Oxazolines auxiliaries

In removing the oxazoline auxiliary from the products, Richards and coworkers have demonstrated the use of the diastereoselective ferrocenyloxazoline lithiation in the synthesis of conformationally constrained amino acid derivatives (Scheme 146) °. Amination of 305 was achieved by nitration, reducing to the amino group after removal of the oxazoline under standard conditions. Using the trick of silylating the more reactive diastereotopic site, it was possible to make either enantiomer of 321 from the same oxazoline starting material. 

Gawley and coworkers showed that oxazolines can be used in place of formamidines for asymmetric alkylations of tetrahydroisoquinolines. A number of substituted oxazolines were evaluated as chiral auxiliaries, and one derived from valinol was found to be optimal. Interestingly, the same enantiomer of valinol affords the opposite enantiomers of the substituted tetrahydroisoquinoline when incorporated into formamidine or oxazoline auxiliaries. An example is shown in Scheme 58, as applied to a synthesis of laudanosine and the morphinan 9-7 -0-methylflavinantine. ° ... 

An oxazoline auxiliary has been used to alkylate stereoselectively and regioselectively isoindoline at the a- and a -positions to produce the C2-symmetric amine (12), as shown in Scheme 23. ... 

When hydrogen bonds can be formed between 2 and hydroxylic solvents such as CD3OD, the selectivity dropped considerably, as expected [119]. The [4 + 2] cycloaddition of 2 can also be highly diastereoselective with aliphatic dienes. With sorbic acid derivatives 194 having a removable chiral 2,2-dimethyl-oxazoline auxiliary, 195 was isolated with an almost perfect stereocontrol during the addition process (Scheme 51) [120],... 

The combination of a hindered oxazoline auxiliary, Pd(OAc)2, h, and PhI(OAc)2 was shown to be a powerful protocol for the selective catalytic and asymmetric iodination of unactivated C-H bonds of methyl, cyclopropyl, and aryl groups for instance, compounds 152, 154, and 156 were easily converted under mild conditions into iodo derivatives 153,155, and 157 in good yields and excellent diastereoselectivity <05AG(E)2112>. 

Scheme 3.31. Mechanism for asymmetric alkylation of a tetrahydro-isoquinoline using an oxazoline auxiliary [192].

In 1989. Kelly Rein began an investigation into the use of an oxazoline chiral auxiliary to elfect diastereosclcctive additions of Grignard reagents based tin the Scebach discovery. The initial effort 46 used an oxazoline auxiliary derived front valine ( laltle 5.3. entry 5), one that we had used previously in studies of asymmetric alkylations ol... 

She then developed a successful approach using the valine-derived oxazoline auxiliary (.V-4-iso-propyloxazolinc Table 5.3. entries 5-8) 46.67. Later, Pingsheng Zhang optimized the process with a better auxiliary as indicated by the examples in... 

The main limitation of the acetal methodology is competitive benzylic deprotonation and low efficiency of the acetal removal. Blocking the benzylic position with a methyl group was reported [85]. Aminals can be removed easily but the lithiation was shown to generate significant amounts of meta and para substitution [32,47]. An oxazolidine auxiliary (in 43), on the other hand, gave quantitative conversions to ort/zo-substituted products diastereospecifically [47]. Removal of this auxiliary was not reported, however. Oxazoline auxiliary was also used [126]. 

In 2005, Yu and co-workers reported an oxazoline auxiliary approach for the chemo- and diastereoselective iodination reactions of C—H bonds of methyl, cyclopropyl, and aryl groups under mild conditions (Table 5.1). These oxazoline substrates can be readily prepared from their corresponding carboxylic... 

In 2007, Xia and You realized the synthesis of planar chiral ferrocene derivatives by utilizing the chiral oxazoline auxiliary strategy. As shown in Scheme 5.3, the planar chiral ferrocene derivative (S,Pp)-5 was obtained as a single... 

The Meyers oxazoline auxiliary provides an efficient means of performing Michael addition to prochiral alkenes with excellent diastereofacial selectivity.shown below this allows convenient access to chiral -alkylated acids (83). Note, however, that the facial selectivity is opposite to that observed in the alkylation of oxazoline anions (section 5.3.1). 

One of the most important discoveries made by the natural product chemist Kupchan was the unusual lignan-derived podophyllotoxin, which has clinical applications as a powerful and selective antineoplastic. The problem of synthesising it asymmetrically is solved elegantly using the chiral oxazoline auxiliary (see section 5.4.1). 

Meyers reported one of the first approaches to diastereoselective alkylations of enolates derived from carboxylic acids through the use of optically active amino acid-derived oxazolines [67-69]. As an example, alkylation of 79 with ethyl iodide gave 80 with high stereoinduction (Scheme 3.13) [70]. Subsequent hydrolytic opening and cleavage of the oxazoline auxiliary furnished optically active u-substituted carboxylic acid 81 in 80 % ee. 

Meyers reported an important extension of the method to the asymmetric synthesis of chiral biphenyl derivatives [76]. In this regard, the Grignard reagent derived from aryl bromide 60 underwent addition to oxazoline 61 to furnish chiral biaryl derivative 62 (dr=88 12. Scheme 12.8) [77]. After removal of the oxazoline auxiliary, the chiral biphenyl served as a key intermediate in the total synthesis of the antileukemic lignan steganone (63). 

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