The regioselective Wacker oxidation of internal allylamines: synthesis of functionalized and challenging ß-amino ketones.

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

Multifunctional Heteropentalenes: From Synthesis to Optoelectronic Applications.

In the broad family of heteropentalenes, the combination of two five-membered heterocyclic rings fused in the [3,2-b] mode has attracted the most significant attention. The relatively straightforward access to these structures, being a consequence of the advances in the last two decades, combined with their physicochemical properties which match the requirements associated with many applications has led to an explosion of applied research. In this Perspective, we will discuss the recent progress of heteropentalenes' usefulness as an active element of organic light-emitting diodes and organic field-effect transistors. Among the myriad of possible combinations for the different heteroatoms, thieno[3,2-b]thiophenes and 1,4-dihydropyrrolo[3,2-b]pyrroles are subject to the most intense studies. Together they comprise a potent optoelectronics tool resulting from the combination of appreciable photophysical properties, chemical reactivity, and straightforward synthesis.

Synthesis of chiral branched allylamines through dual photoredox/nickel catalysis.

Allylamines are versatile building blocks in the synthesis of various naturally occurring products and pharmaceuticals. In contrast to terminal allylamines, the methods of synthesis of their branched congeners with internal, stereodefined double bonds are less explored. This work describes a new approach for the preparation of allylamines via cross-coupling of alkyl bromides with simple 3-bromoallylamines by merging the photoredox approach and Ni catalysis. The reaction proceeds under mild conditions, under blue light irradiation, and in the presence of an organic dye, 4CzIPN, as a photocatalyst. The scope of suitable reaction partners is broad, including alkyl bromides bearing reactive functionalities (e.g., esters, nitriles, aldehydes, ketones, epoxides) and N-protected allylamines, as well as N-allylated secondary and tertiary amines and heterocycles. The employment of non-racemic starting materials allows for rapid and easy construction of complex multifunctional allylamine derivatives without the loss of enantiomeric purity.

An entry to non-racemic ß-tertiary-ß-amino alcohols, building blocks for the synthesis of aziridine, piperazine, and morpholine scaffolds.

A method for the preparation of enantiopure ß-tert-amino alcohols bearing a tetrasubstituted C-stereocenter, as well as their conversion into selected medicinally privileged heterocyclic systems (morpholines, aziridines, piperazines) is reported. These compounds were obtained through enantiospecific sigmatropic rearrangement of allyl carbamates as a key step. The latter were prepared from the corresponding ß,ß'-dialkyl-substituted non-racemic allyl alcohols. In addition, an asymmetric synthesis of such highly substituted allylic alcohols via either enantioselective 1,2-reduction of enones, enzymatic kinetic resolution, or a functionalization of chiral propargyl alcohols, with discussion of scope and limitations of each method is reported.

The synthesis of unnatural α-alkyl- and α-aryl-substituted serine derivatives.

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.

The Synthesis of α-Aminophosphonates via Enantioselective Organocatalytic Reaction of 1-(N-Acylamino)alkylphosphonium Salts with Dimethyl Phosphite.

α-Aminophosphonic acids are phosphorus analogues of α-amino acids. Compounds of this type find numerous applications in medicine and crop protection due to their unique biological activities. A crucial factor in these activities is the configuration of the stereoisomers. Only a few methods of stereoselective transformation of α-amino acids into their phosphorus analogues are known so far and all of them are based on asymmetric induction, thus involving the use of a chiral substrate. In contrast, we have focused our efforts on the development of an effective method for this type of transformation using a racemic mixture of starting N-protected α-amino acids and a chiral catalyst. Herein, a simple and efficient stereoselective organocatalytic α-amidoalkylation of dimethyl phosphite by 1-(N-acylamino)alkyltriphenylphosphonium salts to enantiomerically enriched α-aminophosphonates is reported. Using 5 mol% of chiral quinine- or hydroquinine-derived quaternary ammonium salts provides final products in very good yields up to 98% and with up to 92% ee. The starting phosphonium salts were easily obtained from α-amino acid derivatives by decarboxylative methoxylation and subsequent substitution with triphenylphosphonium tetrafluoroborate. The appropriate self-disproportionation of enantiomers (SDE) test for selected α-aminophosphonate derivatives via achiral flash chromatography was performed to confirm the reliability of the enantioselectivity results that were obtained.

Total synthesis of levetiracetam.

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.

The synthesis of non-racemic ß-alkyl-ß-aryl-disubstituted allyl alcohols and their transformation into allylamines and amino acids bearing a quaternary stereocenter.

A synthesis of non-racemic ß-alkyl-ß-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 ß-alkyl-ß-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.

The Synthesis of Chiral ß,ß-Diaryl Allylic Alcohols and Their Use in the Preparation of α-Tertiary Allylamines and Quaternary α-Amino Acids.

An approach to nonracemic ß,ß-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.

The Synthesis of 5-Amino-dihydrobenzo[b]oxepines and 5-Amino-dihydrobenzo[b]azepines via Ichikawa Rearrangement and Ring-Closing Metathesis.

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.

The Synthesis of α,α-Disubstituted α-Amino Acids via Ichikawa Rearrangement.

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.

Approach to Monobactams and Nocardicins via Diastereoselective Kinugasa Reaction.

A Kinugasa reaction between copper(I) acetylides and cyclic nitrones derived from chiral amino alcohols and glyoxylic acid is reported. The stereochemical preferences observed in this reaction are discussed. The alkyne molecule approaches the nitrone exclusively anti to the large substituent next to the nitrogen atom to provide the cis-substituted ß-lactam ring preferentially. The six-membered oxazinone ring can be opened by reduction with lithium borohydride. Deprotection of the ß-lactam nitrogen atom can be achieved by lithium in liquid ammonia reduction or by CAN oxidation, depending on the substituents attached to the four-membered azetidinone ring. The adducts obtained by the Kinugasa reaction provide an attractive entry to a variety of monocyclic ß-lactam structures related to monobactams and nocardicins.

Synthesis of polyhydroxylated piperidine and pyrrolidine peptidomimetics via one-pot sequential lactam reduction/Joullié-Ugi reaction.

A direct approach to the synthesis of polyhydroxylated piperidine and pyrrolidine peptidomimetics is described. The presented strategy is based on one-pot reduction of sugar-derived lactams with Schwartz's reagent followed by a multicomponent Ugi-Joullié reaction.

Synthesis of ß- and γ-hydroxy α-amino acids via enzymatic kinetic resolution and cyanate-to-isocyanate rearrangement.

A new strategy for stereoselective preparation of all four isomers of ß- and γ-hydroxy α-amino acids is presented. The developed procedure is based on enzymatic kinetic resolution and cyanate-to-isocyanate rearrangement as key steps. Stereocontrol is achieved by proper choice of the starting hydroxyacid, the course of kinetic resolution, and the stereospecific sigmatropic rearrangement step, which proceeds with full chirality transfer.

Synthesis of polyhydroxylated quinolizidine and indolizidine scaffolds from sugar-derived lactams via a one-pot reduction/Mannich/Michael sequence.

A direct approach to the synthesis of indolizidine and quinolizidine scaffolds of iminosugars is described. The presented strategy is based on a one-pot sugar lactam reduction with Schwartz's reagent followed by a diastereoselective Mannich/Michael tandem reaction of the resulting sugar imine with Danishefsky's diene. The stereochemical course of the investigated reaction has been explained in detail. The obtained bicyclic products are attractive building blocks for the synthesis of various naturally occurring polyhydroxylated alkaloids and their derivatives.

Total synthesis of lacosamide.

Total synthesis of anticonvulsant amino acid, lacosamide, is reported. The key step is stereospecific allyl cyanate-to-isocyanate rearrangement, which proceeds with chirality transfer. The enantiopure starting material for the rearrangement step was accessed from ethyl L-lactate.

Total synthesis of ezetimibe, a cholesterol absorption inhibitor.

Ezetimibe (1), a strong ß-lactamic cholesterol absorption inhibitor, was synthesized from (R)-6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one 7. Independent pathways were analyzed in order to select the optimal one, which involved 1,3-dipolar cycloaddition with C-(4-benzyloxyphenyl)-N-(4-fluorophenyl)-nitrone (8), intramolecular nucleophilic displacement at the benzylic position of the lactone, cleavage of the N-O bond, elimination of a water molecule, hydrogenation of the double bond, rearrangement of the six-membered lactone ring into a ß-lactam moiety, and final deprotection of the phenolic hydroxyl group. Highly stereoselective Sc(OTf)3-catalyzed 1,3-dipolar cycloaddition was the most crucial step of the synthesis. Owing to the rigid transition state of the cycloaddition, the absolute configuration of the starting lactone controlled the formation of other stereogenic centers of the final molecule 1.

A practical preparation of the key intermediate for penems and carbapenems synthesis.

A novel, practical and stereoselective synthesis of (3R,4R)-4-acetoxy-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone, a key intermediate in the preparation of ß-lactam antibiotics is reported. The crucial step of the synthesis is based on the Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade between silyl protected (R)-3-butyn-2-ol and the nitrone derived from benzyl hydroxylamine and benzyl glyoxylate. The obtained adduct is subjected to debenzylation with sodium, or lithium in liquid ammonia followed by oxidation with lead tetraacetate to afford the final product.

A formal synthesis of ezetimibe via cycloaddition/rearrangement cascade reaction.

A formal synthesis of a powerful cholesterol inhibitor, ezetymibe 1, is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from acetonide of L-glyceraldehyde and suitable C,N-diarylnitrone. The adduct with (3R,4S) configuration at the azetidinone ring, obtained with high stereoselectivity, was subsequently subjected to deprotection of the diol side chain followed by glycolic cleavage and base-induced isomerization at the C3 carbon atom to afford the (3S,4S) aldehyde, which has been already transformed into ezetimibe by the Schering-Plough group.

Direct, catalytic synthesis of carbapenams via cycloaddition/rearrangement cascade reaction: unexpected acetylenes' structure effect.

Reactions of acetylenes derived from glyceraldehyde and propargyl aldehyde show remarkable reactivity in Kinugasa cycloaddition/rearrangement cascade process catalyzed by Cu(I) ion. Reactions proceed by formation of a rigid dinuclear copper(I) complex in which each copper ion is coordinated to one or both oxygen atoms in the acetylene molecule and to both triple bonds. It has been demonstrated that one oxygen atom can be replaced by the phenyl ring, which is able to coordinate the copper ion by the aromatic sextet. Kinugasa reactions that proceed in a high yield can also be performed in the presence of a catalytic amount of the copper salt to provide products in an acceptable yield without a decrease of diastereoselectivity.