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Synlett 2005(16): 2420-2424  
DOI: 10.1055/s-2005-872698
LETTER
© Georg Thieme Verlag Stuttgart · New York

Ligand-Mediated Enantioselective Synthesis of Acyclic Pyrrole Carbinols

Darren J. Dixon*a, Mark S. Scottb, Chris A. Luckhurstc
a School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
b The University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
c AstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, UK
Fax: +44(161)2754939; e-Mail: Darren.Dixon@man.ac.uk;
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Publication History

Received 8 July 2005
Publication Date:
21 September 2005 (online)

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Abstract

The enantioselective synthesis of acyclic pyrrole carbinols via ligand-mediated addition of lithium pyrrolate to ­aldehydes, and subsequent exploitation of the resulting stereocentre as a stereodirecting group in syn- or anti-selective 1,3-reductions of ketone functionality in the parent aldehyde is described.

Key words

aldehydes - asymmetric synthesis - ligands - lithium - pyrrole carbinol

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Lithium pyrrolate shows low solubility in non-polar solvents, marginally higher solubility in ethereal solvents. Almost complete dissolution is observed at the operating concentration of 0.1 M.

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( R )-1-Hydroxy-2,2-dimethyl-1-pyrrol-1-yl-pentan-3-one ( 2i). To a rapidly stirred solution of pyrrole (730 µL, 10.5 mmol) in toluene (100 mL) was added n-BuLi (4.0 mL, 10 mmol, 2.5 M in hexane) at 0 °C. The solution was allowed to warm to room temperature over 5 min before 7a (2.42 g, 10.0 mmol) was added in one portion. The reaction was allowed to stir for 25 min at this temperature before cooling to -78 °C and the aldehyde 1i (1.28 g, 10 mmol) was added over 5 s via syringe. After 30 min at this temperature the reaction was quenched by the rapid addition of a pre-cooled solution of AcOH (15 mmol) in THF (15 mL). After a further 30 min the reaction was allowed to warm to 0 °C over 15 min before being filtered though a pad of silica (6 cm × 6 cm) and concentrated under reduced pressure to give the crude product. 1H NMR and HPLC analysis indicated a conversion of 95% and ee of 46%. Purification by flash column chromatography eluting with hexane-EtOAc (20:1 to 1:5) yielded 2i as a pale brown oil (1.56 g, 80%), 7a as a white solid (2 g, 70%) together with further 2i (13%) contaminated with 7a (25%). HPLC indicated no change in ee. [α]D 25 = +18.2 (c 1.1, CDCl3). 1H NMR (400 MHz): δ = 6.71 (2 H, t, J = 2.2 Hz, CHCHN), 6.13 (2 H, t, J = 2.2 Hz, CHCHN), 5.43 (1 H, br d, J = 3.9 Hz, NCHOH), 4.36 (1 H, br, OH), 2.52-2.41 (2 H, m, CH2), 1.8 (3 H, s, CH3), 1.13 (3 H, s, CH3), 1.02 (3 H, t, J = 7.1 Hz, CH2CH3). 13C NMR (100 MHz): δ = 217.8 (C), 120.3 (CH), 108.2 (CH), 87.8 (CH), 52.4 (C), 32.4 (CH2), 22.9 (CH3), 19.5 (CH3), 7.5 (CH3). IR (film): νmax = 3445 (br), 2978, 1698, 1472, 1261, 1081 cm-1. MS (ESI): m/z calcd for C13H13NO +: 196.1332. Found: 196.1335 [MH+].

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(1 R ,3 R )-2,2-Dimethyl-1-pyrrol-1-yl-pentane-1,3-diol ( 4a). To a solution of 2i (231 mg, 1.18 mmol) in Et2O (6 mL) was added freshly prepared zinc borohydride (24 mL, 3.6 mmol, ca. 0.15 M in Et2O) at -35 °C. After stirring for 8 h the reaction was quenched with MeOH (5 mL) followed by the addition of sodium potassium tartrate solution (15 mL) and EtOAc (25 mL) then stirred for 10 min. The layers were separated and the aqueous phase further extracted with EtOAc (2 × 50 mL). The combined organics were washed with brine (15 mL), dried (MgSO4) and the solvent removed under reduced pressure. Analysis of the crude material by 1H NMR gave a selectivity of 94:6. The crude product was purified by flash column chromatography eluting with hexane-EtOAc (20:1 to 1:5) gave 4a as a colourless oil (209 mg, 90%) as a 16.6:1 mixture of diastereomers. [α]D 25 = +5.2 (c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 6.81 (2 H, t, J = 2.0 Hz, CH=CHN), 6.14 (2 H, t, J = 2.0 Hz, CH=CHN), 5.33 (1 H, s, NCHOH), 4.26 (1 H, br, OH), 3.26 [1 H, dd, J = 10.5, 1.9 Hz, CH(OH)CH2], 2.69 (1 H, br, OH), 1.55 (1 H, dqd, J = 14.1, 7.1, 1.8 Hz, CH aHbCH3), 1.40-1.28 (1 H, ddq, J = 14.1, 10.5, 7.1 Hz, CHa H bCH3), 1.00 (3 H, s, CCH 3), 0.98 (3 H, t, J = 7.1 Hz, CH2CH 3), 0.67 (3 H, s, CCH 3). 13C NMR (100 MHz, CDCl3): δ = 119.7 (CH), 107.5 (CH), 89.2 (CH), 79.3 (CH), 43.6 (C), 24.2 (CH2), 20.5 (CH3), 14.3 (CH3), 11.0 (CH3). IR (film): νmax = 3399 (br), 2972, 1472, 1261, 1077, 969 cm-1. MS (ESI): m/z calcd for C11H20NO2 +: 198.1489. Found: 198.1492 [MH+].

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( R )-5-Hydroxy-4,4-dimethyl-hept-2-enoic Acid tert -Butyl Ester ( 13). To a suspension of NaH (17 mg, 0.42 mmol, 60% in mineral oils) in THF (1 mL) was added tert-butyl diethylphos-phonoacetate (0.12 mL, 0.5 mmol) at 0 °C. A solution of 4a (55 mg, 0.28 mmol) in THF (1 mL) was added dropwise and stirred for 20 min. The reaction was then filtered through a plug of silica (4 cm × 4 cm) and eluted with Et2O. Concentration under reduced pressure followed by flash column chromatography eluting with hexane-Et2O (20:1 to 1:5) gave (R)-13 as a colourless oil (61 mg, 97%). [α]D 25 = +4.9 (c 1.0, CHCl3). 1H NMR (400 MHz): δ = 6.87 (1 H, d, J = 16.0 Hz, CH=CH), 5.72 (1 H, d, J = 16.0 Hz, CH=CH), 3.24 [1 H, br dd, J = 10.4, 2.0 Hz, CH(OH)], 1.55 [1 H, m, CH(OH)CH aHb], 1.48 [9H, s, C(CH 3)3], 1.24 [1 H, m, CH(OH)CHa H b], 1.05 [6 H, s, C(CH3)2], 0.98 (3 H, t, J = 7.3 Hz, CH2CH 3). 13C NMR (100 MHz): δ = 166.3 (C), 154.1 (CH), 121.3 (CH), 80.3 (C), 80.0 (CH), 41.7 (C), 28.1 (CH3), 24.7 (CH2), 22.8 (CH3), 22.4 (CH3), 11.2 (CH3). IR (film): νmax = 3418 (br), 2968, 1715, 1696, 1646, 1461, 1367, 1317, 1160, 976 cm-1. MS (ESI): m/z calcd for C13H25NO3 +: 246.2064. Found: 246.2063 [MH+].