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Synlett 2003(8): 1096-1100
DOI: 10.1055/s-2003-39893
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Chiral Monomers with Minimal Functional Group Linkages for Suspension Co-polymerization: A Suzuki Coupling Approach

Alison N. Hulme*a, Sarah A. Barrona, Andrew J. Walkerb
a School of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, UK
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Fax: +44(131)6504743; e-Mail: Alison.Hulme@ed.ac.uk;
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Publikationsverlauf

Received 11 April 2003
Publikationsdatum:
11. Juni 2003 (online)

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Abstract

A new strategy for the synthesis of chiral monomers for co-polymerization with styrene is described. Suzuki coupling of 4-vinylphenylboronic acid with chiral aryl triflates 5 and 13, and subsequent elaboration has resulted in chiral monomers 9 and 10. One of these monomers 10 has subsequently been incorporated into a polystyrene gel-type resin 16 with a functional group loading of 0.48 mmolg-1.

Key words

palladium - polymers - amino alcohols - ligands - asymmetric catalysis

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The conditions previously optimised for the coupling of methyl ester 5 and 4-vinylphenylboronic acid were found to give incomplete conversion to Suzuki product 14 resulting in a tricky separation of unreacted triflate 13 and product 14.

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Methyl (2S)-2-N-(tert-butoxycarbonyl)-3-[p-(p-vinylphenyl)phenyl]-propanoate (14), Rf [CH2Cl2:MeOH (95:5)] 0.92; mp 110 °C; [α]D +61.6 (c 0.6, CHCl3); IR (CHCl3 solution)/cm-1 3429, 3365, 2979, 1740, 1712, 1498, 1366, 1166, 756; δH (250 MHz, CDCl3) 7.57-7.44 and 7.25-7.17 (8 H, m), 6.75 (1 H, dd, J = 17.6 Hz, 10.9 Hz), 5.78 (1 H, dd, J = 17.6 Hz, 0.9), 5.27 (1 H, dd, J = 10.9 Hz, 0.9 Hz), 5.02 (1 H, d, J = 7.7 Hz), 4.62 (1 H, d, J = 7.9 Hz), 3.73 (3 H, s), 3.19-3.05 (2 H, m), 1.42 (9 H, s); δC (62.9 MHz, CDCl3) 172.2, 155.0, 139.9, 139.3, 136.4, 136.2, 135.0, 129.6 (2 C), 126.9 (4 C), 126.5 (2 C), 113.8, 79.9, 54.2, 52.2, 37.8, 28.2 (3 C); m/z (FAB) 382 ([M + H]+, 7%), 326 (25), 193 (25), 154 (100), 57 (28); HRMS (FAB) C23H28NO4 [M + H]+ requires 382.2018, found 382.2004.

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(3S)-3-N-(tert-Butoxycarbonyl)-2-methyl-4-[p-(p-vinylphenyl)phenyl]-butan-2-ol, Rf [CH2Cl2/MeOH (90:10)] 0.51; mp 150-151 °C; [α]D -69.0 (c 2.0, CHCl3); IR (CHCl3 solution)/cm-1 3377, 2980, 1669, 1529, 1172, 757; δH (200 MHz, CDCl3) 7.52-7.45 and 7.29-7.26 (8 H, m), 6.76 (1 H, dd, J = 17.5 Hz, 10.8 Hz), 5.79 (1 H, d, J = 17.5 Hz), 5.27 (1 H, d, J = 10.8 Hz), 4.66 (1 H, d, J = 9.2 Hz), 3.74-3.70 (1 H, m), 3.12 (1 H, d, J = 13.8 Hz), 2.68 (1 H, d, J = 13.8 Hz), 2.58 (1 H, br s), 1.30 (15 H, m); δC (50.3 MHz, CDCl3) 156.5, 140.4, 138.6, 138.2, 136.4 (2 C), 129.6 (2 C), 127.0 (2 C), 126.8 (2 C), 126.6 (2 C), 113.8, 79.4, 72.9, 60.3, 35.5, 28.1 (3 C), 27.5, 26.5; m/z (FAB) 382 ([M + H]+, 2%), 373 (5), 309 (9), 301 (14), 193 (43), 57 (100); HRMS (FAB) C24H32NO3 [M + H]+ requires 382.2382, found 382.2399.
(3S)-3-Amino-2-methyl-4-[p-(p-vinylphenyl)phenyl]-butan-2-ol (10), Rf [CH2Cl2/MeOH (90:10)] 0.23; mp 114-115 °C; [α]D -44.2 (c 0.5, MeOH); IR (CHCl3 solution)/
cm-1 3402, 3343, 3280, 2976, 1497, 1389; δH (200 MHz, CD3OD) 7.57-7.44 and 7.32-7.28 (8 H, m), 6.75 (1 H, dd, J = 17.8 Hz, 10.8 Hz), 5.79 (1 H, d, J = 17.8 Hz), 5.22 (1 H, d, J = 10.8 Hz), 3.02 (1 H, dd, J = 13.2 Hz, 2.7 Hz), 2.88 (1 H, dd, J = 10.7 Hz, 2.7 Hz), 2.34 (1 H, dd, J = 13.2 Hz, 10.7 Hz), 1.27 (3 H, s), 1.23 (3 H, s); δC (62.9 MHz, CD3OD) 139.6, 138.7, 138.0, 136.0, 135.8, 128.9 (2 C), 126.1 (2 C), 126.0 (2 C), 125.8 (2 C), 112.1, 71.5, 61.3, 37.1, 24.7, 22.9; m/z (FAB) 282 ([M + H]+, 56%), 264 (17), 222 (19), 193 (100), 88 (31), 43 (27); HRMS (FAB) C19H24NO [M + H]+ requires 282.1858, found 282.1858; Anal. Calcd for C19H23NO: C, 81.10; H, 8.24; N, 4.98, found C, 80.59; H, 8.16; N, 4.73.

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(3S)-4-Biphenyl-3-N-(tert-butoxycarbonyl)-2-methyl-butan-2-ol, Rf [hexane/EtOAc (80:20)] 0.14; mp 137-138 °C; [α]D -61.2 (c 1.0, CHCl3);IR (CHCl3 solution)/cm-1 3442, 2980, 1700, 1503, 1368, 1169; δH (250 MHz, CDCl3) 7.58-7.25 (9 H, m), 4.65 (1 H, d, J = 9.6 Hz), 3.80-3.69 (1 H, m), 3.13 (1 H, dd, J = 14.2 Hz, 3.4 Hz), 2.71 (1 H, br s), 2.62 (1 H, d, J = 14.2 Hz), 1.41-1.25 (15 H, m); δC (62.9 MHz, CDCl3) 156.3, 141.0, 139.0, 137.9, 129.5, 128.6 (3 C), 126.9 (5 C), 79.2, 72.8, 60.2, 35.3, 28.1 (3 C), 27.4, 26.5;
m/z (FAB) 356 ([M + H]+, 19%), 300(57), 282(75), 167(100), 57(91); HRMS (FAB) C22H30NO3 [M + H]+ requires 356.2225, found 356.2225; Anal. Calcd. for C22H29NO3: C, 74.33; H, 8.22; N, 3.94, found C, 73.82; H, 8.24; N, 4.06. (3S)-3-Amino-4-biphenyl-2-methyl-butan-2-ol (15), Rf [CH2Cl2/MeOH (90:10)] 0.23; mp 65-66 °C; [α]D -40.2 (c 1.0, CHCl3); IR (nujol)/cm-1 3404, 3341, 3270, 1487, 754; δH (200 MHz, CD3OD) 7.60-7.54 and 7.44-7.29 (9 H, m), 3.03 (1 H, d, J = 13.4 Hz), 2.89 (1 H, d, J = 11.0 Hz), 2.35 (1 H, dd, J = 13.4 Hz, 11.0 Hz), 1.28 (3 H, s), 1.24 (3 H, s); δC (50.3 MHz, CD3OD) 142.3, 140.7 (2 C), 130.8 (2 C), 129.9 (2 C), 128.2 (3 C), 127.9 (2 C), 73.5, 63.2, 39.0, 26.6, 24.8; m/z (FAB) 256 ([M + H]+, 85%), 238 (35), 196 (20), 167 (100), 88 (24), 43 (28); HRMS (FAB) C17H22NO [M + H]+ requires 256.1701, found 256.1706.

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A dry 500 mL 3-necked flask equipped with overhead stirrer, condenser and septum was charged with distilled water (135 mL) which was subsequently degassed and purged with argon. PVA (675 mg, 87-89% hydrolysed, average MW = 85000-146000) was added and the reaction mixture was stirred at 125 °C for 10 minutes before being cooled to 0 °C. Two further dry flasks were separately charged with THF (50 mL) and toluene (50 mL), each being degassed and purged with argon. The amino alcohol monomer 10 (1.84 g, 6.55 mmol) was added to the THF ensuring dissolution before addition of the toluene. AIBN (211 mg, 1.28 mmol), styrene (9.94 mL, 86.7 mmol) and divinylbenzene (5.25 mL, 29.5 mmol) were then added to the organic phase with each of the monomers being washed with 1% aqueous NaOH (10 mL) and water (2 × 10 mL) immediately prior to use. The monomer phase was added via cannulation over a period of 10 minutes to the cooled aqueous phase which was stirred at 350 RPM. The height of the paddle impeller was positioned ˜ 3 cm below the surface of the reaction mixture as this depth was found to visually reduce horizontal flow. Stirring was then continued at 0 °C for 1 hour. The reaction mixture was then heated to 80 °C with constant stirring at 350 RPM under argon for 18 hours. The polymer beads were collected by filtration through a 100 micron mesh sieve and washed with water (500 mL), THF (500 mL) and methanol (500 mL). The polymeric material was then dried under reduced pressure at 40 °C to constant mass and sieved between 500 and 100 micron mesh sieves affording cross-linked amino alcohol polymer(16) as colourless free flowing beads (3.40 g, 23%), IR (KBr disc)/cm-1 3446, 3025, 2923, 1601, 1493, 1452, 758, 698; Anal. Calcd. for polymer: C, 90.69; H, 7.81; N, 0.70, found C, 89.74; H, 8.05; N, 0.67, loading = 0.48 mmolg-1; N2 BET adsorption < 10 m2g-1; resin swelled to 5.2 times its own volume in CH2Cl2.
A significant proportion of the polymeric product was found to contain larger colourless beads mixed with plastic residue which were retained in the 500 micron mesh sieve (4.34 g, 30%), IR (KBr disc)/cm-1 3446, 3025, 2918, 1601, 1493, 1452, 758, 699; Anal. Calcd. for polymer: C, 90.69; H, 7.81; N, 0.70, found C, 89.89; H, 8.08; N, 0.70, loading = 0.50 mmolg-1; N2 BET adsorption < 10 m2g-1; resin swelled to 4.7 times its own volume in CH2Cl2.