Vinylepoxides as Versatile Substrates for Allylations of Amino Acids and Peptides

Abstract

Vinyl epoxides are excellent substrates for Pd-catalyzed allylic alkylations of chelated enolates. Nucleophilic attack on the predominantly formed syn/syn π-allyl complexes occurs regioselectively at the distal position. The E-configured product is formed preferentially, depending on the substitution pattern and the reaction conditions used.

Key words

allylic alkylation - amino acids - chelates - epoxides - palladium

References and Notes

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8

The syn/anti terminology was used to describe the relative orientation of the substituents at the allylic position relative to the hydrogen at the central position of the π-allyl-Pd complex.

18

General procedure for the allylic alkylation with vinyl epoxides: In a Schlenk tube, hexamethyldisilazane (168 mg, 1.04 mmol, 2.8 equiv) was dissolved in anhydrous THF (2.0 mL). After the solution had been cooled to -78 ˚C, n-BuLi (1.6M, 0.58 mL, 0.93 mmol, 2.5 equiv) was added slowly. The solution was stirred for 10 min before the cooling bath was removed and the solution was stirred for a further 10 min. In a second Schlenk flask, ZnCl₂ (56 mg, 0.41 mmol, 1.1 equiv) was dried with a heat gun under vacuum then dissolved in THF (2.0 mL). After the solution had been cooled to room temperature, Tfa-Gly-OtBu (85 mg, 0.374 mmol, 1 equiv) was added. The freshly prepared LHMDS solution was cooled again to -78 ˚C before the Tfa-Gly-OtBu/ZnCl₂ solution was added slowly. This solution was stirred for 30 min at -78 ˚C. At the same time, a solution of [(allyl)PdCl]₂ (1.4 mg, 3.8 µmol, 1.5 mol%) and Ph₃P (4.9 mg, 18.8 µmol, 7.5 mol%) was prepared in THF (0.5 mL). After stirring for 5 min the vinylepoxide (0.25 mmol, 0.7 equiv) was added and the solution was added directly to the enolate at -78 ˚C. The reaction mixture was allowed to warm to r.t. overnight then diluted with ether and hydrolyzed with 1M HCl. The layers were separated and the aqueous layer was extracted twice with ether. The combined organic layers were dried (Na₂SO₄), the solvent was evaporated in vacuo, and the crude product was purified by flash chromatography (silica gel; hexanes-EtOAc).

19

Spectroscopic and analytical data of some selected products.
Compound ( E )-4: ^¹H NMR (400 MHz, CDCl₃): δ = 6.96 (d, J = 4.9 Hz, 1 H), 5.75 (dtt, J = 15.3, 5.4, 1.0 Hz, 1 H), 5.56 (dtt, J = 15.3, 7.3, 1.4 Hz, 1 H), 4.54 (q, J = 5.5 Hz, 1 H), 4.10 (dd, J = 5.4, 1.4 Hz, 2 H), 2.69 (dddd, J = 14.2, 7.2, 5.2, 1.0 Hz, 1 H), 2.54 (dddd, J = 14.2, 7.2, 6.1, 1.0 Hz, 1 H), 1.49 (s, 9 H); ^¹³C NMR (100 MHz, CDCl₃): δ = 169.2, 156.6 (J = 37.9 Hz), 134.5, 124.2, 115.6 (J = 287.6 Hz), 83.6, 62.9, 52.6, 34.6, 28.0.
Compound ( Z )-4: ^¹H NMR (400 MHz, CDCl₃): δ (selected signals) = 7.48 (br s, 1 H), 5.88 (dtt, J = 10.9, 6.7, 1.3 Hz, 1 H), 5.50 (dtt, J = 10.9, 7.9, 1.1 Hz, 1 H), 4.46 (q, J = 6.8 Hz, 1 H), 4.19 (dd, J = 6.7, 1.1 Hz, 2 H), 2.75 (dddd, J = 14.4, 7.9, 4.9, 1.1 Hz, 1 H), 2.65 (dddd, J = 14.4, 7.9, 6.8, 1.1 Hz, 1 H), 1.49 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 169.2, 132.5, 126.3, 83.4, 57.8, 52.5, 29.4, 27.9. HRMS (CI): m/z [M + H]⁺ calcd for C₁₂H₁₉F₃NO₄: 298.1221; found: 298.1241. Anal. Calcd for for C₁₂H₁₈F₃NO₄ (297.27): C, 48.48; H, 6.10; N, 4.71. Found: C, 48.32; H, 6.02; N, 4.96.
Compound 5a: Major diastereomer: ^¹H NMR (400 MHz, CDCl₃): δ = 7.33 (dd J = 8.2, 6.9 Hz, 2 H), 7.28 (t, J = 7.1 Hz, 1 H), 7.22 (d, J = 8.5 Hz, 2 H), 6.68 (d, J = 8.6 Hz, 1 H), 5.98 (ddt, J = 15.4, 8.5, 1.5 Hz, 1 H), 5.79 (dtd, J = 15.4, 5.2, 0.8 Hz, 1 H), 4.85 (dd, J = 8.6, 5.9 Hz, 1 H), 4.16 (dd, J = 5.2, 1.0 Hz, 2 H), 3.93 (dd, J = 8.4, 6.0 Hz, 1 H), 1.38 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 168.4, 156.7 (J = 37.5 Hz), 138.0, 133.3, 128.7, 128.1, 128.1, 127.7, 115.6 (J = 287.9 Hz), 83.6, 62.7, 56.9, 50.7, 27.8. Minor diastereomer: ^¹H NMR (400 MHz, CDCl₃): δ (selected signals) = 6.85 (d, J = 8.4 Hz, 1 H), 4.78 (t, J = 8.5 Hz, 1 H), 4.11 (dd, J = 5.2, 1.1 Hz, 2 H), 3.65 (t, J = 8.8 Hz, 1 H), 1.22 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 168.8, 138.3, 133.1, 128.9, 128.7, 128.2, 127.6, 115.7 (J = 287.5 Hz), 114.2, 83.3, 62.6, 52.7, 27.5. HRMS (CI): m/z [M - C₄H₉O]⁺ calcd for C₁₄H₁₃F₃NO₃: 300.0848; found: 300.0861.
Compound 8: ^¹H NMR (400 MHz, CDCl₃): δ = 6.88 (d, J = 5.0 Hz, 1 H), 5.59 (ddt, J = 15.3, 6.2, 0.8 Hz 1 H), 5.49 (dtd, J = 15.3, 7.6, 0.9 Hz, 1 H), 4.52 (q, J = 5.3 Hz, 1 H), 4.25 (quint, J = 6.8 Hz, 1 H), 3.87 (dt, J = 8.1, 7.3 Hz, 1 H), 3.76 (dt, J = 8.0, 6.4 Hz, 1 H), 2.67 (dddd, J = 13.8, 7.5, 5.4, 0.8 Hz, 1 H), 2.53 (dq, J = 13.7, 5.9 Hz, 1 H), 2.02 (m, 1 H), 1.95-1.82 (m, 2 H), 1.56 (m, 1 H), 1.49 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 169.2, 156.4 (J = 37.7 Hz), 136.8, 123.3, 115.6 (J = 288.0 Hz), 83.5, 78.8, 68.0, 52.6, 34.3, 32.1, 28.0, 25.7. HRMS (CI): m/z [M - C₄H₉]⁺ calcd for C₁₁H₁₃F₃NO₄: 280.0797; found: 280.0793.
Compound 17a: Major diastereomer: ^¹H NMR (400 MHz, CDCl₃): δ = 7.57 (d, J = 7.7 Hz, 1 H), 7.34-7.18 (m, 5 H), 6.47 (d, J = 7.6 Hz, 1 H), 5.61 (dt, J = 15.3, 5.6 Hz, 1 H), 5.47 (dt, J = 15.2, 7.2 Hz, 1 H), 4.70 (q, J = 7.3 Hz, 1 H), 4.46 (ddd, J = 7.5, 6.4, 5.0 Hz, 1 H), 4.03 (m, 2 H), 3.11 (dd, J = 13.8, 7.7 Hz, 2 H), 2.56 (dt, J = 14.0, 6.7 Hz, 1 H), 2.37 (dt, J = 14.0, 6.6 Hz, 1 H), 1.46 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 170.0, 169.2, 157.0 (J = 37.6 Hz), 135.4, 133.9, 129.2, 128.6, 127.3, 125.2, 115.6 (J = 287.6 Hz), 82.6, 62.7, 54.7, 52.5, 37.9, 34.9, 27.9. Minor diastereomer: ^¹H NMR (400 MHz, CDCl₃): δ (selected signals) = 7.47 (d, J = 7.8 Hz, 1 H), 6.39 (d, J = 7.7 Hz, 1 H), 5.27 (dt, J = 15.1, 7.3 Hz, 1 H), 1.43 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃):
δ = 170.0, 169.0, 156.9 (J = 37.8 Hz), 135.4, 133.9, 129.2, 128.8, 127.3, 125.0, 82.7, 62.8, 52.3, 38.4, 34.7, 27.9. HRMS (CI): m/z [M + H]⁺ calcd for C₂₁H₂₈F₃N₂O₅: 445.1906; found: 445.1942.