Fluorine-induced diastereodivergence discovered in an equally rare enantioselective syn-aza-Henry reaction

Abstract

A comparison of enantioselective aza-Henry reactions with both non-fluorinated and α-fluoro nitroalkanes reveals an unusual reversal of diastereoselection favoring the rare syn-aza-Henry product as a result of fluorine-based diastereodivergence.

Secondary Orbital Effect Involving Fluorine is Responsible for Substrate‐Controlled Diastereodivergence in the Catalyzed syn‐aza‐Henry Reaction of α‐Fluoronitroalkanes

“…We recently reported a subset of catalyzed aza-Henry reactions whose diastereoselection diverged, not depending on a change of catalyst, but instead on the absence or presence of fluorine at the nitronate nucleophilic carbon (Scheme 2A, Equation ( 2)). [10] That study outlined an apparent hierarchy, in which the combination of aryl and fluorine substitution at the nitronate carbon led to anti-adducts (Scheme 2, Equation (1), Types I-II), while alkyl and fluorine substitution led to the unusual syn-adducts (Scheme 2, Equation ( 2), Types III-IV). The unusual effect of an α-fluorine on nitroalkane acidity has long been known, [11,12] but its role in the facial selectivity of nitronates is a new discovery.…”

Enantioselective Synthesis of cis- and trans-Cycloheptyl β-Fluoro Amines by Sequential aza-Henry Addition/Ring-Closing Metathesis

“…31d Once optimized, this addition led to a good yield (83%) of α-fluoro-β-aminonitroalkanes 2. The major addition product (8.8:1 dr) was determined to be the less common syn-diastereomer, 30,31 as we recently noted in a more general study, 35 produced in high enantiomeric excess (94% ee). Importantly, the minor antidiastereomer was produced in 90−92% ee.…”

“…39 A chiral bis(amidine) (BAM) catalyst was applied to the aza-Henry step, leading to the β-amino-αfluoronitroalkane in 76% yield and good stereoselection (8:1 dr, 92% ee (major)). 35 Notably, only 1.2 equiv of the nitroalkane were needed to achieve good yield. The adduct was immediately subjected to RCM, providing benzocycloheptene 11 in 97% yield.…”

“…This procedure followed the approach for 8 , except for the preparation of the α-amido sulfone 9 from ortho -vinyl benzaldehyde . A chiral bis­(amidine) (BAM) catalyst was applied to the aza-Henry step, leading to the β-amino-α-fluoronitroalkane in 76% yield and good stereoselection (8:1 dr, 92% ee (major)) . Notably, only 1.2 equiv of the nitroalkane were needed to achieve good yield.…”

Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis

“…While they can be prepared using chiral auxiliaries, catalytic asymmetric methods are underdeveloped. , Tertiary nitroalkanes can be easily converted to the corresponding amines through nitro group reduction. Consequently, methods for preparing tertiary nitroalkanes stereoselectively are highly attractive but underdeveloped, typically involving transition metal-catalyzed allylic alkylation or organocatalytic Michael additions and Aza-Henry reactions …”