N-Boc Derivatives Research Articles

A highly chemoselective Boc protection of amines using sulfonic-acid-functionalized silica as an efficient heterogeneous recyclable catalyst

A facile and versatile method for the chemoselective Boc protection of amines has been developed by a treatment with (Boc)2O in the presence of sulfonic-acid-functionalized silica as a catalyst. The method is general for the preparation of N-Boc derivatives of aliphatic (acyclic and cyclic), aromatic, and heteroaromatic amines; primary and secondary amines; aminols, amino-esters; and sulfonamides. The catalyst works under heterogeneous conditions and can be recycled.

A rate enhancement of tert-butoxycarbonylation of aromatic amines with Boc 2O in alcoholic solvents

A rate enhancement of tert-butoxycarbonylation of aromatic amines by Boc 2O in alcohols compared to aprotic solvents was demonstrated. Kinetic analysis by NMR suggested that the reaction in CD 3OD was faster than in CDCl 3 by a factor of 70. Reactions between Boc 2O and various aliphatic and aromatic amines in ethanol provided the N-Boc derivatives in good to excellent yields in short reaction times.

Dynamic Thermodynamic and Dynamic Kinetic Resolution of 2-Lithiopyrrolidines

Dynamic resolution has been studied as a method for the asymmetric synthesis of 2-substituted pyrrolidines. Highly enantioselective electrophilic substitutions of racemic 2-lithiopyrrolidines in the presence of a chiral ligand have been achieved. The organolithium compounds were prepared by tin-lithium exchange from the corresponding tributylstannanes and n-butyllithium or by deprotonation of N-(tert-butyloxycarbonyl)pyrrolidine with sec-butyllithium. A range of N-substituents and chiral ligands were investigated for the dynamic resolution. Electrophilic quench of the resolved diastereomeric 2-lithiopyrrolidine-chiral ligand complexes provided the enantiomerically enriched 2-substituted pyrrolidines. With N-alkyl derivatives, the resolution occurs conveniently at (or just below) room temperature and either enantiomer of the product can be formed by appropriate choice of the chiral ligand. The asymmetric induction occurs as a result of a thermodynamic preference for one of the diastereomeric complexes. The minor complex was found to have a faster rate of reaction with the electrophile. The use of N-allylic derivatives provides a means to prepare the N-unsubstituted pyrrolidine products. Best results were obtained with the N-2,3-dimethylbut-2-enyl derivative, and this N-substituent could be cleaved using 1-chloroethyl chloroformate. With N-Boc-2-lithiopyrrolidine, the enantioselectivity arises by a kinetic resolution and high levels of asymmetric induction in the presence of excess n-butyllithium can be obtained. Dynamic kinetic resolution of the N-Boc derivative is limited in the scope of electrophile that can be used.

Hybrid α/β-peptides: For-Met-Leu-Phe-OMe analogues containing geminally disubstituted β2,2- and β3,3-amino acids at the central position

The two fMLF-OMe analogues For-Met-beta(3)hAc(6)c-Phe-OMe (6) and For-Met-beta(2)hAc(6)c-Phe-OMe (12) and their corresponding N-Boc derivatives 5 and 11 have been synthesized and their biological activity towards human neutrophils evaluated. The N-formyl peptides 6 and 12 exhibit good activity as chemoattractans and 12 is highly active in superoxide anion production. The preferred solution conformation of the two N-formyl derivatives has been discussed.

Construction of an Advanced Tetracyclic Intermediate for Total Synthesis of the Marine Alkaloid Sarain A

In work directed toward a total synthesis of the marine alkaloid sarain A (1), the advanced intermediate 54, containing all the key elements and the seven stereogenic centers of sarain A, has been successfully synthesized from bicyclic lactam 4, previously prepared via an intramolecular stereospecific [3 + 2]-azomethine ylide dipolar cycloaddition. Intermediate lactam 4 could be efficiently converted to N-Boc derivative 12. Introduction of a two-carbon fragment into lactam 12 which eventually becomes the C-7',8' syn diol of the "eastern" ring was then achieved by C-acylation of the corresponding enolate with methoxyacetyl chloride followed by a highly stereoselective ketone reduction with Zn(BH4)2 to afford alcohol 16. Intermediate 16 has the incorrect C-7' relative stereochemistry for sarain A, but this problem was conveniently remedied by inverting the C-7' center via an intramolecular Ohfune-type cyclization of the silyl carbamate derived from Boc mesylate 27 to produce the key cyclic carbamate 28. It was then possible to convert acetal 28 to allylsilane 32 followed by cyclization to the alkaloid tricyclic core 33 via an allylsilane/N-sulfonyliminium ion cyclization. Formation of the "western" macrocyclic ring has been successfully addressed using functional group handles at C-3' and N-1' on the tricyclic core via a ring-closing olefin metathesis (RCM) strategy with the second-generation Grubbs ruthenium catalyst to produce intermediate macrolactam 47. A chelation-controlled addition of ethynylmagnesium bromide to advanced aldehyde 51 afforded a single diastereomeric adduct 53 which is tentatively assigned to have the correct C-7',8' syn-diol stereochemistry. This adduct could be rearranged to the conveniently protected amino carbonate 54 which is set up for construction of the remainder of the eastern ring of sarain A.

Novel examples of the N-methyl effect on cyclisations of N-Boc derivatives of amino alcohols. A theoretical study

New examples of the N-methyl effect on the cyclisation of N- tert-butoxycarbonyl derivatives of amino alcohols are reported. Ab initio studies for the displacement step with formation of the five-membered heterocycle indicate that the increase of the nucleophile character of the carbonyl oxygen of the carbamate group with the N-methyl substitution is responsible for the acceleration of the cyclisation step.

A novel oxidative side-chain transformation of α-amino acids and peptides by methyltrioxorhenium/H 2O 2 system

N-Boc derivatives of Met, Cys, and Trp, the properties of which resemble those of the respective amino acid residues present in proteins, are efficiently oxidized by methyltrioxorhenium and H 2O 2. A high regioselectivity for the oxidation of these residues when embedded into peptides was also found.

Diastereoselective [2+2]-cycloaddition reactions of unsymmetrical cyclic ketenes with imines: synthesis of modified prolines and theoretical study of the reaction mechanism.

The synthesis of enantiomerically pure modified proline derivatives was achieved by using spiro beta-lactams as starting material that were prepared in turn by the [2+2]-cycloaddition of unsymmetrical cyclic ketenes with optically active imines. A theoretical study of the [2+2]-cycloaddition reaction, using density-functional methods, gave insights on the origin of the observed stereoselectivity of the Staudinger reaction. The spiro beta-lactams were transformed in the N-Boc derivatives and subjected to nucleophilic ring opening, affording the corresponding enantiomerically pure modified proline derivatives, isolated as orthogonally protected compounds.

Hybrid alpha/beta3-peptides with proteinogenic side chains. Monosubstituted analogues of the chemotactic tripeptide For-Met-Leu-Phe-OMe.

The alpha/beta3-mixed tripeptides R-CO-beta3-HMet-Leu-Phe-OMe (1a,b), R-CO-Met-beta3-HLeu-Phe-OMe (2a,b) and R-CO-Met-Leu-beta3-HPhe-OMe (3a,b) (a, R = tert-butyloxy-; b, R = H-), analogues of the potent chemoattractant For-Met-Leu-Phe-OMe, have been synthesized by classical solution methods and fully characterized. The activities of the new analogues as chemoattractants, superoxide anion producers and lysozyme releasers have been determined on human neutrophils. Whereas all of the three N-formyl derivatives are significantly less active than the parent tripeptide as chemoattractants, compound 1b has been found to be highly active as a superoxide anion producer and 3b as a lysozyme releaser. The results show that the replacement of the native Leu residue at the central position is, in each of the examined cases, the least favourable modification. The three N-Boc derivatives are, as expected, devoid of activity as agonists, but they are all good inhibitors of chemotaxis. Information on the solution conformation has been obtained by examining the involvement of the NH groups in intramolecular H-bonds using 1H NMR. The conformation of the N-Boc analogue 1a has also been determined in the crystal state by x-ray diffraction analysis. The molecule is extended at the beta3-HMet residue (phi1 = -87 degrees; theta1 = 172 degrees; psi1 = 126 degrees) and no intramolecular H-bond is present.

Enzyme-catalyzed enantiomeric resolution of N-Boc-proline as the key-step in an expeditious route towards RAMP

For the preparation of both enantiomers of N-carbamoyl-2-methoxymethylpyrrolidine, the precursors of Enders’ chiral auxiliaries, SAMP and RAMP, enzyme-catalyzed kinetic resolution of racemic N-carbamoyl, N-Boc, N-Cbz proline esters and prolinols were examined. B. licheniformis protease (subtilisin) preferentially hydrolyzed the ( R)-carbamoylproline ester with an enantiomeric ratio (E) of 10. To a hydrophobic N-Cbz proline ester, subtilisin showed lower selectivity ( E=2.8), and in contrast, a purified protease (isozyme A) from the earthworm showed the preference of ( S)-enantiomer ( E=13.6). In a practical sense, C. antarctica lipase B (Chirazyme L-2) was effective for the hydrolysis of both N-Boc and N-Cbz derivatives with E >100. The e.e. of ( R)- N-carbamoyl-2-methoxymethylpyrrolidine was raised to be >99.9% by recrystallization at the N-Boc-prolinol stage, which was derived from the ( R)- N-Boc-proline methyl ester (98.7% e.e.) through a preparative-scale enzyme-catalyzed resolution (49% yield) of the racemic substrate.

Efficient and simple one-pot conversion of resin-bound N-Fmoc amino acids and dipeptides into N-Boc derivatives

Wang resin bound N-fluorenylmethoxycarbonyl (Fmoc) amino acids and dipeptides were efficiently converted into the corresponding N-tert-butoxycarbonyl (Boc) derivatives using two different “one-pot” procedures: potassium fluoride / di-tert-butyl carbonate and potassium fluoride / tert-butyl S-(4,6-dimethylpyrimidin-2-yl) thiolcarbonate.

An unusual behaviour of N-( tert-butoxycarbonyl)- and N-pivaloyl-(methylthio)anilines in metallation reactions

The metallation reaction of N-Boc-and N-Piv-(methylthio)anilines are here described. The results show that N-Boc derivatives are metallated only by superbases to give products substituted at the thiomethylic group. N-Piv derivatives show a different behaviour: ortho-derivative is metallated by both butyllithium and superbase at the thiomethylic carbon atom, while para-derivative is metallated in ortho to the N-Piv group by butyllithium and at the thiomethylic carbon atom by superbase. The meta-derivative is metallated only by superbase at the thiomethylic carbon atom.

Enantiomerically Pure β-Amino Acids: A Convenient Access to Both Enantiomers of trans-2-Aminocyclohexanecarboxylic Acid

Enantiomerically pure trans-2-aminocyclohexanecarboxylic acid is an important building block for helical β-peptides. We report here that this amino acid can be obtained from trans-cyclohexane-1,2-dicarboxylic acid in good yield by a simple one-pot procedure comprising cyclization to the anhydride, amide formation with ammonia, and a subsequent Hofmann-type degradation with phenyliodine(III) bis(trifluoroacetate) (PIFA) as the oxidant. The N-Fmoc- and N-BOC-protected derivatives were obtained by treatment of the amino acid with Fmoc-OSu and BOC2O, respectively. The N-BOC derivative could be prepared in even better overall yield by a one-pot procedure leading directly from trans-cyclohexane-1,2-dicarboxylic acid to the N-BOC-protected amino acid. Both enantiomers of the starting trans-1,2-cyclohexanedicarboxylic acid can be obtained easily and in large quantities by separating commercially available racemic trans-1,2-cyclohexanedicarboxylic acid using either (R)- or (S)-1-phenethylamine. X-ray crystallography of the diastereomerically pure salt obtained from (R)-1-phenethylamine revealed that the configuration of the diacid component is (1R,2R), and not (1S,2S) as reported in the literature. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis and activity on human neutrophil functions of fMLF-OMe analogs containing alkyl spacers at the central position

We report here the synthesis and activity of new analogs of the N-formyl and N- tert-butyloxycarbonyl (Boc) derivatives of the tripeptide Met-Leu-Phe-OMe containing an achiral ω-amino acid residue replacing the hydrophobic central leucine. The tripeptides HCO-Met-NH-(CH 2) n -CO-Phe-OMe and Boc-Met-NH-(CH 2) n -CO-Phe-OMe ( n=3–5) containing the central homomorphic residue of 5-aminopentanoic acid (δ-aminovaleric acid; δ-Ava; n=4) and the two non-homomorphic residues of 4-aminobutanoic acid (γ-aminobutyric acid; γ-Abu; n=3) and 6-aminohexanoic acid (ε-aminocaproic acid; ε-Aca; n=5) have been examined. The activity as agonists and antagonists in chemotaxis, lysozyme release, and superoxide anion production of the new analogs has been determined. The N-Boc derivatives 2a and 2b, incorporating the γ-Abu and the δ-Ava residues, show good and selective antagonist activity on superoxide anion production.

MILD AND CONVENIENT ONE POT SYNTHESIS OF N-HYDROXYIMIDES FROM N-UNSUBSTITUTED IMIDES

A new, one pot synthesis of various N-hydroxyimides from N-unsubstituted imides is described. Imides are first transformed into their N-Boc derivatives, which are next reacted with aqueous hydroxylamine, providing crystalline hydroxylammonium salts of the corresponding N-hydroxyimides. Filtration and acidic workup affords pure N-hydroxyimides.

ChemInform Abstract: Reaction Between Hydrazines and Chiral α-Acetylenic Ketones: Synthesis of Novel Enantiomerically Pure Pyrazolyl-β-amino Alcohols.

Abstract A simple and efficient methodology toward the stereoselective synthesis of novel, enantiomerically pure, pyrazolyl-β-amino alcohols is presented. Thus, when hydrazines 4a,b were allowed to react at 0°C with chiral α-acetylenic ketones of type 3, pyrazolyl oxazolidine derivatives 5a–d were formed with total regioselectivity in 92–97% yield. Subsequent oxazolidine ring opening by means of TFA, and re-protection of the amino group as the N-Boc derivatives, afforded enantiopure amino alcohols 7a–d.

On the Question of the Diastereoselective Alkylation of 4-Unsubstituted 3-Amino β-Lactams. A Concise Synthesis of α-Branched α-Amino β-Lactams and their Coupling with α-Amino Acid Esters

The reaction of [(4 S)-2-oxo-4-phenyloxazolidin-3-yl]acetic acid chloride with N-methylidene-bis-[(trimethylsilyl)methyl]amine and triethylamine in refluxing chloroform leads to a 4-unsubstituted β-lactam able to undergo highly asymmetric alkylations at the α-position of the β-lactam ring. The resulting adducts can be efficiently transformed into N-unsubstituted α-branched 3-amino β-lactams as the cyclisized forms of α-branched β-aminoalanines or transformed into their imide N-Boc derivatives, which are suitable substrates for non-proteinogenic peptide synthesis, by reaction with α-amino esters.

Reaction between hydrazines and chiral α-acetylenic ketones: synthesis of novel enantiomerically pure pyrazolyl-β-amino alcohols

A simple and efficient methodology toward the stereoselective synthesis of novel, enantiomerically pure, pyrazolyl-β-amino alcohols is presented. Thus, when hydrazines 4a, b were allowed to react at 0°C with chiral α-acetylenic ketones of type 3, pyrazolyl oxazolidine derivatives 5a– d were formed with total regioselectivity in 92–97% yield. Subsequent oxazolidine ring opening by means of TFA, and re-protection of the amino group as the N-Boc derivatives, afforded enantiopure amino alcohols 7a– d.

Improved synthesis of paroxetine hydrochloride propan-2-ol solvate through one of metabolites in humans, and characterization of the solvate crystals.

Paroxetine, a potent and selective inhibitor of 5-hydroxytryptamine (serotonin) uptake, was prepared through a piperidine derivative, which was reported to be one of the paroxetine metabolites in humans. Thus, the piperidine derivative was converted to its N-tert-butoxycarbonyl (N-Boc) derivative, which was then converted to N-Boc paroxetine. Paroxetine hydrochloride propan-2-ol (isopropyl alcohol (IPA)) solvate crystals were directly obtained from the N-Boc paroxetine by adding hydrogen chloride to the N-Boc paroxetine IPA solution. The amount of IPA content in the crystals was reduced by drying with a continuous change of powder X-ray diffraction patterns. Other characterizations of the solvate crystals were also conducted.

A New and Efficient Synthesis of Unnatural Amino Acids and Peptides by Selective 3,3-Dimethyldioxirane Side-Chain Oxidation

N-Boc derivatives of Leu, Met, Thr, Trp, and Pro, the properties of which resemble those of the respective α-amino acid residues present in proteins, rapidly oxidize in the presence of 3,3-dimethyldioxirane to give different products depending on the structure of the oxidizable group in the side chain. A high regioselectivity for the oxygen atom insertion into the γ-CH bond of Leu residues with respect to the weaker α-CH bond was observed. A position selectivity in the oxidation of peptides containing more than one Leu residue was also found.