Evan’s chiral auxiliaries

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

A polymer-supported oxazolidine aldehyde 226 was developed for asymmetric chemistry <02JOC6646> as well as a soluble polymer-bound Evan s chiral auxiliary <02TA333> and 3,5-disubstituted oxazolidin-2-one 227 anchored on a solid phase <02TL8327>. 

Fukuyama et al. synthesized the alcohol 39 using Evans s chiral auxiliary in the total synthesis of leustroducsin B (37), a potent colony-stimulating factor inducer via NF-kB activation at the transcription level15 (Scheme 2.In). The asymmetric aldol reaction between 38 and the requisite aldehyde proceeded smoothly to afford 39. Protection of the secondary alcohol as the TES ether and removal of the chiral auxiliary with LiSEt furnished the thioester 40. 

An alternative to the Evans chiral auxiliary described in the chapter is this oxazoHdinone, made from natural (S)-(-)-phenylalanine. What strategy is used for this synthesis and why are the conditions and mechanism of the reactions important synthesis of Evans s chiral auxiliary from (S)-phenylalanine 0... 

Scheme 12.20 Selective alkylation using immobilized Evan s chiral auxiliary 52.

A scheme for the preparation of (3i )- and (3iS)-piperazic acid derivatives, including those fused to a 1,2-diazepine ring, using Evan s chiral auxiliary methodology have been reported <94MIP11353>. 

Construction of the cyclopentane ring was accomplished by utilization of Trosf s Pd-mediated diastereoselective [3+2] trimethylenemethane (TMM) cycloaddition [4] on the cinnamate 5 having an Evans type chiral auxiliary [4b], The resulting diastereomeric mixture (3 1 at best) of 7a and 7b was separated by careful silica gel column chromatography (7a is less polar than 7b under normal phase). Puri-... 

Having noticed certain limitations of chlorotitanium aldol reactions on Evans et al. s chiral auxiliary,21 in 1997 Crimmins and others developed a brilliant protocol to achieve a highly diastereoselective aldol reaction.22 Asymmetric aldol... 

Chiral auxiliaries can be used in plenty of other reactions, and one of the most common types is the alkylation of enolates. Evans s oxazolidinone auxiliaries are particularly appropriate here because they are readily turned into enolizable carboxylic acid derivatives. 

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. 

If stoichiometric quantities of the chiral auxiliary are used (i.e., if the chiral auxiliary is covalently bonded to the molecule bearing the prochiral centres) there are in principle three possible ways of achieving stereoselection in an aldol adduct i) condensation of a chiral aldehyde with an achiral enolate ii) condensation of an achiral aldehyde with a chiral enolate, and iii) condensation of two chiral components. Whereas Evans [14] adopted the second solution, Masamune studied the "double asymmetric induction" approach [22aj. In this context, the relevant work of Heathcock on "relative stereoselective induction" and the "Cram s rule problem" must be also considered [23]. The use of catalytic amounts of an external chiral auxiliary in order to create a local chiral environment, will not be considered here. 

The azomethine ylide was generated by treatment of A -benzyl-Af-(methoxy-methyl)-trimethylsilylmethylamine (155) with TFA and underwent the required cycloaddition step with chiral dipolarophile 156, stereocontrol being induced by Evan s auxiliary. The ot, p-unsaturated acid dipolarophile was tethered to a chiral oxazoladine in two easy, high-yielding steps. The auxiliary served three purposes to give asymmetric control to the reaction, to allow for separation of the reaction products by generating column separable diastereoisomers, and hnally to activate the olefin in the cycloaddition step (Scheme 3.45). 

The chiral auxiliaries H-A developed by Evans et al. 176) were derivatives of naturally occurring amino acids. The (S)-proline-derived amide enolates (164) as well as the (S)-valine-derived amide enolates (166) and imide enolates (165) have proven to be exceptionally versatile chiral nucleophiles. 

Oxazolidones, chiral, (1) and (2). Evans et al. have prepared these two chiral 2-oxazolidones by reaction of phosgene with (S)-valinol and (IS, 2R)-norephedrine, respectively, and used them as recyclable chiral auxiliaries for carboxylic acids in cnantioselective reactions of the derived imides. 

Another type of substitution reaction is increasing in popularity—the use of an allylic substrate, such as an allyl acetate where the nucleophile is introduced with stereochemical control in the presence of a palladium catalyst and a chiral ligand. Reactions where a chiral anion, be it derived from a chiral heteroatom group, such as a sulfoxide, or an auxiliary, such as Evans s oxazolidinones, are not included in this chapter because the alkyl halide is usually relatively simple and the stereochemical selectivity is derived from the system itself. 

Asymmetric. syn-aldol condensation reactions employing chiral auxiliaries were reported in 1981 by both Masamune et al.2 and Evans et al.3 Masamune et al. introduced boron enolates obtained from (.S )-mandclic acid, which underwent... 

In a broad program of using chiral oxazolidinones in asymmetric synthesis,100 Evans s group published a paper in 1992 on the synthesis and utilization of fV-sulfinyl oxazolidinones as new sulfinylating agent.87 Two chiral auxiliaries were used in the study oxazolidinones derived from (4R, 5S)-norephedrine 74101 and (45)-phenylalanine 75.102 The corresponding fV-sulfinyl oxazolidinones 77 and 78 were obtained either by sulfmylation of the metallated oxazolidinone or by oxidation of the derived N-sulfenamides (Table 15). 

We have introduced you to this chiral auxiliary before any other because it is more commonly used than any other. It is a member of the oxazolidinone (the name of the heterocyclic ring) family of auxiliaries developed by David Evans at Harvard University, and is easily and cheaply made from the amino acid (S)-valine. Not only is it cheaply made it can also be recycled. The last step of the route above, transesterification with benzyl alcohol, regenerates the auxiliary ready for re-use. synthesis of Evans s oxazolidinone chiral auxiliary from (S)-valine NH2 NH2... 

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