Chemoselective O-acylation of hydroxyamino acids and amino alcohols under acidic reaction conditions: History, scope and applications

• Tor E. Kristensen

Beilstein J. Org. Chem. 2015, 11, 446–468, doi:10.3762/bjoc.11.51

• derivatives of many amino acids often become annoyingly strenuous due to the necessity of employing protecting groups, on one or more of the amino acid functionalities, during the synthetic sequence. However, in the case of hydroxyamino acids such as hydroxyproline, serine, threonine, tyrosine and 3,4

• ; organocatalysis; serine; threonine; tyrosine; Introduction Any adept researcher within the field of organic synthetic chemistry will be mindful of the outstanding importance of amino acids as inexpensive chiral starting materials in the synthesis of a nearly infinite variety of synthetic end products. This

• -threonine or L-tyrosine with a solution prepared from acetic anhydride, concentrated aqueous HClO4 and glacial acetic acid (excess acetic anhydride ensured consumption of water and formation of anhydrous conditions prior to acetylation) [9][10]. The remaining acetic anhydride was quenched with water after

Synthesis and biological evaluation of a novel MUC1 glycopeptide conjugate vaccine candidate comprising a 4’-deoxy-4’-fluoro-Thomsen–Friedenreich epitope

• Manuel Johannes,
• Maximilian Reindl,
• Bastian Gerlitzki,
• Edgar Schmitt and
• Anja Hoffmann-Röder

Beilstein J. Org. Chem. 2015, 11, 155–161, doi:10.3762/bjoc.11.15

• -threonine building block 7a [49] affording the desired ß-configured 4’-deoxy-4’-fluorodisaccharide 8 in 80% yield. Subsequent two-step protecting group manipulation and acidolysis of the tert-butyl ester finally provided the orthogonally protected 4’-fluoro-TF-SPPS-building block 11 in 85% yield over three

• the 4’-deoxy-4’-fluoro-TF-antigen-threonine conjugate 12 towards enzymatic degradation by ß-galactosidase from bovine testes. Thus, the work presented herein is an example of the successful application of strategically fluorinated glycopeptide derivatives as a tool to improve the immunogenicity and

(2R,1'S,2'R)- and (2S,1'S,2'R)-3-[2-Mono(di,tri)fluoromethylcyclopropyl]alanines and their incorporation into hormaomycin analogues

• Armin de Meijere,
• Sergei I. Kozhushkov,
• Dmitrii S. Yufit,
• Christian Grosse,
• Marcel Kaiser and
• Vitaly A. Raev

Beilstein J. Org. Chem. 2014, 10, 2844–2857, doi:10.3762/bjoc.10.302

• -threonine (4) and (2S,3R)-β-methylphenylalanine (3), using the Belokon' approach with (S)- and (R)-2-[(N-benzylprolyl)amino]benzophenone [(S)- and (R)-10] as reusable chiral auxiliaries have been developed. Three new fluoromethyl analogues of the naturally occurring octadepsipeptide hormaomycin (1) with

• corresponding (2S,1'S,2'R)- [see Scheme 3, derived from (S)-10] and (2R,1'S,2'R)-3-(2'-fluoromethylcyclopropyl)alanines [derived from (R)-10] in good to excellent yields. The chiral auxiliary was recovered as the hydrochloride of 2-[(N-benzylprolyl)amino]benzophenone (~95%). (R)-allo-Threonine (4) is

• commercially available, but extremely expensive (from 77.80 € for 250 mg to 60.80 € for 25 mg). Therefore a simple and inexpensive access to (R)-allo-threonine was desirable. The synthesis of 4 from (R)-threonine as a chiral precursor was performed according to the known protocol reported by Tanner et al [29

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• conditions. The obtained products could be transformed smoothly into many complex and potentially useful compounds, through diverse derivatization, without significant losses of enantiomeric excesses. 2.13 Annulations through tandem RC/Michael reactions In 2012, using the chiral threonine-derived phosphine

Carbohydrate PEGylation, an approach to improve pharmacological potency

• M. Eugenia Giorgi,
• Rosalía Agusti and
• Rosa M. de Lederkremer

Beilstein J. Org. Chem. 2014, 10, 1433–1444, doi:10.3762/bjoc.10.147

• is transferred to the glycan by a sialyltransferase. The serine or threonine residues in the O-glycosylation sites serve as acceptors for GalNAc using a convenient GalNAc transferase. This unit can be galactosylated by a galactosyltransferase and both, the monosaccharide and the disaccharide, may be

Amino acid motifs in natural products: synthesis of O-acylated derivatives of (2S,3S)-3-hydroxyleucine

• Oliver Ries,
• Martin Büschleb,
• Markus Granitzka,
• Dietmar Stalke and
• Christian Ducho

Beilstein J. Org. Chem. 2014, 10, 1135–1142, doi:10.3762/bjoc.10.113

• -α-amino acids serine and threonine, (2S,3S)-3-hydroxyleucine can be found as a substructure of several bioactive natural products. This structural motif often serves as a 'three-way-junction', as for instance in azinothricin [1], citropeptin [2], kettapeptin [3], pipalamycin [4], dentigerumycin [5

Olefin cross metathesis based de novo synthesis of a partially protected L-amicetose and a fully protected L-cinerulose derivative

• Bernd Schmidt and
• Sylvia Hauke

Beilstein J. Org. Chem. 2014, 10, 1023–1031, doi:10.3762/bjoc.10.102

• perdeuteration of an alkynoate derived from L-threonine (giving a 2,2,3,3-tetradeuterated amicetose) [26], enantioselective hydroboration of hetero Diels–Alder adducts [27], stereoconservative diazotation of L-glutamic acid [28][29], diastereoselective addition of methylmagnesium bromide to enantiopure 2

A unified approach to the important protein kinase inhibitor balanol and a proposed analogue

• Tapan Saha,
• Ratnava Maitra and
• Shital K. Chattopadhyay

Beilstein J. Org. Chem. 2013, 9, 2910–2915, doi:10.3762/bjoc.9.327

• developed using an efficient fragment coupling protocol which proceeded in good overall yield. Keywords: azepane; balanol; Garner’s aldehyde; PKC inhibitor; ring-closing metathesis; Introduction Protein kinase C (PKC) is a family of phospholipid-dependent kinases that phosphorylate serine and threonine

The regulation and biosynthesis of antimycins

• Ryan F. Seipke and
• Matthew I. Hutchings

Beilstein J. Org. Chem. 2013, 9, 2556–2563, doi:10.3762/bjoc.9.290

• reaction in phenylacetate catabolism [35] resulting in hydryoxylation of C-2 [33]. 3-Aminosalicylate serves as the starter unit and is presented to the NRPS, AntC. The AntC protein possesses two modules organised as follows: C1-A1-T1-C2-A2-KR-T2. The A1 domain activates and loads threonine onto T1

• , followed by condensation of 3-aminosalicylate and threonine promoted by C1. The A2 domain activates and loads pyruvate onto T2. Pyruvate is subsequently stereospecifically reduced by the KR domain and condensed with threonine by C2. The PKS, AntD posseses one module composed of the domains KS-AT-ACP-TE

• ketoreductase, AntM catalyses the stereoselective reduction of the β-keto group, which precedes AntDTE – promoted regiospecific macrolactonisation and release of the nine-membered dilactone. Sandy et al. heterologously produced and purified AntCDEFGM and used building monomers anthranilate, L-threonine

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

Flow synthesis of phenylserine using threonine aldolase immobilized on Eupergit support

• Jagdish D. Tibhe,
• Hui Fu,
• Timothy Noël,
• Qi Wang,
• Jan Meuldijk and
• Volker Hessel

Beilstein J. Org. Chem. 2013, 9, 2168–2179, doi:10.3762/bjoc.9.254

• Jagdish D. Tibhe Hui Fu Timothy Noel Qi Wang Jan Meuldijk Volker Hessel Micro Flow Chemistry and Process Technology, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, the Netherlands 10.3762/bjoc.9.254 Abstract Threonine

• was achieved at 20 minute residence time. Finally, the productivity of the reactor was calculated, extrapolated to parallel run units, and compared with data collected previously. Keywords: Eupergit; flow chemistry; immobilized enzyme; threonine aldolase; Introduction Enzymes are bio-based catalysts

• metal complexes [36]. Enzymes overcome these drawbacks as they are not toxic and they can be obtained easily from microorganisms. Threonine aldolases (TA) are a class of enzymes which is PLP (pyridoxal-5’-phosphate) dependent and can catalyze the aldol reaction between glycine and a variety of aromatic

Synthesis of mucin-type O-glycan probes as aminopropyl glycosides

• David Benito-Alifonso,
• Rachel A. Jones,
• Anh-Tuan Tran,
• Hannah Woodward,
• Nichola Smith and
• M. Carmen Galan

Beilstein J. Org. Chem. 2013, 9, 1867–1872, doi:10.3762/bjoc.9.218

• -deoxy-D-galactose to serine or threonine. This saccharide forms the inner part of the characteristic core oligosaccharides from where glycans are extended through common core (di- and trisaccharide) structures, cores 1–8 [6][7][8]. The mucin-type oligosaccharides identified to date have remarkable

Antifreeze glycopeptide diastereomers

• Lilly Nagel,
• Carsten Budke,
• Axel Dreyer,
• Thomas Koop and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 1657–1667, doi:10.3762/bjoc.8.190

• –55 tripeptide units -Ala-Ala-Thr- glycosylated at the threonine side chains. Despite the structural homology among all the fish species, divergence regarding the composition of the amino acids occurs in peptides from natural sources. Although AFGPs were discovered in the early 1960s, the adsorption

• , peptides containing monosaccharide-substituted allo-L- and D-threonine building blocks were assembled by solid-phase peptide synthesis (SPPS). The retro-inverso AFGP analogue contained all amino acids in D-configuration, while the allo-L-diastereomer was composed of L-amino acids, like native AFGPs, with

• replacement of L-threonine by its allo-L-diastereomer. Both glycopeptides were analyzed regarding their conformational properties, by circular dichroism (CD), and their ability to inhibit ice recrystallization in microphysical experiments. Keywords: bioorganic chemistry; circular dichroism; glycopeptides

Asymmetric organocatalytic decarboxylative Mannich reaction using β-keto acids: A new protocol for the synthesis of chiral β-amino ketones

• Chunhui Jiang,
• Fangrui Zhong and
• Yixin Lu

Beilstein J. Org. Chem. 2012, 8, 1279–1283, doi:10.3762/bjoc.8.144

• , entries 5–7). Among them, the cinchonine based thiourea C-1 turned out to be the best catalyst, and the Mannich product was isolated with 58% ee (Table 1, entry 7). In addition, we also examined several other bifunctional catalysts based on amino acids [43][44], including threonine derived Thr-1 [45], and

• tryptophan based Trp-1 [46], as well as threonine incorporated multifunctional catalyst CD-3 [47]. However, no further improvement could be achieved (Table 1, entries 8–10). The influence of different imines on the reaction was subsequently explored, and it was found that the electronic nature of the

Chiral multifunctional thiourea-phosphine catalyzed asymmetric [3 + 2] annulation of Morita–Baylis–Hillman carbonates with maleimides

• Hong-Ping Deng,
• De Wang,
• Yin Wei and
• Min Shi

Beilstein J. Org. Chem. 2012, 8, 1098–1104, doi:10.3762/bjoc.8.121

• intermolecular [3 + 2] cycloaddition of MBH carbonates with methyleneindolinones to afford the corresponding spirocyclopentaneoxindoles in good yields and high ee values in 2011 [49]. Moreover, Lu and co-workers have recently explored a series of thiourea-phosphine catalysts derived from L-threonine, which are

Synthetic glycopeptides and glycoproteins with applications in biological research

• Ulrika Westerlind

Beilstein J. Org. Chem. 2012, 8, 804–818, doi:10.3762/bjoc.8.90

• functional groups. After ligation the side-chain thiol could be removed by Raney nickel treatment. Employing the desulfurization methodology, thiol amino acids could be converted to alanine, valine, phenylalanine and threonine residues [71][72][73][74][75][76]. As an alternative to Raney nickel reduction, a

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• multidrug resistance [59]. The patellamide gene cluster consists of seven genes, expression of which in E. coli leads to the production of the peptides [59]. Heterocyclization of serine, cysteine and threonine, respectively is catalyzed by the heterocyclase PatD [60]. In contrast to other heterocyclases

• Microcystis and Planktothrix [64][65]. Post-translational modification of microviridins is achieved by the activity of two closely related ATP grasp ligases, MdnB and MdnC (MvdC and D in Planktothrix). The enzymes introduce two ω-ester linkages between threonine and aspartate and serine and glutamate (MdnC

• of bacteria. The characteristic feature of the group is lanthionine bridges, which are formed by dehydration of serine or threonine followed by intramolecular addition of cysteine thiols to the resulting dehydro amino acids. Lantipeptides exhibit a variety of bioactivities, in particular

A novel high-yield synthesis of aminoacyl p-nitroanilines and aminoacyl 7-amino-4-methylcoumarins: Important synthons for the synthesis of chromogenic/fluorogenic protease substrates

• Xinghua Wu,
• Yu Chen,
• Herve Aloysius and
• Longqin Hu

Beilstein J. Org. Chem. 2011, 7, 1030–1035, doi:10.3762/bjoc.7.117

• equiv) relative to the azide used. The reaction was typically complete within 0.5 h at 0 °C for OSu-activated esters or −10 °C for mixed anhydrides. For sterically hindered amino acid OSu esters, such as isoleucine, valine and threonine, however, the reaction was slower and required room temperature to

• obtained. We also found that the hydroxy group of tyrosine and threonine did not need to be protected. No significant intermolecular esterification was observed under the present reaction conditions and the desired p-nitroanilides were obtained in excellent yields (Table 1, entries 2 and 3). Furthermore

Synthesis of glycosylated β³-homo-threonine conjugates for mucin-like glycopeptide antigen analogues

• Florian Karch and
• Anja Hoffmann-Röder

Beilstein J. Org. Chem. 2010, 6, No. 47, doi:10.3762/bjoc.6.47

• bioavailability for tumour immunotherapy. Towards this end, TN and TF antigen conjugates O-glycosidically linked to Fmoc-β3-homo-threonine were prepared in good yield via Arndt–Eistert homologation of the corresponding glycosyl α-amino acid derivative. By incorporation of TN-Fmoc-β3hThr conjugate into the 20

• increased biological half-life. Keywords: glycopeptide; glycosylamino acids; β3-homo-threonine; MUC1 antigens; solid-phase synthesis; Introduction Glycosylation is the predominant co- and post-translational modification in higher organisms responsible for tailoring and fine-tuning of the activity of

• -3,4,6-tri-O-acetyl-2-acetamido-2-deoxy-galactopyranosyl]-β3-homo-threonine 2a: Procedure A: The synthesis followed the general procedures GP1 and GP2. Amounts: 150 mg (0.22 mmol) 1a. Yield: 90 mg (0.13 mmol), 60%, colourless amorphous solid. Analytical RP-HPLC (Luna, MeCN–H2O + 0.1% TFA, 20:80 → 60:40

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32