Oxazolines, alkylation hydrolysis

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. ... 

Variations and Improvements on Alkylations of Chiral OxazoUnes Metalated chiral oxazolines can be trapped with a variety of different electrophiles including alkyl halides, aldehydes,and epoxides to afford useful products. For example, treatment of oxazoline 20 with -BuLi followed by addition of ethylene oxide and chlorotrimethylsilane yields silyl ether 21. A second metalation/alkylation followed by acidic hydrolysis provides chiral lactone 22 in 54% yield and 86% ee. A similar... 

Chiral oxazolines have also been utilized for the synthesis of ehiral ketones bearing quaternary earbon stereoeenters. As shown below, reaetion of substituted oxazoline 30 with 2 equiv PhLi followed by treatment with benzyl bromide gives ketone 33 upon aeidie hydrolysis. This reaetion is believed to proeeed via addition of PhLi to keteneimine 31 to afford metalated enamine 32, whieh undergoes alkylation at the nueleophilie earbon to provide 33 after aqueous workup. ... 

P-amino acid products. Treatment of oxazoline 53 with 7V-lithiopiperidine followed by alkylation with iodomethane affords aniline derivative 54 in 94% yield and 99% de. Hydrolysis of the oxazoline group provided amino acid 55 in 92% yield and >99% ee. 

Since ketone R)-16 was prepared in a non-selective way when an achiral imino enolate was alkylated, it was considered whether alkylation of chiral enolates, such as that of oxazoline 18, with benzyl bromide 14, would provide stereoselective access to the corresponding alkylation product 19 with R-configuration at C(8) (Scheme 4). Indeed, alkylation of 18 with 14 gave the biaryl 19 and its diastereoisomer almost quantitatively, in a 14 1 ratio. However, reductive hydrolysis using the sequence 1. MeOTf, 2. NaBH4, and 3. H30", afforded hydroxy aldehyde 20 in 25% yield at best. Furthermore, partial epimerization at C(8) occurred (dr 7.7 1). An alternative route, using chiral hydrazones, was even less successful. 

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). 

A similar asymmetric addition occurs in the case of chiral a,P-unsaturated oxazolines, and yields chiral dialkylpropanoic acids after hydrolysis (Scheme 108).382-384 A different type of reaction of chiral oxazolines leads to both chiral dialkylpropanoic acids and chiral dialkylacetic acids. In this case the chelated lithium oxazoline derivative is alkylated stereospecifically, as a consequence of the metalloenamine reactivity and the chelate geometry. 

The efficient phase-transfer-catalyzed alkylation strategy with le was successfully applied by Jew and Park to the asymmetric synthesis of a-alkyl serines, using phenyl oxazoline derivative 53 as a requisite substrate [28]. The reaction is general, however, and provides a practical access to a variety of optically active a-alkyl serines through acidic hydrolysis of 54 (Scheme 5.26). 

The Ugi group has designed a new class of convertible isocyanides, namely alkyl 2-isocyano-2-methylpropyl carbonates [7], prepared from commercially available 4,4-dimethyl-2-oxazoline. The Ugi-4CR of 11 afforded the expected products 12, which were converted into N-acyl a-amino acid esters 13 and N-acyl a-amino acids by in situ hydrolysis (Scheme 2.5) [7]. 

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. ... 

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). ... 

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... 

Meyers and coworkers [169, 253, 324] have proposed the use of oxazolines 1.86 (Y = RCH2). The deprotonation of these oxazolines by LDA at -90°C gives a chelated lithium azaenolate 5.29, whose upper face is shielded by the phenyl substituent Alkylation takes place at -78°C on the open face and, after acidic hydrolysis, the corresponding chiral acids are obtained with good enantiomeric excesses if R = Me, Et, -Bu or PhCH2. Lower ee s are observed if R = OMe or Cl (Figure 5.20). 

Methyl-l-phenylisoquinoline (380) is obtained when the oxazoline (379) is heated with phosphorus pentoxide. An efficient synthesis of alkylated and dialkylated acetic acids consists in the alkylation of 4,5-dihydro-oxazoline bound to polystyrene, followed by hydrolysis." The asymmetric synthesis of a series of a-alkylphenylacetic acids C H2 +i CHPhC02H ( = 1-5) from the chiral oxazoline (381) has been described. Another example of the use of oxazolines for asymmetric synthesis is the preparation of the optically active binaphthyl (383) from 1-lithionaphthalene and compound [382 R = (—)-menthyl]. The stereoselective formation of threo-dXdoX products (385 = Et, Pr, n-pentyl, etc from the chiral boron compound... 

In 1982, Evans reported that the alkylation of oxazolidinone imides appeared to be superior to either oxazolines or prolinol amides from a practical standpoint, since they are significantly easier to cleave [83]. As shown in Scheme 3.17, enolate formation is at least 99% stereoselective for the Z(0)-enolate, which is chelated to the oxazolidinone carbonyl oxygen as shown. From this intermediate, approach of the electrophile is favored from the Si face to give the monoalkylated acyl oxazolidinone as shown. Table 3.6 lists several examples of this process. As can be seen from the last entry in the table, alkylation with unactivated alkyl halides is less efficient, and this low nucleophilicity is the primary weakness of this method. Following alkylation, the chiral auxiliary may be removed by lithium hydroxide or hydroperoxide hydrolysis [84], lithium benzyloxide transesterification, or LAH reduction [85]. Evans has used this methology in several total syntheses. One of the earliest was the Prelog-Djerassi lactone [86] and one of the more recent is ionomycin [87] (Figure 3.8). 

Groups other than a carbonyl can stabilize a carbanion. Meyers described the preparation of a-lithio derivatives of dihydro-1,3-oxazines (282) and 2-oxazolines (284) and their use in alkylation and condensation reactions via a-lithio derivatives such as (283). Meyers treated the commercially available 285 with n-butyl-lithium to form the a-lithio derivative (286), stabilized by chelation with the nitrogen. When iodomethane was added, a carbanion displacement reaction occurred to give 287.The imine unit in 287 was reduced with borohydride (sec. 4.4.A) to give amine 288, and hydrolysis produced the aldehyde (in this case propanal). 

Diastereoselectivity is also observed in reactions of carbanions derived from imines and hydrazones, when those species contain a chiral center or a chiral auxiliary (sec. 9.4.F). Asymmetric imines can be used, and chiral oxazoline derivatives have also been prepared and used in the alkylation sequence (sec. 9.3.A). Meyers showed that chiral oxazoline 478 could be alkylated to give the ethyl derivative, 479. A second alkylation generated the diastereomeric product 480, and hydrolysis provided the chiral lactone (481) in 58% yield and with a selectivity of 70% ee for the (R) enantiomer. 53 As pointed out in Section 9.4.F.ii, hydrazone carbanions can be used for alkylation or condensation reactions. In a synthesis of laurencin. Holmes -l prepared the asymmetric hydrazone 483 (prepared by Enders by reaction of cycloheptanone and the chiral hydrazine derivative called SAMP, 482-A-amino-(2S)-(methoxymethyl)pyrrolidine)- - and showed that treatment with LDA and reaction with iodomethane gave an 87% yield of the 2-ethyl derivative in >96% de. Ozonolysis cleaved the SAMP group to give (/ )-2-ethylcycloheptane (484) in 69% yield. The enantiomer of 482 is also known (it is called RAMP, A-amino-(27 )-(methoxymethyl)pyrrolidine). 

As imido esters, dihydro-1,3-oxazines of type 14 display reactivity similar to 2-oxazolines (see p 135). The a-C-H bonds of the 2-alkyl group are CH-acidic. They are metalated by reaction with butyllithium and then undergo C-C forming reactions with electrophiles such as haloalkanes, oxiranes or carbonyl compounds. The dihydro-1,3-oxazines 16, which are obtained from 15 by a-metalation and alkylation, undergo reduction with NaBH4 forming 17. Acid hydrolysis cleaves the cyclic aminal function of 17 yielding aldehydes 18 ... 

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