The origin of the stereoselectivity in the asymmetric Michael reaction using chiral imines/secondary enamines under neutral conditions: a computational investigation

The diastereoselectivity in the asymmetric Michael reaction using chiral imines/secondary enamines under neutral conditions has been investigated with the help of AM1 calculations. The energetic differences between the two competing transition states involving enamino ketones 7d, 7g and methyl acrylate are in good agreement with the stereoselectivities observed with the corresponding chiral imines, derived from 1-phenylethylamine (de 95%) and from 1-cyclohexylethylamine (de 45%). The calculated transition structures indicate that steric factors govern the π-facial discrimination.     

Nitroalkenes as electrophiles in the asymmetric Michael reaction involving chiral imines/enamino esters

Addition of 2-nitropropene to the chiral imine derived from 2-methylcyclopentanone and (S)-1-phenylethylamine furnished the expected Michael adduct. The latter compound was then efficiently converted into (R)-pentalenone through a Nef reaction. Condensation of the enamino ester derived from 2-carbethoxycyclopentanone and (S)-1-phenylethylamine with 1-nitropropene gave with excellent diastereo- and enantioselectivity the corresponding Michael adduct.     

Enantioselective synthesis of (+)-α-vetivone through the Michael reaction of chiral imines

(+)-α-Vetivone has been synthesised in nine steps. The absolute stereochemistry of the two stereogenic centres is controlled in the same key step involving the stereoselective Michael addition of a chiral imine of 4-isopropylidene-2-methylcyclohexanone to phenyl crotonate.     

Asymmetric synthesis of 1,4-disubstituted 3-methylidenedihydroquinolin-2(1H)-ones

A series of enantiomerically pure or highly enriched (R)- or (S)-3-methylidenetetrahydroquinolin-2-ones was readily prepared by highly diastereoselective Michael additions of various Grignard reagents to quinolin-2(1H)-ones, containing an (R,R)- or (S,S)-di(1-phenylethylamino)phosphoryl group as chiral auxiliary, followed by Horner-Wadsworth-Emmons olefination of formaldehyde. An efficient synthesis of the starting (R,R)- and (S,S)-3-({di[(1-phenylethyl)amino]}phosphoryl)-1-alkyl-quinolin-2(1H)-ones is also described. The relative and absolute configurations of the intermediate adducts and final methylidenequinolinones were established by NMR and X-ray analysis.     

Asymmetric synthesis of cis-2,4-disubstituted azetidin-3-ones from metal carbene chemistry

Several chiral cis-2,4-disubstituted azetidin-3-ones were prepared as single diastereoisomers from N-protected amino acids, employing a highly stereoselective copper carbenoid N–H insertion reaction of diazoketones. These azetidin-3-ones were then converted into fully substituted azetidines in a few steps in good to high yields.     

Highly convergent synthesis of chiral bicyclophosphinates by domino hydrophosphinylation/Michael/Michael reaction

Diastereoselective domino reactions of iminoalcohols and allenyl H-phosphinates produce chiral phosphorus bicycles in a regio- and stereoselective fashion. A predictive model for diastereoselection is used for these new chiral phosphinic esters.     

Asymmetric Michael reaction: novel efficient access to chiral β-ketophosphonates

The asymmetric Michael reaction between chiral β-enaminophosphonates derived from (S)-1-phenylethylamine and various electrophilic alkenes furnished β,β-disubstituted ketophosphonates in good yields and with excellent enantioselectivity.     

Preparation of 2,2-disubstituted 1,2-dihydro-3H-indol-3-ones via oxidation of 2-substituted indoles and Mannich-type reaction

A novel preparative method for 2,2-disubstituted 1,2-dihydro-3H-indol-3-ones through the oxidation of 2-arylindoles followed by a Mannich-type reaction with carbon nucleophiles is described.     

Asymmetric synthesis of 1,3-thiazolidine-derived spiro-β-lactams via a Staudinger reaction between chiral ketenes and imines

Enantiomerically pure 1,3-thiazolidine-derived spiro-β-lactams were stereoselectively synthesised by means of a Staudinger ketene–imine reaction starting from optically active N-Boc-1,3-thiazolidine-2-carboxylic acid derivatives and imines. The reactions were stereoselective and afforded spiro-β-lactams with a relative trans-configuration. The absolute configuration of the new stereocentres was assigned on the basis of the well-accepted mechanism and confirmed by means of the X-ray crystal structure analysis. The spiro-β-lactams were transformed into enantiomerically pure chiral monocyclic β-lactams by opening the thiazolidine ring and recovering the chiral auxiliary.     

Asymmetric reduction of enantiopure imines with zinc borohydride: stereoselective synthesis of chiral amines

The first application of zinc borohydride in the reduction of enantiopure imines for the stereoselective preparation of both the enantiomers of secondary amines is described. A possible explanation of the stereoselectivity and of the reaction mechanism is suggested on the basis of theoretical calculations.     

Microwave-assisted one-pot synthesis of 2,3-disubstituted 3H-quinazolin-4-ones

A practical synthesis of 2,3-disubstituted 3H-quinazolin-4-ones 1 with broad chemistry scope is described. The key step is the microwave promoted one-pot, two-step reaction sequence combining anthranilic acids, carboxylic acids, and amines providing efficient access to this important class of heterocycles.     

Highly enantioselective synthesis of 3,3-disubstituted 4-piperidones by michael alkylation of chiral piperidone imines

A method for the highly enantioselective synthesis of (3S)- and (3R)-3,3-disubstituted 4-piperidones with an optical purity of 98% based on the deracemizing alkylation of 3-substituted 4-piperidones during Michael addition of their chiral imines to electrophilic alkenes was developed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1072–1078, August, 1992.     

Asymmetric synthesis of trans-3-amino-4-alkylazetidin-2-ones from chiral N,N-dialkylhydrazones

Enantiopure N,N-dialkylhydrazones 3 smoothly react with N-benzyloxycarbonyl-N-benzyl glycine as an aminoketene precursor to afford trans-3-amino-4-alkylazetidin-2-ones 4 as single diasteromers. As an exception, hydrazone 3f (R = OBn) affords cis-(3R,4R)-4f under modified conditions. N-N Bond cleavage of cycloadducts 4 afforded free azetidinones 5 in high yields. [structure: see text]     

Electroreductive intramolecular coupling of chiral alpha-imino esters: stereoselective synthesis of mixed ketals of cis-2,4-disubstituted azetidine-3-ones

The electroreduction of chiral aromatic alpha-imino esters prepared from (S)-alpha-amino acids, such as (S)-valine, (S)-leucine, and (S)-phenylalanine, in the presence of chlorotrimethylsilane and triethylamine afforded four-membered cyclized products, mixed ketals of cis-2,4-disubstituted azetidine-3-ones, stereospecifically (>99% de, 85-99% ee). The best result of the electroreductive cyclization was obtained using Bu(4)NClO(4) as a supporting electrolyte and a Pt cathode. The absolute stereochemistry of the obtained single stereoisomers was confirmed to be 2R,3R,4S by X-ray crystallography. Calculations for the transition states of the cyclization support the stereospecific formation of the (2R,3R,4S)-isomers.     

Chlorotrimethylsilane promoted asymmetric Michael reaction of chiral enamines of α-alkyl β-keto esters

By the promotion of chlorotrimethylsilane, asymmetric Michael reaction of the chiral enamines (2) of α-alkyl β-keto esters (1) with methyl vinyl ketone and ethyl acrylate proceeded to afford, after hydrolysis, either enantiomer of the corresponding adducts (4) in a good enantioselectivity.     

Asymmetric Negishi reaction for sterically hindered couplings: synthesis of chiral binaphthalenes

A new synthetic approach affording, for the first time chiral binaphthalene derivatives via an asymmetric Negishi reaction, in good yields (55–95%) and good enantioselectivities (49–85% ee), is reported.     

Asymmetric Michael addition of N-boc-protected oxindoles to nitroalkenes catalyzed by a chiral secondary amine

New mission for prolinol ethers: A secondary-amine-catalyzed Michael addition of N-Boc-protected oxindoles to nitroalkenes through a Br?nsted base activation mode has been developed, furnishing the products in excellent yields (88-98?%), diastereoselectivities (d.r.=98:2->99:1) and high to excellent enantioselectivities (82->99?%?ee; see scheme).