Boron-Catalyzed α-Functionalizations of Carboxylic Acids

Catalytic, chemoselective, and asymmetric α-functionalizations of carboxylic acids promise up-grading simple feedstock materials to value-added functional molecules, as well as late-stage structural diversifications of multifunctional molecules, such as drugs and their leads. In this personal account, we describe boron-catalyzed α-functionalizations of carboxylic acids developed in our group (five reaction types). The reversible boron carboxylate formation is key to the acidification of the α-protons and enolization using mild organic bases, allowing for chemoselective and asymmetric bond formations of carboxylic acids. The ligand effects on reactivity and stereoselectivity, substrate scopes, and mechanistic insights are summarized.     

Reaction of α-Pinene with Haloacetic Acids

The reactions of -pinene with chloro-, bromo-, and trichloroacetic acids, accompanied by isomerization of -pinene, were studied.     

Effect of Temperature on The Solubility of α-Amino Acids and α,ω-Amino Acids in Water

The aqueous solubilities of glycine, dl-α-alanine (2-aminopropanoic acid), dl-α-aminobutyric acid (2-aminobutanoic acid), dl-α-norvaline (2-aminopentanoic acid), dl-α-norleucine (2-aminohexanoic acid), β-alanine (3-aminopropanoic acid), γ-aminobutyric acid (4-aminobutanoic acid), 5-aminovaleric acid (5-aminopentanoic acid), and 6-aminocaproic acid (6-aminohexanoic acid) were determined from 293.15 to 323.15 K at intervals of 5.00 K using the gravimetric method. The temperature dependence of the solubility of α-amino acids and α,ω-amino acids in water is well described by the van’t Hoff equation. Linear van’t Hoff plots were used to determine the differential enthalpy of solution. The results obtained are compared with reported values in literature and are discussed in terms of the position of the ionic groups in the hydrocarbon chain.     

Polyenolates of Unsaturated Carboxylic Acids in Synthesis. Synthesis of Unsaturated α-Amino Acids and β-Hydrazing Acids

Regioselective reaction of lithium diene-and triene-diolates 1 and 2 with O-diphenylphosphinyl hydroxylamine affords unsaturated α-amino acids 3 and 4. Addition to DEAD leads selectively to γ-hydrazino unsaturated acids 5 and 6.     

Catalytic Asymmetric Hydrogenation of α-Acetamido Cinnamic Acids

Abstract

The homogeneous catalytic asymmetric hydrogenations of substituted cinnamic acids by (l-Benzyl-3,4-(R,R)-bis(diphenyl-phosphino) pyrrolidine (COD) Rh)BF₄ 6, easily prepared from L-tartaric acid has been studied. Contrary to other catalysts, this Rhodium (I) complex affords very high chemical and optical yields of N-acetylated amino acids under mild conditions even when using substrate to catalyst ratio as high as 16000. The method has been successfully applied for the preparation of L-Phenylalanine and L-Dopa.     

Synthesis of α-N-Ethylamino Acids and their Derivatives

 A new synthesis of α-N-ethylamino acids starting from α-amino acids using hexafluoroacetone as protecting and activating agent is described. The hexafluoroacetone-protected N-ethylamino acid derivatives obtained are activated lactons. Therefore, they can be directly transformed without the need of an additional activation step with various nucleophiles into the corresponding carboxylic acid derivatives.     

Diastereoselective Synthesis of Enantiopure Cyclic α-Aminophosphonic Acids

A new and efficient route for the synthesis of cyclic aminophosphonic acids by the reaction of dialkylchlorophosphites with β-aldiminoalcohols has been described.     

Membrane Transport of the Zwitterionic Aromatic α-Amino Acids by α-Aminophosphonates

Abstract

Bghly selective biological transport of amino acids is usually mediated by carrier proteins. The application of such membrane systems for the analysis and separation of amino acids has long studied. This work is devoted to the transport of zwitterionic form of aromatic a-amino acids such as d,l-Phe, d,l-DOPA, d,l-His, d,l-Tyr, d,l-Trp, via supported liquid membrane (SLM). The lipophilic α-aminophosphonates (I).

R₁ amyl or 2-ethylhexyl; R₂, R₂-(CH₂)4-(CH₂)5-CH₃ & (CH₃), C₄ H(CH₉) & H; H & H; have been used as carrier in the membrane systems composed of a porous polymeric support (Millipore Type FA) impregnated with 10^?1 M carrier in o-nitrophenyl n-octyl ether (amino acid concentration in source phase is 10^?3 M). The cell for membrane extractions is presented on Fig I.     

Synthesis of Enantiomerically Enriched α-Bromonitriles from Amino Acids

Two methods were investigated for the preparation of six chiral α-bromonitriles with different optic purities. The nitrous deamination of amino acids gives α-bromoacids, which react with chlorosulfonyl isocyanate followed by triethylamine to afford α-bromonitriles with moderate enantiomeric excess. However, the dehydration of corresponding α-bromoamids using thionyl chloride gives α-bromonitriles with good enantiomeric excess up to 94%. The use of phosphoryl chloride instead of thionyl chloride results in more than 30% racemization as determined by high-performance liquid chromatograpic analysis.     

Cobalt-Catalyzed Asymmetric Deuteration of α-Amidoacrylates for Stereoselective Synthesis of α,β-Dideuterated α-Amino Acids

A cobalt-catalyzed deuteration of amidoacrylates using deuterated methanol afforded α,β-dideuterio-α-amino esters in excellent enantiomeric ratios (mostly >95 : 5) and almost complete deuteration (99 %). The new protocol was used to prepare dideuterio-α-amino acid fragments in some drugs. Furthermore, the stereoselective deuteration was applied in a concise synthesis of dideuterio l -DOPA.     

Syntheses of α-Amino Phosphinic Acids via Oxo-iminium Salts

Nitrones 2a , 2b obtained from the aldehydes 1a , 1b , are used for the syntheses of the N-ethoxy iminium salts 4a and 4b . In the following procedure 4a and 4b react to several esters of phosphinic acids 6a - 6d .     

Synthesis of Boc-Amino Tetrazoles Derived from α-Amino Acids

A simple route for the synthesis of Boc-protected tetrazole analogs of amino acids starting from N ^α-Boc amino acids has been described. The [2 + 3] cycloaddition of Boc-α-amino nitrile and sodium azide in the presence of a catalytic amount of zinc bromide yielded the desired tetrazoles in good yields and purity. All the compounds obtained have been characterized by ¹H and ¹³C-NMR and mass spectral studies.     

Convenient Syntheses of Aroylamino Acids and α-amino ketones

C-Acylamino acid, especially aroylamino acid is a key and still currently interest compound for the pharmaceutical intermediate in which β-arylserine prepared by the reduction in an example would be physiologically important.     

Enantioselective Synthesis of α-Thiocarboxylic Acids by Nitrilase Biocatalysed Dynamic Kinetic Resolution of α-Thionitriles

The enantioselective synthesis of α-thiocarboxylic acids by biocatalytic dynamic kinetic resolution (DKR) of nitrile precursors exploiting nitrilase enzymes is described. A panel of 35 nitrilase biocatalysts were screened and enzymes Nit27 and Nit34 were found to catalyse the DKR of racemic α-thionitriles under mild conditions, affording the corresponding carboxylic acids with high conversions and good-to-excellent ee. The ammonia produced in situ during the biocatalytic transformation favours the racemization of the nitrile enantiomers and, in turn, the DKR without the need of any external additive base.     

Study of dissociation of α-alkyl-substituted dicarboxylic acids

Dissociation of α-alkyl-substituted dicarboxylic acids low-soluble in water was studied by the method of pH-potentiometry titration. Equilibrium constants of the dissociation at 25°C were determined.     

Ring-Closing Metathesis in the Synthesis of Cyclic α-Amino Acids

The review summarizes recent advances in the synthesis of cyclic -amino acids via intramolecular ring-closing metathesis of dienes and enynes.     

Study on the Reaction of α-Ketohemithioacetal

Aromatic α-sulfinyl carboxylic acids can be rearranged to hemithioacetals or other derivatives of glyoxylic acid under the action of acid reagents was first reported by Pummerer¹. Later, Russell and coworkers applied this rearrangement to β-ketosulfoxides, synthesized α-ketohemithioacetal², which can be transformed to α-keto alcohol, α-keto aldehyde and α-hydroxy alcohol, α-hydroxy acid³. Furthermore, Hall and Poet reported that α-ketohemithio-acetal can be rearranged to the corresponding α-hydroxythioester in the presence of magnesium nitrate and sodium acetate or tertiary amine⁴. However, few reports of reaction of α-ketohemithioacetal can be seen in literature.     

Study on the Reaction of α-Thiobenzoylthioformylmorpholine

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HPLC Determination of α-Amino Acids in Phytoplanktonic Marine Cells

Abstract

A procedure for the quantitative determination of 17 amino acids in a marine matrix using HPLC is reported. Pre-column derivatization with o-phthalaldehyde, separation on C₁₈-bonded silica with phosphate buffer (pH 7.2)-acetonitrile as eluent and fluorescence detection have been used. The good variation coefficient (average 2% with working curves in real matrix) and the low detection limit (1-5 fmoles) make the procedure suitable for the determination of total or free amino acids in matrix cultures.