Evans’ oxazolidinone chiral auxiliarie

A different approach to enantioselective electrophilic fluorination is the use of chiral auxiliary groups on the substrate this converts the problem into a diastereo-selective fluorination. The ground-breaking work in this field was done since 1992 by the Davis group [207], by fluorination of imide enolates modified by Evans oxazolidinone chiral auxiliary [208] using N-fluoro-o-benzenedisulfonimide (NFTh) as the electrophilic fluorination agent (Scheme 2.94). 

Anti-aldols by Lewis acid-catalysed reactions with Evans oxazolidinones Chiral Auxiliaries... 

The succinate core can be prepared by alkylation of a simple carboxylic acid (74a or b) with a bromoacetate using the Evans oxazolidinone chiral auxiliary derived from phenylalanine (chapter 27). The branched alkyl group must be present in the substrate for alkylation and the second acid group added in the alkylation so that there is no competition between two carbonyl groups during enolate formation. After hydrolysis (91% yield) the alkylated succinic acid 77 has >95% ee. Notice that the two acid groups are differentiated by this procedure.10... 

For an early discussion of the Evans oxazolidinone chiral auxiliaries, see D. A. Evans, J. V. Nelson,... 

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... 

L. Wessjohn and co-workers successfully applied the CrCl2-mediated Reformatsky reaction for the synthesis of C1-C6 fragment of epothilones. In their approach, they utilized the Evans (R)-4-benzyl-oxazolidinone chiral auxiliary to control the absolute stereochemistry. The chromium-Re/brmafsAy reaction between the (R)-4-benzyl-3-(2-bromoacetyl)-oxazolidinone and 2,2-dimethyl-3-oxo-pentanal occurred with complete chemoselection providing the product with 63% yield and as a single diastereomer. 

We (Novartis) reported ] an enantioselective synthesis of (2S,2 71)- zyf/iro-methylphenidate (3) utilizing Evans (S)-4-benzyl-2-oxazolidinone chiral auxiliary to control the diastereofacial selectivity in the hydrogenation of enamine intermediate (65 Scheme 16). Acylation of (S)-4-benzyl-V-phenylace-tyl-2-oxazolidinone (61) with the mixed anhydride 63, followed by deprotection of the V-Boc group with TFA, and neutralization of the reaction mixture with NaHCOs afforded the enamine intermediate 65. Hydrogenation of enamine 65 with 10% Pd-C in ethyl acetate furnished 66 in 95% yield with an excellent diastereoselectivity (97 5). Treatment of 66 with methanol in the presence of EnR afforded the desired... 

Michael additions with 8-phenylmenthyl esters of unsaturated acids Chiral auxiliaries attached elsewhere in asymmetric Michael additions Other Chiral Auxiliaries in Conjugate Addition The Evans oxazolidinones Chiral sulfoxides Asymmetric Birch Reduction Birch reduction of benzene Asymmetric Birch reduction of heterocycles... 

SCHEME 10 26 The use of Evans et al. oxazolidinone chiral auxiliaries in ijn-selective aldol reaction. 

SCHEME 10.27. Chemical evolution leading to the Evans group oxazolidinone chiral auxiliaries. 

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

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

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

Although the racemization of the a-carbon can now be considered a potential problem, the synthesis of 32-peptides has been achieved in the same way as seen for 33-peptides. As the 32-amino acids cannot be prepared from the analogous a-amino acids, Seebach and co-workers 5,7 opted to use Evans oxazolidinone chemistry to produce enantiomerically pure 32-amino acids. Alkylation of 3-acyloxazolidin-2-ones 17 with A-(chloromethyl)benzamide yielded the products 18 with diastereomeric ratios between 93 7 and 99 1 (Scheme 8). Removal of the chiral auxiliary (Li0H/H202) and debenzoylation (refluxing acid) was followed by ion-exchange chromatography to yield the free 32-amino acids 20 which were converted by standard means into Boc 21 or benzyl ester 22 derivatives for peptide synthesis. 

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. 

A stereocontrolled synthesis of the biologically active neolignan (+)-dehydrodiconiferyl alcohol, which was isolated from several Taxus species, was achieved via Evans asymmetric aldol condensation [58] using ferulic acid amide derived from D-phenylalanine. The reaction steps are shown in Fig. 9. This stereocontrolled reaction is also useful for preparing the enantiomer of (+)-dehydroconiferyl alcohol using chiral auxiliary oxazolidinone prepared from L-phenylalanine. This reaction also enables the syntheses of other natural products that possess the same phenylcoumaran framework. 

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. 

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. 

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 ... 

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). 

Dianion aldol condensation reactions with Evans oxazolidinones or Oppolzer sultams as chiral auxiliaries have been demonstrated to be a useful method to generate the core skeleton of furofurans with diastereoselectivities of 5 1-20 1. Stereoselective total syntheses of the furofuran lignans (-l-)-eudesmin, (+)-yangambin, (—)-eudesmin, and (-)-yangambin according to this procedure have been reported (Equation 102) <2006TL6433>. 

Oxazolidinones, such as 4 and 5, have been introduced by Evans as very useful chiral auxiliaries. These compounds are prepared from readily available chiral amino alcohols and are successfully employed in a variety of different stereoselective reactions."... 

The C33-C37-unit of (-F)-calyculin A (a marine natural product) is an amide derived from 5-0-methyl-4-deoxy-4-dimethylamino-D-ribonic acid that has been prepared by Evans and co-workers [250]. A-Protection of sarcosine as benzyl carbamate affords acid 118 which is activated and used to iV-acylate the (5)-phenylalanine-derived oxazolidinone. This gives 119 that is methoxymethylated diastereoselectively (98 2) to give 120. Reductive removal of the chiral auxiliary, followed by Swem oxidation forms aldehyde 121 with little racemization if... 

Phenylalanine-derived oxazolidinone has heen used in O Scheme 52 as a chiral auxiliary for as)rmmetric cross-aldolization (Evans-aldol reactions [277,278,279,280,281,282,283,284, 285]). The 6-deoxy-L-glucose derivative 155 has heen prepared by Crimmins and Long [286] starting with the condensation of acetaldehyde with the chlorotitanium enolate of O-methyl glycolyloxazohdinethione 150. A 5 1 mixture is obtained from which pure 151 is isolated by a single crystallization. After alcohol silylation and subsequent reductive removal of the amide, alcohol 152 is obtained. Swem oxidation of 152 and subsequent Homer-Wadsworth-Emmons olefination provides ene-ester 153. Sharpless asymmetric dihydroxylation provides diol 154 which was then converted into 155 (O Scheme 60) (see also [287]). 

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