Chiral conjugate additions

The primary disadvantage of the conjugate addition approach is the necessity of performing two chiral operations (resolution or asymmetric synthesis) ia order to obtain exclusively the stereochemicaHy desired end product. However, the advent of enzymatic resolutions and stereoselective reduciag agents has resulted ia new methods to efficiently produce chiral enones and CO-chain synthons, respectively (see Enzymes, industrial Enzymes in ORGANIC synthesis). Eor example, treatment of the racemic hydroxy enone (70) with commercially available porciae pancreatic Hpase (PPL) ia vinyl acetate gave a separable mixture of (5)-hydroxyenone (71) and (R)-acetate (72) with enantiomeric excess (ee) of 90% or better (204). 

Unsaturated chiral oxazolines have been employed in conjugate addition reactions... 

The sesquiterpenoid hydrocarbons (5)-a-curcumene (59) and (5)-xanthorrhizol (60) were prepared by asymmetric conjugate addition of the appropriate aryllithium reagent to unsaturated oxazoline 56 to afford alcohols 57 (66% yield, 96% ee) and 58 (57% yield, 96% ee) upon hydrolysis and reduction. The chiral alcohols were subsequently converted to the desired natural products. ... 

Chiral Cu(ll)-complexes ofbis-oxazolines as Lewis acids for catalyzed cycloaddition, carbonyl addition, and conjugate addition reactions 99PAC1407. 

Gothelf presents in Chapter 6 a comprehensive review of metal-catalyzed 1,3-di-polar cycloaddition reactions, with the focus on the properties of different chiral Lewis-acid complexes. The general properties of a chiral aqua complex are presented in the next chapter by Kanamasa, who focuses on 1,3-dipolar cycloaddition reactions of nitrones, nitronates, and diazo compounds. The use of this complex as a highly efficient catalyst for carbo-Diels-Alder reactions and conjugate additions is also described. 

Quite a number of asymmetric thiol conjugate addition reactions are known [84], but previous examples of enantioselective thiol conjugate additions were based on the activation of thiol nucleophiles by use of chiral base catalysts such as amino alcohols [85], the lithium thiolate complex of amino bisether [86], and a lanthanide tris(binaphthoxide) [87]. No examples have been reported for the enantioselective thiol conjugate additions through the activation of acceptors by the aid of chiral Lewis acid catalysts. We therefore focussed on the potential of J ,J -DBFOX/ Ph aqua complex catalysts as highly tolerant chiral Lewis acid catalyst in thiol conjugate addition reactions. 

The l ,J -DBFOX/Ph-transition metal aqua complex catalysts should be suitable for the further applications to conjugate addition reactions of carbon nucleophiles [90-92]. What we challenged is the double activation method as a new methodology of catalyzed asymmetric reactions. Therein donor and acceptor molecules are both activated by achiral Lewis amines and chiral Lewis acids, respectively the chiral Lewis acid catalysts used in this reaction are J ,J -DBFOX/Ph-transition metal aqua complexes. 

Sdi ir 6.1. Diactereocelectivity in conjugate addition of organociipratec to chiral o/clic enonec. 

A result equivalent to an allylic substitution reaction with a chiral leaving group can also be achieved by a two-step procedure involving a conjugate addition reaction and a subsequent elimination reaction, as demonstrated by Tamura et al., wbo studied the reaction shown in Scheme 8.15 [27]. 

The Hantsch pyridine synthesis provides the final step in the preparation of all dihydrop-yridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. Tlie need to produce unsymmetrically subsrituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate foniis an aldol product (30) with aldehyde 29 conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8]. 

The conjugate addition of lithium cuprates to cinnamates 1 bearing a chiral oxazolidine or imidazolidine ring at the ortho position produced 2 in good to excellent yield upon hydrolysis14. 

I.5.2.I.I.4. Conjugate Addition of Chiral Organometallic Reagents External Stoichiometric Chiral Ligands... 

Butvlcyclohexanone by Conjugate Addition of a Chiral Hetcrocuprate Derived from C to 2-Cyclo-hexenone (Table 4, Entry 9) Typical Procedure ... 

The conjugate addition to acyclic enones is summarized in Table 5. The chiral hetero-cuprate derived from (S)-prolinol or cinchonidine produced products of low enantiomeric excess on treatment with chalcone (entries 3 and 4), while the cuprate from (S)-yV-methylpro-linol gave 64% ee (entry 6). Under more dilute conditions, 88% cc was obtained (entry 5). (2[Pg.909]

Table 5. Conjugate Addition to Acyclic Enones with External Chiral Ligands O, O...

The reaction of butyllithium with 1-naphthaldehyde cyclohexylimine in the presence of (/C )-l,2-diphenylethane-1,2-diol dimethyl ether in toluene at —78 °C, followed by treatment with acetate buffer, gave 2-butyl-1,2-dihydronaphthalene-l-carbaldehyde, which was then reduced with sodium borohydride in methanol to afford (1 R,2.S)-2-butyl-1 -hydroxymcthyl-1,2-dihydronaphthalene in 80% overall yield with 91 % ee83. Similarly, the enantioselective conjugate addition of organolithium reagents to several a,/J-unsaturated aldimines took place in the presence of C2-symmetric chiral diethers, such as (/, / )-1,2-butanediol dimethyl ether and (/, / )- ,2-diphenylethane-1,2-diol dimethyl ether. 

Combination of nickel bromide (or nickel acetylacetonate) and A. A -dibutylnorephcdrinc catalyzed the enantioselective conjugate addition of dialkylzincs to a./Tunsaturated ketones to afford optically active //-substituted ketones in up to ca. 50% ee53. Use of the nickel(II) bipyridyl-chiral ligand complex in acetonitrile/toluenc as an in situ prepared catalyst system afforded the //-substituted ketones 2, from aryl-substituted enones 1, in up to 90% ee54. 

Alkenylcuprates bearing a stereogenic center at the y-position were prepared and used for the synthesis of prostaglandin derivatives. Thus, the conjugate addition of 1 to chiral 2 followed by protonation gave 3 with very high diastereoselectivity623,81. 

In contrast, the diastereoselectivity of the conjugate addition of a chiral alkenylcoppcr-phosphinc complex to 2-mcthyl-2-cyclopentenone was dictated by the chirality of the reagent63. The double Michael addition using the cyclopentenone and 3-(trimethylsilyl)-3-buten-2-one and subsequent aldol condensation gave 4 in 58 % overall yield. The first Michael addition took place from the less hindered face of the m-vinylcopper, in which chelation between copper and the oxygen atom fixed the conformation of the reagent. 

An example for synthesis of the chiral [l-keto ester 69 is illustrated in equation 64. It involves conjugate addition of the dipotassium / -keto ester 68 to vinyl sulfone 67 followed by in situ quenching with allyl bromide54. The method provides a new procedure to sevenring annulation product 70 that is a potential precursor for (l)-(-)-cytochalasin C. 

Conjugate addition of chiral amines to allenic and acetylenic sulfones has been reported73. The reaction 112 with (—)-ephedrine gives only one of the two possible diastereomeric oxazolines in high yield (equation 89). 

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