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Synlett 2007(1): 0099-0102  
DOI: 10.1055/s-2006-956456
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
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Publication History

Received 21 August 2006
Publication Date:
20 December 2006 (online)

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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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6

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.

7

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%.

8

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.

9

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

11

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).

12

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.

14

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.