Ketone propionate-derived chiral

We have already collected some powerful tools for use in stereocontrolled aldol reactions, but we have not finished. We shall see now in Paterson s synthesis of (+)-discodermolide, how reagent control is used not to enhance the intrinsic substrate selectivity, but to overturn it. The aldol reaction is undoubtedly one of the most powerful ways of making carbon-carbon bonds and nature thinks so too. There are numerous natural products that are replete with 1,3 related oxygen functionality. Many of these are acetate or propionate-derived in nature. The methods detailed above developed from studies into the syntheses of these natural products. The manipulations of chiral ethyl ketones of this kind are of particular interest when it comes to natural products that are polypropionate-derived. 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

The development of enantioselective aldol reactions has been widely studied in conjunction with the synthesis of natural products. Highly enantioselective aldol reactions have been achieved by employing chiral enolates of ethyl ketones and propionic acid derivatives.(1) On the other hand, achieving high asymmetric induction in the asymmetric aldol reaction of methyl ketones is still a problem.(2)... 

The reaction of enolates with aldehydes or ketones to produce /3-hydroxy carbonyl derivatives is a very common and a very useful way to make carbon-carbon bonds. A fundamental stereochemical feature of the reaction is diat two new chiral centers are produced from achiral starting materials. Hence syn and anti diastereomers will be produced, each as a pair of enantiomers. This is shown schematically for the reaction of a propionate enolate with isobutyraldehyde. Because they have different energies, the syn and anti diastereomers will be... 

At the time, many unsuccessful attempts were made to improve the selectivity of the mismatched anti aldol reaction mentioned above, outlining the limitations of some chiral ligands or auxiliaries at overcoming inherent substrate bias in anti aldol reactions. Since the completion of this work, we have introduced the lactate-derived ketones (/ )- and (S)-39, which should now allow the stereoselective synthesis of the ebelactones. As shown in Scheme 9-75, each enantiomer of the parent ketone acts as a propionate equivalent with a covalently attached auxiliary which will overturn the facial bias of most aldehydes [27, 28]. 

The two faces of a chiral aldehyde are diastereotopic, and reaction with an achiral enolate can therefore give two diastereomeric products. Qualitatively, the major and minor products of such a reaction are determined by the intrinsic diastereofacial preference of the chiral aldehyde, which may be evaluated by the use of Cram s rule or one of its more modem derivatives. Quantitatively, the diastereomeric ratio in such a reaction is a function of the enolate. An example is seen in Scheme 8. 2-Phenylpropanal reacts with the lithium enolates of acetone, pinacolone, methyl acetate and N,N-dimethylacetamide to give 3,4-syn and 3,4-ant diastereomers in ratios of 3 1 to 4 1. With ethyl ketones and propionate esters, the diastereofacial ratio is approximately 6 1 and with methyl isobutyrate only a single isomeric product is produced. This tendency of more bulky nucleophiles to give higher diastereofacial ratios in reactions... 

The first task was to prepare the chiral sulfoxide. The synthesis began with the conversion of methyl propionate (144) to keto-sulfide 145. Enzymatic reduction of the ketone using Baker s Yeast gave 146 with decent enantiose-lectivity. A directed oxidation of the sulfide provided an unequal mixture of sulfoxides 147 and 148 (and presumably minor amounts of material derived from the 4-5% of ent- 46 present in the starting material) from which 148 could be isolated in 50% yield. Dehydration of the alcohol provided 149 (along with some of the Z isomer). Notice that Mori decided to place the alcohol beta to the sulfoxide in the precursor of 149. There might be a number of reasons for this, but one is that it facilitated the elimination reaction (dehydration) because of the electron-withdrawing properties of the sulfoxide. 

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