Stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine

The stereoconvergent synthesis of N-Boc-(2R,3S)-3-hydroxy-2-phenylpiperidine from (R)-1-(2-((tert-butyldimethylsilyl)oxy)-1-phenylethyl)piperidin-2-one is described. The key steps involved are α-hydroxylation of quiral lactam with O₂, stereoconvergent reduction of (R)- or (S)-3-(benzyloxy)-piperidin-2-one with Red-Al® which afforded in both cases the trans-bicyclic oxazolidine in high stereoselectivity after chromatographic purification and a stereospecific Grignard addition to chiral bicyclic oxazolidine.     

Synthese des substances de groupe sanguin—IX: Une synthese du 2-o-(α-l-fucopyranosyl)-3-o-(α-d-galactopyranosyl)-d-galactose,le determinant antigenique du groupe sanguin b

The trisaccharide 2-O-(α-L-fucopyranosyl)-3-O-(α-D-galactopyranosyl)-D-galactose has been synthesised stereospecifically using the imidate procedure. Allyl 3-O-benzoyl-4,6-O-benzylidene-β-D-galactopyranoside was first α-L-fucosylated by 1-O-(N-methyl)-acetimidyl-2,3,4-tri-O-benzyl-β-L-fucopyranose then, after O-debenzoylation, α-D-galactosylated by 1-O-(N-methyl)-acetimidyl 2,3,4,6-tetra-O-benzyl-β-D-galactopyranose. The resulting tri-saccharide has also been obtained from allyl 2-O-benzoyl-4,6-O-benzylidene-β-D-galactopyranoside after α-D-galactosylation, O-debenzoylation and α-L-fucosylation. The glycosylations were performed at room temperature in nitromethane in the presence of p-toluenesulfonic acid. Deallylation followed by catalytic hydrogenolysis gave the B blood-group antigenic determinant. The allyl group was also selectively transformed into hydroxyethyl group.     

Stereoselective synthesis of novel N-(α-l-arabinofuranos-1-yl)-l-amino acids

In lead detoxification, the α-anomer of N-glycocyl-l-amino acid is more potent than its β-anomer. Here a six-step-reaction route for stereoselectively preparing N-(α-l-arabinose-1-yl)-l-amino acids is reported. Treating l-arabinose with acetic anhydride and sodium acetate provided 1,2,3,5-tetra-O-acetyl-l-arabinofuranose in 90% yield. After removing the 1-acetyl group, the thus formed 2,3,5-tri-O-acetyl-l-arabinofuranose and N-(2-nitrophenylsulfonyl)-l-amino acid t-butylesters were treated with triphenylphosphine to perform Mitsunobu dehydration and form 2,3,5-tri-O-acetyl-l-arabinofuranosyl-l-[N-(2-nitrophenylsulfonyl)]amino acid t-butylesters 2a–f, and the ratios of their α- to β-anomer ranged from 8/1 to 9/1. Chromatographic separation provided epimerically pure 2a–f-α and 2a–f-β. In the presence of CF₃CO₂H, 2a–f-α and 2a–f-β were converted to α- and β-anomers of N-(2,3,5-tri-O-acetyl-l-arabinofuranosyl)-N-(2-nitrobenzenesulfonyl)-l-amino acids, 3a–f-α and 3a–f-β, in 87–92% yields. While in the presence of NaOCH₃, 3a–f-α and 3a–f-β were converted to α- and β-anomers of N-(l-arabinofuranosyl)-N-(2-nitrobenzenesulfonyl)-l-amino acids, 4a–f-α and 4a–f-β, in 90–96% yields. Treating 4a–f-α and 4a–f-β with N-ethyldiisopropylamine (DIPEA) and thiophenol, their 2-nitrophenylsulfonyl groups were removed, and the α- and β-anomers of N-(l-arabinose-1-yl)-l-amino acids were formed in 70–79% yields. The bioassay confirmed that the lead detoxification activity of the α-anomer was significantly higher than that of the β-anomer.     

Straightforward, racemization-free synthesis of peptides with fairly to very bulky di- and trisubstituted glycines

Several fully protected tri- and pentapeptides containing a central symmetrical α,α-dialkyl glycine residue, with the alkyl group varying from methyl or ethyl to benzyl, were synthesized in good yields by a strategy based on the Ugi-Passerini reaction. Each Ugi-Passerini adduct was selectively cleaved and the product submitted to an assisted N,N′-dicyclohehylcarbodiimide coupling to an amino acid or dipeptide ester, respectively. Tripeptides as the above but containing a 4-methoxybenzyl group at the nitrogen atom of the central residue were also synthesized in fair to good yields by N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide assisted couplings. The results reported here show that our strategy is appropriate for routine synthesis of peptides incorporating these moieties.     

Synthesis of the four diastereoisomers of 3-thymine-1-(butoxycarbonyl)aminocyclopentane-1-carboxylic acid

Synthetic routes to all four diastereoisomers of 3-thymine-1-(^tbutoxycarbonyl)aminocyclopentane-1-carboxylic acid have been developed starting from the commercially available (S)-dimethyl malate. The key step in the synthesis involves dialkylation of N-(diphenylmethylene)glycine ethyl ester with 1,4-diiodo-2(S)-trityloxybutane.     

Microwave-assisted ethylene–alkyne cross-metathesis: synthesis of chiral 2-(N-1-acetyl-1-arylmethyl)-1,3-butadienes

Chiral 1-arylpropargyl amides, which are resistant to undergoing ethylene–alkyne cross-metathesis at atmospheric pressure, were reacted under microwave irradiation to afford enantiomerically enriched 2-(N-1-acetyl-1-arylmethyl)-1,3-butadienes within a few minutes. Enantiomerically enriched amides underwent ethylene–alkyne cross-metathesis with retention of configuration at the propargylic/allylic position. A series of chiral 2-(N-1-acetyl-1-arylmethyl)-1,3-butadienes were synthesised with ee ⩾95%; these latter compounds could be used as building blocks for the synthesis of new antifungal and antiaromatase agents.     

Synthesis of 1-halophenyl 4-(2-imidazolyl)-1-butanones and 5-(2-imidazolyl)-1-pentanones and their ketalization with glycerol

An alternate synthesis of 1-(2,4-dichlorophenyl)-4-(2-imidazolyl)-1-butanones 5d is presented after 1-[(dimethylamino)methyl- and 1-methyl]-2-lithioimidazole failed to be substituted satisfactorily by 2-(2,4-dichlorophenyl)-2-(3-iodopropyl)-1,3-dioxolane ( 3b ). The Pinner addition of ethanol to 2-(2,4-dichlorophenyl)-2-(3-cyanopropyl)-1,3-dioxolane yielded the corresponding imidate which was reacted with 1-amino-2,2-dimethoxyethane to form an amidine. Hot dilute hydrochloric acid converted this ami-dine to the 2-imidazolyl ketone 5b . Syntheses of homologous 1-(4-chloro- and 2,4-dichlorophenyl)-4-(2-imidazolyl)-1-pentanones 20 are described. Ketalizations of 5 and 20 with glycerol formed imidazolyl 1,3-dioxolanyl alcohols. Selective N- and O-alkylations of some of these imidazolyl alcohols are described.     

Catalyst-free Mannich-type reaction of 1-(N-acylamino)alkyltriphenylphosphonium salts with silyl enolates

A catalyst-free reaction of 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates with silyl enolates was developed to prepare β-amino carbonyl compounds. The reported method is a useful approach for the preparation of N-protected β-amino esters as well as N-protected β-amino ketones. The starting 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates are readily available from N-protected α-amino acids. Therefore, the presented approach can be considered a new method for the α-homologation of N-protected α-amino acids to prepare β-amino acid derivatives.     

Synthetic analogues of polynucleotides—XIII: The resolution of dl-β-(thymin-1-yl)alanine and polymerisation of the β-(thymin-1-yl)alanines

dl-β-(Thymin-1-yl)alanine has been resolved into d(+) and l(?) forms. The pure d(+) form was obtained by fractional crystallisation of the (+)α-methylphenylethylamine salts of the α-N-formyl derivatives. The pure l(?) isomer was obtained on a small scale by chromatography of the same salts. The optically active amino acids and the dl-mixture were polymerised by the mixed anhydride procedure to give polymers which showed no evidence of base stacking or of interaction with polyadenylic acid. The molecular weights of the polymers were in the range 2–4 × 10³. These were determined by end group assay which involved the synthesis of α-N-(2,4-dinitrophenyl)-dl-β-(thymin-1-yl)alanine as a standard.     

A new convenient synthesis of N-acyl-2-(dimethoxyphosphoryl)glycinates

Easily accessible N-acyl-2-triphenylphosphonioglycinate tetrafluoroborates react smoothly with trimethylphosphite in the presence of methyltriphenylphosphonium iodide to give N-acyl-2-(dimethoxyphosphoryl)glycinates in good or very good yields. The dimethoxyphosphorylglycinates may be isolated by column chromatography, or used directly for the Wadsworth-Emmons synthesis of α,β-dehydro-α-amino acids in a one-pot procedure without purification.     

Hydrogen bond activated glycosylation under mild conditions

Herein, we report a new glycosylation system for the highly efficient and stereoselective formation of glycosidic bonds using glycosyl N-phenyl trifluoroacetimidate (PTFAI) donors and a charged thiourea hydrogen-bond-donor catalyst. The glycosylation protocol features broad substrate scope, controllable stereoselectivity, good to excellent yields and exceptionally mild catalysis conditions. Benefitting from the mild reaction conditions, this new hydrogen bond-mediated glycosylation system in combination with a hydrogen bond-mediated aglycon delivery system provides a reliable method for the synthesis of challenging phenolic glycosides. In addition, a chemoselective glycosylation procedure was developed using different imidate donors (trichloroacetimidates, N-phenyl trifluoroacetimidates, N-4-nitrophenyl trifluoroacetimidates, benzoxazolyl imidates and 6-nitro-benzothiazolyl imidates) and it was applied for a trisaccharide synthesis through a novel one-pot single catalyst strategy.

A mild glycosylation system was developed using glycosyl imidate donors and a charge-enhanced thiourea H-bond donor catalyst. The method can be used for the effective synthesis of O-, C-, S- and N-glycosides and chemoselective one-pot glycosylation.     

Generation and reactivity of polyanions derived from 1-[1-(benzotriazol-1-yl)alkyl]-1H-benzotriazoles

1-[1-(Benzotriazol-1-yl)alkyl]-1H-benzotriazoles undergo deprotonation with n-BuLi at the α-position of the N-substituent and at the 7-position of benzotriazole to afford polyanions. Treatment of these polyanions with electrophiles allows the preparation of highly functionalized benzotriazole derivatives.     

An expeditious and efficient synthesis of β-d-galactopyranosyl-(1→3)-d-N-acetylglucosamine (lacto-N-biose) using a glycosynthase from Thermus thermophilus as a catalyst

Mutant glycosynthases or transglycosidases obtained from a Thermus thermophilus β-d-glycosidase (TtbGly) efficiently catalyzed the synthesis of β-(1→3)-disaccharides. Unfortunately, this regioselectivity was changed to the β-(1→4) one when N-acetylglucosamine derivatives were used as acceptors, thus precluding the possibility of synthesizing d-Galp-β-(1→3)-d-GlcpNAc (lacto-N-biose) or d-Glcp-β-(1→3)-d-GlcpNAc, which are useful synthons for the synthesis of antigen determinants. In contrast, we show in this work that, in the presence of phenyl 2-amino-1-thio-β-d-glucopyranoside, the ‘normal’ β-(1→3) regioselectivity of E338G TtbGly glycosynthase takes place. Thus, transglycosylations using α-galactosyl or α-glucosyl fluorides gave the corresponding phenyl β-d-glycopyranosyl-(1→3)-2-amino-2-deoxy-1-thio-β-d-glucopyranosides in high yields (88–97%). Subsequent selective N-acylation followed by NBS/water deprotection of the thiophenyl group afforded lacto-N-biose in high overall yields.     

Asymmetric synthesis of α-amino aldehydes from sulfinimine (N-sulfinyl imine)-derived α-amino 1,3-dithianes. Formal synthesis of (−)-2,3-trans-3,4-cis-dihydroxyproline

Hydrolysis of sulfinimine-derived N-sulfinyl α-amino 1,3-dithianes with aqueous 1,3-dibromo-5,5-dimethylhydantoin affords the corresponding N-tosyl α-amino aldehydes in good yield and high enantiomeric purity. These aldehydes can be reduced to amino alcohols and undergo the Wittig reaction to give allylic amines without epimerization. The utility of this methodology is illustrated in a formal synthesis of (−)-2,3-trans-3,4-cis-dihydroxyproline.     

Application of cyclic sulfates in the synthesis of enantiomers of 1-[3-(4-aryl-piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidin-2-one

The synthesis of enantiomers of 1-[3-(4-aryl-piperazin-1-yl)-2-hydroxy-propyl]-pyrrolidin-2-one derivatives is described. These enantiomers were synthesized starting from (R)- or (S)-1-chloro-2,3-dihydroxypropane using relevant cyclic sulfates as chiral intermediates. The enantiomeric purities of the final compounds were in the range of 99.3–100.0%, as determined by high performance liquid chromatography. The final compounds were found to display moderate potency as ligands for α₁-adrenoreceptors.     

Synthesis of 1-(pyrrolidin-2-ylmethyl)-1H-azoles and their piperidine-derived homologues

A convenient preparation of 1-(pyrrolidin-2-yl)-1H-pyrazoles, -imidazoles, and -1H-1,2,4-triazoles, 1-(piperidin-2-yl)-1H-pyrazoles and -1H-1,2,4-triazoles, and 1-(piperidin-3-yl)-1H-1,2,4-triazoles by alkylation of azoles (viz. pyrazoles, imidazoles, and triazoles) with N-Cbz-prolinol mesylate or its analogues and subsequent deprotection is reported. The two-step method allows for synthesis of the title compounds in 16–65% yields. The utility of the procedure has been demonstrated by multigram preparation of a 15-member building block mini-library for the lead-oriented synthesis of compound libraries. These building blocks perfectly fit the definition of low-molecular-weight hydrophilic three-dimensional templates, which leave much room for the lead-oriented synthesis of the compound libraries.      

Copper-catalyzed asymmetric conjugate addition of Grignard reagents to 1-(N,N-diisopropylcarbamoyloxy)-1-tosyl-1-alkenes

A copper-catalyzed conjugate addition of Grignard reagents to 1-(N,N-diisopropylcarbamoyloxy)-1-tosyl-1-alkenes led to 1-(N,N-diisopropylcarbamoyloxy)-1-tosyl-2-branched alkanes. Various copper ligands were screened for this reaction. From certain substrates and allylmagnesium bromide, several Josiphos ligands gave low to moderate asymmetric inductions, along with good diastereoselectivity. The stereochemistry of the 1-(N,N-diisopropylcarbamoyloxy)-1-tosyl-2-branched alkanes from this reaction was assigned by comparison with the same products from another synthetic route using chiral pool synthesis and stereoselective lithiation methods.     

Elaboration and structural studies of cyclo 1:1-[α/α-N-amino]mers

In order to investigate the ability of self-organization of the alternance of α-amino and α-N-amino-acids the synthesis of cyclo 1:1-[α/α-N-amino]mers has been achieved by an iterative sequence of deprotection and coupling reactions followed by a macrocyclization step. The self-assembling of N-amino deprotected cyclo-oligomers has been characterized using X-ray diffraction experiments and FT-IR analysis.     

Synthesis of (2S)-2-amino-3-(1H-4-indolyl)propanoic acid,a novel tryptophan analog for structural modification of bioactive peptides

A convenient, multigram synthesis of a novel α-amino acid (2S)-2-amino-3-(1H-4-indolyl)propanoic acid (1a), is reported. An Fmoc–t-Boc derivative of this novel regioisomer of the natural aromatic amino acid tryptophan could be readily incorporated into bioactive synthetic peptides using standard solid phase synthesis. The synthesis featured the use of Schöllkopf chiral auxiliary reagents for chirality induction during a key step.     

Elimination of benzotriazolyl group in N-(α-benzotriazol-1-ylalkyl)amides and N-(α-benzotriazol-1-ylalkyl)sulfonamides: their self-coupling and cross-coupling reactions with carbonyl compounds

The elimination of benzotriazolyl group from N-(α-benzotriazol-1-ylalkyl)amides and N-(α-benzotriazol-1-ylalkyl)sulfonamides are readily realized with samarium diiodide as a reducing agent. The resulting intermediates undergo a dimerization or cross-coupling reaction with carbonyl compounds, thus affording the corresponding dimers or α-hydroxyalkylated sulfonamides in moderate yields.