Synthesis and application of oxadiazines as chiral ligands for the enantioselective addition of diethylzinc to aldehydes

A series of oxadiazines derived from l-phenylalanine bearing phenolic substituents have been synthesized in a multistep, one pot process. This process involves the reaction of a mixed anhydride with a β-hydrazino alcohol, methanesulfonylation of the alcohol moiety, and base induced cyclization. The resultant oxadiazines were employed in the asymmetric addition of diethylzinc to aldehydes.

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(S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)phenyl acetateC21H24N2O3[α]D24=+153.0 (c 1.78, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)

(S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)-6-methylphenyl acetateC22H26N2O3[α]D24=+124.0 (c 1.31, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)

(S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)phenolC19H22N2O2[α]D23=+164.7 (c 0.16, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)

(S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)-6-methylphenolC20H25N2O2[α]D24=+157.1 (c 1.24, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)

(S)-5-Benzyl-4-isopropyl-2-(2-methoxy-3-methylphenyl)-5,6-dihydro-4H-1,3,4-oxadiazineC21H26N2O2[α]D24=+179.6 (c 0.98, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)

(S)-5-Benzyl-4-isopropyl-2-(1-methoxynaphthalen-2-yl)-5,6-dihydro-4H-1,3,4-oxadiazineC24H26N2O2[α]D24=+191.3 (c 1.21, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)

(S)-5-Benzyl-2-(3-tert-butyl-2-methoxyphenyl)-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazineC24H32N2O2[α]D24=+156.1 (c 1.11, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)

(S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)naphthalen-1-olC23H25N2O2[α]D24=+179.6 (c 0.98, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)

(S)-2-(5-Benzyl-4-isopropyl-5,6-dihydro-4H-1,3,4-oxadiazin-2-yl)-6-tert-butylphenolC23H30N2O2[α]D24=+146.9 (c 1.03, CHCl3)Source of chirality: l-phenylalaninolAbsolute configuration: (S)