A common approach to the total synthesis of l-arabino-, l-ribo-C18-phytosphingosines, ent-2-epi-jaspine B and 3-epi-jaspine B from d-mannose

A common strategy for the total syntheses of the protected l-arabino- and l-ribo-C₁₈-phytosphingosine (8 and 9, respectively), HCl salts of ent-2-epi-jaspine B (ent-6) and 3-epi-jaspine B (7) with efficient use of both flexible building blocks 26 and 27 was achieved. The key step of this approach was [3,3]-sigmatropic rearrangement of allylic trichloroacetimidate 21 and thiocyanate 22, which were derived from the known 2,3:5,6-di-O-isopropylidene-d-mannofuranose 18 as the source of chirality. The side chain functionality was installed utilizing a Wittig reaction.     

Oxazine formation by MsCl/Et3N as a convenient tool for the stereochemical interconversion of the hydroxyl group in N-acetyl 1,3-aminoalcohols. Asymmetric synthesis of N-acetyl l-xylo- and l-arabino-phytosphingosines

Use of MsCl/Et₃N was proven to provide a convenient synthetic tool for the stereochemical intercoversion of the hydroxyl group in N-acetyl 1,3-aminoalcohols. Thus, under these conditions, the alcohols 4 and 6 smoothly converted to the oxazines 5 and 7, respectively, which were hydrolyzed to generate the corresponding inverted alcohols 6 and 4 in one pot. Further elaboration of 4 and 6 led to the efficient asymmetric synthesis of N-acetyl l-xylo- and l-arabino-phytosphingosines (11 and 15), respectively, via olefin cross metathesis reactions.     

Enantioselective synthesis of d-ribo-(2S,3S,4R)-C18-phytosphingosine using double stereodifferentiation

An enantioselective synthesis of d-ribo-C₁₈-phytosphingosine as its tetraacetate derivative 10, starting from d-mannitol and employing the Sharpless asymmetric dihydroxylation reaction on allylic alcohol 6 as the key step, is described.     

The first asymmetric synthesis of (2S,3S,4R)-3-amino-2-hydroxymethyl-4-hydroxypyrrolidine

The novel (2S,3S,4R)-3-amino-2-hydroxymethyl-4-hydroxypyrrolidine 5 has been produced in an efficient synthesis from trans-4-hydroxy-l-proline 8. The key step involves a tethered aminohydroxylation of the alkene 7 to introduce regio- and stereoselectively the amino alcohol functionality in the resulting products 6 and 13. Subsequent deprotection steps furnish the target molecule 5 as well as several differentially protected analogues.     

An efficient synthesis of d-ribo- and l-lyxo-phytosphingosine from d-tartaric acid

The preparations of d-ribo- and l-lyxo-phytosphingosines (1, 2) are described. Chelation-controlled addition of tetradecylmagnesium bromide to pentylidene-protected d-threitol aldehyde 6 afforded the key intermediate tetrol 7, providing the desired l-lyxo stereochemistry of phytosphingosine. Inversion at C4 of intermediate 7 provided the d-ribo stereochemistry.     

An efficient synthesis of d-ribo-C18-phytosphingosine and l-arabino-C18-phytosphingosine from d-fructose

d-ribo-C₁₈-phytosphingosine and l-arabino-C₁₈-phytosphingosine were synthesised starting from commercially inexpensive d-fructose. Metal-mediated fragmentation and stereoselective reduction were used as key steps to provide the hydrophilic portion of d-ribo and l-arabino phytosphingosines. Grubbs’ cross-metathesis and hydrogenation allowed the incorporation of hydrophobic tail.     

A new simple route to deoxyamino sugars from non-sugar material: synthesis of d-tolyposamine and 4-epi-d-tolyposamine and formal synthesis of d-vicenisamine

A new, simple strategy has been formulated for the synthesis of deoxyamino sugars from a non-sugar starting material. Starting from the enantiomerically pure diol obtained from ethyl sorbate by Sharpless asymmetric dihydroxylation, the synthesis of two types of 2,3,4,6-tetradeoxy-4-amino sugars—d-tolyposamine and 4-epi-d-tolyposamine—, and formal synthesis of 2,4,6-trideoxy-4-amino sugar—d-vicenisamine—were performed.     

Enantioselective total synthesis of (2S,3R,4R)-d-xylo-phytosphingosine from substituted azetidin-2-one

Enantiomerically pure (2S,3R,4R)-d-xylo phytosphingosine is synthesized in 36% overall yield in seven steps from known β-lactam (8) derived from d-mannitol triacetonide.     

Stereoselective synthesis of (3S,4S)-tert-butyl-N-Boc-3-ethyl-4-hydroxy-l-prolinate and (3S,4R)-tert-butyl-N-Boc-3-ethyl-4-hydroxy-l-prolinate

Diastereomers of tert-butyl-N-Boc-3-ethyl-4-hydroxy-l-prolinate 1 and 2 have been synthesized in six steps starting from readily available Boc-protected trans-4-hydroxy-l-proline. The key reactions in the synthesis are asymmetric reductions, firstly on the 4-ketoproline intermediate 6 and secondly on the 3-exocyclic olefin bond of the resulting allylic alcohol 7 or 8. Reaction conditions were optimized in order to control the stereochemistry of the three chiral centers.     

Synthesis of d-gluco-, l-ido-, d-galacto-, and l-altro-configured glycaro-1,5-lactams from tartaric acid

The d-gluco-, l-ido-, d-galacto-, and l-altro-configured glycaro-1,5-lactams 1-4 were prepared from the known tartaric anhydride 5 via the aldehyde 6. These lactams are known (1) or potential (2-4) inhibitors of β-d-glucuronidases and α-l-iduronidases. Olefination of 6 to the (E)- and (Z)-alkenes 7 or 8, followed by reagent or substrate controlled dihydroxylation, lactonization, azidation, reduction, and deprotection led in 10 steps and in overall yields of 11-20% to the title lactams.     

Practical synthesis of d-[1-C]mannose, l-[1-C] and l-[6-C]fucose

The chemical synthesis of ¹³C-labeled mannose and fucose is important for the preparation of molecular probes used in the conformational study of the oligosaccharide portions of glycoproteins. A new method for the synthesis of the title [1-¹³C]-labeled compounds via the corresponding olefin compounds, which are in turn derived from d-mannitol or l-arabinose by efficient introduction of ¹³C, by the Wittig reaction using Ph₃P¹³CH₃I and n-BuLi, is described. The introduction of ¹³CH₃I to produce the [1-¹³C]- and [6-¹³C]-labeled compounds was accomplished in 62%, 56%, and 71% yields, respectively. All mannose and fucose protons, from H-1 to H-6, were observed by the HMQC-TOCSY technique using 1:1 mixtures of [1-¹³C]- and [6-¹³C]-labeled compounds.     

S-2-Amino-4-cyanobutanoic acid (β-cyanomethyl-l-Ala) as an atom-efficient solubilising synthon for l-glutamine

Glutamine (Gln) is often a difficult amino acid to incorporate during solution-phase peptide synthesis, owing to poor solubility and unwanted dehydrations as side-reactions. Current approaches to solving these problems are highly atom-inefficient. N^α-Cbz-β-cyanomethyl-l-Ala is readily accessible by dehydration of Cbz-l-Gln. β-Cyanomethyl-l-Ala can be incorporated into short peptides easily by conventional methods. The nitrile is stable to the hydrogenolysis conditions used to remove Cbz and to acidic deprotection but is quantitatively hydrated to the γ-carboxamide of l-Gln with hydrogen peroxide. Thus β-cyanomethyl-l-Ala may represent a new, soluble, perfectly atom-efficient synthon for l-Gln.     

Inclusion compounds of l,d-dipeptide with small sulfoxides: flexible sheet structure of (S)-phenylglycyl-(R)-phenylglycine

A heterochiral l,d-dipeptide, (S)-phenylglycyl-(R)-phenylglycine (SR-1), formed inclusion compounds with some small dialkyl sulfoxides. By their single-crystal X-ray analyses, we observed monolayer structures, where SR-1 molecules are arranged in parallel to construct a wavy sheet. The sulfoxides were accommodated in a channel cavity between the monolayers of SR-1 by hydrogen bonding with ⁺NH₃ of SR-1. Notably, the sheet of SR-1 is so flexible to change its wavy degree in response to the volume of the included sulfoxides. Furthermore, we could analyze the structure of crystalline SR-1 without any sulfoxide, which has a bilayer structure.     

Total synthesis of natural cis-3-hydroxy-l-proline from d-glucose

Synthesis of cis-3-hydroxy-l-proline from d-glucose is reported. The methodology involves conversion of d-glucose into N-benzyloxycarbonyl-γ-alkenyl amine which on 5-endo-trig-aminomercuration gave the pyrrolidine ring skeleton with sugar appendage in 25% yield. Alternatively, N-benzyloxycarbonyl-γ-alkenyl amine on hydroboration-oxidation, mesylation and intramolecular S_N2 cyclisation afforded pyrrolidine ring compound in high yield. Hydrolysis of 1,2-acetonide functionality, NaIO₄ cleavage followed by oxidation of an aldehyde into acid and hydrogenolysis afforded cis-3-hydroxy-l-proline in overall 29% yield from d-glucose.     

Pyrogallol[4]arenes as artificial receptors for l-carnitine

Complexation thermodynamics of pyrogallol[4]arenes with l-carnitine and other biologically important ammonium ions were investigated by isothermal titration calorimetry.     

Mechanism of complex formation between [AuCl4] and l-methionine

The kinetics of the reaction between the tetrachloroaurate(III) ion and l-methionine (l-Met) (0.1 M HClO₄, pH 1.0–2.5) have been studied spectrophotometrically using a stopped-flow technique at different temperatures. Initially, the fast substitution reaction was ascribed to the formation of the short-lived square-planar Au(III)–(l-Met) that was followed by the replacement of a Cl⁻ ligand and a subsequent, slower reduction to Au(I)–(l-Met). This is an intermolecular process, involving attack on the [AuCl₄]⁻ complex by an outer-sphere l-methionine. The activation parameters (ΔH^≠ and ΔS^≠) for substitution and reduction were determined. IR spectroscopy indicates that l-methionine acts as a bidentate ligand, most likely coordinating via the S and N atoms, while ¹H and ¹³C NMR data indicate methionine sulfoxide as the final product. Finally, the components of the reaction were treated thermally in order to investigate the solid phase synthesis of the resulting complex.     

Stereoselective synthesis of (2R,3S,4S)-3-hydroxy-4-methyl-2-tetradecyl-4-butanolide starting from 2,5-anhydro-d-mannitol

A novel approach to natural β-hydroxy-γ-lactone 2 from 2,5-anhydro-d-mannitol (1) is described. The key reactions in this synthesis include stereoselective methylation of aldehyde 3 with lithium dimethylcuprate, an intramolecular radical cyclization of seleno carbonate 11 and an intermolecular cross-metathesis of 3-allyl-4-hydroxy-γ-lactone 16 with 1-tridecene.     

Experimental and theoretical studies on inversion dynamics of dichloro(l-difluoromethionine-N,S)platinum(II) and dichloro(l-trifluoromethionine-N,S)platinum(II) complexes

Fluorinated analogues of methionine such as l-S-(difluoromethyl)homocysteine (l-difluoromethionine; DFM) and l-S-(trifluoromethyl)homocysteine (l-trifluoromethionine; TFM) have been demonstrated to be interesting analogues for incorporation into peptides and proteins. The presence of the fluorine nucleus adjacent to the sulfur atom in the side chain not only serves to alter the nucleophilicity and electron density of the sulfur atom but it can function as an important NMR spectroscopic (¹⁹F) probe. Additional information on the properties of these fluorinated amino acid analogues was obtained by studying their interactions with dipotassium tetrachloroplatinate (K₂PtCl₄). The resulting complexes, dichloro(l-difluoromethionine-N,S)platinum(II) and dichloro(l-trifluoromethionine-N,S)platinum(II) were investigated with respect to their sulfur inversion rates utilizing dynamic NMR methods. Inversion barriers for the DFM- and TFM-platinum complexes were experimentally determined to be 16.4 ± 0.2 and 18 ± 1 kcal/mol, respectively. Density functional calculations at the B3LYP/SDD level were also performed to model the structures and energies of the ground and transition states for these complexes.     

New pyrano[3,4-b]indoles from 2-hydroxymethylindole and l-dehydroascorbic acid

2-Hydroxymethylindole reacts with l-dehydroascorbic acid under mild conditions to give (3R,3aR,10cS)-3-[(1S)-1,2-dihydroxyethyl]-3a,10c-dihydroxy-3a,5,6,10c-tetrahydrofuro[3′,4′:5,6]pyrano[3,4-b]indol-1(3H)-one. Its tosyl derivative undergoes cyclization to form a pentacyclic ketal derivative.     

Short asymmetric synthesis of (S,S)-PDP using l-prolinol derivative as economic starting material

(S,S)-PDP (5d) and its backbone (2S,2′S)-bipyrrolidine (1) have been extensively applied as the scaffold of various chiral ligands in catalytic asymmetric syntheses. In this study, new short asymmetric syntheses of these two important C₂-symmetrical nitrogen heterocycles have been accomplished employing economically available l-prolinol derivative 10 as the starting material. Excellent diastereoselectivity was achieved of the key Grignard addition to imine intermediate utilizing (S)-N-tert-butanesulfinamide as the chiral auxiliary.