Bioinspired Total Synthesis of Complex Nucleoside Antibiotics A201A,A201D and A201E

Herein, bioinspired total syntheses of A201A, A201D, and A201E based on a previously reported biosynthetic pathway are presented. The challenging 1,2-cis-furanoside, a core structure of the A201 family, was obtained by remote 2-quinolinecarbonyl-assisted glycosylation. We accomplished the total synthesis of A201A and A201E based on the critical 1,2-cis-furanoside moiety through late-stage glycosylation without any interference from basic dimethyl adenosine. We also confirmed the absolute configuration of A201E by total synthesis. This modular synthesis strategy enables efficient preparation of A201 family antibiotics, allowing the study of their structure–activity relationships and mode of action. This study satisfies the increasing demand for developing novel antibiotics inspired by the A201 family.     

Convenient use of ortho-formylphenyl thioglycoside for regioselective conjugation with glycosyl acceptors towards regioselective 1,2-cis-glycosylation

A facile methodology is proposed for regioselective conjugation between glycosyl donors and acceptors towards the development of regioselective 1,2-cis-glycosylation method. ortho-Formylphenyl 1-thio-β-d-galactopyranoside was regioselectively tethered to methyl α-d-glucopyranoside under acidic condition to furnish an 4,6-O-arylidene acetal-linked conjugate. This conjugate can be readily converted to an ether-linked 4-O- or 6-O-derivative by regioselective cleavage of the acetal ring. In the glycosylation reaction, the ether-linked 4-OH conjugate was found to show excellent 1,2-cis selectivity via an intramolecular 1,9-transfer.     

Cover Picture: Regioselective and Stereospecific β-Arabinofuranosylation by Boron-Mediated Aglycon Delivery (Angew. Chem. Int. Ed. 46/2023)

Regio- and stereoselective formation of the 1,2-cis-furanosidic linkage has been in great demand for efficient synthesis of biologically active natural glycosides. In this study, we developed a regioselective and β-stereospecific d -/l -arabinofuranosylation promoted by a boronic acid catalyst under mild conditions. The glycosylations proceeded smoothly for a variety of diols, triols, and unprotected sugar acceptors to give the corresponding β-arabinofuranosides (β-Arbf) in high yields with complete β-stereoselectivity and high regioselectivity. The regioselectivity was completely reversed depending on the optical isomerism of the donor used and was predictable a priori using predictive models. Mechanistic studies based on DFT calculations revealed that the present glycosylation occurs through a highly dissociative concerted S_Ni mechanism. The usefulness of the glycosylation method was demonstrated by the chemical synthesis of trisaccharide structures of arabinogalactan fragments.     

Facile Access to cis‐2,6‐Disubstituted Tetrahydropyrans by Palladium‐Catalyzed Decarboxylative Allylation: Total Syntheses of (±)‐Centrolobine and (+)‐Decytospolides A and B

cis‐2,6‐Tetrahydropyran is an important structural skeleton of bioactive natural products. A facile synthesis of cis‐2,6‐disubstituted‐3,6‐dihydropyrans as cis‐2,6‐tetrahydropyran precursors has been achieved in high regio‐ and stereoselectivity with high yields. This reaction involves a palladium‐catalyzed decarboxylative allylation of various 3,4‐dihydro‐2H‐pyran substrates. Extending this reaction to 1,2‐unsaturated carbohydrates allowed the achievement of challenging β‐C‐glycosylation. Based on this methodology, the total syntheses of (±)‐centrolobine and (+)‐decytospolides A and B were achieved in concise steps and overall high yields.     

Total Synthesis of Terpioside B

The first total synthesis of terpioside B ( 1 ) has been accomplished. Key steps include the stereoselective installments of a set of challenging 1,2-cis-glycosidic linkages. Thus, α(1,4)-linked d -galactoside was effectively constructed from a 1,2-anhydrogalactose donor and an unprotected 1,6-anhydrogalactose acceptor by using a boron-mediated aglycon delivery (BMAD) method. In addition, α-l -fucofuranosides were stereoselectively and simultaneously constructed by remote group-assisted 1,2-cis-α-stereoselective glycosylations.     

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.     

Synthesis of 1,2-cis-Configurated Glycosylphosphonates

A synthesis of 1,2-cis-configurated, non-isosteric phosphonate analogues of aldose-1-phosphates is described. Treatment of 1-O-acyl-glycoses 1 , 7 , 13 , and 19 with trialkyl phosphite in the presence of trimethylsilyl trifluoromethanesulfonate gave the 1,2-cis-configurated glycosylphosphonates 2 , 4 , 8 , 10 , 14 , 16 , 20 , and 22 as the major anomers and the 1,2-trans-configurated glycosylphosphonates 3 , 5 , 9 , 11 , 15 , 17 , 21 , and 23 as the minor anomers. The 1,2-cis-configurated phosphonates 4 , 10 , 16 , and 22 were deprotected to give the (β-D -glucopyranosyl)phosphonate 6 , the (β-D -mannopyranosyl)phosphonate 12 , the (β-D -ribofuranosyl)phosphonate 18 , and the (β-D -arabinofuranosyl)phosphonate 24 , respectively, in high yields. The preferred formation of 1,2-cis-configurated phosphonates is explained by postulating an equilibrium between the anomeric phosphonium-salt intermediates (such as 25 and 26 ) and a stabilization of the cis-configurated salts through formation of a pentacoordinated species (such as 28 ).     

Hydrogen bond-assisted 1,2-cis O-glycosylation under mild hydrogenolytic conditions

A hydrogen bond-assisted α-selective glycosylation reaction by using 4,6-dibenzyloxy-1,3,5-triazin-2-yl (DBT) β-glycosyl donors was developed for the efficient construction of 1,2-cis-α-glycosidic bond in natural products. This method was applied successfully to the direct synthesis of complex oligosaccharide-derived glycolipids with simple protecting chemistry. Mechanistic studies using the NMR spectroscopy and DFT calculation provide a proof of concept for hydrogen bond-assisted glycosylation reaction towards α-specific construction of O-glycosidic linkage.     

Total Synthesis of Tiacumicin B: Study of the Challenging β-Selective Glycosylations**

We give a full account of the total synthesis of tiacumicin B (Tcn-B), a natural glycosylated macrolide with remarkable antibiotic properties. Our strategy is based on our experience with the synthesis of the tiacumicin B aglycone and on unique 1,2-cis-glycosylation steps. We used sulfoxide anomeric leaving-groups in combination with a remote 3-O-picoloyl group on the donors that allowed highly β-selective rhamnosylation and noviosylation that rely on H-bond-mediated aglycone delivery. The rhamnosylated C1–C3 fragment was anchored to the C4–C19 aglycone fragment by a Suzuki–Miyaura cross-coupling. Ring-size-selective Shiina macrolactonization provided a semiglycosylated aglycone that was engaged directly in the noviolysation step with a virtually total β-selectivity. Finally, a novel deprotection method was devised for the removal of a 2-naphthylmethyl ether on a phenol, and efficient removal of all the protecting groups provided synthetic tiacumicin B.     

Benzo- and indoloquinolizine derivatives. VI—configuration and conformation of 4b,5,6,7,8,8a,10,11,16,16b-decahydrodibenz[f,h]indolo[2,3-a]quinolizine diastereoisomers. A 270 MHz 1H NMR study

The synthesis of a D/E cis isomer of the title compound is described. In an attempt to obtain the other D/E cis isomer, epimerisation reactions were studied. The configuration and conformation of the isomers are determined on the basis of their ¹H NMR spectra. The shift of the 16b proton on N-9 protonation indicates the quinolizidine conformation. At 270 MHz, the ABCD system of the C-10 and C-11 methylenes can be analysed. The ²J(C-10H₂), together with the multiplicity of H-8a, allows an unequivocal assignment of a cis-anti-cis structure to the only D/E cis isomer obtained.     

Studies in the Total Synthesis of Himastatin: A Revision of the Stereochemical Assignment

A stereoisomer of the natural product and not himastatin, an unusual dimeric depsipeptide with promising antibiotic and antitumor properties, was obtained from pyrroloindoline anti-cis- 1 . This result led to a revision of the proposed stereostructure. The new stereostructure was confirmed by the total synthesis, which involves stereoselective access to the pyrroloindoline syn-cis- 1 and the 5-hydroxypiperazic acid subunit and features a Stille coupling for the formation of the central carbon–carbon bond.     

Efficient synthesis of the 2-amino-6-chloro-4-cyclopropyl-7-fluoro-5-methoxy-pyrido[1,2-c]pyrimidine-1,3-dione core ring system

An optimized total synthesis of the 2-amino-6-chloro-4-cyclopropyl-7-fluoro-5-methoxy-pyrido[1,2-c]pyrimidine-1,3-dione core structure of a new fluoroquinolone-like class of antibacterial agents is described. This synthesis is highlighted by a nearly quantitative ring-closing reaction to form the pyrido[1,2-c]pyrimidine core. This bicyclic ring system serves as a scaffold for a family of biologically active compounds.     

Results and problems of O-Glycoside synthesis

Considerable problems attend the synthesis of biologically important natural products whose carbohydrate components display a greater or lesser degree of complexity. The present progress report surveys recent developments in the formation of O-glycosidic bonds starting from 1-halo sugars and from sugar 1,2-orthoesters. Particular emphasis is placed on attempts to reach a better understanding of the steric course of glycosylation reactions on the basis of mechanistic considerations. Studies on the silver-salt dependence of the Koenigs-Knorr synthesis led to improvements in preparative applications and to new concepts concerning the reaction course. The introduction of sugar 1,2-orthoesters as glycosylation components has greatly enriched our preparative armoury for the synthesis of trans glycosides. Remarkable progress has also been made in the synthesis of cis glycosides, in part by exploiting novel neighbouring group effects.     

Regioselective and 1,2‐cis‐α‐Stereoselective Glycosylation Utilizing Glycosyl‐Acceptor‐Derived Boronic Ester Catalyst

Regioselective and 1,2‐cis‐α‐stereoselective glycosylations using 1α,2α‐anhydro glycosyl donors and diol glycosyl acceptors in the presence of a glycosyl‐acceptor‐derived boronic ester catalyst. The reactions proceed smoothly to give the corresponding 1,2‐cis‐α‐glycosides with high stereo‐ and regioselectivities in high yields without any further additives under mild reaction conditions. In addition, the present glycosylation method was successfully applied to the synthesis of an isoflavone glycoside.     

Stereoselective synthesis of aryl 1,2-cis-furanosides and its application to the synthesis of the carbohydrate portion of antibiotic hygromycin A

An efficient methodology for the synthesis of aryl 1,2-cis-furanosidic linkages has been developed with 2-quinolinecarbonyl (Quin) group substituted furanose ethyl thioglycosides as glycosyl donors. The method permits a wide range of phenol acceptors to be used, thus resulting in the formation of structurally diverse phenol furanosides in good to excellent chemical yields with complete 1,2-cis anomeric selectivity. The synthetic utility of the approach has been demonstrated by concise preparation of the carbohydrate portion of antibiotic hygromycin A.     

Proton magnetic resonance studies of compounds with bridgehead nitrogen: XXVIII—Stereochemical studies with perhydropyrido[1,2-c] [1,6,3]dioxazocines and 2-alkylperhydropyrido[1,2-c] [1,3,6]oxdiazocines

A series of perhydropyrido[1,2-c][1,6,3]dioxazocines and 2-alkylperhydropyrido[1,2-c][1,3,6]oxdiazocines have been prepared. 6-p-Nitrophenyl-3,4-dimethylperhydropyrido[1,2-c][1,6,3]-dioxazodioxazocine is shown to adopt the cis fused ring conformation in solution with the nitrogen lone pair axial with respect to the piperidine ring. The 2-alkylperhydropyrido[1,2-c][1,3,6]oxdiazocines adopt a similar cis fused ring conformation and with increasing steric requirement of the 2-alkyl substituent the 8-membered ring increasingly favours the chair-chair conformation, rather than the chair–boat conformation favoured by the 2-methyl substituted compound.     

Synthesis and reactions of “biginelli-compounds”. Part I

Various reactions of 2-oxo(or thioxo)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid derivatives (Biginelli-compounds) were investigated. The site of methylation and acylation on 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester 1a and its 2-oxo derivative 9a was studied. The synthesis of pyrimido[2,3-b]thiazines and thiazolo[3,2-a]pyrimidines was accomplished by condensation of 1a with 1,3-and 1,2-dielectrophiles. A Dimroth-like rearrangement yielding 6H-1,3-thiazines can be observed when 1a was treated with dimethylformamide and phosphorus oxychloride. The formation of indeno[1,2-d]pyrimidines can be achieved by intramolecular Friedl-Crafts acylation of 9a and 13 , respectively. Finally a route for the preparation of 4,6-disubstituted-pyrimidine-5-carbonitriles is presented, starting with Biginelli-compound 25 .     

A Stereoselective Glycosylation Approach to the Construction of 1,2-trans-β-d-Glycosidic Linkages and Convergent Synthesis of Saponins

Conventional syntheses of 1,2-trans-β-d - or α-l -glycosidic linkages rely mainly on neighboring group participation in the glycosylation reactions. The requirement for a neighboring participation group (NPG) excludes direct glycosylation with (1→2)-linked glycan donors, thus only allowing stepwise assembly of glycans and glycoconjugates containing this type of common motif. Here, a robust glycosylation protocol for the synthesis of 1,2-trans-β-d - or α-l -glycosidic linkages without resorting to NPG is disclosed; it employs an optimal combination of glycosyl N-phenyltrifluroacetimidates as donors, FeCl₃ as promoter, and CH₂Cl₂/nitrile as solvent. A broad substrate scope has been demonstrated by glycosylations with 12 (1→2)-linked di- and trisaccharide donors and 13 alcoholic acceptors including eight complex triterpene derivatives. Most of the glycosylation reactions are high yielding and exclusively 1,2-trans selective. Ten representative, naturally occurring triterpene saponins were thus synthesized in a convergent manner after deprotection of the coupled glycosides. Intensive mechanistic studies indicated that this glycosylation proceeds by S_N2-type substitution of the glycosyl α-nitrilium intermediates. Importantly, FeCl₃ dissociates and coordinates with nitrile into [Fe(RCN)_nCl₂]⁺ and [FeCl₄]⁻, and the ferric cationic species coordinates with the alcoholic acceptor to provide a protic species that activates the imidate, meanwhile the poor nucleophilicity of [FeCl₄]⁻ ensures an uninterruptive role for the glycosidation.     

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.     

A New Synthesis of Benzylidene Acetals

Aryl-halo-diazirines react under basic conditions with 1,3-cis-, 1,2-cisand 1,2-trans-diols to give acetals. Yields are high. Diastereoselectivities depend upon the diol and upon the reaction conditions. Thus, reaction of the 1,3-cis-diol 1 (Scheme 1) with 2 gave 3 as a single diastereoisomer. The 1,2-cis-diols 4 and 7 led to the endo- and exo-acetals 5 / 6 (93:7) and 8 / 9 (ca.10:1), respectively, The 1,2-trans-diols 10 , 16 , and 19 reacted with 2 to afford 11 / 12 (90:10), 17 / 18 (1:1), and 20 / 21 (6:1), respectively. Reaction of the (4-nitrophenyl)diazirine 13 with 10 at higher temperatures yielded 14 / 15 (6:4). The uracil moiety, the acetamido group, and the enol-ether moiety are compatible with the reaction conditions. The diastereoselectivity is rationalized on the basis of a reaction sequence involving alkoxy-halogen exchange, which is regioselective or not, thermolysis of the ensuing alkoxydiazirine(s), protonation of the alkoxycarbene to form an (E)-configurated oxycarbenium ion, and attack of the neighboring oxy or hydroxy group, which is only possible for a limited range of conformers.