Direct Conversion of Esters to Hydroxyamides on Solid Support - a Key Step en route to Bisoxazoline Ligands

Abstract

A method for converting esters into β-hydroxyamides via their direct reaction with β-aminoalcohols was implemented for the first time on solid support. The transformation is performed under basic conditions and presumably includes transesterification followed by rapid intramolecular O,N-acyl transfer. The technique was successfully tested on monoesters as well as malonates. The transformation of malonates is a key step in the on-resin assembly of bisoxazoline ligands, demonstrated here for the first time.

solid-phase synthesis - aminoalcohols - amides - aminolysis - oxazolines

References

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Typical Procedure: LDA (0.6 mL, 2 M solution, 15 equiv) was added dropwise at 10 °C to a solution of ethanolamine (0.l mL, 20 equiv) in dry DMF (2 mL). In another flask 1a (100 mg, 0.08 mmol, 1 equiv) was suspended in dry DMF (2 mL). The solution of the first flask was cannulated into the suspension of 1a and stirred for 18 h at r.t. The resin was then filtered and washed sequentially with DMF, DMF/H₂O, H₂O, THF, CH₂Cl₂ and dried under vacuum.The product was analyzed by acidolytic cleavage using ¹H NMR, indicating quantitative yield.
IR (on-resin, KBr): ν 3408, 1649 cm^-1.
Cleaved product (bis trifluoroacetate ester). ¹H NMR (200 MHz, CDCl₃/TFA): δ = 7.07 (bs, 1 H), 4.51 (t, J = 5.0 Hz, 2 H), 4.43 (t, J = 6.4 Hz, 2 H), 3.75 (q, J = 5.0 Hz, 2 H), 2.45 (t, J = 7.6 Hz, 2 H), 1.80 (m, 4 H), 1.45 (m, 2 H). ¹³C NMR (50 MHz, CDCl₃/TFA): δ = 173.4, 68.4, 65.4, 39.2, 34.7, 27.0, 24.8, 24.5. MS (CI): found m/z, 368.1, calcd for C₁₂H₁₆F₆NO₅ (M + 1) 368.1.

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For serine: Weissberg, A.; Portnoy, M. unpublished results.

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Typical Procedure for Bisoxazoline Assembly on solid Support: The bromohexanol solution (21 µL, 2 equiv) in CH₂Cl₂ (1.5 mL) was added dropwise to a suspension of Imidate Wang resin (100 mg, 0.08 mmol) in cyclohexane (1.5 mL). The reaction was stirred at r.t. for 5 min. Then BF₃·Et₂O (5 µL) was added, and the suspension was stirred at r.t. for another 10 min. The resin was filtered and washed with CH₂Cl₂, THF, CH₂Cl₂. The resin was dried under vacuum, and then suspended in anhyd DMF (3 mL). In another flask diethyl malonate was added dropwise to the suspension of NaH (20 mg, 5 equiv) in dry DMF (3 mL). After 5 min stirring this solution was cannulated to the resin suspension and the reaction mixture was stirred for 24 h at 60 °C. The resin was filtered, washed and dried under vacuum, and then suspended in anhyd THF (3 mL) to which LDA (0.2 mL, 2 M solution, 25 equiv) was added. The reaction mixture was stirred for 1 h. Then CH₃I (50 µL, 10 equiv) was added and the reaction mixture was stirred for an additional 22 h at r.t. The resin was filtered washed and dried under vacuum. The conversion to diamide was executed as above (ref. [10] ). Afterwards, the resin was suspended in anhyd THF (3 mL) for 10 min, and then DIPEA (1.5 mL) and MsCl (2 mL) were added at 10 °C. The reaction mixture was stirred for 48 h at r.t. The resin was filtered, washed and dried under vacuum. The resin was suspended in anhyd THF to which LDA (1 mL, 2 M solution, 12.5 equiv) was added. The reaction mixture was stirred for 24 h at r.t. The resin was filtered, washed and dried under vacuum. According to acidolytic cleavage the product was obtain in overall 75% yield.
Gel-phase ¹³C NMR (100 MHz, C₆D₆): δ = 168.3, 71.9, 66.7, 53.9, 36.5, 29.5 (3 carbons), 25.7, 24.0, 21.3.

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