First Stereoselective Synthesis of a Pro-Pro E-Alkene Dipeptide Isostere

Abstract

A stereoselective synthesis of a proline-proline E-alkene isostere is described. Starting from N-Boc-l-proline the new stereo­center is generated by diastereoselective alkenylation and sub­sequent Ireland-Claisen rearrangement. The relative configuration of the double bond and the new generated stereocenter were determined by X-ray crystallography.

proline - E-alkene - dipeptide isostere - Felkin-Anh ­selective alkenylation - Ireland-Claisen rearrangement

References

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10

Preparation of Compound 4.
A 4.63 g (0.67 mol) piece of lithium rod (1 cm diameter) was flattened to a thickness of about 1-2 mm with a clean hammer. The flattened lithium was cut into pieces of approximately 1 × 0.2 mm and put under argon into a dry flask containing Et₂O (150 mL) and broken glass pieces. 1-Chlorocyclopentene (0.23 mol, 23.74 g, freshly distilled from CaCl₂) was then added in one portion and the mixture was stirred at r.t. for 3 h (exothermic!) and heated at 50 °C oil bath temperature for 1 h. The resulting suspension was allowed to cool down to r.t. and the supernatant solution was transferred to another flask by syringe and diluted with Et₂O (650 mL). The solution was cooled to -78 °C and aldehyde 1 (99.3 mmol, 19.8 g) dissolved in Et₂O (400 mL) was added dropwise. The solution was maintained at -78 °C for 3 h, and then quenched by the addition of i-PrOH (10 mL) and warmed up to r.t. After adding sat. NaHCO₃ (400 mL) the mixture was vigorously stirred for 10 min. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried with Na₂SO₄ and concentrated. Flash chromatography on silica (CH₂Cl₂-EtOAc 10:1 to 4:1) yielded alcohol 2 (22.28 g, 3.37 mmol, 84%) as a colorless solid. [α]_D ²² -83.2 (c 2.03, CHCl₃), R _f = 0.22 (CH₂Cl₂-EtOAc, 5:1). ¹H NMR (500 MHz, DMSO-d ₆, 340 K): δ = 5.58-5.49 (m, 1 H), 4.58 (br s, 1 H), 4.48-4.39 (m, 1 H), 3.84-3.71 (m, 1 H), 3.38-3.31 (m, 1 H), 3.24-3.17 (m, 1 H), 2.33-2.17 (m, 4 H), 1.92-1.85 (m, 2 H), 1.82 (q, J = 7.4 Hz, 2 H), 1.70-1.60 (m, 2 H), 1.41 (s, 9 H). ¹³C NMR (125 MHz, DMSO-d ₆, 340 K): δ = 145.9, 123.5, 77.7, 70.3, 59.7, 46.4, 31.9, 31.3, 27.9, 24.3, 23.3, 22.7. HRMS (ESI): m/z calcd for C₁₅H₂₅NNaO₃ [M + Na⁺]: 290.1732; found: 290.1737.

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15

Preparation of Compound 7. A solution of the alcohol 4 (83.0 mmol, 22.14 g) and pyridine (249 mmol, 20 mL) in THF (40 mL) was cooled to 0 °C and freshly prepared tert-butyldimethylsilyloxyacetyl chloride (83.3 mmol, 17.39 g) dissolved in THF (40 mL) was added dropwise. The reaction was stirred at 0 °C for 1 h and at r.t. for further 30 min. Then the mixture was diluted with TBME and washed with 0.5 N HCl, sat. NaHCO₃ and brine, dried with MgSO₄ and concentrated. Flash chromatography on silica (pentane-TBME, 9:1) gave ester 3 (30.65 g, 69.72 mmol, 74%) as a colorless oil. At 0 °C n-butyllithium (2.5 M in hexane, 143 mmol, 57 mL) was added dropwise to a solution of diisopropylamine (156 mmol, 22 mL) in THF (250 mL). The solution was stirred at 0 °C for 15 min and cooled to -100 °C. A mixture of chlorotrimethylsilane (384 mmol, 48.5 mL) and pyridine (419 mmol, 34 mL) in THF (100 mL), that was previously prepared by addition of chlorotrimethylsilane to a solution of pyridine in THF at 0 °C, was added dropwise to the LDA solution at -100 °C. After 5 min a solution of ester 3 (34.9 mmol, 15.34 g) in THF (120 mL) was added dropwise and the solution was stirred at -100 °C for 30 min, warmed up to r.t. over 1.5 h and stirred at r.t. for 1.5 h. The reaction was quenched with 1 M HCl (400 mL) at 0 °C and extracted with TBME. The combined organic extracts were washed with brine, dried with Na₂SO₄ and concentrated to give acid 6 (15.04 g, 342 mmol, 98% crude yield) as a pale yellow oil. Without further purification acid 6 was dissolved in THF (60 mL) and treated with tetrabutylammonium fluoride (68.2 mmol, 17.82 g) dissolved in THF (60 mL) at 0 °C. The solution was warmed to r.t. and stirred for 1.5 h. After addition of 0.5 M HCl (300 mL) the mixture was stirred for 10 min and extracted with EtOAc. The organic layer was washed with brine, dried with Na₂SO₄ and concentrated to give the α-hydroxy acid as a pale yellow oil. The crude α-hydroxy acid was dissolved in 500 mL EtOAc and cooled to 0 °C. A solution of Pb(OAc)₄ (37.5 mmol, 16.63 g) dissolved in CHCl₃ (80 mL) was added dropwise. The mixture was stirred at 0 °C for 15 min, quenched with ethyleneglycol (50 mL), diluted with EtOAc and washed with H₂O and brine. The organic layer was dried with Na₂SO₄ and concentrated to yield the aldehyde as a yellow oil. Due to its instability the β,γ-unsaturated aldehyde was used without purification and dissolved in MeOH (300 mL). The solution was cooled to 0 °C and NaBH₄ (68.2 mmol, 2.58 g) was added in small portions under vigorous gas evolution. The mixture was stirred for 30 min at 0 °C and again NaBH₄ (34.1 mmol, 1.29 g) was added. After stirring for further 30 min sat. NH₄Cl (200 mL) was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried with Na₂SO₄ and concentrated. Flash chromatography on silica (pentane-EtOAc, 1:1) gave alcohol 7 (7.07 g, 25.1 mmol, 74% over 4 steps, 93% per step) as a colorless solid. An X-ray sample was obtained by subsequent crystallization from CH₂Cl₂-cyclohexane. [α]_D ²² +4.2 (c 1.01, CHCl₃). R _f = 0.23 (cyclohexane-EtOAc, 1:1). ¹H NMR (500 MHz, DMSO-d ₆): δ = 5.17-5.12 (m, 1 H), 4.44-4.38 (m, 1 H), 4.28-4.12 (m, 1 H), 3.42-3.33 (m, 1 H), 3.27-3.14 (m, 3 H), 2.47-2.35 (m, 2 H), 2.18-2.07 (m, 1 H), 2.03-1.91 (m, 1 H), 1.84-1.75 (m, 1 H), 1.74-1.59 (m, 3 H), 1.53-1.41 (m, 3 H), 1.34 (s, 9 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 153.3, 123.0, 77.5, 64.4, 55.9, 46.5, 45.7, 32.3, 29.0, 28.3, 27.9, 23.5, 22.9. HRMS (ESI): m/z calcd for C₁₅H₂₅NaO₃ [M + Na⁺]: 304.1889; found: 304.1902.

16 Hoffmann RW. Chem. Rev.  1989,  89:  1841 

17

Analytical data of compound 10. [α]_D ²⁰ -31.2 (c 0.7, CHCl₃). R _f = 0.21 (EtOAc-cyclohexane, 2:1), 0.25 (CHCl₃-MeOH, 10:1); t _R = 10.18 min (solvent A: doubly distilled H₂O; solvent B: MeCN, 75% B to 100% B in 25 min, flow: 0.7 mL/min, ϑ = 30 °C, UV detection at 220 nm). ¹H NMR (500 MHz, DMSO-d ₆): δ = 12.11 (br s, 1 H), 7.90 (d, J = 7.5 Hz, 2 H), 7.65 (d, J = 7.5 Hz, 2 H), 7.42 (t, J = 7.5 Hz, 2 H), 7.43 (t, J = 7.5 Hz, 2 H), 5.46-5.35 (m, 0.5 H), 5.34-5.23 (m, 0.5 H), 4.40-4.14 (m, 4 H), 3.33-3.27 (m, 2 H), 3.19-3.09 (m, 1 H), 2.64-2.52 (m, 0.5 H), 2.03-1.93 (m, 1 H), 1.87-1.65 (m, 5 H), 1.56-1.44 (m, 0.5 H). Integrals show fraction numbers because of occurrence of rotamers, at 340 K only one signal set was observed. HRMS (ESI): m/z calcd for C₂₆H₂₇NNaO₄ [M + Na⁺]: 440.1838; found: 440.1837.