Intramolecular Staudinger Ligation towards Biaryl-Containing Lactams

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

• 1a Schmidt U. Meyer R. Leitenberger V. Griesser H. Lieberknecht A. Synthesis  1992,  1025 
• 1b Schmidt U. Leitenberger V. Griesser H. Schmidt J. Meyer R. Synthesis  1992,  1248 
• 1c Bois-Choussy M. Cristau P. Zhu J. Angew. Chem. Int. Ed.  2003,  42:  4238 
• 1d Krenitsky PJ. Boger DL. Tetrahedron Lett.  2003,  44:  4019 
• 2 David O. Meester WJN. Bieräugel H. Schoemaker HE. Hiemstra H. van Maarseveen JH. Angew. Chem. Int. Ed.  2003,  42:  4373 
• 3a Köhn M. Breinbauer R. Angew. Chem. Int. Ed.  2004,  43:  3106 
• 3b Lin FL. Hoyt HM. van Halbeek H. Bergman RG. Bertozzi CR. J. Am. Chem. Soc.  2005,  127:  2686 
• 3c Soellner MB. Nilsson BL. Raines RT. J. Org. Chem.  2002,  67:  4993 
• 4 He Y. Hinklin RJ. Chang J. Kiessling LL. Org. Lett.  2004,  6:  4479 
• 5 Imamoto T. Watanabe J. Wada Y. Masuda H. Yamada H. Tsuruta H. Matsukawa S. Yamaguchi K. J. Am. Chem. Soc.  1998,  120:  1635 
• 6 For a similar approach using phenyl disulfide for the introduction of sulfur, see: Sugama H. Saito H. Danjo H. Imamoto T. Synthesis  2001,  2348 
• 9 The absolute configuration of 3 was determined by comparison with the known (R)-tert-butyl(hydroxy-methyl)methylphosphine borane. The alcohol was converted to the thioacetate in two steps followed by acetyl group removal to give the chiral thiol, see: Nagata K. Matsukawa S. Imamoto T. J. Org. Chem.  2000,  65:  4185 
• 10a Suzuki A. Acc. Chem. Res.  1982,  15:  178 
• 10b Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 
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• 13 ω-Azido acids were obtained from ω-amino acids by a diazo-transfer reaction: Lundquist JT. Pelletier JC. Org. Lett.  2001,  3:  781 
• 14 For an extensive review on applications of borane-protected phosphines see: Brunel JM. Faure B. Maffei M. Coord. Chem. Rev.  1998,  180:  665 
• 18 Eshdat L. Shabtai E. Saleh SA. Sternfeld T. Saito M. Okamoto Y. Rabinovitz M. J. Org. Chem.  1999,  64:  353 
• 19 For the first example of atropenantioselective macrocyclizations see: Islas-Gonzalez G. Bois-Choussy M. Zhu J. Org. Biomol. Chem.  2003,  1:  30 

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.