Evans chiral auxiliaries

The main disadvantages of Evans auxiliaries 22 and 23 are that they are expensive to purchase and inconvenient to prepare, as the preparation involves the reduction of (5 )-valine 24 to water-soluble (b )-valinol, which cannot be readily extracted to the organic phase. The isolation of this water-soluble vali-nol is difficult and requires a high vacuum distillation, which is not always practical, especially on an industrial scale. Therefore, an efficient synthesis of Evans chiral auxiliary 25 has been developed, as depicted in Scheme 2-1930 ... 

S)-4-isopropyl-2-oxazolidinone, 82% Scheme 2-19. Synthesis of Evans chiral auxiliary 25. 

Asymmetric aldol condensation of aldehyde and chiral acyl oxazolidinone, the Evans chiral auxiliary. 

Elsewhere, Faita et al. (438) bound the Evans chiral auxiliary to Wang or Merrifield resin for use as a dipolarophile in cycloadditions with C,N-diphenyl-nitrone. Yields on both resins are significantly reduced in comparison to the solution phase reaction (43-20% compared to 95%) but are unaffected by addition of magnesium perchlorate or scandium triflate catalyst. A one-pot process has been reported by Hinzen and Ley (439) that oxidizes secondary hydroxylamines to the... 

It has been demonstrated that optically active oxetanes can be formed from oxazolidinone 92, a crotonic acid moiety functionalized with Evans chiral auxiliary (Scheme 18) <1997JOC5048>. In this two-step aldol-cyclization sequence, the use of 92 in a deconjugative aldol reaction, with boron enolates and ethanal, led to formation of the syn-aldol 93. This product was then converted to the corresponding oxetanes, 94a and 94b, via a cyclization with iodine and sodium hydrogencarbonate. This reaction sequence was explored with other aldehydes to yield optically active oxetanes in similar yields. Unlike previous experiments using the methyl ester of crotonic acid, in an analogous reaction sequence rather than the oxazolidinone, there was no competing THF formation. 

The first example of a chiral-auxiliary-induced [2+2] cycloaddition between 02 and oxazolidinone-functionalized enecarbamates, which proceeds with complete diastereoselectivity as a result of steric repulsions, has been reported to afford 57 <02JACS8814>. The optically active enecarbamates bearing Evans chiral auxiliary were photooxygenated at -35 °C with 5,10,15,20-tetrakis(pentafluorophenyl)porphine (TPFPP) as sensitizer and an 800 W sodium lamp as light source. The dioxetanes 57 were obtained exclusively, but they readily decomposed at room temperature to the expected carbonyl products because of their thermally labile nature. The absolute configuration of the dioxetanes 57 was established by reduction to the corresponding diols with L-methionine. 

An alternative to the Evans chiral auxiliary described in the chapter is this oxazolidinone, made from natural phenylalanine. What strategy is used for this synthesis and why are die conditions and mechanism of the reactions important ... 

Chiral a-halo esters (72a) and (72b) and a-halo imide (72c) have been prepared in high diastereomeric purity by the use of Oppolzer s chiral auxiliary (71a) and (71b) and Evans chiral auxiliary (71c), respectively. The reactions of (72a), (72b) and (72c) with azide ion proceeded with inversion of configuration (Scheme 30). In the latter reaction, the use of NaNs (DMF or DMSO, 0 C) has been reported to afford 2-5% epimerization. The azides thus prepared were transformed into the corresponding amino acids with high chemical and optical yields. 

Valinol 27 and phenylalaninol 29 are used to make the Evans chiral auxiliaries used in asymmetric aldol reactions (chapter 27) and Evans prefers reduction with borane itself as its complex with Me2S. The phenylalanine based auxiliary 30 is generally preferred as the compounds are more likely to be crystalline and can easily be made11 on a 150 g scale. 

The oxazoline 184 provides an attractive approach to lactacystin as it is a protected form of 3-hydroxyleucine. The other half of the molecule was made in the LeukoSite synthesis by a very different method the alkylation of an Evans chiral auxiliary. This was chosen partly because they wished to vary the alkyl group on the pyrrolidone ring and we use the propyl compound as example. The phenylalanine derived oxazolidinone 193 (chapter 27) was acylated and then the titanium enolate of 194 was alkylated to give 195 with very high selectivity and the chiral auxiliary removed to give the simple acid 196. 

We then achieved the enantioselective synthesis of (IS, 3S,lR)-96 as shown in Figure 4.47,82 Evans chiral auxiliary was attached to acid A, giving B. Methylation of B and subsequent hydrolysis of the product afforded C. Acid C was converted to D. Then, intramolecular Diels-Alder reaction of D furnished E. Methylenation of E with Tebbe reagent yielded the desired (15 ,35, 7/ )-96.82 It was shown definitely that only ( S,3S,lR)-96 is bioactive, while other isomers are inactive.83 It must be added that a-himachalene obtained from Himalayan deodar Cedrus deodara possesses the opposite 1 R,1S configuration. Insects and plants sometimes produce similar compounds with different absolute configuration. 

A recently new designed Wang resin supported Evans chiral auxiliary (52) has been shown to perform Evans asymmetric alkylation on solid support (Scheme 12.19) [34, 35], Preparation of the auxiliary started with coupling of Fmoc-piperidine-4-carboxylic acid to Wang resin. Subsequent removal of the Fmoc protection was followed by coupling to N-protected (2J ,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid. After deprotection, the amino-alcohol moiety was converted into the oxazolidinone auxiliary 52 using carbonyldiimidazole (CDI). 

The immobilized Evans chiral auxiliary 56 has also been employed in asymmetric a-alkylation of resin-bound propionic amide [13, 27]. Reductive cleavage afforded the a-benzylated propanol (2-methyl-3-phenylpropanol). 

To circumvent this problem, a different route to access optically pure a-methyl butyrolactone (65) was attempted using Evans chiral auxiliary chemistry. A-Acylation of oxazolidinone with 4-pentenoyl chloride afforded 70, which was treated with NaHMDS and Mel to give 71... 

An aldol reaction is the addition of an enolate to an electrophile, where the electrophile is an aldehyde or a ketone. You have already seen earlier in this chapter how enolates can be used to make new C-C bonds enantioselectively when we explained how to control enolate alkylation with Evans chiral auxiliaries. Evans auxiliaries also provide one of the most straightforward ways of carrying out asymmetric aldol reactions, and we will start with an example before explaining how asymmetric aldol reactions can be done using catalytic methods. 

Scheme 10.39 Copper-catalyzed carbozincation of substituted cyclopropenes directed by Evans chiral auxiliary [34].

Under similar azide transfer to enolate conditions, the unexpected primary amide that arose from the hydrolysis of the Evans chiral auxiliary was also isolated (eq 25). Double enolization of the bisamide followed by trapping of the dianion with trisyl azide provided the diazido diastereoisomers in 4 1 ratio (eq 26). ... 

The aldol reaction is an important carbon-carbon bond formation reaction. The general concept of the reaction involves the nucleophilic addition of a ketone enolate to an aldehyde to form a P-hydroxy ketone, or aldol , a structural unit found in many naturally occurring molecules and pharmaceuticals. Since the aldol addition reaction creates two new stereocenters, up to four stereoisomers may result. The Evans aldol reaction performs a diasteroselective aldol transformation using an Evans s acyl oxazolidinone (also known as Evans chiral auxiliary), a chiral carbonyl compound that creates a temporary chiral enolate for the aldol addition. Upon subsequent removal of the auxiliary, the desired aldol stereoisomer is revealed. ... 

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