A Poly(ethylene glycol) Supported Chiral Auxiliary for Asymmetric Michael Reactions

Abstract

The synthesis of a novel polymer-bound l-valine derived auxiliary 10 is reported. Its synthetic use is demonstrated in asymmetric copper(II)-catalyzed Michael reactions of cyclic β-oxo esters 12 with methyl vinyl ketone (2), yielding the corresponding addition products 3 with quaternary stereocenter in selectivities up to 99% ee. The immobilized auxiliary 10 can be recovered by simple precipitation from diethyl ether.

Key words

chiral auxiliary - Michael addition - immobilization - quaternary stereocenters - soluble polymer

References

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8

Load values were calculated by ¹H NMR integrals with the polymer signal at δ = 3.45-3.80 ppm as a standard. In the case of 13b the signal at δ = 4.13 ppm (2 H) and for 15b the signal at δ = 2.22 ppm (3 H) were used for integration.

9

Supported N -(2-Ethoxycarbonyl-1-cyclohexenyl)-l- valine(4-hydroxypiperidide) (13b).
Immobilized auxiliary 10 (2.50 g, 1.54 mmol), 12b (3.00 g, 17.6 mmol) and one drop of TFA in abs. toluene (8 mL) were heated at 55 ºC for 16 h. Two fold precipitation from abs. Et₂O (80 mL) yielded 13b (2.58 g, 99%) as a pale yellow polymer. ¹H NMR (300 MHz, CDCl₃): δ = 1.00 (d, ³ J = 6.9 Hz, 3 H, CH₃), 1.03 (d, ³ J = 6.9 Hz, 3 H, CH₃), 1.26 (t, ³ J = 7.1 Hz, 3 H, CH₂CH ₃), 1.47-1.68 (m, 6 H), 1.77-1.92 (m, 2 H), 1.95-2.14 (m, 2 H), 2.21-2.32 (m, 3 H), 3.23-3.36 (m, 2 H), 3.50-3.74 (m, 140 H, PEG-H), 3.91-4.01 (m, 1 H), 4.13 (q, ³ J = 7.2 Hz, 2 H, OCH₂), 9.31 (d, br, ³ J = 8.8 Hz, 1 H, NH) ppm. All other signals are overlapped by resonances of the polymer backbone. ¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 14.65 (CH₃), 18.42 (CH₃), 19.90 (CH₂ CH₃), 22.35 (CH₂), 22.57 (CH₂), 23.91 (CH₂), 26.75 (CH₂), 30.74 (CH₂, br, C-3′), 31.81 (CH₂, br, C-3′), 31.98 (CH, CHCH₃), 39.45 (CH₂, br, C-2′), 42.69 (CH₂, br, C-2′), 58.38 (CH, CHNH), 58.74 (CH₂, OCH₂), 74.36 (CH, OCH), 91.47 (C, C-2′′), 157.51 (C, br, CNH), 170.48 (C, CON), 170.62 (C, COO) ppm. IR (ATR): 1/λ = 3483 (w, br), 2882 (s), 1645 (m), 1592 (m), 1466 (m), 1359 (m), 1341 (s), 1279 (m), 1233 (s), 1146 (m), 1103 (vs), 1063 (vs), 948 (s), 841 (s) cm^-1. Anal. Calcd for 13b assuming 44 ethylene oxide units in a polymeric backbone of 2000 Da at 72% load: C, 56.77; H, 9.18; N, 1.62. Found: C, 56.42; H, 9.18; N, 1.57.

10

Supported ( R )- N -[2-Ethoxycarbonyl-2-(3-oxobutyl)-1- cyclohexyliden e-l-valine (4-hydroxypiperidide)] (15b).
To a solution of polymer 13b (0.40 g) in acetone (2 mL) was added Cu(OAc)₂·H₂O (4.0 mg, 0.02 mmol). The mixture was stirred for 1 h at 23 ºC, then 2 (1.00 g, 14.3 mmol) was added. After stirring of the mixture for 2 d, the product polymer was precipitated from Et₂O (50 mL) to yield a brown polymer 15b (0.39 g, 99%). ¹H NMR (300 MHz, CDCl₃): δ = 0.88 (d, ³ J = 6.2 Hz, 3 H, CHCH ₃), 0.92-1.02 (m, 3 H, CHCH ₃), 1.25 (t, ³ J = 7.1 Hz, 3 H, CH₂CH ₃), 1.41-1.90 (m, 8 H), 2.09-2.16 (m, 7 H), 2.22 (s, 3 H, COCH₃), 2.31-2.70 (m, 2 H), 2.51 (t, ³ J = 6.2 Hz, 2 H), 2.72-3.38 (m, 2 H), 3.44-3.81 (m, 131 H, PEG-H), 3.98-4.23 (m, 2 H), 4.11-4.21 (m, 2 H, OCH₂) ppm. ¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 18.92 (CH₃), 25.19 (CH₂), 28.40 (CH₂), 29.96 (CH₂), 32.58 (CH₂), 38.87 (CH₂, NCH₂), 42.87 (CH₂, NCH₂) 60.82 (CH, CHN), 67.55 (CH, OCH), 141.78 (C, CN), 173.91 (C, COO), 208.46 (C, CO) ppm. Missing signals cannot be identified from background noise.

11

Ethyl ( R )-2-Oxo-1-(3-oxobutyl)cyclohexanecarboxylate ( 3b). [15]
Polymer 15b (1.00 g, 0.52 mmol) was stirred in HCl (2 mL, c = 1 mol dm^-3) at 0 ºC for 3 h. H₂O (20 mL) was added, and the mixture was then extracted with Et₂O (3 × 20 mL). The combined ether layers were washed with H₂O (50 mL), dried (MgSO₄) and evaporated to give 3b (108 mg, 0.45 mmol, 87% reg. 15b) as a colorless oil with 97% purity (determined by ¹H NMR spectroscopy). GC for determination of ee value: Bondex unβ [16] [20 m × 0.3 mm with hydrogen carrier gas (0.4 bar)], 120 °C isotherm; t _R(R) = 29.75 min; t _R(S) = 30.88 min, 97% ee.
Extraction of the water layers with CH₂Cl₂ (3 × 50 mL), subsequent washing of the combined CH₂Cl₂ layers with H₂O (50 mL), drying (MgSO₄) and removal of all volatile materials under high vacuum gave the re-isolated polymer 10 (867 mg).