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Synlett 2006(6): 865-868  
DOI: 10.1055/s-2006-939059
LETTER
© Georg Thieme Verlag Stuttgart · New York

Intramolecular Staudinger Ligation towards Biaryl-Containing Lactams

Géraldine Massona, Tim den Hartoga, Hans E. Schoemakerb, Henk Hiemstraa, Jan H. van Maarseveen*a
a Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands
b DSM Research, Life Science Products, PO Box 18, 6160 MD Geleen, The Netherlands
Fax: +31(020)5255670; e-Mail: jvm@science.uva.nl;
Further Information

Publication History

Received 23 December 2005
Publication Date:
14 March 2006 (online)

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Abstract

Both 15- and 16-membered biaryl-type lactams were prepared in good yield using the intramolecular Staudinger ligation strategy.

Key words

biaryls - macrolactams - cyclizations - atropisomerism - ring contractions

    References and Notes

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7

To a cooled (-78 °C) solution of sparteine (0.70 mL, 3.04 mmol) in Et2O (10 mL), s-BuLi (1.30 M in cyclohexane; 2.40 mL, 3.12 mmol) was added. After stirring for 15 min, dimethylphenylphosphine borane (366 mg, 2.77 mmol) was added via cannula as a solution in Et2O (10 mL). After 3 h at -78 °C, the solution was slowly added to a suspension of sublimed sulfur (98 mg, 3.06 mmol) in THF (40 mL), and the reaction was warmed to r.t. The resulting mixture was stirred for 16 h at r.t., then 2 N HCl (20 mL) was added and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2; PE-EtOAc, 95:5 to 9:1) to afford 3 as a pasty white solid (268 mg, 59%). [a]D 25 -8.9 (c 1.6, CHCl3); 92% ee. 1H NMR (400 MHz, CDCl3): δ = 2.71 (dd, J = 5.2, 14.0 Hz, 1 H), 2.52-2.43 (m, 1 H), 1.97-1.92 (m, 1 H), 1.29 (d, J = 10.4 Hz, 3 H), 1.27 (d, J = 13.6 Hz, 9 H), 0.39 (qd, J = 96.0, 13.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 28.03 (d, J = 31.2 Hz), 25.4 (d, J = 1.8 Hz), 15.39 (d, J = 26.9 Hz), 4.00 (d, J = 35.5 Hz). 31P NMR (162 MHz, CDCl3): δ = 31.41 (q, J = 59.0 Hz).

8

Recrystallization to increase the ee was impossible because the product is a pasty solid.

11

The boronic acid component for the Suzuki coupling from 7 was prepared by lithium-halogen exchange with n-BuLi and treatment with triethyl borate.

15

Intramolecular Staudinger Ligation Reaction: General Procedure Precursor 12d (132.0 mg, 0.24 mmol) and DABCO (110.0 mg, 0.98 mmol) was dissolved in THF (240 mL) and then heated at reflux. Upon completion of the reaction a sat. aq solution of NH4Cl (excess) was added. The resulting mixture was stirred for 1 h then the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2; PE-EtOAc, 9:1 to EtOAc) to afford 17d as a white solid (52 mg, 61%). 1H NMR (400 MHz, MeOD): δ = 7.66 (dd, J = 2.0, 8.0 Hz, 1 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.25 (s, 1 H), 7.20-7.15 (m, 2 H), 4.74 (d, J = 14.4 Hz, 1 H), 3.94 (d, J = 14.4 Hz, 1 H), 3.71-3.78 (m, 1 H), 3.07-3.01 (m, 1 H), 2.30 (s, 3 H), 2.21 (s, 3 H), 2.27-1.99 (m, 2 H), 1.80-1.58 (m, 4 H), 1.57-1.39 (m, 2 H). 13C NMR (100 MHz, MeOD): δ = 175.9, 170.9, 143.1, 143.0, 140.8, 139.7, 135.7, 134.2, 133.9, 132.2, 131.6, 130.7, 128.2, 127.5, 43.8, 41.2, 37.3, 30.5, 29.1, 27.4, 30.0, 19.6.

16

Attempts to produce 17c via lactamization of the pentafluorophenyl ester analogue of 12c using an aza-Wittig reaction failed.

17

The atropenantiomers were separated by analytical HPLC analysis using a chiral Daicel OD-H column with heptane-i-PrOH (98:2) as the eluent.