect exerted by the nitro group on C-2, (Path a, Fig. 3).…”

“…Firstly, the hydroarylation reaction was performed in a classical way in the presence of Ph 3 P and an excess of iodoarene (3 equiv.) which gave the C-6 arylated isomer, precursor of AR-148, as the minor isomer (3 : 4 = 70 : 30) 14 (Fig. 1c).…”