A convenient approach toward the synthesis of enantiopure isomers of DMDP and ADMDP

A practical method for the synthesis of five-membered iminocyclitols, pyrrolidine alkaloids bearing multiple hydroxyl substituents, has been developed. All of the eight key intermediates, enantiopure tri-O-benzyl cyclic nitrones, are prepared from four cheap, readily available d-aldopentoses. The nucleophilic addition of cyclic nitrones with vinyl magnesium chloride and TMSCN shows high 2,3-trans stereoselectivity. To construct the 2,3-cis configurations, inversion of the C-2 nitrile group is achieved via an elimination-reduction sequence. Using this approach, five isomers of DMDP and six isomers of ADMDP are prepared efficiently. In the biological evaluation, iminocyclitol 27 is a new and potent inhibitor against β-hexosaminidase with an IC₅₀ value of 0.2 μM.     

Stereocontrolled asymmetric synthesis of alpha-hydroxy-beta-amino acids. A stereodivergent approach

The stereocontrolled asymmetric synthesis of alpha-hydroxy-beta-amino acids has been investigated via the Lewis acid-promoted cyanation of (5R,6S)-2-acetoxy-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazines with trimethylsilyl cyanide. Base-catalyzed hydrolysis of the resulting cyano compounds proceeds with excellent stereoselectivity, providing access to diastereomerically pure oxazine-2-carboxylic acids which were readily converted to each enantiomer of the alpha-hydroxy-beta-amino acids isothreonine and nor-C-statine.     

Stereocontrolled access to orthogonally protected anti,anti-4-aminopiperidine-3,5-diols through chemoselective reduction of enantiopure beta-lactam cyanohydrins

The cyanosilylation of enantiopure 4-oxoazetidine-2-carbaldehydes with tert-butyldimethylsilyl cyanide was promoted by either molecular sieves or catalytic amount of sodium carbonate to give O-silylated beta-lactam cyanohydrins with good yield and diastereoselectivity. In contrast, Lewis acids did not effectively promote the cyanosilylation under different experimental conditions, and instead hydrocyanation took place affording the corresponding free cyanohydrins in variable yield and selectivity. Starting from beta-lactam cyanohydrin hybrids, two concise, complementary stereocontrolled routes to optically pure orthogonally protected anti,anti-4-amino-3,5-piperidine diols were achieved. Key features of the first approach include chemoselective reductive opening of the beta-lactam ring with LiBH4 to a 3-amino-5-hydroxy pentanenitrile followed by reductive cyclization of a conveniently functionalized cyanomesylate derivative with NaBH4/NiCl2. The second approach involves LiAlH4 reduction of protected anti,anti-4-amino-3,5-dihydroxypiperidin-2-ones, which were easily obtained by chemoselective reduction of the cyano group in the beta-lactam cyanohydrin hybrids with NaBH4/NiCl2 and subsequent intramolecular rearrangement of the resulting amino beta-lactams. Both routes make use of an oxidative N-dearylation with diacetoxyiodobenzene of a 4-methoxyphenylamino group as a common synthetic step. Specifically, the utility of this novel reaction sequence has been demonstrated by the synthesis of fully orthogonally protected sialidase inhibitors.     

Stereocontrolled synthesis of clerodin homolog A synthetic approach to structure-activity relationships

In order to elucidate the structure-activity relationships of the antifeeding diterpenes having a $\text{neo}$-clerodane skeleton, clerodin homolog $\text{5}$ was stereoselectively synthesized through 18 steps $\text{via}$ a key intermediate $\text{11}$. Perhydrofuro[2,3-b]furan ring in the synthesized homolog was more unstable than that of the natural product, and gave a $\text{tri}$-MeOH adduct $\text{3}$ in a similar behavior to that of the model compounds $\text{1}$ and $\text{2}$.     

Practical and convenient enzymatic synthesis of enantiopure alpha-amino acids and amides

Catalyzed by the nitrile hydratase and the amidease in Rhodococcus sp. AJ270 cells under very mild conditions, a number of alpha-aryl- and alpha-alkyl-substituted DL-glycine nitriles 1 rapidly underwent a highly enantioselective hydrolysis to afford D-(-)-alpha-amino acid amides 2 and L-(+)-alpha-amino acids 3 in high yields with excellent enantiomeric excesses in most cases. The overall enantioselectivity of the biotransformations of nitriles originated from the combined effects of a high L-enantioselective amidase and a low enantioselective nitrile hydratase. The influence of the substrates on both reaction efficiency and enantioselectivity was also discussed in terms of steric and electronic effects. Coupled with chemical hydrolysis of D-(-)-alpha-phenylglycine amide, biotransformation of DL-phenylglycine nitrile was applied in practical scale to produce both D- and L-phenylglycines in high optical purity.     

A convenient approach to an advanced intermediate for (+)-lactacystin synthesis

A fully stereoselective preparation of the advanced intermediate 24 for the synthesis of (+)-lactacystin from known 1,2:5,6-di-O-isopropylidene-α-d-gulofuranose (2), as the source of chirality, has been achieved. The C-5 methyl group was introduced via a Wittig olefination followed by Pd/C-mediated hydrogenation of the conformationally restricted alkene 11 in a highly stereoselective manner. The stereogenic tetrasubstituted carbon centre at C-3, with an amino group, was installed stereoselectively via an Overman rearrangement, which was efficiently controlled by a saccharide environment.     

Stereocontrolled synthesis of clerodin homolog: A Synthetic approach to structure-activity relationships

In order to elucidate the structure-activity relationships of the antifeeding di-terpenes, clerodin homolog $\text{5}$ was stereoselectively synthesized through 18 steps $\text{via}$ a key intermediate $\text{12}$. The perhydrofuro[2,3-b]furan ring in the synthesized homolog was less stable than that of the natural product, and its reactivity on methanolysis and potency of the antifeeding activity were almost the same as those of a 2,6-di-methylphenyl derivative $\text{10}$ which is more sterically restricted than a phenyl derivative $\text{2}$. The findings supported the hypothesis for the relationships on the structure (stereostructure) and activity of biological active substances. The methodology is conceptually termed “Dynamic structure-activity relationships,” and is effective from the standpoint of drug design.     

A convenient access to 3-cyanoflavones

Reaction of β-bromo α-alkylthiocinnamonitriles with various substituted methyl salicylates followed by treatment with AlCl₃/PhNO₂ provides 3-cyanoflavones.     

A convenient access to 1,5-anhydroketoses

A convenient, versatile entry into the 1,5-anhyroketose series is described and their conversion into enolones, enolone oximes and γ-pyrones.     

New and convenient approach for synthesis of metconazole

In terms of environmental and food supply protection, development of green, efficient, and less toxic pesticides is of great importance and in continuous demand. Metconazole, a triazole antiseptic, possesses such advantages, being environmentally friendly and high efficiency with broad-spectrum activity against bacteria and fungi. However, previously reported synthetic routes for metconazole have many disadvantages, for example, requiring multiple steps, being complicated, and suffering from high cost. We report herein a new, convenient, and high-yield four-step (aldol condensation, dimethylation, hydrogenation, and one-pot triazolation) synthesis for metconazole with relatively low cost.     

New convenient synthesis of iridol. An approach to the synthesis of ubiquinones

A strategy for the synthesis of ubiquinones, in which iridol is the key intermediate, has been developed, together with a new convenient synthesis of iridol (2,3-dimethoxy-5-methylphenol) starting from the easily available 4-methylphenol and using mild conditions and friendly and high-yielding reactions.     

A new convenient route to enantiopure 2-coumarinyloxypropanals: application to the synthesis of optically active geiparvarin analogues

A new convenient route to enantiopure 2-coumarinyloxypropanals is described: Rosenmund reduction of (R)- or (S)-2-coumarinyloxypropanoyl chlorides afforded in good yields the corresponding 2-coumarinyloxypropanals. Their subsequent aldolic condensation with 3(2H)-furanones, followed by dehydration, led to enantiopure geiparvarin analogues now being investigated as promising antitumoral compounds.     

A simple route to enantiopure bis-lactones: synthesis of both enantiomers of epi-nor-canadensolide, nor-canadensolide, and canadensolide

A simple strategy has been developed for the synthesis of both enantiomers of nor-canadensolide, epi-nor-canadensolide, and an intermediate to canadensolide. An orthoester Claisen rearrangement of an appropriately constructed allyl alcohol derivative prepared from R-(+)-2,3-di-O-cyclohexylidine glyceraldehyde followed by epoxidation of the resulting unsaturated esters produced hydroxy-lactones, which on oxidation gave keto-lactones. Stereoselective reduction of the keto-carbonyl using either a chelation controlled or a non-chelation controlled process led to the natural or the epi-series, respectively. The interplay of the electronic effect between the polar groups and the steric effect of the β-substituent during reduction of the keto-lactones turned out to be the key factors in deciding the stereochemical outcome. Regeneration of the aldehyde functionality latent in the ketal moiety of the hydroxy-lactones provided the lactols, which on oxidation gave the bis-lactones.     

A novel chemo-multienzymatic synthesis of bioactive cyclophellitol and epi-cyclophellitol in both enantiopure forms

A new route to synthesize cyclophellitol and epi-cyclophellitol from racemic starting materials in enantiopure forms has been developed. The synthesis involves a multi-enzymatic biotransformation pathway of the novel cyano-cyclitol (1R,4S,5R,6R)/(1S,4R,5S,6S)-4,5,6-trihydroxycyclohex-2-enecarbonitrile by a cooperative use of lipase, nitrile hydratase, and amidase.     

A two-directional approach to enantiopure 1,4-difluoro-cyclohexenes: synthesis of difluorinated cyclitol analogues

Enantiopure 1,4-difluoro-cyclohexenes were prepared from readily available acetonide-protected (3 S,4 S)-hexa-1,5-diene-3,4-diol. In a two-directional mode, a double cross-metathesis reaction using allyltrimethylsilane as the olefinic partner, followed by electrophilic fluorination, afforded diastereomeric acetonide-protected 3,6-difluoro-octa-1,7-diene-4,5-diols. These dienes were found to be suitable substrates for ring-closing metathesis, delivering cyclohexenes featuring fluorine atoms on the two allylic positions flanking the double bond. Upon dihydroxylation, novel difluorinated cyclitol analogues were formed.     

A convenient chromatography-free access to enantiopure 6,6′-di-tert-butyl-1,1′-binaphthalene-2,2′-diol and its 3,3′-dibromo,di-tert-butyl and phosphorus derivatives: utility in asymmetric synthesis

A simple chromatography-free high-yielding synthesis of the hexane-soluble enantiopure 6,6′-di-tert-butyl-1,1′-binaphthalene-2,2′-diol 3 (6,6′-di-tert-butyl BINOL) using Friedel–Crafts reaction on 1,1′-binaphthalene-2,2′-diol 1 (BINOL) is described. The enantiomeric purity was fully maintained in the reaction. Compound 3 has been used as an entry point for the convenient chromatography-free synthesis of 3,3′,6,6′-tetra-tert-butyl BINOL 4 and 3,3′-dibromo-6,6′-di-tert-butyl BINOL 5. A straightforward route to enantiopure bisphosphites [(6,6′-R₂C₂₀H₁₀O₂)P]₂[O₂C₂₀H₁₀-6,6′-R₂] [R = H 15, t-Bu 16] by simply reacting phosphorochloridite (6,6′-R₂C₂₀H₁₀O₂)PCl [R = H 20, t-Bu 6] with metallic sodium is highlighted. The identity of 15 and 16 as their selenium-oxidized products 17 and 18 (at phosphorus center) is confirmed by X-ray crystallography (17 in the enantiopure form and 18 as racemate). Various enantiopure phosphoramidites of the modified BINOL have been synthesized. It is established that even when the phosphoramidites derived from the unsusbstituted BINOL 1 fail to give an appreciable optical induction in the asymmetric reduction of acetophenone/phenacyl chloride, those derived from 3 do induce moderate chiral induction (up to 30% ee in the case for acetophenone and 43% ee in the case of phenacyl chloride), thus leaving scope for further improvement in ee for related reactions.     

Stereocontrolled synthesis of enantiopure anticancer cyclopentenone prostaglandin analogues: (−)- and (+)-TEI-9826

The synthesis of both enantiomers of TEI-9826 has been accomplished in seven steps with an overall yield of 44% starting from diastereomeric camphor protected 3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxycyclopent-2-enones. The key steps include a fully diastereoselective hydrogenation of the endocyclic carbon–carbon double bond in the cyclopentenone ring controlled with a chiral diol moiety and the conversion of the latter into a new transposed olefinic bond.     

Boron trifluoride-induced reactions of phenylglycidyl ethers: a convenient synthesis of enantiopure, stereodefined fluorohydrins

Ring-opening hydrofluorination of enantiomerically pure (2S,3S)-3-arylglycidyl ethers (aryl = phenyl, 4-trifluoromethylphenyl) by boron trifluoride-diethyl ether under mild conditions provides β-fluoro alcohols in good yield in a stereospecific manner with complete regiocontrol.     

A simple,convenient and expeditious approach to cineol

A convenient two‐step protocol preparation of cineol (1‐isopropyl‐4‐methyl‐7‐oxabicyclo[2,2,1]heptane) from α‐terpineol (p‐menth‐1‐en‐8‐ol) is reported. The phenylselenoetherification of α‐terpineol with PhSeX (X = Cl, Br, I) as a key step is described. α‐Terpineol reacts with PhSeX to form the corresponding phenylselenoether in short reaction time and in quantitative yield. A subsequent reduction with Bu₃SnH to cineol proceeds in high yield (98%) © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:468–470, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20044