Oxazolidinone N-acyl

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. 

TABLE 9.29. ENANTIOSELECTIVE FREE RADICAL CONJUGATE ADDITIONS TO a,p-UNSATURATED N-ACYL OXAZOLIDINONES... 

Using a similar concept, a square-planar bis(imine)/Cu(OTf)2 complex has been developed, and it has been shown that the 2,6-dichlorophenyl-substituted bis(imine) ligand is, in general, the most effective for the asym metric Diels-Alder reaction of N-acyl oxazolidinones (83-94% ee) [31] (Eq. 16),... 

Scheme 14 The alkylation of N-acyl oxazolidinone 43 to afford diastereomers 47 and 48 investigated under continuous flow at —100 °C.

The direct transmetallation of alkenyl, acyl, and alkylzirconocenes to a copper catalyst and subsequent conjugate addition is also possible without a detour via another metal like zinc. For example, Wipf and Takahashi182 reported the highly diastereoselective 1,4-addition of in situ-prepared alkylzirconocenes (e.g., 246) to chiral N-acyl oxazolidinone 245 and similar substrates in the presence of BF3 OEt2 and catalytic amount of CuBr-SMe2, giving adducts of the type 247 with moderate to good yield (Equation (13)). 

Scheme 14 Alternative acyl-like radical addition reactions with N-acyl oxazolidinone derivatives of amino acids...

Stereoselective Conjugate Addition of Organoaluminium Compounds to Carbohydrate Derived N-Acyl Oxazolidinones According to Scheme 10.59 (Ref. [147,148])... 

Narasaka reported that TADDOL-TiCl2 was able to catalyze asymmetric DA reaction of cyclopentadiene with oxazolidinone derivatives of acrylates in the presence of 4A MS [148]. A remarkable solvent effect on the enantioselectivity was observed, and high enantioselectivity was attained using mesitylene as the solvent. Cycloadditions to oxazolidinone derivatives of acrylates were also efficiently catalyzed by dendritic or polymer-supported TADDOL-Ti catalysts [149]. From the structural determination of the 3-(( )-3-cinnamoyl)-l,3-oxazolidin-2-one adduct, it can be deduced that the transition state involves binding of the dienophile to the titanium catalyst via the N-acyl-oxazolidinone [19a] (Scheme 14.59). The diastereo-and enantioselectivity of this type of catalyst are thus probably owing to both electronic and steric effects from TADDOL ligand. 

A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of N-acyl oxazolidinones." Two enantiomerically pure derivatives which are readily available have received the most study. The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

Scheme 4.52 Aldol additions of N-acyl-oxazolidinones 229 carrying a-hetero substituents.

A research group at Novartis also utilized Evans aldol reaction in a straightforward synthesis of (/ ,/ )-methylphenidate hydrochloride (ritalin hydrochloride), the drug well known for the treatment of attention deficit hyperactivity disorder (AD HD). In the key step, displayed in Scheme 4.58, N-acylated oxazolidinone 249, the standard boron enolate addition to 5-chloropentanal, yielded 250 as a single diastereomer that was transformed in several steps into Ritalin hydrochloride. In the aldol step, temperatures lower than -20 °C could be avoided, what makes the procedure applicable in a manufacturing scale [130]. 

Scheme 4.74 Application of the Mannich reaction of N-acyl oxazolidinone 335 in a synthesis of the p-lactam ezetimibe.

Chiral auxiliaries feature in two amiiKxleoxysugar syntheses. The L-forosamine derivative 54 (Scheme 16) was prepared from the N-acylated oxazolidinone 53 derived from L-phenylalanine, and used in the total synthesis of the macrolide antibiotic lepicidin A. Key steps were asymmetric aldol condensation (step i) and Clurtius reaction (acid to isocyanate with capture by fluorenylmethanol stq) iv). The 5-amino-2,5-dideoxy-D-rhreo-pentoside 57 and 3,5-diamino-2,3,5-trideoxy-l>-e/yrhro-pentoside 58 were synthesized by conventional triflate displacenoent reactions from iodolactone 56,... 

The Evans oxazolidinones are one of the most important types of chiral auxiliary in organic synthesis. They were first reported in 1981 in the context of a diastereoselective aldol addition. The high levels of asymmetric induction associated with their use and the ease of preparation of these auxiliaries are two important reasons why they have become so firmly entrenched in organic synthesis. Oxazoh-dinones are readUy formed by the condensation of chiral, nonracemic 1,2-amino alcohols and a suitable carbonate species (e.g., diethylcarbonate and triphosgene)Once formed, the oxazolidinone (cf. 55, Scheme 7.30) may be iV-acylated by treatment with, for example, n-BuIi and an acid chloride. The resulting N-acyl oxazolidinones (cf. 202) have been used in a variety of enolate-based transformations. 

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... 

Crimmins et al. further expanded the utility of the Evans alkylation procedure to include hydroxyl-protected a-hydroxy carboxylic acids (Table 7.4). The derived N-acyl oxazolidinones were deprotonated with NaHMDS to... 

Evans has pioneered the use of carboximide-derived enolates in diastereo-selective enolate alkylation reactions [15, 82]. As discussed in subsequent chapters, N-acyl oxazolidinones (such as 114, 115, and 116) enjoy a unique position in asymmetric synthesis as chiral auxiliaries with wide applications in numerous mechanistically unrelated asymmetric transformations, among them aldol (Chapter 4), Diels-Alder (Chapter 17), enolate amination (Chapter 10), and conjugate addition (Chapter 12) reactions. Oxazolidinones 114 and 115 generally lead to Ca-substituted carboximide products in one dia-stereomeric series (cf 119, dr>99 1), while the complementary diastereo-meric adducts such as 122 dr =98 2) can be accessed through the use of oxazolidinone 116 (Scheme 3.18) [82]. 

As carboxylic acid derivatives, the enolates derived from N-acyl oxazolidinones approximate the reactivity patterns of thioesters the derived alkali metal enolates display moderate nucleophilicity [82]. Investigations of these systems have revealed that there is a pronounced difference in alkylation rates between the various alkali metal enolates. Thus, although the reactivity of the lithium enolates is limited (reaction temperatures = 0°C), the corresponding sodium enolates undergo allcylation at lower temperatures (-78 °C). This feature resulted in higher observed diastereoselectivity for the corresponding sodium enolates in the alkylation reactions. 

There are numerous noteworthy structural aspects of N-acyl oxazolidinones that give them a central role as auxiliaries for a large array of asymmetric transformations. Although the enolization reaction of esters and ketones can lead to mixtures of cis- and trans-enolates, the oxazolidinone imi-des exclusively form the corresponding cis-enolates. This observation has been attributed to the pronounced destabilization of the trans-enolate and the transition state structure leading to its formation as a consequence of A, 3 steric interactions (cf 124, Scheme 3.19) [15]. A second important feature of the oxazolidinone enolates relates to the ability of the auxiliary carbonyl functionality to form a chelate with coordinatively unsaturated metal centers (cf 118,121, or 125). This organizing feature provides rigidity to the en-... 

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