Enolates from Evans’ oxazolidinones

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... 

Titanium enolates. These enolates have generally been prepared by transmet-talation of alkali-metal enolates or silyl enolate ethers. Surprisingly, Evans et al. find that a titanium enolate can be prepared directly from the oxazolidinone 1 by reaction with TiCl4 (1 equiv.) in CH2C12 and shortly thereafter with ethyldiisopropyl-amine (or triethylamine) at 0°. The enolate may actually be an ate complex (2a)... 

One of the most successful and widely used methods for diastereoselective aldol addition reactions employs Evans imides 17 and the derived dialkyl boryleno-lates [8J. The 1,2-svn aldol adducts are typically isolated in high diastereoisomeric purity (>250 1 dr) and useful yields. More recent investigations of Ti(IV) and Sn(II) enolates by Evans and others have considerably expanded the scope of the aldol process [9], In 1991, Heathcock documented that diverse stereochemical outcomes could be observed in the aldol process utilizing acyl oxazolidinone imides by variation of the Lewis acid in the reaction mixture [10]. Thus, for example, in contrast to the, l-syn adduct (21) isolated from traditional Evans aldol addition, the presence of excess TiCL yields the complementary non-Evans 1,2-syn aldol diastereomer. This and related observations employing other Lewis acids were suggested to arise from the operation of open transition-state structures wherein a second metal independently activates the aldehyde electrophile. 

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... 

A highly versatile auxiliary is the Evans oxazolidinone imide (Figure 5.4c, see also Scheme 3.16), available by condensation of amino alcohols [86,87] with diethyl carbonate [86]. Deprotonation by either LDA or dibutylboron triflate and a tertiary amine affords only the Z(0)-enolate. Scheme 5.12 illustrates open and closed transition structures that have been postulated for these Zf0)-enoIates under various conditions, and Table 5.4 lists typical selectivities for the various protocols. The first to be reported (and by far the most selective) was the dibutylboron enolate (Table 5.4, entry 1), which cannot activate the aldehyde and simultaneously chelate the oxazolidinone oxygen [75]. Dipolar alignment of the auxiliary and approach of the aldehyde from the Re face of the enolate affords syn adduct with outstanding diastereoselection, presumably via the closed transition structure illustrated in Scheme 5.12a [75]. The other syn isomer can be formed under two different types of conditions. In one, a titanium enolate is postulated to chelate the oxazolidinone... 

Oxazolidinones have proven to be extremely useful auxiliary groups in a variety of synthetic reaction types. Thus, the Evans auxiliaries are useful in the control of configuration in enolate alkylations and concerted cycloadditions, to name a few of the more important applications. Sibi and his collaborators at North Dakota State University have pioneered the use of these auxiliary groups in radical transformations mediated by Lewis acids [21-24]. Consider the general conformational questions that arise in a carboximide, such as 12, derived from an oxazolidinone (Eq. 18). The conformer 12 is disfavored by steric factors while 13 and 14 have similar steric demands. In the absence of any chelating Lewis acid, one expects that 13 would be of lower energy than 14 because of the opposed dipoles of the anti carbonyls in this conformation. 

The most successful imide systems for diastereoselective aldol addition reactions are, without question, the oxazolidinones 50-52 developed by Evans. These furnish syn aldol adducts with superb selectivity for a broad range of substrates (Scheme 4.5) [6, 13, 45-47). A hallmark of these system is that enolization yields exclusively the Z-enolates, which can be understood on the basis of steric considerations. Two important discoveries in the area proved critical to the unparalleled success enjoyed by Evans auxiliaries for diastereoselective aldol addition reactions. The first of these was the disclosure by Mukaiyama that the combination of di-n-butylboryl trifluorometh-anesulfonate (n-Bu2BOTf) and diisopropyl ethyl amine can be employed for the generation of dialkylboron enolates from ketones [48]. The second key observation was by Roster, who observed that aldol additions of boron enolates proceeded with higher levels of simple induction [49], This phenomenon is attributed to the short B-0 distances in the attendant Zimmer-man-Traxler transition state structure [14, 47]. 

In addition to the advances in auxiliary-controlled acetate aldol addition reactions, a number of innovative solutions for the preparation of propionate-derived 1,2-anti products have also appeared using auxiliaries other than Evans oxazolidinone. The various successful approaches to anti aldol adducts stem from the design of novel auxiliaries coupled with the study of metal and base effects on the reaction stereochemistry. Masamune documented that the addition of optically active ester enolate 112 to aldehydes afforded anti aldol adduct 113 in superb yield and diastereoselectivity (Equation 10) [70]. After careful selection of the reaction conditions for the enolization of the ester [71], the aldol addition was successfully carried out with a broad range of substrates including aliphatic, aromatic, unsaturated, and functionalized aldehydes. An attractive feature of this process is the subsequent facile removal of the auxiliary (LiOH, THF/H2O) to afford the corresponding acid without concomitant deterioration of the configurational integrity of the products [70]. 

The central point of Evans s methodology is the induction of a 7t-enantiotopic facial differentiation through a conformationally rigid highly ordered transition state. Since the dialkylboron enolates of AT-acyl-2-oxazolidinones exhibit excellent syn-diastereoselectivity syn.anti >97 3) when reacted with a variety of aldehydes, Evans [14] studied the aldol condensation with the chiral equivalents 32 and 38. which are synthesised from fS)-valine (35) and the hydrochloride of (15, 2R)-norephedrine (36) (Scheme 9.11), respectively, and presently are commercially available. 

In a related contribution O Brien described the AA on styrenes and converted the amino alcohols into enantiopure diamines by using a reaction strategy similar to Janda s [83], Further synthetic applications of the AA include a new access to Evans chiral oxazolidinones [84], the enantioselective synthesis of a-amino ketones from silyl enol ethers [85], the stereoselective synthesis of cyclohexyl norstatine [86], and a route towards amino cyclitols by aminohydroxy-lation of dienylsilanes [87]. 

The approach for the enantioselective aldol reaction based on oxazolidinones like 22 and 23 is called Evans asymmetric aldol reaction.14 Conversion of an oxazolidinone amide into the corresponding lithium or boron enolates yields the Z-stereoisomers exclusively. Reaction of the Z-enolate 24 and the carbonyl compound 6 proceeds via the cyclic transition state 25, in which the oxazolidinone carbonyl oxygen and both ring oxygens have an anti conformation because of dipole interactions. The back of the enolate is shielded by the benzyl group thus the aldehyde forms the six-membered transition state 25 by approaching from the front with the larger carbonyl substituent in pseudoequatorial position. The... 

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. 

Fig. 10.38. Evans synthesis of enantiomerically pure a-alkylated carboxylic acids. The amides are derived from oxazolidinones and yield Z -enolates with high stereoselectivity. The alkylating agent attacks in both cases from the side that is opposite to the side of the substituent highlighted in red.

Another explanation takes into account that boat- and twist-shaped six-membered, closed transition states can successfully compete with the chair model. " Evans et al. pointed out that in a-unsubstituted enolate reactions, missing allyl strain interactions lead to lower selectivity in diastereoselective aldol reactions.Calculations indicate that a twist-boat can easily be formed from the U-configuration of a-unsubstituted enolates. The possible transition state in this case has a geometry like 34 and is favored by the chelating character of the complexation mode for the zinc cation and the outward-pointing substituents of the oxazolidinone moiety. This twist-boat transition state correctly predicts the stereochemical outcome of the reaction. 

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]). 

Most metal enolates are generated by transmetalation from Li enoiates. However, Ti-enolates can be formed by action of TiCiyz -PrjNEt on carbonyl confounds [404,1042] and Zr-enolates can be generated by similar reactions with Zr(0-/ert-Bu)4 [1245], Lithium E-endates are obtained by deprotonation of ketones or esters with a branched Li-amide (LDA, LICA, LOB A, LTMP) in a weakly polar medium (THF or THF-hexane), while Z-enolates are formed by using LDA or LHMDS in the presence of HMPA or DPMU [1016], Tertiary amides always give Z-endates, and difunctionalized derivatives such as Evans s oxazolidinones 5.30 and 5.31 are chelated to the metal prior to enolization. 

Derivatives of Evans s oxazolidinones 1.116 and 1.117 have been broadly developed for use in aldol reactions [160, 167, 407, 408], The reactions of aldehydes with lithium enolates are usually poorly stereoselective, but remarkable results have been obtained from boron, tin(II) and titanium enolates. The boron... 

Abstract The A(1,2) and A(1,3) strains and their control on the conformational and reactivity profiles of substrates are discussed. The application of A(1,3) strain to the facial selectivity of reactions such as [2,3] and [3,3] sigmatropic shifts, intramolecular SN2 reactions, hydroboration, enolate alkylation, etc. is highlighted. The high diastereoselectivity observed in the reactions of enolates derived from 4-substituted /V-al kanoyl-1,3-oxazolidinones (Evans enolates) with electrophiles is discussed. 

In 1982, Evans reported that the alkylation of oxazolidinone imides appeared to be superior to either oxazolines or prolinol amides from a practical standpoint, since they are significantly easier to cleave [83]. As shown in Scheme 3.17, enolate formation is at least 99% stereoselective for the Z(0)-enolate, which is chelated to the oxazolidinone carbonyl oxygen as shown. From this intermediate, approach of the electrophile is favored from the Si face to give the monoalkylated acyl oxazolidinone as shown. Table 3.6 lists several examples of this process. As can be seen from the last entry in the table, alkylation with unactivated alkyl halides is less efficient, and this low nucleophilicity is the primary weakness of this method. Following alkylation, the chiral auxiliary may be removed by lithium hydroxide or hydroperoxide hydrolysis [84], lithium benzyloxide transesterification, or LAH reduction [85]. Evans has used this methology in several total syntheses. One of the earliest was the Prelog-Djerassi lactone [86] and one of the more recent is ionomycin [87] (Figure 3.8). 

In any treatment of auxiliary-based alkylations (as well as aldol additions, enolate oxidations, Mannich and Michael reactions), clearly, the carboximide enolates pioneered by the group of Evans are the center of attention. Developed in the early 1980, JV-acyl derivatives of oxazolidinones 45-47 (Scheme 4.9) became the epitomes of chiral auxiliaries [7,28] with countless applications in natural products and drug syntheses. The enantiomeric oxazolidinones (S)- and (R)-47 derived from the corresponding enantiomer of phenylalanine have the advantage that, when used for various transformations, the corresponding products have a higher tendency to crystallization and were shortly later added [29] to this collection of classics. 

---