4- alkyl-2-oxazoline-4-carboxylates

Alkyl oxazoline-5-carboxylates 71, precursors of P-amino-a-hydroxycarboxylic acids, have been produced by iodocyclisation of alkyl 3-benzamidocatboxylates 70. The oxazolines can be resolved enzymatically <99SL1727>. The amides 72 are cyclised to N-aryloxazolium salts 73 by fluoroboric acid <99EJ0297>. 

It is generally true that restrictions on conformational mobility minimize the number of competing transition states and simplify analysis of the factors that affect selectivity. Chelation of a metal by a heteroatom often provides such restriction and also often places the stereocenter of a chiral auxiliary in close proximity to the a-carbon of an enolate. This proximity often results in very high levels of asymmetric induction. A number of auxiliaries have been developed for the asymmetric alkylation of carboxylic acid derivatives using chelate-enforced intraannular asymmetric induction. The first practical method for asymmetric alkylation of carboxylic acid derivitives utilized oxazolines and was developed by the Meyers group in the 1970 s (Scheme 3.16a), whose efforts established the importance and potential for chelation-induced rigidity in asymmetric induction (reviews [77-79]). In 1980, Sonnet [80] and Evans [81,82] independently reported that the dianions of prolinol amides afford more highly selective asymmetric alkylations (Scheme 3.16b). 

In readily available (see p. 22f.) cyclic imidoesters (e.g. 2-oxazolines) the ot-carbon atom, is metallated by LDA or butyllithium. The heterocycle may be regarded as a masked formyl or carboxyl group (see p. 22f.), and the alkyl substituent represents the carbon chain. The lithium ion is mainly localized on the nitrogen. Suitable chiral oxazolines form chiral chelates with the lithium ion, which are stable at —78°C (A.I. Meyers, 1976 see p. 22f.). 

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. ... 

Oxazolines have also been obtained from aziridines and carboxylic imidazolides via iV-acylaziridinesJ1271 Isomerization of the Af-acylaziridines can be achieved by heating with a catalytic amount of tetrabutylammonium iodide or bromide. The transformation can be carried out as a one-pot reaction in quantitative yield (solvents THF, CHC13, benzene) with a wide spectrum of substituents R (R = H, alkyl, c-C6Hi i, C6H5,3-pyridyl). 

The amide derived from the carboxylic acid in Ugi adducts is in most cases tertiary, and therefore it cannot serve as nucleophilic partner in post-condensation transformations, unless a post-Ugi rearrangement converts it into a free amine [52, 54]. An exception is represented by Ugi adducts derived from ammonia, which give rise to two secondary amides, each of them potentially involved, as nucleophile, in nucleophilic substitution processes. Four competitive pathways are in principle possible (N- or 0-alkylations of the two amides), and the reaction is mainly driven by the stability of the formed rings. In the example shown in Fig. 12, 0-alkylation of the carboxylic-derived amide is favoured as it generates a 5-membered ring (oxazoline 62), while the alternative cyclization modes would have formed 3- or 4-membered rings [49]. When R C02H is phthalic acid, however, acylaziridines are formed instead via Walkylation [49]. In both cases, the intramolecular 8 2 reactions takes place directly under the Ugi conditions. 

A procedure for enantioselective synthesis of carboxylic acids is based on sequential alkylation of the oxazoline 8 via its lithium salt. Chelation by the methoxy group leads preferentially to the transition state in which the lithium is located as shown. The lithium acts as a Lewis acid in directing the approach of the alkyl halide. This is reinforced by a steric effect from the phenyl substituent. As a result, alkylation occurs predominantly from the lower face of the anion. The sequence in which the groups R and R are introduced... 

First of all a 2-substituted oxazoline (1) is formed by cyclocondensation of a carboxylic acid ester with 2-aminoethanol and a small amount of (1) is converted with an alkylating agent (e.g., methyl tosylate) to the activated, ionic form (2). 

Chiral oxazolines have been used in the chiral-selective assembly of carboxylic acids and lactones. The chiral oxazoline (407) was prepared using a commercially available chiral aminodiol. Metallation at -78 °C gave a lithiooxazoline which was alkylated with a variety of alkyl halides to afford on acid hydrolysis a-alkylalkanoic acids (409) of the (S)-configuration (72-82% e.e.). The methoxyamino alcohol released during the hydrolysis could be recycled to produce again the chiral oxazoline (Scheme 91) (79PAC1255). 

The group of Jew and Park successfully utilized dihydrocinchonidine-derived 6f as an efficient catalyst for the asymmetric alkylation of o-biphenyl-2-oxazoline- and o-biphenyl-2-thiazoline-4-carboxylic acid tert-butyl esters (16a and 16b) under mild solid-liquid phase-transfer conditions (Scheme 2.13) [32,33]. These reactions are... 

Oxazolines, 2-alkyl-, to protect hydroxyl and carbonyl groups in carboxyl groups, 265-266... 

The chiral ferrocenylphosphine.gold(I)-catalyzed aldol reaction of a-alkyl a-isocya-nocarboxylates 92 with paraformaldehyde gives optically active 4-alkyl-2-oxazoline-4-carboxylates 93 with moderate to good enantioselectivity [46], The absolute configuration (S) of the product indicates that the reaction occurs selectively at the si face of the enolate as illustrated in Fig. 2. These oxazolines 93 can be converted into a-alkyl-serine derivatives 94 (Sch. 24). 

Oxazolines 175 and 176 are thus synthons for carboxylic acids this is another indirect method for the oc alkylation of a carboxylic acid, " representing an alternative to the malonic ester synthesis (10-67) and to 10-70 and 10-73. The method can be adapted to the preparation of optically active carboxylic acids by the use of a chiral reagent. Note that, unlike 170, 175 can be alkylated even if R is alkyl. However, the C=N bond of 175 and 176 cannot be effectively reduced, so that aldehyde synthesis is not feasible here. 

Carboxylic acids and esters frequently must be protected against the attack of organometallic reagents, e.g. metal alkyls and hydrides, and reducing agents like LiAlH. For this purpose they usually are converted to orthoesters, oxazolines or oxazoles. 

Oxazolines (75) may be formed from carboxylic acids by condensation with either 2-amino alcohols or aziridines (Scheme 74). They are stable to Grignard reagents and to L1A1H4 and are cleaved either by acid-catalyzed hydrolysis or dcoholysis. A disadvantage of the oxazolines is that they retain reactivity towards alkylating reagents. On the other hand, this forms the basis for an alternative deprotection in the presence of acid sensitive structures. After methylation the oxazolines can be hydrolyzed to the free acids with 2 M NaOH (94% yield). ... 

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