Oxazolidinone alkylation

The utility of the Al-acyl oxazolidinone alkylation has been demonstrated in the context of numerous total syntheses. For instance, in 2003, Evans and Connell used this method in the asymmetric total synthesis of the antifungal macrolide (-l-)-roxaticin 221. (+)-Roxaticin 221 is a pen-taene macrolide isolated from an unidentihed streptomycete similar to Strepfomyces ruber. Like similar compounds, it shows antifungal but not antibacterial activity. In the alkylation step (Scheme 7.32), 202 was treated with TiCLj and EtsN to provide the required Z-(0)-enolate, which was then treated with BOMCl to afford 209 in 99% yield and >200 1 diastereoselectivity. Removal of the auxiliary was... 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

The synthesis of the E-ring intermediate 20 commences with the methyl ester of enantiomerically pure L-serine hydrochloride (22) (see Scheme 9). The primary amino group of 22 can be alkylated in a straightforward manner by treatment with acetaldehyde, followed by reduction of the intermediate imine with sodium borohydride (see 22 —> 51). The primary hydroxyl and secondary amino groups in 51 are affixed to adjacent carbon atoms. By virtue of this close spatial relationship, it seemed reasonable to expect that the simultaneous protection of these two functions in the form of an oxazolidi-none ring could be achieved. Indeed, treatment of 51 with l,l -car-bonyldiimidazole in refluxing acetonitrile, followed by partial reduction of the methoxycarbonyl function with one equivalent of Dibal-H provides oxazolidinone aldehyde 52. 

The optically active oxazolidinone derivative 3, readily obtainable from serine (see Appendix), is alkylated to give predominantly the cw-product98. The auxiliary is removed by acid hydrolysis to give the 2-amino alcohol. 

Lewis acid induced alkylation of 4-alkoxy-3,5-dialkyl-2-oxazolidinones with allylsilanes gives the 4-allyl derivatives with complete irons stereoselectivity114,115. Cleavage of the oxazolidi-none ring with aqueous sodium hydroxide in ethanol leads to vicinal twP -aminoalkanols. 

Water, which can be taken to a minimum by the use of molecular sieves, can produce a lactamide either through direct reaction with the aziridinone intermediate, or upon hydrolysis of oxazolidinone self-condensation products, previously obtained also in the presence of a strong non-nucleophilic base (H ) (ref. 17). The recently reported 0-self-alkylation compound H bears the (S,S)-configurations at the unreacted C-Br and newly formed C-0 bonds. The presence of bromine was expedient for the x-ray assessment of configuration at the two chiral centers of 11 which forms in high diastereoisomeric excess (ref. 5). 

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. 

Vinyl epoxides are highly useful synthetic intermediates. The epoxidation of dienes using Mn-salen type catalysts typically occurs at the civ-olefin. Epoxidations of dienes with sugar-derived dioxiranes have previously been reported to react at the trans-olefin of a diene. A new oxazolidinone-sugar dioxirane, 9, has been shown to epoxidize the civ-olefin of a diene <06AG(I)4475>. A variety of substitution on the diene is tolerated in the epoxidation, including aryl, alkyl and even an additional olefin. All of these substitutions provided moderate yields of the mono-epoxide with good enantioselectivity. 

Oxazolidinones have also been used as intermediates in simple transformations utilising their peculiar reactivity. The absolute configuration of WBoc-P-aminoalcohol 213 can be easily inverted via Sn2 cyclisation to oxazolidinone 214 <00TL10071>. Treatment with Olah s reagent (HF-Pyridine) of 4-alkyl-5,5-diphenyl-oxazolidinones 216 afforded the corresponding a-(fluorodiphenylmethyl)alkylamines 217 <00TA2033>. 

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. 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted much interest for their various applications in different synthetic transformations.2 Such simple structures, directly related to far better known chiral oxazolidinones,11,12,57 have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations, but mainly in condensation of their /V-acyl derivatives with aldehydes. Chiral OZTs have shown interesting characteristics in anti-selective aldol reactions58 or combined asymmetric addition. 

RM Freidinger, JS Hinkle, DS Perlow, BH Arison. Synthesis of 9-fluorenylmethox-ycarbonyl-protected V-alkyl amino acids by reduction of oxazolidinones. J Org Chem 48, 77, 1983. 

The two-step activation of oxazolidinones is depicted in Fig. 8.26. Hydrolysis yields an A-(l -hydroxy alkyl) derivative, which breaks down to liberate the peptide or A-acylamino acid (Fig. 8.26, Reactions a and b). Since oxazolidinones are prepared by the condensation of a peptide and an aldehyde (Fig. 8.26, Reaction c), the reverse reaction (i. e., one-step activation) cannot be excluded. Examples of this type of prodrug are provided by a series of oxazolidinones of the general structure 8.190 (R = PhCH20 R = H, Me, i-Pr, or PhCH2 R" = H, Me, or Ph Fig. 8.26) [248]. In phosphate buf-... 

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 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. 

A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of /V-acyl oxazolidinones.59 The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

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. 

Alkoxy-2(3/f)-oxazolones 47 react with aliphatic and aromatic aldehydes in the presence of Lewis acid catalysts to produce alkyl 2-oxazolidinone-4-carbox-ylates 291 ° by successive ring opening and reclosure. 

Alkyl- or 3-aryl-2,4-oxazolidinediones via photochemical cyclization, ° organonickel-mediated carbonylation, ° cyclization of A-alkenyl-a-acet-amides, ° carboxylation and cyclization of 2-propynamides, °" cyclization of (9-carbamates of a-hydroxy acetic acids and esters,cyclization of a-hydroxy acetamides,and catalytic asymmetric dihydroxylation (ADH) of A-alkenoyl-2-oxazolidinones. ... 

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