Michael-type Alkylation Research Articles

Stereodivergent Construction of Vicinal Acyclic Quaternary-Tertiary Carbon Stereocenters by Michael-Type Alkylation of α,α-Disubstituted N-tert-Butanesulfinyl Ketimines.

Vicinal quaternary-tertiary carbon stereocenters were constructed with excellent stereoselectivity via aza-enolization of enantioenriched acyclic N-tert-butanesulfinyl ketimines bearing two sterically similar α-linear alkyl substituents followed by conjugate addition to nitroalkenes. Further changes of the absolute configuration of the sulfinyl group and/or the α-stereocenter in the ketimine allowed the facile stereodivergent synthesis of all four diastereomers of the Michael-type alkylation adducts. This reaction is a successful example of acyclic stereocontrol based on stereoselective α-deprotonation for the formation of fully substituted aza-enolates from ketone derivatives.

Squaramide-catalysed asymmetric Friedel-Crafts alkylation of naphthol and unsaturated pyrazolones.

The first method for highly efficient asymmetric Michael-type Friedel-Crafts alkylation of naphthol and unsaturated pyrazolones has been accomplished under mild reaction conditions. In the presence of the chiral squaramide catalyst, a wide range of substrates are tolerated in excellent yields (up to 99%) with reasonable enantioselectivities (up to 96% ee).

Site-Selective δ-C(sp3 )-H Alkylation of Amino Acids and Peptides with Maleimides via a Six-Membered Palladacycle.

The site-selective functionalization of unactivated C(sp3 )-H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site-selective δ-C(sp3 )-H alkylation of amino acids and peptides with maleimides via a kinetically less favored six-membered palladacycle in the presence of more accessible γ-C(sp3 )-H bonds. Experimental studies revealed that C-H bond cleavage occurs reversibly and preferentially at γ-methyl over δ-methyl C-H bonds while the subsequent alkylation proceeds exclusively at the six-membered palladacycle that is generated by δ-C-H activation. The selectivity can be explained by the Curtin-Hammett principle. The exceptional compatibility of this alkylation with various oligopeptides renders this procedure valuable for late-stage peptide modifications. Notably, this process is also the first palladium(II)-catalyzed Michael-type alkylation reaction that proceeds through C(sp3 )-H activation.

ChemInform Abstract: Novel Synthesis of Optically Active Lactones from 4-Thianone.

Enantioslective synthesis (>92% e.e.) of quaternary carbon centers through Michael-type alkylation of chiral imines of 3-alkyl-4-thianones with methyl acrylate and successive diastereoselective synthesis of optically active lactones are described

The asymmetric Michael-type alkylation of chiral β-enamino esters: critical role of a benzyl ester group in the racemization of adducts

In contrast with keto diester ( R)- 10a bearing a methyl ester group at the quaternary carbon center, the benzyl ester analogue ( R)- 10a partially racemized during workup, thereby revealing that the nature of the ester group at the quaternary carbon center has a critical role in the rate of racemization of such Michael adducts.

Alkylation of remote non-activated δ-carbon atoms: Addition of δ-carbon radicals, generated by 1,5-hydrogen transfer in alkoxy radical intermediates, to activated olefins

A free radical introduction of a functionalized alkyl chain onto remote non-activated δ-carbon atoms (Michael type alkylation) has been achieved. Photolysis of suitable alkyl nitrites involves generation of δ-alkyl radicals and in the presence of radicophilic olefins, intermolecular addition takes place and affords δ-alkylated products in 36–80% yields. δ-Alkylation is also achieved in the reaction of alkyl benzenesulfenates with tributyltin hydride (TBTH), in the presence of activated olefins and introduction of a functionalized alkyl chain involves alkoxy and δ-carbon radicals. Products with functionalized alkyl chains were obtained in 36–86% yields. δ-Alkylation of alkyl benzenesulfenates also occurs in the reaction with hexabutylditin in the presence of activated olefins.

Stereocontrolled Elaboration of Quaternary Carbon Centers through the Asymmetric Michael-Type Alkylation of Chiral Imines/Secondary Enamines: Enantioselective Synthesis of (+)-Vincamine

An enantioselective synthesis of (+)-vincamine (1) has been developed. The key strategic element was the stereocontrolled elaboration of a quaternary carbon center (future C-20 center of 1) by using the asymmetric Michael reaction involving chiral imines/secondary enamines under neutral conditions. Thus, addition of enaminolactam (S)-12, derived from ketolactam 7 (itself prepared in four steps from commercially available tryptamine) and (S)-1-phenylethylamine, to methyl acrylate led, after hydrolytic workup, to adduct (R)-6 with a 90% stereoselectivity. The critical removal of the additional keto group of 6 was then examined. After extensive experimentation, we finally established that the most efficient deoxygenation procedure was the Wolff−Kishner reduction of the corresponding keto acid, which proceeded with a 55% yield. The cornerstone [ABD]-tricyclic lactam ester 38 thus obtained was next cyclized under Bischler−Napieralski reaction conditions to afford, after catalytic hydrogenation of the intermediary iminium perchlorate salt, a mixture of the desired, known indoloquinolizidine 5 and its epimer 39, in a ratio of 6:1, respectively. Basic treatment of 5 led to (+)-homoeburnamonine 4, which was finally converted, according to a known procedure, into our goal (+)-vincamine (1). Thus, synthesis of (+)-vincamine (1) has been achieved by a linear sequence of 15 chemical operations, starting from tryptamine, with an overall yield of 1.2%.

Stereocontrolled elaboration of quaternary carbon centers involving the asymmetric michael-type alkylation of chiral imines: an efficient enantioselective access to (+)-vincamine

Michael adduct (S)- 5 b , resulting from the condensation of chiral imine 4 with methyl acrylate, was transformed in two steps into lactone (S)- 8 b . Tryptamine-induced ring-opening of this lactone gave 9, which was finally converted in three steps into the key tricyclic derivative (S)- 11 b , a known precursor of (+)-vincamine 1.

Free radical alkylation of the remote nonactivated δ-carbon atom

A free radical introduction of functionalized alkyl chains into the δ-carbon atom (Michael type alkylation) of alkyl nitrites and alkyl benzenesulfenic-O-esters was achieved.

Biomimetic Modeling of the Decomposition of 2‘-Chloro-2‘-deoxynucleotides by Ribonucleotide Reductases To Give 3(2H)-Furanones Which Can Effect Mechanism-Based Inactivation by Michael-Type Alkylation1

Biomimetic Modeling of the Decomposition of 2‘-Chloro-2‘-deoxynucleotides by Ribonucleotide Reductases To Give 3(2<i>H</i>)-Furanones Which Can Effect Mechanism-Based Inactivation by Michael-Type Alkylation¹

Enantioselective Synthesis of Homologous Methyl-Substituted Bicyclic Enones Through Michael-Type Alkylation of Chiral Imines

Abstract The preparation of 4a-methyl-substituted bicyclic enones in high enantiomeric purity is described, involving a Michael alkylation of (R)- or (S)-1-phenylethyl imines of the corresponding (±)-2-methylcyclopentanone, 2-methyl-cyclohexanone, 2-methylcycloheptanone, and 2-methylcyclooctanone with methyl vinyl ketone.

The asymmetric Michael process involving chiral imines: structure of (±)-p-nitrobenzyl 2-(2,2-dimethyl-1-phenylpropylamino)-1-cyclopentene-1-carboxylate

The enantioselective synthesis of quatemary carbon centres through Michael-type alkylation of chiral imines proceeds with high enantiomeric excess with 1-phenylethylamine as auxiliary, while 2,2-dimethyl-1-phenylpropylamine was found to be completely inactive. The crystal structure of a non-reactive be based on the latter auxiliary reveals a conformation identical with that of the reactive and highly selective 1-phenylethylamine. The phenyl ring is almost perpendicular to the enamino ester plane (torsion angle C-N-C-Ph 71.8 o ). The enamino ester group is planar and is stabilized by a hydrogen bond between the imine group and the carbonyl group of the ester

Synthesis of Optically Active Lactones and 3-Cyclopentenone from Optically Active 3,3-Dialkyl-4-thianones

Abstract The Optically active 3,3-dialkyl-4-thianones 3 and 4 were prepared in moderate yields with about 90% enantiomeric purity using an asymmetric process involving a Michael-type alkylation of chiral 3-alkyl-4-thianimines with methyl vinyl ketone or methyl acrylate. The diketones 3 were then transformed into new heterocycles 5 by base-induced cyclization. 3-Methyl- and 3-allyl-3-(2-methoxycarbonylethyl)-4-thianone ((+)-4a and (+)-4b) were converted into the bicyclic lactones (−)-6 and (−)-7, respectively. The stereochemistry of the sulfone (+)-8 derived from the lactone (−)-6a was determined by a X-ray crystal structure analysis. Desulfurization of the lactone (−)-6b using nickel boride afforded the corresponding lactone (+)-9. A synthesis of optically active 2-alkyl-2-methyl-3-cyclopentenone (S)-(+)-15 via the Ramberg–Bäcklund reaction from the keto ester (R)-(+)-4a was also accomplished.

Novel Synthesis of Optically Active Lactones from 4-Thianone

Enantioslective synthesis (>92% e.e.) of quaternary carbon centers through Michael-type alkylation of chiral imines of 3-alkyl-4-thianones with methyl acrylate and successive diastereoselective synthesis of optically active lactones are described

ChemInform Abstract: Asymmetric Michael Type Alkylation of Chiral Imines. Enantioselective Syntheses of (‐)‐Geosmin and Two Other Related Natural Terpenes, as well as enant‐(+)‐Geosmin.

Abstract Natural (−)-geosmin 11 , (+)-octalone 14 (from Vetiveria zizanioides ), and (+)-octalin 15 (from Bazzania fauriana and B. angustifolia ) have been prepared in high chemical and enantiomeric yields via the asymmetric process involving Michael-type alkylation of chiral imines 6 and 12 . Enant -(+)-geosmin has been also synthesized by the same procedure.

Asymmetric Michael-type alkylation of chiral imines. Enantioselective syntheses of (−)-geosmin and two other related natural terpenes, as well as enant-(+)-geosmin

Natural (−)-geosmin 11, (+)-octalone 14 (from Vetiveria zizanioides), and (+)-octalin 15 (from Bazzania fauriana and B. angustifolia) have been prepared in high chemical and enantiomeric yields via the asymmetric process involving Michael-type alkylation of chiral imines 6 and 12. Enant-(+)-geosmin has been also synthesized by the same procedure.

An efficient asymmetric spiroannulation process

After hydrolytic work-up, intramolecular Michael-type alkylation of imine 11 gave spiro adduct 13 with a high degree of control of the two newly created asymmetric centers.

Enantioselective synthesis of ring-C aromatic steroids by asymmetric Michael-type alkylation of chiral imines.

Optically active phenanthrones 7 and 12 were prepared, using the asymmetric process involving Michael-type alkylation of chiral imines. Compound 12 was then transformed into the ring-C aromatic steroid 16.

Enantioselective synthesis of quaternary carbon centers through Michael-type alkylation of chiral imines

On prepare des cyclanones chirales disubstituees en 2,2 par alkylation des imines chirales des cyclanones monosubstituees