Flexible approach for the asymmetric synthesis of (−)-hyacinthacine A1 and its 7a-epimer

The diastereoselective nucleophilic addition of organic boronic ester to 3-hydroxy-2-substituted N-acyliminium ions 9 led to the formation of 2,5-cis-pyrrolidine 10, from which a convenient synthesis of (−)-7a-epi-1 was developed. In addition, an efficient asymmetric synthesis of (−)-hyacinthacine A1 1 was achieved through the reduction/ring-opening process.     

A facile synthesis of 1,4-dideoxy-1,4-imino-l-ribitol (LRB) and (−)-8a-epi-swainsonine from d-glutamic acid

A facile synthesis of (−)-8a-epi-swainsonine 2 and 1,4-dideoxy-1,4-imino-l-ribitol (LRB) 4 has been achieved by using the versatile building block 3, which was available from cheap d-glutamic acid. The new forming stereogenic center in synthesis of 2 was constructed by highly selective reduction of the ketone 13 with Li(t-BuO)₃AlH in THF (dr=95:5).     

A facile approach to trans-4,5-pyrrolidine lactam and application in the synthesis of nemonapride and streptopyrrolidine

An efficient approach to trans-4-hydroxylpyrrolidine lactams 1 starting from amino acid is described. The utility of this method has been demonstrated in the synthesis of antipsychotic nemonapride 3 and antiangiogenic streptopyrrolidine 4. Compared four synthetic stereoisomers of natural streptopyrrolidine 4 in term of spectroscopic and physical data, the absolute structure of the natural product was proposed as (4S,5S)-configuration.     

Asymmetric synthesis of ceramide sphingolipid based on (2S,3S,4S)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidine lactam

A facile approach to the versatile chiral building block 2 was developed based on glutamic acid, whereby a new method for asymmetric synthesis of sex pheromone 1 was explored from cheap glutamic acid.     

Chiral diamines for asymmetric synthesis: an efficient RCM construction of the ligand core of (−)- and (+)-sparteine

An efficient RCM-based approach was applied to the total asymmetric synthesis of a tricyclic diamine and, formally, of its enantiomer, widely known as efficient and versatile chiral ligands of the sparteine-like type.     

Formal syntheses of (−)- and (+)-aphanorphine from (2S,4R)-4-hydroxyproline

We describe the efficient formal syntheses of both natural (−)-aphanorphine and unnatural (+)-aphanorphine from the same commercially available amino acid, (2S,4R)-4-hydroxyproline. The tricyclic framework was constructed by intramolecular Friedel-Crafts reaction. (1R,4S)-1-Methyl-8-methoxy-3-(4-toluenesulfonyl)-2,3,4,5-tetrahydro-1,4-methano-3-benzazepine (8) was synthesized in six steps from sulfonamide 3; (−)-aphanorphine methyl ether 24 was obtained in seven steps from lactone 10. Intramolecular etherification of 18 proceeded with excellent stereoselectivity in the presence of BF₃·OEt₂, which has paved an efficient synthetic route to a series of medicinally attractive heterocycles.     

An efficient synthesis of (−)-3-deazaaristeromycin

The coupling reaction of 4-chloro-1H-imidazo[4,5-c]pyridine (6-chloro-3-deazapurine) and (3aS,4S,6R,6aR)-tetrahydro-2,2-dimethyl-6-vinyl-3aH-cyclopenta-[d][1,3]dioxo-4-ol under Mitsunobu reaction conditions provides, after three subsequent straightforward reactions, ready access to the highly biologically active (−)-3-deazaaristeromycin. The versatility of this procedure opens access to a diverse pool of 3-deazapurine carbocyclic nucleosides.     

A short enantioselective synthesis of (−)-chloramphenicol and (+)-thiamphenicol using tethered aminohydroxylation

An efficient enantioselective synthesis of (−)-chloramphenicol (1) and (+)-thiamphenicol (2) is described. These antibiotics have been synthesized from commercially available 4-nitrobenzaldehyde and 4-(methylthio)benzaldehyde, respectively, using tethered aminohydroxylation and Sharpless asymmetric epoxidation as the chirality inducing steps.     

Asymmetric total synthesis of B-ring modified (−)-epicatechin gallate analogues and their modulation of β-lactam resistance in Staphylococcus aureus

Two enantiomerically pure B-ring modified analogues of (−)-epicatechin gallate were synthesised and their modulation of β-lactam resistance using three strains of methicillin resistant Staphylococcus aureus (BB 568, EMRSA-15 and EMRSA-16) evaluated. Sub-inhibitory concentrations (12.5 and 25 mg/L) of the two analogues fully sensitised each of the three MRSA strains to oxacillin, reducing the MIC to less than 0.5 mg/L, identical to levels achieved with ECg. Lower concentrations demonstrated that the position and degree of hydroxylation of the B-ring is important for activity.     

Studies on Cu(I)-catalyzed synthesis of simple 3-substituted 1,2-allenes and optically active 2-substituted secondary 2,3-allenols

The sequential treatment of terminal alkynes or propargylic alcohols with n-BuLi and MOMCl afforded the corresponding propargylic methyl ethers, which would react with primary alkyl Grignard reagents under the catalysis of CuBr to afford 3-substituted 1,2-allenes or 2-substituted secondary 2,3-allenols, respectively. The reaction may be applied to the synthesis of optically active 2-substituted secondary 2,3-allenols with up to >99% ee without any protection to the free hydroxyl group in the starting 4-hydroxy-2-alkynyl methyl ethers.     

The use of (−)-8-phenylisoneomenthol and (−)-8-phenylmenthol in the enantioselective synthesis of 3-functionalized 2-azabicyclo[2.2.1]heptane derivatives via aza-Diels-Alder reaction

The asymmetric aza-Diels-Alder reaction of the (1R)-8-phenylmenthyl or (1R)-8-phenylisoneomenthyl glyoxylate-derived N-benzylimine with cyclopentadiene resulted in the enantioselective synthesis of the corresponding pure [(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-ene]-3-carboxylates (80 or 69% yield, respectively). Reduction of these cycloadducts with LiAlH₄ afforded pure (−)-[(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-yl]methanol. Furthermore, a reaction sequence based on Barbier-Wieland degradation of both (1S,3-exo)-adducts afforded pure (+)-(1R)-2-benzoyl-2-azabicyclo[2.2.1]heptan-3-one. In the course of the two transformation sequences referred, the chiral auxiliaries were recovered in a virtually quantitative way.     

5-(1,3-Dioxolan-2-yl)-2-furanylzinc bromide; direct preparation, and its application for the synthesis of 5-substituted furan derivatives

5-(1,3-Dioxolan-2-yl)-2-furanylzinc bromide was easily prepared by the direct insertion of active zinc to 2-bromo-5-(1,3-dioxolane)furan under mild conditions. Of interest, the resulting organozinc was successfully coupled with aryl halides and acid chlorides affording the corresponding coupling products in good to excellent yields.     

An enantioselective total synthesis of (S)-(−)-licochalcone E: determination of the absolute configuration

The absolute configuration of (−)-licochalcone E (1) was determined to be (S) via the first enantioselective total synthesis of the compound. The chirality in (S)-(−)-licochalcone E (1) was installed by asymmetric methylation of the Evans' oxazolidinone derivatives.     

An efficient one-pot four-step domino reaction for the synthesis of C2-substituted 3-methylcyclohex-2-enones

An efficient one-pot four-step domino reaction of substituted β-ketoesters has been optimized giving rise to a large panel of C2-substituted 3-methylcyclohex-2-enones, an important scaffold for the preparation of various initiators for cationic or radical cyclizations. The developed methodology is quite general and applicable to a wide range of β-ketoester substrates, allowing the introduction of various functionalities at the C2 position of the 3-methylcyclohex-2-enones, in good to excellent yields.     

An efficient method for the synthesis of 9-β-D-2′-deoxyribofuranosyl-6-methylpurine

A new method for the preparation of 9-β-D-2′-deoxyribofuranosyl-6-methylpurine from inosine (1) is described. Inosine was converted to 6-chloropurinenucleoside (4) via acetylation, chlorination, and deacetylation. Compound 4 was transformed to the key intermediate 6-methylpurinenucleoside (7) via protection of the 2′,3′,5′-hydroxy groups of 4 with 3,4-dihydropyran to give compound 5, then methylation at the 6-position of 5 with dimethyl copper lithium gave compound 6; depyranylation of 6 led to the subsequent selective protection of the 3′,5′-hydroxy groups of 7 with O[Si(I-Pr)₂Cl]₂ followed by reaction with phenyl chlorothionoformate to give compound 9. Compound 9 was then converted to the target compound 11 via 2′-deoxidation and 3′, 5′-desilylation. The structures of these products were identified by Mass Spectrum (MS), ¹H-NMR (Nuclear Magnetic Resonance) spectra and elemental analysis. Translated from Chinese Journal of Organic Chemistry, 2006, 26(10): 1394–1397 (in Chinese)     

Efficient and straightforward preparation of a building block for (−)-teubrevin G synthesis via chemically diversed oriented synthesis

A rapid and efficient methodology to highly functionalised molecular units well suited as scaffolds for diversity-oriented molecular construction in the synthesis of natural products is reported herein. A key macrocyclic intermediate in the synthesis of the neo-clerodane diterpene (−)-teubrevin G was successfully synthesized in a 5-step sequence in a 70% overall yield using a novel intramolecular coupling between an allylborating agent and a 1,5-dialdehyde moiety.     

A mild and efficient method for large scale synthesis of 3-aminocoumarins and its further application for the preparation of 4-bromo-3-aminocoumarins

A wide variety of 3-aminocoumarins have been synthesized in large scale from the corresponding 3-acetamidocoumarins by regioselective cleavage of carbon–nitrogen bond using 70% sulfuric acid under reflux conditions. The synthesized 3-aminocoumarins were further brominated regioselectively at the 4-position of 3-aminocoumarin using BDMS as brominating agent.     

A straight synthesis of 2–(α-substituted N-tosylaminomethyl)-2,5-dihydrofurans by the reaction of N-sulfonylimines with arsonium 4-hydroxyl- cis -2-butenylides

On treatment of N-tosylimines (1) and 4-hydeoxyl- cis-butenyl arsonium salt (5) with KOH in acetonitrile at room temperature, 2–(α-substituted N-tosylaminomethyl)-2, 5-dihydrofurans (4) were obtained in moderate yields. The arsonium salt (5) acts formally as an equivalent of 2,5-dihydrofuran synon. A plausible mechanism was proposed for this new 5-membered cyclization reaction.     

Terminating catalytic asymmetric Heck cyclizations by stereoselective intramolecular capture of η-allylpalladium intermediates: total synthesis of (−)-spirotryprostatin B and three stereoisomers

A catalytic intramolecular Heck reaction, followed by capture of the resulting η³-allylpalladium intermediate by a tethered diketopiperazine, is the central step in a concise synthetic route to (−)-spirotryprostatin B and three stereoisomers. This study demonstrates that an acyclic, chiral η³-allylpalladium fragment generated in a catalytic asymmetric Heck cyclization can be trapped by even a weakly nucleophilic diketopiperazine more rapidly than it undergoes diastereomeric equilibration.     

From determination of enantiopurity to the construction of complex molecules: The Horeau principle and its application in synthesis

In 1973, Horeau and co-workers reported a technique capable of upgrading the enantiopurity of a scalemic mixture (for example, [(R)-enantiomer]?>?[(S)-enantiomer]). This method involved coupling the compound of interest to a simple, bifunctional reagent in order to form a statistical mixture of (R,R)-, (S,S)-, and (R,S)-stereoisomers. Separation of the two diastereomers and cleavage of the incorporated coupling agent effectively removes the minor, (S)-enantiomer from the major, (R)-enantiomer; thereby increasing the enantiopurity of the starting compound. Since that time, this concept of removing a minor enantiomer through the statistical formation of diastereomeric compounds (the Horeau principle) has also been applied when sequential enantioselective reactions are performed on a substrate, when multiple enantioenriched fragments are coupled together, and for determining the enantiopurity of the initial scalemic mixture. Under the right circumstances, the Horeau principle can be deployed in an iterative fashion in order to access material with extremely high enantiopurity (>99.999% ee). This review provides comprehensive coverage of the underlying theory behind the Horeau principle and its application in organic synthesis.