Synthesis of 2,4,5-triaminocyclohexanecarboxylic acid as a novel 2-deoxystreptamine mimic

Since aminoglycosides have been known to exert their antibacterial activities by binding to various RNA targets, 2-deoxystreptamine served as a particularly important model in understanding RNA-small molecule interaction. Herein, 2,4,5-triaminocyclohexanecarboxylic acid was prepared as a novel 2-deoxystreptamine (2-DOS) mimic, which replaces highly flexible glycosidic bonds of aminoglycosides with amide bonds and may improve binding selectivity toward RNA targets through increased rigidity and additional hydrogen-bonding capability. This unnatural g-amino acid can also be used as a potential component for synthetic foldamers.     

The neomycin biosynthetic gene cluster of Streptomyces fradiae NCIMB 8233: genetic and biochemical evidence for the roles of two glycosyltransferases and a deacetylase

An efficient protocol has been developed for the genetic manipulation of Streptomyces fradiae NCIMB 8233, which produces the 2-deoxystreptamine (2-DOS)-containing aminoglycoside antibiotic neomycin. This has allowed the in vivo analysis of the respective roles of the glycosyltransferases Neo8 and Neo15, and of the deacetylase Neo16 in neomycin biosynthesis. Specific deletion of each of the neo8, neo15 and neo16 genes confirmed that they are all essential for neomycin biosynthesis. The pattern of metabolites produced by feeding putative pathway intermediates to these mutants provided unambiguous support for a scheme in which Neo8 and Neo15, whose three-dimensional structures are predicted to be highly similar, have distinct roles: Neo8 catalyses transfer of N-acetylglucosamine to 2-DOS early in the pathway, while Neo15 catalyses transfer of the same aminosugar to ribostamycin later in the pathway. The in vitro substrate specificity of Neo15, purified from recombinant Escherichia coli, was fully consistent with these findings. The in vitro activity of Neo16, the only deacetylase so far recognised in the neo gene cluster, showed that it is capable of acting in tandem with both Neo8 and Neo15 as previously proposed. However, the deacetylation of N-acetylglucosaminylribostamycin was still observed in a strain deleted of the neo16 gene and fed with suitable pathway precursors, providing evidence for the existence of a second enzyme in S. fradiae with this activity.     

Ready protease-catalyzed synthesis of carbohydrate-amino acid conjugates

The protease-catalyzed synthesis of amino acid est-carbohydrate conjugates as glycopeptide analogues has been achieved in a highly regioselective and carbohydrate-specific manner using amino acid vinyl ester acyl donors and minimally or completely unprotected carbohydrate acyl acceptors, which together probed active sites of proteases to reveal yield efficiencies that are modulated by the carbohydrate C-2 substitutent, and that may be exploited to allow selective one-pot syntheses.     

Reductive Amination of the Lysine N ε-Amino Group Leads to a Bivalent Glyco-Amino Acid Building Block Suited for SPPS

Aiming at the synthesis of structurally altered glycopeptides to probe multivalency effects in carbohydrate recognition, a glyco-amino acid building block was prepared, carrying a bivalent carbohydrate branching unit. This new mannosylated lysine derivative was shown to be fully suitable for solid-phase peptide synthesis.     

Modular Synthesis of Nona-Decasaccharide Motif from Psidium guajava Polysaccharides: Orthogonal One-Pot Glycosylation Strategy

The synthesis of long, branched, and complex carbohydrate sequences remains a challenging task in chemical synthesis. Reported here is an efficient and modular one-pot synthesis of a nona-decasaccharide and shorter sequences from Psidium guajava polysaccharides, which have the potent α-glucosidase inhibitory activity. The synthetic strategy features: 1) several one-pot glycosylation reactions on the basis of N-phenyltrifluoroacetimidate (PTFAI) and Yu glycosylation to streamline the chemical synthesis of oligosaccharides, 2) the successful and efficient assembly sequences (first O3′, second O5′, final O2′) toward the challenging 2,3,5-branched Araf motif, 3) the stereoselective 1,2-cis-glucosylation by reagent control, and 4) the convergent [6+6+7] one-pot coupling reaction for the final assembly of the target nona-decasaccharide. This orthogonal one-pot glycosylation strategy can streamline the chemical synthesis of long, branched, and complicated carbohydrate chains.     

De novo synthesis of aceric acid and an aceric acid building block

The de novo synthesis of an aceric acid thioglycoside building block and the total synthesis of the plant carbohydrate aceric acid are described via a highly convergent strategy. Aldol reaction of acetaldehyde and a protected tartaric acid derivative provided the open chain carbohydrate. Subsequent acid treatment yielded the aceric acid thioglycoside in 35% total yield over five steps. Oxidative cleavage of the thioketal in the open chain carbohydrate and basic hydrolysis of the methyl ester furnished fully deprotected aceric acid in 31% yield over six steps.     

生物有机化学及合成化学界面之最新探索: 生物系统中醣识别研究之化学-酶催化探讨

此报告叙述醣中介细胞粘附最近之研究工作, 其中包括合成之新方法发展,细胞粘附过程中牵连之酶抑制及仿醣之设计及合成。     

Total synthesis of everninomicin 13,384-1--Part 4: explorations of methodology; stereocontrolled synthesis of 1,1'-disaccharides, 1,2-seleno migrations in carbohydrates, and solution- and solid-phase synthesis of 2-deoxy glycosides and orthoesters

Methods for the stereocontrolled construction of 1,1'-disaccharides, 2-deoxy glycosides, and orthoesters are reported. Specifically, a tin-acetal moiety was utilized to fix the anomeric stereochemistry of a carbohydrate acceptor leading to an efficient and stereoselective synthesis of 1,1'-disaccharides, while a newly discovered 1,2-phenylseleno migration reaction in carbohydrates opened entries to 2-deoxy glycosides and orthoesters. Thus, reaction of 2-hydroxy phenylselenoglycosides with DAST led to 2-phenylselenoglycosyl fluorides which reacted with carbohydrate acceptors to afford, stereoselectively, 2-phenylselenoglycosides. The latter compounds could be reductively deselenated to 2-deoxy glycosides or oxidatively converted to orthoesters via the corresponding ketene acetals.     

Modular Synthesis of Nona‐Decasaccharide Motif from Psidium guajava Polysaccharides: Orthogonal One‐Pot Glycosylation Strategy

The synthesis of long, branched, and complex carbohydrate sequences remains a challenging task in chemical synthesis. Reported here is an efficient and modular one‐pot synthesis of a nona‐decasaccharide and shorter sequences from Psidium guajava polysaccharides, which have the potent α‐glucosidase inhibitory activity. The synthetic strategy features: 1) several one‐pot glycosylation reactions on the basis of N‐phenyltrifluoroacetimidate (PTFAI) and Yu glycosylation to streamline the chemical synthesis of oligosaccharides, 2) the successful and efficient assembly sequences (first O3′, second O5′, final O2′) toward the challenging 2,3,5‐branched Araf motif, 3) the stereoselective 1,2‐cis‐glucosylation by reagent control, and 4) the convergent [6+6+7] one‐pot coupling reaction for the final assembly of the target nona‐decasaccharide. This orthogonal one‐pot glycosylation strategy can streamline the chemical synthesis of long, branched, and complicated carbohydrate chains.     

Facile and stereo-controlled synthesis of 2-deoxynojirimycin, Miglustat and Miglitol

A novel and facile synthesis of a series of the biologically significant iminosugar derivatives including 2-deoxynojirimycin, Miglustat and Miglitol is reported. The synthesis features a strategic double inversion mechanism for securing the desired stereochemistry at C5 position of such glucose-type carbohydrate mimetics, representing a practical and remarkable improvement on the previously reported method that suffers from the loss of the stereo-control during the reaction process.     

Adventures in Carbohydrate Chemistry: New Synthetic Technologies, Chemical Synthesis, Molecular Design, and Chemical Biology A list of abbreviations can be found at the end of this article. Telemachos Charalambous was an inspiring teacher at the Pancyprian Gymnasium, Nicosia, Cyprus

The field of carbohydrate chemistry has occupied the minds and hearts of many scientists for over a hundred years and, as we enter the twenty-first century, it continues to be both vigorous and challenging. Among the most exciting aspects of organic chemistry in the last few decades has been the interplay between the specialized subdisciplines of carbohydrate chemistry and total synthesis, each enabling and advancing the other in new directions and towards greater heights. In this review article we highlight our own adventures at the interface of these disciplines, which were driven for the most part by objectives in chemical synthesis and chemical biology. Specifically, we describe our interests and efforts to utilize carbohydrates as starting materials for total synthesis, to invent and develop new synthetic technologies for carbohydrate synthesis, to construct complex oligosaccharides in solution or on solid support, and to utilize carbohydrate templates as scaffolds for peptide mimetics and for molecular diversity construction. Finally, applications of the developed synthetic strategies and enabling technologies towards the solution of biologically significant problems are discussed.     

A convenient synthesis of orthogonally protected 2-deoxystreptamine (2-DOS) as an aminocyclitol scaffold for the development of novel aminoglycoside antibiotic derivatives against bacterial resistance

The development of new aminoglycoside analogues to reduce the emergence of bacterial resistance has become a topic of high interest. We describe here a rapid and facile access to orthogonally protected 2-deoxystreptamine (2-DOS), a meso-diaminocyclitol known to be a pivotal component of most active aminoglycosides. Our synthetic approach started from highly protected methyl alpha-D-glucopyranoside which in turn was converted by a Ferrier rearrangement into an enantiopure polyfunctionalized cyclohexane ring. Finally, two different N-protected groups were successively introduced. The first one was inserted as an oximino benzylether followed by a diastereofacial hydride reduction, working with Me(4)NBH(OAc)(3) only in TFA at low temperature rather than in AcOH as usual. The second group was introduced by displacement of a hydroxyl group through a Mitsunobu reaction using a DPPA-DIAD-Ph(3)P system for azide transfer.     

A concise synthesis of sugar isoxazole conjugates

A synthesis of novel 3,5-disubstituted isoxazole–carbohydrate conjugates is described. The title compounds are obtained from 3-deoxy-3-C-nitromethyl derivatives of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose via nitrile oxide intermediates. The developed approach provides the first examples of isoxazolyl sugars where the azole fragment is attached to C(3) of the carbohydrate through a C–C bond. Isoxazoles can be valuable linkers in glycoconjugate chemistry and this is demonstrated by the synthesis of a glycocluster containing five carbohydrate residues attached to a central glucose platform.     

Direct one-pot highly enantioselective assembly of polyketide and carbohydrate synthons

A short, direct, catalytic, enantioselective synthesis of polyketide segments and carbohydrates is presented. The novel, direct, one-pot, organocatalytic asymmetric tandem cross-aldol/Horner-Wittig-Emmons reactions assemble polyketide and carbohydrate derivatives in good yield with 93-98% ee. The one-pot catalytic asymmetric tandem reaction was applied to a highly enantioselective formal de novo synthesis of the rare carbohydrate, l-altrose.     

Total synthesis of brasoside and littoralisone

The first total syntheses of littoralisone (1) and brasoside (2) have been achieved in 13 overall steps. Both natural products are forged from a common intermediate which is rapidly assembled using organocatalytic technology, including a proline-catalyzed alpha-aminoxylation and a contra-thermodynamic intramolecular Michael addition. Application of the two-step carbohydrate synthesis technology has enabled to access a selectively substituted glucose derivative for use as an intramolecular cycloaddition tether. This synthesis culminates with an intramolecular [2+2] photocycloaddition that serves to support the proposed biosynthetic origins of 1 from 2.     

Solution and solid-support synthesis of a potential leishmaniasis carbohydrate vaccine

The synthesis of a potential carbohydrate vaccine for the parasitic disease leishmaniasis is described. New solution- and solid-phase synthetic strategies were explored for the assembly of a unique tetrasaccharide antigen found on the Leishmania lipophosphoglycan. An initial solution-phase synthesis relied on thioglycosides as building blocks and the establishment of the central disaccharide from lactal via an oxidation-reduction sequence. A second approach was completed both in solution and on solid support. The solid-phase synthesis relied on assembly from monosaccharide units and was used to evaluate different glycosylating agents in the efficient installation of the galactose beta-(1-->4) mannoside. Glycosyl phosphates proved most successful in this endeavor. This first solid-phase synthesis of the Leishmania cap provided rapid access to the tetrasaccharide in 18% overall yield while requiring only a single purification step. The synthetic cap tetrasaccharide was conjugated to the immunostimulator Pam3Cys to create fully synthetic carbohydrate vaccine 1 and to the carrier protein KLH to form semisynthetic vaccine 2. Currently, both constructs have entered initial immunological experiments in mice targeted at the development of a vaccine against the parasitic disease leishmaniasis.     

Synthesis of a staurosporine analogue possessing a 7-azaindole unit instead of an indole moiety

The synthesis of a new staurosporine analogue possessing a 7-azaindole unit instead of an indole moiety is described. This synthesis could be achieved by coupling a sugar moiety previously tosylated in 2′ position to the azaindolocarbazole aglycone. Nucleophilic substitution on the carbon bearing the tosyl group yielded to the key cyclization leading to a compound in which the carbohydrate part is linked to both indole and azaindole nitrogens.     

A new efficient and practical synthesis of 2-deoxy-l-ribose

An efficient and practical route for large-scale synthesis of 2-deoxy-l-ribose starting from l-ascorbic acid was developed in eight steps without chromatographic purification for all intermediates. Additionally, (2S,3R)-3,4-epoxy-1,2-O-isopropylidenebutane-1,2-diol, a versatile intermediate in carbohydrate synthesis, was also prepared readily in excellent yield as a key intermediate.     

Dynamic Kinetic Stereoselective Glycosylation via RhII and Chiral Phosphoric Acid-Cocatalyzed Carbenoid Insertion to the Anomeric OH Bond for the Synthesis of Glycoconjugates

Chemical synthesis of glycoconjugates is essential for studying the biological functions of carbohydrates. We herein report an efficient approach for the stereoselective synthesis of challenging α-linked glycoconjugates via a Rh^II/chiral phosphoric acid (CPA)-cocatalyzed dynamic kinetic anomeric O-alkylation of sugar-derived lactols via carbenoid insertion to the anomeric OH bond. Notably, we observed excellent anomeric selectivity, excellent diastereoselectivity, broad substrate scope, and high efficiency for this glycosylation reaction by exploring various parameters of the cocatalytic system. DFT calculations suggested that the anomeric selectivity was mainly determined by steric interactions between the C2-carbon of the carbohydrate and the phenyl group of the metal carbenoid, while π/π interactions with the C2−OBn substituent on the carbohydrate substrate play a significant role for diastereoselectivity at the newly generated stereogenic center.     

Synthesis of alpha-fluorosulfonate and alpha-fluorosulfonamide analogues of a sulfated carbohydrate

The first synthesis of sulfonamide and sulfonate analogues of a sulfated carbohydrate in which the ester oxygen of the sulfate is replaced with a CHF or CF2 group is reported. This was accomplished by electrophilic fluorination of the protected sulfonate and sulfonamide precursors. [reaction: see text].