Acyl Oxazolidinone Research Articles

Synthesis of (-)-Cytisine Using a 6- endo aza-Michael Addition.

An asymmetric synthesis of (-)-cytisine has been achieved. The piperidine C-ring was formed using a stereodivergent intramolecular 6- endo aza-Michael addition. The B-ring was established by intramolecular pyridine N-alkylation. The absolute stereochemistry was established by an Evans acyl oxazolidinone enolate alkylation reaction that proceeded with an unexpected stereochemical outcome due to participation of the pyridine nitrogen lone pair.

A Simple Method for Asymmetric Trifluoromethylation of N-Acyl Oxazolidinones via Ru-Catalyzed Radical Addition to Zirconium Enolates

A Ru-catalyzed direct thermal trifluoromethylation and perfluoroalkylation of N-acyloxazolidinones has been developed. The reaction is experimentally simple and requires inexpensive reagents while providing good yields of products with good levels of stereocontrol. Preliminary studies have shown notable compatibility with functional groups, aromatics, and certain heteroaromatic substituents. The described method provides a useful alternative for the synthesis of fluorinated materials in an experimentally convenient manner.

Dual Ti–Ru Catalysis in the Direct Radical Haloalkylation of N‐Acyl Oxazolidinones

Waste not, want not: A mechanistic study of the ruthenium-catalyzed haloalkylation of titanium enolates led to the development of a process that is catalytic in both metals: titanium and ruthenium (see scheme; Bn=benzyl, PMP=1,2,2,6,6-pentamethylpiperidine). Catalytic turnover was observed in the formation of the titanium enolates from N-acyl oxazolidinones, and insight was gained into the inhibitory effect of the amine base.

Dual Ti–Ru Catalysis in the Direct Radical Haloalkylation of N‐Acyl Oxazolidinones

Eine mechanistische Studie der Ru-katalysierten Halogenalkylierung von Titanenolaten führte zur Entwicklung eines Prozesses, der bezüglich des Titans wie auch des Rutheniums katalytisch ist (siehe Schema; Bn=Benzyl, PMP=1,2,2,6,6-Pentamethylpiperidin). Bei der Bildung der Titanenolate aus N-Acyloxazolidinonen wurde katalytischer Umsatz beobachtet, und es wurden Einblicke in die Inhibitorwirkung der Aminbase erhalten.

Importance of C−N Bond Rotation in N-Acyl Oxazolidinones in their SmI2-Promoted Coupling to Acrylamides

A detailed mechanistic investigation was undertaken to determine the dominating factors of the postelectron transfer steps in the SmI(2)-promoted carbon-carbon bond forming reaction between N-acyl oxazolidinones and acrylamides. Competition experiments were performed by reacting two N-acyl oxazolidinones with a limiting amount of N-t-butyl acrylamide, and from the product distribution, the relative reactivity values (RV) for a series of N-acyl oxazolidinones were then calculated against N-pivaloyl oxazolidinone as the reference. An almost linear correlation was obtained for the simple alkyl N-acyl oxazolidinones when ln RV was plotted against the activation barriers for C-N bond rotation (s-trans to s-cis) obtained by DFT calculations, implying that C-N bond rotation from the s-trans to s-cis conformation is one of the essential parameters controlling the reactivity. These results were substantiated by other competition experiments carried out for the corresponding imide derivatives, where rotation is not necessary for obtaining bidentate coordination and where no such correlation as described above was observable. The finding that the reactivity of the simple N-acyl oxazolidinones for these SmI(2)-mediated transformations correlates with the activation barriers for C-N bond rotation may have implications for other useful synthetic organic reactions involving similar substrates. Finally, these studies were extrapolated to understanding the poor reactivity of N-acyl oxazolidinones, as those derived from Evans chiral auxiliaries, with N-tert-butyl acrylamide. These couplings appear to be dominated by the activation energy for addition because of arising syn-pentane interactions in the transition-state for C-C bond formation. We demonstrate that the addition of Lewis acids can have a beneficial effect on the coupling yields.

Can Decarbonylation of Acyl Radicals Be Overcome in Radical Addition Reactions? En Route to a Solution Employing N-Acyl Oxazolidinones and SmI2/H2O

The application of acyl radicals in radical addition reactions in the absence of a CO atmosphere is generally limited to aryl or alpha-unsubstituted alkyl acyl radicals due to competing decarbonylations where the rate constant for this degradation process surpasses 104 s-1. In this work, a potential solution to avoid the problem of decarbonylations is presented employing N-acyl oxazolidinones which are reduced to acyl radical equivalents in the presence of samarium diiodide and water. In the company of an acrylamide, acrylate, or acrylonitrile, the product from a formal acyl radical addition is obtained in yields up to 87%. Examples are given where the decarbonylation rate constants even exceed 108 s-1. It is proposed that the reaction proceeds via a ketyl-like intermediate.

Synthesis of a 5-oxo-2-Tetrahydrofuranyl Derivative of an Evans Auxiliary via a Novel Reaction Induced by Nucleophiles

A 5-oxo-2-tetrahydrofuranyl derivative of an Evans auxiliary could be obtained through a previously unknown 'rearrangement' ofthe oxazolidinone moiety in an α-benzoxy-γ-aldehyde acyl oxazolidinone in 60-97% yields on treatment with a range of nucleophiles.

Racemic Auxiliaries: Applications to Asymmetric Synthesis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Racemic auxiliaries: applications to asymmetric synthesis

Racemic auxiliaries have been successfully used to achieve asymmetric synthesis. Racemic Evans aldol products were obtained from racemic acyl oxazolidinones with good diastereocontrol. The enantiomers of the racemic aldol products were resolved by a lipase-catalysed acylation reaction. Hydrolysis afforded enantiomerically enriched oxazolidinones and enantiomerically enriched β-hydroxy acids.

Lewis Acid-Promoted Transesterification of N-Acyl Oxazolidinones under Mild Conditions

N-Acyl oxazolidinones are smoothly converted to the corresponding esters by Lewis acid-promoted transesterification. Mild reaction conditions suppress epimerization or racemization of chiral substrates and allow acid-sensitive groups to survive.

ChemInform Abstract: An Efficient Strategy for the Synthesis of α,α′-cis and trans-Disubstituted Medium Ring Ethers.

An asymmetric alkylation-ring-closing metathesis strat- egy was developed for the construction of a,a'-disubstituted medi- um ring ethers. The approach features an asymmetric alkylation of highly functionalized a-alkoxy acyl oxazolidinones followed by ring closure effected by Grubbs ' ruthenium catalyst. The relation- ship between diene conformation and the rate of ring-closure was examined.

Enzyme-assisted asymmetric total synthesis of (-)-podophyllotoxin and (-)-picropodophyllin.

Described is the first catalytic, asymmetric synthesis of (-)-podophyllotoxin and its C(2)-epimer, (-)-picropodophyllin. Asymmetry is achieved via the enzymatic desymmetrization of advanced meso diacetate 20, through PPL-mediated ester hydrolysis. A second key feature of the synthesis is the strategically late introduction of the highly oxygenated natural ring E through an arylcopper species. The successful implementation of this approach augers well for the introduction of other functionalized rings E for future SAR work. The synthesis begins from piperonal, which is fashioned into isobenzofuran (IBF) precursor 14 in three steps (bromination, acetalization, and halogen-metal exchange/hydroxymethylation). Interestingly, treatment of 14 with HOAc in commerical dimethyl maleate (contains 5% dimethyl fumarate) leads to a nearly equimolar mixture of fumarate- (15) and maleate-IBF Diels-Alder adducts (16 and 17), indicating that IBF 11 reacts about 15 times faster with dimethyl fumarate than with dimethyl maleate. With scrupulously pure dimethyl maleate a 2.8:1 endo:exo mixture of maleate DA adducts is still obtained. On the other hand, the desired meso diester 16 is obtained pure and in nearly quantitative yield by employing neat dimethyl acetylene dicarboxylate as the dienophile, followed by catalytic hydrogenation. Reduction (LiAlH(4)) of 16 provides meso diol 19, which is then treated with Ac(2)O, BzCl, and PhCH(2)COCl to provide the corresponding meso diesters, 20-22. Screening of these meso benzoxabicyclo[2.2.1]heptyl substrate candidates across a battery of acyl transfer enzymes leads to an optimized match of diacetate 20 with PPL. Even on 10-20 g scales, asymmetry is efficiently introduced here, yielding the key chiral intermediate, monoacetate 25 (66% isolated yield, 83% corrected yield, 95% ee). Protecting group manipulation and oxidation (Swern) provide aldehyde 27b, which undergoes efficient retro-Michael ring opening to produce dihydronaphthalene 30, in which the C(3) and C(4) stereocenters are properly set. Following several unsuccessful approaches to the intramolecular delivery of ring E (via Claisen rearrangement, Heck-type cyclization, or radical cyclization), a highly diastereoselective, intermolecular conjugate addition of the arylcopper reagent derived from (3,4,5-trimethoxy)phenylmagnesium bromide and CuCN to acyl oxazolidinone 50 was developed (85% yield, only the required alpha-stereochemistry at C(1) is observed). The conjugate addition product is converted to (-)-picropodophyllin in two steps (lactonization, SEM deprotection) or to (-)-podophyllotoxin, in three steps, through the introduction of a C(2)-epimerization step, under Kende conditions, prior to the final conjugate addition.

An Efficient Strategy for the Synthesis of α,α′-cis and trans-Disubstituted Medium Ring Ethers

An asymmetric alkylation-ring-closing metathesis strategy was developed for the construction of α,α′-disubstituted medium ring ethers. The approach features an asymmetric alkylation of highly functionalized α-alkoxy acyl oxazolidinones followed by ring closure effected by Grubbs' ruthenium catalyst. The relationship between diene conformation and the rate of ring-closure was examined.

Total Synthesis of (+)-Laurencin: An Asymmetric Alkylation−Ring-Closing Metathesis Approach to Medium Ring Ethers

[formula: see text] The enantioselective total synthesis of (+)-laurencin 1 is achieved in 18 steps from (S)-(+)-4-benzyl-3-benzyloxyacetyl-2-oxazolidinone. The key steps in this synthesis are an asymmetric glycolate alkylation leading to acyl oxazolidinone 2 and a subsequent ring-closing olefin metathesis to construct the oxocene core of 1. The approach to medium ring ethers utilized in this synthesis provides a general and efficient route to the cyclic core of other marine natural products.

Highly Diastereoselective Synthesis of Pederic Acid Derivatives.

A highly diastereoselective synthesis of methyl pederate (2) is described. A critical feature of the successful route is the introduction of the key C(7)-stereocenter at the stage of 4 via an enantioselective, syn-selective aldol reaction of aldehyde 5 and the chiral acyl oxazolidinone 6. Aldehyde 5, in turn, was prepared from the readily available aldol derivative 7 via a chelate-controlled reaction with allyltrimethylsilane. Intermediate 4 was elaborated to 2 via the intermediacy of 7-O-(3,4-dimethoxybenzyl)pederic acid (3), an intermediate in Kishi's syntheses of mycalamides A and B and onnamide A, by way of methyl pyranoside 10 and the fully protected pederic acid derivative 11.

Stereoselective Michael Addition Reactions of Acylated Oxazolidinones to Ethyl 3-Trifluoromethylacrylate

Abstract Michael addition reactions of acyl oxazolidinones to ethyl 3-trifluoromethylacrylate were found to proceed smoothly with a high degree of diastereo- as well as diastereofacial selectivity at the new carbon–carbon bond.