Boc Deprotection Research Articles

1,3,5-Tri- and 1,3,4,5-Tetra-Substituted 1,4-Diazepin-2-one Solid-Phase Synthesis

Solid-phase syntheses of 1,3,5-tri-substituted and 1,3,4,5-tetra-substituted 1,4-diazepin-2-ones 15-18 have been accomplished by employing inexpensive commercially available alpha- and beta-amino acids on Wang resin. Reductive amination of the imine formed by condensation of Wang aldehyde resin respectively with beta-alaninate 2 and beta-homophenylalaninate 3, followed by aminoacylation with a set of alpha-N-Boc amino acids (Phe epsilon-( Z)-Lys, and Leu) gave tertiary amide resins 7 and 8. Exposure of resins 7 and 8 to an excess of vinyl magnesium bromide in the presence of copper cyanide gave the corresponding gamma,delta-unsaturated ketone resins 9 and 10 by way of a cascade addition. Diazepinones were made by Boc deprotection and intramolecular reductive amination. To diversify the heterocycle, N-alkylation was performed using a series of alkyl halides. Alternatively, diazepinones 15e-g were obtained from treatment of methyl beta-alaninate resins 4 and 20 under similar copper-catalyzed cascade conditions to afford the gamma,delta-unsaturated ketone 21, which was acylated using alpha-N-Fmoc-amino acids (Phe, Trp, gamma-(t-Bu)-Glu). Formation of diazepinones 15 followed a similar protocol, after Fmoc removal with piperidine. Cleavage of the heterocycles with TFA/TES 95:5 gave the N1-p-hydroxybenzyl diazepinones 15-18 in overall isolated yields from 6 to 24% after purification in purities ranging from 81 to 100% according to LCMS analysis.

Mechanism of N-octadecyl- N′-maleoyl- l-phenylalanine self-assembled into supramolecular structures

N-Octadecyl- N′-maleoyl- l-phenylalanine (ODMA- l-Phe) was synthesized through the condensation, deprotection and acidylation reaction of BOC- l-phenylalanine, octadecylamine and maleic anhydride. ODMA- l-Phe can self-assemble in some organic solvents and turned them into thermally reversible physical supramolecular organogels. The morphology of ODMA- l-Phe aggregates was characterized by polarized optical microscopy (POM) and field emission scanning electron microscope (FE-SEM). The aggregates of ODMA- l-Phe were needle-like fibrils with diameters of approximately 100–200 nm. The mechanism of ODMA- l-Phe self-assembly in organic solvents was investigated using 1H NMR and circular dichroism (CD). The results indicated that hydrogen bonding was one of the main driving forces for the self-assembly of ODMA- l-Phe.

Convergent and Stereospecific Synthesis of Molecules Containing α-Functionalized Guanidiniums via α-Guanidino Acids

To introduce chirality and functional groups adjacent to guanidiniums to modulate specificity and affinity in recognition, N,N'-bis(Boc)-alpha-guanidino acids were synthesized from alpha-amino acid methyl esters. Protected alpha-guanidino acids coupled to cyclohexylamine and trans-1,4-diaminocyclohexane in good yield and with retention of stereochemistry. Boc deprotection was conducted under mild acidic conditions (0.5 M HCl/EtOAc) to minimize epimerization. The deprotected guanidinium is configurationally stable under more acidic conditions. This approach represents a practical, convergent, stereospecific methodology to introduce chiral alpha-substituted guanidinium groups into molecules.

Synthesis and epimerization of phenylalanyl 4-aminocyclophosphamides

Peptide and amino acid conjugates of (4 R)- and (4 S)-4-aminocyclophosphamides (4-NH 2-CPA, 3) were designed as prodrug forms of phosphoramide mustard. Four diastereomers of Boc-Phe-4-NH-CPA ( 6) were synthesized stereospecifically from homoserine ( R or S) and the protection strategy was optimized for the homoserine hydroxyl group during the construction of the 1,3,2-oxazaphosphorinane ring. The Phe-4-NH-CPA isomers of the trans-configuration ((2 S,4 R)- and (2 R,4 S)-) were found to be less stable than the corresponding isomers of the cis-configuration ((2 R,4 R)- and (2 S,4 S)-) and to undergo epimerization of the C-4 chiral center in the presence of 25% TFA used during Boc deprotection. The synthetic route developed should be applicable to the synthesis of a variety of peptide and amino acid conjugates of 4-aminocyclophosphamide.

Efficient Routes for the Synthesis of 1,4,7,10,13-Pentaazacyclohexadecane-14,16-dione

The synthetic access to 1,4,7,10,13-pentaazacyclohexadecane-14,16-dione was significantly improved from an overall yield of 1% to 33%. The procedure involved the use of COCF3 or DDE as highly selective protecting groups for primary amines and of Boc to protect the secondary amine functions. The reaction of a tris-Boc protected tetraethylenepentamine with malonic acid gave the macrocycle in a 44% yield, the same reaction with malonyl chloride, however, yielded only 3.6% of the desired product. Boc deprotection and removal of the trifluoroacetate salts gave access to the final product, 1,4,7,10,13-pentaazacyclohexadecane-14,16-dione, in an overall yield of 33%.

Photochemistry of 4-(2‘-Aminoethyl)quinolones: Enantioselective Synthesis of Tetracyclic Tetrahydro-1aH-pyrido[4‘,3‘:2,3]- cyclobuta[1,2-c] Quinoline-2,11(3H,8H)-diones by Intra- and Intermolecular [2 + 2]-Photocycloaddition Reactions in Solution

Enantioselective [2 + 2]-photocycloaddition reactions on 4-(2'-aminoethyl)quinolones in solution were studied using the enantiomerically pure complexing agent 1 as source of chirality. The intermolecular reactions of fully N-protected substrates 5a-5c with different 2-alkyl-substituted acrylates 12-15 represent the first systematic study on the diastereoselectivity of their intermolecular [2 + 2]-photocycloadditions to unsymmetrically 1,1-disubstituted olefins (75-91% yield, d.r. = 58/42-95/5). N-Benzylic-protected photoproducts exo-16a/b-19a/b could easily be converted into lactams 20a/b-23a/b by a sequence of Boc deprotection and thermal lactamization (74-98% yield). Identical products 20a-22a were directly accessible by the intramolecular [2 + 2]-photocycloaddition of acrylic acid amides 2-4 (41-61% yield). The suitability of both pathways for an enantioselective reaction variant was proven (70-92% ee). Thus, tetracyclic lactams possessing the carbon framework C were obtained with good yields and enantioselectivities of up to 92% ee in intramolecular reactions. Comparative investigation of both routes showed that quinolone dimerization was the single most decisive factor preventing a complete chirality transfer. Functional group manipulations were successfully conducted with the primary photoproduct exo-17a. Finally, a new and unexpected type of benzylic hydrogen abstraction-radical cyclization reaction was discovered for substrate 5a, which explains the photochemical instability of substrates 2-5 under short wavelength irradiation (lambda = 300 nm).

RETRACTED: Biomimetic approach to Galbulimina type I alkaloids

On treatment with trifluoroacetic acid the tetraene precursor 23 underwent Boc deprotection, condensation and an iminium ion accelerated intramolecular Diels-Alder cycloaddition resulting in an iminium species 12, which was further converted into himbacine 1, himbeline 3 and himandravine 4, three out of four Galbulimina type I alkaloids thus providing strong evidence for the proposed biogenesis of this important family of alkaloids.

A Convenient Synthesis of 1′‐H‐Spiro‐(indoline‐3,4′‐piperidine) and Its Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A convenient synthesis of 1′- H-spiro-(indoline-3,4′-piperidine) and its derivatives

A simple synthetic route has been developed to prepare 1′- H-spiro(indoline-3,4′-piperidine) ( 1d ). Dialkylation of 2-fluorophenylacetonitrile with N-( tert-butyloxycarbonyl)-bis(2-chloroethyl)amine ( 5 ) gave 6 . Deprotection of Boc followed by cyclization resulted 1d in 67% overall yield. Selective Boc or Cbz protection of 1′- N gave 1a or 1b with 90 and 85% yield, respectively. Thus, in a five-step procedure, 1a and 1b were synthesized from commercially available reagents in over 50% overall yield. All 3 compounds ( 1a , 1b and 1d ) can be utilized as templates to synthesize compounds for GPCR targets.

Base‐Labile tert‐Butoxycarbonyl (Boc) Group on Phenols.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Base-labile tert-butoxycarbonyl (Boc) group on phenols

Phenols are deprotected with weak bases from their tert-butoxycarbonyl (Boc) derivatives. Boc deprotection with bases can avoid side reactions during the deprotection with acids. We note the lability of the Boc to bases and are able to utilize it as a new cleavage condition for synthetic studies.

Towards a selective Boc deprotection on acid cleavable Wang resin

Deprotection of the Boc group of an amino acid attached to the Wang resin has been investigated. Several conditions, including bases, solvents and reaction time, were studied. Quantitative yield of Boc deprotection was achieved with less than 10% loss of resin loading with trimethylsilyltriflate. This reagent allows the replacement of tert-butyl to TMS group, leading to a new temporary urethane protection readily hydrolyzed.

Lipopolycationic telomers for gene transfer: synthesis and evaluation of their in vitro transfection efficiency.

We report on the synthesis of a series of lipopolyamine telomers I-14,n, I-18,n, and II-18,n and on their in vitro gene-transfer capability. Their structure consists of a polyamine polar moiety, including n primary amine functions (from 1 to 70), connected to a hydrophobic moiety, including two hydrocarbon C14 or C18 chains, through a mercaptopropanoyl or mercaptoglyceryl unit and an amide or ether function. They were obtained by telomerization of N-[2-[(BOC)aminoethyl]]acrylamide with N,N-ditetradecyl- and N,N-dioctadecylpropanamide-3-thiol and rac-1,2-dioctadecyloxypropane-3-thiol, respectively, then BOC deprotection. For N/P ratios (N = number of telomer amine equivalents; P = number of DNA phosphates) from 0.8 to 10, these lipopolyamines condensed DNA, with or without the use of DOPE, forming lipopolyplexes or teloplexes of mean sizes less than 200 nm. Some trends, structure-activity and structure-toxicity relationships, were established to achieve both highest in vitro transfection levels and cell viability. Thus, DNA formulations based on telomers I-14,20 and I-18,20 and for N/P ratios lower than 5 led to the most efficient teloplex formulations for plasmid delivery to lung epithelial A549 cells.

Enantiospecific synthesis of 1-azafagomine.

For the first time the two enantiomeric forms of the glycosidase inhibitor 1-azafagomine have been synthesised starting from D- and L-xylose. D-Xylose was converted to the 2,3,5-tribenzylfuranose, which upon reductive amination with tert-butyl carbazate gave the protected 1-hydrazino-1-deoxypentitol in high yield. N-acetylation, mesylation of the 4-OH, removal of the Boc group, cyclisation and deprotection gave (+)-1-azafagomine ((+)-1). By a similar sequence of reactions, L-xylose was converted to (-)-1-azafagomine ((-)-1). Enzymatic and other routes to optically pure 1-azafagomine were also studied. Compound (-)-1 is a potent competitive glycosidase inhibitor, while (+)-1 has no biological activity. The inhibition of almond beta-glucosidase by (-)-1 was found to be slow owing to a slow binding step of inhibitor to enzyme, with no subsequent conformational rearrangement. The rate constants for binding and release were found to be 3.3 x 10(4)M(-1)s(-1) and 0.011 s(-1), respectively, yielding Ki = 0.33 microM.

A convergent liquid-phase synthesis of salmon calcitonin.

Salmon calcitonin (sCT) was prepared in good yield and high purity by the condensation of Nalpha-Boc-cyclic decapeptide, Boc-C1SNLSTC7VLG-OH (1,7-disulfide), with protected docosapeptide (Psc)LSQE(OPse)LHK(Psc)LQTYPRTNTGSGTP-NH2 x 3TFA, followed by deprotection of Boc with trifluoroacetic acid and Psc/Pse with piperidine. The 2-(phenylsulfonyl)ethoxycarbonyl (Psc) and 2-(phenylsulfonyl)ethyl (Pse) protecting groups were recently developed. The two peptides were built up by stepwise and fragment condensation using appropriate Nalpha-Boc-amino acids and subsequent deprotection in solution. The synthetic sCT exhibited hypocalcemic potency of more than 4000 IU/mg in rats.

Novel applications of ethyl glyoxalate with the Ugi MCR

This letter describes novel high-yielding solution phase preparations of 1,4-benzodiazepine-2,5-dione, diketo-piperazine, ketopiperazine and dihydroquinoxalinone libraries via a UDC (Ugi/de-Boc/cyclization) strategy in combination with ethylglyoxalate. The methodology represents a ‘three step, one-pot procedure’, employing the Ugi multi-component reaction (MCR), followed by Boc deprotection and cyclization.

The solution phase synthesis of diketopiperazine libraries via the Ugi reaction: Novel application of Armstrong's convertible isonitrile

This communication describes the generation of high-yielding solution phase diketopiperazine libraries via a ‘3-step, 1-pot’ procedure, employing the Ugi multi-component reaction (MCR), followed by BOC deprotection and cyclization to diketopiperazine (DKP). Exploitation of Armstrong's convertible isonitrile in the Ugi reaction utilising an ‘internal nucleophile’ approach for diketopiperazine formation is presented.

A Selective Photoaffinity Ligand for the Kainate Class of Excitatory Amino Acid Receptor

The isopropenyl side chain of kainic acid (KA) has been replaced with a trifluoromethyldiazoketone group, resulting in a derivative ("diazoKA") that gives efficient photo-induced crosslinking to the active site of the KA class of glutamate receptor. The incorporation of this functional group is accomplished via a simple, one step coupling of a carboxylic acid and 2,2,2-trifluorodiazoethane in a procedure that should be generally applicable to the preparation of other photoaffinity labels. Major advantages include excellent stability towards acidic conditions, even Boc and t-butyl ester deprotection, as well as a reduced tendency to undergo (non-productive) Wolff rearrangement after binding and irradiation. The observed crosslinking paves the way for identifying the active site residues of the KA receptor.

ChemInform Abstract: Extremely Mild Reagent for Boc Deprotection Applicable to the Synthesis of Peptides with Thioamide Linkages.

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Extremely mild reagent for Boc deprotection applicable to the synthesis of peptides with thioamide linkages

SnCl4 in organic solvents acts as an extremely mild reagent for Boc deprotection even in the presence of the acid-labile thioamide moiety with excellent yields.