Enantioselective synthesis of cyclopropanes that contain fluorinated tertiary stereogenic carbon centers: a chiral α-fluoro carbanion strategy

Chiral transfer: the fluorinated sulfoximine (see scheme; Ts=p-toluenesulfonyl) was synthesized and used as the first chiral fluoromethylenation reagent for the synthesis of cyclopropanes that contain fluorinated tertiary stereogenic carbon centers in good yields, good diastereoselectivity, and excellent enantioselectivity.     

Organocatalytic synthesis of quaternary stereocenter bearing a fluorine atom: enantioselective conjugate addition of α-fluoro-β-ketoesters to nitroalkenes

The catalytic enantioselective conjugate addition reaction of α-fluoro-β-ketoesters to nitroalkenes promoted by chiral bifunctional organocatalysts is described. The treatment of α-fluoro-β-ketoesters with nitroalkenes under mild reaction conditions afforded the corresponding Michael adducts containing a fluorinated quaternary stereogenic center with excellent enantioselectivity (up to >99% ee).     

Catalytic enantioselective synthesis of chiral γ-butyrolactones

A tandem catalytic asymmetric aldol reaction/cyclization of β,γ-didehydro-γ-lactones with aldehydes was achieved using chiral tin dibromide as a chiral precatalyst and sodium alkoxide as a base precatalyst. Optically active trans-β,γ-disubstituted γ-butyrolactones were selectively obtained in moderate to high yields with up to 99% ee from γ-aryl-substituted β,γ-didehydro-γ-butyrolactones and bulky aliphatic aldehydes.     

Cascade cycloaddition reactions involving dimethylhydrazones of α-substituted acroleins

Unusual cascade cycloaddition reactions with dimethylhydrazones of -trimethylsilyloxyalkylacroleins acting as azadienes were found. Depending on the nature of the dienophile, the reactions give either fused heterocyclic compounds (when two consecutive Diels—Alder reactions take place) or azabicyclic compounds, resulting from the [2+4]- and [2+3]-cycloaddition cascade.     

The first synthesis of N,O-protected β-isoserines bearing two adjacent quaternary stereogenic centers and their corresponding β-lactams

The reaction of chiral (2S)-enolates of dioxolan-4-ones, derived from lactic and mandelic acids, with (S_R)-tert-butyl sulfinyl ketimines, derived from butan-2-one, pentan-2-one, and decan-2-one, afforded conformationally restrained β^2,2,3,3-isoserines bearing two adjacent quaternary stereogenic centers in the form of N-sulfinyl protected 1′-amino-dioxolan-4-ones. The selective acid-induced removal of the sulfinyl protecting group provided the corresponding 1′-aminodioxolanones, whose base-induced cyclization afforded the corresponding chiral tetra-substituted 3-hydroxy-β-lactams. The synthesis of a dipeptide by reaction coupling between the 1′-aminodioxolanone (2S,5R,1′R)-19 and N,N-dimethylglycine was successfully achieved.     

Enantioselective organocatalytic synthesis of quaternary α-amino acids bearing a CF3 moiety

A highly enantioselective Friedel-Crafts reaction catalyzed by a chiral phosphoric acid was developed. N-Boc-protected ethyl trifluoropyruvate imine was activated by 6 mol % of catalyst and reacted with a wide variety of indole derivatives to afford quaternary α-amino acids in excellent yields (up to 99%) and high enantioselectivities (up to 98:2 er).     

Expedient synthesis of α-substituted fluoroethenes

A mild and efficient synthesis of 1-aryl-1-fluoroethenes from benzothiazolyl (aryl)fluoromethyl sulfones and paraformaldehyde, under DBU- or Cs(2)CO(3)-mediated conditions at room temperature, is described. A comparable diethyl fluoro(naphthalen-2-yl)methylphosphonate reagent does not react with paraformaldehyde under these mild conditions. The utility of the methodology for synthesis of terminal α-fluoroalkenes bearing electron-withdrawing functionalities is also shown.     

The asymmetric synthesis of chiral cyclic α-hydroxy phosphonates and quaternary cyclic α-hydroxy phosphonates

A highly practical, catalytic enantioselective cyclic phosphite addition to aldehydes and ketones was developed. The reaction rate of the asymmetric hydrophosphonylation was significantly enhanced by the addition of silver carbonate. Particularly, significant improvement has been achieved on the asymmetric hydrophosphonylation of unactivated ketones, giving quaternary α-hydroxy phosphonates with excellent enantioselectivity (up to 99% ee).     

Enantioselective Diels-Alder reaction of α-(acylthio)acroleins: a new entry to sulfur-containing chiral quaternary carbons

A catalytic and enantioselective Diels-Alder reaction of α-(carbamoylthio)acroleins induced by an organoammonium salt of chiral triamine is described. α-(Carbamoylthio)acroleins are designed and synthesized as new sulfur-containing dienophiles for the first time. The Diels-Alder reaction affords chiral tertiary thiol precursors with up to 91% ee.     

Asymmetric synthesis of quaternary α-amino acids using d-ribonolactone acetonide as chiral auxiliary

We describe a new simple methodology to prepare enantiopure α,α-dialkylglycines based on the use of commercially available d-ribonolactone as a chiral auxiliary. Enantiopure α-methyl and α-butyl series are prepared through diastereoselective alkylation and subsequent Schmidt rearrangement of α,α-dialkylacetoacetates of d-ribonolactone acetonide. Absolute configuration was assigned through preparation of enantiopure 4,4-disubstituted 3-methyl-2-pyrazolin-5-ones.     

Camphor-based oxazaphospholanes as chiral templates for the enantioselective synthesis of α-chlorophosphonic acids

Constrained camphor-derived oxazaphospholanes have provided an efficient entry for the preparation of enantiomerically enriched α-chlorophosphonic acids.     

Asymmetric epoxidation of α-substituted acroleins catalyzed by diphenylprolinol silyl ether

Asymmetric epoxidation of α-substituted acroleins with hydrogen peroxide has been catalyzed by diphenylprolinol diphenylmethylsilyl ether to afford α-substituted-β,β-unsubstituted-α,β-epoxy aldehyde with excellent enantioselectivity and the generation of a chiral quaternary carbon center. The method was applied to a short synthesis of (R)-methyl palmoxirate.     

Lewis base promoted intramolecular acylcyanation of α-substituted activated alkenes: construction of ketones bearing β-quaternary carbon centers

A novel phosphine-promoted intramolecular acylcyanation of α-substituted activated alkenes has been developed, which provides a unique access to densely functionalized acyclic ketones bearing β-quaternary carbon centers with a remarkable feature that both α- and β-positions of activated alkene are functionalized.     

Asymmetric synthesis of 3-substituted pyrrolidones via α-alkylation of a chiral non-racemic γ-lactam

3-Alkyl pyrrolidones 9 were synthesized in good yield and high diastereoselectivity by α-alkylation of the new chiral non-racemic lactam 8 derived from (R)-(−)-phenylglycinol. After debenzylation and introduction of an electron-withdrawing group, 3-methylpyrrolidone 10 is easily hydrolyzed in a basic medium to produce γ-aminobutyric acid (GABA) analogue 13.     

Effect of high pressure on the organocatalytic asymmetric Michael reaction: highly enantioselective synthesis of γ-nitroketones with quaternary stereogenic centers

The significant effect of hydrostatic pressure on the difficult organocatalytic 1,4-conjugate addition of nitroalkanes to prochiral sterically congested β,β-disubstituted enones is demonstrated. This approach allows for the synthesis of γ-nitroketones containing quaternary stereogenic centers with good yields, excellent enantioselectivity, and low loading (1-5 mol %) of simple chiral primary amine catalysts.     

Asymmetric assembly of 2-oxindole and α-angelica lactone units to construct vicinal quaternary chiral centers

The first organocatalytic asymmetric assembly of Morita-Baylis-Hillman carbonates of isatins and α-angelica lactone has been studied, affording multifunctional products containing two valuable pharmacophores and vicinal quaternary chiral centers in high stereoselectivity (up to 92% ee, dr >95:5).     

Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide

A Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide is described. Asymmetric allylic substitution using acyclic β-keto esters with a nitrogen functional group at the α-carbon as prochiral nucleophiles proceeded in the presence of 5 mol % of Pd catalyst, 10 mol % of chiral diaminophosphine oxide 1j, BSA, and appropriate additives, affording the corresponding quaternary α-amino acid derivatives in excellent yield and in up to 92% ee.     

Organocatalytic α-amination-allylation-RCM strategy: enantioselective synthesis of cyclic hydrazines

A highly enantioselective method for the synthesis of cyclic hydrazines by using organocatalytic α-amination-allylation-RCM strategy is described. Proline-catalyzed α-amination of aldehydes followed by indium-mediated one-pot allylation of the crude α-hydrazino aldehydes produces 1,2-aminoalcohols in high enantio- and diastereoselectivities. The 1,2-aminoalcohols are further converted into cyclic hydrazines by using ring-closing metathesis (RCM) reaction.     

Enantiodivergent syntheses of γ-substituted butenolides with tertiary and quaternary asymmetric centers

Continuous nucleophilic addition with several organometallic reagents to tricyclic lactone (−)-1 proceeded diastereoselectively. Newly generated tertiary and quaternary asymmetric centers were controlled by the order in which the nucleophilic reagents were added. Using this methodology, enantiodivergent syntheses of several γ-substituted butenolides with tertiary and quaternary asymmetric centers were established from a single chiral material.