N-protecting Group Research Articles

Facile Synthesis of N-protected Amino Acid Esters Assisted by Microwave Irradiation

A highly efficient and safe methodology for synthesis of various N-protected amino acid ethyl esters have been established in this study. This methodology employs orthoesters as both esterification reagent and solvent for protected amino acids. The reactions were carried out under microwave irradiation in neutral conditions for only 2 min, resulting in highly pure crude products in most cases. This strategy works with a variety of N-protecting groups, such as acid labile protecting group: BOC and tBu; base labile protecting group: Fmoc; hydrogenation labile protecting group: Z and Na/NH3 labile protecting group: Tos, thus providing facile access to numerous valuable building blocks for solid phase synthesis. Further reduction of the crude protected amino acid ethyl ester by sodium borohydride under mild conditions led to the corresponding protected β-amino alcohols with excellent yield, as demonstrated by three examples.

Biocatalytic application of nitrilases from Fusarium solani O1 and Aspergillus niger K10

The nitrilases from Fusarium solani O1 and Aspergillus niger K10 showed a broad substrate specificity for carbocyclic and nonaromatic heterocyclic amino nitriles, the preferred substrates being five-membered γ-amino nitrile (±)- 1a, six-membered γ-amino nitriles (±)- 3a, (±)- 5a and (±)- 6a, pyrrolidine-3-carbonitriles (±)- 9a and (±)- 10a as well as piperidine-4-carbonitriles 14a and 15a. Both enzymes showed a strong diastereopreference for cis- vs. trans-γ-amino nitriles. The electronic and steric effects of N-protecting groups affected the reactivity of the nitriles. Amides as by-products of the nitrilase-catalyzed reaction were produced from heterocyclic amino nitriles (±)- 9a, (±)- 10a, 14a and 15a by the A. niger enzyme but only from nitrile (±)- 9a by the F. solani enzyme.

Double Functionalization of N-Boc-3-(Tosylmethyl)indole Exploiting the ­Activating Properties of the Tosyl Group

The anion prepared from N-Boc-3-(tosylmethyl)indole using NaH in DMF can be readily functionalized by reaction with various electrophiles. The obtained sulfonyl indoles, upon removal of the N-protecting group, undergo nucleophilic attack via a vinylogous imino derivative, leading to branched 3-substituted indoles.

Diastereoselective arylation of l-proline derivatives at the 5-position

Diastereoselective introduction of nucleophiles into l-proline derivatives at the 5-position was achieved with suitable selection of N-protecting group. N-Methoxycarbonylated or benzyloxycarbonylated l-proline derivatives reacted with arene to give cis-arylated products. On the other hand, N-benzoylated l-proline derivative preferentially gave trans-arylated product, which could be easily transformed into optically active C 2-symmetrical pyrrolidine derivative. Such derivative 5 worked well as an organic activator in the asymmetric reduction of aromatic imines by Cl 3SiH.

Intramolecular Nicholas Reaction: Stereoselective Synthesis of 5-Alkynylproline Derivatives

The intramolecular Nicholas reaction of propargylic alcohols derived from N, N-acyl-diprotected omega-semialdehydes obtained from glutamic acid provided stereoselectively 5-alkynylproline derivatives. The suitable choice of the N-protecting group (tosyl or benzoyl derivative) permitted control of the stereochemistry during the ring formation. Semiempirical calculations of the species involved in the cyclization support the observed stereochemistry.

High regioselectivity in electrochemical α-methoxylation of N-protected cyclic amines

N-Protecting groups of α-substituted cyclic amines strongly affected the regioselectivity in electrochemical methoxylation of these compounds. Namely, N-acyl derivatives were transformed into α′-methoxylated compounds, while N-cyano derivatives changed into α-methoxylated derivatives. Furthermore, Lewis acid catalyzed nucleophilic substitution of the α-methoxylated compounds protected with cyano group afforded α,α-disubstituted cyclic amines.

NHC-Catalyzed Staudinger Reaction

A chiral N-heterocyclic carbene catalyzed Staudinger reaction of ketenes with N-Boc imines has been developed. Catalyst 1 in combination with Cs2CO3 has been found to be effective for this reaction. After investigating different N-protecting groups, N-Boc imines are found to be suitable for this reaction. With 10 mol% of triazolium salt 1, good to high yields (53-75%) and excellent enantioselectivities (er = 95:5 to >99:1) are obtained for a wide variety of ketenes and imines.

Asymmetric Friedel−Crafts Alkylation of Pyrroles with Nitroalkenes Using a Dinuclear Zinc Catalyst

The catalytic enantioselective and atom economic Friedel−Crafts alkylation of pyrroles with nitroalkenes under mild reaction conditions using a dinuclear zinc catalyst is reported. The versatility of the reaction is demonstrated by the conversion of a number of differentially substituted nitroalkenes with differentially substituted pyrroles. Tandem addition reactions to form 2,5-disubstituted pyrroles are also demsonstrated. All pyrrole alkylations have been carried out without using N-protecting groups, which also enhances the efficiency by which substituted pyrroles may be synthesized. The reactions result in good yields and excellent enantioselectivities.

A Ceric Ammonium Nitrate N-Dearylation of N-p-Anisylazoles Applied to Pyrazole, Triazole, Tetrazole, and Pentazole Rings: Release of Parent Azoles. Generation of Unstable Pentazole, HN5/N5-, in Solution

The reaction of cerium(IV) ammonium nitrate (CAN) with a range of N-(p-anisyl)azoles in acetonitrile or methanol solvents leads to N-dearylation releasing the parent NH-azole and p-benzoquinone in comparable yields. The scope and limitations of the reaction are explored. It was successful with 1-(p-anisyl)pyrazoles, 2-(p-anisyl)-1,2,3-triazoles, 2-(p-anisyl)-2H-tetrazoles, and 1-(p-anisyl)pentazole. The dearylation renders the p-anisyl group as a potentially useful N-protecting group in azole chemistry. The azole released in solution from 1-(p-anisyl)pentazole is unstable HN5, the long-sought parent pentazolic acid. p-Anisylpentazole samples were synthesized with combinations of one, two, and three 15N atoms at all positions of the pentazole ring. The unstable HN5/N5- produced at -40 degrees C did not build up in the solution but degraded to azide ion and nitrogen gas with a short lifetime. The 15N-labeling of the N3- ion obtained from all samples proved unequivocally that it came from the degradation of HN5 (tautomeric forms) and/or its anion N5- in the solution.

Investigation of a Flexible Enantiospecific Approach to Aziridines

A flexible approach to functionalized and enantioenriched aziridines has been developed from an intermediate aziridinylmethyl tosylate. This protocol features a Cu-catalyzed Grignard substitution reaction that allows a range of functionalized organic fragments to be incorporated. Moreover, a convenient one-pot procedure is outlined that allows the trityl group to be exchanged for a range of common N-protecting groups.

A convenient synthesis of orthogonally protected 2-deoxystreptamine (2-DOS) as an aminocyclitol scaffold for the development of novel aminoglycoside antibiotic derivatives against bacterial resistance

The development of new aminoglycoside analogues to reduce the emergence of bacterial resistance has become a topic of high interest. We describe here a rapid and facile access to orthogonally protected 2-deoxystreptamine (2-DOS), a meso-diaminocyclitol known to be a pivotal component of most active aminoglycosides. Our synthetic approach started from highly protected methyl alpha-D-glucopyranoside which in turn was converted by a Ferrier rearrangement into an enantiopure polyfunctionalized cyclohexane ring. Finally, two different N-protected groups were successively introduced. The first one was inserted as an oximino benzylether followed by a diastereofacial hydride reduction, working with Me(4)NBH(OAc)(3) only in TFA at low temperature rather than in AcOH as usual. The second group was introduced by displacement of a hydroxyl group through a Mitsunobu reaction using a DPPA-DIAD-Ph(3)P system for azide transfer.

Dimerization and Isomerization Reactions of α-Lithiated Terminal Aziridines

The scope of dimerization and isomerization reactions of alpha-lithiated terminal aziridines is detailed. Regio- and stereoselective deprotonation of simple terminal aziridines with lithium 2,2,6,6-tetramethylpiperidide (LTMP) or lithium dicyclohexylamide (LiNCy2) generates trans-alpha-lithiated terminal aziridines. These latter species can then undergo dimerization or isomerization reactions depending on the nature of the N-protecting group. alpha-Lithiated terminal aziridines bearing N-alkoxycarbonyl (Boc) protection undergo N- to C-[1,2] migration to give N-H trans-aziridinylesters. In contrast, aziridines bearing N-organosulfonyl [tert-butylsulfonyl (Bus)] protection undergo rapid dimerization to give 2-ene-1,4-diamines or, if a pendant alkene is present, diastereoselective cyclopropanation to give 2-aminobicyclo[3.1.0]hexanes. All of these reactions were used as key steps in the preparation of synthetically and biologically important targets.

Reduction of pentafluorophenyl esters to the corresponding primary alcohols using sodium borohydride

Primary alcohols and chiral N-protected 2-amino alcohols can be obtained in high yields from the reaction of pentafluorophenyl esters of the corresponding carboxylic acids with sodium borohydride in THF under mild conditions. This reductive method is rapid and compatible with various functional groups as well as with the most common N-protective groups Z, Boc and Fmoc.

Substrate effect on α-chymotrypsin activity in aqueous solutions of “big-head” ammonium salts

The effect of two ammonium salts with a bulky head group, the tetrabutylammonium bromide (TBABr) and the surfactant cetyltributylammonium bromide (CTBABr) on α-chymotrypsin hydrolysis rate toward three peptidyl substrates was investigated. N-Succinyl- l-phenylalanine- p-nitroanilide (SP pNA), N-succinyl- l-alanyl- l-alanyl- l-phenylalanine- p-nitroanilide (SAAP pNA) and N-succinyl- l-alanyl- l-alanyl- l-prolyl- l-phenylalanine- p-nitroanilide (SAAPP pNA), which contain the same chromogenic and N-protecting groups, but a different number of amino acidic residues, were selected. The relative activity showed a bell-shaped dependence on additive concentration, with a maximum which ranged from 1 × 10 −3 M to 5 × 10 −3 M for CTBABr and at 0.3 M for TBABr. Both the additives induced α-chymotrypsin superactivity, but their effect decreased as the peptide chain length of the substrate increased. Analysis of the kinetic parameters indicated that the activation was mainly due to an increase in k cat values, probably caused by enzyme conformational changes induced by the additives, while K M remained almost unchanged. The very notable effect of both CTBABr and TBABr on SP pNA hydrolysis rate and the limited activation with SAAP pNA and SAAPP pNA could be probably due to non-specific interactions between the additives and the subsites next to the catalytic point within α-chymotrypsin active site, not allowed with the longer amino acidic chain substrates.

Studies Directed to the Synthesis of Oligochitosans — Preparation of Building Blocks and Their Evaluation in Glycosylation Studies.

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Rhodium-Catalyzed Reductive Mannich Coupling of Vinyl Ketones to N-Sulfonylimines Mediated by Hydrogen

Catalytic hydrogenation of methyl vinyl ketone (MVK) and ethyl vinyl ketone (EVK) in the presence of N-(o-nitrophenylsulfonyl)imines 8a-13a at ambient pressure with tri-2-furylphosphine-ligated rhodium catalysts enables formation of Mannich products 8b-13b and 8c-13c with moderate to good levels of syn-diastereoselectivity. As revealed by an assay of various N-protecting groups, excellent yields of reductive Mannich product also are obtained for N-arylimines 1a-4a, although diminished levels of syn-diastereoselectivity are observed. Coupling of MVK to imine 8a under a deuterium atmosphere provides deuterio-8b, which incorporates a single deuterium atom at the former enone beta-position.

Synthesis of Benzomorphan Analogues by Intramolecular Buchwald—Hartwig Cyclization.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Exploiting the regioselectivity of pyroglutamate alkylations for the synthesis of 6-azabicyclo[3.2.1]octanes and 4-azabicyclo[3.3.0]octanes

Depending on the N-protecting group of pyroglutamates, the reactivity can be directed to the formation of 6-azabicyclo[3.2.1]octanes or 4-azabicyclo[3.3.0]octanes, which are conformationally restricted glutamate analogues.

Preparation of Cyclopenta-Fused N-, O-, and S-Heterocycles by Lewis Acid Catalyzed Nazarov Reaction

The products of carbonylative coupling between lactam-, lactone- and thiolactone-derived vinyl triflates and alkenylboronic acids are suitable substrates for the Lewis acid catalyzed Nazarov reaction. The most efficient Lewis acids for the Nazarov reaction are scandium(III) and indium(III) triflates (3-15 mol%) in 1,2-dichloroethane, which provide the Nazarov products in moderate to excellent yield (53-86%). The electrocyclization rate depends also on the heteroatom (N, O, S) and the N-protecting group. On the whole, the entire procedure is an expeditious synthesis of hexahydro[1]pyrindenes, -cyclopenta[b]pyrans, and -cyclopenta[b]thiopyrans of noteworthy interest as they form the structural core of several natural molecules.

Chemoenzymatic approach to enantiopure piperidine-based β-amino esters in organic solvents

This research concentrates on the enantioselectivities of lipase-catalysed reactions with methyl esters of 2-piperidylacetic acid and 3-piperidinecarboxylic acid derivatives. N-Acetylated 2-piperidylacetic acid methyl ester displayed good enantioselectivity ( E = 66) in a 1:1 mixture of diisopropyl ether and butyl butanoate in the presence of lipase PS-C II from Burkholderia cepacia. The reaction is known as interesterification with butyl butanoate rather than alcoholysis with the butanol, because butyl butanoate has to be first hydrolysed or go through alcoholysis with MeOH in order to release butanol. Other N-protective groups (Boc, Ns, Fmoc and Bzn) gave excellent enantioselectivity ( E >200) under the same conditions, and a gram-scale resolution was performed with N-Boc-2-piperidylacetic acid methyl ester. Reaction with a 3-piperidylcarboxylic acid derivative took place with disappointingly low enantioselectivity ( E = 4), with Candida antarctica lipase B being the best of the lipases screened.