Enantioselectivity ester enolates

Example 3, Enantioselective ester enolate-Claisen Rearrangement ... 

Some advancement has been described for the development of a catalytic enantioselective ester enolate Claisen rearrangement. The strong Lewis basic carboxylate functionality present in the Claisen product effectively coordinates with Lewis or Bronsted acids prohibiting the catalytic turnover. Corey has reported the use of stoichiometric bromoborane 175 to generate chiral boron enolate which undergoes [3,3]-sigmatropic rearrangement to yield 176. ° Kazmaier relied on excess quinidine 178 to provide for asymmetric induction in the conversion of 177 to amino acid 179. ... 

Scheme 5.99 Enantioselective ester enolate-imine condensation mediated by the stoichiometric additive 379.

The value of 2-acyl-1,3-dithiane 1-oxides in stereocontrolled syntheses has been extended to the enantioselective formation of (3-hydroxy-y-ketoesters through ester enolate aldol reactions <00JOC6027>. 

A stochiometric approach was applied by Van Koten and co-workers [29], who used chiral carbosilane dendrimers as soluble supports in the in situ ester enolate-imine condensation in the synthesis of /Mactams (e.g. 19, Scheme 20). The formation of the /Mactam products proceeded with high trans selectivity, and with the same level of stereoinduction as was earlier established in reactions without the dendritic supports, (i.e. the use of the enantiopure dendritic support did not affect the enantioselectivity of the C-C bond formation). After the reaction, the dendrimer species could be separated from the product by precipitation or GPC techniques and reused again. 

As with other ester enolate rearrangements, the presence of chiral ligands can render the reaction enantioselective. Use of quinine or quinidine with the chelating metal leads to enantioselectivity (see entry 21 in Scheme 6.12). 

Another enantioselective synthesis of longifolene, shown in Scheme 13.27, uses an intramolecular Diels-Alder reaction as a key step. The alcohol intermediate is resolved in sequence B by formation and separation of a menthyl carbonate. After oxidation, the pyrone ring is introduced by y addition of the ester enolate of methyl 3-methylbutenoate. 

Enantioselective condensation of aldehydes and enol silyl ethers is promoted by addition of chiral Lewis acids. Through coordination of aldehyde oxygen to the Lewis acids containing an Al, Eu, or Rh atom (286), the prochiral substrates are endowed with high electrophilicity and chiral environments. Although the optical yields in the early works remained poor to moderate, the use of a chiral (acyloxy)borane complex as catalyst allowed the erythro-selective condensation with high enan-tioselectivity (Scheme 119) (287). This aldol-type reaction may proceed via an extended acyclic transition state rather than a six-membered pericyclic structure (288). Not only ketone enolates but ester enolates... 

Asymmetric hydraxylation of lithium enolates of esters and amides.2 Hydroxylation of typical enolates of esters with ( + )- and (-)-l is effected in 75-90% yield and with 55-85% ee. The reaction with amide enolates with ( + )- and ( — )-l results in the opposite configuration to that obtained with ester enolates and with less enantioselectivity. Steric factors appear to predominate over metal chelation. 

Asymmetric formation of /i-lactams (38) in high ee has been achieved by reaction of achiral imines (36) with a ternary complex of achiral lithium ester enolate (35), achiral lithium amide, and a chiral ether ligand (37) (in either stoichiometric or catalytic amount) 45 the size and nature of the lithium amide have a considerable effect on the enantioselectivity of the ternary complex. 

The ester enolate-imine condensation, also called Gilman-Speeter reaction, is another well-accepted method for (3-lactam synthesis (Scheme 4) [67-69]. In 1997, Tomioka reported the first example of a direct catalytic enantioselective synthesis of (3-lactam by using this method [70]. The active reagent is a ternary complex (comprising LDA, the ester enolate, and tridentate amino diether), which finally affords the (3-lactam compounds in high yields and good ee values. 

An ion-pair derived from the substrate and solid NaOH forms a cation-assisted dimeric hydrophobic complex with catalyst 39c, and the deprotonated substrate occupies the apical coordination site of one of the Cu(II) ions of the complexes. Alkylation proceeds preferentially on the re-face of the enolate to produce amino acid derivatives with high enantioselectivity. However, amino ester enolates derived from amino acids other than glycine and alanine with R1 side chains are likely to hinder the re-face of enolate, resulting in a diminishing reaction rate and enantioselectivity (Table 7.5). The salen-Cu(II) complex helps to transfer the ion-pair in organic solvents, and at the same time fixes the orientation of the coordinated carbanion in the transition state which, on alkylation, releases the catalyst to continue the cycle. 

Among several chiral cyclic and acyclic diamines, (R,R)-cyclohexane-l,2-diamine-derived salen ligand (which can adopt the gauche conformation) was most effective in providing high enantioselectivity [38]. Further, the introduction of substituents at the 3,4, 5 and 6 positions on the aromatic ring of catalyst 39c was not advantageous, and resulted in low enantioselectivity [32,37,39]. The metal ions from first-row transition metals - particularly copper(II) and cobalt(II) - that could form square-planar complexes, produced catalytically active complexes for the asymmetric alkylation of amino ester enolates [38]. 

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on a,/S-unsaturated esters.27 Michael adducts have been obtained in ees up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction has been found to be determined by both the relative configuration of the stereogenic centres borne by the amide and the solvent. 

The use of a heteroatom a to the ester carbonyl group allows for the formation of a chelate with the metal counterion hence, the geometry of the ester enolate can be assured.336-338358359 This approach was used in the rearrangement of the glycine allylic esters 13 to y,8-unsaturated amino acids in good yields and excellent diastereoselectivity (Scheme 26.13).358 The enantioselectivity could be reversed by using quinidine instead of quinine. 

SCHEME 134. Enantioselective condensation of a lithium ester enolate on an imine in the presence of a chiral diether618... 

Highly enantioselective alkylations a to acyclic diene complexes have been developed. Deprotonation of (91) with LDA to form an ester enolate, followed by reaction with iodomethane, gives the alkylated prodnct (92) in excellent yield with 82% ee (Scheme 153). Stereospecific remote alkylation was used in a synthesis toward macrolactin A (Scheme 154). In the synthetic seqnence, the primary... 

The formation of carbon-carbon bonds by conjugate addition of carbonucleophiles to a,/3-unsaturated systems has been studied intensively and reviewed over the past few years . Interestingly, applications with simple, unstabilized lithium enolates are relatively rare. Most reported examples are limited to the addition of stabilized enolates, such as those derived from malonates or acetoacetates. Nevertheless, some diastereo- and enantioselective versions of the conjugate addition, even with unstabilized lithium enolates, are well known. In 2004, Tomioka and coworkers studied the influence of a chiral diether (191) on the 1,4-addition of lithium ester enolates (189) to a,-unsaturated ketones (equation 51) . Their investigations showed that good enantioselectivities were obtained with cyclic enones, like 2-cyclopentenone (190) addition to a mixture of 189 and 191 gave the desired 1,4-adduct (R)-192 with 74% ee, but only 47% yield. Unfortunately, also the Peterson product 193 was formed in a yield of 22% by initial 1,2-addition of the enolate to the Michael acceptor. 

TABLE 15. Enantioselective Michael additions of ester enolates using chiral amides (equation 53)... 

Aldol Reaction. In addition to the allyl derivatives (2) (eq 1), titanium ester enolates derived from chloride (1) react with aldehydes, affording aldol products after hydrolysis. Compared to the analogous reagents prepared from Chlow(cyclopentadienyl)bis[3-0-( 1,2 5,6-di-0-isopropylidene-a-D-glucofuranosyl)]-titanium the enantioselectivity of these... 

Ester Enolate Aldol Additions to Aldehydes. Among the first examples of aldol additions employing chiral Lewis bases as catalysts were the additions of trichlorosilyl ketene acetals to aldehydes. Silyl ketene acetal 7 could be generated by metathesis of methyl tributylstannylacetate with SiCL. Treatment of 7 with benzaldehyde and 10 mol % of a phosphoramide in CH2CI2 at —78°C afforded aldol products in good to high yields with moderate enantioselectivities for all phosphoramides employed. Reaction of 7 with pivalaldehyde provided aldol products in similar yields and with slightly improved enantioselectivities. The increase in stereoselection is presumably attributed to a less com-... 

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