Oxazolidinones in asymmetric

In a broad program of using chiral oxazolidinones in asymmetric synthesis,100 Evans s group published a paper in 1992 on the synthesis and utilization of fV-sulfinyl oxazolidinones as new sulfinylating agent.87 Two chiral auxiliaries were used in the study oxazolidinones derived from (4R, 5S)-norephedrine 74101 and (45)-phenylalanine 75.102 The corresponding fV-sulfinyl oxazolidinones 77 and 78 were obtained either by sulfmylation of the metallated oxazolidinone or by oxidation of the derived N-sulfenamides (Table 15). 

Ager, D. J. Prakash, I. Schaad, D. R. Chiral Oxazolidinones in Asymmetric Synthesis, Aldrichim. Acta 1997, 30, 3-12. 

Many auxiliaries currently in use are derived from 1,2-amino alcohols (140). These are readily available from natural sources with little or no synthetic manipulation and can react in a variety of ways to form conformationally well-defined (usually cyclic) auxiliary systems. The use of oxazolidinones in asymmetric synthesis was developed by Evans et al., and these oxazolidinones have been used extensivelvin a... 

The first report of the use of N-acyl oxazolidinones in asymmetric alkylation was by Evans et al. in 1982. The reactions described were found to proceed with high levels of diastereoselectivity and with very good yields (Table 7.2). The primary factor in determining the stereochemical course of the reaction is the geometry of the enolate intermediate. Studies have shown the level of /Z-enolate control transfers directly to the level of diastereoselectivity of the alkylated product. Conveniently, it has also been established that the use of bulky bases (e.g., EDA and NaHMDS) for the deprotonation of A-acyl oxazolidinones strongly favors formation of the Z-(0)-enolate. Another factor influencing the stereochemical course of the reaction is the nature of the auxiliary itself. In particular, the ability of the... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted much interest for their various applications in different synthetic transformations.2 Such simple structures, directly related to far better known chiral oxazolidinones,11,12,57 have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations, but mainly in condensation of their /V-acyl derivatives with aldehydes. Chiral OZTs have shown interesting characteristics in anti-selective aldol reactions58 or combined asymmetric addition. 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

Conversion of 2 to the highly crystalline oxazolidinone 3 with phosgene has been described by Thornton who has employed this substance as a chiral auxiliary in asymmetric aldol reactions of its N-propionyl derivative. Kelly has also used an oxazoline derived from 3 as a chiral auxiliary in asymmetric alkylation of a glycolate enolate. Oxazolidinone 3 has also been prepared from 2 with diethyl carbonate in the presence of potassium carbonate. The conversion of 2 to the oxazolidinone 3 is accomplished using triphosgene in this procedure because of the high toxicity of phosgene. 

A promising unprecedented application of the chiral enecarbamates Ic in asymmetric synthesis is based on the ship-in-the-bottle strategy, which entails the oxidation of these substrates in zeolite supercages . In this novel concept, presumably dioxetanes intervene as intermediates, as illustrated for the oxidation of the chiral enecarbamate Ic in the NaY zeolite (Scheme 6). By starting with a 50 50 mixture of the diastereomeric enecarbamates (45, 3 R)-lc and (45, 3 5 )-lc, absorbed by the NaY zeolite, its oxidation furnishes the enantiomerically enriched (ee ca 50%) S -methyldesoxybenzoin, whereas the (4R,3 R)-lc and (4R,3 S)-lc diastereomeric mixture affords preferentially (ee ca 47%) the R enantiomer however, racemic methylbenzoin is obtained when the chirality center at the C-4 position in the oxazolidinone is removed. Evidently, appreciable asymmetric induction is mediated by the optically active oxazolidinone auxiliary. 

Although N-amino derivatives of oxazolidinones were sporadically reported in the literature [41-43], no applications in asymmetric synthesis were known prior to our... 

Recently, Oppolzer s group reported on the synthesis and use of a new sulfinylating agent,107 the /V-sulfinyl sultam 82, as part of a broad program on the use of the versatile bornane-10,2-sultam 81 in asymmetric synthesis.108 The condensation of p-TolSOCI with 81 in THF, using dimethylaminopyridine (DMAP) as catalyst, gave the /V-(p-tolylsulfinyl)bornane- 10,2-sultam as a 6.2 1 diastereomeric mixture. Crystallization of the mixture from E O/hexane afforded pure 82 in 77% yield. X-ray analysis showed the absolute configuration at the sulfinyl sulfur to be (/ ). The reaction has been shown to be kinetically controlled, in contrast to the results obtained when n-BuLi was used instead of DMAR In the latter case, the reaction was under thermodynamic control, in accord with the result obtained by Evans with iV-sulfinyl oxazolidinone (Scheme 25). 

Chiral Ligands. Bidentate chelation of dirhodium(II) compounds by chiral oxazolidinones creates asymmetric sites on the metal, leading to induction in cyclopropanations and carbon-hydrogen insertion reactions. The oxazolidinones are less effective in this capacity than are the pyrrolidines. ... 

Precursor of Useful Chiral Ligands. OPEN is widely used for the preparation of chiral ligands. Organometallic compounds with these ligands act as useful reagents or catalysts in asymmetric induction reactions such as dihydroxylation of olefins, transfer hydrogenation of ketones and imines, Diels-Alder and aldol reactions, desymmetrization of meso-diols to produce chiral oxazolidinones, epoxidation of simple olefins, benzylic hydroxylation, and borohydride reduction of ketones, imines, and a,p-unsaturated carboxylates. ... 

Narasaka has demonstrated that TADDOL-Ti dichloride prepared from TADDOL and Cl2Ti(OPr )2 in the presence of MS 4A acts as an efficient catalyst in asymmetric catalytic Diels-Alder reactions with oxazolidinone derivatives of acrylates, a results in extremely high enantioselectivity (Sch. 45) [112]. Narasaka reported an intramolecular version of the Diels-Alder reaction, the product of which can be transformed into key intermediates for the syntheses of dihydrocompactin and dihydromevinolin (Sch. 46) [113]. Seebach and Chapuis/Jurczak [114] independently reported asymmetric Diels-Alder reactions promoted by chiral TADDOL- and 3,3 -diphenyl BINOL-derived titanium alkoxides. Other types of chiral diol ligands were also explored by Hermann [115] and Oh [116]. 

Michael additions with 8-phenylmenthyl esters of unsaturated acids Chiral auxiliaries attached elsewhere in asymmetric Michael additions Other Chiral Auxiliaries in Conjugate Addition The Evans oxazolidinones Chiral sulfoxides Asymmetric Birch Reduction Birch reduction of benzene Asymmetric Birch reduction of heterocycles... 

Other oxazolidinones have been used as chiral auxiliaries in asymmetric aldol reactions. Bomane derivatives 1.121 (X = O or S) and 1.122 are readily transformed into V-acyl derivatives. The reactions of their boron or titanium enolates with aldehydes give the same selectivities as Evans s reagents [426, 428, 429, 431, 436], iV-Acylimidazolidinones 1.131 and 1.132 [449, 1270] lead to similar results, but the selectivities observed are somewhat lower. 

Oxazolidinones are useful heterocyclic compounds in organic synthesis. They have a wide range of applications in asymmetric syntheses as chiral reagents and, since they have good antibacterial properties, in medicinal chemistry [53]. Oxazolidinones can be synthesized in traditional solvents such as acetonitrile [54] or DMF [5 5], but it is more environmentally friendly to use scC02 [56]. In the reaction an internal propargyl alcohol, carbon dioxide, and a primary amine participate in a cycloaddition reaction under supercritical conditions to give 4-alkylene-l,3-oxazoli-din-2-ones (Equation 4.30). 

Some thermally forbidden [2 + 2]-cycloaddition reactions can be promoted by Lewis acids1-6. With chirally modified Lewis acids, the opportunity for application in asymmetric synthesis of chiral cyclobutanes arises (for a detailed description of these methods see Sections D.l. 6.1.3.. D.l. 61.4. and references 7, 28-30). Thus, a chiral titanium reagent, generated in situ from dichloro(diisopropoxy)titanium and a chiral diol 3, derived from tartaric acid, catalyzes the [2 + 2]-cycloaddition reaction of 2-oxazolidinone derivatives of a,/ -unsalurated acids 1 and the ketene thioacetal 2 in the presence of molecular sieves 4 A with up to 96 % yield and 98% ee. Fumaric acid substrates give higher yields and enantiomeric excesses than acrylic acid derivatives8. Michael additions are almost completely suppressed under these reaction... 

Kanemasa et al. reported an asymmetric conjugate addition reaction of thiol to A-crotonyl oxazolidinone in the presence of Ni(II)-DBFOX/Ph catalyst [20] (Table 8.2). In this reaction. Proton Sponge (1) is indispensable for high enantioselectivity, and thioether was obtained in 84-99% yield with 91-94% ee. 

Lewis acid-catalyzed intramolecular Diels-Alder reactions of trienes, bearing an inducing moiety, e.g. oxazolidinones 62 or sultam 63, have been widely examined and employed in natural product synthesis. The cycloadducts were obtained in high yield with excellent stereoselectivities. Among the Lewis acids studied in asymmetric intramolecular Diels-Alder reactions with auxiliary 11, a chiral catalyst [(Bomyl)AlCl2] proved to be highly efficient (72% de, 25-75%). 

Oxazolidinones are frequently used as chiral auxiliaries in asymmetric transformations, as ligands for metal catalysts, and as precursors to vicinal amino alcohols. These common structural motifs in natural products and pharmaceuticals have spurred interest in the development of methods for their preparation. Espino and Du Bois reported the synthesis of indane-appended oxazolidinone 215 via Rh-catalyzed C-H insertion of carbamate ester 214. A variety of other carbamates was found to be competent substrates for this reaction. The role of magnesium oxide as additive was presumed to be as scavenger of acetic acid generated from the iodinane oxidant. 

In the first formal asymmetric synthesis of phorbol, a tigliane diterpene, Wender and co-workers utilized a chiral oxazolidinone-based asymmetric aldol reaction to produce chiral alcohol 43, a non-Evans syn product as a single diastereomer in 96% yield. ... 

Chiral titanocene derivatives can also be used as catalysts in asymmetric DA reaction [150] (Scheme 14.60). The reaction of oxazolidinone derivatives and cyclopentadiene was realized using enantiopure l,2-ethylenebistetrahydroindenyl-Ti(OTf)2 as the catalyst. The bistetrahydroindenyl-derived titanium complex with chiral biphenyl tether was also employed for the same reaction, giving the DA product with moderate enantiomeric excess [151]. 

Many of the chiral auxiliaries described earlier serve excellently in asymmetric Diels-Alder reactions. The Evans oxazolidinones (116)t l and the Oppolzer camphor sultams (117)t l are exceptionally good in this regard and, as shown, actually give opposite products. 

The applications of primary and secondary amine-ureas and -thioureas in asymmetric organocatalysis have been reviewed (138 references), as has the use of oxazolidinones as chiral auxiliaries in asymmetric aldols employed in total synthesis (193 references). 

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