First Stereoselective Synthesis of a Tyr-Tyr E-Alkene Isostere

Nina G. Bandur; Klaus Harms; Ulrich Koert

doi:10.1055/s-2006-956456

LETTER

First Stereoselective Synthesis of a Tyr-Tyr E-Alkene Isostere

Nina G. Bandur, Klaus Harms, Ulrich Koert*
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße, 35043 Marburg, Germany
Fax: +49(6421)2825677; e-Mail: koert@chemie.uni-marburg.de;

Abstract

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Abstract

A stereoselective synthesis of a tyrosine-tyrosine E-alkene isostere is described. Starting from N-Fmoc-O-(tert-butyl)tyrosine as N-terminal component, the E double bond was generated by a Julia-Kocieński olefination. An enantioselective aldol reaction was applied to synthesize the required aldehyde. The configuration of the new stereocenter was determined by X-ray crystallography.

Key words

tyrosine - E-alkene - dipeptide isostere - aldol reaction - Julia-Kocieński olefination

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Referenzen

References and Notes

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Analytical Data of Sulfone 4.
R _f = 0.11 (cHex-TBME, 2:1); [α]_D ²⁷ -9.1 (c 1.23, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.67-7.53 (m, 5 H), 7.11-7.03 (m, 2 H), 6.99-6.89 (m, 3 H), 4.84-4.67 (m, 1 H), 4.13 (dd, J = 15.3, 9.1 Hz, 1 H), 3.97 (dd, J = 15.3, 3.6 Hz, 1 H), 3.11 (dd, J = 13.8, 7.0 Hz, 1 H), 3.04 (dd, J = 13.8, 6.8 Hz, 1 H), 1.33 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 156.8 (q, J = 38 Hz), 155.1, 153.6, 131.7, 129.75 (2 C), 129.72 (2 C), 129.3, 125.1 (2 C), 124.6 (2 C), 78.8, 57.5, 47.5, 38.7, 28.8 (3 C). IR (film): ν = 3323 (m), 2982 (m), 2932 (w), 1703 (s), 1559 (m), 1508 (m), 1354 (s), 1220 (m), 1156 (s), 899 (w), 879 (w), 764 (m), 689 (w), 639 (m), 522 (m) cm^-1. HRMS (ESI): m/z calcd for C₂₂H₂₄F₃N₅NaO₄S [M + Na⁺]: 534.1393; found: 534.1401.

Compound 5 was prepared from 3-(4-hydroxyphenyl)prop-ionic acid by the following sequence: 1. i. BnCl, KI, K₂CO₃, acetone, reflux, 2 d; ii. NaOH, H₂O, reflux, 2 d, 80%; 2. i. PvCl, TEA, -20 °C, 2 h; ii. (R)-4-benzyl-1,3-oxazolidin-2-one, LiCl, 12 h, r.t., 91%; 3. Pd(OH)₂/C, H₂ (1 atm), MeOH-EtOAc (1:1), 3 h, 99%; 4. TBDPSCl, imidazole, DMF, 0 °C to r.t., 12 h, 89%.

Preparation of Compound 6. A solution of 5 (7.02 mmol, 3.96 g) in CH₂Cl₂ (40 mL) was cooled to 0 °C and TiCl₄ (7.72 mmol, 0.85 mL) was added dropwise. After 5 min, diisopropylethyl amine (DIPEA, 8.01 mmol, 1.4 mL) was added whereupon the solution turned dark purple. After the mixture was stirred at 0 °C for 1 h a solution of 1,3,5-trioxane (8.01 mmol, 0.72 g) in CH₂Cl₂ (5 mL) was added, followed by TiCl₄ (7.37 mmol, 0.81 mL). The mixture was stirred for 3 h at 0-10 °C. Then, sat. NH₄Cl solution (50 mL) was added and the layers were separated. After extraction with additional CH₂Cl₂ (3 × 50 mL) the organic layers were pooled and washed subsequently with H₂O (2 × 25 mL) and brine (50 mL). After drying with Na₂SO₄ and evaporation of solvents the residue was purified by flash column chromatography on silica (300 g, TBME-pentane 1:2 to 1:1) to give compound 6 as a colorless oil (5.97 mmol, 3.55 g, 85%). R _f = 0.37 (c-Hex-EtOAc, 1:1); [α]_D ²⁴ -75.0 (c 0.98, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.74-7.65 (m, 4 H), 7.43-7.26 (m, 9 H), 7.24-7.16 (m, 2 H), 6.96 (pd, J = 8.5 Hz, 2 H), 6.67 (pd, J = 8.5 Hz, 2 H), 4.44 (dddd, J = 9.4, 7.6, 3.5, 2.1 Hz, 1 H), 4.26-4.13 (m, 1 H), 4.03 (dd, J = 9.1, 2.1 Hz, 1 H), 3.90-3.70 (m, 2 H), 3.83 (dd, J = 8.2, 8.2 Hz, 1 H), 3.23 (dd, J = 13.5, 3.3 Hz, 1 H), 2.86 (dd, J = 13.4, 7.6 Hz, 1 H), 2.76 (dd, J = 13.4, 5.3 Hz, 1 H), 2.73 (dd, J = 13.3, 3.7 Hz, 1 H), 2.26 (br s, 1 H), 1.08 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 175.5, 154.3, 153.2, 135.5 (4 C), 135.2, 133.0, 133.0, 132.9, 130.5, 129.9 (2 C), 129.8 (2 C), 129.5 (2 C), 128.9 (2 C), 127.7 (2 C), 127.4, 119.6 (2 C), 66.0, 63.0, 55.5, 47.1, 37.9, 34.0, 26.5 (3 C), 19.4. IR (KBr): ν = 3506 (m, br), 3029 (w), 2930 (m), 2857 (m), 1780 (s), 1697 (s), 1510 (s), 1390 (m), 1350 (w), 1255 (s), 1210 (m), 1112 (m), 917 (m), 701 (s), 501 (m) cm^-1. HRMS (ESI): m/z calcd for C₂₈H₃₅NSiNaO₄ [M + Na⁺]: 500.2228; found: 500.2229.

No other stereoisomer was detected in the NMR spectra. For the assignment of the stereochemistry of 6, see Figure [1] .

<A NAME="RG27806ST-10A">10a</A> Evans DA. Urpi F. Somers TC. Clark JS. Bilodeau MT. J. Am. Chem. Soc. 1990, 112: 8215

<A NAME="RG27806ST-10B">10b</A> Takacs JM. Jaber MR. Vellekoop AS. J. Org. Chem. 1998, 63: 2742

The crystal data of compound 6a has been deposited in the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 616493. Crystal data: C₂₁H₂₃NO₅, M = 369.40, orthorhombic, P2₁2₁2₁, a = 7.0200(4) Å, b = 13.4213(10) Å, c = 19.5897(12) Å, α = 90°, β = 90°, γ = 90°, V = 1845.7(2) Å³, Z = 4, D _calcd = 1.329 g/cm³, 16972 collected reflections, 3696 independent (R _int = 0.0390), R1 = 0.0265, wR2 = 0.0686 (all data).

Preparation of Compound 9. A solution of sulfone 4 (0.17 mmol, 85 mg) in 1,2-dimethoxyethane (DME, 1 mL) was cooled to -78 °C and NaHMDS (2 M in THF, 0.37 mmol, 0.18 mL) was added. The resulting yellow solution was stirred at -78 °C for 30 min and aldehyde 8 dissolved in DME (0.5 mL) was added. The solution allowed to warm to r.t. overnight. Then phosphate buffer (1 M, 2 mL) and TBME (4 mL) were added. After the layers were separated the aqueous layer was extracted with additional TBME (3 × 4 mL). The combined organic extracts were dried with Na₂SO₄ and after evaporation of solvents the residue was purified by flash column chromatography (8 g, TBME-pentane, 1:10) followed by a second chromatography (8 g, acetone-pentane, 1:10). The pure product 9 was obtained as a colorless oil. The determination of the E/Z selectivity of 2.3:1 and the separation of the isomers was done after THP deprotection affording compound 10.
E -Isomer: R _f = 0.41 (c-Hex-EtOAc, 1:1); [α]_D ²⁵ -31.2 (c 1.06, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.05-6.84 (m, 8 H), 6.23 (br d, J = 7.2 Hz, 1 H), 5.33 (dd, J = 15.2, 7.3 Hz, 1 H), 5.25 (dd, J = 15.4, 7.3 Hz, 1 H), 4.59 (ddd, J = 13.8, 7.0, 6.8 Hz, 1 H), 3.51 (dd, J = 10.6, 4.6 Hz, 1 H), 3.34 (dd, J = 10.3, 7.3 Hz, 1 H), 2.80 (dd, J = 13.6, 6.4 Hz, 1 H), 2.75 (dd, J = 13.0, 7.7 Hz, 1 H), 2.64 (dd, J = 12.9, 5.8 Hz, 1 H), 2.54-2.34 (m, 1 H), 2.49 (dd, J = 12.7, 8.0 Hz, 1 H), 1.67 (br s, 1 H), 1.32 (s, 9 H), 1.31 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 156.3 (q, J = 37 Hz), 154.5, 153.7, 134.6, 134.1, 131.0, 129.9, 129.7 (2 C), 129.5 (2 C), 124.3 (2 C), 124.0 (2 C), 117.7, 78.5, 78.2, 64.9, 53.2, 47.1, 40.1, 36.7, 28.82 (3 C), 28.80 (3 C). HRMS (ESI): m/z calcd for C₂₉H₃₈F₃NNaO₄ [M + Na⁺]: 544.2645; found: 544.2655.
Z -Isomer: R _f = 0.42 (c-Hex-EtOAc, 1:1); [α]_D ²⁴ +25.2 (c 1.04, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.07-6.82 (m, 8 H), 6.39 (br d, J = 6.0 Hz, 1 H), 5.41 (dd, J = 10.8, 10.4 Hz, 1 H), 5.31 (dd, J = 10.8, 9.0 Hz, 1 H), 4.59 (ddd, J = 14.4, 7.9, 7.0 Hz, 1 H, 5-H), 3.70 (dd, J = 10.5, 4.4 Hz, 1 H), 3.41 (dd, J = 10.1, 9.5 Hz, 1 H), 3.06-2.92 (m, 1 H), 2.63 (dd, J = 13.4, 5.1 Hz, 1 H), 2.37 (dd, J = 13.9, 7.3 Hz, 1 H), 2.30 (dd, J = 13.9, 6.0 Hz, 1 H), 2.25 (dd, J = 13.5, 9.2 Hz, 1 H), 1.70 (br s, 1 H), 1.29 (s, 9 H), 1.23 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 156.8 (q, J = 37 Hz), 154.6, 153.7, 135.1, 134.3, 130.3, 129.7, 129.6 (2 C), 129.5 (2 C), 124.4 (2 C), 124.0 (2 C), 117.5, 78.5, 78.2, 65.9, 49.3, 43.8, 39.4, 37.2, 28.8 (3 C), 28.7 (3 C). HRMS (ESI): m/z calcd for C₂₉H₃₈F₃NNaO₄ [M + Na⁺]: 544.2645; found: 544.2651.

<A NAME="RG27806ST-13">13</A> De Mico A. Margarita R. Parlani L. Vescovi A. Piancatelli G. J. Org. Chem. 1997, 62: 6974

Analytical Data of Compound 11.
R _f = 0.24 (c-Hex-EtOAc, 1:1); [α]_D ¹⁹ -30.7 (c 0.32, CHCl₃). ¹H NMR (500 MHz, 343 K, DMSO-d ₆): δ = 11.98 (br s, 1 H), 7.85 (pd, J = 7.6 Hz, 2 H), 7.63 (pd, J = 7.6 Hz, 2 H), 7.40 (pt, J = 7.4 Hz, 2 H), 7.31 (pt, J = 7.4 Hz, 2 H), 7.25-7.11 (m, 1 H), 7.05 (pd, J = 8.3 Hz, 2 H), 7.03-6.97 (m, 2 H), 6.83 (pd, J = 8.5 Hz, 2 H), 6.78 (pd, J = 8.5 Hz, 2 H), 5.57-5.42 (m, 2 H), 4.28-4.17 (m, 2 H), 4.15-4.07 (m, 1 H), 4.14 (t, J = 6.8 Hz), 3.17-3.06 (m, 1 H), 2.90 (dd, J = 13.7, 7.6 Hz, 1 H), 2.69-2.57 (m, 3 H), 1.26 (s, 9 H), 1.22 (s, 9 H). ¹³C NMR (500 MHz, 343 K, DMSO-d ₆): δ = 177.4, 153.2, 153.1 (2 C), 143.61, 143.59, 140.4 (2 C), 133.1, 132.64, 132.58, 129.3 (2 C), 129.1 (2 C), 127.3, 127.1 (2 C), 126.6 (2 C), 124.7 (2 C), 122.7 (2 C), 122.6 (2 C), 119.6 (2 C), 77.2, 77.1, 65.1, 53.6, 49.6, 46.5, 37.0, 28.28 (3 C), 28.26 (3 C); one benzylic carbon atom was not observed because of a superposition with the DMSO-d ₆ signal. HRMS (ESI): m/z calcd for C₄₂H₄₇NNaO₆ [M + Na⁺]: 684.3296; found: 684.3313.