Stereoselective synthesis conjugate addition

Stereoselective intramolecular conjugate addition reactions (Scheme 4) of dithiane anions tethered to an a,/ -unsaturated nitrile have been developed to advantage for the synthesis of axially substituted indolizidines and quinolizidines.81 The control of axial nitrile orientation by a peg-in-a-pocket template effect has been discussed. 

Hart, D.J. and Lai, C. (1989) Total synthesis of the axane-4 family of sesquiterpenoids using a stereoselective intramolecular conjugate addition. Synlett, 49-51. 

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). 

H )-Euranones are useful building blocks in the synthesis of a variety of organic compounds. In addition, they often serve as valuable synthetic intermediates in the stereoselective construction of substituted y-butyrolactones via conjugated addition to the Q ,/3-unsaturated carbonyl moiety or catalytic hydrogenation of the double bond (88JOC1560). 

Giblin, G.M.P., Jones, C.D., Simpkins, N.S. (1997) A Concise Stereoselective Synthesis of Epi-batidine Employing Conjugate Addition to an Alkenyl Sulfone Intermediate as the Key Step. Syniett, 589-590. 

There have been many applications of conjugate additions in synthesis. Some representative reactions are shown in Scheme 8.2. Entries 1 and 2 are examples of addition of lithium dimethylcuprate to cyclic enones. The stereoselectivity exhibited in Entry 2 is the result of both steric and stereoelectronic effects that favor the approach syn to the methyl substituent. In particular, the axial hydrogen at C(6) hinders the a approach. 

In the synthesis shown in Scheme 13.15, racemates of both erythro- and threo-juvabione were synthesized by parallel routes. The isomeric intermediates were obtained in greater than 10 1 selectivity by choice of the E- or Z-silanes used for conjugate addition to cyclohexenone (Michael-Mukaiyama reaction). Further optimization of the stereoselectivity was achieved by the choice of the silyl substituents. The observed stereoselectivity is consistent with synclinal TSs for the addition of the crotyl silane reagents. 

Diastereoselective conjugate addition of nucleophiles to enones, enals, and enoates occurs with high stereocontrol and constitutes a powerful method in stereoselective synthesis.185... 

The stereoselective synthesis of rac-chokols A (61) and G (62) from the same precursor gem-boriozirconocene 59 involves a conjugate addition to 2-methylcyclopentenone to give the common intermediate 60. The latter is then transformed through a series of reactions to provide the chokols in overall yields of 16% and 17%, respectively (Scheme 7.19) [131],... 

Similarly, 1,4-conjugated addition (242) of lithium divinylcyanocuprate to 238 gave the adduct 239, which on treatment with potassium carbonate in methanol produced the epoxide 240, a key intermediate for the synthesis of the carbocycline 241 through highly stereoselective processes. 

Scheme 3.7. Diastereoselective formation of /S-silyl ( )- or (Z)-ester enolates by silylcuprate conjugate addition followed by alkylation with aldehydes [49]. Stereoselective synthesis of ( )-and (Z)-allyl silanes [50].

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

Welch s stereoselective synthesis centered about the tandem conjugate addition of a methyl group and allylation to produce 583 (Scheme XLVI). A second methylation, combined with oxidation of the allyl sidechain, gave 584 which was successfully cyclized under Claisen conditions. Trapping of the enolate as in 585 permitted differentitation between the two potential ketone carbonyl groups. 

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