Exploitation of Intramolecular Glaser–Eglinton–Hay Macrocyclization for the Synthesis of New Classes of Optically Active Aza-Oxo-Thia Polyether Macrocycles from Amino Alcohol Building Blocks

Abstract

We report an intramolecular Glaser–Eglinton–Hay coupling as an unprecedented route for assembling optically active aza-oxo polyether macrocycles containing a 1,3-diyne unit from enantiopure amino alcohol building blocks and suitable linkers. Furthermore, the conversion of the 1,3-diyne unit of the aza-oxo polyether macrocycles into a thiophene ring led to the assembly of new classes of optically active aza-oxa-thia (heterotopic) polyether macrocycle analogues of classical 18-C-6 and 18-C-5 systems.

Key words

alkynes - amino alcohols - cross-coupling - crown compounds - macrocycles - Glaser–Eglinton–Hay reaction

• References and Notes

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• 10 Cyclization of Diynes 5 to Macrocycles 6; General Procedure A mixture of the appropriate diyne 5 (0.2 mmol), Cu(OAc)₂·H₂O (1 equiv), and DMSO (2 mL) was heated at 110 °C for 6 h in air. The mixture was then diluted with H₂O (4 mL) and the solution was filtered and washed with EtOAc (3 or 4 × 5 mL). Next, the combined layers were extracted with EtOAc (3 × 5 mL). The organic layers were combined, dried (Na₂SO₄), filtered, and evaporated in vacuo. The crude residue was purified by column chromatography (Al₂O₃, EtOAc/hexane = 20:80).
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• 12 Conversion of Diyne-Containing Macrocycles 6 into Thiophene-Containing Macrocycles 7; General Procedure A mixture of the appropriate macrocyclic diyne 6 (0.10 mmol), Na₂S·xH₂O (90 mg), CuI (10 mol%), and 1,10-phenanthroline (15 mol%) in DMF (0.5 mL) was heated at 90 °C for 9 h in air. Workup as described in Ref. 10 gave a crude residue that was purified by column chromatography (silica gel, EtOAc/hexane = 20:80). Thiophene-Containing Macrocyclic Ether 7a Pale-yellow liquid; yield: 33 mg (42%); [α]_D ²⁵ –29.08 (c 0.09, CH₂Cl₂); R_f = 0.55 (20% EtOAc–hexanes). IR (CH₂Cl₂): 2923, 1600, 1493, 1452, 1259 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.58 (dd, J₁ = 7.5, J₂ = 1.6 Hz, 2 H), 7.41–7.37 (m, 8 H), 7.31–7.27 (m, 8 H), 7.24–7.19 (m, 6 H), 7.00 (t, J = 7.4 Hz, 2 H), 6.85 (dd, J₁ = 8.2, J₂ = 0.7 Hz, 2 H), 6.77 (s, 2 H), 4.65 (d, J = 12.8 Hz, 2 H), 4.50 (d, J = 12.8 Hz, 2 H), 4.26–4.24 (m, 4 H), 4.07–3.89 (m, 8 H), 3.73 (d, J = 14.0 Hz, 2 H), 3.55 (dd, J₁ = 13.9, J₂ = 9.2 Hz, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 156.7, 141.5, 140.4, 139.8, 130.3, 129.0, 128.7, 128.5, 128.2, 128.0, 127.6, 126.9, 126.7, 126.0, 120.8, 111.6, 69.4, 67.7, 66.4, 61.9, 55.1, 47.8. HRMS (ESI): [M + H]⁺ calcd for C₅₂H₅₃N₂O₄S: 801.3726; found: 801.3734.