Pyrrolidone chiral

Enantioselective synthesis of the antidepressant rolipram can be done by the asymmetric Michael addition of the enolate of IV-acetyloxazolidone to nitrostyrene. Chirally branched pyrrolidones like rolipram are highly active antidepressants with novel postsynaptic modes of action. The synthesis is shown in Scheme 4.13.78... 

Menthyl chloroformate, chiral derivatizing reagent, 6 76t Menthyl esters, 24 524 Menthyl pyrrolidone carboxylate, 24 525 Menthyl salicylate, 24 524 physical properties of, 22 14t Menthyl valerate, 24 524 Mentoring, of technical service personnel, 24 346-347... 

Chiral, nonracemic, monocyclic y-lactams have been alkylated. One such lactam, 5-ethoxy-4-hy-droxy-l-isopropyl-2-pyrrolidone (5), is obtained as an 82 18 mixture of the (4S,5Jt)- and (4S,5S)-isomers from (S )-2-hydroxybutanedioic acid (4), via the crystalline, enantiomerically pure (A)-3-acetoxy-1 -isopropyl-2,5-pyrrolidinedione, in a five-step procedure with 57 % overall yield19,20. 

The dibasic side chain at position 7 can be alternatively provided by a substituted amino alkyl pyrrolidine. Preparation of that diamine in chiral form starts with the extension of the ester function in pyrrolidone (46-1) by aldol condensation with ethyl acetate (46-2). Acid hydrolysis of the (3-ketoester leads to the free acid that then decarboxylates to form an acetyl group (46-3). The carbonyl group is next converted to an amine by sequential reaction with hydroxylamine to form the oxime, followed by catalytic hydrogenation. The desired isomer (46-4) is then separated... 

It is also possible to prepare chiral PANI by in situ polymerisation with CSA, and in this case the reaction can afford chiral nanotubes [63]. The optically active materials contain nanotubes with 80 to 200 nm outer diameter and an internal diameter of between 20 and 40 nm, as revealed through microscopy images. A self-assembly process was proposed in which anilinium cations and CSA anions form micelles which act as templates for the growing polymer chains. Nanotubes are also formed when (R)- or (S)-2-pyrrolidone-... 

Chiral rhodium(II) carboxamides are exceptional catalysts for highly enantio-selective intermolecular cyclopropenation reactions (50). With ethyl diazoacetate and a series of alkynes, use of dirhodium(II) tetrakis[methyl 2-pyrrolidone-5-(R)-carboxylate], Rh2(5R-MEPY)4, in catalytic amounts ( 1.0 mol %) results in the formation of ethyl eyelopropene-3-earboxylates (eq 4) with enantiomeric excesses... 

The high degree of enantiocontrol in C-H insertion reactions with such a diversity of diazoacetates suggests unique advantages for chiral dirhodium(II) catalysts derived from pyrrolidone-5-carboxylates. Both lactone enantiomers are accessible from a single diazo ester, and the absence of by-products of similar composition allows convenient product isolation. 

In connection with the total synthesis of grandisol, an asymmetric addition of ethylene on chiral heterocyclic aminals and ketals was examined (Scheme 23). The selectivity can be high, with a preferred approach of ethylene from the less hindered side, especially when chiral pyrrolidone 97 or furanones 100 were used in place of cyclic enones [70]. The diastereoisomeric excess of 101 or 102 remains modest with 5-menthyloxy furanone, even if the dark addition of nucleophiles or radicals on 100 occurs with a total facial selectivity. From a detailed analysis of the dependence of the product ratio with temperature and substituents, it was proposed that a pyramidalization of the (3-carbon in the relaxed of the... 

This is the first detailed procedure for the synthesis of a chiral dirhodium(ll) carboxamide catalyst and its application to intramolecular cyclopropanation. The preparation of the ligand, methyl 2-pyrrolidone-5(R)-carboxylate, is adapted from the procedure of Ackermann, Matthes, and Tamm.2 The method for ligand displacement from dirhodium(ll) tetraacetate is an extension of that reported for the synthesis of dirhodium(ll) tetraacetamide.6 The title compound, (1 R,5S)-(-)-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one, is a synthetic precursor to (1 R,3S)-(+)-cis-chrysanthemic acid.5... 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

Semicorrinato)copper catalysts have also been used for intramolecular cyclopropanation reactions of alkenyl diazo ketones (eq 9 and eq 10). In this case the (semicorrinato)copper catalyst derived from complex (5) proved to be superior to related methylene-bis(oxazoline)copper complexes. Interestingly, analogous allyl diazoacetates react with markedly lower enantioselectivity under these conditions, in contrast to the results obtained with chiral Rh complexes which are excellent catalysts for intramolecular cyclopropanations of allyl diazoacetates but give poor enantioselectivities with alkenyl diazo ketones (see Dirhodium(II) Tetrakis(methyl 2-pyrrolidone-5(S -carboxylate ) Moderate enantioselectivities in the reactions... 

Matsumura and his coworkers [38] have employed the 2-pyrrolidone anion, in DMF solution, to deprotonate arylacetic acid esters with subsequent oxidative dimerization of the corresponding carbanions. This study includes a useful comparison between the electrochemical and chemical generation of the 2-pyrrolidone anion (by fluoride anion displacement in A-trimethylsilyl-2-pyrrolidone). The advantage lies with the electrochemical route, which gave yields of final product of 80%, compared with the 30% obtained with the chemically generated base (Scheme 10). The overall process, formation of dimethyl 2,3-diphenylsuccinates, is not only efficient and convenient but also operates with high diastereoselectivity when under the control of an oxazolidinone chiral auxiliary (Scheme 10). 

Dirhodium(II) catalysts that possess chiral 2-pyrrolidone-5-carboxylate ester ligands (mepy) are the most effective among those of dirhodium or copper for highly diastereoselective and enantioselective intermolecular cyclopropenation reactions between l-alkynes and diazoesters (eq. (9)). Product yields are moderate, and enantiomeric excesses range from 40 to 98 %. Interestingly, the (R) or (5) catalyst produces the cyclopropene-l-carboxylate respectively with the (/ ) or (5) configuration [26]. 

C4 chiral synthetic units are also important for the syntheses of pharmaceuticals and their intermediates. For example, optically active 4-chloro-3-hydroxybutyrate (CHB) and 4-chloro-3-hydroxybutyronitrile (BN) are key compounds as C4 chiral building blocks for the syntheses of L-carnitine [16], l-GABOB [17], / -hydroxybuty-ric acid, 3-hydroxy-y-butyrolactone, and 4-hydroxy-2-pyrrolidone. Recently, CHB has been reported as being used for synthesizing an intermediate for HMG-CoA reductase inhibitor for hyperlipidemia (Fig. 11) [18]. 

The oxazoline 184 provides an attractive approach to lactacystin as it is a protected form of 3-hydroxyleucine. The other half of the molecule was made in the LeukoSite synthesis by a very different method the alkylation of an Evans chiral auxiliary. This was chosen partly because they wished to vary the alkyl group on the pyrrolidone ring and we use the propyl compound as example. The phenylalanine derived oxazolidinone 193 (chapter 27) was acylated and then the titanium enolate of 194 was alkylated to give 195 with very high selectivity and the chiral auxiliary removed to give the simple acid 196. 

A template-guided synthesis of water-soluble chiral-conducting PAn in the presence of (S)-(—)- and (R)-(+)-2-pyrrolidone-5-carboxylic acid [(S)-PCA and (R)-PCA] has been reported to produce nanotubes.228 The structures prepared have outer diameters of 80-220 nm with an inner tube diameter of 50-130 nm. It was proposed that the tubular structures form as a result of the hydrophobic aniline being templated by the hydrophilic carboxylic acid groups of the PCA in aqueous media during chiral tube formation. The resultant tubes were shown to be optically active, suggesting that the PAn chains possess a preferred helical screw. 

Asymmetric hydrocarboxylation may be applied to the synthesis of chiral A -protected amino carboxylic acids, pyrrolidones or proline precursors. With this synthetic target in mind hydrocarboxylation of/f-substituted A -vinyl- and A -allylphthalimides is catalyzed with palla-dium(ll) chloride in the presence of the chiral phosphanes Diop or DIOCOL28. Although high product selectivities and regioselectivities are achieved, only very low asymmetric inductions are observed (up to 4% ee)28. Until now the best results in a vinyl imide hydrocarboxylation are achieved with, V-vinylsuccinimide in the presence of palladium(II) chloride and (-)-Diop with a 17.1 % ee12. 

On this basis, in a joint effort with Martin and Muller (1991a), Doyle developed a series of dinuclear rhodium 2-pyrrolidone-5-carboxylate complexes that might give better enantiomeric ratios in cyclopropanations (see also Muller and Polleux, 1994). This was indeed the case for a series of intramolecular cyclopropanations of allyl diazoacetates with the complex Rh2((55)-MEPY)4 obtained with chiral methyl 2-pyrrolidone-5-carboxylate (MEPY = 8.178) an ee between 65 and 94 o was found. Doyle et al. (1993 a) continued that work with additional inter- and intramolecular cyclopropanations as well as with intramolecular CH insertions. Doyle and his coworkers again obtained good-to-excellent enantioselectivity with the same catalyst. Examples are given in Schemes 8-75 to 8-77. 

Asymmetric cyclopropanation. The ability to effect ligand exchange between rhodium(II) acetate and various amides has lead to a search for novel, chiral rhodium(II) catalysts for enantioselective cyclopropanation with diazo carbonyl compounds. The most promising to date are prepared from methyl (S)- or (R)-pyroglutamate (1), [dirhodium(ll) tetrakis(methyl 2-pyrrolidone-5-carboxylate)]. Thus these complexes, Rh2[(S)- or (R)-l]4, effect intramolecular cyclopropanation of allylic diazoacetates (2) to give the cyclo-propanated y-lactones 3 in 65 S 94% ee (equation 1). In general, the enantioselectivity is higher in cyclopropanation of (Z)-alkenes. 

Ni(0)/AlMe3-catalysed asymmetric intramolecular hydrocarbamoylation reactions can be carried out by using cbiral ligand 41, providing pyrrolidones in bigb yields and enantioselectivities (Scheme 14.73). It is believed that a Ni-Al bimetallic complex supported by tbe chiral ligand (42) is formed and this bimetallic species has superior reactivity. ... 

The first step is acetylation of the sulfoxide oxygen and the release of an acetate ion (7 8 Scheme 20.31. Recent computational studies have shown that the initial acetylation step is rate determining and that the release of the acetate ion proceeds by stabilization of the acetate by coordination with a positively charged sulfur, which yields an achiral sulfurane 11. It is generally accepted that the formation of this sulfurane is responsible for the poor enantioselectivity shown in the reactions of chiral sulfoxides. However, sulftirane formation can be avoided by some additives, for exanple, iV,iV-dimethylacetamide (DMAC), iV-methyl-2-pyrrolidone (NMP), or the acetate trap DCC. ... 

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