Synthesis trifluoromethylated /-amino

Figure5.31 Synthesis of a-trifluoromethyl amino acids starting from trifluoromethyl fluorooxazole by Claisen rearrangement. ...

A special one-pot deprotection-transacylation method involves coupling of activated Fmoc amino acids with Aloc-protected amino acid esters.The Aloc-deprotection proceeds with palladium/phenylsilane in the presence of the acylating species. Using Fmoc-Phe-F the synthesis of the sterically demanding dipeptide Fmoc-Phe-(Me)Aib-OMe was accomplished in a yield of 65% A similar one-pot approach to the acylation of the even more difficult hindered and weakly nucleophilic a-trifluoromethyl amino acid esters involves the intermediate A-Teoc protection. Thus treatment of ( )-Teoc-a-(a-CF3)Leu-OMe with Fmoc-Gly-F and a catalytic amount of tetraethylammonium fluoride in acetonitrile at 50 °C for 1-2 weeks gave ( )-Fmoc-Gly-(a-CF3)Leu-OMe (77%... 

An efficient method for the asymmetric synthesis of /3-trifluoromethylated -amino ketones via addition of ketone-derivative enolates to trifluoromethylated sulfinylimine has been developed, with good chemical yields and excellent diastereo-selectivities (up to 99 1 dr) ... 

Bravo and co-workers report asymmetric syntheses of fluoroalkylamino compoimds via chiral sulfoxides and the stereoselective synthesis of p-fluoroalkyl-p-amino alcohol units using chiral sulfoxides and the Evans aldol reaction. Begde and colleagues discuss the stereoselective and enantioselective synthesis of trifluoromethyl amino alcohols and fluoroalkyl isoserinates. Hoffman reports the aysmmetric fluorination of a-aminoketones, while... 

Oxazol-5(2H)-one, 2-benzylidene-4-methyl-tautomerism, 6, 186 Oxazol-5(2ff)-one, 2-methylene-isomerization, 6, 226 Oxazol-5(2H)-one, 2-trifluoromethyl-acylation, 6, 201 Oxazol-5(4ff)-one, 4-allyl-thermal rearrangements, 6, 199 Oxazol-5(4H)-one, 4(arylmethylene)-Friedel-Crafts reactions, 6, 205 geometrical isomerism, 6, 185 Oxazol-5(4ff)-one, 4-benzylidene-2-phenyl-configuration, 6, 185 photorearrangement, 6, 201 Oxazol-5(4ff)-one, 4-benzyl-2-methyl-Friedel-Crafts reactions, 6, 205 Oxazol-5(4ff)-one, 4-methylene-in amino acid synthesis, 6, 203 Oxazol-5(4ff) -one. 2-trifluoromethyl-hydrolysis, 6, 206 Oxazolones... 

Testing the limits of carbene stabilization by substituents, Bertrand and coworkers reported the synthesis and analysis of (amino)(aryl)carbenes where only one substituent can contribute to the stability of the carbene center. Carbene 30 was designed to have the amino substituent as a jr-donor and the 2,6-bis(trifluoromethyl)... 

Similar ring systems were prepared <97JHC1693> by Coppo and Fawzi from the reaction of substituted ethyl 5-[methyl(methylsulfonyl)amino]-l 7/-pyrazole-4-carboxylates 119 with sodium hydride. This gave the 7-substitued 1,7-dihydro-l-methylpyrazolo[3,4-c][l, 2]thiazin-4(37/)-one 2,2-dioxides 120 in fair to good yield (Scheme 30). They also extended this synthesis by treating methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate 121 with sodium hydride in dimethylformamide to yield l-methyl-7-(trifhioromethyl)-l//-pyrido[2,3-c][l,2]thiazin-4(3//)-one 2,2-dioxide 122 in 79% yield (Scheme 31) <98JHC499>. 

The possibility of studying the structure and dynamic properties of proteins by F NMR requires the use of labeled proteins with fluorine. Various approaches can be envisioned trifluoroacetylation or derivatization of side chains by direct fluorination or trifluoromethylation or with small fluorinated molecules. It is also possible to incorporate a fluorinated amino acid into a protein, by using either a classical chemical synthesis or a biosynthetic approach. It is obvious that the chemical synthetic... 

Racemization is not encountered when 4-unsubstituted-5(477)-oxazolones or 4,4-disubstituted-5(477)-oxazolones are used as reagents. Indeed, 4-unsubstituted-5(47/)-oxazolones function as glycine synthons in the synthesis of A-acylglycyl-a-amino acids. For example, aminolysis of 2-(trifluoromethyl)-5(47/)-oxazolone with a-methylphenylalanine affords A-(trifluoroacetyl)glycyl-a-methylphenylalanine. 4,4-Disubstituted-5(4//)-oxazolones, readily available by alkylation of the monosubstituted derivatives, are very useful intermediates in the synthesis of peptides that incorporate ot,ot-disubstituted amino acids. As an example, 4-(aryl-methyl)-2-phenyl-4-(trifluoromethyl)-5(4//)-oxazolones 260 are key intermediates... 

The Henry nitro-aldol condensation involves the use of P-amino alcohols as the building blocks of fluoromethyl ketones. Although this method has been used extensively in the synthesis of monofluoropeptides (Table 2),19-121 it is more widely utilized as a method for synthesizing trifluoromethyl ketones and the details of the reaction will be discussed in Section 15.1.4.3.2. 

The second most prevalent method for synthesizing a,a-difluoroalkyl ketones is a modification of the Dakin-West acylation reaction. This method utilizes difluoroacetic anhydride to form an anhydride with the chosen amino acid, which rapidly cyclizes and activates the a-carbon, where acylation then occurs. Although this method has been used to synthesize many a,a-difluoroalkyl ketones (Table 5)J7A25 261 the modified Dakin-West reaction has primarily been used in the synthesis of trifluoromethyl ketones. Since the syntheses of a,a-difluoroalkyl and trifluoromethyl ketones are identical, the details of this method will be discussed in Section 15.1.4.3.1. 

The nucleophilic addition of a trifluoromethyl anion or its equivalent to an activated carboxylic acid derivative is another potential method for the synthesis of trifluoromethyl ketones (Scheme 8). Due to the well-known instability of the trifluoromethyl anion, the organometallic approach (Section 15.1.4.3.3) is often difficult to utilize. However, a trifluoromethyl anion equivalent, (trifluoromethyl)trimethylsilane (CF3TMS), was developed in 1984 by Ruppert and co-workers.[30] This reagent, known as Ruppert s reagent, is stable and does not undergo fluoride elimination like other equivalent trifluoromethyl anions. An obvious limitation to this method is that it is only useful for the synthesis of a-amino trifluoromethyl ketones unless other fluoroalkyl analogues of Ruppert s reagent are developed. 

Scheme 8 Synthesis of Trifluoromethyl Ketones by Reaction of (Trifluoromethyl)trimethylsilane with Amino Acid Oxazolidin-5-ones[301...

The synthesis (Scheme 9) begins with the appropriate 1-trifluoromethyl-substituted enol ether 43, where R1 is an amino acid side chain or another appropriate carbon chain. The enol ether undergoes reaction with MCPBA in CH2C12 to give the corresponding epoxy ether 44. The epoxy ether is cleaved by reaction of a wide variety of secondary amines to give the a-amino trifluoromethylated ketone 45. Only a few compounds have been synthesized by this method. 35,36 ... 

A new, efficient and general synthesis of 4-amino-3-arylcinnolines has been described recently, starting from arylhydrazines and aryl trifluoromethyl ketones, and the following is a typical example. Addition of a THF solution of the hydrazone formed from phenylhydrazine and 2-trifluoroacetylthiophene to 5 equivalents of KHMDS in THF at -78°C, then slow warming of the mixture to room temperature and stirring at room temperature for several hours, gave 4-amino-3-(2-thienyl)cinnoline in 68% yield after work-up (quench with ether, then a wash with brine). 

Katagiri, T. Uneyama, K. Stereospecific substitution at a-carbon to trifluoromethyl group application to optically active fluorinated amino acid synthesis. Chirality 2003, 35, 4-9. 

---