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Synlett 2009(16): 2625-2628  
DOI: 10.1055/s-0029-1218018
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Furanoid Amino Acids via a Domino Michael-Aldol-Addition-Cyclization Approach

Uli Kazmaier*, Christian Schmidt
Institut für Organische Chemie, Universität des Saarlandes, 66123 Saarbrücken, Germany
Fax: +49(681)3022409; e-Mail: u.kazmaier@mx.uni-saarland.de;
Further Information

Publication History

Received 7 July 2009
Publication Date:
10 September 2009 (online)

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Abstract

Chelated enolates undergo Michael addition towards halogenated α,β-unsaturated esters in a highly stereoselective fashion. The enolates formed can be trapped with aldehydes in a stereoselective aldol reaction, before subsequent cyclization gives rise to substituted furanoid amino acids. Up to for stereogenic centers can be formed in this new one-pot reaction.

Key words

aldol reaction - amino acids - chelates - cyclization - domino reaction - Michael addition

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Michael Product 8
¹H NMR (500 MHz, CDCl3): δ = 1.47 (s, 9 H), 2.82-2.88 (m, 1 H), 3.58 (dd, J = 11.5, 6.4 Hz, 1 H), 3.63 (dd, J = 11.5, 6.2 Hz, 1 H), 3.65-3.69 (m, 1 H), 3.70 (s, 3 H), 4.72 (dd, J = 4.9, 8.2 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 27.9 (q), 33.0 (t), 39.6 (t), 44.5 (d), 52.3 (q), 54.1 (d), 84.2 (s), 115.7 (q, J = 287.7 Hz), 157.4 (q, J = 37.6 Hz), 168.2 (s), 172.4 (s). HRMS (CI): m/z calcd for C13H20NO5F3Cl [M + H]+: 362.0937; found: 362.1010.

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Cyclopropyl Amino Acid 9
¹H NMR (500 MHz, CDCl3): δ = 1.06 (ddd, J = 8.9, 5.7, 5.7 Hz, 1 H), 1.29 (ddd, J = 9.2, 5.2, 5.2 Hz, 1 H), 1.49 (s, 9 H), 1.71-1.75 (m, 1 H), 1.84 (dt, J = 8.8, 4.6 Hz, 1 H), 3.67 (s, 3 H), 4.07-4.12 (m, 1 H), 6.98 (d, J = 7.9 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 12.7 (t), 17.7 (d), 23.6 (d), 27.5 (q), 51.8 (q), 54.3 (d), 83.8 (s), 115.4 (q, J = 287.8 Hz), 156.6 (q, J = 37.6 Hz), 168.2 (s), 173.0 (s). HRMS (CI): m/z calcd for C13H19F3NO5 [M + H]+: 326.1215; found: 326.1258. Anal. Calcd for C13H18F3NO5 (325.28): C, 48.00; H, 5.58; N, 4.31. Found: C, 48.07; H, 5.39; N, 4.28.

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Michael-Aldol Product 10a
Major diastereomer: ¹H NMR (500 MHz, CDCl3): δ = 1.50 (s, 9 H), 3.08-3.12 (m, 1 H), 3.19 (dd, J = 9.9, 4.4 Hz, 1 H), 3.66 (br s, 1 H), 3.41 (s, 3 H), 3.91 (dd, J = 12.1, 4.0 Hz, 1 H), 4.00 (dd, J = 12.1, 5.9 Hz, 1 H), 4.81 (dd, J = 8.4, 4.6 Hz, 1 H), 5.10 (d, J = 4.4 Hz, 1 H), 7.24-7.34 (m, 6 H). ¹³C NMR (125 MHz, CDCl3): δ = 27.8 (q), 41.8 (d), 43.8 (t), 50.6 (d), 52.0 (s), 53.7 (d), 71.3 (d), 84.4 (s), 115.6 (q, J = 287.8 Hz), 124.9 (d), 128.4 (d), 127.8 (d), 140.8 (s), 156.9 (q, J = 38.0 Hz), 168.2 (s), 173.4 (s).
Minor diastereomer: ¹H NMR (500 MHz, CDCl3): δ = 1.47 (s, 9 H), 2.90-2.95 (m, 1 H), 3.01 (dd, J = 9.8, 1.4 Hz, 1 H), 3.08 (br s, 1 H), 3.40 (s, 3 H), 3.73 (t, J = 10.9 Hz, 1 H), 4.11 (dd, J = 19.9, 5.0 Hz, 1 H), 4.91 (d, J = 9.8 Hz, 1 H), 4.95 (dd, J = 8.4, 4.8 Hz, 1 H), 7.26-7.35 (m, 5 H), 9.05 (d, J = 8.3 Hz, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 27.8 (q), 41.6 (t), 42.8 (d), 52.1 (d), 52.3 (s), 52.5 (d), 71.8 (d), 83.5 (s), 115.6 (q, J = 287.8 Hz), 126.6 (d), 128.8 (d), 129.1 (d), 140.3 (s), 156.9 (q, J = 38.0 Hz), 168.5 (s), 172.0 (s).

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General Procedure for Domino Michael-Aldol Additions-Cyclizations In a Schlenk flask HMDS (0.3 mL, 1.42 mmol) was dissolved in THF (2 mL). The solution was cooled to -78 ˚C before n-BuLi (1.6 M, 0.78 mL, 1.25 mmol) was added. The cooling bath was removed and the solution was allowed to warm up for 15 min, before it was cooled again to -90 ˚C. In a second Schlenk flask ZnCl2 (80 mg, 0.57 mmol) was dried with a heat gun under high vacuum, before it was dissolved in THF (3 mL). After addition of TFA-Gly-Ot-Bu (115 mg, 0.5 mmol) the solution was cooled to -90 ˚C, before the freshly prepared LHMDS solution was added. 20 min later the Michael acceptor (0.42 mmol) was added in THF (2 mL). After 2 h the corresponding aldehyde (0.85 mmol) was added, and the reaction mixture was hold at -60 ˚C for 6 h. After addition of DMPU (1.5 mL) the reaction mixture was allowed to warm to r.t. overnight. The solution was diluted with hexanes-Et2O (9:1) before it was washed twice with NH4Cl (20 mL each). The aqueous phase was extracted twice with CH2Cl2, and the combined organic layers were dried (Na2SO4). After evaporation of the solvent under vacuum the crude product was purified by flash chromatography (silica, hexanes-EtOAc).

18

Spectroscopic and Analytical Data of Selected Products 11a
4,5-syn-11a: ¹H NMR (500 MHz, CDCl3): δ = 1.48 (s, 9 H), 3.19 (s, 3 H), 3.20 (dtd, J = 9.6, 8.9, 7.5 Hz, 1 H), 3.33 (t, J = 8.9 Hz, 1 H), 3.80 (t, J = 9.6 Hz, 1 H), 4.39 (dd, J = 9.2, 7.5 Hz 1 H), 4.53 (t, J = 9.0 Hz, 1 H), 4.91 (d, J = 8.5 Hz, 1 H), 7.01 (d, J = 8.9 Hz, 1 H), 7.20-7.30 (m, 5 H). ¹³C NMR (125 MHz, CDCl3): δ = 27.9 (q), 44.7 (d), 51.7 (q), 53.4 (d), 54.1 (d), 70.9 (t), 82.5 (d), 84.3 (s), 115.6 (q, J = 287.6 Hz), 126.5 (d), 128.0 (d), 128.2 (d), 137.9 (s), 157.0 (q, J = 38.0 Hz), 168.2 (s), 171.8 (s).
4,5-anti-11a: ¹H NMR (500 MHz, CDCl3): δ = 1.46 (s, 9 H), 2.92 (t, J = 8.2 Hz, 1 H), 3.13-3.18 (m, 1 H), 3.68 (s, 3 H), 4.13 (d, J = 7.0 Hz, 2 H), 4.55 (t, J = 8.2 Hz, 1 H), 4.96 (d, J = 8.4 Hz, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 7.20-7.36 (m, 5 H). ¹³C NMR (125 MHz, CDCl3): δ = 46.7 (d), 52.5 (q), 55.2 (d), 55.2 (d), 70.3 (t), 83.9 (d), 84.2 (s), 115.6 (q, J = 287.6 Hz), 125.8 (d), 128.6 (d), 128.2 (d), 139.2 (s), 157.0 (q, J = 38.0 Hz), 168.2 (s), 171.8 (s). HRMS (CI): m/z calcd for C20H25F3NO6 [M + H]+: 432.1634; found: 432.1658. Anal. Calcd for C20H24F3NO6 (431.41): C, 55.68; H, 5.61; N, 3.25. Found: C, 55.63; H, 5.61; N, 3.04.