Phenylalanine boronic acid

The Suzuki coupling of p-phenylalanine boronic acid (60) with 2-chloropyrazine under microwave irradiation afforded 4-pyrazinylphenylalanine (61) as a free amino acid in high yield [40]. The amino group and carboxyl group were well tolerated under microwave irradiation and offered a straightforward approach to the synthesis of unprotected 4-arylphenylalanines [40]. 

There have also been efforts in designing selective thrombin inhibitors by varying the PI position. For example, incorporation of m-cyano-substituted phenylalanine boronic acid analogues into R-(D)Phe-Pro-OH dipeptides produced several highly effective thrombin inhibitors such as H-(D)Phe-Pro-boroPhe(m-CN)-OH [62]. The cyano group enhances binding by several orders of magnitude. Because of its struc-... 

Asymmetric hydrogenation of bromo-substituted aromatic a-enamides 14 affords the corresponding bromo-amino acid derivatives 15, which subsequently is subjected to Pd-catalyzed cross-coupling with aryl and vinyl boronic acids. In addition to diverse phenylalanine derivatives 16, a broad array of other novel aromatic and heterocyclic amino acids have been produced rapidly from a small number of bromo-functionalized intermediates [24], This same two-step process may be applied to the production of many other classes of aromatic and heterocyclic chiral building blocks, such as arylalkylamines, amino alcohols, diamines, and directly on peptides as well. 

This is analogous to the extraction of sugars with boronic acids described earlier. The recovery of phenylalanine from a fermentation broth has been simplified by using a microporous poly(tetrafluoroethylene) membrane with tri-/j-octylmethylammonium chloride in toluene in the pores.133 Phenylalanine can also be separated using the quaternary ammonium salt with 2-nitrophenyl octyl ether in a cellulose triacetate membrane.134 Kerosene flowing in hollow fiber membranes can remove 99.9% of organic pollutants, such as benzene, p dichlorobenzenc, chloroform, and carbon tetrachloride, from wastewater outside the fibers.135... 

Unprotected 4-heteroaryl phenylalanines have been prepared by microwave-assisted Suzuki-Miyaura reactions. Amino adds containing the biaryl motif have several interesting applications in medicinal chemistry and this method enabled their synthesis without protection of the amino acid. Optically pure boronic acids could be used without racemization (Scheme 15.16) [49]. 

Nevertheless, current knowledge of biochemical systems and synthetic techniques may allow us to explore them from a slightly different perspective. Namely, what would life look like with an expanded genetic code—that is, with additional amino acids added into the proteins of life. Indeed, over the past few years chemists have been able to utilize native biochemical systems as well as evolved tRNA molecules (which we will discuss in Chapter 25) to load many unique amino acids into proteins of interest at any specific point desired in a number of different cells, including those of yeast, some mammals, and bacteria like E. coli. Some of the unnatural amino acids are shown below. They include ones with unique metals (like selenium), reactive functional groups (such as a ketone and an azide) that can be used for additional chemistry, and a boronic acid that can be used to bind certain sugars covalently. These synthetic amino acids are all derivatives of phenylalanine, but many other amino acid parent structures can be used as well. 

In addition to PBLs mentioned above, the Schultz lab also reported boronic acid-modified proteins. Specifically, the Schultz lab successfully incorporated a boronic acid-modified phenylalanine (p-boronophenylalanine, 7, Figure 2) into protein for the selection of lectin mimics with... 

The convergent total synthesis of (S,S)-isodityrosine has been accomplished from natural a-amino acids, l-tyrosine, and L-phenylalanine (Scheme 20.49). In this synthesis, boronic acid is used as the aryl donor, and tyrosine derivatives are used as the phenolic partner [148]. 

A series of novel hydrophobic, bulky x Suzuki coupling of a-amino acid derivatives with boronic acids to afford these aromatic substituted amino acids in high yields and with high enantioselectivity (Equation 9) [10]. 

Firooznia has reported the synthesis of 4-substituted phenylalanine derivatives via cross-coupling of protected (4-pinacolylboron)phenylalanine derivatives such as 61 with aryl and alkenyl iodides, bromides and triflates [44]. They have further shown that BOC derivatives of (4-pinacolylboron)phenylalanine ethyl ester 61 or the corresponding boronic acids undergo Suzuki-Miyaura reactions with a number of aryl chlorides in the presence of PdCl2(PCy)3 or NiCl2(dppf), respectively providing diverse sets of 4-substituted phenylalanine derivatives of type 62 [45]. This strategy has also been used for the synthesis of enantiomerically enriched 4-substituted phenylalanine derivatives (Scheme 3.28) [46]. 

An entry to. yyrt-2-methoxy-3-hydroxycarboxylic acids is also opened using similar methodology. Thus the norephedrine derived (4/ ,5S)-3-(2-methoxy-l-oxoethyl)-4-methyl-5-phenyl-1,3-oxazolidine-2-one 23105a, as well as the phenylalanine derived (4S)-4-benzyl-3-(2-methoxy-l-oxoethyl)-l,3-oxazolidin-2-one 25105b, can be added to aldehydes via the boron enolates to give, after oxidative workup, the adducts in a stereoselective manner (d.r. 96 4, main product/sum of all others). Subsequent methanolysis affords the methyl esters. 

Asymmetric syntheses of (3- amino acids result from the addition of chiral enolates (399) to nitrone (400) via A-acyloxyiminium ion formation (642, 643). Regioselective convergence is obtained in the reactions of chiral boron- and titanium- enolates (399a,b), (401), and (402). This methodology was used in preparing four stereoisomers of a-methyl- 3-phenylalanine (403) in enantiomeric pure form (Scheme 2.179) (644). 

Asymmetric halogenation of carboxylic acid derivatives has also been achieved by D.A. Evans (refs. 11,12) via chiral N-acyl oxazolidones. For instance, an N-acyl oxazolidone prepared by acylation of the (4S)-benzyl-2-oxazolidone chiral auxiliary derived from (S)-phenylalanine, is converted to its (Z)-dibutyl boron enolate, which is added to a NBS slurry, at low temperature (Fig. 6) ... 

More curiously, N-tosylated phenylalanine derivatives [10] and phenyllactic acid [11] can also be converted into 2-phenylnaphthalene in moderate yields whereas 3,4-dimethoxyphenyllactic acid treated with boron tribromide gives Kagan s ether in almost the same yield as 3,4-dimethoxyphenylethanal does [11]. In these cases, the decomposition of aryllactic acid or alanine derivatives may give arylethanal with the formation of water and carbon monoxide, Fig. (4). 

BFg adducts of glycine, a- and /5-alanine, and phenylalanine have been synthesized. Their i.r. spectra give evidence for the boron being coordinated to the oxygen atom of a carboxy-group on the amino-acid ligand. 

A thorough screen of amino acids and their derivatives led to the application of chiral ligand 98 derived from phenylalanine in the intermolecular arylation of cyclopropane derivatives (Scheme 27) [52]. Albeit not practical, the addition of the catalyst and ligand in two batches at 40°C was optimal for the yield and enantioselectivity. Traces of water were also required in the transformation, and it was speculated that water aided in the transmetalation step. Ph-BPin was the best nucleophile, while the employment of alkyl boronic esters required increased... 

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