Evans oxazolidinones, asymmetric

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

Application of asymmetric alkylation with Evans auxiliaries Aldol Reactions with Evans Oxazolidinones The syn aldol reaction with boron enolates... 

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... 

Scheme 3.17. Evans s asymmetric alkylation of oxazolidinone imides [83].

The asymmetric aldol reaction using the Evans oxazolidinone auxiliary has been used in a number of syntheses. Suggest reagents for the preparation of the imide 2, used in a synthesis of cytovaricin and explain the stereoselectivity of this reaction. Suggest how you would obtain the other syn aldol product and explain the difference in the stereoselectivity. 

The final fragment is a simple chiral carboxylic acid, so we need a method for its asymmetric synthesis. The most obvious choice is probably an asymmetric alkylation using Evans oxazolidinone auxiliary formation of the appropriate derivative of hexanoic acid is simple, and the enolate will be alkylated diastereoselectively by methyl iodide. You would probably take this approach if you need to make a few grams for initial studies. 

Yamazaki et al. employed the Evans oxazolidinone enolate in diastereoselective Michael additions to /I-CF3 acrylates to afford intermediate allyl silyl ketene acetals [8]. The products were isolated as ca. 2 1 mixtures of pentenoic acids and Michael addition adducts (Scheme 4.59). The rearrangement of the silyl ketene acetal was catalyzed by PdCl2(CH3CN)2. The rearrangement apparently occurred via the Z-silyl ketene acetal and exhibited high 1,2-asymmetric induction. Aspects of stereochemical control and Pd catalysis have been discussed previously (cf Scheme 4.25). 

Li and co-workers developed a novel asymmetric halo aldol reaction using Evans oxazolidinones as chiral auxiliaries for tandem I-C/C-C bond formations. This reaction provides a practical approach to a variety of halo aldols of a non-Evans type that cannot be easily prepared by other methods. Excellent diastereoselectivity (> 95% de) and yields (80-93%) have been obtained. This reaction can be considered as a Lewis acid (Et2Al-I)-promoted Morita-Baylis-Hillman (MBH) process. 

The Evans oxazolidinone methodology is quite versatile and quite apart from its use in aldol reactions (section 5.3.3) lends itself well to the asymmetric synthesis of carboxylic acids substituted in the a-position with oxygen, nitrogen, and carbon.ti l The auxiliary shown is derived from (+)-norephedrine and the opposite enantiomers of the products are available from the valine-derived auxiliary. 

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. 

Guided by the success of the Evans and related auxiliaries, several attempts were made to use enantiomerically pure a-bromoacyl oxazolidinones for stereoselective Reformatsky reactions. Fukuzawa and coworkers developed the reaction of various bromoacetyl oxazolidinones 323 as an alternative to an asymmetric acetate aldol addition. The conversion was mediated by samarium iodide and yielded P-hydroxy carbonyl compounds 325 with high diastereoselectivity in optimal combinations of auxiliary group and aldehyde. Among the different auxiliaries, the geminal dimethyl- and diphenyl-substituted ones performed better than the original Evans oxazolidinones. The stereochemical outcome was rationalized by assuming that an O-bound samarium(III) enolate reacts via a chair-like... 

Atrasentan (58, Scheme 2.9), a potent and selective endothelin receptor antagonist developed by Abbott Laboratories (Abbott Park, IL), contains a substituted pyrroh-dine core that was initially accessed in optically pure form via a late-stage classic resolution." A more recent synthesis of atrasentan employs an Evans oxazolidinone in an asymmetric alkylation reaction to introduce the C3 stereocenter on the pyrrolidine ring. To this end, the mixed anhydride 53 was coupled with the L-valine-derived oxazolidinone 54... 

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. 

Asymmetric aldol condensation of aldehyde and chiral acyl oxazolidinone, the Evans chiral auxiliary. 

The initial work on the asymmetric [4-1-2] cycloaddition reactions of A -sulfinyl compounds and dienes was performed with chiral titanium catalysts, but low ee s were observed <2002TA2407, 2001TA2937, 2000TL3743>. A great improvement in the enantioselectivity for the reaction of AT-sulfinyl dienophiles 249 or 250 and acyclic diene 251 or 1,3-cyclohexadiene 252 was observed in the processes involving catalysis with Cu(ll) and Zn(ii) complexes of Evans bis(oxazolidinone) (BOX) ligands 253 and 254 <2004JOC7198> (Scheme 34). While the preparation of enantio-merically enriched hetero-Diels-Alder adduct 255 requires a stoichometric amount of chiral Lewis acid complex, a catalytic asymmetric synthesis of 44 is achieved upon the addition of TMSOTf. 

The control of the three consecutive asymmetric centers in a-alkylated y-amino-p-hydroxy acids is achieved by aldol condensation of a chiral aldehyde and a chiral reagent (Scheme 17 and Table 6), e.g. boron enolate 43,150 79 oxazolidinones of Evans type lit80 or 45 [68>69>801 or Brown s or Roush s crotylorganoboron reagents 46[81 and 47J81,82 respectively. 

With Chiral Bis(oxazoline)/metal Complexes Several research groups have developed chiral Lewis acids by using chiral 1,3-bis(oxazoline) ligands for asymmetric Diels-AIder reactions. Evans designed C2-symmetric bis(oxazoline)/Cu(II) complexes derived from chiral bis(oxa-zoline)and Cu(OTf)2, and applied them to asymmetric cycloadditions of acryloyl oxazolidinones and thiazolidine-2-thione analogues. Attractive features of this catalyst system include a clearly interpretable geometry for the catalyst-dienophile complex, which rationalizes the sense of asymmetric induction for the cycloaddition process [26] (Eq. 8A.14). 

The approach for the enantioselective aldol reaction based on oxazolidinones like 22 and 23 is called Evans asymmetric aldol reaction.14 Conversion of an oxazolidinone amide into the corresponding lithium or boron enolates yields the Z-stereoisomers exclusively. Reaction of the Z-enolate 24 and the carbonyl compound 6 proceeds via the cyclic transition state 25, in which the oxazolidinone carbonyl oxygen and both ring oxygens have an anti conformation because of dipole interactions. The back of the enolate is shielded by the benzyl group thus the aldehyde forms the six-membered transition state 25 by approaching from the front with the larger carbonyl substituent in pseudoequatorial position. The... 

A stereocontrolled synthesis of the biologically active neolignan (+)-dehydrodiconiferyl alcohol, which was isolated from several Taxus species, was achieved via Evans asymmetric aldol condensation [58] using ferulic acid amide derived from D-phenylalanine. The reaction steps are shown in Fig. 9. This stereocontrolled reaction is also useful for preparing the enantiomer of (+)-dehydroconiferyl alcohol using chiral auxiliary oxazolidinone prepared from L-phenylalanine. This reaction also enables the syntheses of other natural products that possess the same phenylcoumaran framework. 

An excellent asymmetric induction has also been observed by Snider et al. [164] in a hetero Diels-Alder reaction with the N-crotonyl oxazolidinone 2-172 which had already been used by Evans for the all carbon cycloaddition [ 164b]. Reaction of isobutene with 2-172 in the presence of Me2AlCl for 40 h at -30 °C in CH2C12 provided a mixture of the alcohol 2-174 and the lactone 2-175 via the primarily formed cycloadduct 2-173. Treatment of the mixture with sodium carbonate gave the lactone 2-175 as a pure enantiomer (Fig. 2-48). 

Asymmetric [4 + 2] cycloaddition reactions of A-sulfinyl compounds and dienes have been developed <2002TA2407, 2000TL3743>. Excellent enantioselectivity is observed for the preparation of product 148 by the reaction of A-sulfinyl dienophiles 146 and acyclic diene 147 catalyzed with Cu(II) and Zn(II) complexes of Evans bis(oxazolidinone) ligands (Scheme 74) <2004JOC7198>. 

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). 

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). 

Similar high levels of asymmetric induction using the oxazolidinone methodology developed by Evans have been observed. In contrast to Davis observations with amides - the sodium enolates were preferred in these cases, allowing diastereomeric ratios in the range 90 10-99 1 to be realized (Scheme 22). 

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... 

Next, Evans et al. [15] reported that Cu-based catalysts were superior in the Diels-Alder reaction of the oxazolidinone 9 with cyclopentadiene 8. ITie (5,5)-bis(oxazo-line)-Cu(II) and -Zn(II) complexes were very effective catalysts of the reaction. The optimum tert-butyl ligand 13-Cu(II) complex afforded (2S)-endo-ll with > 98 % ee. In contrast, the optimum catalyst system for the phenyl-substituted ligand 12-Zn complex afforded the enantiomeric (R) product, (2R)-endo-ll, with 92 % ee. The different direction of asymmetric induction was explained in terms of the geometry of cata-lyst-dienophile complexes at the corresponding metal centers. The bis(oxazoline)-Zn(II) complex-catalyzed reaction proceeded via the tetrahedral chiral Zn-dienophile complex VIII, in a manner similar to the bis(oxazoline)-Mg catalyst reported by Corey [13], whereas the reaction catalyzed by the cationic bis(oxazoline)-Cu complex proceeded via the square-planar Cu(II)-dienophile intermediate VII, so the diene preferred to approach from the opposite si face of the bound dienophile with s-cis configuration, avoiding steric repulsion by one of the tert-butyl substituents on the oxazoline rings. 

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