Fluorinated prolines

Diastereoselective fluoro-functionalization of proline derivatives produces fluorinated prolines. Both enantiomerically pure 4-trifluoromethyl and 4-difluoromethyl prolines 268 and 270 have been prepared (see Scheme 9.57) [85]. The key reaction for the stereo-controlled synthesis is diastereoselective Pd-catalyzed hydrogenation of 267 and 269. 

Raines and co-workers have used fluorinated proline to explore stereoelectronic influences on the stability of collagen. Collagen is the most abundant protein in mammals and consists of three polypeptide chains that form an extended triple helix. Each polypeptide is com-... 

Figure 16.7 Fluorinated prolines in collagen, (a) The trans/cis isomerization of amide bonds and main-chain angles of proline residues. The n —> interaction, depicted by a dashed line,...

Dipolar addition of azomethine ylides to electron-deficient olefins is a versatile route to nitrogen-containing heterocycles. Applying this approach to ( )-ethyl 3-fluoroacrylates utilizing L-menthol as a chiral auxiliary provides a stereoselective and regioselective synthesis of enantiopure-fluorinated prolines 28 and 29. Careful... 

FIGURE 3.15 Asymmetric s3mthesis of side chain-fluorinated prolines. 

The probing of triple helical stability with fluorinated prolines was extended to (25,3R)- and (25,35)-fluoroprolines. It was found that peptide having 35-FPro in the X-position and 4R-FPro in the Y-position do form a triple helix, albeit less stable than... 

Trifluoromethyl and difluoromethylpyroglutamic acids (42 and 43) were prepared from the corresponding fluorinated proline derivatives by ruthenium-mediated oxidation. The process was made difficult by the tendency of the substrates to form pyrrole derivatives under the conditions of the oxidation (Fig. 3.21)... 

Bonini, B.F. Boschi, F. Franchini, M.C. Fochi, M. Fini, F. Mazzanti, A. Ricci, A. First 1,3-dipolar cycloaddition of azomethine yhdes with ( )-ethyl 3-fluoroacrylate regio- and stereoselective synthesis of enantiopure fluorinated prolines. Synlett 2006, 543-546. 

Asymmetric aza-Michael addition of purine bases to a,/8-unsaturated aldehydes can be catalysed by the fluorinated proline derivative (123b), giving rise to the corresponding acyclonucleosides with <99% ee. Notably, the simpler derivative (123a), as well as proline itself (124), gave inferior results (< 10% ee). ... 

Liu and coworkers have recently published the synthesis of (3) and (4), as well as several other fluorinated pyrrole analogues (not shown), by aminofluorination of allenes the synthetic approach is shown in Scheme 3 [15], This strategy takes advantage of a selective, silver-catalyzed intramolecular fluorination reaction, but the approach works best with substrates that possess electron-withdrawing R -groups on the 3-position. Because of this limitation, the yield of (3) is significantly higher than (4), 80 % versus 28 %, respectively. 4-Fluoro-pyrrole-2-carboxylic acid (5a, Fig. 2), synthesized from a fluorinated proline, was explored as a potential intermediate on the route to (3), but only extensive decomposition products were observed when (5a) was subject to flash pyrolysis [16]. 

The successful use of [ F]FDG in oncology PET imaging has prompted the design of several other radiopharmaceuticals, such as [ F]FLT ([ F]fluorothymi-dine, used as cellular proliferation marker. Scheme 36) [152-154], F-MISO ([ F] fluoromisonidazole, used to assess tissue hypoxia. Scheme 37) [155], c/s-4-[ F] fluoro-L-proline (used as abnormal collagen synthesis marker. Scheme 38) [156] and 0-(2-[ F]fluoroethyl)-L-tyrosine (used as amino acid transport and/or protein synthesis marker. Scheme 39) [157]. All these fluorine-18-labelled molecules have been prepared by aliphatic nucleophilic fluorination followed by a deprotection reaction. 

Most of the fluoro derivatives of proline described in the literature are fluorinated in the 4 position. 4-Fluoroprolines are able to mimic 4-hydroxyproline, present in some proteins and polypeptides. On the other hand, 4-fluorination could suppress oxidative metabolism or modified ring conformation of ligands.The labeled analogues may be used as probes in PET (positron emission tomography) for localization of tumors... 

Fluorinated y -amino alcohols have been prepared in moderate yield, but high de and very high ee, using a proline-catalysed cross-Mannich reaction of fluorinated aldimines with aliphatic aldehydes, followed by NaBH4 reduction.35... 

Basically, two different routes are conceivable for their asymmetric construction 1) nucleophilic substitution reaction with a fluoride anion and 2) electrophilic addition of fluoronium cations to activated or masked carbanions. First attempts on enantioselective nucleophilic fluorination date back to the pioneering work of Hann and Sampson [3]. In an ambitious dehydroxylation/fluorination sequence the authors reacted a racemic a-trimethylsiloxy ester with a half molar equivalent of an enantiomerically pure proline-derived aminofluorosulphurane in hope to achieve a kinetic resolution. Unfortunately, the fluorinated product was obtained without significant enantiomeric excess. 

The (S)-proline-catalyzed Mannich reactions of aldehyde donors and N-PMP-protected imines of fluorinated aldehyde, such as CF3CHO, C2F5CHO, and PI1CF2CHO, were also used for the expedient synthesis of fluorinated aminoalco-hols [81]. 

Various chiral amines can catalyze the direct enantioselective a-fluorination of aldehydes. Enders and Hiittl have focused on the use of Selectfluor for the a-fluorination of aldehydes and ketones [24a], For the aldehydes, no enantiomeric excess was reported using L-proline as the catalyst. In an attempt to perform direct enantioselective a-fluorination of ketones, cyclohexanone was used as the model substrate and a number of chiral amines were tested for their enantioselective properties however, the enantiomeric excess was rather low and in the range of 0 to 36% ee. 

The enantiomeric excess of the (S)-proline-catalyzed a-fluorination was generally found to be rather low. For example, the enantiomeric excess of 70 was determined to be 29%. Because of the importance of enantiopure organofluorine compounds we studied the efficiency of several organocatalysts with respect of the asymmetric a-fluorination of cyclohexanone as the model substrate and Selectfluor as the fluo-rinating agent (Scheme 16). Unfortunately, neither (S )-proline nor its derivatives were able to catalyze the a-fluorination with high stereoselectivity. The highest enantiomeric excess was observed with trans-4-hydroxy-(5)-proline (36% ee). 

Asymmetric alkylation of imines has been employed most frequently for the construction of chiral amino moieties involved in the syntheses of nitrogen heterocycles and amino acids [17]. This approach is also useful for fluorinated amino acid synthesis as shown in Scheme 9.7. Mannich reaction of enolate with imino ester 23 in the presence of L-proline gives a-amino esters 24 and 25 enantio-and diastereoselectively [18]. 

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