Asymmetric enolate alkylations

The A -acyl derivatives of 4-substituted-3,4,5,6-tetrahydro-27/-l,3-oxazin-2-ones proved to behave as effective chiral auxiliaries in asymmetric enolate alkylations and aldol reactions, the stereoselectivities of which were found to be higher for 4-isopropyl than for 4-phenyl derivatives <2006OBC2753>. The transformations of 4-isopropyl-6,6-dimethyl-3-propa-noyl-3,4,5,6-tetrahydro-2/7-l,3-oxazin-2-one 251 to 252 or 253 proceeded with excellent diastereoselectivities (Scheme 47). 6,6-Dimethyl substitution within the oxazine ring facilitated exclusive exocyclic cleavage upon hydrolysis of the C-alkylated and the aldol products 252 and 253, to furnish a-substituted carboxylic acids 254 or a-methyl-/ -hydroxycarboxylic acids 256. 

Scheme 3.16. Early examples of asymmetric enolate alkylations (a) Meyers s oxazolines [77-79] (b) Evans s [81,82] and Sonnet s [80] proline amide alkylations. ...

The aldol addition reaction, and the related crotyl metal additions (section 5.1), have figured prominently in the total synthesis of a number of complex natural products (reviews [48,140-142]). Figure 5.8 illustrates those mentioned in the preceding discussion, along with others selected from the recent literature, with the stereocenters formed by stereoselective aldol addition indicated ( ). For the Prelog-Djerassi lactone and ionomycin, recall (Figure 3.8) that most of the other stereo-centers were formed by asymmetric enolate alkylation. 

SCHEME 13.44. Asymmetric enolate alkylation in the synthesis of cyanthiwigin F. 

The first three sections of this chapter describe diastereoselective alkylations of chiral enolates including heteroatom-substituted enolates [15, 20]. Section 3.4 deals with the class of enolate alkylations that have typically been included under the rubric of chiral-auxiliary-controlled processes. As suggested by the term, the auxiliary is only transiently utilized and, following alkylation, is subsequently excised. The facile use of chiral auxiliaries in asymmetric enolate alkylations has played and continues to play a pivotal role in the stereoselective formation of new C-C bonds. After a brief survey of the relatively few developments in catalytic enantioselective enolate alkylations (Section 3.5) [21, 22], selected examples of enolate a-hydroxylations (Section 3.6) [23-25] and a-halogenations (Section 3.7) [26, 27] are covered. The corresponding a-aminations of enolates are discussed in Chapter 10, describing stereoselective formation of a-amino acids. 

Asymmetric Enolate Alkylations Using Chiral Auxiliaries... 

The investigations of Enders, Evans, and others have demonstrated the versatility of chiral auxiliaries based on the proline skeleton [80]. Katsuki designed and utilized a C2-symmetric, 2,5-disubstituted pyrrolidine auxiliary for asymmetric enolate alkylations (Equation 10) [81]. Enolates prepared from 112 generally undergo alkylations with superb diastereoselectivity dr >95 5). However, in contrast to the prolinol amide-derived systems described above, accessibility of the chiral auxiliary hinged upon a multi-step synthetic preparation involving resolution, and the hydrolytic removal of the auxiliary necessitated considerably harsher reaction conditions. 

In addition to the asymmetric induction mentioned above, sultam 53 can also be used to prepare enantiomerically pure amino acids (Scheme 2-29 and Table 2-10).55 Me AI-mediated acylation of 53 with methyl A-[bis(methylthio)-methylene]glycinate 56 provided, after crystallization, glycinate 57, which can serve as a common precursor for various a-amino acids. In agreement with a kinetically controlled formation of chelated (Z)-enolates, alkylation happened from the SZ-face of the a-C, opposite to the lone pair electrons on the sultam nitrogen atom. High overall yield for both the free amino acid 58 and the... 

Synthetic applications of the asymmetric Birch reduction and reduction-alkylation are reported. Synthetically useful chiral Intermediates have been obtained from chiral 2-alkoxy-, 2-alkyl-, 2-aryl- and 2-trialkylsllyl-benzamides I and the pyrrolobenzodlazeplne-5,ll-diones II. The availability of a wide range of substituents on the precursor benzoic acid derivative, the uniformly high degree of dlastereoselection in the chiral enolate alkylation step, and the opportunity for further development of stereogenic centers by way of olefin addition reactions make this method unusually versatile for the asymmetric synthesis of natural products and related materials. 

Transition Metal-Catalyzed Asymmetric Aliylic Alkylations of Enolates... 

Significant progress has been made on the asymmetric Pd-catalyzed aliylic alkylation of prochiral enolates, with a number of ligands now available that provide products with high ee. Trost was the first to demonstrate that high enantiomeric excesses were capable with ketoester substrates [29] now asymmetric aliylic alkylation of ketoesters and simple ketone substrates has been achieved in several more cases. Table 4 summarizes the ligands, substrates, and ee for recent examples. 

Scheme 8.1 also illustrates an important feature of asymmetric phase-transfer catalysis, namely that the catalyst is involved in two different steps of the mechanism. Thus, the rate of reaction increases because the catalyst accelerates the substrate deprotonation step, but the asymmetric induction occurs during the subsequent enolate alkylation step. 

Stereoselectivity is often controllable, but it seems to be inconsistent from one type of enolate to another. For example, most heterocyclic five-membered ring enolates seem to prefer syn addition495,518,519 while lactones often give a m -alkylation371,495,520. Asymmetric induction has been used successfully in complex enolate alkylation. The use of the novel, chiral PTC, A-(/ -(trifluoromethyl)benzyl)cinchonium bromide (PTBCBr) has also been used for stereocontrolled alkylation (equation 67) giving an enantiomeric excess of 92%521. 

Both resolution and Sharpless asymmetric dihydroxylation were successful in the synthesis of Crixivan but the best method is one v e shall keep till later. Only one stereogenic centre remains, and its stereoselective formation turns out to be the most remarkable reaction of the whole synthesis. The centre is the one created in the planned enolate alkylation step,... 

Stereoselective functionalization of enolates derived from 2-acyl-2-alkyl-1,3-dithiane 1-oxides Stereoselective enolate alkylation. There has been much interest over recent years in the enantio- and diastereocontrol of enolate alkylation.19 Most methods which do not rely on asymmetric alkylating agents hinge on a derivatization of the ketonic substrate with an enantiomerically pure auxiliary. Examples of such chiral auxiliaries include oxazolines20 and oxazolidi-nones.21 We reasoned that the sulfoxide unit present in our 2-acyl-2-alkyl-1,3-dithiane 1-oxide substrates might be expected to influence the transition-state geometry of a ketone enolate, perhaps by chelation to a metal counterion, and hence control the stereochemistry of alkylation. 

Asymmetric Mannich reactions.24 Our enolate alkylation methodology has been subsequently extended to include asymmetric Mannich reactions. The Mannich reaction can be viewed as an imino analogue of the aldol reaction and is a very common synthetic method for the preparation of P-aminoketones. 

It is worthwhile to apply the memory of chirality principle to asymmetric alkylation of a-amino acids because nonproteinogenic a,a-disubstituted-a-amino acids are important class of compounds in the fields of medicinal and biological chemistry.21 Typical methods for their asymmetric synthesis involve chiral auxiliary-based enolate chemistry 22-24 However, the most straightforward synthesis would be direct asymmetric a-alkylation of the parent a-amino acids in the absence of external chiral sources. Asymmetric... 

In 1999 Trost and Schroder reported on the first asymmetric allylic alkylation of nonstabilized ketone enolates of 2-substituted cyclohexanone derivatives, e.g. 2-methyl-1-tetralone (45), by using a catalytic amount of a chiral palladium complex formed from TT-allylpaUadium chloride dimer and the chiral cyclohexyldiamine derivative 47 (equation 14). The addition of tin chloride helped to soften the lithium enolate by transmetala-tion and a slight increase in enantioselectivity and yield for the alkylated product 46 was observed. Besides allyl acetate also linearly substituted or 1,3-dialkyl substituted allylic carbonates functioned well as electrophiles. A variety of cyclohexanones or cyclopen-tanones could be employed as nucleophiles with comparable results . Hon, Dai and coworkers reported comparable results for 45, using ferrocene-modified chiral ligands similar to 47. Their results were comparable to those obtained by Trost. 

Enolate Alkylations with Transition Metal Coordinated Electrophiles. Coordination of various transition metals to dienes and aromatic compounds sufficiently activates these compounds to nucleophilic addition, resulting in high asymmetric induction at the a-center. However, the manganese complexes of various benzene derivatives couple with lithium enolates in low selectivity at the nascent stereogenic center on the ring (eq 15). ... 

This methodology has been used to provide efficient protocols for the asymmetric allylic alkylation of p-keto esters, ketone enolates, barbituric acid derivatives, and nitroalkanes. Several natural products and analogs have been accessed using asymmetric desymmetrization of substrates with carbon nucleophiles. The palladium-catalyzed reaction of a dibenzoate with a sulfonylsuccinimide gave an advanced intermediate in the synthesis of L-showdomycin (eq 3). ... 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

As an extension of the elegant applications of chiral A -acyloxazolidinones to asymmetric aldolizations and enolate alkylations, Diels-Alder reactions of the unsaturated derivatives (351) and (355) were first described in 1984 (Scheme 86, Table 19). ... 

On the other hand, unsaturated aldehydes and ketones were obtained using allylic alcohols as alkene components [68]. Similarly, allyl f-butyldimethylsilyl ether and N-allylamides gave silyl enol ethers [69] and enamides [70], respectively. The ruthenium-catalyzed alkene-alkyne coupling was successfully combined with the palladium-catalyzed intramolecular asymmetric allylic alkylation [71] to provide a novel one-pot heterocyclization method [72]. 

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