Synthesis of five-MemberedConformationally Locked 2´,4´-Carbocyclic ribo - Thimidine.
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Synthesis of five-MemberedConformationally Locked 2´,4´-Carbocyclic ribo- Thimidine. Khobragade Premkumar Anandrao Chembiotek, Hinjewadi, Pune
description
Synthesis of five-MemberedConformationally Locked 2´,4´-Carbocyclic ribo - Thimidine. Khobragade Premkumar Anandrao Chembiotek, Hinjewadi, Pune. Antisense therapeutic agent. 65%. 95%. Reagents and conditions: Acetone, sulphuric acid, rt, overnight. - PowerPoint PPT Presentation
Transcript of Synthesis of five-MemberedConformationally Locked 2´,4´-Carbocyclic ribo - Thimidine.
Synthesis of five-MemberedConformationally Locked 2´,4´-Carbocyclic ribo- Thimidine.
Khobragade Premkumar AnandraoChembiotek, Hinjewadi, Pune
ON
NH
O
O
O
DMTrO
PN
O CN
Antisense therapeutic agent.
Reagents and conditions:
(i) Acetone, sulphuric acid, rt, overnight.(ii) Oxalyl chloride, DMSO, , -78 °C, DIPEA, DCM .
O
O
O
O
O
O
D-Glucose
O
O
O
O
O
OHi) ii)
95% 65%
O
O
O
O
O
O
i)O
O
O
O
O
OH
ii)O
O
O
O
O
BnO62% 75%
Reagents and conditions:
(i) Sodium Borohydride, EtOH, rt, 2 hr, (ii) NaH, BnBr, -5 °C to rt overnight.
O
O
O
O
O
BnO
O
O
O
OH
OH
BnO
O
O
O
BnO
HO
i) ii)
65%
Reagents and conditions:
(i) 80% AcOH, rt, overnight, (ii) Sodium metaperiodate, THF, Water, rt, 4 hr.
O
O
O
BnO
HO
O
O
O
BnOOH
OHO
O
O
BnOOH
BnOi) ii)
Reagents and conditions:
(i) NaOH, formalin, rt, overnight; (ii) NaH, BnBr, -5 °C to rt, 4 hr.
63% 66%
O
O
O
BnOOH
BnOO
O
O
BnOO
BnOO
O
O
BnO
BnOi) ii)
Reagents and conditions:
(i) Oxalyl chloride, DMSO, -78 °C, DIPEA, DCM,(ii) PPh3+CH3Br-, 1.6 M butyllithium in hexane, THF, -78 °C to rt overnight.
87%
O
O
O
BnO
BnOO
O
O
BnO
BnO
OH
O
O
O
BnO
BnOi) ii)
Reagents and conditions:80%
(i) 9-BBN, THF, 3 N NaOH, 33% H2O2,(ii) Oxalyl chloride, DMSO, -78 °C, DIPEA, DCM, PPh 3+CH3Br-, 1.6 M butyllithium in hexane, THF, -78 °C to rt overnight.
95% 70%
O
O
O
BnO
BnOO
OAc
OAc
BnO
BnOO
OAcBnO
BnO N
NH
O
Oi) ii)
Reagents and conditions:
(i) Acetic acid, acetic anhydride, triflic acid, rt, 30 min. (ii) persilylated thymine, TMSOTf, CH3CN, 0 °C to rt, overnight.
80%
O
OAcBnO
BnO N
NH
O
OO
BnO
BnO N
NH
O
O
OH
O
OCSOPhBnO
BnO N
NH
O
Oi) ii)
Reagents and conditions:
(i) 27% methanolic NH3,rt, overnight,(ii) DMAP, phenyl chlorothionoformate, pyridine,rt, overnight.
72%
O
OCSOPhBnO
BnO N
NH
O
OO
BnO N
NH
O
O
OBn
ON
NH
O
O
OH
OHi) ii)
Reagents and conditions:
(i) Bu3SnH, toluene, AIBN, 4 h,(ii) 20% Pd(OH)2/ C, Ammonium Formate, Methanol, Reflux, 8 h.
73% 76%
ON
NH
O
ODMTrO
OH
ON
NH
O
O
O
DMTrO
PN
O CN
i) ii)ON
NH
O
O
OH
OH
Reagents and conditions:
(i) DMTr-Cl, Pyridine, Overnight,(ii) 2-cyanoethyl N,N-diisopropylphosphoramidochloridite, DIPEA, dry THF, overnight.
74% 80%
Thank you.
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