Azobisisobutyronitrile → 3,6-anhydro-1,2-dideoxy-1-(diethoxyphosphinyl)-1,1-difluoro-4,5,7-tris-O-(phenylmethyl)-D-manno-heptitol

HRID 2166287Notes

Reaction equation

HRID 2166287 reaction equation
[C:1]1([CH2:7][O:8][C@H:9]2[C@H:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:14]([CH2:24]OCC3C=CC=CC=3)[O:13][C@@H:10]2[CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]N(C(C)C)C(C)C.[F:41][CH:42]([P:44](=[O:51])([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])[F:43].C1N=CN(C(N2C=NC=C2)=S)C=1.C(OP(OCC)(C(F)(F)[C@@H]([C@H]1O[C@H](COCC2C=CC=CC=2)[C@@H](OCC2C=CC=CC=2)[C@@H]1O[CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)O)=O)C.C(OP(OCC)(C(F)(F)[C@@H](O)[C@H]1O[C@H](COCC2C=CC=CC=2)[C@@H](OCC2C=CC=CC=2)[C@@H]1OCC1C=CC=CC=1)=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>O1CCCC1.C1(C)C=CC=CC=1>[CH2:49]([O:48][P:44]([O:45][CH2:46][CH3:47])([C:42]([F:43])([F:41])[CH2:24][C@H:14]1[O:13][C@H:10]([CH2:11][O:12][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C@@H:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C@@H:15]1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:51])[CH3:50]

Participants

10

Reactant 7

HCID 6547AzobisisobutyronitrileHCID 802641,1'-ThiocarbonyldiimidazoleHCID 2758305Phosphonic acid, (difluoromethyl)-, diethyl esterHCID 108364862,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannoseHCID 886089602,5-anhydro-7-deoxy-7-(diethoxyphosphinyl)-7,7-difluoro-1,3,4-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitolHCID 886090023,6-anhydro-1-deoxy-1-(diethoxyphosphinyl)-1,1-difluoro-4,5,7-tris-O-(phenylmethyl)-D-glycero-D-galacto-heptitolHCID 178506924HCID 178506924, compound

Product 1

HCID 151171743,6-anhydro-1,2-dideoxy-1-(diethoxyphosphinyl)-1,1-difluoro-4,5,7-tris-O-(phenylmethyl)-D-manno-heptitol

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

In accordance with Flowchart A, 2,5-anhydro-D-mannose 1 is treated with acetyl chloride in anhydrous methanol at reflux, followed by neutralization with lead carbonate, giving 2,5-anhydro-D-mannose, dimethyl acetal 2, which is treated with sodium hydride in dimethylformamide, followed by reaction with benzyl bromide, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)--D-mannose, dimethyl acetal 3, which is treated with tetrafluoroboric acid in acetonitrile, giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose 4. Compound 4 is reacted with a solution of lithiodiisopropylamine in tetrahydrofuran, and (difluoromethyl) phosphonic acid, diethyl ester at -75° C., giving a mixture of 3,6-anhydro-1-deoxy-(diethoxyphosphinyl)-1,1-difluoro-4,5,7-tris-O-(phenylmehyl)-D-olvcero-D-galacto-heptitol and 2,5-anhydro-7-deoxy-7-(diethoxyphsophinyl)-7,7-difluoro-1,3,4-tris-O-(phenylmethyl)-D-glycero-Dmanno-heptitol, 5. The mixture 5 is reacted with N,N'-thiocarbonyldiimidazole in tetrahydrofuran, giving a mixture of 3,6-anhydro-1-deoxy-1-(diethoxyphosphinyl)-1,1-difluoro-4,5,7-tris-O-(phenylmethyl)-D-glycero-D-galacto-heptitol, 0-1H-imidazole-1-carbothioate and 2,5-anhydro-7-deoxy-7-(diethoxyphosphinyl)-7,7-difluoro-1,3,4-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol, 0-1H-imidazole-1-carbothioate 6. The mixture 6 is treated with n-tributyl stannous hydride and 2,2'-azobisisobutyronitrile in dry toluene under argon with heat, then purified by chromatography, giving 3,6-anhydro-1,2-dideoxy-1-(diethoxyphosphinyl)-1,1-difluoro-4,5,7-tris-O-(phenylmethyl)-D-manno-heptitol 7, which is treated first with boron trifluoride etherate in acetic anhydride at 0° C., giving acetate derivative 8, which is reacted with sodium ethoxide in ethanol under argon, giving 3,6-anhydro-1,2-dideoxy-1-(diethoxyphosphinyl)-1,1-difluoro-4,5-bis-O-(phenylmethyl)-D-manno-heptitol 9. Compound 9 is treated with diphenyl chlorophosphate in pyridine under argon at ice bath temperature, giving 3,6-anhydro-1,2-dideoxy-1-(diethoxyphosphinyl)-1,1-difluoro-3,4-bis-O-(phenylmethyl)-D-manno-heptitol, 7-(diphenyl phosphate) 10 which is catalytically hydrogenated, giving 3,6-anhydro-1,2-dideoxy-1-(diethoxyphosphinyl)-1,1-difluoro-D-manno-heptitol, 7-(diphenyl phosphate) 11. Compound 11 is treated with trimethylsilyl bromide in deuterated chloroform under argon, giving 3,6-anhydro-1,2-dideoxy-1,1-difluoro-1-phosphono-D-manno-heptitol, 7-(diphenyl phosphate) 12 which is then catalytically hydrogenated giving the product 3,6-anhydro-1,2-dideoxy-1,1-difluoro-1-phosphono-D-manno-heptitol, 7-dihydrogen phosphate 13. ##STR10##

Workup

  1. customgiving
  2. customgiving
  3. temperaturewith heat
  4. custompurified by chromatography

Sources & evidence

ORD record
ord-cb00edda674142aebfa2d3910d1b3da5
Source dataset
uspto-grants-1990_07
Patent number
US04943629

Reaction notes

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