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

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

References and Notes

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14

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.

15

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.

16

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).

17

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.