A valuable and direct method to access 2-substituted-2-phenyloxetanes by electrophilic quenching of the corresponding 2-lithiated derivative has, for the first time, been described. 2-Lithiated-2-phenyloxetane was found to be configurationally unstable. Evidence is presented to show that electron-transfer processes are also operative in the coupling reactions with electrophiles.

Functionalized oxetanes are useful building blocks in the preparative chemistry as well as in synthesis of drugs, materials, agrochemicals [1]. In this communication we report the preliminary results of the first chemo-enzymatic synthesis of optically active 2,4-disubstituted oxetanes, prepared by cyclization of optically active 1,3-diols [2], in turn obtained by steroselective reduction of the corresponding 1,3-diketones with yeasts. The stereoselective reduction of symmetrical and nonsymmetrical substituted 1,3-diketones was investigated in the presence of some conventional and non-conventional yeast strains (Saccharomyces cerevisiae, Kluyveromyces marxianus, Baker’s yeast, etc.). Optically active aldols were obtained with high stereopreference by baker’s yeast, and then diastereoselectively converted in the corresponding diols (dr> 95%) which were then cyclized into the corresponding 2,4-disubstituted oxetanes in good yields, with high diastereoisomeric ratio (dr) and enantiomeri excess up to 80 %.

The reaction of ortho-lithiated aryloxiranes with various enaminones affords straightforwardly new functionalized isochromanes, as a mixture of two epimeric stereoisomers, in reasonable to very good yields (50-90%). The two diastereomers, which show a high structural variability, could be easily separated by column chromatography.

In this communication we report the solution and the solid structure of -lithiated orthotrifluoromethyl styrene oxide 1-Li. Single crystal X-ray diffraction analysis of 1-Li reveals a self-assembled heterochiral dimeric structure with a rare central six-membered (O-Li-C)2 planar core, which is unprecedented in Li/oxygen carbenoids. Multinuclear magnetic resonance (1H, 13C, 19F, 7Li) studies suggest 1-Li exists in THF solution as a mixture of two interconverting diastereomeric dimeric aggregates, each one featuring a single -contact between lithium and a carbon atom.

The presence of an electron-donating methoxy group at the 4-position of 4-phenyl-3,5-dimethyl-1,2,4-triazole is beneficial to lateral metalation/functionalization of this ring system once sBuLi is employed as the base and THF is used as the solvent at –78 °C; this opens up an alternative approach towards the synthesis of several 1,2,4-triazole derivatives. Both carbon- and heteroatom-based halides are competent electrophiles for this transformation, as are aliphatic and aromatic aldehydes and ketones, isocyanates, carboxylic acid derivatives, and alpha,beta-unsaturated carbonyl compounds. The easy elaboration of such a group to phenol derivatives also provides greater flexibility in synthetic design.

Optically active molecules are important building blocks for the synthesis of many chemicals and biologically active compounds. Among the known catalysts, isolated enzymes have some advantages over conventional methods in the asymmetric synthesis, such as chemo-, regio-, and stereo-selectivity, together with very mild reaction conditions [1]. The asymmetric synthesis accomplished by using whole-cells has also further advantages [2, 3] because all the necessary cofactors and all required substances for their regeneration are present in their natural environment, thus making the catalytic system more efficient [4]. Many research groups have focused their attention on looking for non-conventional yeasts, to study in comparison to the deeply investigated Saccharomyces cerevisiae [5]. For several years our interests focused on using non-conventional yeasts to prepare new EPCs: among these, thermotolerant Kluyveromyces marxianus CBS 6556, not widely investigated in asymmetric synthesis, was preliminarly and successfully used by us for the stereoselective bioreduction of prostereogenic keto-esters to prepare optically active building-blocks in the synthesis of pharmacologically active compounds [6, 7]. These studies allowed also the isolation of an unkown ADH from this yeast [8], able to mediate the highly stereoselective bioreduction of prostereogenic 3-oxo esters. Herein, we report the continuation of such studies, in which the Kluyveromyces marxianus CBS 6556 is used in the bioreduction of various prochiral ketones, with the aim to deepen its substrate specificity, turnover rate, regio- chemo- and enantioselectivity.

Oxetane nudges in the DoM direction! Regioselective ortho-lithiation induced by an oxetane ring has been achieved. The reaction provides easy access to ortho-functionalized 2-aryloxetanes also through a lithiation/borylation Suzuki–Miyaura cross-coupling. The lithiation-directing ability of oxetane and the proton transfer mechanism have been investigated by competitive metalation and kinetic isotope effect studies.

Reverse [3+2] cycloaddition of α-lithiated phenyltetrahydrofuran was successfully tamed at −78 °C in toluene in the presence of TMEDA, thereby providing easy access to diverse tetrahydrofuranyl-containing functional frameworks.

The use of microorganism growing cells is a well recognized methodology in biocatalyzed organic reactions. A non-conventional thermotolerant Kluyveromyces marxianus yeast strain was used for the bioreduction of different arylketones. Differently substituted ketones were converted into the corresponding (S)-alcohols with up to 96% enantiomeric excess under very mild reaction conditions. Kluyveromyces marxianus represents a promising biocatalyst for the production of optically active 1-arylethanols.

The configurational stability of some lithiated fluorinated styrene oxides has been investigated. Chemical studies have shown that in ethereal solvents α-lithiated ortho-, meta-, and para-fluorostyrene oxides (2-Li, α-5-Li, and α-6-Li) are all configurationally stable in the reaction time scale, whereas a-lithiated ortho-, meta-, and paratrifluoromethylstyrene oxides (9-Li, 13-Li, and 14-Li) are configurationally unstable. Optically active oxiranyllithiums 2-Li and 9-Li, could be stereospecifically generated and quenched with electrophiles. The corresponding derivatives were then successfully subjected to regiospecific ring-opening reactions with amines to give fluorinated ßamino alcohols with a stereodefined quaternary carbinol center, which are useful synthons in medicinal chemistry. The barriers of inversion have been calculated (Eyring equation) for oxiranyllithiums 9-Li, 13-Li, and 14-Li by determining the enantiomeric ratios after electrophilic quenching on aging the enantioenriched organolithium for different times in THF; in the case of 9-Li, activation parameters have also been determined. Mechanisms that may be responsible of the racemization oxiranyllithiums 9-Li, 13-Li, and 14-Li undergo once generated are also discussed.

This paper focuses on alfa-lithiated oxazolinyloxiranes and oxazolinylaziridines, their generation, reactions, and synthetic applications. The ability of the oxazoline ring in providing stabilization to such alfa-heterosubstituted carbanions either through electronic effects and coordinative action has been stressed as well as the contribution to the configurational stability or instability of such species. IR spectroscopic data, multinuclear NMR investigations, and ab initio calculations planned to get insights on chemical properties and structural features have been carried out. A number of new reactions including alkylations, addition reactions, hydroxyalkylations, cyclopropanations, lactonizations, and rearrangements have been discovered, giving access to a variety of substances including: aziridinolactones, epoxylactones, aryl alkanones, polysubstituted cyclopropanes, cyclopropanefused lactones, dihydro-oxazoloisoquinolines, diversely functionalized oxazolines, and products that can be derived from them by synthetic elaboration.

This paper focuses on α-lithiated oxazolinyloxiranes and oxazolinylaziridines, their generation, reactions, and synthetic applications. The ability of the oxazoline ring in providing stabilization to such α-heterosubstituted carbanions either through electronic effects and coordinative action has been stressed as well as the contribution to the configurational stability or instability of such species. IR spectroscopic data, multinuclear NMR investigations, and ab initio calculations planned to get insights on chemical properties and structural features have been carried out. A number of new reactions including alkylations, addition reactions, hydroxyalkylations, cyclopropanations, lactonizations, and rearrangements have been discovered, giving access to a variety of substances including: aziridinolactones, epoxylactones, aryl alkanones, polysubstituted cyclopropanes, cyclopropanefused lactones, dihydro-oxazoloisoquinolines, diversely functionalized oxazolines, and products that can be derived from them by synthetic elaboration.

The configurational stability of some sulfurated styrene oxides has been investigated. Chemical studies have shown that in THF at 157 K α-lithiated ortho- and paraphenylthiostyrene oxides are configurationally unstable and undergo a fast racemization on the time scale of the reaction, whereas α-lithiated meta-phenylthiostyrene oxide retains its stereochemical integrity for at least 60 min. The deprotonation-trapping methodology has also been employed for the preparation of a sulfurated β-aminoalcohol effective for the fight against phytopathogenic fungi.

This chapter focuses on the generation, chemistry, and synthetic applications of oxygen-stabilized organolithiums such as α-lithiated acyclic and cyclic alkyl and vinyl ethers, carbamates, and epoxides. Lithiation is achieved normally by deprotonation, transmetalation (usually Sn–Li exchange), or reductive lithiation. In this chapter, the configurational stability of such lithiated intermediate has been especially addressed as well as the stereochemistry of their reactions for the asymmetric synthesis of a variety of substances of interest in several fields.

The transformation of epoxides into other compounds by exploiting the reactivity of the oxirane ring has emerged as a powerful tool in organic synthesis. Moreover, the rapid development of efficient and practical methods for the preparation of epoxides in enantiopure form has encouraged chemists to make such transformations easy to carry out, chemo-, regio-, and stereoselective, as well as of general applicability. This chapter describes reductions of the epoxides grouped in two different types: (1) reduction to alcohols and (2) deoxygenation to alkenes. It focuses on reactions that allow the preparation of alcohols by reductive ring opening of epoxides with particular emphasis on synthetic methods that are regioselective and stereoselective, compatible with other functional groups, and that have been used in the preparation of useful target molecules. The deoxygenation of epoxides, which may be seen as masked or protected forms of alkenes, is another important method that is useful for the preparation of functionalized alkenes of interest in organic synthesis in general and in medicinal chemistry in particular. Relevant advances in these fields since the first edition of comprehensive organic synthesis in 1991 are reported; older but still used methods will also be mentioned.

The conjugate addition of organometallics to nitroalkenes provides a useful method for nitro-alkylation. This type of addition is much pursued in organic synthesis as the nitro group can be easily transformed into various functional groups including carbonyl derivatives by the Nef reaction, amines by reduction, nitriles, imines by other transformations1. While 1,4-conjugated additions of organozinc reagents (R2Zn and RZnX) have been extensively studied2, applications of alkali-metal zincates in fundamental organic transformations are still in their infancy3. This type of reagents show unique, synergistic chemical characteristics which cannot be replicated by their monometallic (organolithium/organozinc) counterparts. In this Communication, we compare the kinetic reactivity of two different alkali-metal zincates (namely triorgano- and tetraorganozincates) in Deep Eutectic Solvents and under neat conditions towards variously substituted nitroalkenes. It will be shown that, under optimized reaction conditions (0 °C and with no added solvents) Michael additions promoted by aliphatic and aromatic organozincates take place with high regio- and chemoselectivity providing the expected nitroalkanes in yields to up to >98%, and with no replacement of the vinylic nitro group by the alkyl group, which often remains a complication. Isolation of key intermediates, and stereochemical aspects will be discussed as well.

Kluyveromyces marxianus CBS 6556 growing cell versatility in the enantioselective reduction of ketone-carbonyl functionality to the corresponding alcohols was exploited. In particular, methyl ketones were reduced to (S)-alcohols with ee up to 96%. Longer chain alkyl ketones afford, in the same experimental condition, (R)-alcohols with ee up to 84%. Interestingly, carbon-carbon double and triple bond of ketones can also be reduced in the presence of Kluyveromyces marxianus CBS 6556 yeast. Endocyclic carbonyl functionality, such as 2-tetralone carbonyl, is also quantitatively reduced to its (S)-alcohol with ee = 76%.

The employment of hexane/TMEDA dramatically hampers racemization of those lithiated styrene oxides (trifluoromethyl-, chloro-, and thiophenyl-substituted) which have been proven to be configurationally unstable in THF on the time scale of their reactions. The barriers to inversion and the activation parameters calculated (Eyring equation) for reactions run in THF, THF/TMEDA, and hexane/TMEDA suggest the intervention of peculiar eantiomerization mechanisms for each case. The role of TMEDA in both coordinating and non-coordinating solvents has also been questioned and discussed in light of the kinetic data gathered, and a model of deprotonation in hexane/TMEDA has also been proposed. The synthetic benefits of our results became apparent by setting up an asymmetric synthesis of an industrially relevant antifungal agent.

Three distinct stereoselective reactions, catalysed by using a chiral primary amine through different activation methods, have been successfully carried out for the first time in bio-based eutectic mixtures, thereby affording functionalised molecules in very high enantioselectivity. The use of these unconventional and biorenewable reaction media also provides opportunities for facilitating the recovery and the recycling of the chiral catalyst.

An efficient one-pot double Suzuki-Miyaura cross--coupling reaction between bifunctional phenylene-1,4-bis(potassium trifluoroborate) and aryl and heteroaryl bromides is described. The scope and limitations of this methodology that enables the synthesis of tri(hetero)aryl derivatives, potentially useful as drugs and in the field of materials science, have also been probed.

It has always been a firm conviction of the scientific community that the employment of both anhydrous conditions and water-free reaction media is required for the successful handling of organometallic compounds with highly polarised metal–carbon bonds. Herein, we describe how, under heterogeneous conditions, Grignard and organolithium reagents can smoothly undergo nucleophilic additions to gchloroketones, on the way to 2,2-disubstituted tetrahydrofurans, “on water”, competitively with protonolysis, under batch conditions, at room temperature and under air. The reactivity of the above organometallic reagents has also been investigated in conventional anhydrous organic solvents and in bio-based eutectic and low melting mixtures for comparison. The scope and limitations of this kind of reaction are discussed.