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.

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 

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.

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 

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.

12 Walker SD. Barder TE. Martinelli JR. Buchwald SL. Angew. Chem. Int. Ed.  2004,  43:  1871 

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 

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.

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