Highly stereoselective synthesis of β,γ-disubstituted and α,β,γ-trisubstituted butyrolactones

β,γ-Disubstituted butyrolactones were produced effectively and steroeselectively from arsonium ylides generated in situ and substituted olefins. The transformation could be realized in one-pot or in two steps, which depended on the electronic properties of the olefins. With the adjustment of the solvent and in the presence of EtOH, α,β,γ-trisubstituted butyrolactones were also obtained in high yield from arsonium ylides and substituted olefins.     

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.     

Asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives

Herein we report the asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives 22, 25 and 26, key intermediates of a novel immunomodulator, using Seebach’s method. This synthetic method can be applied to the large scale synthesis of chiral sphingosine 1-phosphate-1 (S1P₁) receptor agonists, with significant improvements to the previously reported method with regard to the reaction temperature.     

Preparation of sugar derived β,β′-dihydroxy α,α-disubstituted α-amino acids

A novel strategy for the preparation of β,β′-dihydroxy α,α-disubstituted α-amino acids bearing a sugar moiety has been developed. The procedure is based on two Henry reactions: the first Henry reaction involves a sugar aldehyde and nitroethanol to furnish a sugar derived α-hydroxymethyl α-nitroalkanol while the second Henry reaction is between this nitro sugar and formaldehyde. This sequence provided the expected epimers of sugar derived α,α-dihydroxymethyl α -nitroalkanols, from which the corresponding β,β′-dibenzyloxy α-N-benzyloxycarbonylamino esters were easily obtained. All rights reserved.     

Enantioselective synthesis of α,α-disubstituted amines from nitroalkenes

Disubstituted nitroalkenes were converted into enantiomerically enriched amines (isolated as their hydrochloride salts) with enantiomeric excesses of 88 to >95% in three steps: (a) highly stereoselective conjugate addition of the potassium salt of 4-phenyloxazolidin-2-one; (b) radical-mediated removal of the nitro group; (c) cleavage of the oxazolidinone.     

Catalytic, asymmetric synthesis of α,α-disubstituted amino acids

Copper(salen) complex 1 has been found to catalyse the asymmetric alkylation of enolates derived from a variety of amino acids. There is a clear relationship between the size of the side chain in the substrate and the enantioselectivity of the process, so that the enantioselectivity decreases in the order alanine>aminobutyric acid>allylglycine>leucine>phenylalanine>valine. A transition state model which accounts for the influence of the size of the side chain on the enantioselectivity of the reactions is presented.     

Iron-catalyzed asymmetric epoxidation of β,β-disubstituted enones

The combination of Fe(OTf)(2) and novel phenanthroline ligands enables the catalytic asymmetric epoxidation of acyclic β,β-disubstituted enones, which have been a heretofore inaccessible substrate class. The reaction provides highly enantioenriched α,β-epoxyketones (up to 92% ee) that can be further converted to functionalized β-ketoaldehydes with an all-carbon quaternary center.     

Rhodium-catalyzed asymmetric 1,4-addition of sodium tetraarylborates to β,β-disubstituted α,β-unsaturated esters

A rhodium-catalyzed 1,4-addition of sodium tetraarylborates to β,β-disubstituted α,β-unsaturated esters has been developed. Highly efficient asymmetric catalysis has also been described to create quaternary carbon stereocenters at the β-position of esters by tuning the ester group of substrates and employing a readily available chiral diene ligand.     

Efficient, enantioselective synthesis of a β,β-disubstituted carboxylic acid by Ru-XylPhanePhos-catalyzed asymmetric hydrogenation

Enantioselective preparation of a key α_vβ₃ integrin antagonist intermediate was accomplished via catalytic asymmetric hydrogenation of the corresponding β,β-disubstituted α,β-unsaturated carboxylic acid bearing a 3-quinolinyl moiety. The successful application of a Ru-(R)-XylPhanePhos catalyst to this type of substrate is unprecedented. In situ NMR experiments of pre-catalyst formation/activation by CH₃CO₂H, and reaction parameter modification, revealed that [Ru(COD)(CF₃CO₂)₂]₂/(R)-XylPhanePhos is a highly active and efficient catalytic system.     

Catalytic asymmetric synthesis of α,β-disubstituted α,γ-diaminophosphonic acid precursors by Michael addition of α-substituted nitrophosphonates to nitroolefins

Michael additions of α-substituted nitrophosphonates to various nitroolefins are shown to proceed with high diastereo- and enantioselectivity when catalyzed by a quinine-derived thiourea-tertiary amine bifunctional catalyst and generate α,γ-diaminophosphonic acid precursors with contiguous quaternary and tertiary stereocenters.     

Asymmetric synthesis of α,β-substituted β-aminoalkanamides and stereochemical determination

Highly enantiomerically enriched β-aminoalkanamides 12 and β-phenylaminoalkanamides 13 have been prepared by the addition reaction of α-lithiated 2-alkyl-2-oxazolines 9-Li, derived from optically active oxazolines 9, to N-cumyl nitrones 2. The relative stereochemistry of alkanamides 5 and 6 has been established by 1D-NOESY experiments carried out on the related pyrimidinones 7, whereas the absolute configuration of alkanamides 12 and 13 has been confirmed by an X-ray analysis.     

Copper-catalyzed synthesis of 2,4-disubstituted allenoates from α-diazoesters

A Cu-catalyzed method for coupling α-substituted-α-diazoesters with terminal alkynes to give substituted allenoates is described. Key to the development of a selective method was the recognition that an adventitous base catalyzes the isomerization to form the allenoate product. A plausible mechanism is proposed, based in part on evidence against a mechanism that involves a Cu(I)-acetylide as a low-valent intermediate.     

Novel chemistry of β-carbolines. Expedient synthesis of polycyclic scaffolds

Functionalization of β-carbolines is a challenge as numerous natural alkaloids with different biological activities present this heterocycle. The RCM is used herein with allyl-, vinyl-, ethynyl-, and propargyl-β-carbolines to generate additionally fused hetero- and carbocycles, and it is combined with other cyclization processes to achieve great molecular complexity in one synthetic step. Thus, an RCM-Diels-Alder sequence gives pentacyclic compounds related with certain alkaloids. On the other hand, vinylpyrrolo[2,1-a]-β-carbolines and vinyl-β-carbolines give different products upon reaction with activated dienophiles. Thus, a novel domino processes affords complex polycycles like 35-38. Other alkynes like 3-butyn-2-one give a Stevens rearrangement.     

Enantioselective synthesis of β-amino acids. Part 10: Preparation of novel α,α- and β,β-disubstituted β-amino acids from (S)-asparagine

Perhydropyrimidinone (S)-1 is alkylated with very high diastereoselectivity to give trans products (2S,5R)-3, (2S,5R)–4 and (2S,5R)-5. Dialkylation of (S)-1 also proceeds with complete stereoselectivity to afford adducts (2S,5R)-6, (2S,5S)-6, (2S,5R)-7 and (2S,5S)-7. Hydrolysis (6N HCl, 100°C) of monoalkylated derivative (2S,5R)-3 gives enantiopure α-substituted β-amino acid (R)-8. Hydrolysis of dialkylated adducts 6 and 7 affords enantiopure α,α-disubstituted β-amino acids (R)- or (S)-9 and (R)- or (S)-10. Related iminoester (2S,6S)-2 is alkylated with complete diastereoselectivity to give products (2S,6S)-11–13 whose hydrolysis under relatively mild conditions (2N CF₃CO₂H, CH₃OH, 100°C) affords enantiopure N-benzoylated β,β-disubstituted β-amino acid esters (S)-14–16, with intact double bonds in the olefinic substituents.     

An Expedient Synthesis of β-Chloro-β-nitroolefin Derivatives

β-Chloro-β-nitroolefin derivatives 2 were prepared from the reaction of β-nitroolefins 1 with HCl / DMF / Oxone system in moderate to good yields.

     

Oxazoline-mediated highly stereoselective synthesis of α,β-substituted-β-aminoalkanamides, potential precursors of unnatural β-amino acids

The reaction of α-lithiated-2-alkyl-2-oxazolines 1-Li with aliphatic, aromatic and heteroaromatic N-cumyl nitrones results in the stereoselective formation of N-cumyl-1,6-dioxa-2,9-diazaspiro[4,4]nonanes 3 which equilibrate with the hydroxylamino derivatives 4. Such equilibrating mixtures can be easily transformed into β-amino alkanamides 5 under reductive conditions, whereas acidic hydrolysis with trifluoroacetic acid (TFA) furnishes high yields of β-phenylamino alkanamides 6 via a cumene hydroperoxide-type rearrangement. Derivatives 5 and 6 provide a backbone of potentially useful unnatural β^2,2,3-amino acids.     

Reaction of aspartic acid derivatives with Grignard reagents—synthesis of γ,γ-disubstituted α- and β-amino-butyrolactones

A series of γ,γ-dimethyl and γ,γ-diphenyl substituted α- and β-amino-butyrolactones have been prepared in enantiomerically pure form using l-aspartic acid as a chiral building block. For the final Grignard reaction the difference in chemical reactivity between the carboxyl groups of aspartic acid was increased or inverted by preparing the corresponding semiesters, diesters and anhydrides. The resulting hydroxyacids and hydroxyesters lactonised in most cases during work up. Thus, (2S)-2-ethoxycarbonylamino-succinic acid-4-methylester 1 reacted with methylmagnesium iodide to form (3S)-3-ethoxycarbonylamino-5,5-dimethyl-tetrahydrofuran-2-one 2b. Two interesting side products were obtained and were found to result from attack at the C-1 carboxylic acid rather than the C-4 carboxylic ester group leading to (3S)-3-ethoxycarbonylamino-4-oxo-pentanoic acid methylester 3 and (4S)-4-ethoxycarbonylamino-5,5-dimethyl-tetrahydrofuran-2-one 5a.