Chiral lithium enolates aldol reaction diastereoselectivity

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Traditional models for diastereoface selectivity were first advanced by Cram and later by Felkin for predicting the stereochemical outcome of aldol reactions occurring between an enolate and a chiral aldehyde. [37] During our investigations directed toward a practical synthesis of dEpoB, we were pleased to discover an unanticipated bias in the relative diastereoface selectivity observed in the aldol condensation between the Z-lithium enolate B and aldehyde C, Scheme 2.6. The aldol reaction proceeds with the expected simple diastereoselectivity with the major product displaying the C6-C7 syn relationship shown in Scheme 2.7 (by ul addition) however, the C7-C8 relationship of the principal product was anti (by Ik addition). [38] Thus, the observed symanti relationship between C6-C7 C7-C8 in the aldol reaction between the Z-lithium enolate of 62 and aldehyde 63 was wholly unanticipated. These fortuitous results prompted us to investigate the cause for this unanticipated but fortunate occurrence. 

A particularly attractive version of this reaction relies on the action of a catalytic chiral lithium binaphtholate and an excess of water on trimethoxysilylenol ether119. The tetralone enolate thus generated was directly employed in an aldol reaction, which turned out to be poorly diastereoselective but highly enantioselective for both diastereomers (Scheme 27). 

Stereoselective aldol condensation. Heathcock and Buse have previously employed 2-methyl-2-trimethylsiloxy-3-pentanone (1) in a highly stereoselective route to 3-hydroxy-2-methylcarboxylic acids (8, 295). Aldol condensation of the lithium enolate derived from 1 with a chiral aldehyde yields ery//iro-aldols, which are cleaved with periodic acid to -hydroxy carboxylic acids. However, when 1 is condensed with a chiral aldehyde such as 2, two eryt/iro-products (3 and 4) are produced. Heathcock and co-workers now report that the 1,2-diastereoselectivity of these aldol condensations can be enhanced by use of the ketone 5. Reaction of racemic 5 with racemic aldehyde 2 furnishes a single (racemic) adduct 6. 

The most smdied O-bonded transition metal enolates are titanium enolates . The reason for their success has beeu recognized in the fact that titanium enolates show an enhanced stereochemical control in C—C bond-forming reactions over simple lithium enolates and the possibility of incorporating chiral ligands at the titanium centre, a possibility which has lead to enantioselective aldol reactions with excellent enantiomeric excess. Moreover, titanium euolates have been used in oxidation reactions with remarkable diastereoselectivity. 

Aldol reactions of chiral dioxolanones (113) and (114) are summarized in Scheme 6 and Table 9. ° With both (113) and (114), essentially perfect diasterofacial selectivity is observed. The simple dia-stereoselection is modest to good, and is dependent on the enolate counterion. For the lithium and magnesium enolates, the sense of simple diastereoselection is the same as is observed with the achiral dioxolanone (107) and the chiral dioxolanone (110). Use of the zirconium enolate generally reverses the sense of simple diastereoselection, although the isomer ratios are not very high in some cases. 

Chiral acetate (204) shows excellent diastereofacial selectivity and has obvious utility as a reagent for asymmetric aldol reactions. As shown in equation (122), reaction of (204) with benzaldehyde provides diastereomers (205) and (206). As shown in Table 23, entry 1, the diastereoselectivity is 83% if the lithium enolate is formed in the conventional manner and the aldol reaction is carried out in THF at -78 C. A significant improvement is obtained by using the magnesium enolate (Table 23, entry 5), and diastereoselectivity of up to 98% is obtained by the use of very low reaction temperatures (Table 23, entries 10-13). 

Asymmetric aldol reactions. The chiral N-propionyloxazolidinone (1), prepared in several steps from (lR)-(—)-camphorquinone, undergoes highly diastereoselective aldol reactions with the additional advantage of high crystallinity for improving the optical purities of crude aldols. Either the lithium enolate or the titanium enolate, prepared by transmetalation with ClTi(0-(-Pr)3, reacts with aldehydes to form syn-adducts with diastereomeric purities of 98-99% after one crystallization. The observed facial selectivity is consistent with metal chelation of intermediate (Z)-enolates (supported by an X-ray crystal structure of the trapped silyl enol ether). The lithium enolate also exhibits... 

A single diastereomer 93, however, results from addition of the lithium enolate 92 derived of t-butyl thiopropanoate to the chiral, enantiomerically pure aldehyde 91. The transformation is a key carbon-chain-elongation step in Woodward s synthesis of erythromycin A (Eq. (37)) [166]. Somewhat lower diastereoselectivity is observed in the aldol reaction between the lithium enolate 95 and the chiral aldehyde 94, a transformation used in a synthesis of maytansin (Eq. (38)). The diastereomeric adducts 96a and 96b result in a ratio of 90 10 [167]. 

Further selected examples of diastereoselective aldol reactions between lithium enolates and chiral aldehydes are given in Eqs. (42) [171], (43) [172], and (44) [173]. In the last example, the salt-free generation of the lithium enolate was occasionally found to be crucial to stereoselectivity [174]. 

A variety of other chiral lithium amides, for example 106 and 108, have been applied more recently to bring about enantioselective aldol additions. As sho vn in Eqs. (48) [179] and (49) [180], both simple diastereoselectivity and induced stereroselectivity can be induced by these reagents. In the latter reaction, the enolate itself becomes chiral, because of desymmetrization of ketone 107 on deprotonation. 

Later, Yamamoto and coworkers developed the axially chiral ester 183 for asymmetric acetate aldol additions. After formation of the lithium enolate with LDA, the reaction with various aldehydes yielded P-hydroxy esters 184 in very high diastereoselectivity. It was shown, for two adducts, that a nearly quantitative saponification leads to P-hydroxy carboxylic acids 176 and liberates phenol 185 in nearly quantitative yield and undiminished optical purity (Scheme 4.40) [100]. The authors discuss a twist-boat as well as an open transition state for rationalizing the preferred Re-face attack to the aldehyde, observed with (R,R)-configured acetate 183. Yamamoto s procedure is impressive because of its stereoselectivity, but one has to be aware that the chiral auxiliary 185 is by far not as readily accessible as others also enabling the asymmetric acetate aldol addition. 

In contrast, reaction of diethyl propionylphosphonate with lithium bis-(trimethylsilyl)amide (LiHMDS) at -78 °C gave the expected enolate as evidenced by its highly diastereoselective condensation with benzaldehyde, leading to the formation of 3-hydroxy-2-methyl-3-phenylpropionic acid (equation 91) " . An attempt was made to develop this concept to enantioselective aldol condensation. However, condensation of a cyclic chiral propionylphosphonamidate (31), synthesized from ( S)-A-isopropyl-4-aminobutan-2-ol, with benzaldehyde yielded 3-hydroxy-2-methyl-3-phenylpropionic acid in disappointingly low 47% e.e. (equation 92)... 

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