Asymmetric total syntheses of (+)-2,5-dideoxy-2,5-imino-d-glucitol [(+)-DGDP] and (−)-1-deoxymannojirimycin [(−)-DMJ] via an extended chiral 1,3-oxazine

The asymmetric total syntheses of (+)-2,5-dideoxy-2,5-imino-d-glucitol [(+)-DGDP] 1 and (?)-1-deoxymannojirimycin [(?)-DMJ] 2 were achieved using an extended chiral 1,3-oxazine. The key synthetic strategies included extension of the chirality of anti,syn-oxazine 3 using diastereoselective dihydroxylation, and piperidine and pyrrolidine ring formation. Starting from readily available anti,syn-oxazine 3, (+)-DGDP 1 was synthesized in 5 steps with 31.6% overall yield and (?)-DMJ 2 was synthesized in 4 steps with 60.6% overall yield.     

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).     

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.     

Stereocontrolled construction of tetrasubstituted tetrahydrofurans: synthesis of 2,5-anhydro d-glucitol

A highly stereoselective construction of 2,3,4,5-tetrasubstituted tetrahydrofurans has been accomplished by an unusual intramolecular 5-endo-tet cyclization of 2,3-epoxy alcohols involving hydroxyl nucleophile. The method has been utilized for the synthesis of 2,5-anhydro d-glucitol through two different approaches starting from the chiral molecule, l(+)-diethyl tartarate or from the non-chiral compound, allyl bromide or cis-but-2-ene-1,4-diol. This synthetic method is a useful example of 5-endo-tet cyclization of 2,3-epoxy alcohols.     

A concise synthesis of 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and HomoDMDP from l-xylose

A short and practical procedure for the preparation of C-2 substituted polyhydroxypyrrolidines is described. The C-2 substituent is introduced by a stereoselective addition of a Grignard reagent to a 2,3,5-protected aldofuranose and the cyclization to the pyrrolidine ring system is performed through a bis-mesylation/double nucleophilic displacement sequence. The efficiency of the methodology was demonstrated by its application to the synthesis of HomoDMDP and DMDP.     

Stereo-controlled approach to pyrrolidine iminosugar C-glycosides and 1,4-dideoxy-1,4-imino-l-allitol using a d-mannose-derived cyclic nitrone

Intramolecular N-alkylation of 2,3-O-isopropylidene-5-O-methanesulfonyl-6-O-t-butyldimethylsilyl-d-mannofuranose-oxime 7 afforded a five-membered cyclic nitrone 9, which on N-O bond reductive cleavage followed by deprotection of -OTBS and acetonide functionalities gave 1,4-dideoxy-1,4-imino-l-allitol (DIA) 3. Addition of allylmagnesium chloride to nitrone 9 afforded α-allylated product 10a in high diastereoselectivity providing an easy entry to N-hydroxy-C1-α-allyl-substituted pyrrolidine iminosugar 4a after removal of protecting group, while N-O bond reductive cleavage in 10a afforded C1-α-allyl-pyrrolidine iminosugar 4b.     

New entry to pyrrolidine homoazasugars: conversion of d-arabinose into 2,5-anhydro-2,5-imino-d-glucitol via aminohomologation

The title homoazasugar, also referred as (2R,5S)-bis(hydroxymethyl)-(3R,4R)-dihydroxypyrrolidine, has been synthesized by addition of 2-lithiothiazole to the 2,3,5-tri-O-benzyl-d-arabinofuranose-derived nitrone---hydroxylamine mixture followed by reductive N-dehydroxylation and conversion of the thiazole ring into the hydroxymethyl group.     

A short and efficient synthesis of 1,5-anhydro-d-glucitol 6-phosphate

The important d-glucose and d-glucose 6-phosphate analogues 1,5-anhydro-d-glucitol and 1,5-anhydro-d-glucitol 6-phosphate were prepared from methyl-d-glucoside in high yield and purity. Protecting of the hydroxyl groups as their allyl ether followed by reductive cleavage of the glycosidic linkage with triethylsilane formed the protected anhydroglucitol. No ring rearrangement or ring contraction was observed during the reduction step. Using the PdCl₂-CuCl₂-activated charcoal system, the allyl ether bond was cleaved with a low loading of the catalyst (0.0025 equiv per allyl group). 1,5-Anhydro-d-glucitol 6-phosphate was prepared by the phosphylation of 1,5-anhydro-d-glucitol.     

The synthesis of the molecular chaperone 2,5-dideoxy-2,5-imino-d-altritol via diastereoselective reductive amination and carbamate annulation

The iminosugar 2,5-dideoxy-2,5-imino-d-altritol (DIA, 2) is a powerful competitive inhibitor of α-galactosidase A and has shown much promise as a pharmacological chaperone for the treatment for Fabry disease. Notwithstanding, syntheses of DIA are in want of optimisation. Accordingly, we report on the total synthesis of DIA in 7 steps and in 22% overall yield from readily available d-tagatose. This is the shortest and most efficient synthesis of DIA to date, with key steps in our synthetic strategy including a diastereoselective reductive amination and an I₂-mediated carbamate annulation.     

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.     

Polyhydroxylated pyrrolidines: synthesis from d-fructose of new tri-orthogonally protected 2,5-dideoxy-2,5-iminohexitols

The readily available 3-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (2) was transformed into its 5-O- (3) and 4-O-benzoyl (4) derivative. Compound 4 was straightforwardly transformed into 5-azido-4-O-benzoyl-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (7) via the corresponding 5-deoxy-5-iodo-α-l-sorbopyranose derivative 6. Cleavage of the acetonide in 7 to give 8, followed by regioselective 1-O-silylation to 9 and subsequent catalytic hydrogenation gave a mixture of (2S,3R,4R,5R)- (10) and (2R,3R,4R,5R)-4-benzoyloxy-3-benzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (12) that was resolved after chemoselective N-protection as their Cbz derivatives 11 and 1a, respectively. Stereochemistry of 11 and 1a could be determined after total deprotection of 11 to the well known DGDP (13). Compound 2 was similarly transformed into the tri-orthogonally protected DGDP derivative 18.     

One-pot inversion of d-mannono-1,4-lactone for the practical synthesis of l-ribose

l-Ribose was synthesized in a concise manner from d-mannono-1,4-lactone using one-pot inversion conditions. Treatment of d-mannono-1,4-lactone with piperidine, followed by mesylation-induced S_N2-type O-alkylation, afforded the desired one-pot inversion in an optimum yield, and the following straightforward transformations provided l-ribose in good yields.     

Efficient synthesis of new N-alkyl-d-ribono-1,5-lactams from d-ribono-1,4-lactone

d-Ribono-1,4-lactone was treated with ethylamine in DMF to afford N-ethyl-d-ribonamide 9a in quantitative yield. Bromination of amide 9a by the system SOBr₂ in DMF or PPh₃/CBr₄ in pyridine led, after acetylation, to epoxide 7. However, treatment of amide 9a with acetyl bromide in dioxane followed by acetylation gave 2,3,4-tri-O-acetyl-5-bromo-5-deoxyl-N-ethyl-d-ribonamide 10a. Methanolysis of 10a, with sodium methoxide, afforded the N-ethyl-d-ribonolactam 11a in 51% overall yields. Using this method, N-butyl, N-hexyl, N-dodecyl, and N-benzyl-d-ribonolactams 11b-e were obtained in good yields (48-53%).     

Stereo-controlled approach to pyrrolidine iminosugar C-glycosides and 1,4-dideoxy-1,4-imino-l-allitol using a d-mannose-derived cyclic nitrone

Intramolecular N-alkylation of 2,3-O-isopropylidene-5-O-methanesulfonyl-6-O-t-butyldimethylsilyl-d-mannofuranose-oxime 7 afforded a five-membered cyclic nitrone 9, which on N–O bond reductive cleavage followed by deprotection of –OTBS and acetonide functionalities gave 1,4-dideoxy-1,4-imino-l-allitol (DIA) 3. Addition of allylmagnesium chloride to nitrone 9 afforded α-allylated product 10a in high diastereoselectivity providing an easy entry to N-hydroxy-C1-α-allyl-substituted pyrrolidine iminosugar 4a after removal of protecting group, while N–O bond reductive cleavage in 10a afforded C1-α-allyl-pyrrolidine iminosugar 4b.     

Polyhydroxylated pyrrolidines, III. Synthesis of new protected 2,5-dideoxy-2,5-iminohexitols from d-fructose

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (6) was straightforwardly transformed into 5-azido-3-O-benzoyl-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (8), after treatment under modified Garegg's conditions followed by reaction of the resulting 3-O-benzoyl-4-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-l-sorbopyranose (7) with lithium azide in DMF. O-debenzoylation at C(3) in 8, followed by oxidation and reduction caused the inversion of the configuration to afford the corresponding β-d-psicopyranose derivative 11 that was transformed into the related 3,4-di-O-benzyl derivative 12. Cleavage of the acetonide of 12 to give 13 followed by O-tert-butyldiphenylsilylation afforded a resolvable mixture of 14 and 15. Compound 14 was transformed into (2R,3R,4S,5R)- (17) and (2R,3R,4S,5S)-3,4-dibenzyloxy-2′,5′-di-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (18) either by a tandem Staudinger/intramolecular aza-Wittig process and reduction of the resulting intermediate Δ²-pyrroline (16), or only into 18 by a high stereoselective catalytic hydrogenation. When 15 was subjected to the same protocol, (2S,3S,4R,5R)- (21) and (2R,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (22) were obtained, respectively.     

Stereoselective synthesis of farnesylphosphoryl β-d-arabinofuranose

Decaprenylphosphoryl β-d-arabinofuranose (DPA) is a key arabinose donor in mycobacteria. In an effort to establish a practical synthetic scheme for DPA, the synthesis of nerylphosphoryl and farnesylphosphoryl β-d-arabinofuranoses has been developed. The products were obtained by coupling of a suitably protected β-d-arabinofuranosyl phosphate intermediate with activated forms of the C₁₀ nerol and C₁₅trans,trans-farnesol and subsequent deprotection.     

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.     

Tetrahydrofuran-mediated radical processes: stereoselective synthesis of d,l-hexestrol

The highly stereoselective synthesis of d,l-hexestrol (1), an inhibitor of microtubule assembly, is developed by using, as a key step, an intermolecular coupling of Co₂(CO)₆-complexed propargyl radicals. The latter are generated by novel complementary processes involving an interaction of tetrahydrofuran with Co₂(CO)₆-complexed propargyl alcohols and cations. An isomerically pure d,l-μ-η²-[3,4-di(4-methoxyphenyl)-1,5-hexadiyne]-bis-dicobalthexacarbonyl (d,l-6) is isolated in 69-91% yield with intermolecular coupling reactions exhibiting an excellent chemo- (0.5-7%) and d,l-diastereoselectivity (90-94%). The structure of d,l-6 is determined by X-ray diffraction. The subsequent steps include BBr₃-induced demethylation of 4-methoxyaryl groups, demetalation with cerium(IV) ammonium nitrate, and hydrogenation of acetylenic termini affording d,l-hexestrol (1).     

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.     

Synthesis of (−)-lentiginosine, its 8a-epimer and dihydroxylated pyrrolizidine alkaloid from d-glucose

The d-glucose derived α,β-unsaturated ester 5 on 1,2-acetonide deprotection, oxidative diol cleavage followed by treatment with N-benzylamine in the presence of NaBH₃CN undergoes reductive amination and a concomitant intramolecular conjugate addition reaction leading to the formation of dihydroxypyrrolidine-ester 6a and monohydroxypyrrolidine-γ-lactone 6b. Intermediates 6a and 6b were efficiently converted to (−)-lentiginosine 3a, its 8a-epimer 3b, and pyrrolizidine azasugar 4 in good overall yield.