Brønsted Acid versus Phase‐Transfer Catalysis in the Enantioselective Transannular Aminohalogenation of Enesultams

Abstract

We have studied the enantioselective transannular aminohalogenation reaction of unsaturated medium-sized cyclic benzosulfonamides by using both chiral Brønsted acid and phase-transfer catalysis. Under optimized conditions, a variety of bicyclic adducts can be obtained with good yields and high enantioselectivities. The mechanism of the reaction was also studied by using computational tools; we observed that the reaction involves the participation of a conformer of the nine-membered cyclic substrate with planar chirality in which the stereochemical outcome is controlled by the relative reactivity of the two pseudorotational enantiomers when interacting with the chiral catalyst.

Chiral non Aromatic Nitrogen-Heterocycles by Asymmetric Intramolecular Haloamination and Haloamidation

“…In alternative, also Co-complex Λ-(S,S)-169 was highly effective for iodoamidation of unsaturated hydrazones 226 carried out with DIDMH, and the corresponding 5-iodomethyl 4,5dihydro-1H-pyrazoles 227 displaying at the tertiary center the same configuration as the bromomethyl derivatives 224, were isolated in good yield and high stereoselectivity (Scheme 65) [155]. It is worth noting that some dihydropyrazoles containing a quaternary chiral center were established as potent kinesin spindle protein (KSP) inhibitors, halting the cellular mitosis [156][157]. Thus, many efforts were directed towards asymmetric iodoamidation of unsaturated arenesulfonyl hydrazones directed towards preparation of dihydropyrazoles bearing either a quaternary center and a iodomethyl functionality suitable for further transformations.…”

“…Unsaturated N-tosyl urea intermediates 258 were prepared by reaction of gem-disubstituted allylamines 257 with tosyl isocyanate and the cyclization, carried out in situ using Niodopyrrolidinone (NIPyr) in the presence of the basic Brønsted catalyst 260, gave the chiral Ntosylimidazolidin-2-ones 259 in good yield with high enantioselectivity (Scheme 77) [157]. Starting from the (Z)-allylamine 261, the cyclization proceeded in a 5-exo-mode leading to imidazolidin-2-one 262 with excellent yield and stereoselectivity, and steric bias due to the double bond configuration overwhelmed electronic factors.…”

“…On the contrary, proceeding through a 6-endomode cyclization directed by electronic factors, the (E)-allylamine 263a led to tetrahydropyrimidin-2(1H)-ones 264a in high yield and stereoselectivity, whereas amine 263b, displaying a trisubstituted double bond, gave the corresponding tetrahydropyrimidin-2(1H)-one 264b with high enantioselectivity but in low yield, probably due to the formation of a quaternary chiral center (Scheme 78) [169]. With the aim of demonstrating the usefulness of this methodology [157], the amine 265 gave in good yield and high enantioselectivity the iodomethyl derivative 266, precursor of the product SCH 388714, 267, a potent and selective NK1 receptor antagonist that is orally active and displays good CNS penetration (Scheme 79) [170]. Scheme 79.…”