A-Fluoroaldehydes

Epoxidation also proceeds (Eq. 141) under mild conditions and with high stereoselectivity (95 5 erythro threo) despite the deactivating effect of the fluorine atom [361]. At a higher oxidation level, the Lausanne group described chemistry of a metallated azomethine derived from a,/Lunsaturated-a-fluoroaldehydes [362]. Highly flexible chemistry allowed alkylation at nitrogen, or at the (fluori-nated) -position, or at the -position (Fig. 8). 

Fluorinated dienes have been described, though again, the incidence is rare. Treatment of an a,/ -unsaturated-a-fluoroaldehyde with chlorotrimethyl silane afforded [369] the l-trimethylsilyloxy-2-fluorobutadiene which underwent [4 + 2] cycloadditions with dienophiles, though more slowly than its non-fluori-nated counterpart, and with lower regioselectivity (Eq. 148). 

Substituted 2-oxazolidones 165 are useful chiral auxiliaries for diastereoselective functionalization at the a-carbon of their amide carbonyl group. The a-fluoroaldehydes 166 were prepared by a series of reactions electrophilic fluorination of the corresponding oxazolidinone sodium enolates with AMluorobenzenesulfonimine reductive removal of the auxiliary with LiBH4 and Dess-Martin oxidation. The aldehydes are so unstable for isolation that they are converted with (R)-/ -toluenesulfinamide to /7-toluenesul(inimines 167, which are isol-able and satisfactorily enantio-enriched. Chiral sulfinimine-mediated diastereoselective Strecker cyanation with aluminum cyanide provided cyanides 168 in excellent diastereose-lectivity, which were finally derived to 3-fluoroamino acids 169 (see Scheme 9.37) [63]. 

Dihydro-2-fluoromethyl-4,4,6-trimethyl-4/f-l,3-oxazine (86) can be deprotonated by treatment with butyllithium, and the anion then reacted with electrophiles such as alkyl halides and carbonyl compounds. Reduction and hydrolysis of the products destroy the heterocycle and releases the corresponding a-fluoroaldehydes. For example, reaction of the anion with 3-chloropropene yields the fluorobutenyl-l,3-oxazine (87), which on reduction and hydrolysis yields 2-fluoropent-4-enal (88) (Scheme 19) <90TL179>. 

Notably, for linear-chained aldehydes, imidazolidinone-derived catalysts gave the highest enantioselection (88% ee). The use of NFSI provided access to quaternary a-fluoroaldehydes in high yields and modest enantio-selectivies using proline, albeit several other organocatalysts were more promising in accessing enantiopure fluorinated-substrates. 

Enders [19], MacMiLan [20], J0rgensen [21], and Barbas [22]. Among these, the most selective were those conditions reported by MacMillan and J0rgensen (Scheme 13.8). Both utilized NFSI as the electrophilic source of fluorine, and both performed an in situ reduction of the a-fluoroaldehydes to facilitate product isolation and analysis. The conditions developed by MacMillan provided the / -enantiomer of the product (conditions A), while J0rgensen s conditions required a remarkably low 1 mol% loading of catalyst and furnished the 5-enantiomer (conditions B). 

From a non-c ohydrate precursor, Davis and Qi achieved the asymmetric synthesis of 2-deoxy-2-fluoro- iylo-D-pyranose (9) (Figure 7) and 2-deoxy-2-fluoro-lyxo-L-pyranose (13). TTie key reaction was the highly diastereoselective fluorination of a chiral enolate using the electrophilic fluorinating agent, N-fluoro(benzenesulfonimide) (NFSi). In another study by Davis (14), the use of a chiral oxazolidinone adjuvant and fluorination with NFSi led to the chiral fluorohydrin 10 (>97% ee), which was oxidized by the Dess-Martin periodinane procedure to the non-racemic a- fluoroaldehyde 11 (94% ee). Conversion of 11 in four steps provided l,2,3-tri-0-acetyl-4-deoxy-4-fluoro-D-arabinopyranose (12) as a 1 1 mixture of anomers which could not be separated by flash chromatography. 

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