A Facile, General Approach to the Synthesis of Electrophilic Acetone Equivalents

Abstract

The facile, high-yielding, yet general synthesis of electrophilic chloroacetone equivalents 11a−f is described. The enol ethers are assembled in three steps starting with trichloride 29 in overall yields of 57−93%. Nucleophilic displacement of the chloromethyl chlorine with a range of organometallic reagents generates dichlorides 30 in yields of 58−99%, which can be dehydrohalogenated with t-BuOK/THF in yields of 87−99% to produce enol ethers 31. Conversion of the allyl chlorides 31 to the corresponding allyl iodides 11 with 72−99% yield completes the synthetic sequence. The entire sequence can be performed in less than 48 h on a >50 mmol scale.

Synthesis of the stable isotope labeled antiviral nucleoside analog [8-13C–7,9-15N2]-ganciclovir

“…12,13 The resulting trichloride was reacted with sodium propionate in the presence of a phase transfer catalyst, tetrabutylphosphonium chloride, to give 3-propionyloxy-2-propionyloxymethoxypropyl-propionate (3). Product 3 eluted at 13.7 min on LC-MS analysis and gave a negative ion spectrum with a major ion corresponding to the loss of a proton from the molecule ([M-H] À ) at m/z=289, together with two adduct ions at m/z=325 and m/z=363, corresponding to [M+ 35 Cl] À and [M+EtCOO] -, respectively.…”

“…Synthesis of [8][9][10][11][12][13] C-7,9-15 N 2 ]-Ganciclovir 3-Propionyloxy-2-propionyloxy-methoxypropylpropionate (3). A mixture of 1,3-dichloro-2-propanol (1, 10 g, 77.5 mmol) and paraformaldehyde (3.02 g, 104 mmol) in CH 2 Cl 2 (100 ml) was cooled down to À5 8C, then gaseous HCl was bubbled into the mixture at À5 8C over 1.5 h. The resulting mixture was kept at À5 8C for 14 h. Sodium sulfate (3 g) was added, and the mixture was stirred at room temperature for 2 h. The solid was filtered off, and the filtrate was washed with aqueous sodium hydroxide (20%, 2 Â 20 ml).…”

“…After stirring at 100 8C for 1 h, a mixture of MeOH (80 ml) and toluene (2 ml) was added to quench the reaction. The reaction mixture was stirred at 100 8C for 0.5 h, then transferred to a 15 ml pressure tube, and evaporated under a nitrogen stream to produce an oil, [8][9][10][11][12][13] C-7,9-15 N 2 ]-N,O-bis-trimethylsilyl-9-(1,3-propionoxy-2-propoxymethyl)-N 2 -propionylguanine (6). Compound 6 was used for the next reaction without further purification.…”

“…Maximal specificity for analysis of ganciclovir could only be obtained with stable isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS). A [ 15 N, 13 C]-analog was required for use as an internal standard because a deuterium-containing analog would separate from the unlabeled ganciclovir during LC-MS analysis as described in the quantitative analysis of peptides. 8 This could compromise precision and accuracy as a result in differential suppression of analyte and internal standard signals by co-eluting contaminants from the biological matrix.…”

“…12 We report the synthesis of [8][9][10][11][12][13] C-7,9-15 N 2 ]-ganciclovir for use in pharmacokinetic studies.…”