Enantiodivergent formal synthesis of (+)- and (-)-cyclophellitol from D-xylose based on the latent symmetry concept

Formal synthesis of (+)- and (-)-cyclophellitol from d-xylose has been accomplished through utilization of the latent plane of chirality present in the starting carbohydrate. The synthetic pathway is suitable for preparation and biological evaluation of cyclophellitol analogues in both enantiomeric series.     

Enantioselective Syntheses of (-)- and (+)-Homocitric Acid Lactones

Highly enantioselective syntheses of enantiomers of homocitric acid lactones (R)-5a and (S)-5b are described. Thermal Diels-Alder cycloadditions of 2a and 2b to 1,3-butadiene produced adducts 3a and 3b, respectively. Oxidative ozonolysis of latter adducts gave products 4a and 4b which after acid treatment afforded a mixture with 5a and 5b as major component. Acid lactones 5a and 5b were converted into their dimethyl esters 6a and 6b which were purified by chromatography. After saponification, the products obtained were crystallized to yield (-)- and (+)-homocitric acid lactones ((R)-5a and (S)-5b). Diastereomeric excess (de) of Diels-Alder adducts 3a and 3b was determined by means of Mosher esters of glycols 8a, 8b, and racemic 8. Diels-Alder cycloaddition products of lactones 2a and 2b to 1,3-butadiene showed a diastereoselectivity of 96%.     

Syntheses of (+)-cytisine, (-)-kuraramine, (-)-isokuraramine, and (-)-jussiaeiine A

Total syntheses of (+)-cytisine, (-)-kuraramine, (-)-isokuraramine, and (-)-jussiaeiine A were achieved via a samarium diiodide-promoted reductive deamination reaction, followed by simultaneous recyclization of a proline derivative to give the corresponding delta-lactam derivative, as a key step.     

Syntheses of (+)-alismoxide and (+)-4-epi-alismoxide

The first total syntheses of (+)-alismoxide and (+)-4-epi-alismoxide are reported. Formal chemo-, regio-, and stereoselective addition of water to 10alpha-acetoxy-1alphaH,5betaH-guaia-3,6-diene afforded the target compounds after reduction. The absolute stereochemistry of (+)-alismoxide has been established. The low [alpha](D) +8.6 value indicates that significant amounts of alismoxide result from biosynthetic processes. Furthermore, the structure of the natural guaienediol isolated from Silphium perfoliatum has been corrected to (-)-alismoxide.     

Syntheses of (+)- and (–)-Methyl 8-Epinonactate and (+)- and (–)-Methyl Nonactate

In four synthetic steps, (+)- and (–)-methyl 8-epinonactate ((+)- and (–)− 4 ) have been derived from (+)- and (–)-7-oxabicyclo[2.2.1]heptan-2-one ((+)- and (–)− 9 ), respectively. The (+)- and (–)-methyl nonactate ((+)- and (–)− 3 ) were obtained from (+)- and (–)− 4 , respectively, by Mitsunobu displacement reactions. Optical resolution of (±)− 9 via chromatographic separation of the corresponding N-methyl-S-alkyl-S-phenylsulfoximides 24 and 25 yielded the starting materials (+)- and (–)− 9 , respectively.     

Total Syntheses of (+)-Goniotriol and (+)- 8-Acetylgoniotriol

Two styryl-pyrones, (+)-goniotriol (1) and (+)-8-acetylgoniotriol (2), which are cytotoxic to human turnout cells, were isolated from the ethanolic extracts of the stem bark of Goniothalamus giganteus Hook. F., Thomas (Annonaceae), in addition (+)-goniotriol was also isolated from the leaves and twigs of Goniothalamus     

A total synthesis of natural cerulenin from D-glucose

$\text{D}$-glucose has served as a chiral synthon in a total synthesis of the fungal metabolite cerulenin.     

Highly efficient total synthesis of the marine natural products (+)-avarone, (+)-avarol, (-)-neoavarone, (-)-neoavarol and (+)-aureol

Biologically important and structurally unique marine natural products avarone (1), avarol (2), neoavarone (3), neoavarol (4) and aureol (5), were efficiently synthesized in a unified manner starting from (+)-5-methyl-Wieland-Miescher ketone 10. The synthesis involved the following crucial steps: i) Sequential BF(3)Et(2)O-induced rearrangement/cyclization reaction of 2 and 4 to produce 5 with complete stereoselectivity in high yield (2 --> 5 and 4 --> 5); ii) strategic salcomine oxidation of the phenolic compounds 6 and 8 to derive the corresponding quinones 1 and 3 (6 --> 1 and 8 --> 3); and iii) Birch reductive alkylation of 10 with bromide 11 to construct the requisite carbon framework 12 (10 + 11 --> 12). An in vitro cytotoxicity assay of compounds 1-5 against human histiocytic lymphoma cells U937 determined the order of cytotoxic potency (3 > 1 > 5 > 2 > 4) and some novel aspects of structure-activity relationships.     

Total synthesis of natural (+)-sesbanimide a and (-)-sesbanimide b

The first total synthesis of natural (+)-sesbanimide A (1) and (-)-sesbanimide B (2), potent antitumor alkaloids isolated from the seeds of the leguminous plant, Sesbania drummondii, has been accomplished starting from D-(+)-xylose. This total synthesis involves efficient construction of the optically active AB-ring system from D-(+)-xylose, introduction of the C₅-unit into the AB-ring system in a form of exo-methylene-γ-lactone, and elaboration of the labile C-ring system at the last stage of the synthesis. The absolute configurations of natural 1 and 2 could be obviously established by our total synthesis.     

Enzymatic synthesis of (-)- and (+)-acetoxyhexamides and (-)- and (+)-hydroxyhexamides.

The enantioselective hydrolysis of (+/-)-4-(1-acetoxyethyl)-N-(cyclohexylcarbamoyl)-benzenesulfona mides 3 with lipase Amano P from Pseudomonas sp. in a water-saturated solvent gave (R)-4-(1-hydroxyethyl)-N-(cyclohexylcarbamoyl)benzenesulfonamide 2 (39%, > 99% ee) and unchanged (S)-3 (50%, 62% ee). On the other hand, enantioselective esterification of (+/-)-2 with lipase Amano P in the presence of vinyl acetate provided (R)-3 (41%, > 99% ee) and unchanged (S)-2 (46%, 78% ee).     

Syntheses of (S)-(+)-trihexyphenidyl hydrochloride and (S)-(+)-procyclidine hydrochloride, two anticholinergics, using (S)-(-)-3-cyclohexyl-3-hydroxy-3-phenylpropanoic acid as chiral synthon

The absolute configuration of the more active (-)-enantiomer of the anticholinergic trihexyphenidyl hydrochloride has been established as (R) by syntheses of (S)-(+)-procyclidine hydrochloride, whose absolute configuration has been established previously, and (S)-(+)-trihexyphenidyl hydrochloride from the same chiral building block, viz. (S)-(-)-cyclohexyl-3-hydroxy-3-phenylpropanoic acid. Both enantiomers of this chiral synthon were prepared by optical resolution of the corresponding racemate, employing (R)- and (S)-1-phenylethylamine, respectively, as resolving agents.     

Convenient synthesis of (+)-valiolamine and (-)-1-epi-valiolamine from (-)-vibo-quercitol

Convenient and practical synthesis of (+)-valiolamine and (-)-1-epi-valiolamine from (-)-vibo-quercitol, 1-deoxy-L-myo-inositol, readily obtained by bioconversion of myo-inositol, is described.     

Total synthesis of (S)-(+)-curcudiol, and (S)-(+)- and (R)-(-)-curcuphenol.

A highly enantioselective synthesis of the versatile chiral synthons possessing one stereogenic center, (S)- and (R)-4-aryl-5-hydroxy-(2E)-pentenoate (3) was achieved based on the enzymatic reaction of (+/-)-3 with commercially available lipases MY-30 or OF-360 from Candida rugosa. Application of (S)-3 and (R)-3 to the total syntheses of(S)-curcuphenol (1), (S)-curcudiol (2), and (R)-curcuphenol (1), respectively, is described.     

Synthetic studies towards pentacyclic quassinoids: total synthesis of unnatural (-)-14-epi-samaderine E and natural (-)-samaderine Y from (S)-(+)-carvone

First total syntheses of unnatural (-)-14-epi-samaderine E (5) and natural (-)-samaderine Y (2) were accomplished from (S)-(+)-carvone (6) in 18 and 21 steps, respectively. The syntheses are short, efficient (with an average yield of 80 % plus for each transformation), enantiospecific, and produce nine new chiral centers. The crucial points of the syntheses included a regioselective allylic oxidation on ring C, regio- and stereoselective reduction of ketone, a stereocontrolled epoxidation, an epoxymethano-bridge formation, a chemoselective Grignard reaction, an intramolecular Diels-Alder reaction, an intramolecular aldol addition, and a newly developed manganese(III)-catalyzed allylic oxidation on ring A.     

Syntheses of (R)-(+)-cibenzoline and analogues via catalytic enantioselective cyclopropanation using (S)-phenylalanine-derived disulfonamide

Cyclopropanation of 3,3-diaryl-2-propen-1-ols 1 with Et₂Zn and CH₂I₂ proceeded in the presence of a catalytic amount of (S)-2-(methanesulfonyl)amino-1-(p-toluenesulfonyl)amino-3-phenylpropane 2 to afford the corresponding cyclopropylmethanols with 20–76% ee. (+)-2,2-Diphenylcyclopropylmethanol 3a (76% ee) was oxidized with IBX in DMSO, followed by NaClO₂, H₂O₂, and NaH₂PO₄ in MeCN–H₂O to give the corresponding acid 5a, which was converted with ethylenediamine, in the presence of PyBOP and Et₃N in CH₂Cl₂, to the amide 6a in quantitative overall yield from 3a. Amide 6a was cyclized at 160 °C under reduced pressure (2 mmHg) to afford (R)-(+)-cibenzoline in 55% yield.     

Total syntheses of racemic, natural (-) and unnatural (+) glyceollin I

The first total syntheses of racemic glyceollin I and its enantiomers are described. A Wittig approach was utilized as an entry to the appropriately substituted isoflav-3-ene so that an osmium tetroxide mediated asymmetric dihydroxylation could be deployed for stereospecific introduction of the 6a-hydroxy group. While using triphenylphosphine hydrobromide, a novel method was found for gently removing MOM from protected phenolic hydroxyl groups present within sensitive systems.     

Enantioselective synthesis of (+)- and (-)-dihydroepiepoformin and (+)-epiepoformin

[reaction: see text] The enantioselective synthesis of both enantiomers of dihydroepiepoformin (1) and (+)-epiepoformin (2) was achieved from (p-tolylsulfinyl)methyl-p-quinols (SR)- or (SS)-3 and (4R,SR)-4, respectively. Key features include the stereocontrolled conjugate addition of AlMe3 to p-quinol 3 and retrocondensation to the ketone functionality, previous to oxidation of the beta-hydroxy sulfoxide moiety of advanced intermediates to the corresponding sulfone.