Stereoselective Synthesis of α-Fluoro-γ-nitro Thioesters under Organocatalytic Conditions

Abstract

Fluorinated monothiomalonates (F-MTMs) were used as building blocks for the stereoselective synthesis of organofluorine compounds. We present conjugate addition reactions between F-MTMs with nitroolefins that proceed under mild organocatalytic conditions and provide access to α-fluoro-γ-nitro thioesters with adjacent tetrasubstituted and tertiary stereogenic centers. Only 1 mol % of a cinchona alkaloid-urea catalyst is necessary to obtain the addition products in excellent yields and stereoselectivities. The methodology allowed for the straightforward synthesis of a fluorinated analogue of the PAR-2 agonist AC-264613.

Organocatalyzed Diastereo‐ and Enantioselective Conjugate Addition of Nitroalkanes to β‐Silylmethylene Malonates: Direct Access to Enantioenriched Organosilanes

“…The synthesis of sila‐analogue 13 of AC264613 was achieved in two steps starting from the acid 5 (Scheme ). The reaction of 5 with N‐hydroxysuccinimide (NHS) and diisopropylcarbodiimide (DIPC) produced in situ NHS ester which upon reaction with hydrazine hydrate yielded hydrazide 12 . Subsequent condensation of 12 with 3'‐bromoacetophenone in presence of catalytic amount of acetic acid in methanol furnished the sila‐analogue 13 of AC264613 (Scheme ).…”

Recent Advances in Asymmetric Organocatalyzed Conjugate Additions to Nitroalkenes

“…Such thioesters are more labile than the corresponding esters and hence easier to be further transformed. In fact, after the reduction of the nitro group, the corresponding fluorinated lactams were synthesized in straightforward way [ 135 ].…”

Synthesis of Monothiomalonates – Versatile Thioester Enolate Equivalents for C–C Bond Formations

“…Among the most straightforward methods are C–C bond formations that utilize thioester enolates . [ ][ ] The formation of thioester enolates under mild conditions is not trivial due to the comparatively low acidity of the H‐atom at the α ‐carbon (C( α )) combined with the reactivity of thioesters towards nucleophilic bases . Organocatalytic methods that use surrogates of thioester enolates have therefore become popular for the stereoselective incorporation of thioester moieties into organic molecules.…”

“…Organocatalytic methods that use surrogates of thioester enolates have therefore become popular for the stereoselective incorporation of thioester moieties into organic molecules. [ ][ ][ ]…”

“…Moreover, MTMs bearing a removable protecting group on the oxoester moiety allow for a controlled addition reaction and subsequent decarboxylation upon removal of the protecting group. Organocatalytic addition reactions between MTMs and electrophiles proceed therefore in the presence of low catalyst loadings (1 – 5 mol‐%) and provide the corresponding addition products in enhanced yields and stereoselectivities compared to reactions with MAHTs . The addition products, among which γ ‐nitrothioesters, β ‐amino thioesters, indoles, dihydrocoumarins and dihydroquinolinones, and oxindoles, [ ][ ] contain aside from the thioester orthogonally addressable functional groups and are therefore valuable synthetic building blocks.…”