Highly efficient methods for the one-pot synthesis of b-substituted enones

A mild and practically-convenient one-pot procedure for the direct b-substitution of enones has been developed using a conjugate addition–oxidation strategy with a full range of copper-based reagents and N-tert-butylphenylsulfinimidoyl chloride; alkyl- and aryl-substituted enones are delivered in good to excellent yields

Studies towards a total synthesis of Hippeastrine

Tricarbonyl(ŋ5 -carboxylic acid methyl ester)iron(1+) hexafluorophosphate(1−) (97) was easily prepared in a moderate yield by a tandem Wittig-Michael addition using (3-methoxycarbonylallyl)triphenylphosphonium bromide (94). The resulting cyclohexa-1,3-dienecarboxylic acid methyl ester (95) was complexed with Fe2(CO)9 to obtain tricarbonyl(cyclohexa-1,3-dienecarboxylic acid methyl ester)iron(0) (96) was converted into the highly electrophilic tricarbonyl(ŋ5 -carboxylic acid methyl ester)iron(1+) hexafluorophosphate(1−) by hydride abstraction using triphenylcarbenium hexafluorophosphate (97). 4-Bromo-1,2-(methylenedioxy)benzene (132), 6-bromopiperonylic acid (98) and 2-bromo-5-methoxy benzoic acid (140) were converted into aryllithium reagents through lithiumbromide exchange by treatment with n-butyllithium. Lithiation and deuteration of 6-bromopiperonylic acid (98) , 2-bromobenzoic acid (136) and of 2-bromo-5-methoxybenzoic acid (140) were investigated by using various reagents such as n-butyllithium, LiHMDS and NaH to find the best route for the arylation of 98 to go onwards our target (+/−)-hippeastrine (107 and 108). Tricarbonyl[ŋ4-1-methyl ester-5-(3',4'-methylenedioxy)phenylcyclohexa- 1,3-diene]iron(0) (134) was prepared by preparing the aryllithium reagent 132 by lithium-bromide exchange and converting it into an organocuprate nucleophile with copper(I) bromide. Arylation with the cation 97 resulted in the formation of the complex 134. Tricarbonyl[ŋ4 -1-methyl ester-5- (3',4'-methylenedioxy-6'-carboxyphenyl)cyclohexa- 1,3-diene]iron(0) (99) was synthesised in the same way as complex (134), using the lithiated 6-bromopiperonylic acid (98) as the reagent. The structures of the compounds were determined by IR, 1HNMR, 13C-NMR spectroscopy and mass spectrometry

ORGANOCUPRATE MEDIATED SYNTHESES OF O, AND N-HETEROCYCLES

ABSTRACT The δ-lactone moiety comprises structural subunits in a number of natural products. Highly substituted δ-lactones are important both in synthetic applications and also as naturally occurring compounds. We have reported a one-pot procedure for the synthesis of trans-4,5-disubstituted tetrahydropran-2-ones from 3-hydroxy-3,6-dihydropyran-2-one involving sequential cuprate mediated allylic substitution and 1,4-conjugate addition reactions. We have now examined the same protocol for synthesis of 4,5,6-trisubstituted δ-lactones. The rich functionalities(i.e. the epoxide, olefin and ester functional groups) in ,δ-epoxy-α,β-enoates provide opportunities for SN2-epoxide opening, allylic substitution, and 1,4-conjugated addtion. The opening of the epoxide with AcCl, AcBr, and benzoyl chloride afforded the -acetoxy--halo-,-enoates and-benzoyloxy--halo-,-enoates , and subsequent copper-mediated allylic SN2\u27 substitution afforded 5-acyloxy-2-alkyl-3,4-enoates. Stereoselective reaction of Grignard reagents, in the presence of catalytic CuCN, with these 5-acyloxy-2-alkyl-3,4-enoates afford 2,3-di-alkyl-4,5-enoates. Sequential treatment of δ-acetoxy-γ-halo-α,β-enoates with RCuCNMgBr and then with R2CuMgBr in a one-pot operation afforded 2,3-di-alkyl-4,5-enoates in good chemical yields and excellent diastereoselectivity. Ozonolysis of 2,3-di-alkyl-4,5-enoates, reduction, and then by cyclization furnished 2,3-di-substituted γ-lactones with excellent diastereomeric ratios. An alternative synthesis of γ-lactones can be achieved by hydrolysis of the 2,3-di-alkyl-4,5-enoates followed by iodolactonization. Although organometallic mediated conjugate addition of alkyl or aryl ligands to 4-pyridones could provide a rapid entry to the highly versatile 2,3-dihydropyridones, the addition of an allyllithium reagent appears to be the only reported example of such a reaction. We now report that a variety of organometallic reagents do undergo conjugate addition reactions with N-carbamoyl-4-pyridones. Asymmetric 1,4-conjugate addition of diethylzinc reagents to N-Boc-4-pyridone was developed. The fully unsaturated 2-pyrones possess aromatic character, and display reactivity patterns characteristic of lactones, 1,3-dienes, and heteroaromatic rings. Although organocopper mediated conjugate addition reactions to 2- and 4-pyrones have not been reported, cuprate reagents could be successfully added by conversion of the pyrones to pyrilium salts with added triflic anhydride. These reactions proceeded with addition of the ligand to the 4-position of the pyrone ring. We now report that organocuprate reagents do indeed undergo 1,4-conjugate addition reactions with 2- and 4-pyrones. With or without the addition of Cu (I) salt, Grignard reagents can also undergo 1,4-conjugate addition reactions to N-carbamoyl-4-pyridones, 2- and 4-pyrones to afford 1,4-adduct in excellent chemical yields in the presence of TMSCl

1, 2-Bis (phenylsulfonyl)-1H-Indole as an Acceptor of Organocuprate Nucleophiles

1,2-Bis(phenylsulfonyl)-1H-indole is a novel example of an electron-deficient indole that undergoes nucleophilic attack at C-3. Though a variety of other organometallic nucleophiles fail to engender nucleophilic substitution, organocuprates produce 3-substituted 2-(phenylsulfonyl)-1H-indoles. These reactions contribute to the growing number of examples of nucleophilic addition to the indole core

Divalent and Multivalent Activation in Phosphate Triesters: A Versatile Method for the Synthesis of Advanced Polyol Synthons

This is the peer reviewed version of the following article: Thomas, C. D., McParland, J. P. and Hanson, P. R. (2009), Divalent and Multivalent Activation in Phosphate Triesters: A Versatile Method for the Synthesis of Advanced Polyol Synthons. Eur. J. Org. Chem., 2009: 5487–5500. doi:10.1002/ejoc.200900560, which has been published in final form at http://doi.org/10.1002/ejoc.200900560. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.The construction of mono- and bicyclic phosphate trimesters possessing divalent and multivalent activation and their subsequent use in the production of advanced polyol synthons is presented. The method highlights efforts to employ phosphate tethers as removable, functionally active tethers capable of multipositional activation and their subsequent role as leaving groups in selective cleavage reactions. The development of phosphate tethers represents an integrated platform for a new and versatile tether for natural product synthesis and sheds light on new approaches to the facile construction of small molecules

HIGHLY REACTIVE FORM OF COPPER AND REAGENTS THEREOF

A novel Zerovalent copper species and an organocopper reagent are disclosed. The Zerovalent copper species is directly produced by reaction of a reducing agent with a combination of copper(I) cyanide or halide and an alkali metal halide salt. The organocopper reagent resulting from the reaction of the zerovalent copper species and an organic compound having one or more stable anionic leaving groups is a stable reagent that will not significantly homocouple and under controlled conditions tolerates the presence of nitrile, epoxide, imine, enone, ketone, ester, allyl and benzyl groups within the organo radical. The reagent can be controlled so that it will selectively add to an organic electrophile such as an acid halide or aldehyde while other less reactive electro philic groups are present. The reagent will also add under controlled conditions to epoxide, enone, imine and ketone groups

Enantioselective Total Synthesis of Macfarlandin C, a Spongian Diterpenoid Harboring a Concave-Substituted cis-Dioxabicyclo[3.3.0]octanone Fragment.

The enantioselective total synthesis of the rearranged spongian diterpenoid (-)-macfarlandin C is reported. This is the first synthesis of a rearranged spongian diterpenoid in which the bulky hydrocarbon fragment is joined via a quaternary carbon to the highly hindered concave face of the cis-2,8-dioxabicyclo[3.3.0]octan-3-one moiety. The strategy involves a late-stage fragment coupling between a tertiary carbon radical and an electrophilic butenolide resulting in the stereoselective formation of vicinal quaternary and tertiary stereocenters. A stereoselective Mukaiyama hydration that orients a pendant carboxymethyl side chain cis to the bulky octahydronapthalene substituent was pivotal in fashioning the challenging concave-substituted cis-dioxabicyclo[3.3.0]octanone fragment