Oxazoline rings synthesis

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 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). 

In a recent modification of the second synthesis (50S) effected for fluvibactin (45) an o-xylene protection group was proposed (reaction of 2,3-dihydroxy-benzoic acid methyl ester with 1,2-di(bromomethyl)benzene) which could be removed later by hydrogenolysis. The formation of the oxazoline ring from protected DHB-L-threonine methyl ester was achieved with Mo(VI) catalysts (e.g. (NH4)2Mo04) without affecting the chiral centers. Derivatization of the primary amino groups of norspermidine with the protected DHB methyl ester was catalyzed by Sb(OC2115)3. 

Here, we will mention synthetic methods that are of general application. Because oxazolines are so often used as intermediates in synthesis, it is impossible to include every oxazoline that has been prepared. Instead, we will illustrate with examples the diversity of structures wherein the oxazoline ring structure is first constructed. 

Scheme 26 Synthesis of [3-Phenylcysteine by Oxazoline Ring Opening11 1...

In another synthesis of quinolines involving imine intermediates, o-oxazoline-substi-tuted anilines (6) react with ketones in dry butanol reflux to give 4-amino-substituted quinolines [e.g. (7)], or 4-quinolones, using tosic acid as catalyst.18 A mechanism involving ketoimine formation with subsequent tautomerization to give an enamine which attacks the oxazoline ring is discussed. 

The next phase of the synthesis was installation of the dimethylamino-oxazoline ring system. This was constructed from the oxazolidinone precursor 19. Oxazolidinone formation occurred when 25 was reacted with thionyl chloride. The more nucleophilic carbonyl of 19 was then O-alkylated with the Meerwein reagent to give an iminium ion that readily participated in a nucleophilic addition/elimination reaction with dime-thylamine to give 26. The final step of the synthesis was O-deacetylation of 26 with sodium methoxide to provide (—)-allosamizoline hydrochloride in 98% yield after acidification. 

Ferrocenoyl chloride (318), ethyl ferrocenecarboxylate (319), and cyanoferrocene (320) are all used as starting materials for the synthesis of 2-ferrocenyloxazolines (321) (Scheme 87). Chirality may be incorporated into the oxazoline ring, and these important chiral compounds have been used to prepare a great number of ferrocene derivatives that are used as catalysts in asymmetric synthesis." " ... 

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). 

Synthesis from n-threose A synthesis of (-)-slaframine (1) has been reported from the 3-deoxy-D-threose derivative 2 by reaction with the chiral ylide 4, obtained from 3, in the presence of KN(TMS)2 to produce 5 in 89% yield (Scheme 1). Subsequent tosylation followed by opening of the oxazoline ring by reduction afforded the alcohol... 

Reaction of furyllithium (60) with L-threonine derived lithium salt 61 afforded the expected ketone 62 in 30% yield. Reduction of 62, using lithium aluminium hydride, gave two alcohols (63 and 64) in a 3 1 ratio. In both carbinols (63 and 64) the oxazoline ring was opened by acid hydrolysis to give the N-benzoyl derivatives 65 and 66, respectively. Alcohol 66 can be used in the synthesis of lincosamine enantiomer, but unfortunately this approach has limited preparative value because of the low yield obtained in the condensation step and, on the other hand, opposite diasteroselectivity obtained in the reduction reaction. 

In a series of reports Gennari et al. demonstrated the synthesis of taxol side chain thioesters protected as oxazolines and oxazolidines. Thus reaction of the enolate of thioester 8.1.8 and TMS-imine 8.1.9 in the presence of chiral borate 8.1.10 gave the side chain thioester 8.1.11 in 60% yield. Compound 8.1.11 was then protected as its acetonide 8.1.12. The oxazoline analog 8.1.13 was synthesized by a similar strategy with an inversion to achieve the desired stereochemistry at C-2 during the formation of the oxazoline ring (299). 

In the polymer synthesis, bisamino-alcohols and phenylene di-isothiocyanates (SCN—R —NCS) yield polythioureas (185) which are ring-closed to the polythiazolines (186) by polyphosphoric acid. The use of other cyclizing reagents is liable to produce polymers containing both thiazoline and the more readily hydrolysable oxazoline rings in the main chain. ... 

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