Chiral auxiliary also oxazolidinone

Chiral active pharmaceutical ingredients, 18 725-726. See also Enantio- entries Chiral additives, 6 75—79 Chiral alcohols, synthesis of, 13 667-668 P-Chiral alcohols, synthesis of, 13 669 Chiral alkanes, synthesis of, 13 668-669 Chiral alkenes, synthesis of, 13 668—669 Chiral alkoxides, 26 929 Chiral alkynes, synthesis of, 13 668-669 Chiral ammonium ions, enantiomer recognition properties for, 16 790 Chiral ansa-metallocenes, 16 90 Chiral auxiliaries, in oxazolidinone formation, 17 738—739... 

Several other oxazolidinones have been developed for use as chiral auxiliaries. The 4-isopropyl-5,5-dimethyl derivative gives excellent enantioselectivity.91 5,5-Diaryl derivatives are also quite promising.92... 

In Entry 5, the aldehyde is also chiral and double stereodifferentiation comes into play. Entry 6 illustrates the use of an oxazolidinone auxiliary with another highly substituted aldehyde. Entry 7 employs conditions that were found effective for a-alkoxyacyl oxazolidinones. Entries 8 and 9 are examples of the application of the thiazolidine-2-thione auxiliary and provide the 2,3-syn isomers with diastereofacial control by the chiral auxiliary. 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

The synthesis in Scheme 13.47 was also based on use of a chiral auxiliary and provided the TBDMS-protected derivative of P-D lactone in the course of synthesis of the macrolide portion of the antibiotic 10-deoxymethymycin. The relative stereochemistry at C(2)-C(3) was obtained by addition of the dibutylboron enolate of an A-propanoyl oxazolidinone. The addition occurs with syn anti-Felkin stereochemistry. 

Reagent control This involves the addition of a chiral enolate or allyl metal reagent to an achiral aldehyde. Chiral enolates are most commonly formed through the incorporation of chiral auxiliaries in the form of esters, acyl amides (oxazolines), imides (oxazolidinones) or boron enolates. Chiral allyl metal reagents are also typically joined with chiral ligands. 

The chiral A/ -propionyl-2-oxazolidones (32 and 38) are also useful chiral auxiliaries in the enantioselective a-alkylation of carbonyl compounds, and it is interesting to observe that the sense of chirality transfer in the lithium enolate alkylation is opposite to that observed in the aldol condensation with boron enolates. Thus, whereas the lithium enolate of 37 (see Scheme 9.13) reacts with benzyl bromide to give predominantly the (2/ )-isomer 43a (ratio 43a 43b = 99.2 0.8), the dibutylboron enolate reacts with benzaldehyde to give the (3R, 25) aldol 44a (ratio 44a 44b = 99.7 0.3). The resultant (2R) and (25)-3-phenylpropionic acid derivatives obtained from the hydrolysis of the corresponding oxazolidinones indicated the compounds to be optically pure substances. 

The preceding reactions illustrate control of stereochemistry by aldehyde substituents. Substantial effort has also been devoted to use of chiral auxiliaries and chiral catalysts to effect enantioselective aldol reactions.71 72 Avery useful approach for enantioselective aldol condensations has been based on the oxazolidinones 1-3, which are readily available in enantiomerically pure form. 

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. 

Some enantiomerically pure substituted 2-oxazolidinones are excellent as chiral auxiliaries. From the pioneering studies 2 conducted in the early 1980 s of the uses of such auxiliaries has emerged what is perhaps the most widely used method today for the preparation of enantiomerically highly enriched a-alkylalkanoic acids, alcohols and aldehydes, that is, the alkylation of enolates from chiral 3-acylated 2-oxazolidinones followed by auxiliary removal2 59. The early work has been reviewed60-62. These enantiomerically pure cyclic imide auxiliaries have been used not only for alkylations but also in a plethora of a-functionalization reactions, such as diastereoselective aldol, a-hydroxylation, a-amination and Diels-Alder reactions and these are discussed elsewhere in this volume. 

Stereosectivity is a broad term. The stereoselectivity in cyclopropanation which has been discussed in the above subsection, in fact, can also be referred to as diastereoselectivity. In this section, for convenience, the description of diastereoselectivity will be reserved for selectivity in cyclopropanation of diazo compounds or alkenes that are bound to a chiral auxiliary. Chiral diazoesters or chiral Ar-(diazoacetyl)oxazolidinone have been applied in metal catalysed cyclopropanation. However, these chiral diazo precursors and styrene yield cyclopropane products whose diastereomeric excess are less than 15% (equation 129)183,184. The use of several a-hydroxy esters as chiral auxiliaries for asymmetric inter-molecular cyclopropanation with rhodium(II)-stabilized vinylcarbenoids have been reported by Davies and coworkers. With (R)-pantolactone as the chiral auxiliary, cyclopropanation of diazoester 144 with a range of alkenes provided c yield with diastereomeric excess at levels of 90% (equation 130)1... 

Although the trend is changing, the use of chiral auxiliaries, such as oxazolidinones, is often thought of as too expensive. There are examples where this approach has been taken to large scale (Chapters 23 and 24). The use of a cheap chiral template can also have advantages (Chapter 25). 

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. 

The aldol reaction illustrated in eq 2 has been applied to the targeted synthesis of a number of complex molecules including Tylosin, Hapalosin, the antibiotic Sinefungin, and the HIV protease Saquinavir inhibitor. Oxazolidinone-type chiral auxiliaries derived from 1 have also been employed for the control of Diels-Alder reactions of attached acryloyl or crotonyl groups. ... 

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). 

Phenylalanine-derived oxazolidinone has heen used in O Scheme 52 as a chiral auxiliary for as)rmmetric cross-aldolization (Evans-aldol reactions [277,278,279,280,281,282,283,284, 285]). The 6-deoxy-L-glucose derivative 155 has heen prepared by Crimmins and Long [286] starting with the condensation of acetaldehyde with the chlorotitanium enolate of O-methyl glycolyloxazohdinethione 150. A 5 1 mixture is obtained from which pure 151 is isolated by a single crystallization. After alcohol silylation and subsequent reductive removal of the amide, alcohol 152 is obtained. Swem oxidation of 152 and subsequent Homer-Wadsworth-Emmons olefination provides ene-ester 153. Sharpless asymmetric dihydroxylation provides diol 154 which was then converted into 155 (O Scheme 60) (see also [287]). 

We have introduced you to this chiral auxiliary before any other because it is more commonly used than any other. It is a member of the oxazolidinone (the name of the heterocyclic ring) family of auxiliaries developed by David Evans at Harvard University, and is easily and cheaply made from the amino acid (S)-valine. Not only is it cheaply made it can also be recycled. The last step of the route above, transesterification with benzyl alcohol, regenerates the auxiliary ready for re-use. synthesis of Evans s oxazolidinone chiral auxiliary from (S)-valine NH2 NH2... 

Aldol reactions using chiral auxiliaries are popular as the stereochemical outcome is usually highly predictable and, as such, they provide a reliable method for the incorporation of adjacent stereocenters. The oxazolidinone-based imides 36 and (ent)-36 are the most commonly employed, and these lead to syn aldol products with high levels of stereocontrol [20]. The reaction can be extended to include a variety of a-heteroatom functionality as in 37 (Scheme 9-13) [21]. Numerous examples of the use of these auxiliaries in the synthesis of polypropionate natural products have been reported. Many related auxiliaries are also available and the camphor-based sultam 38 is notable [22]. 

Optically active 2-alkylbutanedioates are also available from the stereoselective alkylation of chiral imide enolates. Thus, prepared by means of nondestructive and reusable chiral auxiliaries (e.g. chiral oxazolidinones ), dimethyl (7 )-2-terr-butylbutanedioate (>99 /oee)... 

Chiral oxazolidinones are also common chiral auxiliary used in the organic synthesis to provide chiral compounds. In 2004, Glorius et al. described an example of the efficient asymmetric hydrogenation of pyridines through the introduction of a chiral oxazolidinone auxiliary to the 2 position of the pyridine derivatives [52]. 

Miura and coworkers showed that the reaction could also be carried out using catalytic amounts of Cul in the presence of pyridine (95JOC4999). Asymmetric reactions were reported to occur with chiral bisoxazoline ligands producing p-lactams with moderate (40-68%) enantiomeric excesses. Use of an oxazolidinone with a chiral auxiliary appended to the alkyne also provided enantiomerically pure products (02TL5499). In all of these latter reports, mixtures of cis and irons lactam isomers were obtained in which the trans-product predominates. It was also shown that the c/s-isomer could easily be converted to the trans-product when exposed to base. 

Initiated by conjugate addition of iodide ion, which is under stereocontrol by the chiral auxiliary of an iV-alkenyl-2-oxazolidinone, a tandem intramolecular alkylation is also enan-tioselective. Based on this reasoning it is possible to prepare cyclic compounds with new stereocenters of defined absolute configuration. ... 

In addition to amino acids, 1,2-amino alcohols can be used as chiral auxiliaries. The synthesis of the amino acid derivative 16 outlined in Scheme 9.15 is a variation of a Strecker reaction. - Evans oxazolidinone chemistry is well documented, which allows for a wide variety of reactions to be performed with a high degree of predictability. In addition to alkylation reactions to introduce the side chain of an amino acid, the nitrogen group can also be introduced in a variety of ways, one of which is illustrated in Scheme 9.16. ... 

Scheme 6.52. Corey s synthetic approaches to prostaglandins (see also ref. [239], chapter 11) (a) Key hydroxy acid intermediate for the synthesis of PGF2 and PGE2. (b) Early synthesis that relied on resolution for obtaining enantiopure products [240]. (c) 8-Phenylmenthol as a chiral auxiliary [165]. (d) Acryloyl oxazolidinone as dienophile with a chiral catalyst [221,222]. (e) 2-Bromoacrolein as dienophile with a chiral catalyst [215],...

The methods that we have just discussed can be used to control the ratio of syn and anti diastereomeric products. It is often desired to also control the reaction to provide a specific enantiomer. Nearby stereocenters in either the carbonyl compound or the enolate can impose facial selectivity. Chiral auxiliaries can achieve the same effect. Finally, use of chiral Lewis acids as catalysts can also achieve enantioselectivity. Much effort has also been devoted to the use of chiral auxiliaries and chiral catalysts to effect enantioselective aldol reactions." A very useful approach for enantioselective aldol additions is based on the oxazolidinones 4,5, and 6. 

---