Conjugate addition stereoselectivity

Although some significant advances have been made, the problem of conjugated addition stereoselectivity is still far from being completely clarified. For an illustrative example, see ref.116. 

Another inventive total synthesis of ( )-a- and ( )- lycorane is completed by sequential chemoseleclive conjugate addition-stereoselective nitro-Michael cyclization of a to-nitro-a,p,< ),a)-unsaturated ester [32]. This approach is based on the following retrosynthelic analysis (Scheme 9.21). 

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). 

The stereoselective introduction of two methyl groups into / -(- -)-5-hydroxy-methyl-2(5// )-furanone 143 was effected by tritylation followed by the conjugated addition (87JOC1170) of McaCuLi (TMSCl/EtaO, -78°C) and, finally, treatment with LiN(TMS)2/MeI (Scheme 43) (97TL1439). 

The stereoselective conjugate addition of lithium (Z)-dialkenylcuprates to vinyl sulfones gives (Z)-olefms in the range of 70-80% overall yield and no ( )-isomer is detected (equation 66)56. The degree of stereoselectivity is higher than 90%. 

Successful applications of these stereocontrolled conjugate additions have led to asymmetric syntheses of several natural products such as (+ )-cuparenone (39) which involves formation of a quaternary carbon center81, (- )-/ -vetivone (40)8° and steroidal equilenin 4182 the wavy lines in these structures indicate that C—C bond formed stereoselectively under the influence of a temporarily-attached stereogenic sulfoxide auxiliary group. 

Given the above possible reaction mechanism, it is then intriguing to speculate that another approach to the same stereoselective reduction of a vinyl sulphone could be achieved by the use of a suitably sterically hindered organosilane, as outlined in equation (64). Such a reaction would provide an interesting test for the stereoelectronics of a conjugate addition reaction by a second-row heteroatom to a vinyl sulphone. 

Stereoselection of Nucleophilic Conjugate Addition 6.1 Bicyclic Systems... 

The stereoselectivity of conjugate addition and cyclopropanation of the chiral nitrovinyldioxolanes 17 can be effectively controlled <96TL6307>, and good selectivity is observed in the ultrasound-promoted cycloaddition of nitrile oxides to alkenyldioxolanes 18 <95MI877,95JOC7701 >. Asymmetric Simmons-Smith cyclopropanation of 19 proceeds with... 

Potential precursors to stereoselective INOC and ISOC reactions (e.g., 195 and 196, respectively) have been prepared via stereoselective conjugate additions of several allylic alcohols (e.g., 194,X = 0) and an allylic thiol (e.g., 194,X = S) to a chiral (E)-nitro alkene (e. g., 193) that was derived from (P)-2,3-isopropylidene... 

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. 

The catalytic enantioselective addition of vinylmetals to activated alkenes is a potentially versatile but undeveloped class of transformations. Compared to processes with arylmetals and, particularly alkylmetals, processes with the corresponding vinylic reagents are of higher synthetic utility but remain scarce, and the relatively few reported examples are Rh-catalysed conjugate additions. In this context, Hoveyda et al. reported very recently an efficient method for catalytic asymmetric allylic alkylations with vinylaluminum reagents that were prepared and used in Thus, stereoselective reactions... 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

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. 

In addition, Wu and Li recently have developed an efficient rhodium-catalyzed cascade hydrostannation/conjugate addition of terminal alkynes and unsaturated carbonyl compounds in water stereoselectively (Scheme 4.5).88... 

---