Tetrahydrofuran → (1R*,2S*,5S*,6RS)-8-Benzyl-6-(tert-butoxycarbonyl)-2-(3-hydroxypropynyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol

HRID 1017274Notes

Reaction equation

HRID 1017274 reaction equation
C([Li])CCC.[CH2:6]([N:13]1[C@@H:18]2[CH:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@:14]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:15](=[O:28])[CH2:16][CH2:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:35]1C[CH2:38][CH2:37][CH2:36]1>>[CH2:6]([N:13]1[C@@H:18]2[CH:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@:14]1([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C@:15]([C:38]#[C:37][CH2:36][OH:35])([OH:28])[CH2:16][CH2:17]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1

Participants

4

Reactant 3

HCID 8028Tetrahydrofuran2×HCID 69890367(1R*,5S*,6RS)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-oneHCID 178418339Butyllithium

Product 1

HCID 70152056(1R*,2S*,5S*,6RS)-8-Benzyl-6-(tert-butoxycarbonyl)-2-(3-hydroxypropynyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-olYield 71%

Procedure

A solution of n-butyl lithium in hexanes (1.6M, 34 ml, 55.4 mmol) was added dropwise to a stirred solution of O-trimethylsilyl propargyl alcohol (8 ml, 52 mmol) in tetrahydrofuran (40 ml) at −78° C. This solution was added via syringe to a stirred solution of (1R*,5S*,6RS)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-one (Description 24; a 3:1 mixture of C6 epimers, 5 g, 12.7 mmol) in tetrahydrofuran (30 ml) at −78° C. over 30 minutes. The reaction mixture was stirred for 1 hour and quenched with acetic acid (3.1 ml), warm up to room temperature and concentrated in vacuo. The residue was treated with tetrahydrofuran (50 ml) followed by 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (75 ml). The mixture was stirred for 30 minutes and concentrated in vacuo. The residue was treated with ethyl acetate (200 ml), washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (4.05 g, 71%) as a 3:1 mixture of C6 epimers.

Workup

  1. customquenched with acetic acid (3.1 ml)
  2. concentrationconcentrated in vacuo
  3. additionThe residue was treated with tetrahydrofuran (50 ml)
  4. stirringThe mixture was stirred for 30 minutes
  5. concentrationconcentrated in vacuo
  6. additionThe residue was treated with ethyl acetate (200 ml)
  7. washwashed with water and brine
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated
  10. customThe residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate)

Sources & evidence

ORD record
ord-4297ed27243643e2a7cfa671d14ea3c1
Source dataset
uspto-grants-2002_11
Patent number
US06479486B2

Reaction notes

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