Short and Efficient Synthesis of Diazabicycloalkane Dipeptide Mimics

Abstract

A new synthetic route to enantiomerically pure diazabicycloalkanes is reported. Key step of this synthesis is an oxidative cleavage of azabicycloalkene precursors that are synthesized in enantiomerically pure form via aza-Diels-Alder reaction. A range of diazabicycloalkanes with different amino acid side chains have been synthesized and their structure has been elucidated by NMR analysis.

Diels-Alder reactions - heterocycles - peptides - dihydroxylations - peptide mimics

References

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13

Typical Procedure for the Synthesis of Peptidomimetics like 9: 8.86 g (31.0 mmol) of alkene 1 were dissolved in 90 mL tert-BuOH and 90 mL water. 30.4 g (93 mmol) K₃Fe(CN)₆, 12.7 g (93 mmol) K₂CO₃, together with a catalytic amount (100 mg) K₂OsO₂(OH)₄ were added. The resulting yellowish slurry was stirred for 12 h at r.t. Addition of 100 mL water, extraction with ethyl acetate, drying of the combined organics over Na₂SO₄ and removal of the solvent gave the crude product, which was purified by column chromatography on silica gel (hexane/ethyl acetate 1:1, R_f = 0.33) to give 7.53 g (23.6 mmol) of the diol as a yellow oil. This diol was dissolved in abs. EtOH and 500 mg 5% Pd on activated charcoal was added. The suspension was stirred for 24 h under a hydrogen atmosphere and subsequently filtered through a plug of celite. The solvent was removed under reduced pressure to give 6 as a yellow oil in 5.96 g (89% over two steps) yield. ¹H NMR (MeOH-d ₄, 500 MHz): δ = 4.33-4.21 (m, 2 H), 4.10 (ddd, 1 H, J = 8.5 Hz, 2.8 Hz, 1.4 Hz), 4.06 (ddd, 1 H, J = 8.5 Hz, 3.8 Hz, 1.4 Hz), 3.66-3.63 (m, 1 H), 2.96-2.94 (m, 1 H), 2.18-2.16 (m, 1 H), 1.96-1.90 (m, 1 H), 1.89-1.82 (m, 1 H), 1.60-1.51 (m, 1 H), 1.31 (t, 3 H, J = 7.3 Hz), 1.27-1.24 (m, 1 H) ppm. HRMS (FAB) calcd for C₁₀H₁₇NO₄ (MH+): 216.1236. Found: 216.1239.

1.00 g (4.65 mmol) of amine 6 and 1.94 g (9.29 mmol) Cbz-Gly-OH were dissolved in 20 mL abs. DMF. 0.63 g (4.65 mmol) HOBt dissolved in 20 mL abs. DMF as well as 1.15 g (5.58 mmol) DCC, dissolved in 10 mL abs. DMF, was added. The resulting suspension was stirred for 12 h at r.t. under nitrogen. DCU was filtered off and DMF was removed in vacuo. The crude product was purified by column chromatography on silica gel (dichloromethane/MeOH 95:5, R_f = 0.21) to give 1.34 g (71%) of dipeptide 5a as a colourless sticky solid. ¹H NMR (CDCl₃, 500 MHz): δ = 7.37-7.33 (m, 5 H), 5.83 (br, 1 H), 4.33 (s, 1 H), 4.26 (q, 2 H, J = 7.1 Hz), 4.13 (dd, 1 H, J = 17.0 Hz, 5.0 Hz), 4.06 (dd, 1 H, J = 17.0 Hz, 3.5 Hz), 3.98-3.93 (m, 2 H), 3.81 (m, 1 H), 3.73-3.71 (br, 1 H), 3.62-3.60 (br, 1 H), 2.36 (m, 1 H), 2.12-2.10 (m, 1 H), 1.93-1.89 (m, 1 H), 1.77-1.72 (m, 1 H), 1.37-1.33 (m, 1 H), 1.30 (t, 1 H, J = 7.1 Hz) ppm. HRMS (FAB) calcd for C₂₀H₂₇N₂O₇ (MH⁺): 407.1818. Found: 407.1840.
450 mg (1.11 mmol) of diol 5a were dissolved in 20 mL acetone/8 mL water and cooled to -25 °C. 400 mg (1.87 mmol) NaIO₄ were added and the solution was stirred for 30 min at -25 °C. 50 mL brine were added and the resulting aqueous solution was extracted with ethyl acetate. The organics were dried over Na₂SO₄, filtered and the solvent was removed in vacuo to give 290 mg (65%) 7a as a colourless oil. The product contained some minor impurities but was used without further purification in the next step.
290 mg (0.72 mmol) of aminal 7a were dissolved in 25 mL abs. MeOH and 65 mg (1.43 mmol) NaBH₄ were added at 0 °C. The solution was stirred for 1 h at 0 °C. After addition of 25 mL water the solution was stirred for additional 15 min at r.t. The solution was subsequently saturated with NaCl and extracted with ethyl acetate. Drying of the combined organics over Na₂SO₄ and removal of the solvent in vacuo gave the crude product as a 7:3 mixture of diastereoisomers, which was purified by column chromatography on silica gel (hexane/ethyl acetate 1:9, R_f = 0.28, 0.35) to give 119 mg (41%) of 8a as a first fraction and 51 mg (17%) of 8b as a second fraction as colourless oils. ¹H NMR for the major diastereoisomer 8a (CDCl₃, 500 MHz): δ = 7.41-7.34 (m, 5 H), 5.59 (m, 1 H), 5.50 (m, 1 H), 5.19 (s, 2 H), 4.45 (d, 1 H, J = 17.7 Hz), 4.30-4.21 (m, 2 H), 4.05 (d, 1 H, J = 17.7 Hz), 3.82-3.79 (m, 2 H), 3.55-3.50 (m, 2 H), 2.54-2.53 (m, 1 H), 1.85-1.61 (m, 3 H), 1.50-1.42 (m, 1 H), 1.30 (t, 3 H, J = 7.1 Hz) ppm. HRMS (FAB) calcd for C₂₀H₂₆N₂O₇ (MH+): 407.1818. Found: 407.1815.
The combined diastereoisomers 8a and 8b (170 mg, 0.42 mmol) were dissolved in abs. EtOH and 100 mg 5% Pd on activated charcoal was added. The suspension was stirred for 24 h under a hydrogen atmosphere and subsequently filtered through a plug of celite. The solvent was removed under reduced pressure to give 9 as a colourless oil in 107 mg (100%) yield. R_f = 0.54 (dichloromethane/methanol 8:2). ¹H NMR (CDCl₃, 500 MHz): δ = 5.45 (s, 1 H), 4.15 (q, 1 H, J = 7.1 Hz), 3.62-3.57 (m, 3 H), 3.53-3.48 (m, 2 H), 3.18-3.17 (m, 1 H), 2.69-2.65 (m, 1 H), 2.52-2.50 (m, 1 H), 1.68-1.65 (m, 1 H), 1.60-1.52 (m, 1 H), 1.42-1.31 (m, 2 H), 1.31 (t, 3 H, J = 7.1 Hz) ppm. HRMS (FAB) calcd for C₁₂H₂₁N₂O₄ (MH⁺): 257.1501. Found: 257.1532.