Enolexo Aldolizations

An intramolecular amine-catalyzed aldolization in Woodward s total synthesis of steroids. 

As in intermolecular aldol reactions, amine-catalyzed 5-enolexo aldolizations can either lead to aldol condensation (Eqs. (l)-(4)) or addition products (Eq. (5)). These reactions usually involve an aldehyde group as the aldol donor the corresponding amine-catalyzed 5-enolexo aldolizations of ketone donors have so far not been realized. The acceptor carbonyl group can either be an aldehyde or a ketone. 

The regioselectivity of aminocatalytic aldolizations of ketoaldehydes such as 60 and 62 contrasts vith that of the corresponding Bronsted base- 

Contrasting regioselectivity of amine- and base-catalyzed 5-enolexo aldolizations. 

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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... 

In addition to catalyzing the well-known Hajos-Parrish-Eder-Sauer-Wiechert reaction (Scheme 3 Eq. 1), we found in early 2000 that proline also catalyzes intermolecular aldolizations (e.g. Eq. 2). Thereafter, our reaction has been extended to other substrate combinations (aldehyde to aldehyde, aldehyde to ketone, and ketone to ketone Eqs. 3-5) and to enolexo-aldolizations (Eq. 6 Northrup and MacMillan 2002a ... 

Pidathala, C. Hoang, L. Vignola, N. List, B. Direct catalytic asymmetric enolexo aldolizations, Angew. Chem. Int. Ed. 2003,42,2785-2788. 

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). 

Pidathala C, Hoang L, Vignola N, List B (2003) Direct Catalytic Asymmetric Enolexo Aldolizations. Angew Chem Int Ed 42 2785... 

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. 

One of the earliest aminocatalytic intramolecular aldolizations vas applied in Wood vard s 1952 total synthesis of steroids [69]. A 5-enolexo aldol condensation established the D-ring of the steroid skeleton. Hexanedial 52 on treatment vith a catalytic amount of piperidinium acetate gave cyclo-pentenal S3 (Scheme 4.9). 

Since then amine-catalyzed 5-enolexo aldolizations have been applied in a variety of other synthetic contexts (Scheme 4.10) [70-75]. Typically they constitute part of a strategy for the ring contraction of cyclohexenes to cy-clopentenes via oxidative cleavage and aldolization (Eq. (2)). 

Enolexo aldolizations giving aldol addition or condensation products have also been described, examples are shotvn in Scheme 4.13 [77-82]. 

More than the corresponding enolexo-aldolizations, amine-catalyzed 6-enolmdo aldol reactions have frequently been used synthetically. An early example is the synthesis of Hagemaris ester (89) from formaldehyde and acetoacetate via piperidine-catalyzed Knoevenagel-Michael-aldol tandem-reaction follo ved by decarboethoxylation (Scheme 4.14, Eq. (1)) [83]. Related product 91 vas obtained vhen thiophene-carbaldehyde 90 vas used (Eq. (2)) [84]. 

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]. 

Whereas non-asymmetric amine-catalyzed enolexo-aldolizations often give... 

It can be expected that proline-catalyzed enolexo-aldolizations will find utility in natural-product synthesis and that new catalysts will eventually be discovered that lead to improved selectivity in the potentially very useful 5-enolexo variant. 

A computational study using DFT methods has rationalized selectivity, reported previously, for proline-catalysed intramolecular 5-enolexo aldolization of 1,6-dicarbonyl compounds. Steric effects are relatively unimportant and the several contributing controlling factors are quite different to those for 6-enolexo aldolizations known to be much less sensitive to experimental conditions. 

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