P u b l i c a t i o n s

Abstract: Herein, we disclose a new photochemical process to prepare γ-amino acids from allylamines and formic acid salts. The investigated redox-neutral hydrocarboxylation process produces high yields across a wide range of functionalized allylamine substrates with excellent regioselectivity. The developed operationally simple protocol can be readily scaled with low photocatalyst loading (from 1% up to 0.02 mol%) without the need for any precautions to exclude air or moisture. The mechanistic working model utilizes a thiol-catalyzed radical chain process, delivering the hydrogen atom and CO2 from formic acid salt across the alkene substrate through the carboxylate radical (CO2•-), a crucial reactive intermediate 

Abstract: Among the methods of synthesizing the β-lactam ring, the copper(I)-mediated reaction between a nitrone and a terminal alkyne in the presence of an organic base is a remarkably simple and direct strategy. This transformation, known as the Kinugasa reaction, is a cascade process that involves a 1,3-dipolar cycloaddition of a copper acetylide onto the nitrone, followed by a rearrangement step. Initially reported in 1972, this reaction stereoselectively allows access to cis-substituted β-lactam products. Achiral, diastereoselective, and catalytic enantioselective versions of the Kinugasa reaction have been described, both in inter- and intramolecular contexts. To date, only aldimine-derived nitrones have been demonstrated in the reaction.

This chapter presents a comprehensive overview of the Kinugasa reaction. Mechanistic proposals and the factors involved in the stereochemistry of the reaction are followed by a discussion of the scope of the reaction and its limitations. Specifically, the combinations of aldonitrones and terminal alkynes that can be used in the achiral and diastereoselective Kinugasa reaction are presented. Enantioselective and intramolecular variants of the reaction are discussed in detail, as are successful synthetic applications, with an emphasis on the preparation of β-lactam antibiotics. The Kinugasa reaction is compared with more classical and well-established methods of β-lactam synthesis, and finally, typical experimental conditions and examples of procedures for selected variants of the Kinugasa reaction are provided. The Tabular Survey covers Kinugasa reactions performed through the end of 2021.

Abstract: We report a convenient two-step approach to α-amino ketones involving cross-coupling and oxidative cleavage. The cross-coupling reaction creates a divergent functionalization of the molecular platform, e.g., N-(2-bromoallyl)amine, whereas the oxidative cleavage establishes the carbonyl functionality. This strategy allows for an introduction of aryl/heteroaryl and alkyl groups, either through the Suzuki reaction with arylboronic acids or via dual photoredox/Ni-catalysis to install alkyl groups. The oxidative cleavage to provide target α-amino ketones can be realized either by treating with ozone or by employing milder photochemical protocols involving oxygen or photoexcited nitroarenes as oxidants. We successfully demonstrate the scalability of this protocol, which, together with its simplicity, generality, and its ability to provide access to amino ketones that are inaccessible through other strategies, highlights the suitability of this approach for a wide range of applications across the different chemical sciences. 

Abstract: A convenient and general protocol for the palladium-catalysed oxidation of internal allylamine derivatives to β-amino ketones is reported. The transformation occurs at room temperature and shows wide substrate scope as well as high functional group and N-protecting group tolerance. We also describe potential applications of the method, e.g., for the synthesis of bioactive molecules or for simple transformations of selected β-amino ketones to other interesting building blocks.

Abstract: A mild, and versatile, organophotoredox/Ni-mediated protocol was developed for the direct preparation of diverse, enantioenriched allyl carbamates. The reported approach represents a significant departure from classical step-by-step synthesis of allyl carbamates. This dual photoredox/Ni based strategy offers unrivalled capacity for convergent unification of readily available alkyl halides and chiral carbamates derived from 1-bromo-alken-3-ols with high chemoselectivity and efficiency. The reported photoredox/Ni catalyzed cross-coupling reaction is not limited to carbamates, but also to other O-derivatives such as esters, ethers, acetals, carbonates or silyl ethers. To demonstrate the utility of the reported protocol, the resulting allyl carbamates were transformed into functionalized non-racemic allylamines through a sigmatropic rearrangement reaction in enantiospecific manner. This approach allowed for synthesis of enantiomeric allylamines by a simple control of the geometry of a double bond of allyl carbamates. 

Abstract: The synthesis of α-aryl- and α-alkyl-substituted serine derivatives via [3,3]-sigmatropic rearrangement of allyl carbamates as a key step is reported. Allyl carbamates were obtained from the corresponding allyl alcohols. The former were prepared through three approaches. Aryl-substituted ones were synthesized via the Stille coupling reaction of aryl iodides with enantiomerically enriched vinyl stannanes. Conversely, alkyl-substituted allyl alcohols were prepared by an analogous strategy involving the Negishi coupling reaction of enantiomerically enriched vinyl iodides or by enzymatic kineric resolution of the corresponding racemic alcohols. 

Abstract: Total synthesis of levetiracetam, an active ingredient of epilepsy treatment medications, is reported. The reported method is based on a one-pot dehydration/sigmatropic rearrangement of (R,E)-hept-4-en-3-ol carbamate to the corresponding allylamine derivative, an advanced precursor of levetiracetam.

Abstract: A catalyst-free reaction of 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates with silyl enolates was developed to prepare β-amino carbonyl compounds. The reported method is a useful approach for the preparation of N-protected β-amino esters as well as N-protected β-amino ketones. The starting 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates are readily available from N-protected α-amino acids. Therefore, the presented approach can be considered a new method for the α-homologation of N-protected α-amino acids to prepare β-amino acid derivatives.

Abstract: This Microreview covers the reactions of [Cp2Zr(H)Cl] with C=X functionalities, such as amides, lactams, nitriles or isocyanates, as a method for chemoselective preparation of functionalized organic molecules, for instance aldehydes, amines, and amides 

Keywords: Schwartz's reagent, reduction, organozirconium  reagents, nucleophilic addition, imines

Abstract:  A synthesis of non-racemic β-alkyl-β-aryl allyl alcohols and their transformation into allylamines bearing a quaternary stereogenic center is reported. The allyl alcohols were prepared either by Cu-catalyzed enantioselective reduction of enones or by sequential alkylation/hydrostannylation/Stille coupling of non-racemic propargyl alcohols. The prepared β-alkyl-β-aryl allyl alcohols were converted (after carbamoylation) to the corresponding allylamine derivatives through cyanate-to-isocyanate rearrangement/nucleophilic addition with complete chirality transfer. Varying the nucleophilic agents allowed the preparation of various allylamine derivatives, including carbamates, amides, formamides, ureas, and free amines. The ozonolysis/oxidation of the resulting allylamines provided non-racemic quaternary α-amino acids. 

Abstract: An approach to nonracemic β,β-diarylsubstituted allyl alcohols is described. Their synthesis starts from l-lactic acid-derived propargyl alcohol, which is submitted to sequential Sonogashira/Suzuki or Sonagashira/Stille coupling reactions. Both approaches enable the synthesis of either (Z)- or (E)-allylic alcohols regarding the order of introducing coupling agents. The obtained allyl alcohols were applied in the synthesis of nonracemic α-tertiary allylamines via stereocontrolled cyanate-to-isocyanate sigmatropic rearrangement reactions of the corresponding allyl carbamates. The stereoselectivity of the process is controlled by the geometry of the double bond of the starting allyl derivative. As demonstrated, a rearrangement of (S,Z)-allyl carbamates provides (S)-teriary allylamines, whereas the transformation (S,E)-isomers leads to (R)-allylamines 

Abstract: The combination of Ichikawa’s rearrangement and a ring-closing metathesis reaction of allyl carbamates is presented as a method for the preparation of 5-amino-substituted 2,5-dihydro-benzo[b]oxepines, 2,5-dihydro-benzo[b]azepines, and 2,5-dihydro-benzo[b]thiepins. It was demonstrated that the use of nonracemic allyl carbamates enables the synthesis of enantioenriched benzo-fused seven-membered heterocycles. Finally, it was shown that further functionalization of the obtained structures allows access to pharmacologically active 5-amino-substituted 2,3,4,5-tetrahydro-1-benzo[b]oxepine scaffolds. 

Abstract: Allylation and butenylation of N-alkoxycarbonyl-2-tributylstannyl-1,3-oxazolidines derived from (S)-vinylglycinol or (S)-styrylglycinol provide efficient access to stannylated dehydropiperidines and dehydroazepanes after ring-closing metathesis. 

Abstract: An approach to α,α-disubstituted α-amino acids is reported. The key step is allyl cyanate-to-isocyanate rearrangement. As demonstrated, the resultant allyl isocyanates can be directly trapped with various nucleophiles, for instance, alcohols, amines, and organometallic reagents, to provide a broad range of N-functionalized allylamines. The developed method has been successfully applied in the synthesis of two bioactive peptides: 2-aminoadamantane-2-carboxylic acid derived P2X7-evoked glutamate release inhibitor and 4-amino-tetrahydropyranyl-4-carboxylic acid derived dipeptide GSK-2793660, which is currently in clinical trials as cathepsin C inhibitor for the treatment of cystic fibrosis, noncystic fibrosis bronchiectasis, ANCA-associated vasculitis and bronchiectasis.