Auxiliaries, chiral oxazolidones

Oxazolidones as Chiral Auxiliaries Chiral Auxiliary-Mediated Aldol-Type Reactions... 

They also reported the intramolecular version of this asymmetric Diels-Alder reaction [53]. ( , )-Trienecarboximides of type 45 derived from chiral oxazolidones undergo Me2AlCl-catalyzed intramolecular Diels-Alder reactions affording bicyclic compounds 46 with high endo and diastereoselectivity (endolexo = -100 1). The stereochemistry is controlled by the stereogenic center at C4 of the chiral auxiliary (Xc) (Sch. 29). 

Chiral oxazolidones are readily prepared from carbamates of a-amino esters by reduction with NaBHa-Lil in refluxing THF. Note that imides (A-acyloxazolidinones) are reduced to alcohols, therefore the reduction represents a method for recovery of both chiral products and auxiliaries. ... 

Conventional asymmetric aldol reactions have been performed by using chiral enolates and achiral carbonyl compounds. A chiral boron enolate generated from a chiral oxazolidone derivative (26 and 28), dialkylboron tri-fiate, and diisopropylethylamine reacts stereoselectively with aldehydes to afford the corresponding syn aldol adducts (27 and 29) in good yields with excellent diastereoselectivity (Eqs. (8) and (9)) [12]. The opposite sense of asymmetric induction is achieved by changing the chiral auxiliary. Several other chiral auxiliaries have also been developed for highly diastereoselec-tive synthesis of syn aldol adducts (Eqs. (10)-(13)) [13]. 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

The chiral boron enolates generated from /V-acyl oxazolidones such as 7 and 8 (which were named Evans auxiliaries and have been extensively used in the a-alkylation reactions discussed in Chapter 2) have proved to be among the most popular boron enolates due to the ease of their preparation, removal, and recycling and to their excellent stereoselectivity.8... 

A further step towards improved selectivity in aldol condensations is found in the work of David A. Evans. The work of Evans [3a] [14] is based in some early observations from Meyers laboratory [15] and the fact that boron enolates may be readily prepared under mild conditions from ketones and dialkylboron triflates [16]. Detailed investigations with Al-propionylpyrrolidine (31) indicate that the enolisation process (LDA, THE) affords the enolate 32 with at least 97% (Z>diastereoselection (Scheme 9.8). Finally, the observation that the inclusion of potential chelating centres enhance aldol diastereoselection led Evans to study the boron enolates 34 of A(-acyl-2-oxazolidones (33), which allow not only great diastereoselectivity (favouring the 5yn-isomer) in aldol condensations, but offer a possible solution to the problem of enantioselective total syntheses (with selectivities greater than 98%) of complex organic molecules (see below, 9.3.2), by using a recyclisable chiral auxiliary. 

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. 

Acyl-l,3-oxazolidine-2-thiones, chiral (1). Nagao and co-workers1 have prepared the chiral 3-acetyl-l,3-oxazolidine-2-thiones (la and lb) and used them to effect diastereoselective aldol reactions. The two chiral auxiliaries show, as expected, opposite diastereoselectivities, but contrast with the diastereoselectivities observed with chiral 4-alkyl-2-oxazolidones (11, 379-381). This aldol reaction has been used to prepare the chiral azetidinone 4 (equation I) and (-I- )-Prelog-Djerassi lactone. 

Oxazolidones, chiral, (1) and (2). Evans et al. have prepared these two chiral 2-oxazolidones by reaction of phosgene with (S)-valinol and (IS, 2R)-norephedrine, respectively, and used them as recyclable chiral auxiliaries for carboxylic acids in cnantioselective reactions of the derived imides. 

Of similar nature are chiral halogenations using auxiliary groups. Typical examples are the conversion of esters to enantiomerically pure halohydrins (precursors to chiral epoxides) using camphor-10-sulfonic acid derivatives583 and the chiral synthesis of a-amino acid synthons via diastereoselective bromination of TV-acyl oxazolidone derivatives584. 

In order to overcome the problems associated with acid hydrolysis of amides of prolinol, the Evans research group has investigated the diastereoselectivity of the alkylation of imides derived from chiral 2-oxazolidones. Imide enolates are somewhat less nucleophilic than amide enolates, but they have the advantage that their diastereomeric alkylation products are easily separated and the imide linkage is cleaved with a variety of reagents under mild conditions. As shown in Scheme 64, alkylation of the chelated (Z)-enolate of the propionimide derived from (S)-valinol (135) with benzyl bromide occurred in high chemical yield and with high si-face diastereoselectivity. In addition to oxazolidones, imidazoli-diones have proved to be useful chiral auxiliaries for diastereoselective enolate alkylations. ... 

Substituted 2-oxazolidones 165 are useful chiral auxiliaries for diastereoselective functionalization at the a-carbon of their amide carbonyl group. The a-fluoroaldehydes 166 were prepared by a series of reactions electrophilic fluorination of the corresponding oxazolidinone sodium enolates with AMluorobenzenesulfonimine reductive removal of the auxiliary with LiBH4 and Dess-Martin oxidation. The aldehydes are so unstable for isolation that they are converted with (R)-/ -toluenesulfinamide to /7-toluenesul(inimines 167, which are isol-able and satisfactorily enantio-enriched. Chiral sulfinimine-mediated diastereoselective Strecker cyanation with aluminum cyanide provided cyanides 168 in excellent diastereose-lectivity, which were finally derived to 3-fluoroamino acids 169 (see Scheme 9.37) [63]. 

The starting compound was also condensed with an aldehyde in 82-84% yield with more than 98% ee. A corresponding amide from an fi unsaturated acid underwent the Diels-Alder reaction in 86-90% yield with more than 99% ee. The original amino alcohol was probably treated with phosgene to close the oxazolidone ring.63 The less toxic dimethyl carbonate might be a suitable replacement for the phosgene. The use of another chiral auxiliary for alkylation is shown in 10.30.64... 

Asymmetric halogenation of carboxylic acid derivatives has also been achieved by D.A. Evans (refs. 11,12) via chiral N-acyl oxazolidones. For instance, an N-acyl oxazolidone prepared by acylation of the (4S)-benzyl-2-oxazolidone chiral auxiliary derived from (S)-phenylalanine, is converted to its (Z)-dibutyl boron enolate, which is added to a NBS slurry, at low temperature (Fig. 6) ... 

Enantioselective aldol condensation by means of an oxazolidone chiral auxiliary and boron enolate (see 1 st edition). 

As for the characteristic controlling of stereochemistry during aldol reaction, the Evans aldol reaction has been extensively modified through the application of Lewis acids, chiral auxiliaries (e.g., oxazolidone, oxadiazinones, thiazolidinethione " ), chelating metals, etc. 

A "heterocyclic" strategy used an oxazolidone ring as a protected carboxyl (an amide) which also served as a chiral auxiliary. Treatment of 6.127 with a boron triflate, for example, gave boron enolate reagent 6.128 in situ, and it reacted with N-Boc leucinal to form 6.129. Boron enolates have been used in many syntheses as an alternative to lithium or sodium enolate in Aldol reactions.S7 Hydrogcnolysis of the methylthio moiety gave a methylene moiety and treatment of the amide auxiliary with base gave 6.95 (24% overall yield). 

ASYMMETRIC ALDOL REACTIONS USING THE OXAZOLIDONE CHIRAL AUXILIARY... 

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