Highly Diastereoselective and General Synthesis of Primary β-Fluoroamines

Abstract

A short, high yielding protocol has been developed for the highly diastereoselective (dr >20:1) and general synthesis of primary β-fluoroamines by the enantioselective α-fluorination of aldehydes, conversion into the N-sulfinyl aldimine, nucleophilic addition of various organometallic species and 1° amine liberation.

6.06 Synthesis of Fluorides

“…These α-fluoroaldehyde products can be converted to enantiopure β-fluoroamines by chiral sulfinyl imine condensation, chiral sulfinyl group-directed reduction, and deprotection of the sulfinamide to the free amine. 135 A synergistic trifunctional catalytic system combining a palladium catalyst, a chiral nucleophile, and an alkali metal catalyst was used to accomplish the enantioselective α-fluorination of acid chlorides (Scheme 36). 136 The cinchona alkaloid-based nucleophile works cooperatively with the palladium catalyst to form a chiral zwitterion amide-enolate intermediate from the acid chloride for subsequent fluorination.…”

A general, enantioselective synthesis of β- and γ-fluoroamines

“…1); however, the configurational instability of the incipient α-fluoroaldehyde required its immediate conversion to the β-fluoroamine. 7,8 Later efforts utilized a similar strategy, but employed the analogous α-chloroaldehydes, to access chiral N -terminal aziridines 15 and chiral morpholines and piperazines; 16 however, the configurational instability of the α-chloroaldehyde also necessitated immediate, one-pot use. To provide additional flexibility, we developed an approach (Fig.…”

“…7,8,18–20 Conversion to the corresponding triflate, and displacement with benzylamine delivered the desired chiral β-fluoroamines 2a–c (Scheme 2) in high yields (84–96%) and in excellent enantioselectivity (90–94% ee). In essence, this new strategy sets the key stereocenter in a conformationally stabile way, affording the β-fluoroamines with reproducibly high % ee, and higher yields than the first generation chiral β-fluoroamine route.…”

“…1–8,14 We began our attempts with a racemic 4a congener and surveyed a variety of leaving groups for cyanide displacement en route to γ-fluoroamines. Interestingly, when tosylate 6 was employed, all attempts (independent of cyanide source, stoichiometry, solvent, and temperature) afforded a 1,2-bis-cyano adduct 7 (Scheme 4).…”

Synthesis and biological evaluation of cremastrine and an unnatural analogue

“…Ultimately, good yield and moderate diastereoselectivity was observed when TBS-ether 5 was used providing 11 (85% conversion, >4:1 dr ), and the stereochemistry assigned based on the established literature precedent of a six-membered ring chelation control model. 13,14 For large scale preparations, we found that stirring and sonication of the indium metal and bromide before adding the aldimine was crucial to deliver homoallylic sulfinamide 11c with yields comparable to small-scale reactions.…”