Synthesis of the branched-chain sugar aceric acid: a unique component of the pectic polysaccharide rhamnogalacturonan-II

Described herein is the synthesis of 3-C-carboxy-5-deoxy-L-xylose (aceric acid), a rare branched-chain sugar found in the complex pectic polysaccharide rhamnogalacturonan-II. The key synthetic step in the construction of aceric acid was the stereoselective addition of 2-trimethylsilyl thiazole to 5-deoxy-1,2-O-isopropylidene-alpha-L-erythro-pentofuran-3-ulose (2), which was prepared from L-xylose. The thiazole group was efficiently converted into the required carboxyl group via conventional transformations. Aceric acid was also synthesized by dihydroxylation of a 3-C-methylene derivative of 2 followed by oxidation of the resulting hydroxylmethyl group. The C-2 epimer of aceric acid was also synthesized using thiazole addition chemistry, starting from L-arabinose.     

Synthesis and evaluation of 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid as a linker in solid-phase synthesis monitored by gel-phase (19)F NMR spectroscopy

Gel-phase (19)F NMR spectroscopy is a useful monitoring technique for solid-phase organic chemistry due to the high information content it delivers and swift acquisition times, using standard NMR spectrometers. This paper describes the synthesis of the novel linker 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid in 29% yield over seven steps, using nucleophilic aromatic substitutions on 2,4,5-trifluorobenzonitrile as key steps. Following standard solid-phase synthesis a peptide could be cleaved from the linker using 20% TFA in CH(2)Cl(2) in 30 minutes, in contrast to a previously described monoalkoxy linker that requires 90% TFA in water at elevated temperature. A resin-bound peptide could be successfully glycosylated using only two equivalents of a thioglycoside donor, activated with N-iodosuccinimide and trifluoromethanesulfonic acid, and subsequent cleavage and deprotection gave the target glycopeptide. Direct glycosylation of the linker itself followed by mild acidic cleavage gave a fully protected hemiacetal for further chemical manipulation.     

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.     

Versatile synthetic route to carbocyclic N-Acetylneuraminic acid and its derivatives

Sialic acid (N-acetylneuraminic acid) is a carbohydrate that possess a nine carbon backbone, and it is often found at the termini of glycoconjugates in biological systems. Because of this prominence many syntheses have reported routes to sialic acid and many of its derivatives. Most of these compounds retain the endocyclic oxygen atom that becomes part of the ketal glycosidic linkage that joins sialic acid to the penultimate residue in the glycoconjugate. With respect to carba-sialic acid (replacement of the ring oxygen atom with a methylene group) a single synthesis has been reported (Ogawa et al. (Carbohydr. Res., 1995, 269, 53–78) in 30 steps and 0.5% yield. The current report details a robust synthesis of 6a-carba-α-d-sialic acid that involves 18 steps and give a 5% yield using d-quinic acid as the starting material.     

Synthesis of a tetrasaccharide corresponding to the teichoic acid from the cell wall of Streptomyces sp. VKM Ac-2275

A concise chemical synthesis of a tetrasaccharide found in the teichoic acid from the cell wall of Streptomyces sp. VKM Ac-2275 was achieved in high yield. A [2+2] block synthetic strategy has been adopted for the construction of the target tetrasaccharide by exploiting the orthogonal property of a thioglycoside. For the first time, the 2-(4-methoxyphenoxy) ethyl group has been used as the anomeric protecting group to make the glycone moiety with a readily available linker for its conjugation to a protein without destroying the cyclic structure at the reducing end. Yields were high in all of the intermediate steps.     

De novo synthesis of a D-galacturonic acid thioglycoside as key to the total synthesis of a glycosphingolipid from Sphingomonas yanoikuyae

A concise synthesis of a differentially protected D-galacturonic acid (D-GalA) thioglycoside and the construction of a potent immunomodulating glycosphingolipid are described. The key steps of the synthesis are an Evans aldol reaction between a C4 aldehyde and a PMB-protected glycolyloxazolidinone as well as a tandem-PMB-deprotection/cyclization to thioglycosides. The key glycosylation step is optimized by varying the anomeric leaving group, the activating agent, and the solvent system.     

Total synthesis of lathyranoic acid A

The first total synthesis of lathyranoic acid A (1) was accomplished stereoselectively in a linear sequence of 20 steps and an overall yield of 1.4%. This modular synthesis featured a cyclic, stereocontrolled Cu-catalyzed intramolecular cyclopropanation to construct the cis-cyclopropane unit, a Grubbs metathesis to construct the γ-substituted cyclopentenone moiety, and an anion-mediated conjugate addition.     

Efficient synthesis of bongkrekic acid. Three-component convergent strategy

An efficient total synthesis of the apoptosis inhibitor bongkrekic acid was accomplished using a three-component convergent strategy involving a Kocienski-Julia olefination and a Suzuki-Miyaura coupling, in which the longest linear sequence was 18 steps and proceeded in 6.4% overall yield. The torquoselective olefination also contributed to the shortening of the synthesis.     

A total synthesis of (-)-hemiasterlin using N-Bts methodology.

A total synthesis of (-)-hemiasterlin has been accomplished in nine steps from 25(8) (>35% yield overall). An improved enantiocontrolled route to the tetramethyltryptophan subunit 32 was developed using an asymmetric Strecker synthesis (five steps, 50% yield from 25), and the dipeptide 22 was prepared in seven steps, 37% yield from valinol. The synthesis exploits the high reactivity of a Bts-protected amino acid chloride in the difficult peptide coupling of sterically hindered amino acid residues 18 and 20 to form 21 (70%, recrystallized) and also uses N-Bts intermediates for the high-yielding N-methylations of 14 and 31. In addition, the Bts-protected di-tert-butyl N-acylimidodicarbonate 33 is shown to undergo efficient coupling with 22 to form 34 (97% in the coupling step; 79% over the activation; coupling sequence from 32).     

Total synthesis of (+/-)-actinophyllic acid

The first total synthesis of (+/-)-actinophyllic acid (1) is reported. Key steps of this synthesis include an intramolecular oxidative coupling of ketone and malonic ester enolates and an aza-Cope-Mannich rearrangement that assembled the core structure of the natural product's unique ring system. The synthesis was accomplished from di-tert-butyl malonate in 8% overall yield by a concise sequence that proceeds by way of only seven isolated intermediates.     

Synthesis of 7-azabicyclo[2.2.1]heptane-1,4-dicarboxylic acid, a rigid non-chiral analogue of 2-aminoadipic acid

A non-chiral, rigid 7-azabicyclo[2.2.1]heptane-1,4-dicarboxylic acid, an analogue of 2-aminoadipic acid, has been synthesized in six steps from dimethyl-meso-2,5-dibromohexanedioate in 28% total yield. A key step in the synthesis is double alkylation of a dimethyl pyrrolidine-2,5-dicarboxylate by 1-bromo-2-chloroethane.     

Synthesis of protected （2S,4R）-2-amino-4-methyldecanoic acid,a proposed component of culicinins

The protected （2S,4R）-2-amino-4-methyldecanoic acid, a proposed component of culicinins has been synthesized over 10 steps and in total 28% yields using Wittig reaction and Schollkopf amino acid synthesis as key steps.     

Sonochemistry: a powerful way of enhancing the efficiency of carbohydrate synthesis

Using sonication as a means of facilitating organic reactions in carbohydrate chemistry was explored under the conditions used for traditional organic synthesis. An array of representative reactions, including hydroxy group manipulation (acylation, protection/deprotection, acyl group migration), thioglycoside synthesis, azidoglycoside synthesis, 1,3-dipolar cycloaddition and reductive cleavage of benzylidene, commonly used in the synthesis of carbohydrate derivatives was examined. A series of glycosylation reactions that employ thioglycosides, glycosyl trichloroacetimidate, glycosyl bromide and glycosyl acetate as the glycosyl donors was also examined. Our results demonstrate that sonication can significantly shorten the reaction time, enhance the reactivity of reactant and lead to superior yield and excellent stereoselectivity. More importantly, a general protocol of glycosylation may finally be developed. Sonication is compatible to the conditions used for traditional organic synthesis. We believe that sonication can also be applied to other areas of synthetic processes.     

Total synthesis of luminacin D

[reaction: see text] A highly convergent synthesis of the angiogenesis inhibitor luminacin D has been achieved in 13 linear steps (19 steps total, 5.3% overall yield) utilizing a samarium(II) iodide-mediated mixed tandem aldol/Evans-Tishchenko reaction to construct the carbohydrate precursor. The modular synthetic design will allow derivatization at key positions necessary for biochemical mode of action studies.     

Selective preparation of glycosyl sulfone or glycal by treatment of phenyl thioglycoside of N-acetylneuraminic acid with m-chloroperbenzoic acid

Treatment of acetylated phenyl thioglycoside of N-acetylneuraminic acid with m-chloroperbenzoic acid (MCPBA) in CH₂Cl₂ affords quantitatively mixtures of the respective sulfone and glycal free from the sulfoxide. The outcome of the reaction does not depend on the anomeric configuration of the starting thioglycoside. The sulfone can be selectively prepared (yield 100%) by oxidation with an excess of MCPBA and NaHCO₃. In the presence of pyridine (2 equiv.) and MCPBA (2 equiv.), the major product is glycal (yields 81—88%). This version of the reaction can be regarded as a new method for the preparation of sialic acid glycals.     

Total synthesis of the elastin crosslinker (+)-desmopyridine

Desmopyridine, isolated from the acid hydrolysates of bovine ligamentum nuchae, is an elastin crosslinker and an amino acid that has a 3,4,5-trisubstituted pyridine skeleton. Herein we report the first total synthesis of (+)-desmopyridine in 10% yield over six steps starting from 4-aminopyridine via chemo- and regioselective palladium-catalyzed Sonogashira and Negishi cross-coupling reactions.     

Total Synthesis of a Hyperbranched N‐Linked Hexasaccharide Attached to ATCV‐1 Major Capsid Protein without Precedent

The N‐glycans attached to some chloroviruses comprise a hyperbranched core structure without precedent. We are interested in the chemical synthesis of the hexasaccharide attached to ATCV‐1 (Acanthocystis turfacea Chlorella virus 1) for its distinct structure. After exploring four routes, the target hexasaccharide 2 was successfully synthesized for the first time in overall 10% yield over 8 steps from thioglycoside building blocks. This synthetic protocol is characterized by the three‐component one‐pot glycosylation and the regioselective glycosylation reactions. The disclosed synthetic approach to this new type of N‐glycans will facilitate the in‐depth understanding of their biological functions.     

A facile synthesis of cajaninstilbene acid and its derivatives

A facile synthesis of cajaninstilbene and its derivatives by using a building block has been developed.     

A concise and scalable synthesis of high enantiopurity (-)-D-erythro-sphingosine using peptidyl thiol ester-boronic acid cross-coupling

A short and efficient synthesis of high enantiopurity (-)-D-erythro-sphingosine has been achieved in 71% yield over 6 steps from N-Boc-L-serine. The key steps are high yield, racemization-free, palladium-catalyzed, copper(I)-mediated coupling of the thiophenyl ester of N-Boc-O-TBS L-serine with E-1-pentadecenyl boronic acid and the highly diastereoselective reduction of the resulting peptidyl ketone with LiAl(O-t-Bu)3H. By using this concise route (-)-D-erythro-sphingosine can be prepared on large scale and in high enantio- and diastereopurity (ee >99%, de up to 99%).     

Total synthesis of the COPD biomarker desmosine via Sonogashira and Negishi cross-coupling reactions

Desmosine, a crosslinking pyridinium amino acid of elastin, is an attractive biomarker for the diagnosis of chronic obstructive pulmonary disease (COPD). In this study, the total synthesis of (+)-desmosine is reported utilizing chemo- and regioselective Sonogashira and Negishi cross-coupling reactions in 15% yield over six steps.