Oxazolines, hydrolysis

Ring fission occurs readily in many of these compounds. For example, azlactones, i.e. 4JT-oxazolin-5-ones containing an exocyclic C=C bond at the 4-position (508), are hydrolyzed to a-benzamido-a,/3-unsaturated acids (509), further hydrolysis of which gives a-keto acids (510). Reduction and subsequent hydrolysis in situ of azlactones is used in the synthesis of a-amino acids e.g. 508 -> 507). 

Azlactones — see also l,3-Oxazolin-5-ones Erlenmeyer synthesis, 6, 202 hydrolysis, S, 64, 101 tautomerism, 6, 186 unsaturated... 

Oxazolines may be used to react with terminal groups on condensation polymers to improve stability, particularly against hydrolysis. This appears to be of particular interest with poly (ethylene terephthalate). 

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

Variations and Improvements on Alkylations of Chiral OxazoUnes Metalated chiral oxazolines can be trapped with a variety of different electrophiles including alkyl halides, aldehydes,and epoxides to afford useful products. For example, treatment of oxazoline 20 with -BuLi followed by addition of ethylene oxide and chlorotrimethylsilane yields silyl ether 21. A second metalation/alkylation followed by acidic hydrolysis provides chiral lactone 22 in 54% yield and 86% ee. A similar... 

Chiral oxazolines have also been utilized for the synthesis of ehiral ketones bearing quaternary earbon stereoeenters. As shown below, reaetion of substituted oxazoline 30 with 2 equiv PhLi followed by treatment with benzyl bromide gives ketone 33 upon aeidie hydrolysis. This reaetion is believed to proeeed via addition of PhLi to keteneimine 31 to afford metalated enamine 32, whieh undergoes alkylation at the nueleophilie earbon to provide 33 after aqueous workup. ... 

P-amino acid products. Treatment of oxazoline 53 with 7V-lithiopiperidine followed by alkylation with iodomethane affords aniline derivative 54 in 94% yield and 99% de. Hydrolysis of the oxazoline group provided amino acid 55 in 92% yield and >99% ee. 

The sesquiterpenoid hydrocarbons (5)-a-curcumene (59) and (5)-xanthorrhizol (60) were prepared by asymmetric conjugate addition of the appropriate aryllithium reagent to unsaturated oxazoline 56 to afford alcohols 57 (66% yield, 96% ee) and 58 (57% yield, 96% ee) upon hydrolysis and reduction. The chiral alcohols were subsequently converted to the desired natural products. ... 

When the reaction is run with potassium fert-butoxide in THF at -5°C, one obtains (after hydrolysis) the normal Knoevenagel product (32), except that the isocyano group has been hydrated (16-65). With the same base but with DME as solvent the product is the nitrile (33). When the ketone is treated with 31 and thallium(I) ethoxide in a 4 1 mixture of absolute ethanol and DME at room temperature, the product is a 4-ethoxy-2-oxazoline (34). Since 33 can be hydrolyzed to a carboxylic acid and 34 to an a-hydroxy aldehyde, this versatile reaction provides a means for achieving the conversion of RCOR to RCHR COOH, RCHR CN, or RCR (OH)CHO. The conversions to RCHR COOH and to RCHR CN have also been carried out with certain aldehydes (R = H). 

In this aforementioned Heine reaction the initial ring opening takes place by iodide ions. Subsequent ring closure by S 2 displacement of iodide by reaction with the negative oxygen center then leads to the products. This process proceeds with double inversion at the same carbon atom, thus with net retention. Hydrolysis of these oxazolines gives j9-hydroxy-a-amino acids (Scheme 31) [1,38]. The stereochemical course of ring expansion is the same as that observed in Scheme 29. 

Diethylaluminum cyanide mediates conjugate addition of cyanide to a, (3-unsaturated oxazolines. With a chiral oxazoline, 30-50% diastereomeric excess can be achieved. Hydrolysis gives partially resolved a-substituted succinic acids. The rather low enantioselectivity presumably reflects the small size of the cyanide ion. 

Symmetric triblock copolymers of the ABA type, where B was PTHF and A poly(2-methyl-2-oxazoline), PMeOx, were prepared by cationic polymerization with trifluoromethanesulfonic anhydride as a difunctional initiator [58]. Subsequent hydrolysis of the PMeOx blocks with HC1 in a methanol/ water mixture resulted in the formation of the corresponding polyethylen-imine blocks (Scheme 20). Samples with relatively low molecular weight distributions were obtained. 

The oxazoline methodology can be applied in the total synthesis of natural products. For example, in the course of the total synthesis of European pine-saw fly pheromone 47, the key intermediate, chiral a-methyl carboxylic acid 46, was prepared via the reaction of a-lithioethyloxazoline with n-octyl iodide. The product 2-methyl decanoic acid 46 was obtained, after hydrolysis, in 72% ee (Scheme 2-26).51... 

In a similar fashion, the cationic polymerization of 2-oxazolines has been extensively studied and was found to provide the first verified entry to linear-poly(alkyleneimine) architectures. These acylated polymers were first recognized as precursors to linear poly(ethyleneimines) in the early 1960s [25]. Hydrolysis experiments demonstrated that deacylation of these products to linear PEI was possible. The original polymerization mechanism proposed by Tomalia et al. 

FIGURE 6.5 Transfer of acyl between the amino and hydroxyl groups of seryl. (A) Deprotonation of O-acylseryl- induces oxazolidine formation, which is followed by (B) rearrangement to A-acylseryl-. (C) Protonation of the carbonyl of A-acylseryl- by mineral acid results in dehydration to the oxazoline, which is followed by hydrolysis (D) at the double bond giving protonated O-acylseryl-. 

Since ketone R)-16 was prepared in a non-selective way when an achiral imino enolate was alkylated, it was considered whether alkylation of chiral enolates, such as that of oxazoline 18, with benzyl bromide 14, would provide stereoselective access to the corresponding alkylation product 19 with R-configuration at C(8) (Scheme 4). Indeed, alkylation of 18 with 14 gave the biaryl 19 and its diastereoisomer almost quantitatively, in a 14 1 ratio. However, reductive hydrolysis using the sequence 1. MeOTf, 2. NaBH4, and 3. H30", afforded hydroxy aldehyde 20 in 25% yield at best. Furthermore, partial epimerization at C(8) occurred (dr 7.7 1). An alternative route, using chiral hydrazones, was even less successful. 

Upon warming, these oxazolinyl-stabilized lithiooxiranes undergo an electrocyclic a-ring opening to give a-oxo-2-oxazolines after hydrolysis (Scheme 87). However, all attempts to quench the presumed oxazolidine enolate intermediates through reaction with electrophiles failed. 

A common strategy to invert the stereochemistry at the hydroxyl bearing carbon of an amino alcohol involves oxazoline formation with inversion followed by hydrolysis. This strategy has been applied to Taxol resulting in a practical semisynthesis of 2 -epi-Taxol 44 from Taxol 42 (Scheme 8.17). ... 

Kang and co-workers prepared the (3-halo amide arrangement required for oxazoline formation from allylic alcohols via a two-step process. For example, treatment of the allylic alcohol 122 with trichloroacetonitrile and base followed by activation of the double bond with iodine monochloride, provides 123. Hydrolysis of 123 gave 124 from which cyclization provided the oxazoline 18a used for paclitaxel synthesis (Scheme 8.36). 

Hydrolysis is undoubtedly the most common nucleophilic reaction at the 2-position. It is generally used to unmask the hydroxy amide or amino alcohol after synthetic manipulations on the oxazoline ring are completed. Hydrolysis under... 

Strongly acidic conditions gives the amino alcohol. However, the reaction can be stopped at an intermediate stage if it is carried out under mild conditions. For example, the initially formed amino ester can be isolated or trapped in certain cases although it is more commonly rearranged to the hydroxy amide, typically under mildly basic conditions (Schemes 8.88 and 8.89). The configuration of the oxazoline at the 4 and 5-positions is normally retained under the hydrolysis... 

Partial hydrolysis of an oxazoline to produce the hydroxy amide was used extensively in the synthesis of Taxol analogues (Table 8.24 Scheme It is noteworthy that a solution of the amino... 

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