Heteroatom-Substituted Enolates

A number of optically active, heteroatom-substituted carboxylic acid derivatives are excellent substrates for diastereoselective alkylation reactions. The ready availability of such chiral a-, (3-, and y-heteroatom-substituted carboxylic acid derivatives from the chiral pool and, more recently, through the implementation of catalytic, enantioselective methods (such as enantio-selective reduction of / keto esters Chapter 2, Section 2.7) makes this class of alkylations useful for the construction of stereochemically complex systems, particularly those containing quaternary stereogenic centers [54]. Key pioneering experiments in this area were disclosed independently by See-bach [55] and Prater [56]. 

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Table 11 Ratio of Diastereoisomers in the Reactions of Heteroatom-substituted Enol Silanes with Chiral...

The first three sections of this chapter describe diastereoselective alkylations of chiral enolates including heteroatom-substituted enolates [15, 20]. Section 3.4 deals with the class of enolate alkylations that have typically been included under the rubric of chiral-auxiliary-controlled processes. As suggested by the term, the auxiliary is only transiently utilized and, following alkylation, is subsequently excised. The facile use of chiral auxiliaries in asymmetric enolate alkylations has played and continues to play a pivotal role in the stereoselective formation of new C-C bonds. After a brief survey of the relatively few developments in catalytic enantioselective enolate alkylations (Section 3.5) [21, 22], selected examples of enolate a-hydroxylations (Section 3.6) [23-25] and a-halogenations (Section 3.7) [26, 27] are covered. The corresponding a-aminations of enolates are discussed in Chapter 10, describing stereoselective formation of a-amino acids. 

The majority of preparative methods which have been used for obtaining cyclopropane derivatives involve carbene addition to an olefmic bond, if acetylenes are used in the reaction, cyclopropenes are obtained. Heteroatom-substituted or vinyl cydopropanes come from alkenyl bromides or enol acetates (A. de Meijere, 1979 E. J. Corey, 1975 B E. Wenkert, 1970 A). The carbenes needed for cyclopropane syntheses can be obtained in situ by a-elimination of hydrogen halides with strong bases (R. Kdstcr, 1971 E.J. Corey, 1975 B), by copper catalyzed decomposition of diazo compounds (E. Wenkert, 1970 A S.D. Burke, 1979 N.J. Turro, 1966), or by reductive elimination of iodine from gem-diiodides (J. Nishimura, 1969 D. Wen-disch, 1971 J.M. Denis, 1972 H.E. Simmons, 1973 C. Girard, 1974),... 

The Andersen sulphoxide synthesis allows one also to synthesize a variety of a-heteroatom substituted sulphoxides starting from a-heteroatom stabilized carbanions and (—)-(S)-276. The selected examples shown in Scheme 3 are the best illustration of the generality of this approach. The reaction of enolates or enolate like species with (—)-(S)-276 has been used for the synthesis of optically active a-carbalkoxy sulphoxides. For example, treatment of (—)-(S)-276 with the halogenomagnesium enolates of -butyl acetate, t-butyl propionate or t-butyl butyrate resulted in the formation of ( + )-(R)-t-butyl p-toluenesulphinylcarboxylates 298367 (equation 163). 

Only limited precedent exists for the stereoselective enolization and subsequent condensation of a-heteroatom-substituted esters 48a and 48b (eq. [29]). Ireland has examined the enolization process for a-amino ester derivatives where the Claisen rearrangement (chair-preferred transition states) was employed to ascertain enolate geometry (Scheme 10) (43). These results imply that 48a [X = N(CH2Ph)2 ] exhibits only modest selectivity for ( )-enoIate formation under the... 

As will be discussed more thoroughly in Section 3.2.5, transition metal carbene complexes can mediate olefin metathesis. Because heteroatom-substituted carbene complexes are usually less reactive towards olefins than the corresponding nonheteroatom-substituted complexes, it is, e.g., possible to use enol ethers to terminate living polymerization or other types of metathesis reaction catalyzed by a non-heteroatom-substituted carbene complex. Olefin metathesis can also be used to prepare new heteroatom-substituted carbene complexes (Figure 2.15, Table 2.11). 

Ketone enolate 51 could also serve as a two-carbon component in [3 + 2] annulation when reacted with -heteroatom-substituted a,/ -unsaturated acylsilane 52345 Ppj. tjjg enolate of 3-methyl-2-butanone 51 (R = /-Pr) reacts with... 

Some /J-heteroatom substituted a,/J-unsaturated acyl silanes react with methyl ketone enolates in a stepwise stereoselective cyclopentannelation process, formally a [3 + 2] annelation, which may proceed through aldol reaction followed by Brook rearrangement and cyclization (Scheme 111)223. 

Similarly, the [3 + 4] annulation of the E- and Z-isomers of /1-heteroatom-substituted acryloylsilanes 156 with lithium enolates of ,/l-unsaturated methyl ketones 157 gave stereospecifically cis-5,6- and //r/w.v-5,6-disubstituted-3-cycloheptenones 160, respectively (equation 97). The stereospecificity in the annulation was explained by an anionic oxy-Cope rearrangement of the 1,2-divinylcyclopropanediol intermediate 159, which was generated through the Brook rearrangement of the initial 1,2-adduct 158219 - 223. 

Tetradentate chiral proton donors have been used for the asymmetric protonation of samarium enolates formed by the Sml2 reduction of a-heteroatom-substituted carbonyl compounds. For example, Takeuchi examined the reduction of a-heterosubstituted cyclohexanone 12 using Sml2 and the BINOL-derived chiral proton source 13.41 Ketone 14 was obtained in good yield and high enantiomeric excess (Scheme 2.11). Coordination of the proton source to samarium is key to the success of the transformation.41... 

The reduction of a-heteroatom-substituted carbonyl compounds is an excellent method for the generation of Sm(III) enolates that can be used in carbon-carbon bond-forming reactions (see Chapter 5, Section 5.5). 

Similarly, the reversal of the thermochemical stability order upon one-electron oxidation has been demonstrated theoretically and experimentally for several heteroatom substituted carbonyl/enol pairs, e.g. esters [52,53] and acids [54,55]. A recent detailed evaluation of the substituent effect by Heinrich, Frenking and Schwarz using ab initio molecular orbital calculations [56] is summarized in Table 3. Both a- and 7t-donors X stabilize the two cationic tautomeric forms, but with Ji-donating groups (X F, OH, NHj) the enol radical cations are much more stable than the corresponding keto ions. On the other hand, with c-donor/rt-withdrawing substituents this thermochemical preference is less pronounced and in the case X BeH the order of relative stabilities of ionic keto/enol pairs is even reverted. 

A highly diastereo-controlled alkylation at the C4 position of 60, employing chiral tin(II) enolates 6Sa-e of heteroatom-substituted acetyl derivatives 64a-e, provided 66a-e, new synthetic intermediates for l) -heteroatom-substituted carbapenems (see Scheme 13 and Table III) (87CC602). 

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