A New Asymmetric Synthesis of Tricarbonylchromium Complexes of ortho-Substituted Benzaldehydes. Preliminary communication

ortho-Substituted [Cr(CO)₃(benzaldehyde)] complexes are obtained via nucleophilic addition of alkyl- and aryllithium reagents to a [Cr(CO)₃(phenylmethaneimine)] complex followed by endo-hydride abstraction with triphenylmethyl cation. This sequence, when carried out with a [Cr(CO)₃(benzaldehyde SAMP hydrazone)] complex affords substituted derivatives (Me, Bu, Ph, vinyl) with high (?97%) diastereoselectivity and, after hydrolysis, ortho- substituted [Cr(CO)₃(benzaldehyde)] ((S)- 1 ) complexes of high enantiomeric purity.     

Asymmetric Total Synthesis of Stagonolide F

A highly convergent stereoselective total synthesis of stagonolide F is described starting from commercially available 5-hexen 1-ol using asymmetric dihydroxylation, Jacobsen^'s hydrolytic kinetic resolution (HKR), regioselective epoxide ring opening with vinyl Grignard reaction, esterification, and ring-closing metathesis (RCM) as key steps.     

Asymmetric Total Synthesis of Stagonolide G

A simple asymmetric total synthesis of stagonolide G ( 1 ) is described. Asymmetric dihydroxylation, regioselective epoxide ring opening, and vinyl Grignard reactions are involved in generating the stereogenic centers C(4) and C(8), followed by Grubbs‐II‐catalyzed ring‐closing metathesis (RCM).     

New, azide-free transformation of epoxides into 1,2-diamino compounds: synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu)

A new, azide-free transformation of the key precursor epoxide 6 to the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (1, Tamiflu) is described. This sequence represents a new and efficient transformation of an epoxide into a 1,2-diamino compound devoid of potentially toxic and hazardous azide reagents and intermediates and avoids reduction and hydrogenation conditions. Using catalytic MgBr(2).OEt(2) as a new, inexpensive Lewis acid, the introduction of the first amino function was accomplished by opening of the oxirane ring with allylamine followed by Pd/C-catalyzed deallylation to the amino alcohol 16. The introduction of the second amino group was then accomplished via an efficient reaction cascade involving a domino sequence preferably utilizing a transient imino protection. Selective acetylation of the resulting diamine 17 was achieved under acidic conditions providing the crystalline 4-acetamido-5-N-allylamino-derivative 18, which upon deallylation over Pd/C and phosphate salt formation afforded drug substance 1. The overall yield of this route from 6 of 35-38% exceeds the yield of the azide-based process (27-29%) and does not require any chromatographic purification.     

Synthesis of Stereoisomers of Cryptofolione 6'-Mono- and 4', 6'-Di-O-benzyl Ethers

Synthesis of stereoisomers of 6′‐mono‐ and 4′,6′‐di‐O‐benzyl cryptofolione is described through a key intermediate 6 , which was prepared by coupling of iodobenzene 8 with chiral propargyl alcohol 9 under Cosford protocol conditions. Monobenzyl ether 4 is obtained via epoxide 6 opening with vinyl Grignard, followed by cross‐metathesis reaction with a vinyl lactone 11 . Whereas, dibenzyl ether 5 is prepared by epoxide 6 opening with chiral propargyl alcohol 7 followed by simple transformations and finally cis‐Wittig olefination.     

Novel methodology for the synthesis of the benz[a]anthracene skeleton of the angucyclines using a Suzuki-Miyaura/isomerization/ring closing metathesis strategy

The synthesis of the benz[a]anthracene skeleton of the angucyclines is described. Key steps involve the Suzuki-Miyaura reaction, isomerization of an aromatic allyl substituent to the corresponding styrene, and the use of the ring closing metathesis reaction to construct a benzene ring. For example, exposure of 3-allyl-2-bromo-1,4,5-trimethoxynaphthalene to (2-formyl-4-methoxyphenyl)boronic acid under palladium catalysis conditions resulted in the formation of 2-(3-allyl-1,4,5-trimethoxynaphthalen-2-yl)-5-methoxybenzaldehyde. This 2-naphthyl benzaldehyde then underwent a Wittig reaction to furnish 3-allyl-1,4,5-trimethoxy-2-(4-methoxy-2-vinylphenyl)naphthalene. Isomerization of the allyl group of this compound afforded the diene, (E)-1,4,5-trimethoxy-2-(4-methoxy-2-vinylphenyl)-3-(prop-1-en-1yl)naphthalene. Exposure of the formed diene to the Grubbs II catalyst resulted in the formation of the benzanthracene, 3,7,8,12-tetramethoxytetraphene, which was easily oxidized to the corresponding quinone.     

Doped Sol-Gel Materials as Heterogeneous Reagents for Organic Synthesis

We advance the use of reactive doped sol-gel materials as heterogeneous reagents for organic-chemistry synthesis. Three approaches were demonstrated with SiO₂-based materials: Direct physical entrapment of the organic reagent; in-situ generation of an inorganic reagent within the matrix; and covalent attachment of the reagent to the matrix. With the first, entrapped p-toluenesulfonic acid facilitated the 100% yield esterification of benzoic acid with 1-pentanol, and the 100% dehydration of 1-tetralol to 1,2-dihydronaphthalene; with the second approach, a sol-gel oxidant, SiO₂/MnO₂ was used to convert benzyl alcohol to benzaldehyde and 1-tetralol to 1-tetralone; and with the third, anchored propylamine facilitated dehydrobromination reactions resulting in double-bond formation. Several other reactions with these reagents are described, and their reactivities analyzed.     

Synthesis of (+)-(1R,2S,9S,9aR)-octahydro-1H-pyrrolo[1,2-a]azepine-1,2,9-triol: a potential glycosidase inhibitor

The title compound was prepared as a potential glycosidase inhibitor. Key steps in the synthesis are vinyl epoxide aminolysis, ring-closing metathesis, cis-dihydroxylation and then ring closure.     

Synthesis of 1,2,3-trisubstituted cyclopropanes by MIRC reactions of dithianyllithiums with monocarboxylic vinyl epoxide analogues

A variety of cyclopropane derivatives bearing stereochemistry at all three positions on the ring were readily obtained in a high yield of 76-92% and high stereoselectivity (trans:cis > 95:5) when the monocarboxylic vinyl epoxide analogues reacted with dithianyllithiums in the presence of HMPA. This reaction was supposed to be a tandem conjugation addition-opening epoxide ring sequence.     

An Ireland-Claisen approach to lignans: synthesis of the putative structure of 5-epi-eupomatilone-6

A novel Ireland-Claisen approach to the putative structure of eupomatilone-6 is described. The rearrangement established the C3 and C4 stereocenters and concomitantly generated a vinyl epoxide. The C5 oxygen was installed by cyclization of the pentenoic acid carboxyl group onto the vinyl epoxide in an S(N)2' fashion to afford the C5-epi stereochemistry. The natural C5 stereochemistry was accessed via a substrate directed dihydroxylation.     

Nitration of 2- and 4-[2-(2-furyl)vinyl]thiazole derivatives

Nitration of 4-methyl-2-[2-(nitro-2-furyl)vinyl]thiazole with a mixture of concentrated nitric and sulfuric acids leads to 4-methyl-5-nitro-2-[2-(3,5-dinitro-2-furyl)vinyl]thiazole. Under the same conditions 2-methyl- and 2-acetamido-4-[1-R-2-(5-nitro-2-furyl)vinyl]thiazoles (R=CH₃, Cl) are nitrated in the 3 position of the furan ring, 2-amino-4-[1-chloro-2-(5-nitro-2-furyl)vinyl]thiazole is nitrated in the 5 position of the thiazole ring and 2-acetamido-5-nitro-4-[2-(2-furyl)vinyl]thiazole undergoes profound changes. Under the influence of a mixture of of nitric acid and acetic anhydride the latter compound is converted quantitatively to the 5-nitro derivative (with respect to the furan ring), whereas 4-[2-(5-nitro-2-furyl)vinyl]thiazole derivatives do not undergo reaction.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 314–317, March, 1977.     

Regioselective epoxide ring opening. Steroselective synthesis of a tetrahydropyran ring

The stereoselective synthesis of a 2-substituted tetrahydropyran with adjacent alkoxy-bearing stereogenic centre is described. The key steps of this synthesis were the stereoselective epoxidation of an allylic alcohol and the regioselective epoxide ring opening by lithium aluminum hydride. The regio and stereoselective synthesis of a trihydroxyselenide and a trihydroxysulfide is also described. The latter compounds are not suitable for cyclization to tetrahydrofuran ring.     

Quinazolines and 1,4-benzodiazepines. LXXXVII. Synthesis of 1- and 3-phenylimidazo[1,5-a] [1,4]benzodiazepines

The synthesis of the 1-phenylimidazobenzodiazepine 5 from 1 and the anion of the nitrone 2 is described. The 3-phenyl-derivative 14 was prepared via the ammo alcohol 11 which was obtained by condensation of the nitrosamine 9 with benzaldehyde followed by catalytic hydro-genolysis of the nitroso group.     

Synthesis of novel heterocycles related to the dynemicin a ring skeleton

Studies directed towards the construction of the CDE ring framework of dynemycin A ( 1 ) are reported. A series of quinoline based dienophiles containing an activating group (e.g. 5 , Scheme 1), reacted with acyclic dienes (e.g. 4 , Scheme 1) in a Diels-Alder fashion under increased pressure to afford a variety of heterocyclic systems related to the CDE skeleton of dynemycin A. Reaction of dienophile 15 with cyclic diene 29 led to the novel hetereocycle 34 whereas attempted decarbonylation of 41 led to a novel rhodium-promoted intramolecular carbonylation of the terminal acetylene furnishing compound 43 .     

Synthesis of novel perfluoroalkyl-containing polyethers

The synthesis of iodo(perfluoroalkyl)epoxides by radical addition of perfluoroalkyl iodides to allyl glycidyl ether and 1,2-epoxydec-9-ene is described. Dehydroiodination of additional products upon treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gives unsaturated products. The use of Bu₃SnH/Bz₂O₂ as a reduction reagent of iodo(perfluoroalkyl)allyl glycidyl ethers allows to save oxirane ring. Cationic polymerization of saturated or functional (with iodine or double bond) fluoroalkyl oxiranes under action of catalytic amount of BF₃^.Et₂O proceeds only on epoxide group. In case of poly(9-iod-10-(perfluoroalkyl)-1,2-epoxyalkane) iodine atoms are removed by standard zinc reduction.     

Heterocyclic polyfluoro-compounds. Part 34 [1]. Two-way photochemical addition of hexafluoroacetone to 1,2-dichlorofluoroethylene,and the preparation of an oxete

The well-known Paterno-Büchi reaction, which involves oxetan formation by the photochemical addition of a carbonyl compound to a carbon-carbon double bond [2], was extended to the fluorocarbon field by Harris and Coffman [3], who described the photochemical addition of fluoroaldehydes, fluoroketones, and fluoroacyl fluorides to terminal perfluoroolefins and chlorotrifluoroethylene, e.g., Subsequently, Bissel and Fields reported that low yields of oxetans were obtained from acetaldehyde and the olefins, CF₂CF₂, CF₂CFCl, and CF₂CCl₂ [4]. The reaction of hexafluoroacetone with hexafluoropropene involves the triplet state of the ketone [5].     

Ring Opening of a Fatty Epoxide by Diethylacetamido Malonate in Basic Medium by Phase Transfer Catalysis or Under Microwave Irradiation

A fatty epoxide (tetradecyl-oxirane) is reacted with diethyl acetamidomalonate in basic medium, with or without solvent under solid-liquid phase transfer catalysis with LiCl, or under microwave irradiation on supported reagents (KF/Al₂O₃/LiCl). The main product is a lactone which is formed after epoxide ring opening and subsequent cyclisation. We put here into evidence, for the first time, the conjugated advantages of “dry media” reactions, lithium salt effects and microwave irradiation.     

Synthetic studies on taxanes: construction of the tricyclic skeleton on the basis of a [6+2] cycloaddition reaction

The stereoselective synthesis of a tricyclic model compound of taxane diterpenes was achieved. The eight-membered B ring was constructed on the basis of a [6+2] cycloaddition reaction of a dicobalt acetylene complex with an enol silyl ether of cyclohexanone. After conversion of the cobalt complex moiety to an epoxide and introduction of a 3-cyanopropyl group, the A ring was formed via an intramolecular cyclization reaction under basic conditions.     

Total Synthesis and Biological Assessment of Mandelalide A

A new convergent total synthesis of the marine macrolide mandelalide A ( 1 ) has been developed that is based on macrocyclic ring closure by a Shiina‐type macrolactonization and the construction of the requisite precursor seco acid by a highly efficient Sonogashira cross‐coupling reaction between two fragments of comparable complexity. Key steps in the elaboration of the acid building block were the enantioselective, catalytic addition of a protected acetylene to crotonaldehyde and the construction of the tetrahydropyran unit that is embedded in the macrocycle by means of an acid‐catalyzed Prins reaction. The synthesis of the alcohol fragment features the formation of the trisubstituted tetrahydrofuran ring through an acetal cleavage/epoxide opening cascade reaction and a rarely used radical alkynylation of a primary alkyl iodide. Intriguingly, the dihydroxylation of a terminal double bond as part of the synthesis of this building block gave the same major product for both the α‐ and β‐AD‐mix reagents, albeit with moderate or low selectivity. Synthetic mandelalide A ( 1 ) was a potent proliferation inhibitor of A549, HT460, and H1299 human lung cancer cells in vitro, but not of SK‐N‐SH neuroblastoma cells. However, in no case did we observe complete cell kill even at the highest compound concentration tested (5 μm ).     

Synthesis and mesomorphism of modified 2,5-Di(4-dodecoxyphen-1-yl)-c-cyclopentene-pyridines

Herein, we report on a new series of mesomorphic compounds synthesised by directional functionalisation of 2,5-di(4-dodecoxyphen-1-yl-c-cyclopentene-pyridine) on the c-cyclopentene moiety. The first functionalisation of the starting compound gave rise to a racemic product modified with a hydroxyl group on the fused cyclopentene ring. Further oxidation of this alcohol to a prochiral ketone and subsequent enantioselective reduction back to the alcohol afforded a new chiral alcohol. Further, the hydroxyl group of the chiral alcohol could be substituted by fluorine in a S_N2 reaction, leading to a chiral compound with enantiomeric excess (ee) of 66% and chiral nematic liquid-crystalline (LC) phase.