Stereochemistry aldol

Z)-enolates. The product was subjected to selective deprotection of the C4,C4 -methyl ethers with Mgl2, providing the natural structure of hypocrellin A as the major product. The two newly formed stereocenters in the 7-membered ring were determined to conform to the predicted helical (/ -stereochemistry and the syn-aldol stereochemistry. The minor ( )-enolate afforded the anti aldol product, which matched the diastereomeric natural product shiraiachrome A (8). With this step, the first total syntheses of hypocrellin A and shiraiachrome A (symanti = 10 1 syn diastereomer, 92 % ee) were completed. 

The steric influence of the enolate substituents Ri and Rj plays a dominant role in the alteration of kinetic stereoselectivity, whereas the aldehyde ligand appears to contribute to a minor extent. Good correlation between enolate geometry and aldol stereochemistry is possible when Rj is sterically demanding and Rj.is sterically subordinate (Rj = methyl or n-alkyl). In this case dominant path A stereoselection is observed. When R2 becomes sterically demanding (R2 = t-Bu) path B stereoselection is observed and becomes dominant. 

TABLE 3. Yields and aldol stereochemistry of chiral dioxolones... 

Thioamide enolates are also interesting substrates for the stereoselective aldol-type reactions. The aldol stereochemistry is very sensitive to the conditions of preparation of magnesium thioamide enolates and it generally gives different results depending on the procedure used. Illustrations of some aspects of the reactivity are provided in the examples presented below. 

Introduction and definitions Stereoselective and stereospecific Aldol Stereochemistry... 

Introduction and stereochemical control syn,anti and E,Z Relationship between enolate geometry and aldol stereochemistry The Zimmerman-Traxler transition state Anti-selective aldols of lithium enolates of hindered aryl esters Syn-selective aldols of boron enolates of PhS-esters Stereochemistry of aldols from enols and enolates of ketones Silyl enol ethers and the open transition state Syn selective aldols with zirconium enolates The synthesis of enones E,Z selectivity in enone formation from aldols Recent developments in stereoselective aldol reactions Stereoselectivity outside the Aldol Relationship A Synthesis ofJuvabione A Note on Stereochemical Nomenclature... 

Only in modern times has aldol stereochemistry seemed a subject worth studying, or indeed even accessible to chemists. Formerly it was left to look after itself. Then Dubois carried out some simple experiments on the condensations between cyclic ketones and aldehydes in base.3 Though largely neglected at the time, these results showed that if LiOH (not NaOH) was used as the base, the anti aldol predominated. Indeed, with cyclopentanone and /-PrCHO, >95% anti-5 was formed, and syn-5 could not be detected. Later Heathcock4 showed that the lithium enolate of the open chain ketone 6 condensed with PhCHO to give >98 2 syn ami aldol 7. 

Relationship between enolate geometry and aldol stereochemistry... 

The relationship between enolate geometry and aldol stereochemistry has now been well established for many aldol reactions. The geometry of lithium enolates expresses itself through the so-called Zimmerman-Traxler5 transition state which is nothing more than the six-membered cyclic transition state that we met in the last chapter. When a lithium enolate reacts with an aldehyde, both the enolate and aldehyde oxygen atoms coordinate to the lithium atom 10 so that the transition state 11 is a partly unsaturated six-membered ring. 

Corey used an ester and a thioester in combination with an optically pure boron reagent in order to control both relative and absolute aldol stereochemistry.10 The optically pure boron reagent was busy with the absolute control (the details belong in chapter 27 but 69 was 94% ee and 71 97% ee by virtue of the chiral boron reagent). 

The tandem aldol reaction simply involves adding an aldehyde to the lithium enolate before work-up. Since it is a Z-enolate we can expect a syn aldol. The Z -enolate 90 is indeed formed (we are drawing the molecules in a different way to make the aldol stereochemistry clearer) and it does give a syn-aldol with the added advantage that only one of the two possible. vyn-aldols 90 predominates. The two benzylic groups can be removed, the first with CAN , ceric ammonium nitrate, Ce(IV)(NH4)2(N03)6 and the second by reduction, to give one enantiomer of 95. 

The first step is of course the aza-Diels-Alder reaction 218 with no regioselectivity but lots of stereochemistry. The cis ring junction in 217 comes from the cis alkene in maleimide and the endo transition state gives the remaining centre. The next step is an allyl boronate reaction 219 with the aldehyde. Coordination of the aldehyde oxygen with the boron ensures that the aldehyde is delivered to the top face and the aldol stereochemistry comes from the six-membered cyclic transition state. Snieckus comments that the reaction works well as a tandem process because the 4 + 2 cycloaddition is slower than the allyl boronate reaction so the unstable intermediate does not accumulate. This comment has more general application. 

Boron enolates (other names are vinyloxyboranes, enol borinates, or boron enol ethers) are often employed in the aldol reaction because they show higher stereoselectivity than alkali and magnesium enolates. Extensive developmental work in this area has been carried out by Evans, Masamune and Mukaiyama, and their respective coworkers. - - The correspondence between enolate geometry and aldol stereochemistry is exceptional (Z)-enolates give syn/erythro aldol products, whereas ( )-enolates give anti/threo aldol products, albeit with slightly lower selectivity. 

In a 1964 paper, Stiles and coworkers isolated and identified diastereomeric aldols. However, the first person to address the question of aldolization stereochemistry in a serious manner was the French physical organic chemist J.-E. Dubois." His first study was of the KOH-promoted aldolization of cy-clopentanone with several aliphatic aldehydes (equation 93) " the results are summarized in Table 5. In this discussion of the Dubois work, we use the stereochemical descriptors threo and erythro in the same sense that they were employed in the original Dubois papers, in order to avoid confusion for those... 

On the other hand, it has been found that (3-lactams having other substituents at C-1 and C-4 give complex isomer mixtures.A typical example is shown in equation (95) anti and syn aldols (139) and U40) are formed in excellent yield, but in a ratio of 1 1. Another example is seen in the reaction of 3-lactam (141 R = SPh) aldols (142) to (145) are produced in a ratio of 34 27 11 23 (equation 96). Similar results are obtained with the 4-trityl derivative (141 R = CPha) aldols (142) to (145) are formed in a ratio of 32 39 12 l . However, the lithium enolate of 3-lactam (146) reacts with acetaldehyde to give a single aldol (147) in 80% yield (equation 97) The implication from these results is that the meth-oxymethyl group in (146) effects the stereoselectivity, both facial and simple, by coordination of the lithium cation. Again, (147) has anti aldol stereochemistry, as is expected for an ( -enolate. 

Uncatalyzed Additions of Nucleophilic Alkenes to C=X Table 18 Aldol Stereochemistry (equation 110)... 

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