Aldol reaction regioselectivity

Aldol reactions. Regioselective aldol reaction at a more highly substituted a-position of a ketone is promoted by TiCl. This Lewis acid also catalyzes the Baylis-Hillman reaction participated by dimethyl sulfide. ... 

By using the directed aldol reaction, unsymmetrical ketones can be made to react regioselectively. After conversion into an appropriate enol derivative (e.g. trimethylsilyl enol ether 8) the ketone reacts at the desired a-carbon. 

In a recent total synthesis of the novel neurotrophic agent merrilactone A (22, Scheme 4) by Inoue and Hirama [24], key intermediate 21 with the cis-bicyclo[3.3.0] octane framework embedded within the caged pentacycle 22 was elaborated from cyclobutane 18 by a sequence of RCM and immediate cleavage of the resulting bicyclic vicinal diol 19 to raeso-diketone 20. Cyclooctenedione 20 then underwent regioselective transannular aldol reaction at low temperature (LHMDS, THF, -100 °C) to produce a 3 1 mixture of isomers in 85% combined yield. The major isomer 21 with the required stereochemistry was then converted into the racemic natural compound ( )-22 in 19 steps. 

Diastereoselective aldol reactions The boryl enolates of chiral crotonate imides (1) and (2) react with aldehydes to form adducts (3) and (4), respectively, with high diastereoselectivity and complete a-regioselectivity. The method of choice for reductive cleavage of the adducts is formulated for 3 hydrolysis can also be effected with LiOH and H202. 

For example, rhodium catalyzed hydroformylation of 2-formyl-N-allyl-pyrrol gives an approx. 1 1 mixture of iso- and u-aldehydes. The latter cyclizes immediately in an aldol reaction followed by dehydration giving 7-formyl-5,6-indolizine in up to 46% (Scheme 29) [83]. Since here only one of the aldehyde groups can act as the enolate nucleophile this cyclization proceed with high regioselectivity (Scheme 29). 

Momiyama and Yamamoto have recently demonstrated that acid cocatalysts can even influence the outcome of enamine-mediated reactions [63]. In their studies of the acid-catalyzed O- and A-nitroso aldol reaction, they found that the nature of the acid catalyst dictates the regioselectivity of the reaction between preformed enamine species A carboxylic acid catalyst promoted the 0-nitroso aldol reaction whereas a hydrogen bonding catalyst catalyzed the formation of an A-adduct, both in high enantioselectivities(Scheme 10). 

Nitroso-Aldol Reaction In the course of the Yamamoto group s studies on the nitroso-aldol (NA) reachon of enamines substantial rate increases were observed upon addihon of stoichiometric amounts of achiral Br0nsted acid. Furthermore, exclusive regioselective formation of the N- versus 0-adducts could be controlled by the choice of MeOH or AcOH, respechvely, as Br0nsted acids (Scheme 5.60) [113]. Subsequently, enantioselechve versions of both N- and 0-nitroso aldol... 

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at — 72°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioselectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2B0S02CF3, at low temperatures (D A. Evans, 1979). Both types of fraiu-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

C-H insertion a to oxygen would generate p-hydroxy or p-alkoxy esters. Thus, the reaction could be considered as a surrogate of the aldol reaction. In Vol. II, Chap. 16 of this series, the preliminary studies on C-H activation of tet-rahydrofuran were summarized [3]. Since then this reaction has been optimized such that the major C-H activation product 22a can be obtained in 97% ee [17]. The optimum reaction conditions (2 equivalents of THF in hexane at -50 °C) demonstrate the regioselectivity that is possible with this chemistry because no reaction with the solvent was observed under these mild conditions. 

Whereas the thermodynamic route described above relied on reagent control to establish the spongistatin C19 and C21 stereocentres, the discovery of highly stereoselective 1,5-anti aldol reactions of methyl ketones enabled us to examine an alternative,16 substrate-based stereocontrol route to 5. Regioselective enolisation of enantiomerically pure ketone 37, derived from a readily available biopolymer, gave end... 

The reactions also led to high regioselectivity (> 20 1). For alkylated aldehydes unbranched in the a-position, however, low diastereoselectivity (d.r. 1.7 1) and yields of 38% were obtained, although enantioselectivity remained excellent (> 97% ee). Use of aromatic substrates resulted in a d.r. of 1 1 to 1.5 1 only, and the enantioselectivity was in the range 67 to 80% ee [93]. Some representative examples of the L-proline-catalyzed aldol reaction with hydroxyacetone are given in Scheme 6.35. 

Another important contribution is to the regioselectivity of enolate formation from unsym-metrical ketones. As we established in chapter 13, ketones, particularly methyl ketones, form lithium enolates on the less substituted side. These compounds are excellent at aldol reactions even with enolisable aldehydes.15 An application of both thermodynamic and kinetic control is in the synthesis of the-gingerols, the flavouring principles of ginger, by Whiting.16... 

The concept of the proline-catalyzed aldol reaction has been recently extended by List et al. towards the synthesis of aldol products with two stereogenic centers [9]. The desired anti-diols 4 have been obtained in a regio-, diastereo- and enantioselective step starting from achiral compounds. Impressive diastero- and enantioselectivities were observed, with a dia-stereomeric ratio up to dr > 20 1 and ee-values of up to >99% ee (Scheme 2, reaction 2). In addition, the reaction leads to a high regioselectivity of >20 1. 

S)-Proline-catalyzed aldol reactions involving 2-butanone afforded the products of C-C bond formation at the methyl group, the less substituted a-position of the ketone as the major regioisomers (Fig. 2.1) [6, 9]. The regioselectivity of the aldol reaction of 2-butanone was reversed using a proline amide derivative as the catalyst, as shown in Scheme 2.2 [13]. The (S)-proline-catalyzed aldol reactions of cyclohexanone and of cyclopentanone afforded both anti- and syn-products (anti syn 2 1) with moderate enantioselectivities (63-89% ee) [6]. The selectivity... 

The regioselectivities of the aldol reactions of hydroxyacetone were reversed from those of the proline-catalyzed reactions when small peptide catalyst 6 or 7 containing (S)-proline at the N-terminal was used, as shown in Table 2.5 [20]. 

The use of Lewis acid drastically changes the regioselectivity. The highly enantioselective and O-selective nitroso aldol reactions of tin enolates with nitrosobenzene have been developed with the use of (i )-BINAP-silver complexes as catalysts. AgOTf and AgCICL complexes are optimal in the O-selective nitroso aldol reaction in both asymmetric induction (up to 97% ee) and regioselection (0/N= > 99/1), affording amino-oxy ketone. The product can be transformed to a-hydroxy ketone without any loss of enantioselectivity (Equation (71)).224... 

Two dialkyl boranes arc in common use. The bicyclic 9-borabicyclo[3.3.1] nonane (9-BBN), introduced in Chapter 34 as a reagent for diastereoselcctive aldol reactions, is a stable crystalline solid. This is very unusual for an alkyl borane and makes it a popular reagent. It is made by hydroboration of cyclo-octa-1,5-diene. The second hydroboration is fast because it is intramolecular but the third would be very slow. The regioselectivity of the second hydroboration is under thermodynamic control. 

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