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1

Application of Oppolzer's Sultam in the Synthesis of Cyclic alfa-Amino Acids and beta-Amino Acids

Woźniak D., Szymańska A., Ołdziej S., Łankiewicz L., Grzonka Z.

Polish Journal of Chemistry

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2006

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Vol. 80, nr 2

265-277

EN

In this paper we describe the application of Oppolzer's sultam as a chiral auxiliary for the synthesis of cyclic alfa- and beta2-amino acids. The key step of the synthesis is stereoselective alkylation of sultam-derived glycine and beta-alanine Schiff's bases leading to diastereometrically pure products. Final compounds are obtained after mild acidic and next basic hydrolyses of auxiliary groups and can be directly converted into N-tert-butoxycarbonyl- or N-fluorenylmethoxycarbonyl derivatives useful in peptide synthesis. In the case of substrates alkylated with dihalogenoalkanes spontaneous cyclization occurring during removal of the auxiliary groups yields cyclic alfa-amino acids (proline homologues) with reasonable yield and stereoselectivity. Theoretical data explain the differences in tendency for cyclization between alfa- and beta-amino acids.

2

Peptide Bond Modification. I. Simple and Efficient Method of Bloc-GlyPsi[Ch(OH)CH2]Gly-OH Synthesis

Makowiec S., Wiśniewska K., Łankiewicz L.

Polish Journal of Chemistry

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2004

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Vol. 78 / nr 2

315-318

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A Facile Synthesis of Primary and Secondary Amines

Łankiewicz L., Rój A., Szymańska A., Wiczk W.

Polish Journal of Chemistry

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2004

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Vol. 78 / nr 8

1067-1072

EN

A facile synthesis of primary amines (R-CH2-NH2, where R = napht-2-yl, anthr-9-yl, phenyl, p-nitrophenyl) and secondary amines (R-NH-R', where R is as mentioned above for primary amines and R'= methyl) is described. The primary amines were obtained by alkylation of di-tert-butyl imidodicarbonate (Boc2NH) under phase-transfer catalysis (PTC) conditions, followed by acidolytic removal of the amine protecting groups. The secondary amines were obtained from the appropriate primary amines by alkylation of their N-tert-butoxycarbonyl derivatives (Boc-NH-R), followed by Boc group acidolysis. It is worth emphasizing that the substrates for synthesis of secondary amines (Boc-NH-R) were obtained via selective removal of one of the tert-butoxycarbonyl groups from the alkylated di-tert-butyl imidodicarbonates (Boc2N-R).

4

Peptydowe toksyny cyjanobakterii

Łukomska J., Kasprzykowski F., Łankiewicz L., Grzonka Z.

Wiadomości Chemiczne

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2002

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[Z] 56, 1-2

57--82

EN

This review presents chemical and biological aspects of secondary metabolites produced by cyanobacteria. The main goal of the work was to present studies related to microcystins and nodularins. Cyanobacteria (blue-green algae) growing both in freshwater and marine environment release to the medium numerous secondary metabolites. Some of cyanobacteria produce lethal toxins (cytotoxins and biotoxins). Therefore, cyanobacteria can be harmful for mammals, birds and fish, and also cause effects on human health. The secondary metabolites are the mostly derivatives of amino acids and peptides or depsipeptides. The best described among cyanobacteria toxins are the hepatotoxins: microcystins and nodularins. These toxins cause severe intrahepatic haemorrhage and hypovolaemic shock, and act as tumor promoters. Microcystins and nodularins are potent inhibitors of PP1 and PP2A protein phosphatases. Microcystins and nodularins, which are cyclic hepta- or penta-peptides, respectively, consists of various uncoded amino acid residues. The most characteristic and unique amino acid residue is Adda [(2S,3S,8S,9S,4E,6E)-3-amino-9-metoxy-2,6,8-trimethyl-10-phenyl-deca-4,6-dienoic acid]. Typical isolation of these toxins is realized by extraction combined with reversed-phase chromatography. Structure-activity relationship studies of microcystins and nodularins have revealed indispensability of Adda moiety, and two carboxyl groups of aspartic and glutamic acids, for the activity towards phosphatases. The total synthesis of both toxins represents quite a big challenge because of the necessity of preparation of Adda, as well as many other uncoded amino acids (D-erythro-b-methyl-aspartic acid, Masp; dehydroalanine, Dha, or dehydrobutyrine, Dhb, and their N-methyl derivatives etc.) prior to a final cyclization. Syntheses of Adda, the compound with four chiral centers and two specific configurations at the double bonds, were carried out mostly by the condensation of the previously obtained C1-C4 and C5-C10 fragments. Microcystins and nodularins are quite stable compounds in aqueous solution. They can be destroyed and removed by chlorination, or by treatment with ozone (Scheme 9) combined with ultrafiltration. On the other hand, microcystins and nodularins could be modified for example by esterification (Asp and/or Glu residues), transformation of guanidine moiety of arginine, Michael type addition to dehydroamino acids (Dha, Dhb). These modifications provide less toxic compounds, with interesting biological activities.

5

The Efficient Synthesis of Azaamino Acids

Wieczerzak E., Kozlowska J., Łankiewicz L., Grzonka Z.

Polish Journal of Chemistry

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2002

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Vol. 76 / nr 12

1693-1697

EN

An efficient method of synthesis of N-t-butoxycarbonyl-azaamino acid ethyl esters has been described. This method consisted of three stages including: hydrazone formation, its reduction and acylation with ethyl chloroformate. The second step - reduction of the hydrazones to the appropriate hydrazides - was the most challenging. Some reducing agents have been tested, though NaBH3CN was found to lead to the final products with the highest yields in relatively short time and even to allow the selective reduction of C-N bond in the presence of nitro group.

6

Excited State Intramolecular Proton Transfer in 9-Oxo-9,10-dihydro-acridine-4-carboxylic Acid. photophysical and Computational studies

Sobczyk M., Szymańska A., Wiczk W., Łankiewicz L., Karolczak J., Rak J.

Polish Journal of Chemistry

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2002

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Vol. 76 / nr 9

1263-1269

EN

9-Oxo-9,10-dihydro-acridine-4-carboxylic acid in both methanol and acetonitrile possesses a dual fluorescence and complex fluorescence intensity decay, whereas 9-oxo- 9,10-dihydro-acridine-2-carboxylic acid shows only one emission band and monoexponential fluorescence intensity decay. Theoretical calculations, using a semiempirical PM3 method, confirm, in the case of 9-oxo-9,10-dihydro-acridine-4-carboxylic acid, the excited state intramolecular proton transfer process from nitrogen atom to the oxygen of carbonyl of the carboxylic group.

7

Mechanism of Ring Opening Reaction of 4-Benzylidene-2-methyl-5-oxazolone. Part I. Reaction with n-Butylamine

Betłakowska B., Banecki B., Łankiewicz L., Wiczk W.

Polish Journal of Chemistry

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2001

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Vol. 75, nr 3

401-410

EN

The reaction between 4-benzylidene-2-methyl-5-oxazolone (Ox, c = 5.25 _ 10-5 M) with n-butylamine (nBuA, c = 0.026 to 1.66 M) in acetonitrile was studied by UV-Vis spectroscopy using steady-state and stopped-flow apparatus. The amine to Ox molar ratio higher than 500 allows to apply pseudo-first order approximation, whose rate constants depend on amine concentration according to a parabolic equation: kobs = 4.63 _ 0.02 _ CnBuA 2 , indicating a complex reaction mechanism. On the other hand, singular value decomposition (SVD) analysis, as well as global analysis of the data obtained from stopped-flow measurements support a simple A B reaction model. Nonlinear dependence of the pseudo- first order rate constant on amine concentration can be explained, assuming that the oxazolone ring opening reaction by n-butylamine in acetonitrile proceeds as parallel reactions: A + B C and A+2B C. Based on our experimental results and theoretical calculations of the oxazolone ring opening reaction, a mechanism of the reaction between 4-benzylidene-2-methyl-5-oxazolone and n-butylamine is proposed.

8

Wybrane zastosowania bornan-10,2-sultamu (sultamu Oppolzera) w asymetrycznej syntezie organicznej

Szymańska A., Wieczerzak E., Łankiewicz L.

Wiadomości Chemiczne

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2000

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[Z] 54, 9-10

759-791

EN

Among many methods of asymmetric synthesis, the second-generation reactions i.e. the ones applying chiral auxiliary to generate new chiral centers are the most popular and widely used. In the last two decades many new and highly effective chiral auxiliaries were described. Bornane-10,2-sultam, introduced by Oppolzer and co-workers, is one of the most popular and most effective in generating new chiral centers. Utility of bornane-10,2-sultam is due to: - simplicity of a method of its synthesis from the natural, cheap source - camphore, - high yield of connecting to prochiral substrates, - almost quantitative asymmetric induction, - straight-forward removal of the formed product from bornane-sultam, which does not cause the loss of chirality at a new chiral center , - its high recovery after removal of product and possibility of multiple applications. One of the most popular reactions studied in asymmetric synthesis is aldol condensation. This reaction was also studied with application of bornane-10,2-sultam. Depending on the type of used base and Lewis acid either pure "cis" or "trans" isomer can be obtained. The chemical yields of the reactions were also high (50÷90%) N-acylated derivatives of bornane-10,2-sultam have been revealed also as facile precursors of chiral alkylated carboxylic acids, ketones, aldehydes and alcohols. Diastereoisomeric excesses were in many cases above 99% and chemical yields were also very good (in most cases above 80%). Alkylation step can be also applied for asymmetric synthesis of a-amino acids (building blocks of peptides) but it is necessary to use N-[bis(methylthio)methylene]glycine methyl ester for acylation of the sultam. Quite nice selection of amino acids in optically pure form can be obtained by this method. Other possibilities of the sultam usage arise from nucleophilic and electrophilic amination reactions. These methods were applied to obtain amino, azido, hydrazino and N-hydroxyamino acids with high chemical yield and optical purity. Applications of bornane-10,2-sultam derivatives with a,b-unsaturated side chain are also very wide in asymmetric organic synthesis. One of the most popular reaction involving unsaturated compounds is Diels-Alder's cycloaddition. Cyclic compounds formed during this addition are mostly endo-structures. Stereoselectivity is very high (higher than 90 %) and depends on a type of Lewis acid used. Another interesting precursor in this kind of addition reaction seems to be the sultam derivative obtained by the modification with glyoxalic acid. Its application can lead to piran derivatives and substrates of sugar moieties. N-acylated with a,b-unsaturated carboxylic acids sultam derivatives are also good substrates for carbonyl compounds stereoselectively substituted on a- or/and b-carbons (aldehydes, ketones, carboxylic acids) as well as alcohols. For preparation of optically active a,b-disubstituted compounds either Grignard's reagents or Gilman's reagents can be applied with diastereoselectivity in range 70÷95 %. Other possibilities of the "unsaturated" sultam derivatives usage arise from reactions with "hydrogen sources" or oxidation agents. Asymmetric hydride addition or catalytic hydrogenation leads to a,b-disubstituted chiral compounds with good yield and stereoselectivity. Oxidation of double bond, on the other hand, is facile method for obtaining 1,2-diols - superior substrates for ketones, acetals and sugars.

9

Asymetryczna synteza a-aminokwasów

Dąbrowska A., Wiczk W., Łankiewicz L.

Wiadomości Chemiczne

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1998

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[Z] 52, 1-2

1-42

EN

a-Amino acids are among the most important compounds in living organisms. Amino acids are not only constituents of peptides and proteins but they play an important role in many reactions in living cells. There are many excellent methods of the asymmetric synthesis of a-amino acids, but only some of them are versatile. In this work we have reviewed and presented the most versatile methods, giving the best chemical yield and optical purity of the final products. One of the oldest and still useful synthetic routes to racemic a-amino acids is Strecker's method [3], (Scheme 1). Modification of the methods by Weinges et al. [8-11] (Scheme 2) allowed to obtain pure enantiomers of a-amino acids in high yields. Next important group of the methods applies 'glycine anion equivalent'. In this group, 'bislactim-ether' method of Schöllkopf et al. [13-21], (Scheme 3 and Tab. 1] has to be mentioned at first because of the high chemical yield of the transformation and optical purity of the final amino acid. The same type of methodology was employed by Seebach et al., their method utilizing oxazolidinones or imidazolidinones [22-26] (Schemes 4, 5 and Tab.2). Yield and enantiomeric excess (ee) of the final amino acid in the method of Seebach et al., is very high (in most cases >80%). The only inconvenience is connected with drastic conditions of final hydrolysis. The similar, good results were also obtained in methods utilizing enolates obtained from oxazinones [29-31], (Schemes 6-8 and Tabs 3,4). Derivatives of the oxazinones were also applied as 'glycine cation equivalent' in the method in which 'the chiral cation' reacts with nucleophiles [32, 33], (Scheme 9 and Tab.5) with the high chemical yield and ee of the final product. The similar procedures were used in an alkylation of a chiral Schiff base. The best yields and optical purity of the final a-amino acid were obtained by Oppolzer et al. [35,36], who applied a derivative of glycine attached to bornane-10,2-sultam (the derivative of camphor), (Schemes 13,14). The next group of synthetic procedures is based on a reaction of a ring opening of b-lactones obtained from serine [41-43], (Scheme 16) or threonine [44], and aziridines [45-48], (Scheme 17). A nucleophile attack on the b-carbon of the substrate gives amino acid with modified side chain. Despite the high yield and ee selection of possible nucleophiles is limited. Another important methodology is called 'electrophilic amination'. In this procedure a chiral enolate obtained from N-acyl-oxazolidinone [50,52], (Scheme 18,19) or N-acyl-sultam [51, 53 ], (Scheme 21) is aminated either by di-tert-butyl-azodicarboxylate (DBAD), [50, 51], trisyl azide [52], or 1-chloro-1-nitrozo-cyclohexane [53]. Yield of these reactions are high and ee exceeds 95%. Contrary to the 'electrophilic', a 'nucleophilic amination' requires a 'cation equivalent' obtained from a chiral N-acyl-derivatives [54-55]. The reaction usually yields a desired product of good enantiomeric quality. In most cases azide anion is a source of 'nucleophilic amine equivalent' (Schemes 22 and 23). The chiral 2,3-epoxy-1-ols can be also applied in this methodology [57, 58], (Scheme 24). Asymmetric catalytic hydrogenation of a dehydro derivatives of amino acids and peptides is another valuable group of synthetic routes to the single enantiomer of the amino acid. There is a possiblity of heterogenous and homogenous catalysis involving insoluble catalysis [60, 61], (Schemes 25, 26) or soluble [62, 63], (Schemes 27, 28) in medium of the reaction. The best results (yield = 100% and ee>99%) were reprted for the complexes of Rh with chiral phosphines ligands like BINAP or DIPAMP (Scheme 28), [67]. The last method reported in our review is based on the usage of enzymes. The most widely used in this field are the following enzymes : acylases - catalyzing stereoselective removal or synthesis of N-acyl deerivatives [70], (Scheme 30) and proteases - catalyzing methods give in many cases both enantiomers at the same time.