Oxazolidinones, formation from alkyl

The alkylation of enolates from some recently developed 2-oxazolidinone auxiliaries will be briefly discussed. The Diels-Alder reaction of the enantiomerically pure 3-(apocamphane-carbonyl)-2(3//)-oxazolone 13 with anthracene gives, diastereoselectively, a 97 3 ratio of diastereomeric adducts63. Recrystallization followed by removal of the apocamphanecarbonyl auxiliary and acylation gives the diastereomerically pure enantiomer 14 in good yield. Subsequent enolate formation and alkylation gives highly diastereoselective reactions and easily purified products due to the fact that the major product is readily crystallized. Thus alkylation... 

The next phase of the synthesis was installation of the dimethylamino-oxazoline ring system. This was constructed from the oxazolidinone precursor 19. Oxazolidinone formation occurred when 25 was reacted with thionyl chloride. The more nucleophilic carbonyl of 19 was then O-alkylated with the Meerwein reagent to give an iminium ion that readily participated in a nucleophilic addition/elimination reaction with dime-thylamine to give 26. The final step of the synthesis was O-deacetylation of 26 with sodium methoxide to provide (—)-allosamizoline hydrochloride in 98% yield after acidification. 

A silver-ion assisted halohydrin formation from a,p-unsaturated carboxylic acid derivatives was performed with chiral A-enoyl-2-oxazolidinones to form awri-o -halo- S-hydroxy carbonyls in good yields (90-94%, eq 2S). This alternate method of carboxyhalohydrin asymmetric-synthesis produced better diastereoselectivity (up to S,S RJi = 80 20) with AgOAc (or AgNOg) than with Ag2C03. The observed stereoselectivity required a nonnucleophilic (alkyl) substituent on the oxazolidi-none chiral auxiliary. 

This imide system can also be used for the asymmetric synthesis of optically pure a,a-disubstituted amino aldehydes, which can be used in many synthetic applications.31 These optically active a-amino aldehydes were originally obtained from naturally occurring amino acids, which limited their availability. Thus, Wenglowsky and Hegedus32 reported a more practical route to a-amino aldehydes via an oxazolidinone method. As shown in Scheme 2 20, chiral diphenyl oxazolidinone 26 is first converted to allylic oxazolidinone 27 subsequent ozonolysis and imine formation lead to compound 28, which is ready for the a-alkylation using the oxazolidinone method. The results are shown in Table 2-6. 

The key sequence in a somewhat involved stereospecihc total synthesis of a carbacephem starts by preparation of a chiral auxiliary. It is interesting to note that nitrogen is the only atom from this molecule retained in the hnal product. Constmction of this moiety starts with the formation of the carbethoxy derivative (37-2) from L(- -)-phenylglycine (37-1). Selective reduction of the free carboxyl group with borane. THF leads to the hydroxycarbamate (37-3). In a one-pot sequence, this is first cyclized to the corresponding oxazolidinone (37-4) by means of sodium hydride and then alkylated with ethyl bromoacetate (37-5). Saponification of the side chain then affords the chiral acetic acid (37-6). The carboxyl group is then activated by conversion to its acid chloride (37-7). 

The succinate core can be prepared by alkylation of a simple carboxylic acid (74a or b) with a bromoacetate using the Evans oxazolidinone chiral auxiliary derived from phenylalanine (chapter 27). The branched alkyl group must be present in the substrate for alkylation and the second acid group added in the alkylation so that there is no competition between two carbonyl groups during enolate formation. After hydrolysis (91% yield) the alkylated succinic acid 77 has >95% ee. Notice that the two acid groups are differentiated by this procedure.10... 

In 1982, Evans reported that the alkylation of oxazolidinone imides appeared to be superior to either oxazolines or prolinol amides from a practical standpoint, since they are significantly easier to cleave [83]. As shown in Scheme 3.17, enolate formation is at least 99% stereoselective for the Z(0)-enolate, which is chelated to the oxazolidinone carbonyl oxygen as shown. From this intermediate, approach of the electrophile is favored from the Si face to give the monoalkylated acyl oxazolidinone as shown. Table 3.6 lists several examples of this process. As can be seen from the last entry in the table, alkylation with unactivated alkyl halides is less efficient, and this low nucleophilicity is the primary weakness of this method. Following alkylation, the chiral auxiliary may be removed by lithium hydroxide or hydroperoxide hydrolysis [84], lithium benzyloxide transesterification, or LAH reduction [85]. Evans has used this methology in several total syntheses. One of the earliest was the Prelog-Djerassi lactone [86] and one of the more recent is ionomycin [87] (Figure 3.8). 

Two approaches to BIRT-377 (1) are discussed. The focus is the stereoselective synthesis of tran -imidazolidinones such as 16 and cu-oxazolidinones such as 29d. The kinetic and thermodynamic factors governing the cis/trans selectivity in the formation of 16 and 29d were studied, and it was found that neither can assure complete selectivity in favor of either form. It was then found in both cases that a crystallization-driven dynamic transformation can produce, in a very efficient manner, the desired cis isomer in virtually 100% selectivity in the case of 29d, whereas only the tmns isomer is obtained in the case of 16. Self-regeneration of stereocenters is then applied to the alkylation of the enolates derived from 16 and 29d with p-bromobenzyl bromide, followed by routine transformations, to produce 1 in >99.9% ee via two separate processes. 

There are several methods to prepare oxazolidinones from a-amino acids, for the use as templates in alkylation reactions. [3] Our early investigations focused on the protocol by Seebach based on acylation of imine salts of amino acids, [5] but we encountered problems associated with the heterogeneous formation of imine salts on larger scale. A method was then developed by which commercially available (i)-W-Cbz-alanine (24) is reacted with benzaldehyde dimethylacetal(25) in the presence of SOCI2 and ZnCl2 to provide the oxazolidinone 26 with a predominant cw-relationship cis trans ca. 5-15 1) between the phenyl group and the a-methyl group, as shown in Scheme 7.[2i]... 

The release of carbamates from carbamate linkers has been shown by Buchstaller [195] who pubhshed a synthesis for oxazolidinones 217 on sobd supports (Scheme 32). Starting from Wang resin which is reacted with isocyanates 213, Buchstaller formed the reactive hydroxyl group via addition of pyrrolidine to an epoxide 215 former introduced via N-alkylation of the core structure 214 on bead. Nucleophilic ring opening results in the formation of an amino alcohol intermediate that cyclizes spontaneously and gives free oxazolidinones 217 in an overall 71% to quantitative yield in three steps. 

---