Efficient synthesis of an optically pure β-bromo-β,β-difluoroalanine derivative, a general precursor for β,β-difluoroamino acids

An intermediate in a new synthesis approach to β-substituted β-hydroxyaspartame

“…The N atom of the future amine function is involved in a Schiff base with an E con®guration at the C1 H N1 bond. This E con®guration was also found in the X-ray structure of several similar Schiff bases (Laue et al, 2000;Thieme et al, 2000;Katagiri et al, 2001). As shown by the C2ÐN1ÐC1 H ÐC2 H and C2ÐN1ÐC1 H ÐC6 H torsion angles [175.9 (3) and À0.1 (5) , respectively], the geometry of the double bond is slightly distorted.…”

Facile Synthesis of Chiral α‐Difluoromethyl Amines from N‐(tert‐Butylsulfinyl)aldimines

“…However, the general and efficient asymmetric synthesis of α‐difluoromethyl amines still remains a challenge although it has drawn many synthetic endeavors 9–12. 14 The asymmetric hydrogenation of fluorinated imines are usually difficult, and recently Uneyama and co‐workers reported that the palladium‐catalyzed asymmetric hydrogenation of difluoromethyl imino esters proceeded with poor enantioselectivity (30 % ee ) 9. Hydride reduction of the CN bond of chiral difluoromethyl β‐sulfinyl‐ N ‐arylimine only gave 82 % diastereomeric excess 10.…”

“…Difluoropyruvaldehyde N , S‐ ketal was synthesized in three steps from difluoroacetic esters and chiral methyl p‐ tolyl sulfoxide in only 72 % enantiomeric excess 11. Conversion of optically pure β‐bromo‐β,β‐difluoroalanine derivatives into corresponding β,β‐difluoroalanine products led to a decrease in the optical purity (with 80 % ee ) 14. Funabiki et al attempted L ‐proline‐catalyzed asymmetric Mannich‐type reactions with difluoromethyl aldimine, but prolonged reaction times (7 days) were required and the reactions lacked generality 12.…”

Facile Synthesis of Chiral α‐Difluoromethyl Amines from N‐(tert‐Butylsulfinyl)aldimines

“…[14] Funabiki et al attempted l-prolinecatalyzed asymmetric Mannich-type reactions with difluoromethyl aldimine, but prolonged reaction times (7 days) were required and the reactions lacked generality. [12] On the other hand, although Prakash et al elegantly developed the asymmetric synthesis of a-trifluoromethyl amines using TMSCF 3 (TMS = trimethylsilyl) and N-(tert-butylsulfinyl)aldimines, [15] similar asymmetric synthesis of a-difluoromethyl amines using R 3 SiCF 2 H and N-(tert-butylsulfinyl)imines proved problematic due to the low reactivity of R 3 SiCF 2 H reagents.…”