Biagia Musio

Expedient preparation of nazlinine and a small library of indole alkaloids using flow electrochemistry as an enabling technology

An expedient synthesis of the indole alkaloid nazlinine is reported. Judicious choice of flow electrochemistry as an enabling technology has permitted the rapid generation of a small library of unnatural relatives of this biologically active molecule. Furthermore, by conducting the key electrochemical Shono oxidation in a flow cell, the loading of electrolyte can be significantly reduced to 20 mol % while maintaining a stable, broadly applicable process.

Synthesis of optically active arylaziridines by regio- and stereospecific lithiation of N-Bus-phenylaziridine

Alpha,alpha-disubstituted aziridines can be produced in good yields by selective lithiation of N-tert-butylsulfonyl-2-phenylaziridine (n-BuLi/TMEDA, Et(2)O) at the benzylic position and subsequent trapping with a range of electrophiles. Repetition of the lithiation/electrophilic trapping sequence provides a stereocontrolled route to trisubstituted aziridines. Using (R)-N-tert-butylsulfonyl-2-phenylaziridine, the alpha,alpha-disubstituted aziridines can be produced as single enantiomers (er >98:2), indicating that the intermediate organolithium is configurationally stable. Efficient aziridine ring-opening reactions leading to 1,2-diamines and 1,4-diamines are also reported.

Α-vs Ortho-Lithiation of N-Alkylarylaziridines : Probing the Role of the Nitrogen Inversion Process

The lithiation reaction of monophenyl- and diphenylaziridines has been investigated in detail in an effort to understand why the former undergo exclusively or mainly ortho-lithiation while the latter are lithiated exclusively at the alpha-position. Evidence is reported that ruled out the possibility that the alpha-lithiation, observed for the diphenylaziridines, is the result of an ortho- to alpha-translocation phenomenon, thus substantiating a direct alpha-deprotonation process. The role of the aziridine nitrogen lone-pair has been considered: dynamics at the aziridine nitrogen as well as complex-induced proximity effects seem to be responsible for the observed regioselectivity in both monophenyl and diphenylaziridines. It turns out that, by tuning the reaction conditions for the lithiation of trans-1-alkyl-2-methyl-3-phenylaziridines, it is possible to generate with high regioselectivity alpha- and/or ortho-lithiated aziridines, which can be stereoselectively functionalized by electrophilic trapping. A regioselective ortho-functionalization of diphenylaziridines is made possible by halogen- or tin-lithium exchange and by deprotonation of bis-deuterated aziridines.

Lithiation of N-alkyl-(o-tolyl)aziridine: stereoselective synthesis of isochromans.

The lithiation reaction of o-tolylaziridine 1 has been investigated by using the aziridine ring capability to act as a directing metalation group. Trapped with electrophiles, the resulting o-aziridinyl benzyllithium 1-Li gives access to several functionalized aziridines 2a-j. The hydroxyalkylated derivatives 2d-j were converted into important scaffolds such as isochromans 3a-d. A stereoselective preparation of isochromans (R)-3b, (1R,3S)-3d, and (1R,3R)-3d has been developed starting from enantioenriched o-tolylaziridine.

Regio- and stereoselective lithiation of 2,3-diphenylaziridines: a multinuclear NMR investigation.

The alpha-lithiation-trapping sequence of trans-N-alkyl-2,3-diphenylaziridines (s-BuLi or s-BuLi/TMEDA), taking place with a stereochemistry which dramatically depends on the solvent coordinating ability (inversion of configuration in THF and retention in toluene), has been carefully investigated. 1H,13C, and 7Li multinuclear NMR investigations at low temperature suggest that two differently configured lithiated aziridines (monomeric cis-1-Li in THF and dimeric trans-1-Li in toluene) are involved.

Synthesis of 1,2,3,4‐Tetrahydroisoquinolines by Microreactor‐Mediated Thermal Isomerization of Laterally Lithiated Arylaziridines

Flow chemistry: A flow-microreactor-mediated synthesis of 1,2,3,4-tetrahydroisoquinolines (THIQs) is reported (see scheme). Starting from a laterally lithiated aziridine, a tetrahydroisoquinoline lithiated at C4 was generated by thermally induced isomerization. Because the reaction temperature is a crucial parameter, the exquisite thermal control possible in a flow-microreactor system allowed for fast, efficient, and highly reproducible synthesis of functionalized aziridines or THIQs.

Solvent- and Temperature-Dependent Functionalisation of Enantioenriched Aziridines

A highly stereo- and regioselective functionalisation of chiral non-racemic aziridines is reported. By starting from a parent enantioenriched aziridine and finely tuning the reaction conditions, it is possible to address the regio- and stereoselectivity of the lithiation/electrophile trapping sequence, thereby allowing the preparation of highly enantioenriched functionalised aziridines. From chiral N-alkyl trans-2,3-diphenylaziridines (S,S)-1 a,b, two differently configured chiral aziridinyllithiums could be generated (trans-1 a,b-Li in toluene and cis-1 a,b-Li in THF), thus disclosing a solvent-dependent reactivity that is useful for the synthesis of chiral tri-substituted aziridines with different stereochemistry. In contrast, chiral aziridine (S,S)-1 c showed a temperature-dependent reactivity to give chiral ortho-lithiated aziridine 1 c-ortho-Li at -78 °C and α-lithiated aziridine 1 c-α-Li at 0 °C. Both lithiated intermediates react with electrophiles to give enantioenriched ortho- and α-functionalised aziridines. The reaction of all the lithiated aziridines with carbonyl compounds furnished useful chiral hydroxyalkylated derivatives, the stereochemistry of which was ascertained by X-ray and NMR spectroscopic analysis. The usefulness of chiral non-racemic functionalised aziridines has been demonstrated by reductive ring-opening reactions furnishing chiral amines that bear quaternary stereogenic centres and chiral 1,2-, 1,3- and 1,5-aminoalcohols. It is remarkable that the solvent-dependent reactivity observed with (S,S)-1 a,b permits the preparation of both the enantiomers of amines (11 and ent-11) and 1,2-aminoalcohols (13 and ent-13) starting from the same parent aziridine. Interestingly, for the first time, a configurationally stable chiral α-lithiated aziridine (1 c-α-Li) has been generated at 0 °C. In addition, ortho-hydroxyalkylated aziridines have been easily converted into chiral aminoalkyl phthalans, which are useful building blocks in medicinal chemistry.

Microreactor-Mediated Organocatalysis: Towards the Development of Sustainable Domino Reactions

Microreactor-mediated organocatalysed Michael reactions have been developed. By using a soluble proline-derived catalyst, Michael-type reactions, leading to γ-nitroketones, have been optimized in homogeneous and continuous-flow conditions. As proof of principle, an integrated microfluidic system able to perform domino processes useful in the preparation of bicyclo[4.4.0]decanes with six contiguous stereogenic centres has been set up.

BH3-promoted stereoselective β-lithiation of N-alkyl-2-phenylaziridines.

BH(3) complexes of N-alkyl-2-phenylaziridines have been synthesized and their structure and stereochemistry proved with DFT calculations and NMR experiments. It has been demonstrated that the Lewis acid complexation is able to promote a regioselective β-lithiation in 2-phenylaziridino-borane complexes. The lithiated intermediates were configurationally stable, allowing an enantioselective preparation of cis-2,3-disubstituted aziridines.

Synthesis of Functionalized Arylaziridines as Potential Antimicrobial Agents

By using the Suzuki-Miyaura protocol, a simple straightforward synthesis of functionalized 2-arylaziridines has been developed. By means of this synthetic strategy from readily available ortho-, meta- and para-bromophenylaziridines and aryl- or heteroarylboronic acids, new aziridines could be obtained. The cross-coupling reactions occurred without ring opening of the three membered ring. Preliminary results on the antimicrobial activity of the heterosubstituted biaryl compounds have been also included.