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.

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.