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.     

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.     

An efficient approach to d-threo-3-hydroxyaspartic acid for the synthesis of novel l-threo-oxazolines as selective blockers of glutamate reversed uptake

An efficient, stereoselective synthetic strategy to d-threo-3-hydroxyaspartic acid was developed. Starting from l-(2S,3S)-N-benzoyl-3-hydroxyaspartic acid dimethyl ester by a Deoxo-fluor-catalyzed cyclization reaction, an inversion of configuration at the β-center (erythro isomer), was observed. A base-induced epimerization reaction led to the d-trans-isomer, which was hydrolyzed to give d-threo-3-hydroxyaspartic acid with excellent stereoselectivity and overall yield. Starting from d-threo-3-hydroxyaspartic acid, l-threo-oxazolines can be stereoselectively synthesized.     

A new diorganozinc-based enantioselective access to truncated d-ribo-phytosphingosine

The use of a trans α,β-epoxyaldehyde as a precursor of d-ribo-phytosphingosines was studied. The highly stereoselective alkylation of the aldehyde with a diorganozinc reagent was ensured through double asymmetric induction. The regioselective opening of the epoxide in turn gives access to an azide from which a C₁₀ phytosphingosine can be easily prepared.     

Synthesis of eight-membered iminocyclitols from d-glucose

The Baylis-Hillman reaction of 3-O-benzyl-α-d-xylo-pentodialdo-1,4-furanose 2 afforded a diastereomeric mixture of l-ido- and d-gluco-configurated α-methylene-β-hydroxy esters 3a and 3b, respectively, in 1:1 ratio. Conjugate addition of benzyl amine on 3a gave adduct 4a as a major product while, addition of benzyl amine to 3b gave only one diastereomer 4b. Reduction of ester functionality in 4a/4b, opening of 1,2-acetonide functionality followed by reductive amino-cyclization under hydrogenation condition afforded azocanes 1c/1d in good yield.     

Asymmetric syntheses of the methyl glycosides of 2-deoxy-2-aminohexoses: d-allosamine, d-mannosamine, d-idosamine and d-talosamine

A range of the methyl glycosides of 2-deoxy-2-aminohexoses, comprising d-allosamine, d-mannosamine, d-idosamine and d-talosamine, were prepared from the corresponding d-aldopentoses via a seven step synthetic sequence. The doubly diastereoselective conjugate addition of the requisite antipode of lithium N-benzyl-N-(α-methylbenzyl)amide and in situ enolate oxidation with the requisite antipode of camphorsulfonyloxaziridine (CSO) was used as the key, stereodefining step. Sequential reduction of the resultant α-hydroxy-β-amino esters and oxidative cleavage of the C(1)–C(2) diol unit furnished the corresponding α-amino aldehydes. Subsequent N- and O-deprotection gave the target compounds (as mixtures of anomers) in good yield and high diastereoisomeric purity.     

Short and highly stereoselective total synthesis of d-ribo-configured ureido sugars

An highly stereoselective, flexible and very short synthetic approach to d-ribo-configured ureido monosaccharides of the aldose, aldonic acid and alditol series has been performed starting from the 5-(alditol-1-C-yl)-hydantoin intermediates, obtained via aldol-type addition reaction of hydantoin based building blocks to enantiomerically pure aldehydes. A study to assess the stereoselectivity of this reaction has been undertaken and a very high increase of diastereoselectivity was observed depending on the hydantoin protecting group. The imidazolidinone ring elaboration of 5-(alditol-1-C-yl)-hydantoin intermediates to give ureido sugar derivatives was studied.     

Polyhydroxylated pyrrolidines. Part 4: Synthesis from d-fructose of protected 2,5-dideoxy-2,5-imino-d-galactitol derivatives

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-5-O-methanesulfonyl-β-d-fructopyranose (5) was straightforwardly transformed into its d-psico epimer (8), after O-debenzoylation followed by oxidation and reduction, which caused the inversion of the configuration at C(3). Compound 8 was treated with lithium azide yielding 5-azido-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-l-tagatopyranose (9) that was transformed into the related 3,4-di-O-benzyl derivative 10. Cleavage of the acetonide in 10 to give 11, followed by regioselective 1-O-pivaloylation to 12 and subsequent catalytic hydrogenation gave (2R,3S,4R,5S)-3,4-dibenzyloxy-2,5-bis(hydroxymethyl)-2′-O-pivaloylpyrrolidine (13). Stereochemistry of 13 could be determined after O-deacylation to the symmetric pyrrolidine 14. Total deprotection of 14 gave 2,5-imino-2,5-dideoxy-d-galactitol (15, DGADP).     

Diastereoselective nickel-catalyzed reductive couplings of aminoaldehydes and alkynylsilanes: application to the synthesis of d-erythro-sphingosine

A strategy for the nickel-catalyzed reductive coupling of α-aminoaldehydes with silyl alkynes has been developed. The process proceeds with exceptional regiocontrol and diastereoselectivity. A variety of protected serinal derivatives were examined, and Garner aldehyde afforded the highest chemical yields of an easily deprotected coupling product. Use of a C-15 alkyne allowed a direct and efficient synthesis of d-erythro-sphingosine. With this silyl alkyne of interest, coupling reactions were most efficient when trace water was employed with THF as solvent. Using this procedure, d-erythro-sphingosine was prepared by a short sequence, wherein the alkene stereochemistry, C-3 stereocenter, and the C-3-C-4 carbon-carbon bond were all efficiently installed by the key nickel-catalyzed coupling process.     

Synthesis of d-arabinose-derived polyhydroxylated pyrrolidine, indolizidine and pyrrolizidine alkaloids. Total synthesis of hyacinthacine A2

Several new polyhydroxylated alkaloids including pyrrolidines with a long side chain and 3-(hydroxymethyl) indolizidines were prepared from a common nitrone easily obtained from d-arabinose. In addition, a total synthesis of hyacinthacine A₂ has been achieved in five steps and 67.7% overall yield starting from the same d-arabino-derived nitrone. All synthesized compounds have a common structural feature consisting of a pyrrolidine ring with d-arabino configuration.     

Asymmetric syntheses of 6-deoxyfagomin, d-deoxyrhamnojirimycin, and d-rhamnono-1,5-lactam

N-Allyl protected 3-O-benzyloxglutarimide 11 was synthesized as a useful variant of the chiral building block 10. This modification allowed a high-yielding deprotection of the allyl group from the lactam intermediate 14. Starting from this building block, the asymmetric syntheses of aza-sugars 6-deoxyfagomine (2), d-rhamnono-1,5-lactam (6), as well as d-deoxyrhamnojirimycin (5) have been achieved in high regio- and/or diastereo-controlled manner.     

Stereoselective synthesis of 3-glycosyl-5-methoxycarbonyl-isoxazolidines from d-galactose and d-glucose

Regio- and stereoselective cycloaddition of methyl acrylate to C-glycosyl nitrones derived from d-galactose and d-glucose, giving 5-methoxycarbonyl-3-(pentoglycos-5-yl or pentitol-1-yl)isoxazolidines, is reported. Transformation of one of them into a 4-hydroxy-2-(pentoglycos-5-yl)pyrrolidine derivative, potentially useful in a route to polyhydroxy-perhydroazaazulenes, was achieved.     

5-Trihydroxypropyl-dihydrouracil derivatives as precursors of 1-azasugars: application to the stereoselective synthesis of d-galacto-isofagomine

A new route for the synthesis of isofagomine analogues has been carried out by using as precursors enantiopure 5-trihydroxypropyl-dihydrouracil derivatives obtained from aldol-type addition of 1,3-dibenzyl-dihydrouracil to isopropylidene-protected glyceraldehyde. The synthesis of d-galacto-isofagomine is reported.     

Ortho-substituted aryl monoboronic acids have improved selectivity for d-glucose relative to d-fructose and l-lactate

Ortho-substituted aryl monoboronic acids have been found to have improved selectivity for d-glucose compared to d-fructose and l-lactate. These findings are supported by computational studies on the B3LYP/6-31G(d) level using Gaussian. This finding is of interest for development of boronate based d-glucose sensors.     

Synthesis of d-glucose and l-phenylalanine substituted phenylene-thiophene oligomers

Phenylene-thiophene oligomers bearing peracetylated β-d-glucose or N-BOC-l-phenylalanine as chiral substituents were synthesized in good yields by a versatile protocol based on the Suzuki-Miyaura cross-coupling reaction. Aryl iodides bearing the chiral biomolecules as substituents efficiently reacted with pinacol boronates of bi- or terthiophenes leading to the bio-functionalized oligomers in good yields.     

Anion recognition by d-ribose-based receptors

Anion recognition properties of d-ribose-based receptors α- and β-1 were measured by ¹H NMR in CDCl₃ and MeCN-d₃. Receptor β-1 showed effective binding with anions by cooperative hydrogen bonds of cis-diol. The anomeric isomer α-1 is a less effective anion receptor which has similar cis-diol as a recognition site, indicating that the stereo configuration of the anomeric position is of significant influence on the anion recognition ability.     

A highly efficient synthesis of unnatural l-sugars from d-ribose

A preparative and short synthesis of l-ribose and l-apiose was accomplished starting from d-ribose via stereoselective cis-dihydroxylation and C2-hydroxymethylation, respectively. These l-sugars can serve as versatile intermediates for the synthesis of l-nucleosides.     

Enantioselective synthesis of d- and l-α-methylcysteine with hydantoinase

A scalable and cost-effective synthesis of d- and l-α-methylcysteine is described. A key step is d-selective cyclization of N-carbamoyl S-tert-butyl-d,l-α-methylcysteine catalyzed by hydantoinase. d-5-tert-Butylthiomethyl-5-methylhydantoin and N-carbamoyl S-tert-butyl-l-α-methylcysteine were obtained with excellent yield and optical purity, and these compounds were easily separated by filtration. After hydrolysis and cleavage of the tert-butyl group, d- and l-α-methylcysteine hydrochloride were obtained.     

A convenient synthesis of methyl N-acetyl-α-d-lividosaminide from d-glucal

Methyl N-acetyl-α-d-lividosaminide has been synthesised starting from 4,6-di-O-benzyl-d-glucal via a new nitro glucal derivative in six steps.