Auxiliaries, chiral ester enolates

Scheme 8.2S. a-Amidation of chiral ester enolates using di(ter/-butyl)azodicarboxylate and (a) N-methylephedrine [106] or (b) oxazolidinone chiral auxiliaries [107], Azidation of a chir eno ate... 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

Perlmutter used an oxymercuration/demercuration of a y-hydroxy alkene as the key transformation in an enantioselective synthesis of the C(8 ) epimeric smaller fragment of lb (and many more pamamycin homologs cf. Fig. 1) [36]. Preparation of substrate 164 for the crucial cyclization event commenced with silylation and reduction of hydroxy ester 158 (85-89% ee) [37] to give aldehyde 159, which was converted to alkenal 162 by (Z)-selective olefination with ylide 160 (dr=89 l 1) and another diisobutylaluminum hydride reduction (Scheme 22). An Oppolzer aldol reaction with boron enolate 163 then provided 164 as the major product. Upon successive treatment of 164 with mercury(II) acetate and sodium chloride, organomercurial compound 165 and a second minor diastereomer (dr=6 l) were formed, which could be easily separated. Reductive demercuration, hydrolytic cleavage of the chiral auxiliary, methyl ester formation, and desilylation eventually led to 166, the C(8 ) epimer of the... 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

A further attempt has been made to develop a predictive model for chirality transfer achieved through alkylation reactions of ester enolates which feature chiral auxiliaries. " Hippurate esters (30) derived from (lI , 25 )-trani-2-(p-substituted phenyl)cyclohexanols were found, on reaction with benzyl bromide, to give (31) with predominantly the S configuration at the alkylation centre but with no correlation between the degree of stereoselectivity (20-98%) and the electron density on the aromatic ring. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

Fujisawa et al. [89] have reported the stereodivergent synthesis of spiro-[S-1 act a ms 64, 65 (Scheme 17) by reaction of lithium or titanium ester enolates 62 with single chiral imines 63 by taking advantage of different coordination states of the enolate metals. Almost complete reversal of the diastereofacial-discrimination with respect to the C-4 of the (3-lactam skeleton has been attained in this reaction coupled with flexibility in the selection of the enolates and ready removal of the chiral auxiliary. 

The alternative strategy of using d,v-aminoindanol as a chiral auxiliary on the Michael donor has also been explored.81 Chiral amide enolates were reacted with a,P-unsaturated ester 70, and the resultant adducts were reduced and cyclized to 8-lactones 73 to determine the facial selectivity on the Michael acceptor. It is interesting that protected amino alcohol 71 did not lead to significant diastereofacial discrimination, whereas 72 afforded lactone 73 with high 4-(,S )-selectivity (Scheme 24.15). 

From the (/ )-cysteine methyl ester 22 the thi-azolidine 9 is obtained, which can be deproto-nated with LDA. The attack of the methyl iodide on the enolate takes place from the side opposite to the bulky terr-butyl group (23 10). The auxiliary chiral center is removed under acidic conditions and (/ )-2-methylcysteine methyl ester hydrochloride Sb X FICI is obtained. (S)-2-Methyl-cysteine methyl ester hydrochloride ent-5b X FlCl can be prepared in the same way from (Sl-cysteine. 

Mulzer, J, Hiersemann, M, Buschmann, J, Luger, P, l,2 5,6-Di-0-isopropylidene-a-D-gulofuranose as a chiral auxiliary in the diastereoselective C-methylation of ester enolates, Liebigs Ann. Chem., 649-654, 1995. 

The formation and further transformation of esters belongs to the fundamentals of organic chemistry. Moreover, some esters have enormous importance for example triglycerides (1), in the form of fats and oils, are produced in million ton quantities for a number of applications. Other esters, e.g. (2) and (3), are olifactory components waxes, e.g. (4), are used commercially to protect metallic surfaces against corrosion. Aspartame (5) is an important artificial sweetener, and pyrethrin (6) is the prototype of the pyre-throids, an unusually potent class of insecticides. Apart from these more applied considerations, esters are important synthetic intermediates in a number of multistep sequences. Striking examples are chain elongations via Homer alkenation or a-alkylations of ester enolates, in particular the ones stereocon-trolled by chiral auxiliaries. ... 

As will be described below, self-reproduction of chirality can be accomplished through alkylations of endocyclic as well as exocyclic enolates. It generally entails (i) production of a ring containing a temporary, auxiliary chiral center by derivatization of an optically active a-hydroxy or a-amino ester (ii) formation of an enolate by deprotonation at the original asymmetric a-carbon atom (iii) use of intramolecular chirality transfer to control the stereochemistry of alkylation of the enolate and (iv) generation of the chiral a-alkylated ester by hydrolysis. 

Addition of diethyl aluminum chloride at — 78 °C to a,/ -unsaturated oxazolidinone (154) affords an aluminum enolate that, on hydroxylation with (63a), gives the / -ethyl-a-hydroxy amide (155) with high anti selectivity (Equation (38)) <91AG(E)694>. Formation of the enolate of oxazoline thiol ester (156) under chelation (NaHMDS) and stereoelectronic (NaHMDS/HMPA) control gives the syn and anti alcohols (157), respectively, on hydroxylation with (63a) in good to excellent yield and better than 95% diastereoselectivity (Scheme 28) <93JOC6180>. A counterion dependent reversal in stereochemistry has also been reported for the hydroxylation of chiral amide enolates where the auxiliary was 2-pyrrolidinemethanol <85TL3539>. 

The reaction of ester enolates with imines is a general method for the preparation of /5-lactams. This reaction is clearly not a concerted cycloaddition. The enolate adds to the imine generating an arnido ester intermediate. This intermediate, which is usually not isolated, cyclizes to give the /3-lactam. Since this subject has been recently reviewed81, only the stereochemical aspects of this reaction will be discussed here. In this reaction there are four possible sites for the chiral auxiliary. As in ketene imine cycloadditions, stereogenic centers can be introduced into the substituent on the imine carbon (R1), the substituent on the imine nitrogen (R2) or the substituent on the acyl portion of the ester (R3). There is a fourth possibility in these cycloadditions since the stereogenic center can also be introduced into the alkyl portion of the ester (R4), In some cases /r K-/ -lactams are obtained exclusively, while in other cases, mixtures of cis- and trans-isomers are isolated. 

Chiral enolates in which the auxiliary is in the ester portion provide still another route to optically active lactams. Early results indicated that little asymmetric induction was obtained with menthyl enolates. Use of the enolate obtained from 24 did lead to high levels of asymmetric induction. Treatment of 24 with lithium diisopropylamide in tetrahydrofuran, followed by addition of imine 25, gives cf -/(-lactam 26 in 79% yield and 91%ee98. Optically active /3-lactams can be prepared by addition of chiral iron enolates (see Section D.l. 1.1.3.2.) to imines99-101. Addition of aluminum enolate 27 to imine 28, followed by oxidative cyclization with iodine and an amine, affords /(-lactam 29 in 54% yield and >95% ee. 

Scheme 3.15. Controlled stereoselective enolate formation and asymmetric alkylation of a second generation camphor ester enolate chiral auxiliary [75].

While more plentiful, alcohol-based chiral auxiliaries have been limited in their ability to direct the diastereoselective hydroxylation for the preparation of tertiary a-hydroxy acids. Among these, the best results in this series were obtained when oxidation of the enolate of chiral ester substrate 24 with (+)-5 yielded (5)-25.ub The use of (-)-S as the hydroxylating agent, provided a reversal in stereoselectivity, providing (i )-25. Interestingly, when substoichiometric amounts (0.5 equiv) of (+)-5 were used, stereoselectivity improves (94% de), a fact attributed to the matching of the enolate geometry to the oxidant. This speculation is credible, as evidenced by the fact that oxidation with 0.50 equivalent of (-)-5 produces (5)-25 in only 37% de in a stereochemically mismatched case. 

As an example, ferf-butyl (45)-l-methyl-2-oxoimidazolidine-4-carboxylate was used by Nunami and colleagues as a chiral auxiliary for DKR of a-bromo-carboxylic acids. In this case, the nucleophile was a malonic ester enolate and the role of the polarity of the solvent (hexamethylphosphoramide, HMPA) was demonstrated (Scheme 1.2). The alkylated products were further easily converted to chiral a-alkylsuccinic acid derivatives and chiral jS-amino acid derivatives. Moreover, these authors showed that this methodology could be extended to other nucleophiles such as amines." Therefore, the reaction of a diastereomeric mixture of tert-bvAy (45)-l-methyl-2-oxoimidazolidine-4-carb-oxylate with potassium phthalimide predominantly afforded fcrf-butyl (45)-1-methyl-3-((25)-2-(phthaloylamino)propionyl)-2-oxoimidazolidine-4-carboxylate in 90% yield and 94% diastereomeric excess (de). The successive removal of the chiral auxiliary afforded A-phthaloyl-L-alanine. 

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