A Short Synthesis of Conformationally Constrained Unnatural Bicyclic Amino Acids Containing a Nitrogen Atom at the Ring Juncture: (9aR)- and (9aS)-Octahydropyrido[1,2-a]pyrazine-(3S)-carboxylic Acids (Opc)

Abstract

A short and efficient route to conformationally constrained amino acid analogues, (9aR)- and (9aS)-octahydropyrido[1,2-a]pyrazine-(3S)-carboxylate (Opc) has been developed. The new bicyclic amino acid derivatives can be stored and utilized as a modular unit for the construction of unnatural oligopeptides using conventional peptide coupling methods.

Key words

conformationally constrained - unnatural amino acid - bicyclic - peptidomimetic - cyclic sulfamidate

References and Notes

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20

CCDC #660993.

21

Characterization Data for Compound 16 [α]_D ²⁷ -15.0 (c 1.1, CHCl₃). ¹H NMR (300 MHz, CDCl₃):
δ = 0.03 (s, 6 H), 0.88 (s, 9 H), 1.28 (t, 3 H), 1.32-1.70 (m, 6 H), 2.23-2.45 (m, 1 H), 2.50-2.57 (m, 1 H), 2.64-2.76 (m, 3 H), 2.97-3.05 (m, 1 H), 3.38-3.51 (m, 2 H), 3.94 (ABq, J = 13.3 Hz, 2 H), 3.96-3.88 (m, 1 H), 4.26-4.32 (m, 2 H), 7.21-7.32 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = -5.47, 14.28, 18.21, 22.16, 25.39, 25.84, 28.20, 51.06, 52.14, 56.96, 59.58, 60.34, 62.17, 63.70, 126.86, 128.16, 128.22, 139.85, 174.46. HRMS (CI): m/z calcd for C₂₃H₄₁N₂O₃Si
[M + H]⁺: 421.2886; found: 421.2884.

22

Characterization Data for Compound 17 [α]_D ²⁸ -4.1 (c 1.1, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.29 (t, 3 H), 1.37-1.71 (m, 6 H), 2.27-2.45 (m, 2 H), 2.57-2.64 (m, 1 H), 2.82-2.91 (m, 1 H), 2.98-3.05 (m, 1 H), 3.22 (br s, 2 H), 3.35-3.42 (m, 2 H), 3.67-3.76 (m, 1 H), 3.75 (ABq, J = 12.9, 2 H), 4.13-4.24 (m, 2 H), 7.22-7.32 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.25, 23.71, 23.86, 27.05, 52.47, 52.74, 54.38, 59.89, 60.92, 61.95, 63.07, 127.20, 128.35, 128.42, 139.03, 174.90. HRMS (CI): m/z calcd for C₁₈H₂₉N₂O₃ [M + H]⁺: 321.2178; found: 321.2176.

23

Characterization Data for Compound 19 [α]_D ²⁷ -10.5 (c 1.0, CHCl₃). ¹H NMR (300 MHz, CDCl₃):
δ = 1.12-1.29 (m, 2 H), 1.27 (t, 3 H), 1.34-1.41 (m, 1 H), 1.56-1.59 (m, 2 H), 1.65-1.68 (m, 1 H), 1.87-1.96 (m, 2 H), 2.38-2.48 (m, 2 H), 2.70-2.74 (m, 1 H), 2.90-2.97 (m, 1 H), 3.04-3.08 (m, 1 H), 3.40 (s, 1 H), 3.90 (ABq, J = 13.7, 2 H), 4.14-4.24 (m, 2 H), 7.20-7.31 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.78, 24.37, 25.96, 29.91, 53.41, 56.15, 58.27, 59.35, 60.25, 60.62, 61.85, 127.30, 128.65, 129.03, 139.75, 172.83. HRMS (CI): m/z calcd for C₁₈H₂₇N₂O₂ [M + H]⁺: 303.2072; found: 303.2073.

24

Characterization Data for Compound 22 [α]_D ¹¹ -31.3 (c 1.00, CHCl₃).¹H NMR (300 MHz, CDCl₃):
δ = 1.11-1.96 (m, 17 H), 2.24-2.31 (m, 1 H), 2.70-2.88 (m, 2 H), 3.17-3.24 (m, 1 H), 3.62 (d, J = 3.2 Hz, 0.25 H), 3.66 (d, J = 3.2 Hz, 0.25 H), 3.74-3.80 (m, 3.5 H), 4.53 (d, J = 4 Hz, 0.5 H), 4.70 (d, J = 4 Hz, 0.5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 24.02, 24.07, 25.67, 28.64, 28.73, 29.54, 29.56, 46.87, 47.84, 52.58, 54.38, 55.65, 55.81, 55.93, 56.17, 60.70, 60.72, 80.55, 80.60, 155.54, 155.96, 171.68, 171.98. HRMS-FAB: m/z calcd for C₁₅H₂₇N₂O₄ [M + H]⁺: 299.1971; found: 299.1970.

25

Characterization Data for Compound 23 [α]_D ¹¹ +23.9 (c 1.00, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.12-1.28 (m, 2 H), 1.51-1.61 (m, 3 H), 1.72-1.98 (m, 3 H), 2.03 (s, 0.7 H), 2.14 (s, 2.3 H), 2.24 (dd, 0.75 H), 2.33 (dd, 0.25 H), 2.49-2.61 (m, 0.25 H), 2.77-2.80 (m, 0.75 H), 3.09-3.18 (m, 0.9 H), 3.24-3.38 (m, 1.2 H), 3.43-3.54 (m, 0.9 H), 3.75 (s, 2.3 H), 3.79 (s, 0.7 H), 4.22-4.23 (m, 0.08 H), 4.27-4.28 (m, 0.08 H), 4.34-4.37 (m, 0.14 H), 5.17-5.19 (m, 0.7 H). ¹³C NMR (75 MHz, CDCl₃): δ = 21.52, 21.81, 23.98, 25.58, 25.67, 29.55, 29.62, 45.07, 49.88, 52.51, 52.76, 53.12, 55.72, 55.82, 56.04, 56.43, 57.57, 60.63, 60.98, 170.79, 171.01, 171.22. HRMS-FAB: m/z calcd for C₁₂H₂₁N₂O₃ [M + H]⁺: 241.1552; found: 241.1558.

26

Characterization Data for Compound 24 [α]_D ¹¹ -59.2 (c 1.00, CHCl₃). ¹H NMR (300 MHz, CDCl₃):
δ = 1.03-1.31 (m, 2 H), 1.41-2.01 (m, 6 H), 2.12 (s, 1.2 H), 2.23 (m, 1.8 H), 2.34-2.52 (m, 2 H), 2.78-2.86 (m, 1 H), 3.03-3.15 (m, 1 H), 3.29-3.33 (m, 0.4 H), 3.44-3.48 (m, 0.4 H), 3.71-3.78 (m, 0.2 H), 4.32-4.55 (m, 2.6 H), 5.18-5.20 (m, 0.4 H), 7.05 (s, 0.4 H), 7.26-7.69 (m, 5 H), 8.46 (m, 0.6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 21.89, 21.96, 23.81, 23.94, 25.62, 25.89, 29.62, 29.74, 43.78, 43.83, 44.07, 50.02, 52.95, 55.26, 55.52, 55.735, 55.89, 57.70, 60.75, 61.26, 126.29, 127.75, 127.88, 127.91, 128.22, 129.050, 129.14, 138.39, 138.70, 169.76, 170.05, 170.51, 170.91. HRMS-FAB: m/z calcd for C₁₈H₂₆N₃O₂ [M + H]⁺: 316.2025; found: 316.2026.