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.

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.

Optimized Asymmetric Synthesis of Umuravumbolide.

Herein, the asymmetric synthesis of umuravumbolide (1) is described. The new approach features highly stereoselective transformations (dr ≥ 95:5) to install both stereocenters and the Z olefin, which involve a new radical alkylation, an Ando olefination, and a Krische allylation on a Z allylic alcohol, not reported before. The application of such successful reactions, together with the limited use of protecting groups and concession steps, makes it possible to complete the synthesis in 10 steps, resulting in a 39% overall yield from chiral N-acyl oxazolidinone 2.

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.

Stereoselective Alkylation of Chiral Titanium(IV) Enolates with tert-Butyl Peresters.

Here, we present a new stereoselective alkylation of titanium(IV) enolates of chiral N-acyl oxazolidinones with tert-butyl peresters from Cα-branched aliphatic carboxylic acids, which proceeds through the decarboxylation of the peresters and the subsequent formation of alkyl radicals to produce the alkylated adducts with an excellent diastereoselectivity. Theoretical calculations account for the observed reactivity and the outstanding stereocontrol. Importantly, the resultant compounds can be easily converted into ligands for asymmetric and catalytic transformations.

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.

Stereoselective Decarboxylative Alkylation of Titanium(IV) Enolates with Diacyl Peroxides.

Simple treatment of chiral titanium(IV) enolates with diacyl peroxides produces highly diastereoselective decarboxylative alkylations to efficiently deliver the corresponding adducts, most of which are not accessible through any of the current alkylating procedures. Such an unprecedented alkylation proceeds through an SET process that triggers the decomposition of the peroxide into a carbon-centered radical that finally combines with the resulting Cα radical. The procedure has been applied to the enantioselective synthesis of arundic acid.

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.

Stereoselective and Catalytic Synthesis of anti-ß-Alkoxy-α-azido Carboxylic Derivatives.

Direct addition of a chiral N-azidoacetyl thiazolidinethione to a variety of dialkyl acetals catalyzed by a commercially available and structurally simple nickel(II) complex gives access in good yields and a highly stereocontrolled manner to anti-ß-alkoxy-α-azido carboxylic derivatives which, in turn, can be easily converted into a wide array of enantiomerically pure compounds.

Experimental and Computational Evidence of the Biradical Structure and Reactivity of Titanium(IV) Enolates.

Quantum chemical calculations have unveiled the unexpected biradical character of titanium(IV) enolates from N-acyl oxazolidinones and thiazolidinethiones. The electronic structure of these species therefore involves a valence tautomerism consisting of an equilibrium between a closed shell (formally Ti(IV) enolates) and an open shell, biradical, singlet (formally Ti(III) enolates) electronic states, whose origin is to be basically found in changes of the Ti-O distance. Spectroscopic studies of the intermediate species lend support to such a model, which also turns out to be crucial for a better understanding of the overall reactivity of titanium(IV) enolates. In this context, a thorough computational analysis of the radical addition of titanium(IV) enolates from N-acyl oxazolidinones to TEMPO has permitted us to suggest an entire mechanism, which accounts for the experimental details and the diastereoselectivity of the process. All together, this evidence highlights the relevance of biradical intermediates from titanium(IV) enolates and may be a useful contribution to the foundations of a more insightful comprehension of the structure and reactivity of titanium(IV) enolates.

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.

Total synthesis of (+)-herboxidiene/GEX 1A.

A total synthesis of (+)-herboxidiene/GEX 1A has been accomplished from (R)- and (S)-lactate esters in a highly efficient manner. Key steps of the synthesis involve substrate-controlled titanium-mediated aldol reactions from chiral lactate-derived ethyl ketones, an oxa-Michael cyclization, an Ireland-Claisen rearrangement, and a Suzuki coupling. Furthermore, computational studies of the oxa-Michael reaction have unveiled the dramatic influence of intramolecular hydrogen bonds on the stereochemical outcome of such cyclizations, whereas biological analyses have clearly proved the important cytoxicity of (+)-herboxidiene/GEX 1A.

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.

Studies towards the synthesis of tedanolide C. Construction of the C13-epi C1-C15 fragment.

The preparation of an advanced intermediate on route towards the synthesis of tedanolide C is reported here. It is based on the coupling of two fragments of similar size and complexity, which in turn are prepared by highly stereoselective substrate-controlled titanium-mediated aldol reactions from chiral ketones.

Stereoselective Alkylation of (S)-N-Acyl-4-isopropyl-1,3-thiazolidine-2-thiones Catalyzed by (Me3P)2NiCl2.

The structurally simple (Me3P)2NiCl2 complex catalyzes SN1-type alkylations of chiral N-acyl thiazolidinethiones with diarylmethyl methyl ethers and other stable carbenium cations. The former can contain a variety of functional groups and heteroatoms at the α-position. The resultant adducts are isolated as single diastereomers in high yields and can be converted into enantiomerically pure derivatives in a straightforward manner.

Substrate-controlled Michael additions of chiral ketones to enones.

Substrate-controlled Michael additions of the titanium(IV) enolate of lactate-derived ketone 1 to acyclic α,ß-unsaturated ketones in the presence of a Lewis acid (TiCl4 or SnCl4) provide the corresponding 2,4-anti-4,5-anti dicarbonyl compounds in good yields and excellent diastereomeric ratios. Likely, the nucleophilic species involved in such additions are bimetallic enolates that may add to enones through cyclic transition states. Finally, further studies indicate that a structurally related ß-benzyloxy chiral ketone can also participate in such stereocontrolled conjugate additions.

Stereoselective aminoxylation of biradical titanium enolates with TEMPO.

A highly efficient and straightforward aminoxylation of titanium(IV) enolates from (S)-N-acyl-4-benzyl-5,5-dimethyl-1,3-oxazolidin-2-ones with TEMPO has been developed. A wide array of functional groups on the acyl moiety, including alkyl and aryl substituents, olefins, esters, or α-cyclopropyl, as well as α-trifluoromethyl groups, are well tolerated. This transformation can therefore produce the α-aminoxylated adducts in excellent yields with high diastereomeric ratios (d.r.). In turn, parallel additions to the α,ß-unsaturated N-acyl counterparts give the corresponding γ-adducts with complete regioselectivity in moderate to good yields. Removal of the piperidinyl moiety or the chiral auxiliary converts the resultant adducts into enantiomerically pure α-hydroxy carboxyl derivatives, alcohols, or esters in high yields under mild conditions. Finally, a new mechanistic model based on the biradical character of the titanium(IV) enolates has been proposed.

Improving enantioselectivity towards tertiary alcohols using mutants of Bacillus sp. BP-7 esterase EstBP7 holding a rare GGG(X)-oxyanion hole.

Lipases and esterases are important biocatalysts for synthetic organic fine chemistry. An esterase from Bacillus sp. BP-7 (EstBP7) bears in its amino acid sequence a rare GGG(A)X oxyanion hole motif, where an uncommon threonine (T) is found at the third position. Detection of this pattern motivated evaluation of the ability of EstBP7 for conversion of tertiary alcohols. The enzyme was engineered in order to optimize its performance to provide important chiral building blocks: five variants with mutations in the oxyanion hole motif were created to investigate the influence on activity and enantioselectivity in the kinetic resolution of eight acetates of tertiary alcohols. Wild-type enzyme converted all esters of tertiary alcohols assayed with low enantioselectivity, whereas some of the mutants displayed significantly increased E-values. One of the mutants (EstBP7-AGA; Mut 5) showed an E >100 towards a complex tertiary alcohol acetate (2-(4-pyridyl)but-3-yn-2-yl acetate) at low reaction temperature (4 °C). Therefore, the catalytic toolbox was expanded for biocatalysis of optically pure tertiary alcohols valuable for the pharmaceutical industry.