Dimethyl methylphosphonate → dimethyl(S)-(3-methyl-2-oxo-6-phenylhexyl)phosphonate

HRID 59692Notes

Reaction equation

HRID 59692 reaction equation
[CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][C@@H:14]([CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15](OCC)=[O:16].OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:13][C@@H:14]([CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]

Participants

6

Reactant 4

HCID 12958Dimethyl methylphosphonateHCID 516920Potassium bisulfateHCID 90054464(S)-(+)-ethyl 2-methyl-5-phenylpentanoateHCID 178418339Butyllithium

Product 1

HCID 90054415dimethyl(S)-(3-methyl-2-oxo-6-phenylhexyl)phosphonateYield 42.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirring solution consisting of dimethyl methylphosphonate (23.37 g, 188.4 mmol) in THF (400 mL) at −78° C. was slowly added n-butyllithium solution (112 mL, 179 mmol, 1.6 M solution in hexane). The reaction mixture was stirred for 30 minutes, after which time, (S)-(+)-ethyl 2-methyl-5-phenylpentanoate (14mb(i), 28.1 g, 94.2 mmol) in THF (100 mL) was slowly added. The resulting reaction mixture was stirred at −78° C. for two hours and was then allowed to rise to room temperature overnight. The reaction mixture was treated with 5% KHSO4 and extracted with ethyl acetate three times. The organic layer was washed twice with 50:50 water-brine and the organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (60:40 v/v) afforded the title compound (11.9 g, 42%) as a clear oil, pure of unrelated components; TLC Rf 0.22 (solvent system: 60:40 v/v ethyl acetate-heptane); HPLC retention time 14.5 minutes, 5μ Chiralpak IA 250×4.6 mm, ultraviolet detector at 210 nm, 1 mL/min, chiral purity 97.8% (S), 2.19% (R); MS (ESI−) m/z 297.1 (M−H)−; 1H NMR (CDCl3) δ 7.28-7.21 (m, 2H), 7.17-7.12 (m, 3H), 3.76-3.71 (m, 6H), 3.10 (d, J=2.20 Hz, 1H), 3.04 (d, J=2.20 Hz, 1H), 2.79-2.70 (m, 1H), 2.54-2.62 (m, 2H), 1.74-1.54 (m, 3H), 1.42-1.24 (m, 1H), 1.07 (d, J=6.96 Hz, 3H); [α]Tλ=α/cl, [α]21.9D=+0.084/(0.0169 g/1.5 mL)(0.5)=+14.91° (c=1.13, CHCl3).

Workup

  1. customThe resulting reaction mixture
  2. stirringwas stirred at −78° C. for two hours
  3. waitto rise to room temperature overnight
  4. extractionextracted with ethyl acetate three times
  5. washThe organic layer was washed twice with 50:50 water-brine
  6. dry with materialthe organic layer was dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under vacuum
  9. customThe residue was purified by silica gel chromatography
  10. washElution with ethyl acetate-heptane (60:40 v/v)

Sources & evidence

ORD record
ord-ed715711bbda47d292a5271ba35ab3b8
Source dataset
uspto-grants-2016_09
Patent number
US09440919B2

Reaction notes

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