Synthesis of β-fluoro-β-proline

A synthetic strategy towards the novel amino acid β-fluoro-β-proline, a fluorinated analogue of β-proline, is elaborated. The synthesis commences from commercially available methyl 2-fluoroacrylate and involves three steps. The overall yield of β-fluoro-β-proline is 57%.     

Preparation of β-fluoro- and β,β-difluoro-histidinols

Nucleophilic attack of azide on 2-bromo-3-fluoro-3-(1-trityl-1H-imidazol-4-yl)-propan-1-ol (1a) in aprotic solvent occurs on the 2-position to give the 2-azido derivative (2a). Reduction of azide and removal of the trityl group produces β-fluorohistidinol (6a). Elimination of HBr from 1a followed by “FBr” addition to the resulting double bond gives 2-bromo-3,3-difluoro-3-(1-trityl-1H-imidazol-4-yl)-propan-1-ol (1b). Nucleophilic attack of azide followed by reduction and removal of the trityl group, as for the preparation of 6a, gives β,β-difluorohistidinol (6b). Initial attempts, under a variety of conditions, to oxidize the fluorinated histidinol precursors to carboxylic acids have not been successful.     

Regioselective synthesis of β-fluoro-α,β-unsaturated ketones by the reaction of β-diketones with DFMBA

The deoxyfluorination reaction of β-diketones with N,N-diethyl-α,α-difluoro-m-methylbenzylamine (DFMBA) gave β-fluoro-α,β-unsaturated ketones in good yields. The reaction proceeded regioselectively, and only one regioisomer was obtained from the unsymmetrical 1-aryl-1,3-diketones. The reaction is applicable to diketones with a trifluoromethyl group, obtaining good yields of 3,4,4,4-tetrafluorobutenones. We used the resulting β-fluoro-α,β-unsaturated ketones for the reaction with lithium dialkyl cuprates.     

Synthesis of α-Cyano-β-fluoro-α-hydroxyesters

The ring opening fluorination of glycidic gem-cyanoesters was achieved by action of pyridine polyhydrofluoride at 25°C in dichloromethane. The regioselective nucleophilic substitution reaction allows the synthesis of a new class of fluorohydrins with OH, CN and CO₂R on the same carbon atom.     

Synthesis and reactions of α-fluoro-α-amino amides

N-((S)-1-Phenylethyl)halofluoroethanamides have been investigated as precursors to N-protected α-fluoro-α-amino amides by nucleophilic displacement of halide with nitrogen nucleophiles such as potassium phthalimide, sodium succinimide, sodium glutarimide, trimethylamine and sodium azide. With single diastereoisomers of the iodofluoroethanamide, clean inversion of configuration occurs at room temperature, but subsequent epimerisation may occur as a result of the liberated iodide. The α-fluoro-α-amino amides made underwent a wide variety of reactions depending on conditions, but in many cases the carbon-fluorine bond was compromised. However, reacting trimethylamine and N-((S)-1-phenylethyl)iodofluoroethanamide gave the corresponding α-fluorobetaine amide, and subsequent acidic hydrolysis led to α-fluorobetaine as the first example of an ‘unprotected’ α-fluoroamino acid.     

Synthesis of γ-fluoro-α-amino acids by Claisen rearrangement

A series of N-protected glycine and alanine esters 4-7 of different fluorinated allylic alcohols 1 was prepared using the dicyclohexylcarbodiimide/dimethylaminopyridine method. All fluorinated esters of this type failed to react in an esterenolate Claisen rearrangement under the general conditions of the Kazmaier variant of this rearrangement. Change of the solvent from tetrahydrofuran to the less coordinating diethyl ether enabled the rearrangement of N-Boc-protected glycine esters 4a-c of 2-fluoroalken-3-ols 1a-c to form N-Boc-2-amino-4-fluoroalk-4-enecarboxylic acids 8a-c, while the rearrangement failed with N-Boc-alanine esters and all amino acid esters of 2-fluoroallylic alcohol (1e). This might be due to competing deprotonation of the position β to fluorine. Similarly to the esters 4a-c, the TFA-protected glycine esters 5a-c of 2-fluoroalken-3-ols 1a-c were rearranged. Deprotection of the Boc or the TFA group under salt-free conditions yielded the free amino acids 11a-c, which might be seen as mimics for N-alkylasparagines a group of lipoproteins.     

Novel efficient synthesis of β-fluoro-β-(trifluoromethyl)styrenes

CF₃CFBr₂ was employed in catalytic olefination reactions of aromatic aldehydes. In situ prepared hydrazones of aldehydes were transformed to β-fluoro-β-(trifluoromethyl)styrenes by reaction with CF₃CFBr₂ under CuCl catalysis. Based on this reaction, a novel stereoselective approach towards β-fluoro-β-(trifluoromethyl)styrenes was elaborated. Nucleophilic vinylic substitution of fluorine by secondary amines, thiolates and alkoxides in β-fluoro-β-(trifluoromethyl)styrenes was also tested.     

α-Tosyloxylation of fluorosubstituted β-diketones

The interaction of fluorinated -diketones with [hydroxy(tosyloxy)iodo]benzene leads to -tosyloxy--diketones existing in the form of stable hydrates.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 541–542, March, 1994.     

Synthesis and structure of β-aryl-α-nitroacrylates

The method for preparation of ethyl α-nitrocinnamates by nitroacetic acid ester alkenylation with aromatic aldehydes in the presence of acetic acid and β-alanine has been modified. Structures of the prepared compounds have been proved by electronic, IR, ¹H, and ¹³C-{¹H} NMR spectroscopy (including heteronuclear correlation experiments ¹H-¹³C HMQC and ¹H-¹³C HMBC). In solution these compounds exist in the form of Z-isomer; the Z?E isomerization is observed in the case of the compound containing strong electron-donor group [N(CH₃)₂] at benzene ring.     

Synthesis and Crystal Structure of β-Amino-α-Phenyl-α-Ferrocenylethanol

β-Amino-α-phenyl-α-ferrocenylethanol, FcC(OH)(Ph)CH₂NH₂ was prepared by the reduction of cyanohydrin trimethylsilyl ether of benzoylferrocene with lithium aluminum hydride. This new compound was characterized by elemental analysis, IR and ¹H NMR spectroscopy. The structure was also confirmed by a single crystal X-ray study. The compound crystallizes in monoclinic P2₁/c space group with unit cell dimensions: a = 12.5906(17), b = 5.9636(8), c = 19.8320(3) Å, β = 102.047(2)^∘, V = 1456.3(3) ų, Z = 4. The structure exhibits intra- and inter-molecular hydrogen bonding of the type N—H⋅ < eqid1 > ⋅O and O—H⋅ < eqid2 > ⋅N, respectively. The pattern of the inter-molecular hydrogen bonding interaction contains a 10-atom ring with two donors and two acceptors, showing a dimeric crystal packing.     

Highly enantioselective synthesis of α-fluoro-α-nitro esters via organocatalyzed asymmetric Michael addition

Primary amines catalyzed the asymmetric Michael addition of ethyl 2-fluoro-2-nitroacetate to enones to provide chiral α-fluoro-α-nitro ester ketones with two contiguous stereogenic centers, one of which is a fluorinated quaternary chiral center, with excellent enantioselectivities and in moderate to good yields.     

Synthesis of β-Amino-α,α-dichloro Sulfones from Vinyl Sulfones

β-amino-α,α-dichloro sulfones 3 are prepared by the reaction of vinyl sulfone 1 with primary or secondary amines 2in the presence of CCI₄ and NaH.     

α-Aminoxylation of Ketones and β-Chloro-α-aminoxylation of Enones with TEMPO and Chlorocatecholborane

Oxidation of various cyclic and acyclic ketones under mild conditions with chlorocatecholborane, a bulky pyridine base, and TEMPO to the corresponding α-aminoxylated products in good to excellent yields (52-99%) is described. For enones as substrates, products of a β-chloro-α-aminoxylation are obtained (70-89%).     

Rapid, one-pot synthesis of β-siloxy-α-haloaldehydes

The Mukaiyama cross-aldol reaction of α-fluoro-, α-chloro-, and α-bromoacetaldehyde-derived (Z)-tris(trimethylsilyl)silyl enol ethers is described, furnishing anti-β-siloxy-α-haloaldehydes. A highly diastereoselective, one-pot, sequential double-aldol process is developed, affording novel β,δ-bissiloxy-α,γ-bishaloaldehydes. Reactions are catalyzed by C(6)F(5)CHTf(2) and C(6)F(5)CTf(2)AlMe(2) (0.5-1.5 mol %) and provide access to halogenated polyketide fragments.     

Synthesis of 5 β-Chloro-4α-methoxysantonin Oxime

The newderivative 5-chloro-4-methoxysantonin oximewasprepared from5-chloro-4-methoxysantonin by reaction with hydroxylamine hydrochloride in the presence of pyridine. The structure was established by IR, UV, and PMR spectroscopies.     

A Novel Synthesis of β-Hydroxy-α-amino Acids

β-hydroxy-α-amino acids constitute an important class of compounds as naturally occurring amino acids and as components of many complex natural products possessing a wide range of biological activities. [1] As a consequence of the essential role played by these amino acids in the biological systems and their utility as synthetic building blocks, a number of useful strategies have been devised for their preparation. [2]     

Synthesis and Heterocyclization of β-Aroyl-α-diphenylphosphorylpropionic Acids

It has been established that diphenylphosphine oxide reacts smoothly with -aroylacrylic acids with the formation of -aroyl--diphenylphosphorylpropionic acids, which were cyclized under the action of hydroxylamine, hydrazine hydrate, and phenylhydrazine hydrochloride into phospho derivatives of dihydrooxazinone and tetrahydropyridazinone respectively. It was shown that imidazole may serve as nucleophilic protection for the synthesis of dihydropyridazinone derivatives from -aroylacrylic acids.     

α-Alkylation of β-aminobutanoates with lk-1.2-induction

Dilithiated methyl- or ethyl-N-benzoyl-3-aminobutanoates are alkylated or added to benzaldehyde to give products of l- and u,u-configuration respectivly. Several methods are presented by which enantiomerically pure 3-aminobutanoic acid derivatives can be prepared.     

Engineered Biocatalytic Synthesis of β-N-Substituted-α-Amino Acids

Non-canonical amino acids (ncAAs) are useful synthons for the development of new medicines, materials, and probes for bioactivity. Recently, enzyme engineering has been leveraged to produce a suite of highly active enzymes for the synthesis of β-substituted amino acids. However, there are few examples of biocatalytic N-substitution reactions to make α,β-diamino acids. In this study, we used directed evolution to engineer the β-subunit of tryptophan synthase, TrpB, for improved activity with diverse amine nucleophiles. Mechanistic analysis shows that high yields are hindered by product re-entry into the catalytic cycle and subsequent decomposition. Additional equivalents of l -serine can inhibit product reentry through kinetic competition, facilitating preparative scale synthesis. We show β-substitution with a dozen aryl amine nucleophiles, including demonstration on a gram scale. These transformations yield an underexplored class of amino acids that can serve as unique building blocks for chemical biology and medicinal chemistry.