Direct, Stereodivergent, and Catalytic Michael Additions of Thioimides to α,ß-Unsaturated Aldehydes - Total Synthesis of Tapentadol.

Direct and stereodivergent Michael additions of N-acyl 1,3-thiazinane-2-thiones to α,ß-unsaturated aldehydes catalyzed by chiral nickel(II) complexes are reported. The reactions proceed with a remarkable regio-, diastereo-, and enantioselectivity, so access to any of the four potential Michael stereoisomers is granted through the appropriate choice of the chiral ligand of the nickel(II) complex. Simple removal of the heterocyclic scaffold furnishes a wide array of either syn or anti enantiomerically pure derivatives, which can be exploited for the asymmetric synthesis of biologically active compounds, as demonstrated in a new approach to tapentadol. In turn, a mechanism, based on theoretical calculations, is proposed to account for the stereochemical outcome of these transformations.

Copper(I) Iodide Catalyzed [3 + 3] Annulation of Iodonium Ylides with Pyridinium 1,4-Zwitterionic Thiolates for the Synthesis of 1,4-Oxathiin Scaffolds.

The selective assembly of the 1,4-oxathiin nucleus has been treated as a powerful strategy to access this scaffold present in molecules with very interesting properties. In this study, the chameleon-like reactivity of pyridinium 1,4-zwitterionic thiolates is exploited to assemble the 1,4-oxathiin core through a [3 + 3] annulation. The optimal annulation partner has been found to be the iodonium ylide of the cyclic 1,3-diketones. The developed protocol allows the synthesis of a variety of bicyclic 1,4-oxathiin derivatives under very mild conditions under copper(I) iodide catalysis. Access to benzoannulated 1,4-oxathiins has been achieved through iodine-mediated aromatization of the initially obtained bicyclic compounds.

Protected syn-Aldol Compounds from Direct, Catalytic, and Enantioselective Reactions of N-Acyl-1,3-oxazinane-2-thiones with Aromatic Acetals.

A direct and asymmetric syn-aldol reaction of N-acyl-1,3-oxazinane-2-thiones with dialkyl acetals from aromatic acetals in the presence of 2-5 mol % [DTBM-SEGPHOS]NiCl2, TMSOTf, and lutidine has been developed. It has been established that the oxazinanethione heterocycle, used for the first time as a scaffold in asymmetric carbon-carbon bond-forming reactions, can be smoothly removed to give access to a variety of enantiomerically pure compounds with high synthetic value.

Direct and Asymmetric Aldol Reactions of N-Azidoacetyl-1,3-thiazolidine-2-thione Catalyzed by Chiral Nickel(II) Complexes. A New Approach to the Synthesis of ß-Hydroxy-α-Amino Acids.

A direct and asymmetric triisopropylsilyltrifluoromethanesulfonate (TIPSOTf) mediated aldol reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with aromatic aldehydes catalyzed by a chiral nickel(II)-Tol-BINAP complex has been developed (BINAP=2,2'-bis(diphenylphosphino)-1,1'-binaphthyl). The catalytic protocol gives the corresponding anti α-azido-ß-silyloxy adducts with outstanding stereocontrol and in high yields. Theoretical calculations account for the stereochemical outcome of the reaction and lay the foundations for a mechanistic model. In turn, the easy removal of the thiazolidinethione yields a wide array of enantiomerically pure derivatives in a straightforward and efficient manner. Such a noteworthy character of the heterocyclic scaffold together with the appropriate manipulation of the azido group open a new route to the synthesis of di- and tripeptide blocks containing a ß-aryl-ß-hydroxy-α-amino acid.

Direct and Enantioselective Aldol Reactions Catalyzed by Chiral Nickel(II) Complexes.

A direct and asymmetric aldol reaction of N-acyl thiazinanethiones with aromatic aldehydes catalyzed by chiral nickel(II) complexes is reported. The reaction gives the corresponding O-TIPS-protected anti-aldol adducts in high yields and with remarkable stereocontrol and atom economy. Furthermore, the straightforward removal of the achiral scaffold provides enantiomerically pure intermediates of synthetic interest, which involve precursors for anti-α-amino-ß-hydroxy and α,ß-dihydroxy carboxylic derivatives. Theoretical calculations explain the observed high stereocontrol.

Direct, Enantioselective, and Nickel(II) Catalyzed Reactions of N-Azidoacetyl Thioimides with Trimethyl Orthoformate: A New Combined Methodology for the Rapid Synthesis of Lacosamide and Derivatives.

A direct and highly enantioselective reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate catalyzed by Tol-BINAPNiCl2 in the presence of TESOTf and 2,6-lutidine is reported. The heterocyclic scaffold can be easily removed by addition of a wide array of amines to give the corresponding enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high yields. Appropriate manipulation of the N-benzyl amide derivative provides an efficient access to the antiepileptic agent lacosamide through a new enantioselective C-C bond-forming process. DFT computational studies uncover clues for the understanding of the remarkable stereocontrol of the addition of a nickel(II) enolate to a putative oxocarbenium intermediate from trimethyl orthoformate.

Direct and Asymmetric Nickel(II)-Catalyzed Construction of Carbon-Carbon Bonds from N-Acyl Thiazinanethiones.

A wide array of new N-acyl thiazinanethiones are employed in a number of direct and enantioselective carbon-carbon-bond-forming reactions catalyzed by nickel(II) complexes. The electrophilic species are mostly prepared in situ from ortho esters, methyl ethers, acetals, and ketals, which makes the overall process highly efficient and experimentally straightforward. Theoretical calculations indicate that the reactions proceed through an open transition state in a SN1-like mechanism. The utility of this novel procedure has been demonstrated by the asymmetric preparation of synthetically useful intermediates and the total synthesis of peperomin D.

General and stereoselective aminoxylation of biradical titanium(iv) enolates with TEMPO: a detailed study on the effect of the chiral auxiliary.

A comprehensive analysis of the influence of the chiral auxiliary on the α-aminoxylation of titanium(iv) enolates with TEMPO indicated that (S) 4-tert-butyl-1-oxazolidine-2-thione is the most appropriate scaffold to provide a single diastereomer in high yields for a variety of substrates, which converts such a radical reaction into a highly chemo- and stereoselective oxidation.

Diastereoselective and Catalytic α-Alkylation of Chiral N-Acyl Thiazolidinethiones with Stable Carbocationic Salts.

Direct nickel-catalyzed alkylation of chiral N-acyl-4-isopropyl-1,3-thiazolidine-2-thiones using a commercially available nickel(II) complex, (Me3P)2NiCl2, has been developed for tropylium and trityl tetrafluoroborate salts. The reaction provides a single diastereomer of the corresponding adducts in good to high yields, which, in turn, can be easily converted into a wide array of enantiomerically pure compounds that are difficult to obtain by other asymmetric procedures.

Stereoselective Synthesis of the C9-C19 Fragment of Peloruside A.

A concise synthesis of the C9-C19 fragment of peloruside A that is both highly stereoselective and efficient is described. Achieving an overall yield of 23% over 14 steps, this synthesis not only is high yielding but also involves four chromatography steps. This approach is based on the addition of metal enolates of chiral auxiliary scaffolds generated by either catalytic or stoichiometric amounts of nickel(II) or titanium(IV) Lewis acids.