Fully orthogonally protected 2-deoxystreptamine from kanamycin

A fully orthogonally protected and enantiopure 2-deoxystreptamine derivative is prepared in a few straightforward steps from commercially available kanamycin. Resolution of a sterically hindered diacetate was effected by a Verenium esterase and was followed by a chemoselective Staudinger reduction-acylation protocol.     

An efficient synthesis of mimetics of neamine for RNA recognition

As mimetics of neamine, several 4-heterocyclic 2-deoxystreptamine derivatives were chemically synthesized for RNA recognition. Conversion of 4-methylthiomethyl-5,6-di-O-acetyl-diazido-2-deoxystreptamine to the 4-chloromethyl derivative followed by reactions with different nuclophilic reagents gave the 4-heterocyclic 2-deoxystreptamine derivatives in satisfactory yields.     

Efficient preparation of a 1,3-diazidocyclitol as a versatile 2-deoxystreptamine precursor

A synthesis route toward 2-deoxystreptamine, a common structure in many of the clinically important aminoglycosides, is presented. Starting from p-benzoquinone and cyclopentadiene, 2-deoxystreptamine is synthesized with key steps involving Pd(0)-catalyzed rearrangement, a retro-Diels-Alder by flash vacuum thermolysis, and Yb(III)-directed regioselective epoxide opening. The obtained diazidocyclitol 17 is a suitable 2-deoxystreptamine precursor, conveniently protected for incorporation in new aminoglycoside entities.     

Synthesis of orthogonally protected 2-deoxystreptamine stereoisomers

Enantiomerically pure 4,6-diaminocyclohexenols are obtained from carbohydrate derived 1,7-dienes by ring-closing metathesis and palladium catalyzed allylic amination using o-nitrobenzenesulfonylamides as nucleophiles. In the latter reaction the use of a cyclic carbonate as a leaving group proved to be essential to facilitate a smooth substitution. The obtained compounds were converted into orthogonally protected diaminocyclitols, which are stereoisomers of the naturally occurring 2-deoxystreptamine, a constituent of aminoglycoside antibiotics.     

Carbohydrate mimic of 2-deoxystreptamine for the preparation of conformationally constrained aminoglycosides

The synthesis of a carbohydrate mimic of 2-deoxystreptamine (2-DOS) is described starting from d-ribose. Crucial steps of the synthesis involve a stereoselective nitroaldol condensation and deoxygenation via elimination-in situ reduction. Moreover, glycosylation of the carbohydrate 2-DOS derivative with a phenyl thioglycoside donor in the presence of TTBP and AgOTf followed by ring-closing metathesis yielded a conformationally restricted aminoglycoside analogue.     

Mass spectra of partially n-acetylated derivatives of kanamycin a

As part of a program concerned with the chemistry and biochemistry of aminocyclitol antibiotics, a number of selectively N-acetylated kanamycins have been prepared from kanamycin monosulfate and characterized by a study of the electron impact induced fragmentation of two types of derivatives. In one of these, the remaining free amino groups were N-trideuteroacetylated and the N-acylated kanamycins thus obtained, were N.O-methylated. The spectra of these derivatives were useful for the location of the N-acetyl and N-trideu-teroacetyl groups, except in the 2-deoxystreptamine unit. In a second type of derivative, the partially N-acetylated kanamycins were N.O-permethylated converting the free amino groups into dimethylamino groups. In this form, it was possible to locate the site of N-aeelylation on the 2-deoxystreptamine ring. The partially N-acetylated kanamycins have been identified as 1,3,6'-tri-N-acetyl, 3,6',3'-tri-N-acetyl, 3,6'-di-N-acetyl, 1,6'-di-N-acetyl and 6'-N-acetyl kanamycin, from a study of the mass spectra of these two types of derivatives.     

Collisionally activated dissociations of aminocyclitol-aminoglycoside antibiotics and their application in the identification of a new compound in tobramycin samples

Several aminocyclitol-aminoglycoside antibiotics have been studied by tandem mass spectrometry. Glycosidic bond cleavages were the major reactions in the low energy collisionally activated decomposition (CAD) of the protonated antibiotics. Only the glycoside residing on the C6-O of the 2-deoxystreptamine was observed to undergo significant decomposition at the C2-C3 and O-C1 bonds. The comprehension of the CAD of known aminoglycosides aided in the identification of an unknown impurity in tobramycin. The unknown compound was initially detected by reverse phase high-performance liquid chromatography following dinitrofluorobenzene derivatization of the amino groups. The molecular weight of the dinitrobenzene derivative measured by LC mass spectrometry (MS) led to the detection of two isomeric impurities in tobramycin by LC-MS using an amino column. Their CAD spectra were subsequently acquired by LC-MS/MS. One of the two compounds was determined to be a known compound, 6"-O-carbamyltobramycin with the carbamyl group substituted on the glycoside residing on the C6-O of 2-deoxystreptamine. The fragmentation pattern of the other compound was interpreted as that the unknown was also a carbamyltobramycin. The carbamyl group was, however, substituted on 2-deoxystreptamine. It was speculated that the carbamyl group was substituted at the C1 amino group. This compound, to our knowledge, has not been reported before.     

Synthese von selektiv N- funktionalisierten Polyamin-Derivaten

Synthesis of Selectively N-Functionalized Polyamine Derivatives A threefold differently protected derivative 8 of the triamine spermidine ( 2 ) has been prepared in three steps starting from propane-1,3-diamine ( 1 ). The protected spermidine derivative 8 was converted to its spermine analogue 12 , a useful polyamine intermediate. In a convergent way, the fourfold differently protected derivative 18 of the tetraamine spermine ( 3 ) has been obtained by coupling the two different and separately prepared propane-1,3-diamine units 15 and 17 . Spermidine derivative 19 and spermine derivative 20 , both selectively protected at both primary amino groups, have been Prepared from the free polyamines 2 and 3 , respectively, in a direct approach.     

Biosynthesis of Ribostamycin Derivatives by Reconstitution and Heterologous Expression of Required Gene Sets

Ribostamycin is a 4,5-disubstituted 2-deoxystreptamine (DOS)-containing aminoglycoside antibiotics and naturally produced by Streptomyces ribosidificus ATCC 21294. It is also an intermediate in the biosynthesis of butirosin and neomycin. In the biosynthesis of ribostamycin, DOS is glycosylated to generate paromamine which is converted to neamine by successive dehydrogenation followed by amination, and finally ribosylation of neamine gives ribostamycin. Here, we report the biosynthesis of 6′-deamino-6′-hydroxyribostamycin (a ribostamycin derivative or pseudoribostamycin) in Streptomyces venezuelae YJ003 by reconstructing gene cassettes for direct ribosylation of paromamine. A trace amount of pseudoribostamycin was detected with ribostamycin in the isolates of ribostamycin cosmid heterologously expressed in Streptomyces lividans TK24. It has also indicated that the ribosyltransferase can accept both neamine and paromamine. Thus, the present in vivo modification of ribostamycin could be useful for the production of hybrid compounds to defend against bacterial resistance to aminoglycosides.     

Stekeospecific transformation of D-sugar to L-sugar in complex aminoglycoside. Synthesis of a kanamycin B analog having 2,6-diamino-2,4,6-trideoxy-L-arabino-hexopyranose

A 4′-ene derivative of kanamycin B ($\text{4}$) was derived from the epoxide ($\text{1}$) by oxidative elimination of the 4′-phenylseleno group into the allylic alcohol ($\text{3}$). The title compound, 0-(2,6-diamino-2,4,6-trideoxy-β-L-arabino-hexopyranosyl)-(1→4)-0-[3-amino-3-deoxy-α-D-glucopyranosyl-(1→6)]-2-deoxystreptamine ($\text{6}$) was obtained from $\text{4}$ by stereospecific hydrogenation followed by removal of the masking groups, changing the D-sugar moiety of the 4-0-glycoside portion into an L-sugar.     

Synthesis of variolin B

The total synthesis of variolin B from 4-methoxy-7-azaindole is described. The preparation of the protected amino derivative 10 and a coupling reaction of the iodo derivative 12 with 2-acetylamino-4-trimethylstannylpyrimidine are the key steps of the sequence. The use of N-tosyldichloromethanimine for the cyclisation step afforded a good entry to the 9-aminopyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine system. Variolin B was obtained from the triply protected tetracyclic compound 13 in two steps.     

Regiospecific introduction of a branched-chain to kanamycin B and stereospecific transformation of the 2,6-diamino-2,6-dideoxy-D-glucopyranosyl moiety into 2,6-diamino-2,3,4,6-tetradeoxy-3-C-methyl-l-arabino or lyxo-hexopyranosyl,or 2-amino-2,3,4,6-tetradeoxy-5-C-methyl-L-threo-hexopyranosyl

4-O-(2,6-diamino-2,3,4,6-tetradeoxy-3-C-methyl-β-L-arabino and lyxo-hexopyranosyl) and 4-O-(2-amino2,3,4,6-tetradeoxy-5-c-methyl-L-threo-hexopyranosyl-6-O-(3-amino-3-decxy-α-D-glucopyranosyl)-2-deoxystreptamine ($\text{6}$, $\text{7}$ and $\text{12}$) were synthesized from a kanamycin B derivative ($\text{1}$) by regiospecific methylation and stereospecific hydrogenation followed by removal of masking groups, converting a D-sugar moiety (4-O-glycoside portion) into L-sugar. The usual conformation of $\text{6}$ and $\text{7}$ were determined as boat and skew by 250 MHz PMR spectra respectively.     

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.     

Efficient stereocontrolled synthesis of sphingadienine derivatives

Sphinga-4,8-dienines, principal long-chain bases of glycolipids in plants and fungi, were efficiently synthesized from l-serine. Hydrozirconation of pentadec-5-en-1-ynes followed by ZnBr₂-catalyzed addition to Garner's aldehyde afforded protected sphinga-4,8-dienines stereoselectively. The (2S,3R,4E,8E)-9-methyl-sphingadienine derivative was then coupled with 2(R)-acetoxypalmitic acid derivative prepared via asymmetric dihydroxylation to give a protected ceramide, which was converted into the corresponding glucocerebroside in two steps.     

New approach to the stereoselective synthesis of the [4.5] spiroketal moiety of papulacandins

An efficient approach for the stereoselective construction of the spiroketal moiety of papulacandins, based on the condensation of the protected derivative of D-arabino-1,4-lactone 2 with the α-lithiated carbanion of β-phenylsulfonyl dihydrofuran 1, is described.     

Facile preparation of N-protected 2-alkylidene-1,3-imidazolidines

Stereoselective preparation of unsymmetrically protected 2-alkylidene-1,3-imidazolidines was achieved by the reaction of N,N′-protected ethylenediamine, bromopropynamide, and K₃PO₄ in hot DMF. When N-protected aminoethanol was used in place of the protected ethylenediamine, an oxazolidine derivative was produced.     

Synthesis of 3-Aminopyrocatechol via Lithiated Intermediates

We report the synthesis of 3-aminopyrocatechol (7) through electrophilic amination of lithiated pyrocatechol, protected in the form of a ketal. For this purpose the lithiation reaction of protected pyrocatechol (1) was studied. The synthesis of compounds (3) was achieved by the reaction of organolithium derivative (2) and a series of electrophilic reagents. Lithium-t-butyl-N-tosyloxycarbamate (5) was used as the electrophilic aminating reagent. With the cupro derivative (4) the protecting groups in compound (6) are removed in an acid medium by heating in ethanol-HCl solution (4:1).     

The Synthesis of a γ-Keto-α-amino Acid,a Key Intermediate in the Synthesis of Monatin,a New Natural Sweetener

An efficient method was developed for the synthesis of the ketoamino acid 2, a key intermediate in the synthesis of the novel sweet compound, monatin 1. Preparation of 2 entails coupling of a suitably protected indole acetate anion to an aspartic acid derivative.     

A practical synthesis of the peptide part of jaspamide (jasplakinolide), a cyclodepsipeptide from a marine sponge

(S)-Alanyl-(R)-2-bromoabryl-(R)-β-tyrosine found in jaspamide(1) was conveniently synthesized as its protected derivative 2 in good yield.     

Synthesis of p-Trifluoroacetamidophenylethyl O-(2-Acetamido-2-Deoxy-β-D-Galactopyranosyl)-(1→4)-O-β-D- Galactopyanosyl-(1→4)-O-β-D-Glucopyranoside,Containing the Trisaccharide Portion of the Asialo-GM2 Glycolipid

ABSTRACT

The p-trifluoroacetamidophenylethyl β-glycoside 9 of the trisaccharide O-(2-acetamido-2-deoxy-β-D-galactopyranosyl)-(1→4)-O-β-D-galactopyranosyl-(1→4)-D-glucopyranose (gangliotriose, asialo-GM2) was synthesised. The key step was coupling of a suitably protected lactose derivative with a galactosamine thioglycoside derivative using sulfuryl chloride/trifluoromethanesulfonic acid activation.