Crystallisation-induced asymmetric transformation (CIAT) for the synthesis of dipeptides containing homophenylalanine

A novel synthesis of highly enantioenriched dipeptides containing homophenylalanine is described. The process involves a crystallisation-induced asymmetric transformation (CIAT) in a Michael addition followed by exhaustive reduction. A unique example of a formally stereodivergent CIAT in conjugate addition of an achiral N-nucleophile to enantiomerically pure Michael acceptor has been discovered.

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N-[(2E)-4-Oxo-4-phenylbut-2-enoyl]-l-phenylalanineC19H17NO4[α]D20=-4.8 (c 1.0, MeOH)Source of chirality: (S)-PheAbsolute configuration: (2S)

(2S)-{[(2E)-4-Oxo-4-phenylbut-2-enoyl]amino}(phenyl)acetic acidC18H15NO4[α]D25=-158.1 (c 1.0, MeOH)Source of chirality: (S)-PhgAbsolute configuration: (2S)

N-[(2E)-4-Oxo-4-phenylbut-2-enoyl]-l-leucineC16H19NO4[α]D25=-26.4 (c 1.0, MeOH)Source of chirality: (S)-LeuAbsolute configuration: (2S)

N-[(2E)-4-(4-Methoxyphenyl)-4-oxobut-2-enoyl]-l-phenylalanineC20H19NO5[α]D25=0.0 (c 0.5, MeOH)Source of chirality: (S)-PheAbsolute configuration: (2S)

N-[(2E)-4-(4-Methoxyphenyl)-4-oxobut-2-enoyl]-l-leucineC17H21NO5[α]D25=-26.6 (c 1.0, MeOH)Source of chirality: (S)-LeuAbsolute configuration: (2S)

N-[(2E)-4-(4-Methoxyphenyl)-4-oxobut-2-enoyl]-l-valineC16H19NO5[α]D25=-18.1 (c 1.0, MeOH)Source of chirality: (S)-ValAbsolute configuration: (2S)

N-[(2S)-2-(Benzylamino)-4-oxo-4-phenylbutanoyl]-l-phenylalanineC26H26N2O4[α]D25=-18.3 (c 0.36, MeCN:1 M HCl 10:1)Source of chirality: (S)-Phe and stereoselective synthesisAbsolute configuration: (2S,2′S)

(2S)-2-((S)-2-(Benzylamino)-4-oxo-4-phenylbutanamido)-2-phenylacetic acidC25H24N2O4[α]D25=-57.8 (c 1.0, MeOH:1 M HCl 3:1)Source of chirality: (S)-Phg and stereoselective synthesisAbsolute configuration: (2S,2′S)

N-[(2S)-2-(Benzylamino)-4-oxo-4-phenylbutanoyl]-l-leucineC23H28N2O4[α]D25=-8.5 (c 0.5, MeOH:1 M HCl 3:1)Source of chirality: (S)-Leu and stereoselective synthesisAbsolute configuration: (2S,2′S)

Phenylmethanaminium (S)-2-((R)-2-(benzylamino)-4-oxo-4-phenylbutanamido)-4-methylpentanoateC30H37N23O4[α]D25=-20.2 (c 1.0, MeOH:1 M HCl 3:1)Source of chirality: (S)-Leu and stereoselective synthesisAbsolute configuration: (2S,2′R)

Phenylmethanaminium (S)-2-((S)-2-(benzylamino)-4-(4-methoxyphenyl)-4-oxobutanamido)-3-phenylpropanoateC34H37N3O5[α]D25=-18.2 (c 1.0, MeOH:1 M HCl 3:1)Source of chirality: (S)-Phe and stereoselective synthesisAbsolute configuration: (2S,2′S)

Phenylmethanaminium (S)-2-((R)-2-(benzylamino)-4-(4-methoxyphenyl)-4-oxobutanamido)-4-methylpentanoateC31H39N3O5[α]D25=-21.1 (c 1.0, MeOH:1 M HCl 3:1)Source of chirality: (S)-Leu and stereoselective synthesisAbsolute configuration: (2S,2′R)

tert-Butyl [(2S)-1-(benzylamino)-1-oxopropan-2-yl]carbamateC15H22N2O3[α]D25=-22.0 (c 1.0, CHCl3)Source of chirality: (S)-AlaAbsolute configuration: (2S)

N-Benzyl-l-alaninamideC10H14N2O[α]D25=+7.2 (c 1.0, CHCl3)Source of chirality: (S)-AlaAbsolute configuration: (2S)

(S)-1-(Benzylamino)-1-oxopropan-2-aminium (S)-2-((S)-1-(benzylamino)-1-oxopropan-2-ylamino)-4-oxo-4-phenylbutanamido)-3-phenylpropanoateC39H45N5O6[α]D25=-11.0 (c 1.0, MeOH:1 M HCl 3:1)Source of chirality: (S)-Phe, (S)-Ala and stereoselective synthesisAbsolute configuration: (2S,2′S,2″S)

N-[(2S)-2-Amino-4-phenylbutanoyl]-l-phenylalanineC19H22N2O3[α]D25=+20.7 (c 0.5, MeOH:1 M HCl 3:1)Source of chirality: (S)-Phe and stereoselective synthesisAbsolute configuration: (2S,2′S)

(S)-2-((S)-2-Amino-4-phenylbutanamido)-2-phenylacetic acidC18H20N2O3[α]D25=+119.2 (c 0.5, 0.1 M NaOH)Source of chirality: (S)-Phg and stereoselective synthesisAbsolute configuration: (2S,2′S)

(N-[(2S)-2-Amino-4-phenylbutanoyl]-l-leucine)C16H24N2O3[α]D25=-2.0 (c 0.5, MeOH:1 M HCl 3:1)Source of chirality: (S)-Leu and stereoselective synthesisAbsolute configuration: (2S,2′S)

N-[(2R)-2-Amino-4-phenylbutanoyl]-l-leucineC16H24N2O3[α]D25=-40.3 (c 0.5, 0.1 M NaOH)Source of chirality: (S)-Leu and stereoselective synthesisAbsolute configuration: (2S,2′R)

N-[(2S)-2-Amino-4-(4-methoxyphenyl)butanoyl]-l-phenylalanineC20H24N2O4[α]D25=+35.3 (c 0.5, 0.1 M NaOH)Source of chirality: (S)-Phe and stereoselective synthesisAbsolute configuration: (2S,2′S)

N-[(2R)-2-Amino-4-(4-methoxyphenyl)butanoyl]-l-leucineC17H26N2O4[α]D25=-24.7 (c 0.5, 0.1 M NaOH)Source of chirality: (S)-Leu and stereoselective synthesisAbsolute configuration: (2S,2′R)

N-[(2R)-2-(benzylamino)-4-oxo-4-phenylbutanoyl]-l-leucineC23H28N2O4[α]D25=-16.6 (c 0.4, MeOH:1 M HCl 3:1)Source of chirality: (S)-Phe and stereoselective synthesisAbsolute configuration: (2S,2′R)