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Synlett 2020; 31(05): 507-511
Synthesis of α,α-Disubstituted Benzocyclobutane Amino Acids through [2+2] Annulation of Benzyne with Dehydroalanine
Received: 07 November 2019
Received: 07 November 2019
Accepted after revision: 29 December 2019
16 January 2020 (online)
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 wordsbenzyne - aryne - dehydroalanine - α,α-disubstituted benzocyclobutane amino acids - peptidomimetic
- Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1691572.
- Supporting Information
References and Notes
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- 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.