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

The synthesis of 7-membered carbocyclic ß-fluoroamines is accomplished by a combination of the enantioselective aza-Henry reaction of aliphatic N-Boc imines and ring-closing metathesis. Use of reductive denitration gives both diastereomers of the ß-fluoro amine carbocycle, each with high enantiomeric excess.

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

Attention to the aza-Henry reaction, particularly over the past two decades, has resulted in a wide range of effective catalysts for the enantio- and diastereoselective versions, driven by the versatility of the ß-amino nitroalkane products as precursors to secondary amines and vic-diamines. Despite this broad effort, syn-diastereoselective variants are exceedingly rare. We have discovered a subset of α-fluoro nitroalkane additions that are characterized by an unusual crossover in diastereoselection, often delivering the products with high selectivities. We report here a rigorous comparative analysis of non-fluorinated and α-fluoro nitroalkanes in their additions to azomethines. Both homogeneous and heterogeneous catalysis were applied to probe the possibility that this phenomenon might be more widely operative in the enantioselective additions of fluorine-substituted carbon nucleophiles. A complete correlation within four categories is described that uncovered a clear trend, while revealing a dramatic and distinct reversal of diastereoselection that would normally go undetected.