1,3-Propanedithiol → HCID 123486832, compound

HRID 1289886Notes

Reaction equation

HRID 1289886 reaction equation
[CH3:1][O:2][C:3]1[CH:55]=[CH:54][C:6]([C:7]([O:22][CH2:23][C@@:24]2([CH:46]=[CH:47][CH2:48][CH2:49][CH2:50]CCO)[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][SiH2:39][C:40]([CH3:45])([CH3:44])[CH:41]([CH3:43])[CH3:42])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[N-]=[N+]=[N-].COC1C=CC(C(OC[C@@]2(C=CCCCCCN=[N+]=[N-])O[C@@H:85]([N:87]3C=C(C)C(=O)NC3=O)[CH2:84][C@@H]2O[SiH2]C(C)(C)C(C)C)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.CS(Cl)(=O)=O.[N-]=[N+]=[N-].[Na+].C(S)CCS.[F:130][C:131]([F:138])([F:137])[C:132]([O:134]CC)=O>>[CH3:1][O:2][C:3]1[CH:55]=[CH:54][C:6]([C:7]([O:22][CH2:23][C@@:24]2([CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH2:84][CH2:85][NH:87][C:132](=[O:134])[C:131]([F:130])([F:137])[F:138])[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[O:38][SiH2:39][C:40]([CH3:44])([CH3:45])[CH:41]([CH3:42])[CH3:43])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1

Participants

8

Reactant 7

HCID 80131,3-PropanedithiolHCID 9794Ethyl trifluoroacetateHCID 31297Methanesulfonyl chlorideHCID 33557Sodium AzideHCID 33558AzideHCID 123138873HCID 123138873, compoundHCID 123511801HCID 123511801, compound2×

Product 1

HCID 123486832HCID 123486832, compound

Procedure

The above-procedure is more particularly illustrated as follows for the synthesis of 3'-O-[2-cyanoethyl bis (isopropyl) phosphoramidite ]-5'-O-(4,4'-dimethoxytrityl)-4'-(7-trifluoroacetaido-1-hepten-1-yl)-thymidine (8), which is incorporated into an oligonucleotide that is used as a nucleotide probe, and the desired 4'-substituent (biotin) is added at the completion of the synthesis of the oligonucleotide. The starting material is a thymidine that undergoes a five step sequence similar to that disclosed in O-Yang, supra, to protect the 3' position and to place a reactive functional group at the 4' position to yield 3'-O-[(dimethyl-1,1-dimethylethyl)silyl]-4'-hydroxymethyl-thymidine (1). The 4'-group is then oxidized by a Swern oxidation, followed by protection of the 5' position to yield 5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl) silyl]-4'-formyl-thymidine (2). Protecting the 5' position can be accomplished by reacting the compound with 4,4'-dimethoxytritylchloride in pyridine. The reaction takes about 20 hours and is done at room temperature. A reactive functional group is then placed at the 4' position of Compound (2) by a Wittig reaction with 5-hexenyltriphenylphosphonium bromide to yield 5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl)silyl]-4'-(1,7-heptadien-1-yl)-thymidine (3). Compound (3) is subjected to hydroboration followed by an oxidative workup to yield 5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl) silyl]-4'-(7-hydroxy-1-hepten-1-yl)-thymidine (4). Compound (4) is then converted to an azide, 5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl)silyl]-4'-(7-azido-1-hepten-1-yl)-thymidine (5), by a two step reaction: 1) reaction with methanesulfonyl chloride to replace the 4'-hydroxy group with a methanesulfonyloxy group, and then 2) reaction with sodium azide, to replace the 4'-methansulfonyloxy group with an azido group. The 4'-reactive azide group of Compound (5) is then reduced to an amine with 1,3-propanedithiol, then the amine is protected by reaction with ethyl trifluoroacetate for about 24 hours at room temperature to yield 5'-O-(4,4'-dimethoxytrityl)-3'-O-[(dimethyl-1,1-dimethylethyl)silyl]- 4'-(7-trifluoroacetamido-1-hepten-1-yl)-thymidine (6). The 3'-protecting group is then removed to yield 5'-O-(4,4'-dimethoxytrityl)-4'-(7-trifluoroacetamido-1-hepten-1-yl)-thymidine (7). Activation to the phosphite analog, 3'-O-[2-cyanoethyl bis(isopropyl) phosphoramiditel]-5'-O-(4,4'-dimethoxytrityl)-4'-(7-trifluoroacetamido-1-hepten-1-yl)-thymidine (8), is accomplished by treating Compound (7) with 2-cyanoethyl bis(isopropyl) chlorophosphoramidite for about 20 hours at room temperature. Then as described above, the desired substituent can be positioned at the 4' position of Compound (8), or the compound can be incorporated into an oligonucleotide and the desired 4'-substituent added after oligonucleotide synthesis.

Sources & evidence

ORD record
ord-3677b1c82ec34ea2be51fb7f4d6cbae5
Source dataset
uspto-grants-1998_05
Patent number
US05750343

Reaction notes

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