Syn-selective aldol reaction

Typical starting materials, catalysts, and products of the enamine-catalyzed aldol reaction are summarized in Scheme 17. In proline-catalyzed aldol reactions, enantioselectivities are good to excellent with selected cyclic ketones, such as cyclohexanone and 4-thianone, but generally lower with acetone. Hindered aldehyde acceptors, such as isobutyraldehyde and pivalaldehyde, afford high enantioselectivities even with acetone. In general, the reactions are anti selective, but there are aheady a number of examples of syn selective enamine aldol processes [200, 201] (Schemes 17 and 18, see below). However, syn selective aldol reactions are still rare, especially with cychc ketones. 

Phenoxide anions have been proved to be good Lewis base catalysts to promote syn-selective aldol reaction between TMS enolates and aldehydes.31... 

Boron enolates generated from a-heterosubstituted thioacetates by treatment with 105 undergo highly enantioselective and diastereoselective condensations. On the other hand, chiral esters 106 and 107, and amides 108 behave differently. V-Acyl derivatives of the bicyclic isoxazolidine 109 ° readily undergo syn-selective aldol reactions via enol borates. 

As the reasons for the diastereoselectivity of syn-selective aldol reactions are well established we will focus on the selectivity of the ring closure. We have carried out studies on intramolecular oxymercurations of a series of simple alkenols related to 8 and have found that they consistently close to give predominantly syn and not anti products (Fig. 3). 

The complex of NaGeEt, with SmClj promotes a syn-selective aldol reaction of ketones and amides with aldehydes in the presence of HMPA in THF. The enolization step at 0° is followed by treatment of the aldehydes at -78°. 

Stereoselective anti-aldol reactions. As part of a synthesis of (>olypropionate natural products, Evans et al. have studied the stereoselectivity of the reaction of isobutyraldehyde with the chiral -ketoimide la, which has been shown to undergo syn-selective aldol reactions. Surprisingly, the (E)-boron enolate, generated in ether from dicyclohexylchloroborane and ethyidimethylamine, reacts with isobutyraldehyde to give the anti, anti-a Ao 2 and the syn, anti- AAo 2 in the ratio 84 16. Similar diastereoselectivity obtains with the reaction of the isomeric jS-ketoimide lb. 

A focused compound collection of 99 compounds with a fi-lactone core structure was synthesized (Scheme 8.1) [7]. Thirty compounds with a sy -configuration around the P-lactone core were synthesized by syn selective aldol reactions of ethyl esters and aliphatic aldehydes [14]. The syn aldol products were saponified... 

The chiral pool refers to readily available optically active natural products, some of which are commercially used in quantities of 10 -10 tonnes per year [5], Among them, the most inexpensive compounds are a-amino acids, like monosodium L-glutamate, or carbohydrates, like dextrose or sorbitol. The success of the second method depends on the availability of particular catalysts. One rather special example, how efficient stereoselective synthesis can work, is the syn-selective aldol reaction followed by a stereoselective alkene hydroboration and ketone reduction (Figure 1.8) which were used by Paterson et aJ. [26] to synthesize intermediates for the antibiotic oleandomycin. According to Paterson et al., four new stereocenters are formed in only two synthetic steps [9]. For the purpose of separating racemic mixtures... 

Syn-selective aldol reactions involving directly generated thiol ester enoiates were reported to give moderate to good selectivity and moderate yield, as shown in Table 2.11 [29]. Modest anti-selectivity was obtained in reactions of 2-pyridylthiopropionate (entry 7), suggesting the 2-pyridyl moiety could be coordinating with titanium. 

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