‘Safety-Catch’ Propargyl-Based Linker Strategy for the Immobilization of Amines and Carboxylic Acids in SPOS

Abstract

Integral propargyl alcohol and propargyl chloroformate linkers were developed for a ‘safety-catch’ acid-sensitive linker strategy. The syntheses of the integral propargyl linkers were achieved by direct conversion of the solid support starting from Merrifield resin, hydroxymethylpolystyrene or 4-bromopolystyrene. Amines and carboxylic acids have been coupled and released to demonstrate that transformation of the propargyl units to cobalt carbonyl complexes facilitates the cleavage under mild acidic conditions in high purity.

Key words

alkyne complexes - cobalt - linker - palladium - solid-phase

References

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• 19a

  PPh₃ (6 equiv), CCl₄ (3 equiv), -20 °C, 25 min to 0 °C, 16 h, CH₂Cl₂, 92%;

• 19b

  n-BuLi (1.6 M solution in hexane, 2 equiv), -78 °C, 5 h, THF, 71%;

• 19c

  n-BuLi (1.6 M solution in hexane, 1.1 equiv), -78 °C to r.t., 19.5 h, THF, 74%;

• 19d

  DIBALH (1 M in Toluol, 2 equiv), -78 °C to r.t., 16 h, quant.
  Compound 12: ¹H NMR (200 MHz, CDCl₃): δ [ppm] = 7.43-7.29 (m, 7 H, C-H_arom.), 6.92-6.87 (m, 2 H, C-H_arom.), 5.04 (s, 2 H, O-CH₂), 4.46 (s, 2 H, CH₂-OH), 1.78 (br s, 1 H, CH₂-OH). ¹³C NMR (50.3 MHz, CDCl₃): δ [ppm] = 158.97 (O-C_arom.), 136.56 (CH₂-C_arom.), 133.22, 128.66, 128.14, 127.50, 114.89 (C_arom.), 86.00 (CºC), 85.64 (CºC), 70.05 (CH₂-OBn), 51.73 (CH₂-OH); one quaternary signal of the aromatic region is overlapped by the adjacent tertiary signal. Elemental analysis: C₁₆H₁₄O₂ (238.27 g/mol) calcd: C, 80.65; H, 5.92. Found: C, 80.58; H, 6.05. MS (FD): m/z = 238.5 (100.00), 239.5 (16.15), 240.6 (1.60).

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18

All resins prepared have been characterized by IR spectro-
scopy and by elemental analysis before and after immobili-zation [resin 1: nitrogen analysis (route A), bromine and nitrogen analysis (route B); resin 2: chlorine and nitrogen analysis] as well as Fmoc-calibration for resin 1.

25

The in situ deprotection protocol of Y. Fukase, K. Fukase, S. Kusumoto, [10] when applied to propargyloxycarbonyl-protected phenylalanine methylester on 1.5 mmol scale, resulted in a product mixture and unsatisfactory product purity.