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.

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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