Amino acids boron derivatives

It is believed that most of the transition metals are complexed to nitrogen donors, such as are found in amino acids or derivatives of chlorophyll, and that the metals with high ionic potentials, such as beryllium, boron, germanium, titanium, gallium, and major elements such as aluminum and silicon, may be bonded to oxygen donors of degraded lignin. 

To date, the most extensively studied polyboron hydride compounds in BNCT research have been the icosahedral mercaptoborane derivatives Na2[B22H22SH] and Na [(B22H22S)2], which have been used in human trials with some, albeit limited, success. New generations of tumor-localizing boronated compounds are being developed. The dose-selectivity problem of BNCT has been approached using boron hydride compounds in combination with a variety of deUvery vehicles including boronated polyclonal and monoclonal antibodies, porphyrins, amino acids, nucleotides, carbohydrates, and hposomes. Boron neutron capture therapy has been the subject of recent reviews (254). 

Amine boranes have been examined by a variety of spectroscopic methods (24—29). The boron-substituted alpha-amino acids have been utilized in animal model studies. These compounds along with their precursors and selected derivatives have been shown to possess antineoplastic, antiarthritic, and hypolipidemic activity (30—32). The boron amino acid analogues are also being evaluated for possible utility in boron neutron capture therapy (BNCT) (33). 

A series of chiral boron catalysts prepared from, e.g., N-sulfonyl a-amino acids has also been developed and used in a variety of cycloaddition reactions [18]. Corey et al. have applied the chiral (S)-tryptophan-derived oxazaborolidine-boron catalyst 11 and used it for the conversion of, e.g., benzaldehyde la to the cycloaddition product 3a by reaction with Danishefsky s diene 2a [18h]. This reaction la affords mainly the Mukaiyama aldol product 10, which, after isolation, was converted to 3a by treatment with TFA (Scheme 4.11). It was observed that no cycloaddition product was produced in the initial step, providing evidence for the two-step process. 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

The enantioselective inverse electron-demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes described so far were catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminum complexes. However, the glyoxylate-derived nitrone 36 favors a bidentate coordination to the catalyst. This nitrone is a very interesting substrate, since the products that are obtained from the reaction with alkenes are masked a-amino acids. One of the characteristics of nitrones such as 36, having an ester moiety in the a position, is the swift E/Z equilibrium at room temperature (Scheme 6.28). In the crystalline form nitrone 36 exists as the pure Z isomer, however, in solution nitrone 36 have been shown to exists as a mixture of the E and Z isomers. This equilibrium could however be shifted to the Z isomer in the presence of a Lewis acid [74]. 

Aziridine esters are a- and -amino acid derivatives at the same time. A characteristic reaction of a-amino acids is their reaction with triethylboron to give boroxazolidines. We showed that aziridinecarboxylic acids exhibit the expected behavior in their reaction with triethylboron, viz., that they form stable boroxazolidines 34 (Scheme 19) [29]. These boron heterocycles can be reconverted into the free amino acids by treatment with 8-hydroxyquinoline. 

A group of peptide derivatives such as peptide arginals and boronic acid peptide derivatives belong to another class of reversible thrombin inhibitors. One such inhibitor is PPACK (D-Phe-Pro-Arg chloromethyl ketone), which functions as a powerful irreversible thrombin inhibitor by alkylating the histidine residue at the catalytic site of thrombin (58). It, however, is unstable in neutral solution, as it undergoes cyclization and inactivation. However, the D-methyl derivative of D-Phe-Pro-Arg-H (D-Mephe-Pro-Arg-H) called efegatran, with a molecular mass of 515 Da, is a stable selective reversible inhibitor of thrombin with a K. of approximately 100 nM. The basic amino terminus in this compound is responsible for promoting the specificity toward thrombin (63). 

Increasing interest is expressed in diastereoselective addition of organometallic reagents to the ON bond of chiral imines or their derivatives, as well as chiral catalyst-facilitated enantioselective addition of nucleophiles to pro-chiral imines.98 The imines frequently selected for investigation include N-masked imines such as oxime ethers, sulfenimines, and /V-trimcthylsilylimines (150-153). A variety of chiral modifiers, including chiral boron compounds, chiral diols, chiral hydroxy acids, A-sull onyl amino acids, and /V-sulfonyl amido alcohols 141-149, have been evaluated for their efficiency in enantioselective allylboration reactions.680... 

When the medicinal chemistry program began in late 1999, nearly all of the DPP-4 inhibitors known in the literature were derived from a-amino acids, and those lacking an electrophile such as the isoleucyl thiazolidides were considerably less potent than those containing a nitrile or boronic acid such as DPP728. One report suggested that cyclohexylglycine derived inhibitors showed improved potency... 

The enantioselective inverse electron-demand 1,3-dipolar cycloadditions of nitrones with alkenes described so far are catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminium complexes. However, the glyoxylate-derived nitrone 256 favors abidentate coordination to the catalyst, and this nitrone is an interesting substrate, since the products that are obtained from the reaction with alkenes are masked ot-amino acids (Scheme 12.81). 

A series of metal complexes containing trimethylamine boranecarboxylato ionligand [103904-11-6], (CH3)3N BH COO, have been prepared with Co (III), Co (II), Zn(II), Ca(II), Cr(III), and Fe(III) (39,40). This ligand, derived from the boron analogue of the amino acid glycine, behaves similady to organic carboxylato ligands. 

In a parallel study, Wipf and Fritch11041 have shown that also urethane-protected (Boc), and even amino acid segments, are tolerated as acyl compounds on the aziridine nitrogen. The best results were obtained with alkylcopper reagents derived from CuCN and an alkyl-lithium in the presence of boron trifluoride-diethyl ether complex. Some 6-alkylated compounds (11-15%) were isolated as well. This work was extended to a solid-phase procedure that resulted in resin-bound alkene isosteres that could immediately be used in further peptide synthesis.11051 For this purpose, the 2-nitrophenylsulfonyl (oNbs) group was used for nitrogen protection and aziridine activation. It could be readily cleaved with benzenethio-late, which was compatible with the acid-sensitive Wang linker used. 

The resulting triazoles can be N-alkylated by treatment with alkyl halides (0.25 mol/L, 30 equiv., DMF, NaOH), but mixtures of the 1-alkylated and 2-alkylated triazoles are obtained [255]. 1,2,4-Triazoles have also been prepared from N-amino-amidines (amidohydrazones Entry 4, Table 15.20), which were prepared from resin-bound thioamides by S-alkylation with methyl triflate followed by treatment with hydrazine [256]. 1,2,4-Tri azoles undergo Michael addition to polystyrene-bound a-acetamido acrylates to yield triazole-derived a-amino acids (Entry 7, Table 15.20). Benzotriazoles have been N-arylated on insoluble supports by treatment with aryl-boronic acids in the presence of catalytic amounts of copper salts (Entry 8, Table... 

The use of alkenyl boronic acid derivatives 50, which are readily prepared via hydroboration or bromoboration of alkynes, affords the corresponding p,y-unsaturated amino acids (e.g. 52-57) in a geometrically pure form [34], A variety of amines 48, including primary and secondary amines, anilines, amino alcohols and hydroxylamines can effectively participate in this process, while the alkenyl boronic acid can contain alkyl, aryl or bromo-substituents. Although the alkenyl amino acid side chain is introduced through the boronic acid component, the use of more substituted a-keto acids 49 allows the simultaneous incorporation of an additional a-substituent (e.g. 57). 

An alternative multistep approach to the synthesis of a-amino acids, using the boronic acid as the precursor of the carboxylic acid group, was reported by Harwood et al. [56]. Thus, reaction of a chiral morpholinone derivative with furyl boronic acid and various aldehydes gave, in a diastereocontrolled manner, the corresponding adducts which were converted in several steps to the a-amino acids [56],... 

The use of diamine derivatives in the three-component process leads to peptidomimetic heterocycles, such as 2-oxopiperazines (piperazinones) [58], benzopiperazi-nones [58] and benzodiazepines. In fact, the 2-oxopiperazines 89 can be obtained directly in one step via the reaction of a diamine 85 with glyoxylic acid 86 and a boronic acid 87 (Scheme 7.12) [58]. Presumably, the intermediate amino acids 88 can undergo a subsequent boronic acid-catalyzed lactamization [29] to afford 89. A two-step approach was used for the synthesis of benzopiperazinones (e.g. 96) [58]. 

Grigg et al. [61] have recently reported a one-pot reaction involving the initial three-component condensation with a 2-halo-benzylamine 112, ethyl glyoxylate 113 and an aryl boronic acid 114, followed by Pd cyclization in the presence of carbon monoxide to give 116, or in the presence of allene to form dihydroisoquinoline amino acid derivatives 117 (Scheme 7.15). 

Chiral addition of allyl metals to imines is one of the useful approaches toward the synthesis of homoallylic amines. These amines can be readily converted to a variety of biologically important molecules such as a-, / -, and y-amino acids. Itsuno and co-workers utilized the allylborane 174 derived from diisopropyl tartrate and cr-pinene for the enantioselective allylboration of imines. The corresponding iV-aluminoimines 173 are readily available from the nitriles via partial reduction using diisobutylaluminium hydride (DIBAL-H) <1999JOM103>. Recently, iV-benzyl-imines 176 have also been utilized for the asymmetric allylboration with allylpinacol boronate 177 in the presence of chiral phosphines as the chiral auxiliaries to obtain homoallylic A -benzylamines 178 in high yield and selectivity (Scheme 29) <2006JA7687>. 

Finally, the remarkably simple solution came from Evans et al. [21a] and researchers of DuPont [21b] simultaneously. Their method allows the coupling of structurally and electronically diverse phenols and aryl boronic acids in the presence of copper]11) acetate, trie-thylamine or pyridine, and molecular sieves at ambient temperature (Scheme 5). Even phenolic amino acid derivatives react smoothly without racemization. The only limitation has been observed when using orfho-heteroatom substituted boronic acids which resulted in lower product yields. The initial step in the proposed pathway (Scheme 6) is the trans-metallation of the boronic acid residue with the copper salt. 

Other reports for the boron-Mannich reaction include the synthesis of aminophenol derivatives,561 a-arylglycines,576 a growth hormone secretagogue NN703,577 a polyhydroxyindolizine alkaloid uniflorine A,578 and cyclic ct-amino acids.579 The reaction has been applied to solution-phase reactions580 and the solid-phase reaction581-585 for the synthesis of libraries of peptides, a-amino acids, and bicyclic diketopiperazines. The reactions were accelerated by the irradiation of microwave.586... 

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