Evans’ oxazolidinones

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. 

Verma and Ghosh [72] desymmetrized a a-symmetric 3-dimethyl(phe-nyl)silyl substituted glutaric anhydride (127) with Evans oxazolidinone 128 (Scheme 32) as one of the key steps in their synthesis of (+)-preussin. 

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. 

Merck has used the L-phenylalanine-derived Evans oxazolidinone to make matrix metalloproteinase inhibitors such as 45 (Scheme 23.14) (see also Chapter 2).62 The mixed anhydride of 4-butyric acid was reacted with the lithium anion of the oxazolidinone. This was enolized with the standard titanium reagents. An enantioselective Michael addition was then carried out by the addition of t-butyl acrylate at low temperature. The auxiliary was removed with LiOH/peroxides to give the acid, which was further derivatized over multiple steps to yield the desired drug. 

The control of the C8 stereocenter was achieved by alkylation directed by an auxiliary at C7 involving Oppolzer sultams, Enders hydrazones and Evans oxazolidinones (Scheme 5 l-IIl, resp.). Either the corresponding propionate [14, 37] or propionaldehyde [13, 16] equivalents were alkylated with an alkyl iodide representing the principal part of the northern half of epothilones (Scheme 5 1, II), or C-8 of a sui-table chain was methylated diastereoselec-tively (Scheme 5 III, IV). 

While the sultame and the oxazolidinone auxiliaries represent carboxylate equivalents, which have to be reduced (and sometimes re-oxidized) to the required aldehyde function at C7, the strength of Enders SAMP and RAMP auxiliaries is their direct use as aldehyde and ketone equivalents. However, Nicolaou et al. [13, 16] for the synthesis of the protected building blocks 17a-c had to give up the correct oxidation state in order to allow necessary later manipulations. Considering the necessity of reduction, the cheaper and recoverable Evans-oxazolidinones 18 appear to be the auxiliaries of choice, as demonstrated by Schinzer et al. [21, 22, 36]. A similar methylation is described in an early publication of De Brabander et al. [38] where sultame 21 was methylated and reduced to the a-methylaldehyde 20b in only two steps in good yield and enantiomeric excess. 

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>. 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

An anticonvulsant, CI-1008,(16), was recently developed using the Evans oxazolidinone auxiliary 17 derived from (7.S, 2A)-(-)-norephedrine [45], The route was scaled up to produce several hundred kilogram quantities at production and pilot plant scale and provided early clinical trial malerial (Scheme 2). 

Enantiomerically pure spiro oxindoles (Scheme 35) were prepared by using solid-supported N-cinnamoyl Evans oxazolidinone (164) [265]. Thus, chiral oxazolidi-none prepared from L-tyrosine was attached to a Merrifield resin and then N-acylated with the required unsaturated acyl chloride such as cinnamoyl chloride (not shown). The resin (165) was then suspended in aqueous dioxane and treated with proline and N-phenyl isatin at 80-90 °C overnight to give a highly substituted spiro compound (167). 

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). 

SchOllkopfs bislactim ethers Other chiral glycine enolates Williams s method Seebach s relay chiral units Chiral Enolates from Hydroxy Acids Seebach s relay chiral units Chiral Enolates from Evans Oxazolidinones... 

Application of asymmetric alkylation with Evans auxiliaries Aldol Reactions with Evans Oxazolidinones The syn aldol reaction with boron enolates... 

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

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... 

The main Evans oxazolidinones are 87/88, derived from phenylalanine, and 89/90, derived from valine. All are available at a price - higher naturally for the unnatural R-isomers. Generally 87/88 are preferred as most of their derivatives are crystalline so that purification of diastereoisomers is easier.11... 

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... 

Scheme 33 illustrates the use of two standard persistent auxiliaries. The Evans oxazolidinone 33-1 [83] is highly versatile, i.e., suitable for enolate reactions and double bond additions alike. In the enolate alkylation case [reaction (99)] the high diastereoselectivity depends on the formation of a chelate 33-2 which fixes the reaction site in a defined conformation in which one of the diastereofaces is efficiently shielded. The removal of the auxiliary requires the chemoselective cleavage of the exo cyclic amide bond which is sometimes difficult to achieve. In boron mediated aldoltype additions [Scheme 34, reaction (100)] no chelate can be formed so that the extremeley high diastereoselectivity with which the syn-adduct 34-1 is formed must be due to some other effect, presumably allyl 1,3-strain on the stage of the enol borinate 34-1. 

Miscellanea A methodology to prepare a-substituted-P-hydroxy acids and esters has been introduced in solid phase based on an Evans oxazolidinone-based linker to produce enantiospecifk aldol condensations (Figure 15.4). Acids and esters were released by treatment with LiOH and H202 in THF (at -20 °C) or NaOMe in THF, respectively [58, 59], Diels-Alder adducts of oxazolidinone-bound crotonates have also been detached with LiOCH2Ph [60],... 

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