Fluorination by DAST

Thioethers were a-fluorinated by DAST in dichloromethane at ambient temperature [260]. A catalytic amount of SbCI3 was beneficial. 

Protein-tyrosine (PTP) inhibitors are potentially valuable pharmacological tools for studying cellular signal transduction and for therapeutic intervention. Derivatives of 1,1-difluoromethylphosphonic acid are known to be potent PTP inhibitors. An important method for synthesis of these compounds is fluorina-tion of acyl phosphonates by diethylaminosulfur trifluoride (DAST). This method allows synthesis of fcrf-butyl-protected difluoro(aryl)- or (naphthal-enyl)methylphosphonates, which under mildly acidic deprotection conditions afford desirable phosphonic acids [16, 39]. Acyl phosphonate fluorination by DAST has also been utilized for synthesis of a,a-(difluoroprop-2-ynyl)phos-phonates [14]. 

MS[5,NG-1], an aglycon migration different from MS[2,NG-1] outlined in entries 1 and 5, was observed on attempted fluorination by DAST of methyl 2,3-0-isopropylidene-)5-D-ribofuranoside 101 [73] (entry 11). The configuration found in the final ribofuranosyl fluoride 102 is rather the result of the thermodynamic equilibration than a mechanistic consequence. 

The fluorinated thionucleoside 49 was prepared from the corresponding 5 -0-trityl-2 -alcohol by fluorination by DAST with retention of configuration. Use of the sulfoxide gave fluorination with predominant inversion of stereochemistry. ... 

Scheme 15.8 Activation-displacement fluorination by DAST type reagents.

Fluorine has also been introduced onto the E ring. For instance, both epimers of 20-fluorocamptothecin, where the fluorine atom replaces the 20-hydroxyl, have been prepared by total synthesis via stereoselective fluorination with DAST of the (K) and (S) a-hydroxylactone precursors (Figure 4.53). An asymmetric... 

DialkyIamino)trifluoro-A4-sulfanes are unable to convert esters into the corresponding a,a-difluoro ethers due to the low electrophilicity of the carbonyl group. However, this transformation can be carried out if the ester is first converted to a thioester with Lawesson s reagent,56 followed by fluorination with DAST.57 The fluorination step occurs at room temperature and in high yield (see Table 6). 

The replacement of a phenylsulfanyl group in a saccharide monothioacetal by fluorine using DAST in the presence of /V-bromosuccinamidc (NBS) has been reported to occur at temperatures in the range 0-20°C (see Table 8).64... 

Fluorination with DAST is a powerful tool in carbohydrate chemistry. The reaction usually proceeds in high yield with complete inversion. For fluorinations at a specific site to occur, other reactive groups are usually protected by standard protective groups. On the other hand, in several cases primary hydroxy groups in side chains can be substituted selectively by DAST without protection of ring hydroxy groups. Table 5 shows some recent examples of DAST lluorinations in carbohydrate chemistry, another example is the formation of the fluorinated kanamycin B derivative 15 for earlier work, see ref 38. 

Similarly, a-fluoro sulphoxides are prepared by fluorination using DAST [151]. 

Very low (3-8%) enantiomeric excesses are obtained in the fluorination of optically active a-hydroxybenzylphosphonates by DAST or (l,l,2,3,3,3-hexafluoropropyl)diethylamine (PPDA) at 0°C or -78°C. Therefore, despite a previous report that described a stereoselective reaction with... 

Attempts to prepare diethyl fluoromethylphosphonate by DAST fluorination of diethyl hydroxymethylphosphonate gave very low yields (<2%). A different methodology, involving the conversion of the alcohol into the corresponding triflate and a subsequent nucleophilic displacement with TBAF, provided a safe, cheap, and simple route to diethyl fluoromethylphosphonate, which was isolated in 67% yield (Scheme 3.14). ... 

In the fluorination reactions described in Sections A.4.2 and A.4.3 BAST may be replaced by DAST with similar results. 

CycUzations. A one-step eycUzation of A(-hydroxyethyl amides to oxazoles and oxazolines is mediated by DAST. P-Hydroxy carbamates usually undergo fluorination (OH — F), but the N-Boc derivatives afford oxazolidin-2-ones. ... 

The side chain is constructed from ( S)-malic acid via the acetoxyester 34b (Scheme 44) [35]. Reduction of the carboxylic acid with diborane or BMS [33] affords hydroxy ester 323 in essentially quantitative yield. Hydrolysis followed by acidification gives the lactone 275 in moderate yield. Fluorination with DAST proceeds with inversion of configuration, producing the fluoro lactone 324 with > 98% ee. Treatment of this lactone with an excess of methyl-lithium under carefully controlled conditions furnishes the desired fluoro diol 325. 

Burger and coworkers reported syntheses of (25)-4,4-difluoroproline 22 and (25,4/ )-fluoroproline 20 from (5)-aspartic acid. This amino acid was converted to the diazoketone 23 in three steps, an intermediate that contains the requisite carbon skeleton for the proline derivatives. Rhodium-catalyzed cychzation produced the diketoproline derivative 24, and this was fluorinated with DAST to give 25, hydrolysis of which produced 22. Stereoselective reduction of 24 was directed by the concave face to give 26. Fluorination with inversion and hydrolysis produced 20 (Fig. 3.11). 

Fluorination using DAST was employed in the synthesis of the 2 -deoxy-2 -fluoro-P-D-arabinofuranoside of 6-chloropurine (64), and a number of pyrimidine nucleosides with a 2 -deoxy-2 -fluoro-p-L-arabinofuranose unit have been prepared using base-sugar coupling procedures the thymine compound 65 (l-FMAU) had particular potency against The synthesis and antitumour activity of 2, 2 -difluoro-deoxycytidine (gemcyta-bine) has been reviewed by workers at Eli Lilly. ... 

The synthesis of sofosbuvir was based on the convergent condensation of nucleoside PSI-6206 (10) and a phosphoramidating reagent. The discovery synthesis of PSI-6206 started from cytidine in a linear approach (Scheme 1). Cytidine (29) was selectively benzoylated and silylated to 30, which underwent Swem oxidation and MeLi addition, giving exclusively 2 -a-methyl compound 32. Desilylation and benzoylation of 32 yielded benzoylated 2 -a-methyl compound 33, which was converted to 2 -p-methyl-2 -fluorocytidine 34 by DAST fluorination. Deamination of 34 followed by deprotection provided PSI-6206 (10). 

An interesting aspect of the above mechanism is that it has not involved any net oxidation or reduction. Thus, the bromine has remained trivalent throughout. In that sense, the process may remind you of fluorination by SF4 or DAST (Section 6.12). An alternative mechanism, where fluorine is the site of electrophilic attack and BrFj undergoes reductive elimination, is also conceivable. 

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