Enolendo Aldolizations

Amine-catalyzed 6-enolendo aldolizations in the synthesis of Hagemann s ester (89) and aldol 91. 

Typically, aldehydes function as the aldol donor in these reactions but ketones can also be used (Eq. (6)). Both ketones and aldehydes can play the role of the acceptor carbonyl group. 

Piperidine-Catalyzed Synthesis of Aldol 91. A mixture of thiophene-2-carbaldehyde (90, 8 g, 71 mmol) and ethyl acetoacetate (85, 20 g, 154 mmol, 2.1 equiv.) vas cooled to 0 °C and treated vith five drops of piperidine under stirring. After 48 h at room temperature a solid vas formed, isolated by filtration, and recrystallized t vice from diethyl ether to furnish aldol 91 (fine colorless needles Mp. = 106 °C) in almost quantitative yield. 

In enolendo aldolizations the aldol donor is always a ketone whereas both aldehyde and ketone carbonyl groups can serve as the acceptor. 

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A highly diastereo- and enantioselective synthesis of trans-l,2-disubstituted cyclohexanes by means of the first direct catalytic asymmetric 6-enolexo aldoliza-tion has been developed very recently by the List group [120] (previously only 6-enolendo aldolizations had been reported). Dialdehydes were usually used as starting materials and proline was a very effident catalyst for this reaction also. A selected example of this 6-enolexo-aldolization is given in Scheme 6.50 in this... 

Another important fact was reported in the 1980s Agami and co-workers studied the application of proline in an enolendo aldolization reaction. Their mechanistic studies showed nonlinear and dilution effects that suggested the involvement of two molecules of proline in the transition state (Scheme 1.6) [18]. 

Other examples of amine-catalyzed 6-enolendo aldolizations are shown in Scheme 4.15 [85-90]. 

Probably the most important aminocatalytic 6-enolendo aldolizations are used in the syntheses of bicyclic ketones 106 and 109 (the Wieland-Miescher ketone) from triketones 104 and 108 via pyrrolidine-catalyzed cy-cloaldolization (Scheme 4.16) [91-93]. Enones 106 and 109 are important intermediates in natural product synthesis, particularly as AB- and CD-fragments in the synthesis of steroids. It has been convincingly demon-... 

Proline-catalyzed enolendo aldolizations have been applied to a number of substrates, most often in steroid synthesis. Selected products from such Hajos-Parrish-Eder-Sauer-Wiechert reactions are sho vn in Scheme 4.18 [98-104]. 

Although several different catalysts have been studied in such enolendo aldolizations, proline has typically been preferred. It can, ho vever, be advan-... 

Selected products from proline-catalyzed 6-enolendo aldolizations. 

Although amine-catalyzed enolexo aldolizations (Section 4.2.2.1) are relatively common and catalytic asymmetric enolendo aldolizations have been knotvn for three decades (Section 4.3.1.1), the first catalytic asymmetric enolexo aldolizations vere developed only very recently. It vas discovered that a variety of achiral heptanedials (129) and 7-oxoheptanal on treatment vrith a catalytic amount of (S)-proline furnished anti aldols 130 vith excellent enantioselectivity (Scheme 4.23) [120-122]. 

Two competing intramolecular cyclizations (see the aldol condensation-sec. 9.4.A.ii) are illustrated for triketone 205.jn this case, only the favored 6-enolendo-exo-trig product (206) was obtained and not the disfavored 5-enol-endo-exo-trig products (207 and 208). Enolates generally tend to undergo 5-exo-tet reactions at oxygen, whereas 6-enolendo-exo-tet reactions prefer carbon. In order to form a five-membered... 

The Hajos-Parrish-Eder-Sauer-Wiechert synthesis (Scheme 5) was the first example of an intramolecular proline-catalyzed asymmetric aldol reaction. Systematically, this reaction can be described as a 6-enolendo cyclization. In 2003, List et al. described the first example of an intramolecular enolexo aldolization 85). This approach was then used by Pearson and Mans for the synthesis of (-i-)-cocaine 92, starting from the weso-dialdehyde 90 on treatment with (S)-12 86). This desymmetrization process gave 91 as a mixture of epimers with good enantio-selectivity. The tropane skeleton 91 could be further transformed into +)-92 by conventional means (Scheme 21). 

There are tv ro types of intramolecular aldol reaction, enolendo and enolexo aldolizations (Scheme 4.8, Eqs. (1) and (2), respectively). Both types can be catalyzed by amines and several examples have been published. 

The first amine-catalyzed, asymmetric intermolecular aldol reactions were developed by List et al. in 2000 [29-33]. Initially it was found that excess acetone in DMSO containing sub-stoichiometric amounts of (S)-proline reacted with some aromatic aldehydes and isobutyraldehyde to give the corresponding acetone aldols (134) with good yields and enantioselectivity (Scheme 4.25). Particularly high ee were achieved with a-branched aldehydes. Similarly to the intramolecular enolendo variant, the only side-product in proline-catalyzed intermolecular aldol reactions are the condensation products (Scheme 4.25). 

Aldol Reactions.— Baldwin has extended the nomenclature for classifying ring-closures to include intramolecular aldol reactions. Observations of the modes of cyclization of polyketonic substrates have shown that, for example, 6-(enolendo)-exo-trig cyclizations are indeed favoured whereas the five-membered version is disfavoured (Scheme 50). Such generalizations may prove powerful aids to recognition of likely pathways that cyclizations may follow when a multitude of cyclization modes are formally possible, and to the evaluation of the likelihood of success in aldol reactions by which complex cyclic targets are prepared. 

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