Use Of Protecting Groups Research Articles

Preparation of linear oligosaccharides by a simple monoprotective chemo-enzymatic approach

A monoprotective approach, involving acetyl ester as unique protective group in oligosaccharides synthesis, has been developed. Starting from peracetylated monosaccharides and glycals, by using an efficient and selective chemo-enzymatic ‘one-pot’ strategy (a regioselective hydrolysis catalyzed by immobilized lipases followed by a chemical acyl migration), different carbohydrate acceptors, only protected with acetyl ester, can be achieved. If combined with the use of an acetylated glycosyl donor, the glycosylation reaction with these glycosyl acceptors leads to peracetylated oligosaccharides. These compounds can be directly used as intermediates for the synthesis of glycopeptides used as antitumoral vaccines and, at the end of the process, can be easily fully deprotected in only one step. Thus, these key building blocks have been successfully used in glycosylation reactions for an efficient construction of peracetylated disaccharides, such as the biological relevant lactosamine, in multigram scale. Subsequently, glycosylation with the 3OH-tetraacetyl-α- d-galactose, used as carbohydrate acceptor, allowed the synthesis of a peracetylated N-trisaccharidic precursor of the lacto- N- neo-tetraose antigen. Extending this strategy to a 3OH-di-acetyl galactal, one peracetylated precursor of the T tumor-associated carbohydrate antigen has been synthesized. This efficient approach, characterized by the use of the acetyl ester as only protecting group during all the synthetical steps expected, represents an easy and efficient alternative to the classical synthetic methods in carbohydrate chemistry that involve several protecting group manipulation.

Design and Synthesis of Dendritic Molecular Transporter that Achieves Efficient in Vivo Delivery of Morpholino Antisense Oligo

Safe and efficient in vivo delivery of Morpholino antisense oligos was probably the last and most difficult challenge for the broad application of antisense in animal research and therapeutics. Several arginine-rich peptides effective for in vivo delivery of Morpholino antisense oligos require rather complex and expensive procedures for synthesis and conjugation. This work describes the design and synthesis of a dendritic transporter in a most concise manner where the selection of the core scaffold, functional group multiplication, orthogonal protecting group manipulation, solid phase conjugation, and off-resin perguanidinylation of the transporter structure are all orchestrated for efficient assembly. We utilized triazine as a core to provide a site for on-column conjugation to the Morpholino oligo and to anchor functional side arms which, after extension, multiplication, and deprotection, are subsequently converted from primary amines to the eight guanidinium headgroups that serve for transport across cell membranes. Intravenous administration of the delivery-enabled Morpholino into a splice-reporter strain of transgenic living mice results in de novo expression of splice-corrected green fluorescent protein in a broad range of tissues and organs in those treated mice. This rigorously demonstrates that this new dendritic transporter achieves effective delivery of a Morpholino oligo into the cytosol/nuclear compartment of cells systemically in vivo. The practical conjugation process may overcome any availability limitation for routine use by the scientific community, and the efficient delivery ability of this transporter may advance the application of Morpholino antisense technology in animals.

Vinyl Quinones as Diels−Alder Dienes: Concise Synthesis of (−)-Halenaquinone

A concise asymmetric synthesis of (-)-halenaquinone is described. The synthesis features a diastereoselective Heck cyclization to set a quaternary center as well as a novel intramolecular inverse-electron-demand Diels-Alder reaction involving a vinyl quinone. The synthesis is highly convergent and features a minimal amount of protecting group manipulations.

Chemoselective O-Acylation of Aminoalcohols Catalyzed by a Zinc Cluster

A highly O-selective Zn-cluster-catalyzed transesterification reaction was developed. A change from the usual azaphilic nature of Zn2+ ions to rather oxophilic Zn2+ takes place in the cluster. Selective O-acylation of various amino­alcohols without the use of protective groups was thus possible.

Short Synthesis of a Specifically Perdeuterated Hexaethylene Glycol Terminated Alkanethiol

An oligo(ethylene glycol) terminated alkanethiol being an important building block for self-assembled monolayers was synthesized in three steps with high efficiency and without use of protective groups. The same sequence was utilized to prepare a specifically deuterated congener from an isotope-labeled starting material.

A Carbohydrate-Based Approach for the Total Synthesis of Aculeatin D and 6-epi-Aculeatin D

A concise approach for the total synthesis of aculeatin D and 6-epi-aculeatin D employing differentially protected anti, anti-1,3,5-triol alkyne prepared from alpha-D-glucoheptonic-gamma-lactone derivative is documented. Phenol protecting group manipulation for selective O-debenzylation during the hydrogenation of the diyne intermediate and one-pot phenolic oxidation with concomitant spiroketalization highlight the accomplished total synthesis.

Lipase-mediated synthesis of enantiomeric 2,5,6-trideoxy-2,5-iminohexitols

Syntheses of 2,5,6-trideoxy-2,5-imino-d-alditol (2, 6-deoxy-DADP) and its enantiomer (3) from tri-orthogonally protected derivatives of DADP have been developed employing lipase-mediated kinetic desymmetrization and protecting group manipulations. Thus, and as an example, the starting DADP derivative (4) was transformed into a new symmetrical 2,5-bis(hydroxymethyl)pyrrolidine (6) by sequential N-protection and bis-O-desilylation. The lipase-mediated desymmetrization of 6 was best carried out under acetylation conditions to give (2R)-acetyloxymethyl derivative 7. The absolute configuration and ee of 7 were unambiguously established by chemical correlation with a homochiral sample. Compound 7 was straightforwardly transformed into the target 2,5,6-trideoxy-2,5-iminohexitol 3.

Total Synthesis of (+)‐Alexine by Utilizing a Highly Stereoselective [3+2] Annulation Reaction of an N‐Tosyl‐α‐Amino Aldehyde and a 1,3‐Bis(silyl)propene

A novel route towards the polyhydroxylated pyrrolizidine alkaloid (+)-alexine has been developed. A key step in this synthesis is a highly stereoselective [3+2] annulation reaction of N-Ts-alpha-amino aldehyde 7 a (Ts=tosyl) and 1,3-bis(silyl)propene 8 a for the construction of the polyhydroxylated pyrrolidine subunit of the target molecule. Previous synthetic strategies rely on carbohydrates that require several protecting-group manipulations, thereby making the total number of steps relatively high. The [3+2] annulation strategy compares favorably with carbohydrate-based syntheses and constitutes a highly efficient entry to polyhydroxylated alkaloids.

Total synthesis of an antigenic heptasaccharide motif found in the cell-wall lipooligosaccharide of Mycobacterium gordonae strain 989

An antigenic heptasaccharide motif of the cell-wall glycolipid of Mycobacterium gordonae strain 989 has been synthesized in a linear fashion by using a general glycosylation condition and minimum number of protecting group manipulation. All suitably protected monosaccharide intermediates were prepared from commercially available reducing sugars following some novel methodologies recently developed in our laboratory. Most of the synthetic intermediates were obtained as solid compounds in excellent yields.

Tools and ingredients for the biocatalytic synthesis of carbohydrates and glycoconjugates

The presence of multiple functional groups and stereocentres in carbohydrates and glycoconjugates make them challenging targets for synthesis. Although progress in chemical synthesis and engineering is impressive, there is still a need to selectively introduce and remove protecting groups in the total synthesis of target molecules of increasing complexity. Multiple hydroxyl-groups with similar reactivities have to be differentiated in order to form the desired glycosidic bonds in a regio- and stereospecific way. To complement the existing chemical tools and ingredients, biocatalysts for selective carbon–carbon bond formation and glycosylation reactions have been developed. The availability of auxiliary ingredients like transfer reagents is a prerequisite for the development of viable biocatalytic process steps. In the case of dihydroxyacetone-phosphate-dependent aldolases, e.g. fructose-1,6-bisphosphate aldolase (EC 4.1.2.13), the large-scale availability of dihydroxyacetone-phosphate (DHAP) eliminates the need to synthesize the donor DHAP. For the pyruvate-dependent aldolases, e.g. the N-acetylneuraminic acid aldolase (EC 4.1.3.3) and acetaldehyde-dependent aldolases like the 2-deoxy-d-ribose-5-phosphate aldolase (4.2.1.4), the donors pyruvate and acetaldehyde are also available on a large scale. A broad range of natural and recombinant aldolases have been produced in stable lyophilized form. Recombinant transketolase together with a new synthesis of hydroxypyruvates has provided a platform technology for the preparation of monosaccharides, whereby the carbon backbone is extended by a two-carbon unit (C2-elongation). Natural and recombinant glycosyltransferases have been prepared on a large-scale to establish biocatalytic glycosylations in water as highly regio- and stereospecific reaction methodologies without the need for laborious protecting group manipulations, solubility adaptations and complex synthetic schemes. In order to simplify the synthetic manipulations for specific glycosylations, toolkits for β-1,4-galactosylations, α-1,3-galactosylations and α-1,3-fucosylations have been developed for rapid quantitative conversions. The introduction of matched pairs of biocatalysts and transfer reagents as ingredients together with the optimized reaction methodology as tool provide an important starting point for biocatalytic glycomics.

The Synthesis of the New C-Nucleoside 6-Deazaformycin B

The synthesis of the 6-deaza analogue of formycin B is described, through the condensation of lithiated 4-methoxy-2-methyl-3-trifluoroacetamidopyridine with a suitably protected ribonolactone, dehydration of the resulting hemiacetal, reduction and subsequent ring closure followed by protecting group manipulation.

Syntheses of Lewis(x) and dimeric Lewis(x): construction of branched oligosaccharides by a combination of preactivation and reactivity based chemoselective one-pot glycosylations.

Two asymmetrically branched oligosaccharides, LewisX and dimeric LewisX, were assembled in one pot with high yields and exclusive regio- and stereoselectivities. p-Tolyl thioglycosides were utilized as the sole type of building blocks, thus simplifying the overall synthetic design. The reactivity-independent nature of the preactivation based method allows modular assembly of the dimeric LewisX octasaccharide without the need for tedious protective group manipulation to achieve exact anomeric reactivities.

Carbohydrate Chemistry in the Total Synthesis of Saponins

AbstractSignificant examples relating to the total synthesis of natural saponins with potent biological activities are discussed, with major emphasis on the applicability of contemporary glycosylation and protecting group manipulation protocols to the sophisticated scaffolds of steroids/triterpenes. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

A concise route to the C3–C23 fragment of the macrolide palmerolide A

A concise route to the C3–C23 part of the macrolide palmerolide A was developed. This part features the 7,10,11-trihydroxy sector containing the 8 E-double bond as well as the 14,16-diene subunit. The stereocenter at C-7 originated from a Noyori reduction on alkynone 8. The substrate 16 containing an enyne was obtained via a Claisen rearrangement. The vicinal diol at C10,C11 was created by a Sharpless asymmetric dihydroxylation. After selective protecting group manipulations the propargylic alcohol was reduced with Red-Al to the E-alkylic alcohol 26. The conjugated diene in the fragment 40 resulted from a Stille cross-coupling reaction between the vinylstannane derived from alkyne 30 and the vinyl iodide 39. The latter could conveniently be prepared by an aldol/Wittig strategy.

Synthesis of a tetra- and a trisaccharide related to an anti-tumor saponin “Julibroside J28” from Albizia julibrissin

Simple and convergent synthesis of a tetra- and a trisaccharide portions of an antitumor compound Julibroside J(28), isolated from Albizia julibrissin, that showed significant in vitro antitumor activity against HeLa, Bel-7402 and PC-3M-1E8 cancer cell lines is reported. The tetrasaccharide has been synthesized as its p-methoxyphenyl glycoside starting from commercially available D-glucose, L-rhamnose and L-arabinose. The trisaccharide part has been synthesized from commercially available N-acetyl D-glucosamine, D-fucose and D-xylose using simple protecting group manipulations. Sulfuric acid immobilized on silica has been used successfully as a Brönsted acid catalyst for the crucial glycosylation steps.

S-benzoxazolyl as a stable protecting moiety and a potent anomeric leaving group in oligosaccharide synthesis.

As a part of a program for developing new versatile building blocks for stereoselective glycosylation and convergent oligosaccharide synthesis, we demonstrated that S-benzoxazolyl (SBox) glycosides are stable toward major protecting group manipulations employed in carbohydrate chemistry. On the other hand, they can be glycosidated under relatively mild reaction conditions to afford either 1,2-trans or 1,2-cis-linked disaccharides. Selective and chemoselective activations of the SBox moiety were also proved to be feasible, which was demonstrated by synthesizing a number of oligosaccharide sequences.

Overcoming the Demons of Protecting Groups with Amphoteric Molecules

Synthetic organic chemists have long depended on protecting group manipulations when faced with the challenges of chemoselectivity and functional group incompatibility. Overcoming this dependence will improve the overall efficiency of chemical synthesis. By taking advantage of orthogonally reactive functional groups, amphoteric molecules can afford access not only to more efficient and strategic syntheses but also to the development of novel chemical transformations.

First total synthesis of a pentasaccharide repeating unit of the O-antigen of Hafnia alvei PCM 1529

A pentasaccharide repeating unit of the O-antigen of Hafnia alvei has been synthesized in a concise manner. High yielding glycosylation steps and minimum number of protecting group manipulation steps are the key features of this synthesis. A two-step, one-pot phase transfer oxidation protocol has been applied for the preparation of D-galacturonic acid.

Palladium-Catalyzed Stereoselective Formation of α-O-Glycosides

A novel method for palladium-catalyzed stereoselective formation of alpha-O-glycosides has been developed. This strategy relies on the palladium-biaryl phosphine catalyst-glycal donor complexation to control the anomeric selectivity. It does not depend on the nature of the protecting groups on the substrates, thus eliminating the need for cumbersome protecting group manipulations.

Protecting Group Manipulations on Glycosyl Phosphate Triesters

Glucosyl and mannosyl phosphate triester building blocks were differentially protected by protecting group manipulations on competent glycosyl donors. Dibutyl 3,4‐di‐O‐benzyl‐6‐O‐(fluorenylmethoxycarbonyl)‐2‐O‐pivaloyl‐β‐D‐glucopyranoside phosphate, not accessible by other methods, was prepared this way.