Oxazoline ring

A new chiral proton source (111), based on an asymmetric 2-oxazoline ring, has been found to be capable of effecting asymmetric protonation of simple prochiral metal enolates (112) to give corresponding ketones (113) which need not bear polar groups. 

The synthesis depends on (a) the ease of formation and hydrolysis of 2-oxa-zolines (b) the fact that the a-hydrogens retain their acidity in the oxazoline (Why ) and (c the inertness of the 2-oxazoline ring toward the lithio derivative. (The ring is inert toward the Grignard reagent as well, and can be used to protect the carboxyl group in a wide variety of syntheses.)... 

Heterocyclic intermediates are being used more and more in synthesis as protecting groups, readily generated and, when their job is done, readily removed. We have seen two examples of this the temporary incorporation of the carboxyl group into a 2-oxazoline ring (Sec. 26.6), and the temporary formation of tetrahydropyranyl (THP) esters, resistant toward alkali but extremely easily cleaved by acid (Problem 16, p. 692). 

Our research group independently found a catalytic enantioselective proto-nation of preformed enolate 47 with (S,S)-imide 30 founded on a similar concept (Scheme 5) [51]. The chiral imide 30, which has an asymmetric 2-oxazoline ring and is easily prepared from Kemp s triacid and optically active amino alcohol, is an efficient chiral proton source for asymmetric transformation of simple metal enolates into the corresponding optically active ketones [50]. When the lithium enolate 47 was treated with a stoichiometric amount of the imide 30, (K)-en-riched ketone 48 was produced with 87% ee. By a H-NMR experiment of a mixture of (S,S)-imide 30 and lithium bromide, the chiral imide 30 was found to form a complex rapidly with the lithium salt. We envisaged that a catalytic asym-... 

Aliphatic carboxylic acids and esters.2 The reagent (1) is converted into an anion which is alkylated at the C2-methyl group (2). The 2-oxazoline ring is then hydrolyzed by heating in 5-7% ethanolic sulfuric acid to give the ethyl ester (3). Reaction of the lithio salt of (1) with an aldehyde, followed by hydrolysis, leads... 

Poly(2-oxazoline)s are attractive materials because a wide range of different monomers can be polymerized by living CROP, whereby the polymer properties can be significantly altered by changing the substituent on the 2-position of the 2-oxazoline ring. The importance of this side chain on the resulting polymer properties are evident... 

The overall conversion of alkyl halides (418) into N-substituted acetamides (420) can be achieved by sequential N-alkylation of 2-methyl-2-oxazoline, ring cleavage of the resulting salt using NaSePh and oxidative elimination to give the... 

Without additional reagents 2-Oxazoline ring opening Glycosamimides Change in configuration... 

In these reactions, the formation of imidazoline and oxazoline rings corresponds to the reagent orientation previously observed for ynamines (84ZOR1648) and alkenylynamines (83ZOR926), as well as in their reactions with mononucleophiles such as amines (79ZOR1824 81ZOR1807) and alcohols (80ZOR1141). 

A special influence on the course of a reaction by a neighboring group is shown in the reactions of 5-acetyl-leuco(iso)alloxazines - with diazomethane. The methylation occurs neither in the pyrimidine nor in the pyrazine ring, but on the hydroxyl group of a newly formed oxazoline ring. For example,... 

N-Acylaziridine-2-carboxylates readily rearrange to oxazolines under thennal, acidic, or nucleophilic conditions [91, 123-127]. Treatment of trans-aziridine-2-car-boxylate 176 (Scheme 3.63) with Nal in acetonitrile, for example, resulted in ring-expansion product 177 through the so-called Heine reaction. The reaction involves initial opening of the aziridine ring by iodide and subsequent oxazoline ring-closure by Sn2 displacement of the resultant iodide intermediate [127]. 

A series of chiral phosphinous amides bearing pendant oxazoline rings (50, Ri=H,Tr R2=H,Tr, 51, Ri=H,Tr R2=H,Tr and 54, Ri=H,Tr R2=H,Tr in Scheme 41) have been used as ligands in the copper-catalyzed 1,4-addition of diethylzinc to enones. Two model substrates have been investigated, the cyclic 2-cyclohexenone and the acyclic trans-chalcone. The addition products are obtained quantitatively in up to 67% ee [171]. 

The enantioselectivity is thought to result from both steric blocking by the f-butyl substituent on the oxazoline ring and an attractive van der Waals interaction of an aryl ring and the oxazoline ring, as shown in Figure 5.5. 

The product of the reaction in Entry 8 was used in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxy group is determined by the structure of the oxazoline ring formed in the cycloaddition. Entry 9 portrays the early stages of synthesis of the biologically important molecule biotin. The reaction in Entry 10 was used to establish the carbocyclic skeleton and stereochemistry of a group of toxic indolizidine alkaloids found in dart poisons from frogs. Entry 11 involves generation of a nitrile oxide. Three other stereoisomers are possible. The observed isomer corresponds to approach from the less hindered convex face of the molecule. 

The stereoselectivity of the reaction in Entry 5 is also determined by steric factors. Note also that in this case the oxazoline ring serves to stabilize the anion. 

Disoxaril was shown to bind in a hydrophobic pocket below the a depression referred to as the canyon, with the oxazoline ring in the toe region of the binding pocket. The isoxazole ring resides in the heel below the area designated as the pore (Fig. 3). The nitrogen of the isoxazole... 

Analogues with a seven-carbon chain connecting the phenyl and isoxazole rings, and with a substituent on the oxazoline ring, were bound with the isoxazole ring in the toe of the hydro-phobic pocket. 

The influence of substituents connected to the oxazoline ring on the binding orientation of these molecules was intriguing. Since the carbon to... 

Figure 5 Homologues of WIN52084 illustrating an entaniomeric effect. The asymmetric center on the oxazoline ring is designated by asterisk.

Figure 6 WIN52084 bound to HRV-14. The methyl group on the oxazoline ring is pointing toward a hydrophobic pocket formed by Leu106 and Ser107.

Figure 7 Plot of energy vs torsion angle from an energy profiling study resulting from rotating the oxazoline ring of the 5 isomer of WIN52084 about the phenyl ring.

Wisniewska, A., Y. Nishimoto, J. S. Hyde, A. Kusumi, and W. K. Subczynski. 1996. Depth dependence of the perturbing effect of placing a bulky group (oxazoline ring spin labels) in the membrane on the membrane phase transition. Biochim. Biophys. Acta 1278 68-72. 

A series of analogues of the original PHOX catalyst, in which the phenyl bridge is attached to C(4) instead of C(2) of the oxazoline ring (15, Fig. 29.3), were recently synthesized [14]. These catalysts were used to hydrogenate a number of substrates, including a range of 1-phenylbutenoic acids, with >90% ee. 

Another alkyl-bridged PHOX (18, Fig. 29.6) was recently synthesized [17], and used to hydrogenate a series of substituted methylstilbenes in 75-95% ee, and /1-melhylcinnamic esters in 80-99% ee. The hydrogenation results suggest that the selectivity of these catalysts is mainly derived from the substitution at the stereogenic center on the oxazoline ring, with the other stereocenter having a relatively minor effect on the ee-value. 

The ligand synthesis is straightforward, using amino alcohols as the source of chirality in the oxazoline ring, whereas the stereochemistry in the phospholane ring is controlled by an enantioselective deprotonation using sparteine (Scheme 29.2). 

The first of these was the phosphino-benzoxazine catalyst 27 (Fig. 29.14) [27]. This catalyst contains a six-membered benzoxazine ring in place of the five-membered oxazoline ring in the PHOX catalysts. It was hoped that this change would bring the chiral center on the ring into closer contact with the metal, resulting in higher enantioselectivities. However, enantiomeric excesses were only modest with the substrates chosen. 

Catalyst 58, in which the oxazoline ring has been replaced with an imidazoline, gave ee-values in the low 90% region for substrates 36 and 38-40 [42]. However, for certain substrates (see Section 30.5), replacement of the oxazoline by an imidazoline has resulted in significantly higher enantioselectivity. Recently, a number of pyridine- and quinoline-derived iridium complexes 59-62 have been developed, which gave promising enantioselectivities with substrates 36-39 [43, 44]. However, these catalysts cannot yet compete with the most efficient oxazoline-based complexes and complex 14. 

When a chiral auxiliary is present in the oxazoline ring and the boron part is replaced with an achiral bicyclic system (46 bearing 9-BBN), erythro-j/-hydroxy esters (syn-53) can be obtained as the major product upon reaction of the eno-late with several aldehydes.37... 

It is well recognized that chiral tridentate ligands generally form a deeper chiral cavity around the metal center than a bidentate ligand. For example, as mentioned in previous chapters, the chiral tridentate ligand Pybox 120 has been used in asymmetric aldol reactions (see Section 3.4.3) and asymmetric Diels-Alder reactions (see Section 5.7). The two substituents on the oxazoline rings of 120 form a highly enantioselective chiral environment that can effectively differentiate the prochiral faces of many substrates. 

The PHOX ligands can be varied by changing the substitution at phosphorus, the oxazoline ring, and the bridge and thus a high variety can be made available. They have been applied to many catalytic reactions leading to high ee s with the appropriate substitution pattern. 

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