Imides diastereoselective alkylation

TABLE 2-5. Diastereoselective Alkylation Reaction of the Lithium Enolates Derived from Imides 22 and 23... 

The epimeric (+)-a-allokainic acid was constructed by the unsaturated imide/ alkyne alkylative coupling of 9 with trimethylaluminum in 73% yield and 97 3 diastereoselectivity (Scheme 8.11) [33]. This was followed by silyl to carbonate protecting group transposition, stereoselective aUylic reduction, and removal of protecting groups to afford (+)-a-allokainic acid. The complementary nature of these two stereodivergent approaches allowed access to both epimeric natural products. 

Imide enolates derived from (5)-valinol and (15,2/f)-norephe-drine and obtained by either LDA or Sodium Hexamethyldisi-lazide deprotonation (eq 24) exhibit complementary and highly diastereoselective alkylation properties. Mild and nondestructive removal of the chiral auxiliary to yield carboxylic acids, esters, or alcohols contributes to the significance of this protocol in small-and large-scale synthesis. ... 

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. 

Asymmetric aikyiation of imide etiolates.1 The sodium enolates of 3 and 7 are alkylated with marked but opposite diastereoselectivity by alkyl halides. The selectivity is improved by an increase in the size of the electrophile, with methylation being the least stereoselective process. The asymmetric induction results from formation of (Z)-enolates (chelation) with the diastereoselectivity determined by the chirality of the C4-substituent on the oxazolidone ring (equations I and II). The products can be hydrolyzed to the free carboxylic acids or reduced by LiAlH4 to the corresponding primary alcohols and the unreduced oxazolidone (1 or 2). 

In order to maximize the diastereoselectivity observed for an auxiliary, it would appear reasonable that the stereo controlling functional group is in a position in space as close as possible to the newly forming stereogenic centre. Chiral imide auxiliaries such as Evans N-acyloxazolidinones (1.43) are used for asymmetric alkylation and asymmetric aldol condensation (Scheme 1.10). 

For benzyloxymethyl electrophiles, titanium enolates are superior to the corresponding lithium enolates in both yield and alkylation diastereoselectivity (eq 11). Unfortunately, the analogous p-methoxybenzyl-protected (3-hydroxy adducts cannot be obtained by this method. In other cases the titanium methodology complements the corresponding reactions of the lithium and sodium enolates for SNl-like electrophiles. It is noteworthy that imides may be selectively enolized under all of the preceding conditions in the presence of esters (eq 12). 

The superior nucleophilicity and excellent thermal stability of pseudoephedrine amide enolates make possible alkylation reactions with substrates that are ordinarily unreactive with the corresponding ester and imide-derived enolates, such as (3-branched primary alkyl iodides. Also, alkylation reactions of pseudoephedrine amide enolates with chiral (J-branched primary alkyl iodides proceed with high diastereoselectivity for both the matched and mismatched cases (Table 3). ... 

In order to overcome the problems associated with acid hydrolysis of amides of prolinol, the Evans research group has investigated the diastereoselectivity of the alkylation of imides derived from chiral 2-oxazolidones. Imide enolates are somewhat less nucleophilic than amide enolates, but they have the advantage that their diastereomeric alkylation products are easily separated and the imide linkage is cleaved with a variety of reagents under mild conditions. As shown in Scheme 64, alkylation of the chelated (Z)-enolate of the propionimide derived from (S)-valinol (135) with benzyl bromide occurred in high chemical yield and with high si-face diastereoselectivity. In addition to oxazolidones, imidazoli-diones have proved to be useful chiral auxiliaries for diastereoselective enolate alkylations. ... 

Sequential alkylation of the lithium enolate of 897 with methyl iodide and then allyl bromide furnishes dialkylated malate 938 with 96 4 diastereoselectivity. The hydroxyl group is removed via a xanthate ester to give 939, which is then alkylated with 4-bromo-l-butene to give 940 as the major isomer. The mixture is hydrolyzed with base and heated with urea to yield imides 941 and 942 in a 3 1 ratio. After isolation of pure 941 by crystallization, the remaining undesired diastereomer 942 is epimerized to 941 with potassium tert-hutoxide. Oxidation of 941 with ruthenium tetroxide-sodium periodate and esterification of the resulting acids furnishes imide 943. This sequence has produced more than 10 g of 943 in a single run. 

A highly chemo- and diastereoselective three-component reaction of an imine, alkyl vinyl ketone, and imide is catalysed by triphenylphosphine. The first two reactants are... 

In the synthesis of ionomycin published in 1990, the Evans group provided a convincing acid test of their auxiharies in several alkylation and aldol addition steps. Just one of those, the preparation of the alcohol 72, that was required as C-13 to C-16 fragment of ionomycin, may serve as an Ulustrative example, shown in Scheme 4.13. The hthium enolate of imide 48 was alkylated with cinnamyl bromide in a highly diastereoselective manner. The a-branched imide 71 thus obtained was reduced to the alcohol 72 that, after conversion into the primary iodide 15 (Scheme 4.3), served as electrophile in Evans prolinol procedure for chain elongation en route to ionomycin [12b]. 

Yang and coworkers used the a-bromo propionic imide 328 for a diastereoselective Reformatsky reaction that was mediated by diethyl zinc under catalysis of Ni(acac)2 and permitted to use aryl alkyl ketones as the carbonyl components. The... 

Melnyk O, Stephan E, Pourcelot G, Cresson P. Additions diastereoselectives d alkyl, alcenyl, aryl et allyl cuprates a des imides chirales insaturees. Tetrahedron 1992 48 841-850. 

Both procedures normally give (Z)-enolates in greater than 99% selectivity. These react with aldehydes via a cychc six-membered transition state of the Zimmerman-Traxler type, with one face of the imide enolates hindered by the auxiliary, forcing attack of the aldehyde at the opposite face. As with diastereoselective a-alkylations (previous section), the stereodirecting influence of the auxiliaries generally overrides that imposed by ancillary stereogenic centers in the aldehyde substrates . 

The synthesis of e.p. a-[ " C ]amino acids through diastereoselective homologation of protected acyclic or cyclic homochiral glycine building blocks (Figure 11.62) by alkylation of their enolates is a valuable alternative to the electrophilic a-amination of chiral a-unsubstimted imide enolates ". ... 

Other uses of oxazinone enolates have been described by Williams, including the boron enolate 60, in the synthesis of diaminopimelic acid (62), the penultimate precursor of the essential amino acid i.-lysine (Scheme 10.8) [59], Acylated derivatives of Oppolzer s camphor sultam 63 can readily be alkylated in a highly diastereoselective fashion (Scheme 10.9) [60]. Thus, the imide derived from the condensation of 63 and 64 undergoes enolization and subsequent alkylation to furnish protected amino acid derivatives with high selectivity (cf 65, dr > 99 1) [61],... 

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