Question

Draw the two major allylic alcohol intermediates and the two final products in the following two-step synthesis. Show the correct stereochemistry of each compound; if applicable, use wedge/dash bonds to indicate chirality centers, and you must show hydrogens on these centers.

Answer 1

Epoxidation of double bonds has proven to be an effective way of introducing oxygen functionality at both carbon atoms. One or two new stereogenic centers are normally created, often with excellent diastereoselectivity. This transformation is commonly carried out by the action of a peracid (RCO₃H), such as peracetic acid or perbenzoic acid, in chloroform or methylene chloride solution. The configuration of double bond substituents (E or Z) is generally preserved, as shown in equation 1 below. Electron donating substituents on the double bond facilitate this reaction, and in the case of deactivation by conjugated electron withdrawing groups, reaction with alkylhydroperoxide anions often achieves epoxidation by a conjugate addition-elimination pathway (equation 2). Steric hindrance usually diverts epoxidation to the less hindered face of a double bond; however hydrogen bonding to a neighboring hydroxyl group may provide a more powerful orienting influence, as in equation 3. In this case note also the selective epoxidation of the more substituted double bond.

Alternative reaction paths for epoxidation may result in a different diastereoselectivity, as demonstrated above by clicking on the diagram. The trans-fused cycloalkene outlined by the light green box in equation 4 may be epoxidized by a peracid or by base treatment of a bromohydrin intermediate. The upper or ?-face of the double bond is blocked by the angular methyl group, so peracid epoxidation occurs at the other face (designated ?). Addition of HOBr to the double bond is initiated by electrophilic bromine attack at the less-hindered ?-face, and since diaxial addition is favored stereoelectronically, the hydroxyl is bound to the ?-face. An Intramolecular S_N2 reaction then forms the diastereomeric epoxide. A similar strategy permits diastereoselectivity to be achieved for acyclic alkenes, such as that shown in equation 5. Here a nearby nucleophilic carboxyl group is positioned to reversibly open an iodonium intermediate, producing an iodolactone (central structure). Since this is a reversible reaction, the more stable trans-disubstituted lactone is the major product. Base catalyzed opening of the lactone forms an alkoxide species that immediately displaces iodide to give the epoxide product. Note that all the compounds in this equation are chiral and racemic.
It is known that epoxidation of isolated alkenes by tert-butyl hydroperoxide may be catalyzed by transition metal catalysts, and that an allylic hydroxyl facilitates and facially directs the reaction. By clicking on the above diagram a second time, examples of this reaction will be displayed, with equation 8 illustrating the neighboring group influence. Several features should be noted. First, the Z-configuration of the double bond is preserved in the epoxide products. Second, the allylic hydroxyl group exerts a modest facial diastereoselectivity on the reaction. For clarity the chiral carbinol group is drawn in its R-configuration, but the racemic alcohol would yield the same mixture of diastereomers as racemates.
Professor K. B. Sharpless, Scripps Research Institute, has transformed this general epoxidation reaction into a powerful enantioselective procedure, by the addition of a chiral tartrate ester ligand to a titanium alkoxide catalyst. This important synthetic method is outlined in the following diagram.

When mixed with one equivalent of diethyl tartrate, titanium tetraisopropoxide forms a dimeric complex with the loss of two isopropyl alcohol molecules. A proposed structure for this complex is shown on the right, with the titanium atoms colored green. Addition of tert-butylhydroperoxide and an allylic alcohol results in the displacement of two more isopropyl alcohols and the formation of a new reactive catalyst complex. A structure for this complex will also be displayed on the right by clicking on the original structure. In this new drawing the double bond of the allylic alcohol is colored blue, and the peroxide oxygens, one of which becomes the epoxide oxygen, are colored red. A pink arrow indicates the bonding of this oxygen to a prochiral face of the double bond. For primary allylic alcohols of the type shown above, Sharpless epoxidation achieves the remarkable conversion of an achiral substrate into a chiral product with high enantioselectivity.
In the reaction of secondary allylic alcohols, where substituent R² or R³ is an alkyl group (diagram on the right), the allylic alcohol substrate is chiral and the enantiomers react at different rates via diastereomeric transition states. For the racemic alcohol in which R² (or R³) is a cyclohexyl group, the S-enantiomer reacts over 100 times faster than the R-enantiomer, presumably due to steric hindrance of R². This rate difference results in a kinetic resolution of this substrate. The S-enantiomer is converted to its erythro diastereomeric epoxide in 98:2 diastereospecificity, while the R-enantiomer is recovered unchanged in over 96% ee.
A model of the Sharpless catalyst may be examined by .
Other catalyst systems for enantioselective epoxidation, as well as hydroxylation and hydrogenation of carbon-carbon double bonds, have been developed and are used in the manufacture of chiral intermediates. The 2001 Nobel Prize in chemistry was awarded to William S. Knowles, Ryoji Noyori, and K. Barry Sharpless for their seminal work in this important field.