Asymmetric synthesis of deuterated and fluorinated aromatic α,α-disubstituted amino acid derivatives

We herein present organocatalytic approaches to synthesize fluorinated and deuterated α-substituted phenylglycine derivatives. Whereas the addition of diethyl azodicarboxylate to fluorinated α-substituted aldehydes furnishes chiral non-racemic compounds, the use of chloramine-T as a nitrogen source represents a rapid access to sulfamidated fluorinated amino acid precursors. Additionally, further functionalization was achieved through the palladium-catalyzed coupling of a p-bromosubstituted aldehyde with a range of fluorine or deuterium-containing boronic acids. Oxidation of the aldehyde function and cleavage of the protection group of the nitrogen give way to the free fluorinated unnatural amino acids.

Figure optionsDownload as PowerPoint slide

Diethyl 1-(1-oxo-2-(phenyl)propan-2-yl)hydrazine-1,2-dicarboxylateC15H20N2O5[α]D = +48.1 (c 1.00, MeOH)Absolute configuration R

Diethyl 2-naphthylhydrazine-1,2-dicarboxylateC19H22N2O5[α]D = +2.3 (c 1.00, MeOH)Absolute configuration R

Diethyl 1-(2-(2′-fluorophenyl)-1-oxopropan-2-yl)hydrazine-1,2-dicarboxylateC15H19FN2O5[α]D = −3.0 (c 2.90, CHCl3)Absolute configuration R

Diethyl 1-(2-(3′-fluorophenyl)-1-oxopropan-2-yl)hydrazine-1,2-dicarboxylateC15H19FN2O5[α]D = −5.0 (c 4.40, CHCl3)Absolute configuration R

Diethyl 1-(2-(4′-fluorophenyl)-1-oxopropan-2-yl)hydrazine-1,2-dicarboxylateC15H19FN2O5[α]D = +34.1 (c 1.00, CHCl3)Absolute configuration R

Diethyl 1-(1-oxo-2-(3-(trifluoromethyl)phenyl)propan-2-yl)hydrazine-1,2-dicarboxylateC16H19F3N2O5[α]D = +31.6 (c 1.20, CHCl3)Absolute configuration R

Diethyl 1-(1-oxo-2-(4-deuterophenyl)propan-2-yl)hydrazine-1,2-dicarboxylateC15H19DN2O5[α]D = +14.8 (c 5.65, MeOH)Absolute configuration R

Diethyl 1-(1-oxo-2-trideuteromethyl-2-phenyl)propan-2-yl)hydrazine-1,2-dicarboxylateC15H17D3N2O5[α]D = +11.2 (c 4.80, MeOH)Absolute configuration R

Diethyl 1-(2-(4′-bromophenyl)-1-oxopropan-2-yl)hydrazine-1,2-dicarboxylateC15H19BrN2O5[α]D = +34.2 (c 0.71, CHCl3)Absolute configuration R

Dibenzyl 1-(2-(4′-bromophenyl)-1-oxopropan-2-yl)hydrazine-1,2-dicarboxylateC25H23BrN2O5[α]D = +13.3 (c 2.20, CHCl3)Absolute configuration R

Dibenzyl 1-(2-(4′-fluorophenyl)-1-oxopropan-2-yl)hydrazine-1,2-dicarboxylateC25H23FN2O5[α]D = −16.8 (c 1.55, CHCl3)Absolute configuration R

Diethyl 1-(2-(biphenyl-4-yl)-1-methoxy-1-oxopropan-2-yl)hydrazine-1,2-dicarboxylateC22H26N2O6[α]D = −56.8 (c 6.40, CHCl3)Absolute configuration R

Diethyl 1-(2-(4′-fluorobiphenyl-4-yl)-1-methoxy-1-oxopropan-2-yl)hydrazine-1,2-dicarboxylateC22H25FN2O6[α]D = −54.5 (c 1.50, MeOH)Absolute configuration R

Diethyl 1-(1-methoxy-1-oxo-2-(3′,4′,5′-trifluorobiphenyl-4-yl)propan-2-yl)hydrazine-1,2-dicarboxylateC22H23F3N2O6[α]D = −41.9 (c 7.00, MeOH)Absolute configuration R

Diethyl 1-(1-methoxy-1-oxo-2-(2′,3′,4′,5′,6′-pentafluorobiphenyl-4-yl)propan-2-yl)hydrazine-1,2-dicarboxylateC22H21F5N2O6[α]D = −100.0 (c 2.45, CHCl3)Absolute configuration R

Diethyl 1-(1-methoxy-1-oxo-2-(4′-(trifluoromethyl)biphenyl-4-yl)propan-2-yl)hydrazine-1,2-dicarboxylateC23H25F3N2O6[α]D = −46.2 (c 7.00, CHCl3)Absolute configuration R

Diethyl 1-(1-methoxy-1-oxo-2-(2′,3′,4′,5′,6′-pentadeuterobiphenyl-4-yl)propan-2-yl)hydrazine-1,2-dicarboxylateC22H21D5N2O6[α]D = −54.1 (c 4.20, MeOH)Absolute configuration R