Oxazolidinones auxiliary synthesis

As already hinted at above, chiral dioxetanes, obtained through the highly stereoselective [2 + 2] cycloaddition of singlet oxygen to the chiral enecarbamate, provide a convenient preparation of optically active 1,2 diols as building blocks for asymmetric synthesis (Scheme 5) . Reduction of the dioxetane 2c by L-methionine, followed by release of the oxazolidinone auxiliary by NaBH4/DBU reduction, affords the enantiomerically pure like-5 diol (for additional cases, see Table 4 in Reference 19e). 

A promising unprecedented application of the chiral enecarbamates Ic in asymmetric synthesis is based on the ship-in-the-bottle strategy, which entails the oxidation of these substrates in zeolite supercages . In this novel concept, presumably dioxetanes intervene as intermediates, as illustrated for the oxidation of the chiral enecarbamate Ic in the NaY zeolite (Scheme 6). By starting with a 50 50 mixture of the diastereomeric enecarbamates (45, 3 R)-lc and (45, 3 5 )-lc, absorbed by the NaY zeolite, its oxidation furnishes the enantiomerically enriched (ee ca 50%) S -methyldesoxybenzoin, whereas the (4R,3 R)-lc and (4R,3 S)-lc diastereomeric mixture affords preferentially (ee ca 47%) the R enantiomer however, racemic methylbenzoin is obtained when the chirality center at the C-4 position in the oxazolidinone is removed. Evidently, appreciable asymmetric induction is mediated by the optically active oxazolidinone auxiliary. 

Bio-Mega/Boehringer Ingelheim have used an oxazolidinone auxiliary in the synthesis of renin inhibitors (e.g., 40) for the treatment of hypertension and congestive heart failure.58 A multi-step derivitization of the oxazolidinone 41 from reaction of (6)-4-(l-methylethyl)-2-oxazolidinone and 4-bromo-4-pentenoic acid yielded the desired compound. 

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. 

Analogously, after enolization with Ihmds, hypervalent iodine compounds such as PhI(OAc)2 have been used for the stereoselective synthesis of 2,3-disubstituted succinates by using the chiral oxazolidinone auxiliary (45 )-4-(phenylmethyl)-2-oxazolidinone (equation 19) . 

Saul, R, Kopf, J, Koell, P, Synthesis of a new chiral oxazolidinone auxiliary based on D-xylose and its application to the Staudinger reaction. Tetrahedron Asymmetry, 11, 423-433, 2000. 

A so-called open transition state is another possibility. One transition state (33) leading to the product 10 is depicted in the margin. The aldehyde is attacked at its z-face and the heteroaryl substituent is avoiding the bulky oxazolidinone auxiliary. The reason for the fonna-tion of open transition states is not clear in this case, because zinc is a chelating metal ion and should form closed transition states of the Zimmerman-Traxler type. However, it is known that A-acetyl oxazolidinone derivatives such as 9 exhibit no chirality transfer in the aldol process. In the cases described in the literature, both possible diastereomers were obtained in nearly equal amounts. It is true that in the synthesis of 1 the selectivity is fairly low (4 1), but the major product is the unfavored one. 

Chiral oxazolidinones are also common chiral auxiliary used in the organic synthesis to provide chiral compounds. In 2004, Glorius et al. described an example of the efficient asymmetric hydrogenation of pyridines through the introduction of a chiral oxazolidinone auxiliary to the 2 position of the pyridine derivatives [52]. 

In our synthesis [36] of spiruchostatin A, we followed Simon s procedure for the preparation of 3. We too were unable to achieve the Carreira aldol in good yield. Moreover, the reaction requires the preparation of three noncommercial materials the binaphthyl chiral aminophenol, the t-butyl salicaldehyde, and the silyl ketene acetal. Instead, we opted for a diastereoselective aldol with the Nagao auxiliary. For reasons that are not completely clear, the Nagao thiazolidinethione auxiliary exhibits high diastereoselectivity in acetate aldols unlike the more popular Evans oxazolidinone auxiliary. In this case, aldol adduct 7 was obtained in good yield (Scheme 12-3). Unlike the other syntheses, this was coupled directly to the peptide rather than hydrolyzed to the acid 5. 

The asymmetric aldol reaction using the Evans oxazolidinone auxiliary has been used in a number of syntheses. Suggest reagents for the preparation of the imide 2, used in a synthesis of cytovaricin and explain the stereoselectivity of this reaction. Suggest how you would obtain the other syn aldol product and explain the difference in the stereoselectivity. 

The final fragment is a simple chiral carboxylic acid, so we need a method for its asymmetric synthesis. The most obvious choice is probably an asymmetric alkylation using Evans oxazolidinone auxiliary formation of the appropriate derivative of hexanoic acid is simple, and the enolate will be alkylated diastereoselectively by methyl iodide. You would probably take this approach if you need to make a few grams for initial studies. 

The synthesis of both R)- and (5)-enantiomers of 4,4,4-trifluoro-3-methyl-1-butanol (19,20) by Jacobs et al. [54] as building blocks for leuko-triene antagonists Scheme 5.12), demonstrates how oxazolidinone auxiliaries (21) and (22), derived from L-valine and (lS,2/ )-norephedrine, respectively, impart complementary selectivity in alkylation of chelated (Z)-enolates. Similarly, Trova et al. [55] have utilized the iV-acyl oxazolidinone (23), from L-phenylalanine and 3-phenylpropanoyl chloride, for the construction of diastereomeric lactones (24) and (25) as synthons for HIV-1 protease inhibitors Scheme 5.12). Following allylation and hydrolytic removal of the auxiliary, stereocomplementary iodolactonization reactions of... 

Auxiliary Synthesis Both the (S)- and (R)- enantiomers of the camphor-derived ACC 54 are available in seven steps from commercially available and inexpensive (S)- and (R)-camphor sulfonic acid, respectively (Scheme 7.9). The seven-step process provides an overall yield of approximately 40%. A key step in the synthesis of 54 and 55 is the direct A -amination of the corresponding oxazolidinones, 61 and 62. This transformation is effectively achieved in a straightforward manner using a modification of a procedure recently reported by Hynes et al. ° Application of this amination procedure to commercially available (R)- or (5)-4-benzyloxazolidinone ((R)-62 or (S)-62, respectively) provides phenyl alanine-derived auxiliaries (R)-55 or (S)-55 in excellent yield. 

A salient feature of the oxazolidinone auxiliaries is the fact that they are easily synthesized from inexpensive, commercially available starting materials. The L-amino acids valine and phenylalanine provide access to oxazolidi-nones 114 and 115, respectively, while oxazolidinone 116 is conveniently derived from norephedrine. Moreover, their derivatives are typically crystalline, allowing for ease of purification and handling. The general procedure for the preparation of these chiral oxazolidinones is illustrated with the synthesis of the N-propionyl oxazolidinone 127 derived from phenylalanine (130, Scheme 3.20) [86]. 

The applications of oxazolidinone auxiliaries 114-116 in stereoselective enolate bond constructions are countless. A classic example that showcases their general synthetic utility in enolate alkylations is documented in Evans total synthesis of the antibiotic ionomycin (111, Scheme 3.22) [79]. Throughout this synthetic endeavor, no fewer than nine of the 14 stereogenic centers were installed through auxiliary-based enolate chemistry. Eight of these were accomplished through the use of oxazolidinones, with the two examples that involve diastereoselective enolate alkylations depicted in Scheme 3.22. The... 

The use of chiral auxiliaries on either the ketene or the imine components provides a means for the synthesis of optically active /I-lactams [30], Evans reported that chiral ketenes derived from oxazolidinylacetyl chloride 105 are a convenient starting point [96, 97], Since their introduction, these chiral ketenes have been used successfully in numerous synthetic applications including the first asymmetric synthesis of a carbacephem (103), the carbon analogues of the widely used cephalosporin antibiotics (104). Thus, aldimine 106 was allowed to react with acid chloride 105 to afford cis / -lactam 107 in 80% yield (Scheme 11.17) [97]. Ketenes bearing oxazolidinone auxiliaries... 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

The synthesis in Scheme 13.47 was also based on use of a chiral auxiliary and provided the TBDMS-protected derivative of P-D lactone in the course of synthesis of the macrolide portion of the antibiotic 10-deoxymethymycin. The relative stereochemistry at C(2)-C(3) was obtained by addition of the dibutylboron enolate of an A-propanoyl oxazolidinone. The addition occurs with syn anti-Felkin stereochemistry. 

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

Chiral active pharmaceutical ingredients, 18 725-726. See also Enantio- entries Chiral additives, 6 75—79 Chiral alcohols, synthesis of, 13 667-668 P-Chiral alcohols, synthesis of, 13 669 Chiral alkanes, synthesis of, 13 668-669 Chiral alkenes, synthesis of, 13 668—669 Chiral alkoxides, 26 929 Chiral alkynes, synthesis of, 13 668-669 Chiral ammonium ions, enantiomer recognition properties for, 16 790 Chiral ansa-metallocenes, 16 90 Chiral auxiliaries, in oxazolidinone formation, 17 738—739... 

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. 

Optically active 2-oxazolidinones and 2-thiazolidinones are versatile compounds as chiral auxiliaries. 5a b (4R,5S)-4,5-Diphenyl-2-oxazolidinone has been used for the synthesis of optically active amines6 because of its high stereoselectivity and easy deprotection by hydrogenolysis after the reaction. Compared with several preparations73-0 of (4R,5S)-4,5-diphenyl-2-oxazolidinone reported so far, this method,... 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

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