Protecting Group Chemistry Research Articles

Industrial landmarks in the development of sustainable production processes for the β-lactam antibiotic key intermediate 7-aminocephalosporanic acid (7-ACA)

Reflecting its importance as key intermediate for the large scale manufacture of β-lactam-type antibiotic drugs being widely used in antibacterial therapy, tremendous achievements have been made over the past decades in developing both, economically and ecologically attractive production routes for 7-aminocephalosporanic acid (7-ACA). Representative achievements and industrial landmarks thereof are described in this review. With cephalosporin C a starting material being accessible through fermentation is readily available in bulk quantities. Initially a chemical production process in organic medium based on various reagents for protection group chemistry and acyclic amide activation served as the large scale production technology for transforming cephalosporin C into 7-ACA. Subsequently, a bi-enzymatic production in aqueous reaction medium based on the use of a D-amino acid oxidase for side chain modification and glutaryl acylase for side chain cleavage was developed. This biocatalytic approach also turned out as an industrial scale solution and dramatically reduced the amount of waste from 31kg (for the "original chemical process") to less than 1kg. The latest innovation has been the extension of the two-step bi-enzymatic process towards a one-step monoenzymatic process based on a direct cleavage of the acyclic amide bond of cephalosporin C by means of a cephalosporin C acylase. This alternative, economically efficient and sustainable biotechnological process has already been established on industrial scale in recent years. These biotechnological achievements represent industrial landmarks in biocatalysis and examples that modern biocatalysis can contribute to the development and implementation of highly economical as well as sustainable industrial manufacturing processes.

Modular and Stereodivergent Approach to Unbranched 1,5,9,n-Polyenes: Total Synthesis of Chatenaytrienin-4.

An iterative strategy for the stereodivergent synthesis of unbranched 1,5,9,n-polyenes (and -polyynes) was investigated. Starting from a terminal alkyne the iteration cycle consists of a C3 extension (allylation), a chemoselective hydroboration, an alkyne reduction, and an oxidation of the associated alcohol with subsequent C1 homologation. Double bond geometry is controlled using stereoselective alkyne reductions, employing either the Lindlar hydrogenation protocol or an aluminum hydride reduction. In a model sequence it was demonstrated that the strategy is applicable to the synthesis of 1,5,9,n-polyenes with any possible double bond configuration accessible in equally high efficiency and selectivity. It is worth noting that our approach does not require any protecting group chemistry. Furthermore, using the same strategy, the first total synthesis of chatenaytrienin-4, the proposed unsaturated biosynthetic precursor of the bis-THF acetogenin membranacin, was examined. Thus, the all-cis 1,5,9-triene natural product was prepared in 15 steps from commercially available starting materials in 6% overall yield.

New Dioxaborolane Chemistry Enables [(18)F]-Positron-Emitting, Fluorescent [(18)F]-Multimodality Biomolecule Generation from the Solid Phase.

New protecting group chemistry is used to greatly simplify imaging probe production. Temperature and organic solvent-sensitive biomolecules are covalently attached to a biotin-bearing dioxaborolane, which facilitates antibody immobilization on a streptavidin-agarose solid-phase support. Treatment with aqueous fluoride triggers fluoride-labeled antibody release from the solid phase, separated from unlabeled antibody, and creates [(18)F]-trifluoroborate-antibody for positron emission tomography and near-infrared fluorescent (PET/NIRF) multimodality imaging. This dioxaborolane-fluoride reaction is bioorthogonal, does not inhibit antigen binding, and increases [(18)F]-specific activity relative to solution-based radiosyntheses. Two applications are investigated: an anti-epithelial cell adhesion molecule (EpCAM) monoclonal antibody (mAb) that labels prostate tumors and Cetuximab, an anti-epidermal growth factor receptor (EGFR) mAb (FDA approved) that labels lung adenocarcinoma tumors. Colocalized, tumor-specific NIRF and PET imaging confirm utility of the new technology. The described chemistry should allow labeling of many commercial systems, diabodies, nanoparticles, and small molecules for dual modality imaging of many diseases.

Iterative protecting group-free cross-coupling leading to chiral multiply arylated structures.

The Suzuki–Miyaura cross-coupling is one of the most often utilized reactions in the synthesis of pharmaceutical compounds and conjugated materials. In its most common form, the reaction joins two sp2-functionalized carbon atoms to make a biaryl or diene/polyene unit. These substructures are widely found in natural products and small molecules and thus the Suzuki–Miyaura cross-coupling has been proposed as the key reaction for the automated assembly of such molecules, using protecting group chemistry to affect iterative coupling. We present herein, a significant advance in this approach, in which multiply functionalized cross-coupling partners can be employed in iterative coupling without the use of protecting groups. To accomplish this, the orthogonal reactivity of different boron substituents towards the boron-to-palladium transmetalation reaction is exploited. The approach is illustrated in the preparation of chiral enantioenriched compounds, which are known to be privileged structures in active pharmaceutical compounds.

Protecting-Group-Free Synthesis of Well-Defined Glycopolymers Featuring Negatively Charged Oligosaccharides.

Control of the macromolecular architecture is essential to enable sophisticated functions for glycopolymers and to allow a precise correlation between these functions and the polymer structure. A number of biologically important ligands are negatively charged oligosaccharides that are difficult to manipulate in organic solvent and that are hardly amenable to protection/deprotection strategies. RAFT polymerization is a simple and robust technique that enables the synthesis of well-defined glycopolymers directly in aqueous solution and starting from unprotected vinyl glycomonomers. Here I describe how RAFT polymerization can be combined with reductive amination to transform negatively charged oligosaccharides having 5-20 monosaccharide units into well-defined glycopolymers directly in water and without the need to resort to protecting-group chemistry.

On the Orthogonality of Two Thiol-Based Modular Ligations.

The chemoselectivity of two thiol-based modular ligations operating under mild conditions is assessed. For this purpose, a macromolecular scaffold possessing allyl and pentafluorophenyl groups in two distinct parts is employed, which enables facile characterization by NMR spectroscopy ((1)H and (19)F) and size-exclusion chromatography. By using appropriate triggers (introduction of a base or light irradiation), it is possible to direct thiols to an arbitrarily chosen part of the scaffold, without any change to the other part and with no involvement of protecting group chemistry. Dual functionalization experiments are achieved by applying these triggers consecutively with no consideration of the reaction sequence order, evidencing full bidirectionality. A set of one-pot, purification-free procedures that enable near-quantitative to full dual functionalization in (very) short reaction times (17-180 min) is also presented.

ChemInform Abstract: Soft Ruthenium and Hard Broensted Acid Combined Catalyst for Efficient Cleavage of Allyloxy Bonds. Application to Protecting Group Chemistry.

AbstractThe facile protocol allows the quantitative removal of allyl protecting group from ethers, esters, carbonates, and carbamates.

Epicyanohydrin: Polymerization by Monomer Activation Gives Access to Nitrile-, Amino-, and Carboxyl-Functional Poly(ethylene glycol)

Both homo- and copolymerization of the hitherto nonpolymerizable epoxide monomer epicyanohydrin (EPICH) with ethylene oxide (EO) have been studied, employing the monomer activation technique. Tetraoctylammonium bromide or tetrabutylammonium iodide was used as initiator combined with i-Bu3Al to activate the EPICH monomer. The EPICH content was varied from 4 to 16 mol %, yielding well-defined PEG-co-PEPICH copolymers with molecular weights Mn (SEC) ranging from 3700 to 8800 g mol–1. The nitrile groups of the resulting polyethers were further reduced or hydrolyzed to introduce amino, amide, or carboxyl groups at the polyether backbone, circumventing protecting group chemistry. Successful transformation of the functional groups was proven by SEC measurements, 1H NMR, 13C NMR, and FT-IR spectroscopy. These carboxyl-functional PEG copolymers are anionic polyelectrolytes consisting only of purely aliphatic polyether structures with carboxyl groups. The hydrolyzed PEPICH homopolymers represent the first polyether-based analogues of poly(acrylamide) and poly(acrylic acid). In pronounced contrast to poly(acrylic acid), carboxyl-functional PEPICH shows excellent aqueous solubility even at low pH.

ChemInform Abstract: Amphoteric α‐Boryl Aldehyde Linchpins in the Synthesis of Heterocycles

AbstractReview: 56 refs.

ChemInform Abstract: Chemoselective O‐Acylation of Hydroxyamino Acids and Amino Alcohols under Acidic Reaction Conditions: History, Scope and Applications

AbstractReview: 112 refs.

Amphoteric α-Boryl Aldehyde Linchpins in the Synthesis of Heterocycles

Pairing of mutually reactive functional groups in the same molecule affords enabling opportunities in chemical synthesis. Kinetically amphoteric molecules exemplify this scenario and help avoid the pitfalls of protecting-group chemistry by exploiting the innate reactivity of the functional groups. In this perspective, we highlight the recent development of MIDA (N-methyliminodiacetyl) α-boryl aldehydes as amphoteric building blocks that act as linchpins in the synthesis of heterocycles. This short review includes topics ranging from metal-catalyzed cyclization involving B–C–Pd intermediates to the intramolecular Suzuki–Miyaura cross-coupling that affords six- and seven-membered rings. The use of boryl aldehydes in other transformations, including halogenation and oxidation protocols, is also discussed.

Soft ruthenium and hard Brønsted acid combined catalyst for efficient cleavage of allyloxy bonds. Application to protecting group chemistry

We show that a monocationic CpRu(II) complex of quinaldic acid (QAH) and a monocationic CpRu(IV)(π-allyl)QA complex catalyze efficient cleavage of the allyloxy bond in allyl ethers, allyl esters, allyl carbonates, and allyl carbamates in methanol without the need for additional nucleophiles. The only co-product is volatile allyl methyl ether, enhancing operational simplicity during isolation of the deprotected alcohols, acids, and amines. This clean and high-performance catalytic system should contribute to protecting group chemistry during the multistep synthesis of pharmaceutically important natural products. Full details of this system, including the mechanism, are reported.

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

Amino acids, whether natural, semisynthetic or synthetic, are among the most important and useful chiral building blocks available for organic chemical synthesis. In principle, they can function as inexpensive, chiral and densely functionalized starting materials. On the other hand, the use of amino acid starting materials routinely necessitates protective group chemistry, and in reality, large-scale preparations of even the simplest side-chain 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-dihydroxyphenylalanine (DOPA), many O-acyl side-chain derivatives are directly accessible via a particularly expedient and scalable method not commonly applied until recently. Direct acylation of unprotected hydroxyamino acids with acyl halides or carboxylic anhydrides under appropriately acidic reaction conditions renders possible chemoselective O-acylation, furnishing the corresponding side-chain esters directly, on multigram-scale, in a single step, and without chromatographic purification. Assuming a certain degree of stability under acidic reaction conditions, the method is also applicable for a number of related compounds, such as various amino alcohols and the thiol-functional amino acid cysteine. While the basic methodology underlying this approach has been known for decades, it has evolved through recent developments connected to amino acid-derived chiral organocatalysts to become a more widely recognized procedure for large-scale preparation of many useful side-chain derivatives of hydroxyamino acids and related compounds. Such derivatives are useful in peptide chemistry and drug development, as amino acid amphiphiles for asymmetric catalysis, and as amino acid acrylic precursors for preparation of catalytically active macromolecular networks in the form of soluble polymers, crosslinked polymer beads or nanoparticulate systems. The objective of the present review is to increase awareness of the existence and convenience of this methodology, assess its competitiveness compared to newer and more elaborate procedures for chemoselective O-acylation reactions, spur its further development, and finally to chronicle the informative, but poorly documented history of its development.

Joining Hydroxyazobenzene and Mannose under Mitsunobu Conditions

AbstractThe Mitsunobu reaction has been revisited to join hydroxyazobenzene and mannose derivatives to supply photoswitchable glycoconjugates. These are suited to modulating and controlling carbohydrate‐lectin interactions, as well as to switching bacterial adhesion to surfaces. Employing hydroxyazobenzene in a Mitsunobu protocol, free mannose led to a mixture of azobenzene pyranosides and furanosides. Protected reducing mannose derivatives can give good yields of azobenzene β‐D‐mannopyranoside, and unprotected alkyl α‐D‐mannosides can be converted to 6‐O‐azobenzene‐modified glycosides in a single step. Thus, valuable “sweet switches” can be obtained under Mitsunobu conditions, requiring a minimum (or no) protecting group chemistry.

Synthesis and Self-Assembly of Well-Defined pH-Responsive Block Glycopolymers

Two pH-responsive block glycopolymers, poly (ethylene glycol)-b-Poly (2- (diethylamino) ethyl methacrylate-co-2-gluconamidoethyl methacrylate) (PEG113-b-P(DEA55-co-GAMA12)) and poly (ethylene glycol)-b-poly (2-(diethylamino) ethyl methacrylate)-b-poly (2-gluconamido ethyl methacrylate) (PEG113-b-PDEA55-b-PGAMA15), were synthesized via atom transfer radical polymerization (ATRP) by directly or successively polymerization of GAMA and DEA monomers using a PEG-based macroinitiator, respectively, without protecting group chemistry. Those block glycopolymers were confirmed by proton Nuclear Magnetic Resonance (1H NMR) and Gel Permeation Chromatography (GPC), and their self-assembly behaviors were characterized by Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS) and Zeta-potential. The results show both synthetic block glycopolymers were dissolved molecularly in aqueous solution at acidic pH (such as pH 3), thus it can reversibly convert to be two-layer micelles comprising DEA and GAMA cores, PEG coronas with size of around 50 nm, or micelles comprising DEA cores, GAMA and PEG outer coronas with bigger size of 70 nm for PEG113-b- P(DEA55-co-GAMA12) and PEG113-b-PDEA55-b-PGAMA15), respectively, at basic condition. Both glycopolymers have the micellization process at middle pH (pH 6-8), but possess different isoelectric points (pIs) (at pH 8.0 and 7.8) for their pH responsive block of PEG113-b-P(DEA55-co-GAMA12) and PEG113-b-PDEA55-b-PGAMA15 with DEA-co-GAMA random structure or DEA chain only, respectively. This study not only reveals the self-assembly of pH responsive block glycopolymers with different architectures by fixing similar degree polymerization (DP) of their blocks, but also provides a tool to investigate pH induced dynamic covalent interaction between glycopolymers and phenylboronic acid derivatives or a light for designing novel drug delivery carriers.

ChemInform Abstract: Total Synthesis of Aplykurodinone‐1.

The concise total synthesis of aplykurodinone-1 with an unusual cis-fused hydrindane moiety has been accomplished without the need for any protecting group chemistry using a unique SmI2 mediated reductive cascade cyclization reaction and a direct cuprate mediated 1,4-addition. This work represents the first example of the use of a SmI2-mediated intramolecular cascade cyclization reaction between “halide, alkene and aldehyde” groups.

Silane meets click chemistry: towards the functionalization of wet bacterial cellulose sheets.

The modification of cellulosic materials is of great interest in materials research. Wet bacterial cellulose sheets were modified by an alkoxysilane under mild conditions to make them accessible to click chemistry derivatization. For this purpose (3-azidopropyl)triethoxysilane was grafted covalently onto the cellulosic surface. The silanized bacterial cellulose sheets were characterized comprehensively by attenuated total reflectance FTIR spectroscopy, solid-state NMR spectroscopy, thermogravimetric analysis, SEM with energy-dispersive X-ray spectroscopy, and elemental analysis. To demonstrate subsequent click chemistry functionalization, a new fluorophore based on fluorescein was synthesized and clicked to the silane-modified bacterial cellulose. The new method renders bacterial cellulose and other never-dried cellulosic materials susceptible to direct and facile functionalization in an aqueous medium without the need to work in water-free organic phases or to employ extensive protecting group chemistry and functional group interconversion.

Synthesis and sequential deprotection of triblock copolypept(o)ides using orthogonal protective group chemistry.

The synthesis of triblock copolymers based on polysarcosine, poly-N-ε-t-butyloxycarbonyl-l-lysine, and poly-N-ε-t-trifluoroacetyl-l-lysine by ring-opening polymerization of the corresponding α-amino acid N-carboxyanhydrides (NCAs) is described. For the synthesis of N-ε-t-butyloxycarbonyl-l-lysine (lysine(Boc)) NCAs, an acid-free method using trimethylsilylchloride/triethylamine as hydrochloric acid (HCl) scavengers is presented. This approach enables the synthesis of lysine(Boc) NCA of high purity (melting point 138.3 °C) in high yields. For triblock copolypept(o)ides, the degree of polymerization (Xn ) of the polysarcosine block is varied between 200 and 600; poly-N-ε-t-butyloxycarbonyl-l-lysine and poly-N-ε-t-trifluoroacetyl-l-lysine blocks are designed to have a Xn in the range of 10-50. The polypeptide-polypeptoid hybrids (polypept(o)ides) can be synthesized with precise control of molecular weight, high end group integrity, and dispersities indices between 1.1 and 1.2. But more important, the use of tert-butyloxycarbonyl- and trifluoroacetyl-protecting groups allows the selective, orthogonal deprotection of both blocks, which enables further postpolymerization modification reactions in a block-selective manner. Therefore, the presented synthetic approach provides a versatile pathway to triblock copolypept(o)ides, in which functionalities can be separated in specific blocks.

Cross-metathesis of terminal alkynes.

Terminal acetylenes are amongst the most problematic substrates for alkyne metathesis because they tend to undergo rapid polymerization on contact with a metal alkylidyne. The molybdenum complex 3 endowed with triphenylsilanolate ligands, however, is capable of inducing surprisingly effective cross-metathesis reactions of terminal alkyl acetylenes with propynyl(trimethyl)silane to give products of type R(1)-C≡CSiMe. This unconventional way of introducing a silyl substituent onto an alkyne terminus complements the conventional tactics of deprotonation/silylation and excels as an orthogonal way of alkyne protecting group chemistry for substrates bearing base-sensitive functionalities. Moreover, it is shown that even terminal aryl acetylenes can be cross-metathesized with internal alkyne partners. These unprecedented transformations are compatible with various functional groups. The need to suppress acetylene formation, which seems to be a particularly effective catalyst poison, is also discussed.

Total synthesis of aplykurodinone-1.

The concise total synthesis of aplykurodinone-1 with an unusual cis-fused hydrindane moiety has been accomplished without the need for any protecting group chemistry using a unique SmI2 mediated reductive cascade cyclization reaction and a direct cuprate mediated 1,4-addition. This work represents the first example of the use of a SmI2-mediated intramolecular cascade cyclization reaction between "halide, alkene and aldehyde" groups.