Auxiliary-Based Conjugate Additions

In conjugate additions of strong nucleophiles to a,P-unsaturated carbonyl compounds, the chiral auxiliary can be bound to the acceptor or the donor, and several procedures following both concepts have been developed. As outlined in Section 2.2, enolates are involved in two different roles as intermediates that result from the conjugate addition to the a,P-unsaturated carbonyl compound and as nucleophilic reagents in Micheal additions. 

Oppolzer and coworkers took advantage of a diastereoselective protonation of the cis-enolate resulting from the conjugate addition of alkylmagnesium 

The stereochemical outcome of this diastereoselective conjugate addi-tion/protonation is convincingly rationalized by the authors, who have proven that the intermediate enolate 392 is cis configured by a crystal structure of the O-acylated derivative. It was proposed that in the enolate 392, the lone electron pair on the nitrogen atom is located in the plane perpendicular to the Ji-system 

A recent study enlightening the stereochemistry of the Michael addition was performed by Kwan and Evans, based on DFT calculations. The essential result may be considered a synopsis of Heathcock s closed transition states and the 

In summary, the auxiliary-based enolate chemistry is much less developed for conjugate addition reactions than for aldol additions. It seems that the enantiose-lective catalysis in the Michael reaction (see Section 5.5) has, in a sense, surpassed the auxiliary concept. 

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Selective labelling of the two diastereotopic methyl groups of i-leucine (144) has enabled their fates during secondary metabolic reactions to be elucidated [66]. Moreover, in the context of protein interactions, differentiation of the leucine pro-R and pro-S methyl groups in protein NMR spectra allows molecular recognition phenomena to be studied [67]. Recently, efficient routes to both forms of Relabeled leucine, based on application of an auxiliary-controlled stereoselective conjugate addition reaction (Scheme 6.27) have been described [68]. Thus, starting... 

Using these optimized conditions, the conjugate addition of 45 to the malonates 49 in the presence of the solid base provided access to the Michael adducts in good yields and high diastereoselectivities. The removal of the chiral TADDOL auxiliary could be accomplished without epimerization or racemization in this case, too. After esterification of the very polar acid intermediates with diazomethane the corresponding dimethyl esters 52 were obtained with yields of 72-94% and enantiomeric excesses ee of 84-94% (Scheme 1.1.13). 

The first successful approaches were based on the, often Cu-mediated, conjugate addition of organolithium and organomagnesium (Grignard) reagents to o ,/ -unsaturated systems covalently modified with chiral auxiliaries (Scheme 1 ). ... 

As fas as reaction conditions are concerned, two main approaches are usually taken. Either the nucleophilicity of the R5OH to be added is further enhanced by addition of base (normally R50 M +, or nitrogen bases of low nucleophilicity), i.e., base catalysis, or the electrophilicity of the accepting double bond is further increased by adding, e.g., mercuric salts (alkoxymercu-ration), or sources of halonium ions (formation of / -halohydrins). Clearly, the latter protocol, from now on abbreviated as "onium-methods , necessitates a subsequent step for the removal of the auxiliary electrophile, e.g., reductive demercuration of an intermediate /i-alkoxymercu-rial. Whereas base catalysis has successfully been employed with all varieties of acceptors, application of onium-methods thus far appears to be restricted to a,/ -unsaturated carbonyl compounds. Interestingly, conjugate addition of alcohols to a,/l-enones could also be effected photochemically in a couple of cases. 

SCHEME 10.62 The stereochemical course of the conjugate addition of organocuprates to a,P-unsaturated esters can be influenced using sugar-based auxiliaries. 

Initiated by conjugate addition of iodide ion, which is under stereocontrol by the chiral auxiliary of an iV-alkenyl-2-oxazolidinone, a tandem intramolecular alkylation is also enan-tioselective. Based on this reasoning it is possible to prepare cyclic compounds with new stereocenters of defined absolute configuration. ... 

Other auxiliaries are also used, and the choice of auxiliary may depend not only on the selectivity of the reaction under investigation but also on the physical properties of the products. The camphor-based auxiliary of Oppolzer is reputed to confer crystallinity on its derivatives, while the pseudoephedrine auxiliary of Myers is cheap, readily available, and very easy to introduce. More bulky auxiliaries such as 8-phenylmenthol work well where control over long-range interactions, such as conjugate additions, are required. 

Aside from Coreys phenylmenthyl propanoate 424, several chiral enolates have been utilized for Michael additions with substantial degrees of diastereoselectiv-ity. Yamaguchi s group developed a series of chiral amide enolates 436 and studied the conjugate addition to crotonates [210]. Another remarkable early contribution came from Oppolzer and coworkers who used dienolate 437 for diastereoselec-tive consecutive additions to cyclopentenone and allylation [211]. The auxiliaries 436 and 437 served for total syntheses of terpenoid natural products. Diastereos-elective Michael additions were also achieved by means of imidazolidinone-based lithium enolate 438 [212] - another showcase of the efficiency of imidazolidinone 118 [54] (Scheme 4.94). 

Shu Kobayashi of the University of Tokyo found Organic Lett. 2008,10, 807) that the conjugate addition of 25 to 24 mediated by a chiral Ca catalyst proceeded with high enantiocontrol at both of the newly formed stereogenic centers, to give 26. In a chiral auxiliary based approach, Dennis C. Liotta foimd J. Org. Chem. 2008, 73,1264) that condensation of 27 with 28 gave predominantly just two of the possible four diastereomeric azetines. Alkylation of the cis diastereomer, followed by benzoylation and hydrolysis, then delivered the a-quatemary 3-amino acid derivative 29 as a single enantiomerically-pure diastereomer. 

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