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.     

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.     

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.     

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).     

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.     

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.     

d-Phg-l-Pro Dipeptide-derived prolinol ligands for highly enantioselective Reformatsky reactions

Optically pure N-aminoethyl prolinol derivatives 3a-c have been prepared from the dynamic kinetic resolution of N-(α-bromo-α-phenylacetyl) proline ester 1 in asymmetric nucleophilic substitution and subsequent reduction. The peptide-derived prolinols are tested as chiral ligands in the asymmetric addition of Reformatsky reagent to aromatic aldehydes. Chiral ligand 3c has been shown to be effective to produce enantioenriched β-hydroxy esters 5a-j with up to 98% ee.     

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.     

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.     

N-Nosyl as a stereoselectivity-improving and easily removable group in the O-glycosylation of d-allal and d-galactal-derived allyl aziridines. Stereospecific synthesis of 4-amino-2,3-unsaturated-O-glycosides

The glycosylation of alcohols, phenol, and partially protected monosaccharides with the diastereoisomeric d-allal and d-galactal-derived N-nosyl aziridines 2α and 2β leads to the corresponding 4-N-(nosylamino)-2,3-unsaturated-α-O- (6α) and β-O-glycosides and disaccharides (6β), respectively, in a stereospecific substrate-dependent O-glycosylation process. The N-(nosylamino) group of 6α and 6β can easily be deprotected to give the corresponding 4-amino-2,3-unsaturated-O-glycosides 7α and 7β, with an increased value to our glycosylation protocol.     

Synthesis of orthogonally protected d-olivoside, 1,3-di-O-acetyl-4-O-benzyl-2,6-dideoxy-d-arabinopyranose, as a C-glycosyl donor

1,3-Di-O-acetyl-4-O-benzyl-2,6-dideoxy-d-arabinopyranose (11) was synthesised from thiophenyl α-d-mannopyranoside (21) in an eight-step sequence. Tosylation of 21 and subsequent reaction with 2,2-dimethoxypropane gave tosylate 22, which upon treatment with lithium aluminium hydride furnished 6-deoxy glycoside 24 and by-product thiophenyl 6-deoxy-2-O-isopropyl-α-d-arabinopyranoside. The X-ray crystal structure of the latter was determined. Benzylation of the 4-hydroxyl group of 24 and subsequent protecting group manipulation gave d-rhamnosyl bromide 29, which on treatment with zinc-copper couple gave the orthogonally protected d-rhamnal 30. Triphenylphosphine hydrogen bromide catalysed addition of acetic acid to 30 furnished the target molecule 11. The scandium(III) triflate promoted reaction of 11 and 2-naphthol gave the corresponding C-glycoside 36 in 86% yield.     

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.     

Selection of synthetic receptors capable of sensing the difference in binding of d-Ala-d-Ala or d-Ala-d-Lac ligands by screening of a combinatorial CTV-based library

Screening of a combinatorial CTV-based artificial, synthetic receptor library 1 {1-13, 1-13, 1-13} for binding of a variety d-Ala-d-Ala and d-Ala-d-Lac containing ligands (6-11) was carried out in phosphate buffer (0.1 N, pH=7.0). After screening and Edman sequencing, synthetic receptors were found containing amino acid sequences, which are either characteristic for binding dye labeled d-Ala-d-Ala or d-Ala-d-Lac containing ligands. For example, receptors capable of binding d-Ala-d-Ala containing ligands 6, 7, 9 and 11 contained—almost in all cases—at least one basic amino acid residue—predominantly Lys—in their arms. This was really a striking difference with the arms of the receptors capable of binding d-Ala-d-Lac containing ligands 8 and 10, which usually contained a significant number of polar amino acids (Gln and Ser), especially in ligand 8, but hardly any basic amino acids. Use of different (fluorescent) dye labels showed that the label has a profound, albeit not decisive, influence on the binding by the receptor. A hit from the screening of the CTV-library with FITC-peptidoglycan (6) was selected for resynthesis and validation.     

Stereo-conserved synthesis of syn-diarylheptanoids, active principles of Zingiber, starting from d-glucose

A highly efficient and stereo-controlled synthetic strategy has been developed to access syn-diarylheptanoids, for example, 2,3, 4, and 5b starting from d-glucose as a chiral pool. The 3-(R), 5-(S)-syn-diol stereochemistry present in these heptanoids was obtained after conserving C2 and C4 stereochemistry of d-glucose during the course of synthetic transformation. The key features of this synthetic strategy include: (i) conversion of d-glucose to a known chiral template 6 armored with the required 1,3-syn-diol stereochemistry as well as two terminal aldehyde functionalities for building up customized ‘diaryl wings’; (ii) conversion of 6 to 7 via an initial Wittig olefination at the C5-aldehyde; (iii) use of the hemiacetal 7 as a common intermediate to obtain the individual heptanoids via a second Wittig reaction at its anomeric center using appropriately chosen ylides.     

Synthesis of (+)-1-epi-castanospermine from l-sorbose

Diastereoselective synthesis of 1-epi-castanospermine (2) from l-sorbose is described. The successful approach involved the use of 8-azido-2,8-dideoxy-α-l-gulo-oct-4-ulo-4,7-furanosononitrile intermediate (17). This compound was easily made in five steps from 3-O-benzoyl-2-deoxy-4,5:6,8-di-O-isopropylidene-α-l-gulo-oct-4-ulo-4,7-furanosononitrile (7) previously synthesized from l-sorbose. Catalytic hydrogenation of the azido intermediate 17 with Pd-C afforded with total stereocontrol one of the two possible piperidine diastereomers. Acid-catalyzed internal reductive deamination of the nitrile derivative completed the total synthesis of (1R,6S,7R,8R,8aR)-1,6,7,8-tetrahydroxyindolizidine [(+)-1-epi-castanospermine, 2].     

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).     

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%).     

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.     

Synthesis of the N-(tert-butyloxycarbonyl)-O-triisopropylsilyl-d-pyrrolosamine glycal of lomaiviticins A and B via epimerization of l-Threonine

An efficient synthesis of the N-(tert-butyloxycarbonyl)-O-triisopropylsilyl-d-pyrrolosamine glycal of lomaiviticin A (1) and lomaiviticin B (2) is described. The synthesis is highlighted by the epimerization of the l-threonine-derived oxazolidine 10 to oxazolidine 11. This key epimerization reaction, which serves to establish the correct relative configuration of the carbohydrate unit, was made possible only after conformational analysis indicated that substituted oxazolidines may adopt conformations that preclude enolization.     

Stereoselective synthesis of 4-C-methyl-2,3,5-tri-O-benzyl-d-ribofuranose and 4-C-methyl-2,3,5-tri-O-benzyl-l-lyxofuranose

Sugar intermediates 4-C-methyl-2,3,5-tri-O-benzyl-d-ribofuranose (8b) and 4-C-methyl-2,3,5-tri-O-benzyl-l-lyxofuranose (8a) were synthesized by addition of alkylithium reagents to pentanones 3a,b. The nucleophilic additions proceeded with good stereoselectivity and good yields to give the titled compounds in four steps from perbenzylated methyl d-ribofuranoside and methyl 5′-deoxy-d-ribofuranoside.