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Synlett 2008(3): 394-398  
DOI: 10.1055/s-2008-1032059
LETTER
© Georg Thieme Verlag Stuttgart · New York

The Development of an Asymmetric Nicholas Reaction Using Chiral Phosphoramidite Ligands

Natalie Ljungdahl, Núria Parera Pera, Kristian H. O. Andersson, Nina Kann*
Organic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology, 41296 Göteborg, Sweden
Fax: +46(31)7723657; e-Mail: kann@chalmers.se;
Further Information

Publication History

Received 15 August 2007
Publication Date:
16 January 2008 (online)

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Abstract

An asymmetric version of the Nicholas reaction involving the use of chiral phosphoramidite ligands has been developed. Treatment of a cobalt carbonyl complexed propargylic alcohol with two equivalents of the chiral ligand, followed by reaction with a silyl enol ether in the presence of a Lewis acid, afforded, after decomplexation, the desired product in up to 74% ee for the carbon-carbon bond forming step.

Key words

asymmetric synthesis - organometallic reagents - phosphorus - nucleophiles - ligands

    References and Notes

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    General Procedure for the Asymmetric Nicholas Reaction: The phosphoromidite-cobalt-alkyne complex (0.25 mmol) was dissolved in CH2Cl2 (1 mL) and cooled to -30 °C. BF3·OEt2 (47.5 µL, 0.375 mmol,) was added, followed by the dropwise addition of the nucleophile (0.5 mmol). After 16 h, the reaction was quenched with Et3N (69.7 µL, 0.5 mmol), and the solvent was removed in vacuo. Decomplexation was effected by dissolving the residue in THF-H2O (9:1), cooling to -10 °C, followed by the portionwise addition of a 0.18 M solution of cerium ammonium nitrate in THF-H2O (9:1) until the dark red solution turned orange-yellow (the amount of CAN solution used corresponded to approximately 5 equiv in most cases, and up to 10 equiv in a few cases). The reaction mixture was diluted with brine (1 mL) and extracted with Et2O (3 × 2 mL). The combined organic phases were dried over MgSO4 and concentrated. The crude product was purified by flash chromatography, eluting with 5-10% EtOAc in PE. The enantioselectivity was measured by HPLC on both the crude and the pure product, using a Daicel Chiralpak AD-H column (hexane-i-PrOH, 95:5).
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24

General Procedure for the Parallel Synthesis of the Ligands:21 The amine (0.25 mmol) was added to a carousel tube, followed by Et3N (0.25 mmol). The tube was sealed, flushed with argon and cooled to -40 °C. A 0.25 M stock solution of BINOL-chlorophosphite (1 mL) in toluene was added, and the reaction was left to warm overnight. The reaction mixture was rapidly filtered through a small plug of silica gel into a new sealed and degassed carousel tube. The filtrate was washed with toluene (1 mL), and the combined toluene solutions of the ligand were used directly in the next step.Spectral Data for Crude 2b: 1H NMR (400 MHz, CDCl3): δ = 7.80-8.10 (m, 4 H), 7.20-7.60 (m, 12 H). 13C NMR (100 MHz, CDCl3): δ = 145.7, 144.9, 132.0, 131.6, 131.5, 128.7, 128.6, 127.3, 127.2, 127.0 (J = 2.3 Hz), 126.2, 126.1, 121.0, 120.2 (J = 38 Hz). IR: 1298, 1224, 966, 929, 881, 816, 752 cm-1.Spectral Data for Crude 2c: 1H NMR (400 MHz, CDCl3): δ = 7.85-8.00 (m, 4 H), 7.25-7.60 (m, 14 H). 13C NMR (100 MHz, CDCl3): δ = 147.4, 147.1, 132.9, 132.6, 131.8, 131.4, 130.6, 130.0, 128.6 (d, J = 7.6 Hz), 127.1 (d, J = 9.9 Hz), 126.5, 126.4, 125.4, 125.1, 124.5, 123.2, 122.0, 121.8. IR: 1225, 1198, 884, 820 cm-1.

26

General Procedure for the Formation of the Intermediate Cobalt Complexes: The propargylic alcohol (1-butyn-3-ol, 6 or 8) was dissolved in CH2Cl2 in a two-necked flask under argon. An equimolar amount of dicobalt octacarbonyl, dissolved in CH2Cl2, was added. The reaction was protected from light by wrapping the flask in foil, and the solution was stirred at r.t. for 3 h. The mixture was filtered through a short plug of silica, eluting with CH2Cl2, and concentrated, affording the complex as a dark red oil. The ligand (0.25 mmol) was added to a Radleys carousel tube and dissolved in toluene (1 mL). The tube was sealed and flushed with argon. A 0.125 M stock solution of the alkyne-cobalt complex (1 mL) in toluene was added to the tube. The reaction mixture was heated at 50 °C overnight. The solvent was removed in vacuo, and the crude phosphoramidite-cobalt-alkyne complex thus formed was used directly in the Nicholas reaction in the same reaction tube.

30

General Procedure for the Preparation of the Precursor Propargylic Alcohols, Exemplified by 6: 4-Iodoaceto-phenone (500 mg, 2.03 mmol), Pd(PPh3)4 (23.5 mg, 0.020 mmol) and CuI (7.7 mg, 0.040 mmol) were added to a 5-mL microwave reaction tube flushed with argon. Freshly distilled Et3N (2 mL) and anhyd DMF (1 mL) were added, followed by 1-octyn-3-ol (355 µL, 2.43 mmol). The reaction was heated at 100 ºC for 10 min using a Biotage Initiator microwave reactor. The reaction mixture was then filtered through a pad of Celite, diluted with Et2O and washed with brine. Drying over MgSO4 followed by rotary evaporation afforded 6 (390 mg) as an amber-yellow oil. For larger-scale reactions, the reaction was run with conventional heating at 40 ºC for 16 h. Data for 6: 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.4 Hz, 2 H), 7.48 (d, J = 8.4 Hz, 2 H), 4.56-4.64 (m, 1 H), 2.59 (s, 3 H), 1.74-1.84 (m, 2 H), 1.30-1.60 (m, 6 H), 0.89 (t, J = 7.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 197.5, 136.4, 131.9, 128.3, 127.8, 93.8, 84.1, 63.1, 37.8, 31.6, 26.7, 25.0, 22.7, 14.1. IR: 3421, 2931, 2365, 2250, 1684, 1602, 1266, 909, 733 cm-1. Anal. Calcd for C16H20O2: C, 78.65; H, 8.25. Found: C, 78.53; H, 8.65. Compound 8 was prepared from 1-octyn-3-ol and 3,5-dimethyl-1-iodobenzene in the same manner. Data for 8: 1H NMR (400 MHz, CDCl3): δ = 7.07 (s, 2 H), 6.96 (s, 1 H), 4.72-4.80 (m, 1 H), 2.92 (s, 6 H), 1.94 (d, J = 5.2 Hz, 1 H), 1.55 (d, J = 6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 138.00, 130.44, 129.56, 122.47, 90.63, 84.43, 58.95, 24.63, 21.29. Anal. Calcd for C12H14O: C, 82.72; H, 8.10. Found: C, 82.65; H, 8.03.

31

Carousel 12 Reaction Station was obtained from Radleys Discovery Technologies.