Diels-Alder reaction oxazolidinone chiral auxiliaries

In the past Lewis acid-catalyzed [4+2] cycloaddition reactions of chiral alkyl acrylates have been systematically studied. Chiral auxiliaries derived from camphor, menthol and amino acids or from carbohydrates have been developed. Stereochemical and theoretical aspects of these chiral inductors have been intensively reviewed (see. Chapter 6). Asymmetric Diels-Alder reactions of chiral acrylamides derived from Ca-symmetrical secondary amines lead selectively to the cycloadducts in the presence of Lewis acids such as AICI3. In reactions of chiral auxiliaries derived from (iS)-proline and (iS)-prolinol excellent endo/exo selectivities and diastereoselectivities were obtained in the presence of catalytic amounts of Et2AlCl or TiCL. Cycloadducts of chiral crotonoyl derivatives derived from oxazolidinones 62, sultam 63 or for example (S)-lactate IS were obtained with high selectivities in the presence of Lewis acids such as Et2AICl. 

As one of the pioneering works on asymmetric synthesis, Evans and coworkers reported diastereoselective Diels-Alder reaction of acryloyl oxazolidinones mediated by Et2AlCl [140]. Intramolecular version of this cycloaddition was also reported, in which interesting stereochemical difference depending on substituents at oxazo-lidinone ring was found. As an another excellent example, Oppolzer and coworkers reported diastereoselective Diels-Alder reaction of chiral dienophiles equipped with camphorsultam auxiliary [141]. Recently, these diastereoselective reactions were applied to enantioselective synthesis of ceralure Bl, known as Mediterranean fruit fly attr actant (Scheme 6.118) [142]. 

Asymmetric Diels-Alder reactions. Unlike methyl crotonate, which is a weak dienophile, chiral (E)-crotonyl oxazolidinones when activated by a dialkylaluminum chloride (1 equiv.) are highly reactive and diastereoselective dienophiles. For this purpose, the unsaturated imides formed from oxazolidinones (Xp) derived from (S)-phenylalanol show consistently higher diastereoselectivity than those derived from (S)-valinol or (IS, 2R)-norephedrine. The effect of the phenyl group is attributed in part at least to an electronic interaction of the aromatic ring. The reactions of the unsaturated imide 1 shown in equation (I) are typical of reactions of unsaturated N-acyloxazolidinones with cyclic and acyclic dienes. All the Diels-Alder reactions show almost complete endo-selectivity and high diastereoselectivity. Oxazolidinones are useful chiral auxiliaries for intramolecular Diels-Alder... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted much interest for their various applications in different synthetic transformations.2 Such simple structures, directly related to far better known chiral oxazolidinones,11,12,57 have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations, but mainly in condensation of their /V-acyl derivatives with aldehydes. Chiral OZTs have shown interesting characteristics in anti-selective aldol reactions58 or combined asymmetric addition. 

The 3-acyl-2(3F/)-oxazolones function as good dienophiles in cycloaddition reactions with cyclic 2,4-dienes such as cyclopentadienes and anthracenes. Thus, the thermal reaction of 3-acetyl-2(37/)-oxazolone with cyclopentadiene and the hexachloro and hexamethyl derivatives gives endo-cycloadducts exclusively. In particular, the chiral cycloadducts 221 and 223 derived from the diastereoselective Diels-Alder reactions of 3-(2-exo-alkoxy-l-apocamphanecarbonyl)-2(3/7)-oxazo-lones with hexamethylcyclopentadiene and 9,10-dimethylanthracene, respectively, are highly useful as chiral 2-oxazolidinone auxiliaries. The conformationally rigid roofed structures play a crucial role in affording excellent chiral induction (Fig. 5.54). 

Some enantiomerically pure substituted 2-oxazolidinones are excellent as chiral auxiliaries. From the pioneering studies 2 conducted in the early 1980 s of the uses of such auxiliaries has emerged what is perhaps the most widely used method today for the preparation of enantiomerically highly enriched a-alkylalkanoic acids, alcohols and aldehydes, that is, the alkylation of enolates from chiral 3-acylated 2-oxazolidinones followed by auxiliary removal2 59. The early work has been reviewed60-62. These enantiomerically pure cyclic imide auxiliaries have been used not only for alkylations but also in a plethora of a-functionalization reactions, such as diastereoselective aldol, a-hydroxylation, a-amination and Diels-Alder reactions and these are discussed elsewhere in this volume. 

An extensive review of recent advances in the area of asymmetric Diels-Alder reactions has been published.205 Sterically constrained tricyclic 2-oxazolidinones serve as excellent chiral auxiliaries for asymmetric Diels-Alder reactions.206 The Diels-Alder reactions of ( —)-(a,S. 7,S )-colchicinc (109) with hetero- and carbo-dienophiles show... 

Saigo and co-workers reasoned that, by analogy, high levels of diastereofacial discrimination could be achieved in the Lewis acid-mediated Diels-Alder reaction of dienes with oxazolidinone 108-derived dienophiles. Indeed, excellent regioselectivities (endo. exo) and diastereoselectivities were reached in the Diels-Alder reaction of 109 with cyclic and acyclic dienes using Et2AlCl as the activator (Scheme 24.28).107 The selectivities obtained actually surpassed those reported with cis-1 -amino-2-indanol 1 as the chiral auxiliary (93% de) (see Scheme 24.16).82 The additional bulk... 

The aldol reaction illustrated in eq 2 has been applied to the targeted synthesis of a number of complex molecules including Tylosin, Hapalosin, the antibiotic Sinefungin, and the HIV protease Saquinavir inhibitor. Oxazolidinone-type chiral auxiliaries derived from 1 have also been employed for the control of Diels-Alder reactions of attached acryloyl or crotonyl groups. ... 

Diels-Alder Reactions. Chiral a,p-unsaturated imides participate in Lewis acid-promoted Diels-Alder cycloaddition reactions to afford products in uniformly excellent endo/exo and endo diastereoselectivities (eq 50 and 51). Unfortunately, this reaction does not extend to certain dienophiles, including methacryloyl imides, p,3-dimethylacryloyl imides, or alkynic imides. Cycloadditions also occur with less reactive acyclic dienes with high diastereoselectivity (eq 52). Of the auxiliaries surveyed, the phenylalanine-derived oxazolidinones provided the highest diastereoselectivities. This methodology has been recently extended to complex intramolecular processes (eq 53). In this case, use of the unsubstituted achiral oxazolidinone favored the undesired diastereomer. 

Diels-Alder reactions with Oppolzer s chiral sultam Diels-Alder reactions with pantolactone as chiral auxiliary Chiral auxiliaries attached to the diene Improved Oxazolidinones SuperQuats Asymmetric Michael (Conjugate) Additions... 

Scheme 12.23 Asymmetric Diels-Alder reaction using oxazolidinone chiral auxiliary 56.

Evans exploited this concept of chelation in the transition state with the development of a new generation of chiral auxiliaries based on conversion of amino alcohols to oxazolidinone derivatives. As shown in Table 11.16,229 conversion of these auxiliaries (to give the corresponding conjugated amide 268) gave excellent selectivity in the intramolecular Diels-Alder reaction, which generated mixtures of 269 and 270. Coordination with the Lewis acid catalyst generates a complex in which facial selectivity is enhanced relative to the... 

Enantiomerically pure oxazolines and oxazolidinones have found widespread application in organic synthesis as chiral auxiliaries. They have been mainly used for the synthesis of enantiomerically pure amino acids but also as chiral auxiliaries to produce non-racemic enolates as pioneered by Evans.The reaction types proceeding with high stereocontrol include enolate alkylation, enolate oxidation, enolate halogenation, enolate amination, enolate acylation, aldol reaction and Diels-Alder reactions. 

Highly selective Diels-Alder reactions with other chiral auxiliaries attached to the dienophile have been documented. For example, chiral 2-oxazolidinones or the camphor sultam auxiliaries have proven particularly useful. Such cycloaddition reactions, catalysed by an alkylaluminium chloride, occur with a variety of dienes to give adducts in high yield and with very high diastereoselectivity. In many cases these adducts can be obtained diastereomerically pure by crystallization. The reactions are thought to occur by way of complexed ion pairs (e.g. 129), in which the substituent on the auxiliary shields one face of the dienophile from attack by the diene. For example, 2-methylbutadiene (isoprene) gave the adduct 127, which was converted into (i )-(+)-a-terpineol 128 (3.92). ... 

Lewis acid-catalyzed intramolecular Diels-Alder reactions of trienes, bearing an inducing moiety, e.g. oxazolidinones 62 or sultam 63, have been widely examined and employed in natural product synthesis. The cycloadducts were obtained in high yield with excellent stereoselectivities. Among the Lewis acids studied in asymmetric intramolecular Diels-Alder reactions with auxiliary 11, a chiral catalyst [(Bomyl)AlCl2] proved to be highly efficient (72% de, 25-75%). 

Many of the chiral auxiliaries described earlier serve excellently in asymmetric Diels-Alder reactions. The Evans oxazolidinones (116)t l and the Oppolzer camphor sultams (117)t l are exceptionally good in this regard and, as shown, actually give opposite products. 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

The preferred auxiliaries in chemistry at NSC Technologies are oxazolidinones. Oxazolidinones have found widespread use as chiral auxiliaries. A wide range of reactions is available and well documented [5], including aldol alkylations oc-substitution with a heteroatom such as halogenation, aminations, hydroxyla-tions, and sulphenylations Diels-Alder cycloadditions and conjugate additions. 

An important strategy for achieving substrate control is the use of chiral auxiliaries, which are structures incorporated into reactants for the purpose of influencing the stereochemistry. Two of the most widely used systems are oxazolidinones " derived from amino acids and sultams derived from camphorsulfonic acid. These groups are most often used as carboxylic acid amides. They can control facial stereoselectivity in reactions such as enolate alkylation, aldol addition, and Diels-Alder cycloadditions, among others. The substituents on the chiral auxiliary determine the preferred direction of approach. 

Evans has pioneered the use of carboximide-derived enolates in diastereo-selective enolate alkylation reactions [15, 82]. As discussed in subsequent chapters, N-acyl oxazolidinones (such as 114, 115, and 116) enjoy a unique position in asymmetric synthesis as chiral auxiliaries with wide applications in numerous mechanistically unrelated asymmetric transformations, among them aldol (Chapter 4), Diels-Alder (Chapter 17), enolate amination (Chapter 10), and conjugate addition (Chapter 12) reactions. Oxazolidinones 114 and 115 generally lead to Ca-substituted carboximide products in one dia-stereomeric series (cf 119, dr>99 1), while the complementary diastereo-meric adducts such as 122 dr =98 2) can be accessed through the use of oxazolidinone 116 (Scheme 3.18) [82]. 

The most successful and widely employed auxiliaries are without question those of Evans, namely, chiral oxazolidinones, such as 119 (Equation 11) [5, 70]. In studies involving their application in diastereoselective Diels-Alder cycloaddition reactions, Et2AlCl was identified as the optimal Lewis acid. Interestingly, it was noted that the use of more than one equivalent of Et2AlCl had a profound positive effect both on the reaction rate and the stereoselectivity. Evans has proposed that the presence of excess Et2AlCl leads to a dis-... 

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