Eleonora Ballerini

High Pressure Diels−Alder Approach to Hydroxy-Substituted 6a-Cyano-tetrahydro-6H-benzo[c]chromen-6-ones: A Route to Δ6-Cis-Cannabidiol

Diels-Alder cycloaddition reactions of 3-cyanocoumarin, hydroxy-substituted 3-cyanocoumarins and mesyl-substituted 3-cyano-coumarins with methyl-1,3-butadienes carried out under high pressure (11 kbar) are reported. Activation by high pressure allows these reactions to proceed satisfactorily under mild conditions to produce 6a-cyano-hydroxy- and 6a-cyano-mesyl-tetrahydro-6H-benzo[c]chromen-6-ones in moderate to excellent yield. The synthesis of cis-1-hydroxy-9-methyl-3-pentyl-6a,7,10,10a-tetrahydro-benzo[c]chromen-6-one as precursor of Delta(6)-3,4-cis-cannabidiol (Delta(6)-cis-CBD) and Delta(8)-cis-tetrahydrocannabinol (Delta(8)-cis-THC) is outlined.

A waste-minimized protocol for the preparation of 1,2-azido alcohols and 1,2-amino alcohols

Under solvent-free conditions the reaction of epoxides 1a–i with trimethylsilylazide (2) catalyzed by polystiryl-supported fluoride (PS-DABCOF2) has led to the efficient preparation of the corresponding O-TMS protected 1,2-azido alcohols 3a–i that, by treatment with Dowex-H, gave the related 1,2-azido alcohols 4a–i in excellent yields (83–99% and 82–96%, respectively). The use of a flow procedure has allowed us to significantly minimize waste in the preparation of representative 1,2-azido alcohols 4a, 4c and 4i that have been obtained with E-factors of 1.6, 2.1, and 1.9, respectively. The 1,2-amino alcohols 5a, 5c and 5f have been also prepared, in quantitative yields, by reduction of the corresponding O-TMS protected 1,2-azido alcohols 3a, 3c, and 3f by Pd on the Al2O3/HCOOH system.

High-Pressure Access to the Δ9-cis- and Δ9-trans-Tetrahydrocannabinols Family

Diels-Alder reactions of a range of 1-(alkoxy/alkyl-substituted phenyl)buta-1,3-dienes with methyl vinyl ketone and methyl acrylate carried out in ethanol as the reaction medium under 9 kbar pressure were investigated. The use of high pressure as the activating method of the Diels-Alder reactions allows the efficient and endodiastereoselective generation of a series of cis-cyclohexenyl-benzene cycloadducts, which are selectively converted into their trans-epimers. The cis-cyclohexenyl-benzenes and trans-cyclohexenyl-benzenes produced are useful precursors for accessing substituted privileged cis-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene and trans-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene skeletons. The total syntheses of Δ(9)-cis-tetrahydrocannabinol (THC) and Δ(9)-trans-THC, through the use of selected Diels-Alder adducts, are described. Finally, a route for obtaining Δ(9)-trans-THC in both enantiomeric pure forms based on the (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP)-hydrazone method is also reported.

High-Pressure Diels−Alder Cycloadditions between Benzylideneacetones and 1,3-Butadienes: Application to the Synthesis of (R,R)-(−)- and (S,S)-(+)-Δ8-Tetrahydrocannabinol

High-pressure Diels-Alder reactions of various alkoxy/alkyl-substituted benzylideneacetones with methyl-1,3-butadienes are reported. Activation by high pressure (8-11 kbar) in combination with the mild Lewis acid HfCl(4).2THF allows these reactions to efficiently and regioselectively produce a series of ortho-substituted cyclohexenyl-benzene cycloadducts, that are useful precursors for the expeditious construction of the privileged 6,6-dimethyltetrahydro-6H-benzo[c]chromene skeleton. Application to the synthesis of Delta(8)-trans-THC in both enantiomeric pure forms is based on the successful resolution of selected cycloadduct by the SAMP-hydrazone method.

A comparative approach to the most sustainable protocol for the β-azidation of α,β-unsaturated ketones and acids

In this contribution we have used green metrics analysis to compare the material efficiency, environmental impact, and safety-hazard impact in order to compare flow and batch procedures for azidation of α,β-unsaturated carbonyls. It has been proved that flow protocols possess a greener profile over the corresponding batch procedures based on identical chemistries. In this work the new flow procedure described is very efficient; however, the significant uncertainties in the environmental and safety-hazard impact scores are due to the lack of toxicity, hazard, and occupational exposure data available on trimethylsilyl azide and the resin catalysts used here. The results for the new flow procedure show significant and definite improvements over previously published work with respect to waste minimization/material efficiency and are consistent with satisfying green chemistry principles. The results obtained in this work prove the usefulness of our flow-approach for realizing highly efficient processes featuring minimal waste production.

Multistep Flow Procedure for the Waste-Minimized Preparation of N-Boc-ß-Amino Ketones

A clean and efficient protocol for the synthesis of a wide variety of N-Boc-β-amino ketones 3a-g has been defined using flow approach. The multistep procedure is based on the β-azidation of unsaturated ketones, consecutive reduction of the azido group, and concomitant amino group protection, and furnishes the desired products in good yields and very low E-factors ranging from 3.1 to 5.6. In batch conditions and by water as reaction medium, poorer yields and complicated reaction mixtures are obtained. Adoption of the flow approach, which combines transformations performed in solvent-free conditions and in EtOAc, has been essential in order to avoid side reactions, poisoning of the reduction catalyst, and use of minimal amount of reactants.

A new sustainable protocol for the synthesis of nitroaldol derivatives via Henry reaction under solvent-free conditions

A new protocol for the Henry addition of nitroalkanes to aryl- and alkyl-aldehydes promoted by PS-BEMP under solvent-free conditions (SolFC) is presented. The corresponding nitroaldol products were obtained in good yields and short times; furthermore minimization of the reaction waste was achieved by reducing the use of organic solvents. Extension of the protocol was obtained by setting up the tandem Michael-Henry reaction of α,β-unsaturated aldehydes and nitroalkane to yield the corresponding dinitro derivatives.