One-pot reductive-cyclization as key step for the synthesis of rutaecarpine alkaloids

The quinazolinocarboline alkaloids including rutaecarpine (1a), euxylophoricine A (1b), and euxylophoricine C (1c) have been synthesized efficiently from the ring opened β-carboline derivative as key intermediate by a one-pot reductive-cyclization reaction. The key intermediate was prepared from tryptamine (6) following Bischler-Napieralski cyclization, benzoylation, and oxidative cleavage of the exocyclic double bond.     

Radical-initiated cyclization as a key step for the synthesis of oxoprotoberberine alkaloids

The oxoprotoberberine alkaloids 1a-d have been synthesized efficiently from the enamide derivatives 2a-d by a radical-initiated cyclization reaction utilizing n-Bu₃SnH/AIBN and CuCl. The enamide derivatives 2a-d were prepared from phenylethylamine analogues 5a-b, followed by acylation with acetic anhydride, Bischler-Napieralski cyclization with POCl₃ and benzoylation with the corresponding bromobenzoyl chloride, respectively.     

Electrolysis as an efficient key step in the homogeneous polymer-supported synthesis of N-substituted pyrroles

[reaction: see text]. An efficient and general route to the soluble polymer-assisted synthesis of a set of 14 different N-substituted pyrroles using dendritic polyglycerol as a high-loading support is presented. The transformation of furan to the key intermediate 2,5-dialkoxytetrahydrofuran was performed by electrochemical oxidation followed by catalytic hydrogenation with Pt/C in high yield. Both reactions required heterogeneous reagents which can be conveniently used with polyglycerol as a soluble support.     

The synthesis of 2-benzazocines using ring-closing metathesis as a key step

A number of protected 7-isopropoxy-8-methoxy-1,2,3,6-tetrahydro-2-benzazocines were synthesized from 2-allyl-3-isopropoxy-4-methoxybenzaldehyde using ring-closing metathesis as the key step. In addition, two 9-isopropoxy-8-methoxy-3,6-dihydro-2-benzazocines were synthesized from 5-isopropoxy-4-methoxy-2-[(1E)-3-phenyl-2-propenyl]benzaldehyde, which in turn was obtained from the thermal Claisen-Cope rearrangement of 4-methoxy-3-{[(2E)-3-phenyl-2-propenyl]oxy}benzaldehyde. Finally, five of the 2-benzazocine compounds were tested for anti-cancer activity.     

Palladium-catalysed cross-coupling as a key step in the synthesis of pyridyl-benzamides, -benzylamines and -sulfonamides

Novel N-, O- and S-substituted pyridyl-benzamides, -benzylamines and -sulfonamides were prepared by means of palladium-catalysed cross-coupling reactions. The synthetic approach, using Pd₂(dba)₃ as palladium source and rac-BINAP as supporting ligand, proved to be successful for CN, CO and CS cross-coupling reactions. One of the substrates underwent an unexpected nucleophilic aromatic substitution of fluorine, rather than the expected CN cross-coupling reaction.     

General method for the synthesis of substituted phenanthridin-6(5H)-ones using a KOH-mediated anionic ring closure as the key step

Substituted phenanthridin-6(5H)-ones were obtained in a two-step procedure involving a Suzuki cross-coupling reaction followed by a KOH-mediated anionic ring closure. The influence of the nature and the position of the substituents on the cyclization step were studied. This methodology offers a general and practical route to diversely substituted phenanthridin-6(5H)-ones.     

The palladium(0) Suzuki cross-coupling reaction as the key step in the synthesis of aporphinoids

We report a flexible approach to the total synthesis of 4,5-dioxoaporphines based on the palladium(0) catalyzed Suzuki cross-coupling of phenylboronic acids with sterically hindered 2-bromo phenyl acetates or bromo phenyl acetamides, followed by sequential bicyclization of biarylacetamides promoted by oxalyl chloride/Lewis acid. The reduction of 4,5-dioxoaporphines provides a chemoselective entry to aporphines, dehydroaporphines and 4-hydroxy-dehydroaporphines. A three-steps total synthesis for (±)-O,O′-dimethylapomorphine from readily accessible precursors is also reported.     

Electrochemical oxidation of tetramethoxy precursor as a key step for the synthesis of coenzyme Q10

The feasibility of electrosynthesis of coenzyme Q₁₀ (1) by electrooxidation of tetramethoxy precursor (2) has been investigated at carbon, Pt and BDD anodes in a divided cell. The process strongly depends on the applied potential, anode material and water content of the solvent. At carbon anodes in CH₃CN/CH₂Cl₂ + 0.15 M Bu₄NBF₄ at proper operative conditions high faradic efficiency (>60%) and excellent selectivity (95–97%) of the target product were obtained.     

A facile synthesis of the basic steroidal skeleton using a Pauson-Khand reaction as a key step

A high-yield synthesis of steroid-type molecules under mild reaction conditions is achieved in two steps involving nucleophilic addition of alkynyl cerium reagent to an easily enolizable carbonyl compound (beta-tetralone) followed by an intramolecular Pauson-Khand reaction.     

Synthesis of [13]-membered macrocyclic stevastelins via a transesterification reaction as the key step: total synthesis of stevastelin C3

A new synthesis of stevastelin C3 (3), a [13]-membered ring component of the stevastelin family, whose structure was recently revised, is reported. Initially, a macrolactonization approach was attempted to generate the [13]-membered macrolactone but this met with failure, so a translactonization reaction was tried to obtain the targeted stevastelin C3 (3) from the corresponding [15]-membered ring counterpart. Unfortunately, this strategy did not prove successful, and, consequently, we opted to undertake a transesterification reaction from 23, as a means to accommodate the requisite aminoacid moiety at the correct position, to obtain 24. From 24, and through intermediates 25-28, the acyclic precursor of the [13]-membered ring macrolactone, compound 30, was efficiently prepared. By utilizing the synthetic course developed by Chida, we took 30 forward and completed the total synthesis of stevastelin C3 (3).     

Formal synthesis of salinosporamide A using a nickel-catalyzed reductive aldol cyclization-lactonization as a key step

Application of a sequential nickel-catalyzed reductive aldol cyclization-lactonization reaction in a short formal synthesis of salinsporamide A, a potent 20S proteasome inhibitor and anti-cancer compound, is described.     

The asymmetric hydrogenation of 2-phenethylacrylic acid as the key step for the enantioselective synthesis of Citralis Nitrile

A catalytic approach to the enantioselective synthesis of Citralis Nitrile^® (3-methyl-5-phenyl-pentanenitrile, a citrus-type odorant) is described. The key step is the transition-metal catalyzed asymmetric hydrogenation of 2-phenethylacrylic acid. Among the different catalysts tested, the most efficient appears to be the one formed by combining in situ [Ru(benzene)Cl₂]₂ with the atropisomeric diphosphine MeOBIPHEP and triethylamine, which allows us to obtain enantiomeric excesses up to 98% under mild conditions. Very good results (ees >80%) have also been obtained using iridium cationic complexes in combination with a phosphinooxazoline ligand.     

Large-scale synthesis of immunoactivating natural product, pristane, by continuous microfluidic dehydration as the key step

An efficient protocol of dehydration was developed under microfluidic conditions. The method was applied to a multikilogram synthesis of pristane, a biologically important natural product, which is now widely used as an adjuvant for monoclonal antibody production. [reaction: see text].     

Asymmetric synthesis of the erythrinan alkaloid system using a chiral lithium amide base desymmetrisation as the key step

A new asymmetric approach to the erythrinan alkaloid system is described, which involves chiral base desymmetrisation of a ring fused imide and a 6-exo-trig radical cyclisation as the key steps.     

Monoprotection of diols as a key step for the selective synthesis of unequally disubstituted diamondoids (nanodiamonds)

The monoprotection (desymmetrization) of diamondoid, benzylic, and ethynyl diols has been achieved using fluorinated alcohols such as 2,2,2-trifluoroethanol (TFE) under acidic conditions. This practical acid-catalyzed S(N)1 reaction opens the door for the synthesis of novel bifunctional diamondoids. With diamantane as an example, we show that the resulting monoethers can be used to prepare selectively, for instance, amino or nitro alcohols and unnatural amino acids. These are important compounds in terms of the exploration of electronic, pharmacological, and material properties of functionalized nanodiamonds.     

Electrochemical oxidation of 2-substituted piperidines as a key step towards the synthesis of hydroxylated γ-amino acids

2-Substituted piperidines containing different oxygenated side chain functionalities were investigated in the electrochemical, anodic methoxylation. Surprisingly, the configuration of the side chain has a strong influence on the outcome of the electrochemical oxidation. Subsequent elimination of methanol from the oxidation products leads to N-protected eneamides, which upon ozonolysis can be converted to N,N-bisprotected γ-amino aldehydes that are useful building blocks for further synthetic transformations.     

A convergent route to β-hydroxy δ-lactones through Prins cyclisation as the key step: synthesis of (+)-prelactones B, C and V

Reactions of homoallylic alcohols with aldehydes in the presence of acid catalysts gave multisubstituted tetrahydropyrans with the creation of one to three new stereogenic centres in a single-pot process. The utility of this approach is extended to the enantioselective syntheses of (+)-prelactones B, C and V.     

Alkylation of acetylcyclopropane cyclohexylimine by ethylene oxide derivatives as a key step in the synthesis of some insect acetogenin pheromones

The interaction of Li derivatives of acetylcyclopropane cyclohexylimine with ethylene, propylene, and isoprene oxides leads efficiently to the corresponding -cyclopropylketols. The cyclopropylcarbinol corresponding to the first of them is smoothly converted under the action of the couple Me₃SiBr/ZnBr₂ to a linearE-C₇-homoallyl bromide, which is then used in the stereocontrolled synthesis of tridec-4E-enyl and trideca-4E, 7Z-dienyl acetates — components of the sex pheromones of someLepidoptera species.N. D. Selinskii Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 10, pp. 2362–2367, October, 1992.     

Enzymatic resolution of a quaternary stereogenic centre as the key step in the synthesis of (S)-(+)-citalopram

The enzymatic resolution of 4-[(4-dimethylamino)-1-(4^′-fluorophenyl)-1-hydroxy-1-butyl]-3-(hydroxymethyl)-benzonitrile, a useful intermediate in the synthesis of enantiomerically pure citalopram, has been studied. Candida antarctica lipase B (CAL-B) catalyzes the enzymatic acetylation of the primary benzylic alcohol with high enantioselectivity at the quaternary stereogenic centre. The enzymatic enantioselective hydrolysis of the 3-acetyloxymethyl derivative catalyzed by CAL-B is also possible.     

Microwave-assisted solid-phase organic synthesis (MASPOS) as a key step for an indole library construction

[reaction: see text] Microwave-assisted solid-phase organic synthesis (MASPOS) has been demonstrated to significantly facilitate the Cu(II)- or Pd(II)-mediated ring closure of the resin-bound 2-alkynylanilides. Under microwave irradiation at 200 degrees C [for Cu(OAc)(2), NMP] or 160 degrees C [for Pd(MeCN)(2)Cl(2), THF] for 10 min, 1-acyl-2-alkyl-5-arenesulfamoylindoles were obtained, after cleavage from the resin, in 95-99% purities and in 65-82% overall yields via a 5-step synthetic sequence.