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

Nina G. Bandur; Klaus Harms; Ulrich Koert

doi:10.1055/s-2006-956456

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Synlett 2007(1): 0099-0102
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;

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Publication History

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

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

References and Notes

Reviews on peptidomimetics:
1a Giannis A. Kolter T. Angew. Chem., Int. Ed. Engl. 1993, 32: 1244

Search in Google Scholar
1b Gante J. Angew. Chem., Int. Ed. Engl. 1994, 33: 1699

Search in Google Scholar
1c Venkatesan N. Kim BH. Curr. Med. Chem. 2002, 9: 2243

Search in Google Scholar
1d Tourwe D. Synthesis of Peptides and Peptidomimetics, In Methods of Organic Chemistry (Houben-Weyl) Vol. E22c: Goodman M. Felix A. Moroder L. Toniolo C. Thieme Verlag; Stuttgart, New York: 2004.

Search in Google Scholar
2a Hann MM. Sammes PG. Kennewell PD. Taylor JB. J. Chem. Soc., Chem. Commun. 1980, 234

Crossref
2b Hann MM. Sammes PG. Kennewell PD. Taylor JB. J. Chem. Soc., Perkin Trans. 1 1982, 307

Crossref
2c Kranz M. Kessler H. Tetrahedron Lett. 1996, 37: 5359

Crossref Search in Google Scholar
For recent examples, see:
3a Otaka A. Katagiri F. Kinoshita T. Odagaki Y. Oishi S. Tamamura H. Hamanaka N. Fujii N. J. Org. Chem. 2002, 67: 6152

Crossref Search in Google Scholar
3b Oishi S. Kamano T. Niida A. Odagaki Y. Hamanaka N. Yamamoto M. Ajito K. Tamamura H. Otaka A. Fujii N. J. Org. Chem. 2002, 67: 6162

Crossref Search in Google Scholar
3c Tamamura H. Hiramatsu K. Miyamoto K. Omagari A. Oishi S. Nakashima H. Yamamoto N. Kuroda Y. Nakagawa T. Otaka A. Fujii N. Bioorg. Med. Chem. Lett. 2002, 12: 923

Crossref Search in Google Scholar
3d Vasbinder MM. Miller SJ. J. Org. Chem. 2002, 67: 6240

Crossref Search in Google Scholar
3e Tamamura H. Koh Y. Ueda S. Sasaki Y. Yamasaki T. Aoiki M. Maeda K. Watai Y. Arikuni H. Otaka A. Mitsuya H. Fujii N. J. Med. Chem. 2003, 46: 1764

Crossref Search in Google Scholar
3f Wang XJ. Hart SA. Xu B. Mason MD. Goodell JR. Etzkorn FA. J. Org. Chem. 2003, 68: 2343

Crossref Search in Google Scholar
3g Garbe D. Sieber S. Bandur NG. Koert U. Marahiel MA. ChemBioChem 2004, 5: 1000

Crossref Search in Google Scholar
3h Wipf P. Xiao J. Org. Lett. 2005, 7: 103

Crossref Search in Google Scholar
3i Bandur NG. Harms K. Koert U. Synlett 2005, 773

Crossref
3j Fu Y. Bieschke J. Kelly JW. J. Am. Chem. Soc. 2005, 127: 15366

Crossref Search in Google Scholar
3k Reginato G. Gaggini F. Mordini A. Valacchi M. Tetrahedron 2005, 61: 6791

Crossref Search in Google Scholar
4 Gage JR. Evans DA. Org. Synth. 1989, 68: 77

Search in Google Scholar
5 Blakemore PR. Cole WJ. Kocieński PJ. Morley A. Synlett 1998, 26

Thieme Connect
10a Evans DA. Urpi F. Somers TC. Clark JS. Bilodeau MT. J. Am. Chem. Soc. 1990, 112: 8215

Crossref Search in Google Scholar
10b Takacs JM. Jaber MR. Vellekoop AS. J. Org. Chem. 1998, 63: 2742

Crossref Search in Google Scholar
13 De Mico A. Margarita R. Parlani L. Vescovi A. Piancatelli G. J. Org. Chem. 1997, 62: 6974

Crossref Search in Google Scholar

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.