Enantioselective synthesis of (R)-deoxydysibetaine and (−)-4-epi-dysibetaine

Enantioselective synthesis of (R)-deoxydysibetaine and (−)-4-epi-dysibetaine was achieved by employing a samarium iodide-promoted reductive carbon-nitrogen bond cleavage of a proline derivative, as a key reaction.     

Stereoselective syntheses of (−)-chloramphenicol and (+)-thiamphenicol

Chloramphenicol and thiamphenicol have been enantioselectively synthesized using an asymmetric halohydrin reaction as a key step. In particular, halomethoxylation reaction was used, where O-methyl functions as a hydroxyl protecting group and eliminates an additional protection step.     

Total synthesis of (−)-2-epi-lentiginosine by use of chiral 5-hydroxy-1,5-dihydropyrrol-2-one as a building block

We have developed a practical synthesis of the chiral lactam as a new chiral building block for alkaloid synthesis. Lipase-catalyzed kinetic resolution of hydroxylactam 8, followed by isolation-racemization of the chiral acetoxylactam 9 provided the optically pure hydroxylactam 8 in 96.0% yield with >99% ee after five cycles of kinetic resolution-racemization process. Chemical transformation of (S)-hydroxylactam 8 furnished chiral (−)-2-epi-lentiginosine (1) in 20% yield in 10 steps with no loss of enantiomeric excess.     

Selective 3-and 6-OH modification of (-)-clausenamide

(-)-Clausenamide is a drug candidate under Phase I clinical trial for treatment of Alzheimer’s disease(AD).In order to elucidate the substituent related structure-activity relationship,six one-substituent modified(-)-clausenamide analogues were designed,and four of them,namely 3-O-methyl,6-O-methyl,3-des-hydroxyl and 6-des-hydroxyl analogues were prepared by selective 3- and 6- OH modification of(-)-clausenamide.     

Radical cyclizations of acylsilanes in the synthesis of (+)-swainsonine and formal synthesis of (−)-epiquinamide

Radical cyclization of acylsilane is an useful synthetic methodology. To demonstrate the versatility of this method using the cyclization as a key step, polyhydroxylated indolizidine (+)-swainsonine was synthesized through two different bond connection approaches to construct the bicyclic skeleton. In the first approach, we used 2,3-isopropylidene-d-ribono-1,4-lactone (20) as a chiral building block to form the indolizidine skeleton through a 1,6-cyclization. In the second approach, (S)-(+)-5-oxo-2-tetrahydrofurancarboxylic acid (23) was used to construct the same ring system through a 1,5-cyclization. Starting from acid 23, we also synthesized exo-1-hydroxyquinolizidin-4-one (56), which was a synthetic intermediate in the synthesis of polyhydroxylated quinolizidine (−)-epiquinamide.     

N-Cbz sulfilimines as valuable intramolecular nucleophiles for the stereoselective synthesis of (−)-deoxocassine and (+)-desoxoprosophylline

N-Cbz sulfilimine, prepared from the corresponding sulfoxide using the Burgess reagent, has been employed as an intramolecular nucleophile for the regio- and stereoselective preparation of a bromo-carbamate from an alkene. The bromo-carbamate has been utilized as an advanced common synthon for the synthesis of deoxocassine and desoxoprosophylline employing the ene and amidomercuration as key reactions.     

A new route to 3,4-disubstituted piperidines: formal synthesis of (−)-paroxetine and (+)-femoxetine

A new route to 3,4-disubstituted piperidines was developed using chiral 1,4-dihydropyridines as key intermediates, the synthetic utility of which was demonstrated by formal synthesis of (−)-paroxetine and (+)-femoxetine.     

Efficient one-pot synthetic approaches for cannabinoid analogues and their application to biologically interesting (−)-hexahydrocannabinol and (+)-hexahydrocannabinol

This Letter reports new and efficient synthetic approaches for biologically interesting cannabinoid analogues. The key strategies involve ethylenediamine diacetate/triethylamine-catalyzed cyclization. As an application of this methodology, one-step synthesis of biologically active natural (−)-hexahydrocannabinol and its unnatural enantiomer (+)-hexahydrocannabinol was carried out.     

Stereoselective synthesis of tetrahydroisoquinoline alkaloids: (−)-trolline, (+)-crispin A, (+)-oleracein E

Tetrahydroisoquinoline alkaloids, (S)-(−)-trolline, (R)-(+)-crispin A, and (R)-(+)-oleracein E, have been synthesized stereoselectively from the both enantiomers of common intermediate (S)-4 and (R)-4. The key step in the synthesis include a stereoselective Bi(OTf)₃-catalyzed intramolecular 1,3-chirality transfer reaction of chiral non-racemic amino allylic alcohols (S)-6 and (R)-6 to construct both enantiomers of (E)-1-propenyl tetrahydroisoquinoline 4.     

A concise synthesis of (−)-cytoxazone and (−)-4-epi-cytoxazone using chlorosulfonyl isocyanate

A concise synthesis of (−)-cytoxazone and its stereoisomer (−)-4-epi-cytoxazone, novel cytokine modulators, has been accomplished each in six steps from readily available p-anisaldehyde with good diastereoselectivity. Key steps in the synthesis include the regioselective and diastereoselective amination of anti- and syn-1,2-dimethyl ethers with chlorosulfonyl isocyanate and the subsequent regioselective cyclization of the diol to construct the oxazolidin-2-one core. The diastereoselectivity of amination reaction using CSI was explained by the Cieplak electronic model via S_N1 mechanism and neighboring group effect, leading to the retention of the configuration.     

Stereoselective construction of the pyrrolizidine bridgehead stereochemistry by the adjacent hydroxyl group in the synthesis of (+)-heliotridine and (−)-retronecine

Formal total synthesis of (+)-heliotridine (4) and total synthesis of (−)-retronecine (5) were accomplished by using (S)-3-acetoxysuccinimide (6) as the common starting material. The stereogenic center of 6 ended up as C-1 in both alkaloids. The chiral centers at C-7a of the alkaloids were stereoselectively constructed through the help of the adjacent functionality at C-1. The B-rings of the alkaloids were formed through α-sulfonyl radical cyclizations.     

Asymmetric synthesis of (−)-(S,S)-homaline

The asymmetric synthesis of (−)-(S,S)-homaline was achieved in 8 steps from commercially available starting materials using the diastereoselective conjugate addition of the novel lithium amide reagent lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to methyl cinnamate to install the correct stereochemistry. Subsequent functional group manipulation of the resultant β-amino ester and Sb(OEt)₃-mediated macrolactamisation was followed by homodimerisation to give (−)-(S,S)-homaline in 18% overall yield, representing the first asymmetric, and by far the most efficient synthesis of this natural product reported to date.     

Asymmetric synthesis of (−)-codonopsinine

The asymmetric synthesis of (−)-codonopsinine was achieved in 7 steps (from commercially available tert-butyl crotonate) in 5% overall yield and >99:1 dr. The key step in this synthesis involved ring-closing iodoamination of a functionalised homoallylic amine, which occurred with concomitant N-debenzylation, to give a 3-iodopyrrolidine that was elaborated to (−)-codonopsinine.     

Stereoselective syntheses of (+)-proto, (−)-gala quercitols and carba-l-rhamnose from d-(−)-quinic acid

Efficient syntheses of (+)-proto, (−)-gala quercitols and carba-l-rhamnose from d-(−)-quinic acid are described.     

Simple and highly efficient preparation and characterization of (−)-lupanine and (+)-sparteine

In a simple and convenient way, we have improved the non-chromatographic isolation of optically pure (−)-2-oxosparteine ((−)-lupanine) and (+)-sparteine. The fast and efficient method for the determination of the ee of bisquinolizidine alkaloids has been proposed. A relatively simple simple ¹H NMR method has been applied for evaluation of the % ee of enantiomers of the lupanines and sparteines with the chiral dibenzoyltartaric acids as the shift reagents. The ¹H NMR spectra of the bases and the new salts in polar solvents have been measured.The results are confirmed by chiral HPLC method. Additionally, for the first time X-ray analysis of the salt of (−)-lupanine has been performed. The improved method of purification of bisquinolizidine alkaloids will considerably facilitate the employment of these alkaloids as chiral ligands in asymmetric reactions and as pharmacological tools.     

The total synthesis of (−)-tetrahydrolipstatin

Careful control during the bromolactonisation of β,γ-unsaturated acid 3 was required to afford regioselectively the trans-β-lactone 4 as the major diastereomer. Radical debromination of 4 followed by a three-step sequence of reactions afforded the lipase inhibitor (−)-tetrahydrolipstatin.     

Synthesis of the fungal natural product (−)-xylariamide A

The first synthesis of the fungal natural product (−)-xylariamide A 1 is reported. N,O-Bis(trimethylsilyl)acetamide induced coupling of d-tyrosine with (E)-but-2-enedioic acid 2,5-dioxo-pyrrolidin-1-yl ester methyl ester 5 produced the dechloro natural product 6, which was subsequently monochlorinated using oxone and KCl to yield synthetic 1. (−)-Xylariamide A 1, (+)-xylariamide A 2 and (−)-dechloroxylariamide A 6 displayed no cytotoxic or antimicrobial activity.     

Asymmetric syntheses of diarylheptanoid natural products (−)-centrolobine and (−)-de-O-methylcentrolobine via hetero-Diels-Alder reaction catalyzed by dirhodium(II) tetrakis[(R)-3-(benzene-fused-phthalimido)-2-piperidinonate]

Catalytic asymmetric syntheses of (−)-centrolobine and (−)-de-O-methylcentrolobine have been achieved, incorporating a hetero-Diels-Alder (HDA) reaction between 4-aryl-2-silyloxy-1,3-butadienes and phenylpropargyl aldehyde derivatives as a key step. The HDA reaction using dirhodium(II) tetrakis[(R)-3-(benzene-fused-phthalimido)-2-piperidinonate], Rh₂(R-BPTPI)₄, as a chiral Lewis acid catalyst provides exclusively cis-2,6-disubstituted tetrahydropyran-4-ones in up to 93% ee.     

Chiral self-assembly of triorganotin complexes: Syntheses, characterization, crystal structures and antitumor activity of organotin(IV) complexes containing (R)-(+)-methylsuccinic acid, (S)-(+)-methylglutaric acid and l-(−)-malic acid ligands

Six new chiral triorganotin(IV) complexes, {(R₃Sn)₂[C₃H₆(COO)₂]}_n (R = Me: 1; Bu: 2), {(R₃Sn)₂[C₄H₈(COO)₂]}_n (R = Me: 3; Bu: 4), and {(R₃Sn)₂[C₂H₄O(COO)₂]}_n (R = Me: 5; Bu: 6) have been prepared by treatment of (R)-(+)-methylsuccinic acid, (S)-(+)-methylglutaric acid and l-(−)-malic acid, with the corresponding R₃SnCl (R = Me, Bu) and sodium ethoxide in methanol. All the complexes were characterized by elemental analysis, FT-IR, NMR (¹H, ¹³C, ¹¹⁹Sn) spectroscopy and TGA. Except for 3, all of the complexes were also characterized by X-ray crystallography. The structural analyses reveal that complexes 1 and 5 have 2D network structures in which (R)-(+)-methylsuccinic acid and l-(−)-malic acid act as tetradentate ligands coordinated to trimethyltin(IV) ions. Complexes 2 and 4 have 3D metal-organic framework structures in which the deprotoned acids serve as tetradentate ligands. Complex 6 adopts a 1D zigzag chain structure and forms a 2D supramolecular framework through intermolecular C-H?O interactions. In addition, the antitumor activities of complexes 1-6 have been studied. We also have measured the specific rotation of the chiral dicarboxylic acids and the organotin derivatives.     

Synthetic applications of homoiodo allylsilane II. Total syntheses of (−)-andrographolide and (+)-rostratone

The first total synthesis of (−)-andrographolide (1), an ent-Labdane diterpenoid lactone from Asian medicinal herb Andrographis paniculata, was achieved via the biomimetic cyclization of an epoxy homoiodo allylsilane precursor 7. Asymmetric total synthesis of (+)-rostratone (25), an antipodal Labdane diterpenoid, was also accomplished via similar biomimetic cyclization of a readily accessible epoxy homoiodo allylsilane precursor 18.