Oxazoline moieties

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. ... 

Andersson et al. [15,16] (and simultaneously Knight et al. [17]) studied the effect of the length and structure of the bridge between the two oxazoline moieties. They prepared and tested a new class of bis(oxazolines) in which... 

Both the benzylic C-O and the C-N bonds were cleaved during the synthesis of (4)-lactacystin. The hydrogenolysis of the oxazoline moiety on Pd/C, Pd(OH2)/C, or Pd black in MeOH proved unsuccessful, but catalytic transfer... 

In catalytic enantioselective Diels-Alder reactions, Mg11 catalysts bearing chiral auxiliaries, such as chiral bidentate ligands containing oxazoline moieties,27-29 chiral diamines,30 and... 

Sammakia and Stangeland112 reported another type of chiral ligand 119 bearing a chiral oxazoline moiety and tested its asymmetric induction capability in transfer hydrogenation. As shown in Scheme 6-51, 90% or higher ee values were observed in all cases, along with high conversion of the substrates. 

As shown in Scheme 8-11, nucleophilic entry from the a-face (24a) may be hindered by the sterically bulky substituent R2 on the oxazoline moiety therefore entry from the / -face 24/ predominates. Free rotation of the magnesium methoxy bromide may be responsible for the sense of the axial chirality formed in the biaryl product. If the azaenolate intermediate 25 is re-aromatized with a 2 -methoxy substituent complexed to Mg, (iS )-biphenyl product is obtained. Upon re-aromatization of azaenolate 25B, (R)-product is obtained. 

However, this strategy failed when applied to the synthesis of the cyclopeptide lissoclinamide 7. Here, the serine-derived oxazoline moiety could not be selectively thiolyzed in the presence of the threonine-derived oxazoline in the cyclopeptide 334. " The authors attributed this lack of chemoselectivity to the increased stability and thus reduced reactivity, of the serine-derived oxazoline in the macrocyclic scaffold. AU three oxazoline moieties reacted under the prolonged reaction conditions to give the trithio cyclopeptide 335 (Scheme 8.102). The structure of 335 was confirmed by conversion to the tristhiazoline cyclopeptide 336. 

Only one example has been reported in which an acyclic amine was alkylated with this method32. Using the oxazoline derivative of Af-methylbenzeneamine, deprotonation, subsequent alkylation with iodomethane at — 78 °C and removal of the oxazoline moiety afforded the 7 -confi-gurated a-methylbenzenamine in high yield (95%) with a selectivity of 64% ee. This value is nearly the same as that obtained on reaction of the tetrahydroisoquinoline derivatives at that temperature. Thus, as in the case of methanimidamides, no conclusions concerning the effectiv-ity of this approach in acyclic stereoselection can be drawn at present. 

As described above, the phosphorus atom generally plays an important role for the stereoselection in the allylic alkylation. However, other types of chelating compotmds not having phosphorus are also revealed to work as effective chiral ligands. Some N-S chelating ligands 99-103 bearing an oxazoline moiety provide an excellent enantioselectivity... 

The trialkylstannyl derivatives of furane are also frequently employed in Stille coupling. This reaction was utilised, for example, to introduce a chiral oxazoline moiety onto the furane core through the coupling of 2-trimethylstannylfurane and chiral 2-bromooxazoline derivatives (6.30.)40 The furylstannane can be conveniently prepared in a lithiation-stannylation sequence, which makes it an attractive reagent for the introduction of the 2-furyl moiety. 

Ring closure of a 2-methoxyphenyl derivative of propanol to a chroman has also been achieved. Treatment of the aryloxazoline (259) with sodium hydride yielded the chroman (260) (81JOC783). The intramolecular nucleophilic displacement of the o-methoxy group is promoted through oxazoline activation and proceeds through an addition-elimination sequence. The initial attack involves coordination of the metal alkoxide to both the oxazoline moiety and the methoxy group, and aromatization follows with displacement of methoxide ion (Scheme 67). Hydrolysis of the oxazoline moiety to a carboxyl group has been accomplished. 

A modification of Meyer s oxazoline-facilitated methoxy substitution by organometallic reagents has been used to synthesize a biphenyl precursor of cannabinol. A one-pot hydrolysis of the oxazoline moiety, ether cleavage and cyclization yielded the lactone. Cannabinol resulted from the subsequent reaction with methylmagnesium iodide (Scheme 78) (82TL253). 

The nature of the /V-subsiiiuen1 of the aziridine moiety has been found to play an important role in the deprotonation reaction of oxazolinylaziridines.16 An electron-donating group appeared to be the /V-subsiilucnt of choice when the oxazoline moiety has a cis relationship with respect to the proton to be removed. The high stability of the resulting aziridinyllithium may be due to the coordinative effect of the oxazoline ring. 

Finally, homopolymers of bis(oxazoline) ligands have been used to prepare efficient catalysts for cyclopropanation reactions. However, the reduced accessibility to most of the bis(oxazoline) moieties along with the high substitutional lability of copper(I)/(II) leads to a low degree of metal loading. As a consequence, the transmission of chiral information from the metallated polymer is inefficient. The use of suitable dendrimers as cross-linkers in the polymerization process allows a higher level of metallation. 

The use of co-(2-bromophenyl)alkyl-2-oxazolines (13) in base-promoted ring-closure reactions provides a good access to 1-phenyl-indane and 1-phenyl-tetralin derivatives (14) that contain easily manipulated oxazoline moieties. Satisfactory isolated yields of cyclized products 14 are obtained with lithium diisopropylamide (LDA) in THF at room temperature under irradiation with UV light, even when quaternary centers are formed (Scheme 10.39) [55]. The yield of 14 (n= 1, R= Ph) increases to 75% when the reaction proceeds under laboratory light for 48 h at room temperature. 

The addition of carbonylated electrophiles to the 2-lithio derivative of 4-oxazolinyloxazole 132 allowed the efficient preparation of 5-phenyloxazoles 134 bearing a variety of hydroxyalkyl groups at C-2 position and a carboxyl (or formyl) function at C-4. This protocol suppresses the troublesome electrocyclic ring-opening reaction and allows access to the target compounds by simple chemical transformation of the oxazoline moiety of 133 <02JOC3601>. A direct chemoselective C-2 silylation of oxazoles was performed by treatment of the lithiated parent compounds with silyl triflates <02TL935>. 

Acyclic and cyclic ketals derived from aromatic aldehydes have been deprotonated with n-BuLi (4 h) at —45 °C or LDA (24 h) at —45 °C to room temperature, and the corresponding organolithiums 445 and 446 deuteriated with MeOD655,656. 2-Aryl acetal anions show a great tendency to rearrange and/or fragment657 when they bear the electron-withdrawing oxazoline moiety at the para-position. 

Chiral bis(oxazolines) 51 with an oxalylic acid backbone were used for the Ru-catalyzed enantioselective epoxidation of tran5-stilbene yielding franx-l,2-diphenyloxirane in up to 69% ee [24]. The asymmetric addition of diethylzinc to several aldehydes has been examined with ferrocene-based oxazoline ligand 52 [25], resulting in optical yields from 78-93% ec. The imide 53 derived from Kemp s triacid containing a chiral oxazoline moiety was used for the asymmetric protonation of prochiral enolates [26]. Starting from racemic cyclopentanone- and cyclohexanone derivatives, the enantioenriched isomers were obtained in 77-98 % ee. 

Alkylation of this oxazoline is accomplished by metalation with Lithium Diisopmpylamide followed by adding a premixed solution of the electrophile and 2 equiv of HMPA (eq 8). Hydrolysis of the oxazoline moiety affords the enantioenriched 2-chloroalkanoic acids, albeit with low optical purity. ... 

Fujita M, Shoda S, Haneda K, Inazu T, Takegawa K, Yamamoto K. A novel disaccharide substrate having 1,2-oxazoline moiety for detection of transglycosylating activity of endogly-cosidases. Biochim. Biophys. Acta. 2001 1528 9-14. 

---