Aldol reactions syn-anti selectivity

High anti-diastereoselectivity is observed for several aromatic imines for ortho-substituted aromatic imines the two newly formed stereocenters are created with almost absolute stereocontrol. Aliphatic imines can also be used as substrates and the reaction is readily performed on the gram scale with as little as 0.25 mol% catalyst loading. Furthermore, the Mannich adducts are readily transformed to protected a-hydroxy-/8-amino acids in high yield. The absolute stereochemistry of the Mannich adducts revealed that Et2Zn-linked complex 3 affords Mannich and aldol adducts with the same absolute configuration (2 R). However, the diastereoselectiv-ity of the amino alcohol derivatives is anti, which is opposite to the syn-l,2-diol aldol products. Hence, the electrophiles approach the re face of the zinc enolate in the Mannich reactions and the si face in the aldol reactions. The anti selectivity is... 

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. 

Boron enolates of a-benzyloxy esters.1 The triflate 1 converts alkyl benzyloxy-acetates (2) into the boron enolate, which readily undergoes aldol reactions with high yyn-diastereoselectivity. Somewhat higher syn-selectivity obtains with dicyclopen-tylboryl triflate, whereas use of LDA results in slight anti-selectivity (synlanti=34-37 66-63). Diisopropylethylamine is essential for the aldol reaction. Syn-3 is re-... 

Gennari et al. developed a computational model to reproduce the experimental syn/anti setereoselectivity for the aldol reactions of Z and E enol borinates of butanone with acetaldehyde.13 For the reaction of Z-enol borinate 8Z, the chair transition state TS Z-chair A dominates over other three-transition states (Scheme 2.XI). When a Boltzmann distribution was calculated for the competing transition structures, a complete syn/anti selectivity of 99 1 was predicted. The aldol reaction of E-enol borinate 8E with acetaldehyde is, however, calculated to have four transition structures of similar energy (Scheme 2.XII). Although... 

To examine the syn/anti selectivity, Houk examined the aldol reaction of acetaldehyde and propanal with methanamine as catalyst. Reaction 6.19. The E or Z enamine can react to give syn or anti product. They located four TSs 52a-d, shown in Figure 6.22. Again, these TSs are in a half-chair conformation with internal proton transfer. The TSs involving the E isomer are lower than those with the Z isomer. The E isomer prefers to give the anti isomer (52a is 0.7 kcal mol" below 52b), while the Z isomer favors the syn product (52c is 1.4 kcal mol" below 52d) These results are consistent with experiments that show preference... 

Stereoselective reduction of a-alkyl-3-keto acid derivatives represents an attractive alternative to stereoselective aldol condensation. Complementary methods for pr uction of either diastereoisomer of a-alkyl-3-hydroxy amides from the corresponding a-alkyl-3-keto amides (53) have been developed. Zinc borohydride in ether at -78 C gave the syn isomer (54) with excellent selectivity ( 7 3) in high yield via a chelated transition state. A Felkin transition state with the amide in the perpendicular position accounted for reduction with potassium triethylborohydride in ether at 0 C to give the stereochemi-cally pure anti diastereoisomer (55). The combination of these methods with asymmetric acylation provided an effective solution to the asymmetric aldol problem (Scheme 6). In contrast, the reduction of a-methyl-3-keto esters with zinc borohydride was highly syn selective when the ketone was aromatic or a,3-unsaturated, but less reliable in aliphatic cases. Hydrosilylation also provided complete dia-stereocontrol (Scheme 7). The fluoride-mediated reaction was anti selective ( 8 2) while reduction in trifluoroacetic acid favored production of the syn isomer (>98 2). No loss of optical purity was observed under these mild conditions. 

Largely stimulated by the synthesis of 3-lactam antibiotics, there have been widespread investigations into the stereochemical aspects of imine condensations, mainly involving reactions of enolates of carboxylic acid derivatives or silyl ketene acetals. In analogy to the aldol condensation, stereoselectivity of imine condensations will be discussed in terms of two types in this chapter (i) simple dia-stereoselectivity or syn-anti selectivity, when the two reactants are each prochiral (equation 12) and (ii) diastereofacial selectivity, when a new chiral center is formed in the presence of a pre-existing chiral center in one of the reactants (e.g. equation 13). The term asymmetric induction may be used synonymously with diastereofacial selectivity when one of the chiral reactants is optically active. For a more explicit explanation of these terms, see Heathcock s review on the aldol condensation. ... 

Condensation reactions of simple carboxylic acids with imines are of intense interest because of their applications to 3-lactam synthesis. Activation of the carboxylic acid derivative is accomplished by preforming the enolate in situ or by using a silyl ketene acetal derivative with Lewis acid catalysis. The first example of an enolate-imine condensation of this type can be attributed to Gillman and Speeter, who in 1943 reported the synthesis of 3-lactams from Reformatsky reagents and Schiff bases. Subsequently, other workers have investigated the mechanism and syn-anti selectivity of this reaction. A review of these studies by Evans et al. covering work through 1980 has appeared in their review, Stereoselective Aldol Condensations . ... 

Table 1 Syn Anti Selectivity in the Aldol Reactions of Di(cyclopentadienyOchlorozirconium Enolates (Scheme 1)...

The selectivity of the Reformatsky reaction is apparent in Table 9.16, 26,327 taken from Heathcock s work, which shows the syn/anti selectivity for the hydroxy ester products (anti product 580 and syn product 581) resulting from reaction of a-haloesters with ketones and aldehydes. 27 Aldehydes generally show poorer selectivity than do ketones for formation of the anti product. 580. The bromozinc aldolate products from ketones were shown to equilibrate under reaction conditions but those from aldehydes did not. Generally, increasing the size of R in the a-halo-carbonyl derivative led to greater anti selectivity. 

The influence of the presence of carbohydrate solutes had been previously briefly explored by Lubineau and Scherrmann in the case of the Mukaiyama aldol-type reaction of silylenol ethers with aldehydes, which had been found to be accelerated with effects on the syn-anti selectivity similar to what is observed under high pressure. Favoring the syn aldol product was clearly consistent with its smaller transition state volume as compared to the anti one. When this reaction was studied in the presence of carbohydrate solutes, a moderate yield increase was observed, in the same ty -directed selectivity. This effect was however ascribed to slower competitive hydrolysis of the silylenol ether, probably related to a limitation of water activity in the medium, responsible for this undesired side reaction. ... 

Silks and co vorkers reported anti-selective aldol reactions in conjunction vith their investigations on chiral selenium compounds [39]. They discovered that bidentate oxyaldehydes precomplexed vith TiCl4 led to anti aldol products in good yield and vith excellent stereoselectivity, as sho vn in Table 2.35, entries 1 and 2. Presumably, this chelation-controlled reversal of syn/anti selectivity is a phenomenon similar to that vhich Ghosh and co vorkers exploited to produce syn aldols from aminoindanol chiral auxiliaries. Both benzyl and isopropyl oxazolidineselone chiral auxiliaries have comparable anti diastereoselectivity. 

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