Oxazolidinones hydrolysis

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. 

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). 

In an indirect amination process, acyl halides are converted to amino acids. Reaction of the acyl halide with a chiral oxazolidinone leads to a chiral amide, which reacts with the N=N unit of a dialkyl azodicarboxylate [R"02C—N=N—CO2R ]. Hydrolysis and catalytic hydrogenation leads to an amino acid with good enantioselectivity. ... 

Ring D inversion seems to be a crucial step in biogenetic transformations of protoberberines to related alkaloids such as rhoeadine, retroprotoberberine, spirobenzylisoquinoline, and indenobenzazepine alkaloids. 8,14-Cyclober-bin-13-ol 478 derived from berberine (15) was successively treated with ethyl chloroformate, silver nitrate, and pyridinium dichromate (PDC) in dimethyl-formamide to give the keto oxazolidinone 479 (Scheme 98). Heating of 479 with 10% aqueous sodium hydroxide in ethanol effected hydrolysis, retro-aldol reaction, cyclization, and dehydration to provide successfully the... 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

Most of the reactions involving nucleophilic attack at a carbon atom of the ring result in cleavage of the five-membered ring system (which is in most cases either an oxazolidine or an oxazolidinone). Basic hydrolysis of... 

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. 

In a special case, basic hydrolysis of 2-(trichloromethyl)oxazolines 329 gave the oxazolidinone 330 or the amino alcohol 331 depending on the reaction conditions as shown in Table 8.25 (Scheme 8.99). Formation of 330 is presumably the result of facile displacement of the trichloromethyl leaving group. 

As noted, direct acid- or base-catalyzed hydrolysis of the acyl C-N bond in the chiral alkylated 3-acyl-2-oxazolidinones is usually not practical. This is because it is often very slow and/or results in undesired side reactions such as cleavage of the oxazolidinone ring (there are, however, useful exceptions6 31-41). 

Most traditional methods use hydrochloric acid solutions as the acid reagent for the hydrolysis or alcoholysis of fi-lactams. Methanolic solutions of trimethylchloro-silane are able to generate HCI in situ, and the trick has been employed successfully for the methanolysis of fi-lactams in a route to aspartic acid derivatives [60, 61] and 2-oxazolidinones[62], respectively. Recently the use of silica-supported acid reagent has been reported as a convenient alternative. The reagent (Si02-Cl) prepared from admixing silica gel and SOCl2 in dichloromethane and subjected to dryness, is able to run the methanolysis of (1-lactams at room temperature in 20 min [63]. 

The enantiomerically pure oxazolidinone derivative 7 (Scheme 4),14,20 was converted into the metathesis precursor 6 by a sequence of carbamate hydrolysis, amide alkylation and protection of the secondary alcohol as the TBDMS ether in a 95% overall yield. Subsequent [Ru-1] catalysed ROM-RCM converted 6 into the desired dihydropyrrole 5. 

Neri et al89 reported the desymmetrization of A-Boc-serinol 98 by the selective monoacetylation using PPL (porcine pancreas lipase) and vinyl acetate as the acylating agent in organic solvent. The mono acetylated product (R)-99 was obtained after 2 hours with 99% ee and isolated in 69% chemical yield. Traces of the diacetylated product 100 were observed. The cyclization of (R)-99 in basic medium afforded the racemic oxazolidinone 101. The latter was subjected to enzymatic hydrolysis in phosphate buffer affording (R)-... 

Figure 49 Synthesis of ( S )-4-acetoxymethyl-2-oxazolidinone 101 and its enzymatic hydrolysis.

An expeditious enantioselective synthesis ofn-methyltryptophan was accomplished using the Seebach oxazolidinone procedure. The oxazolidinone 36b was prepared from D-tryptophan and pivalaldehyde. Alkylation was carried out without indoIe-A -protection using 2.2 equiv. of LDA and 1.2 equiv. of methyl iodide. Under these conditions, ( -alkylation ocurred preferentially. R-d-methyltryptophan was obtained by hydrolysis of 36c. <95JOC5719>... 

In 1992 Ghosh and co-workers provided the first example of the utility of rigid cis-1 -amino-2-indanol-derived oxazolidinone 36 as the chiral auxiliary in the asymmetric. vv//-aldol reaction.60-61 Aldol condensation of the boron enolate of 37 with various aldehydes proceeded with complete diastereofacial selectivity. Effective removal and recovery of the chiral auxiliary was carried out under mild hydrolysis conditions (Scheme 24.6). As both enantiomers of the chiral auxiliary were readily available, both enantiomers of the. yyn-aldol could be prepared with equal asymmetric induction. 

The amides are derived from oxazolidinones and yield "Z"-enolates with high stereoselectivity. The alkylating agent reacts in both cases from the side that is opposite to the side of the substituent highlighted in red. Alkaline hydrolysis accelerated by hydrogen peroxide proceeds with retention of configuration and yields enantiomerically pure a-alky-lated carboxylic acids X t and X 2 are the chiral amide groups. 

The alkylations of the oxazolidinone-containing amide enolate of Figure 13.43 occur with diastereoselectivities of 93 7 and > 99 1, respectively. The hydrogen peroxide-accelerated alkaline hydrolysis of these compounds occurs with complete retention of the previously established configuration at the a-stereocenter. To date, the Evans synthesis offers the most versatile access to enantiomerically pure a-alkylated carboxylic acids. 

This method, employing methylation by Mel, was used to synthesise pheromones such as (S)-sulcatol 416.176 The oxazolidinone protecting group features a safety-catch which is released by treatment with acid intramolecular assistance to hydrolysis of the secondary amide 415 rapidly generates the free alcohol product 416. 

H)-Oxazolones give hydroxy ketones on alkaline hydrolysis lithium aluminum hydride reacts at the C=N bond to form the corresponding 2-oxazolidinones (Scheme 17). 

The 5(2H)-oxazolones (213) present two sites, C(4) and C(5), to nucleophilic attack they usually react at the latter. The benzylidene derivative (214), the most thoroughly studied member of this class, possesses an additional electrophilic centre at the exocyclic carbon atom. However, alkaline hydrolysis of this compound affords phenylacetamide and benzoylformic acid by acyl-oxygen fission (equation 50). a-Keto acids are also obtained when 2-trifluoromethyl-5(4//)-oxazolones are hydrolyzed, the reaction involving preliminary isomerization to a 5(2//)-oxazolone. The example shown in equation (51) represents the first non-enzymatic synthesis of an optically active a-keto acid. An instance of nucleophilic attack at C(4) of a 5(2//)-oxazolone is the formation of the oxazolidinone (215) in a Grignard reaction (equation 52). However, the typical behaviour of unsaturated pseudooxazolones like (214) is conjugate addition of a nucleophile, followed by further transformations of the resulting 5(4F/)-oxazoIones. This is illustrated by the reaction of compound (214) with benzene in the presence of aluminum chloride to yield, after aqueous work-up, the acylamino acid (216 equation 53). 

Oxazolidinones are virtually neutral they do not give stable salts with acids but they can be alkylated at the nitrogen atom under basic conditions. They are rather resistant to hydrolysis vigorous treatment with alkali yields /3-amino alcohols whereas hydrochloric acid gives /3-chloroalkylamines (equation 82). The combined action of aromatic hydrocarbons and aluminum chloride on 2-oxazolidinones leads to /3-arylethylamines which are formed by alkyl-oxygen fission (equation 83) (80TL1719). 

Af-(Phenylsulfanylmethyl)oxazolidinones derived from camphor 494 can be lithiated with n-BuLi at —78°C to give the chiral formyllithium equivalent 478683 (Scheme 128). This intermediate added to aldehydes in good yields, but lower stereoselectivity than compound 477, to afford crystalline adducts, which allowed the isolation of the major diastereomer 495. Hydrolysis of these adducts gave a-hydroxy aldehydes, which can be oxidized with PCC to the corresponding a-hydroxy acids. 

Hydrolysis of the oxazolidinone 236 gave the corresponding amino alcohol, which without isolation was coupled with the sugar 4-isothiocyanate 2653 to provide the thiourea 452 (Scheme 67).105 Cyclization of 452 to the isourea 453 was carried out with yellow mercuric oxide, and the resulting oxazoline 453 was debenzylated to give... 

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