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Synlett 2005(5): 0773-0776  
DOI: 10.1055/s-2005-863731
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Nina G. Bandur, Klaus Harms, Ulrich Koert*
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany
e-Mail: koert@chemie.uni-marburg.de;
Further Information

Publication History

Received 18 December 2004
Publication Date:
09 March 2005 (online)

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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.

Key words

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

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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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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.

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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.