Removal Of Boc Group Research Articles

Metal-free multicomponent polymerization toward cationic polyamidines

Cationic polymers, also known as polycations, are considered to be the most potential non-viral gene carriers due to their unique advantages such as the ability to bind the negative charge of nucleic acid molecules. Multicomponent polymerization (MCP) is a one-step, tandem strategy to construct complex structures based on multicomponent reactions. Herein, we developed a metal-free MCP method based on three monomers of p-dinitrovinylbenzene (p-DNVB), 1,1-dimethylethyl N,N-dibromocarbamate (BocNBr2), and bis-secondary-amines with a ratio of 1:2:1, to access a library of Boc-substituted polyamidines with well-defined structures and suitable molecular weights (Mw ranging from 4400 Da to 11,000 Da) in high yields (up to 85%) under mild conditions. Upon the removal of Boc groups, a series of water-soluble polymers with cationic property were prepared and their gene binding capability was further evaluated.

Perfluoro-tert-butanol for selective on-resin detritylation: a mild alternative to traditionally used methods.

Solid-phase synthesis of cyclic, branched or side-chain-modified peptides typically involves introduction of a residue carrying a temporary side-chain protecting group that undergoes selective on-resin removal. In particular, Nα-Fmoc-Nε-(4-methyltriphenylmethyl) (Mtt)-protected lysine and its shorter analogues are commercially available and extensively used in this context. Nevertheless, rapid reliable methods for on-resin removal of Mtt groups in the presence of tert-butyloxycarbonyl (Boc) groups are needed. Current commonly used conditions involve low concentrations (1-3%) of trifluoroacetic acid (TFA) in dichloromethane, albeit adjustment to each specific application is required to avoid premature removal of Boc groups or cleavage from the linker. Hence, a head-to-head comparison of several deprotection conditions was performed. The selected acids represent a wide range of acidity from TFA to trifluoroethanol. Also, on-resin removal of the N-(4-methoxytriphenylmethyl) (Mmt) and O-trityl groups (on serine) was investigated under similar conditions. The mildest conditions identified for Mtt deprotection involve successive treatments with 30% hexafluoroisopropanol (HFIP) or 30% perfluoro-tert-butanol [(CF3)3COH] in dichloromethane (3 × 5 or 3 × 15min, respectively), while 30% HFIP, 30% (CF3)3COH, or 10% AcOH-20% trifluoroethanol (TFE) in CH2Cl2 (3 × 5min) as well as 5% trichloroacetic acid in CH2Cl2 (3 × 2min) enabled Mmt removal. Treatment with 1% TFA with/without 2% triisopropylsilane added (3 × 5min), but also prolonged treatment with 30% (CF3)3COH (5 × 15min), led to selective deprotection of an O-Trt group on a serine residue. In all cases, the sequences also contained N-Boc or O-tBu protecting groups, which were not affected by 30% HFIP or 30% (CF3)3COH even after a prolonged reaction time of 4h. Finally, the optimized conditions involving HFIP or (CF3)3COH proved applicable also for selective deprotection of a longer resin-bound peptide [i.e., Ac-Gly-Leu-Leu-Lys(Mtt)-Arg(Pbf)-Ile-Lys(Boc)-Ser(tBu)-Leu-Leu-RAM-PS] as well as allowed for an almost complete deprotection of a Dab(Mtt) residue.

Molecular organized isoindigo based small molecules with terminal thermally cleavable protecting group

The potential of a new series of H-bonded isoindigo (ID) based small molecules as charge transporting materials was examined. The soluble precursor units contained two terminal isoindigo units bearing tert-butoxycarbonyl (Boc) solubilizing substituents. Thiophene, thienothiophene and/or diketo pyrrolopyrrole are used as π-conjugated spacers between the isoindigo units. The protected Boc-ID units are converted to the hydrogen-substituted counterparts by annealing the spin-coated precursor films up to 220 °C. The solid state molecular ordering after Boc thermal decarboxylation was investigated using thermogravimetric analysis, UV–vis spectroscopy and X-ray diffraction analysis. The thermogravimetric analysis confirmed the full removal of Boc groups. It was revealed that the formation of terminal intermolecular hydrogen bonds gave the ability to the deprotected materials to change their molecular ordering to edge-on or face-on orientation based on the spacer size and the π-conjugated length. The [-NH----OC] H-bonding dramatically improved the strength of the intermolecular interactions and induced a significant shift on the wavelength of annealed films. The hole mobilities of isoindigo based organic materials measured by the space charge-limited current (SCLC) method and showed a tenfold improvement after thermal decarboxylation.

Dedicated to a peptide chemist of few words and immense impact: Louis A. Carpino

Dedicated to a peptide chemist of few words and immense impact: Louis A. Carpino

Alternating copolymers with glycyl-glycine and alanyl-alanine side-chain pendants: synthesis, characterization and solution properties

A series of chiral alternating copolymers based on glycyl-glycine attached styrenic monomer (VG) and alanyl-alanine tethered maleimide (MA) are synthesized through reversible addition-fragmentation chain transfer (RAFT) polymerization. The alternating sequential arrangement of the two monomers along the synthetic copolymer chain is systematically established through 1H and 13C NMR spectroscopic investigation. The thermal as well as chiroptical characteristics of the copolymers are also studied. Interestingly, the copolymers show unusual luminescence characteristics in different organic solvents under UV light irradiation, whereas in the solid state they emit blue, green and red fluorescence as witnessed from the corresponding fluorescence microscopy micrographs. Furthermore, after successful Boc group removal, the deprotected copolymers show pH-dependent solubility variation in aqueous solution with an almost invariant transition pH with respect to varying chain lengths of the polymers. Thus, the strategy reported herein offers a notable direction to fabricate various dipeptide-based sequence-controlled polymers with promising applications.

Tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via RhII‐Catalyzed X–H Insertion Reactions

tert‐Butyl 3‐diazo‐2‐oxopyrrolidine‐1‐carboxylate synthesized on multigram scale has been employed to introduce a privilegedNH‐2‐pyrrolidone moiety via oxygen, sulfur and nitrogen atom to partner molecules via RhII‐catalyzed X–H insertion followed by Boc group removal. Further manipulation of pyrrolidine moiety has been exemplified.

Convenient Approach to 2‐Substituted (Thio)morpholin‐3‐ones from α‐Diazoacetates via X‐H Carbene Insertion – Lactamization Sequence

Stepwise coupling of N‐Boc‐protected β‐aminoethanols or β‐mercaptoethylamines with various α‐diazoacetates provides a new, unified approach to constructing (thio)morpholin‐3‐ones. The process involves a Rh2(esp)2‐catalyzed X‐H insertion reaction, Boc group removal and ambient‐temperature lactamization and is conveniently conducted in one‐pot format.

Surface charge of well-defined polymeric nano-stars regulates non-invasive fluorescence imaging of lymph node

Accurate identification of sentinel lymph node (SLN) is crucial for clinical SLN biopsy surgery. Herein, we developed an innovative nanoprobe based on well-defined core crosslinked star (CCS) polymers for non-invasive fluorescence imaging of SLN. A well-defined biodegradable CCS polymer comprising multiple polyethylene glycol (PEG) arms and carboxyl terminal groups (denoted as CCS-COOH) was synthesized successfully by reversible addition-fragmentation chain transfer polymerization with a disulfide-based crosslinker reagent. Besides, CCS-COOH was coupled by tert-butyl carbazate to produce the CCS derivative with neutral butoxycarbonyl (Boc) terminal groups (denoted as CCS-Boc). By the removal of Boc groups, another CCS derivative with positive primary amino terminal groups (denoted as CCS-NH2) was also yielded. These CCS polymers had similar particle size but different surface charge. For SLN fluorescence imaging, the CCS polymers labeled by CY7, a near-infrared probe, exhibited superior in vitro photo-stability to CY7 alone. After intradermal injection of the CY7-labeled CCS polymers in a mouse model, they could efficiently accumulate in the lymph node of the mouse. CY7-labeled CCS-COOH having negatively-charged surface displayed longer duration time and higher fluorescence intensity in the lymph node as compared to its counterparts with neutral or positive charge surface. In vitro and in vivo toxicity tests supported low cytotoxicity of these CCS polymers against cell lines and low systemic toxicity. The results of this work highlight the potential of negatively-charged near-infrared-emitting CCS polymer as a new nanoprobe for safe and efficient SLN imaging.

RAFT derived fatty acid based stimuli responsive fluorescent block copolymers as DNA sensor and cargo delivery agent

Novel capric acid-tryptophan based block copolymers with unique self-assembled feature and fluorescence property have been synthesized via reversible addition fragmentation chain transfer polymerization (RAFT) polymerization. For employing the copolymerization, at first the fatty acid based methacrylate monomer has been efficiently polymerized in presence of 4-cyano-4-(thiobenzylthio)pentanoic acid (CTP) as chain transfer agent (CTA) via RAFT polymerization. The polymerization has been preceded in a controlled fashion as confirmed by their narrow polydispersity and molecular weight determination from several methods. The capric acid based polymer then exploited as macro-CTA to synthesize the copolymers of poly(2-(methacryloyloxy)ethyl caprylate)-block-poly(tert-butyloxycarbonyl tryptophan methacryloyloxyethyl ester) (PCRMA-b-P(Boc-Trp-HEMA)) with variable block length of amino acid segment. Removal of Boc group from the amino acid block results in formation of pH responsive cationic polymers soluble in water depending on their block length. The amphiphilic polymer self-assemble in water forming higher ordered structure is then utilized as a scaffold to encapsulate and delivery of anticancer drug doxorubicin. Finally we provide a fatty acid based polymeric DNA sensor that can bind with DNA followed by significant fluorescence quenching.

ChemInform Abstract: Benzo[d]imidazole and Aliphatic α‐Amino Acid Derived Primary Amines in Asymmetric Aldol Reactions.

Starting from essential α-amino acids, four new benzo[ d ]imidazole and alkyl-chain-substituted primary amines were synthesized. The reaction sequence involves activation of the Boc-amino acid carboxylic acid, reaction with o -phenylenediamine, and subsequent cyclization to benzo[ d ]imidazole. N-Methylation and final Boc group removal afforded four new primary amines. The synthesized amines were preliminarily applied as organocatalysts in an asymmetric version of the aldol reaction between 4-nitrobenzaldehyde and acetone/cyclohexanone, achieving chemical yields of 40–64% and ee and de values up to 65 and 96%, respectively.

Facile RAFT synthesis of side-chain amino acids containing pH-responsive hyperbranched and star architectures

This work reports the design and synthesis of amino acid-based hyperbranched polymers via the combination of self-condensing vinyl polymerization (SCVP) and reversible addition–fragmentation chain transfer (RAFT) polymerization from tert-butyl carbamate (Boc)-L-valine acryloyloxyethyl ester (Boc-Val-HEA) and S-(4-vinyl)benzyl S′-butyltrithiocarbonate (VBBT) with variable degrees of branching (DB), molecular weights (Mn), and chain end functionalities. Copolymerization kinetics reveal that the molecular weight increases and the DB decreases linearly with time as the branch length increases with the conversion of the Boc-Val-HEA monomer. These hyperbranched polymers, P(Boc-Val-HEA-co-VBBT), with tuneable Mn and DB have been further employed via successive RAFT polymerizations for the synthesis of star polymers with variable arm numbers and lengths. The removal of Boc groups from the polymers results in water soluble pH-responsive cationic hyperbranched architectures with tuneable pH responsiveness, differing from 6.8–7.5 due to the incorporation of various degrees of hydrophobic chain end functionalities with the variation of monomer feed compositions. Dynamic light scattering (DLS), atomic force microscopy (AFM) and scanning electron microscopy (SEM) reveal the interesting self-assembly of the Boc-deprotected star polymers in aqueous media with amino acid-based cores and water soluble thermoresponsive arms. Below the hydrophilic to hydrophobic transition pH and temperature, star polymers remain as unimers in aqueous solution. However, above the transition pH (and below the transition temperature), they form multi-micellar aggregates, which further fuse together to form larger aggregates above the transition temperature.

Benzo[d]imidazole and Aliphatic α-Amino Acid Derived Primary Amines in Asymmetric Aldol Reactions

Starting from essential α-amino acids, four new benzo[ d ]imidazole and alkyl-chain-substituted primary amines were synthesized. The reaction sequence involves activation of the Boc-amino acid carboxylic acid, reaction with o -phenylenediamine, and subsequent cyclization to benzo[ d ]imidazole. N-Methylation and final Boc group removal afforded four new primary amines. The synthesized amines were preliminarily applied as organocatalysts in an asymmetric version of the aldol reaction between 4-nitrobenzaldehyde and acetone/cyclohexanone, achieving chemical yields of 40–64% and ee and de values up to 65 and 96%, respectively.

Se-(9-Fluorenylmethyl) Selenoesters; Preparation, Reactivity, and Use as Convenient Synthons for Selenoacids

Se-(9-Fluorenylmethyl) selenoesters are readily prepared, stable precursors to selenocarboxylates, which they liberate on treatment with DBU. Fm selenoesters are compatible with the use of TFA for the removal of Boc groups and with simple peptide bond forming reactions. Amino acid derived selenocarboxylates condense directly with amines to give amides, react smoothly with isocyanates and isothiocyanates to give amides, and couple with electron-deficient azides also to give amides.

Formal Synthesis of Aspidospermidine via the Intramolecular Cascade Transannular Cyclization

A formal synthesis of aspidospermidine is reported through a novel preparation of Stork’s penultimate tricyclic ketone intermediate. The key steps of the synthesis consist of an intramolecular cascade transannular cyclization, triggered by the removal of Boc group, which simultaneously forms the C, D, and E rings of aspidospermidine and conveniently setting up the quaternary stereo­center via decarboxylative alkylation reaction of the β-keto ester.

Improved Synthesis of No-Carrier-Added [*I]MIBG and Its Precursor

3-(Trimethylstannyl)benzyl alcohol was coupled in a Mitsunobu reaction with bis(Boc)-guanidine to give bis(Boc)-protected 3-(trimethylstannyl)benzylguanidine used as precursor for [*I]MIBG. Radioiodination with [¹³¹I]iodine generated from [¹³¹I]NaI and chloramine-T, removal of Boc groups, and purification by HPLC gave no-carrier-added tracer [*I]MIBG (81% radiochemical yield, 99% chemical purity) used for imaging tumors of neuroendocrine origin. The structures of bis(Boc)-guanidine and bis(Boc)-protected 3-(trimethylstannyl)benzylguanidine were secured by single crystal X-ray structure analyses.

Functionalized microgels with acid-cleavable hydrophobic pendant moiety for controlled drug release

Thermosensitive microgels with acid cleavable pendant t -butoxycarbonyl (Boc) groups were prepared through precipitation copolymerization of N -isopropylacrylamide (NIPAAm) and N -( N -Boc-ethylenediamine) methacryloylglycylglycylamide (BEMAGG) with pendent Boc group. The physicochemical characteristics and the drug release behavior from the microgels were greatly influenced by the structural changes upon the removal of Boc groups in acid condition. The size, zeta potentials and the cloud point gradually increased with the acid-triggered removal of the pendant Boc groups from the microgels, which resulted in a much faster drug release of doxorubicin hydrochloride from these microgels in acid condition. These results indicated the great potentials of these functional microgels in the drug delivery systems.

High yielding selective access to spirocyclopropanated 5-oxopiperazine-2-carboxylates and 1,4-diazepane-2,5-diones from methyl 2-chloro-2-cyclopropylideneacetate

The 2-spirocyclopropanated methyl 5-oxopiperazine-2-carboxylate and the 3-spirocyclopropanated 6-chloro-1,4-diazepane-2,5-dione could both be prepared at choice in 93 and 88% yield, respectively, from methyl 2-chloro-2-cyclopropylideneacetate () in a sequence of Michael addition of 3-benzyloxypropylamine, peptide coupling with N-Boc-glycine, Boc-group removal and cyclization. Transformation of the benzyloxypropyl side chain, peptide coupling with N-Boc-(S)-asparagine, deprotection and repeated cyclization led to the octahydro[2H]pyrazino[1,2-a]pyrazinetrione scaffold containing a rigidified mimic of a tripeptide with a DGR motif. The overall yield of after deprotection of (a total of 13 steps in 8 distinct operations) was 30%.

Synthesis of N,N‐Ac,Boc Laurylthio Sialoside and Its Application to O‐Sialylation.

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1,3,5-Trisubstituted 1,4-Diazepin-2-ones

Six 1,3,5-trisubstituted 1,4-diazepin-2-ones were synthesized by a sequence featuring the cascade addition of vinyl Grignard to N-[Boc-aminoacyl]-N-alkyl-beta-amino esters, followed by Boc group removal and annulation by a reductive amination. Relative to the parent sequence employing N-Boc-aminoacyl beta-amino esters to make 3,5-disubstituted heterocycle, the additional N-alkyl substituent caused a noticeable acceleration and gave relatively higher yield in the 1,4-diazepin-2-one annulation.

Synthesis of N, N-Ac,Boc laurylthio sialoside and its application to O-sialylation

The combination of the 5- N- tert-butoxycarbonyl (Boc) group of laurylthio sialoside and cyclopentyl methyl ether (CPME) as a solvent enhanced the reactivity and α-selectivity of the sialyl donor during sialylation. Selective deprotection of the N-Boc group of sialoside, including an acid-sensitive isopropylidene function, was successfully achieved by Yb(OTf) 3–SiO 2. Transformation of N, N-Ac,Boc into an N-acetylglycolyl group of sialoglycoside was easily performed via selective N-deacylation of the mixed Ac- N-Boc carbamate, subsequent Boc group removal, and acylation.