Synthesis of Excitatory Amino Acid Analogues

Abstract

A general route to excitatory amino acid analogues has been developed as exemplified by the synthesis of A-1 and A-2. The key reactions involved were a Negishi coupling of Jackson’s organozinc reagent with vinyl bromide 8 and subsequent ring closure of 15 and 16 using the Mitsunobu reaction.

Key words

excitatory amino acids - Claisen rearrangement - Jackson’s organozinc reagent - Mitsunobu reaction

References and Notes

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14

A-1: white solid; [α]_D ²¹ -103.2 (c = 0.12, H₂O). ¹H NMR (400 MHz, D₂O): δ = 2.40 (dd, J ₁ = 9.0 Hz, J ₂ = 15.5 Hz, 1 H, NCHCH_A H_B), 2.56 (dd, J ₁ = 3.0 Hz, J ₂ = 15.5 Hz, 1 H, NCHCH_A H_B ), 3.29 (d, J = 16.5 Hz, 1 H, ArCH_A H_B), 3.45 (d, J = 16.5 Hz, 1 H, ArCH_A H_B ), 3.84 (dd, J ₁ = 3.0 Hz, J ₂ = 9.0 Hz, 1 H, NCH), 6.83 (d, J = 8.0 Hz, 1 H, Ar), 6.88 (dt, J ₁ = 1.0 Hz, J ₂ = 7.5 Hz, 1 H, Ar), 7.13 (αππαρεντ t, J = 7.5 Hz, 1 H, Ar), 7.19 (d, J = 7.5 Hz, 1 H, Ar). ¹³C NMR (125.7 MHz, D₂O): δ = 38.3, 39.5, 51.9, 90.2, 110.2, 121.9, 125.7, 126.4, 128.8, 158.3, 174.4, 180.0. MS (ES, -ve): m/z (%) = 250.3 (100) [M - H]^-. HRMS: m/z [M - H]^- calcd for C₁₂H₁₃NO₅: 250.0715; found: 250.0713.

16

A-2: white solid; [α]_D ²¹ -16.3 (c = 0.32, H₂O). ¹H NMR (400 MHz, D₂O): δ = 2.17 (dd, J ₁ = 11.5 Hz, J ₂ = 15.5 Hz, 1 H, NCHCH_A H_B), 2.67 (dd, J ₁ = 2.0 Hz, J ₂ = 15.5 Hz, 1 H, NCHCH_A H_B ), 3.16 (d, J = 16.5 Hz, 1 H, ArCH_A H_B), 3.44 (d, J = 16.5 Hz, 1 H, ArCH_A H_B ), 3.70 (dd, J ₁ = 2.0 Hz, J ₂ = 11.5 Hz, 1 H, NCH), 6.80 (d, J = 8.0 Hz, 1 H, Ar), 6.86 (t, J = 7.5 Hz, 1 H, Ar), 7.11 (t, J = 7.5 Hz, 1 H, Ar), 7.16 (d, J = 7.5 Hz, 1 H, Ar). ¹³C NMR (125.7 MHz, D₂O): δ = 39.0, 40.9, 53.8, 91.7, 110.2, 121.8, 125.7, 126.0, 128.7, 157.9, 174.0, 179.1. MS (ES, -ve): m/z (%) = 250.3 (100) [M - H]. HRMS: m/z [M - H]^- calcd for C₁₂H₁₃NO₅: 250.0715; found: 250.0721.