Synthesis of α,α-Disubstituted Benzocyclobutane Amino Acids through [2+2] Annulation of Benzyne with Dehydroalanine

Abstract

A mild and general method for the synthesis of α,α-disubstituted benzocyclobutane amino acids through a [2+2] annulation of benzyne with dehydroalanine is described. Yields up to 88% of the constrained quaternary amino acids can be obtained and its application in peptidomimetic synthesis is demonstrated.

Key words

benzyne - aryne - dehydroalanine - α,α-disubstituted benzocyclobutane amino acids - peptidomimetic

• References and Notes

• 1a McLean TH, Parrish JC, Braden MR, Marona-Lewicka D, Gallardo-Godoy A, Nichols DE. J. Med. Chem. 2006; 49: 5794
• 1b Tsotinis A, Afroudakis PA, Garratt PJ, Bocianowska-Zbrog A, Sugden D. ChemMedChem 2014; 9: 2238
• 1c Stieber J, Wieland K, Stöckl G, Ludwig A, Hofmann F. Mol. Pharmacol. 2006; 69: 1328
• 1d Zheng Q, Tang S, Fu X, Chen Z, Ye Y, Lan X, Jiang L, Huang Y, Ding J, Geng M, Huang M, Wan H. Bioorg. Med. Chem. Lett. 2017; 27: 5262
• 2a Vogt H, Brase S. Org. Biomol. Chem. 2007; 5: 406
• 2b Khosla MC, Stachowiak K, Smeby RR, Bumpus FM, Piriou F, Lintner K, Fermandjian S. Proc. Natl. Acad. Sci. U.S.A. 1981; 78: 757
• 2c Gatos M, Formaggio F, Crisma M, Valle G, Toniolo C, Bonora GM, Saviano M, Iacovino R, Menchise V, Galdiero S, Pedone C, Benedetti E. J. Pept. Sci. 1997; 2: 110
• 3 Ramtohul YK, Blackburn T. Synlett 2008; 1159
• 4 Gilmore CD, Allan KM, Stoltz BM. J. Am. Chem. Soc. 2008; 130: 1558
• 5 For synthesis of monosubstituted amino-benzocyclobutane by using benzyne, see: Feltenberge JB, Hayashi R, Tang Y, Babiash ES. C, Hsung RP. Org. Lett. 2009; 11: 3666
• 6 Ferreira PM. T, Maia HL. S, Monteiro LS, Sacramento J. J. Chem. Soc., Perkin Trans. 1 1999; 3697
• 7 Chang M.-Y, Chen S.-T, Chang N.-C. Synth. Commun. 2003; 33: 1375
• 8 Adams LA, Aggarwal VK, Bonnert RW, Bressel B, Cox RJ, Shepherd J, De Vincente J, Walter M, Whittingham WG, Winn CL. J. Org. Chem. 2003; 68: 9433
• 9 Heaney H. Chem. Rev. 1962; 62: 81
• 10 ¹H NMR NOE observed for selected benzocyclobutane analogues (Figure 2).
• 11a Yoshida H, Shirakawa E, Honda Y, Hiyama T. Angew. Chem. Int. Ed. 2002; 41: 3247
• 11b Yoshida H, Fukushima H, Ohshita J, Kunai A. J. Am. Chem. Soc. 2006; 128: 11040
• 12 Representative Experimental Procedure: Methyl 7-[di(tert-butoxycarbonyl)amino]bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxylate (19a) To a mixture of methyl 2-[di(tert-butoxycarbonyl)amino]prop-2-enoate (18a) (121 mg, 0.4 mmol) and cesium fluoride (213 mg, 1.4 mmol) in MeCN (4.0 mL) was added 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (8a) (377 mg, 1.2 mmol) and the reaction mixture was stirred at rt for 16 h. The volatiles were evaporated; the residue was diluted with water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried with anhydrous Na₂SO₄ and filtered. The filtrate was evaporated and the crude product was purified on an Isco Combiflash chromatography column with 24 g silica gel and a gradient elution of EtOAc/hexanes (0–15%) and a flow rate of 35 mL min^–1 over 20 min to afford the title product 19a as an off-white semi-solid. Yield: 130 mg (86%). ¹H NMR (500 MHz, CDCl₃): δ = 7.37 (d, J = 7.6 Hz, 1 H), 7.34–7.30 (m, 1 H), 7.23–7.18 (m, 1 H), 7.14 (d, J = 7.4 Hz, 1 H), 3.92 (d, J = 14.5 Hz, 1 H), 3.71 (s, 3 H), 3.55 (d, J = 14.6 Hz, 1 H), 1.50 (s, 18 H). ¹³C NMR (126 MHz, CDCl₃): δ = 171.5, 152.7, 144.0, 142.1, 130.2, 127.4, 125.5, 122.9, 83.0, 68.1, 52.9, 44.3, 28.1. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₈NO₆: 378.1911; found: 378.1908. LCMS (ESI): m/z [M + H]⁺ = 378.2, t _R = 1.60 min; 5–100% MeCN/H₂O (0.1% of 10 mM ammonium formate buffer) over 3 min.