Aldol reactions vinylogous

Modified Aldol Reactions - Vinylogous Aldol, Nitroaldol, and Nitrone Aldol Reactions... 

The aldol reaction is one of the oldest and important methods for the construction of carbon-carbon bonds in organic chemistry. A classic aldol reaction is the reaction of two carbonyl compounds, or a carbonyl electrophile with an enol nucleophile, to form a new /3-hydroxy carbonyl compound. The first report was appeared in 1872 (1,2), and later in nearly 140 years, new and powerful variants of these classical aldol reactions, such as Mukaiyama aldol reactions, vinylogous aldol reactions, and reductive aldol reactions, and so on have been developed as one of the most versatile and reliable carbon-carbon bond-forming reactions in the syntheses of many important natural occurring or synthetic molecules (3-6). There now exists a large amount of literature documenting different aspects of aldol reactions, and the stable increasing is predictable. 

Especially with the ordinary aldol reaction a number of side reactions can be observed, as a result of the high reactivity of starting materials and products. For instance, the a ,/3-unsaturated carbonyl compounds 4 can undergo further aldol reactions by reacting as vinylogous components. In addition compounds 4 are potential substrates for the Michael reaction. 

As an extension of this work, these authors have applied this catalyst system to vinylogous asymmetric Mukaiyama-type aldol reactions, involving silyl vinyl ketene acetals and pyruvate esters. These reactions afforded the corresponding y,5-unsaturated a-hydroxy diesters with quaternary centres in high yields and enantioselectivities of up to 99% ee (Scheme 10.25). It was shown that the presence of CF3CH2OH as an additive facilitated the turnover of the catalyst. 

Scheme 10.25 Cu-catalysed vinylogous Mukaiyama-type aldol reactions with Ci-S5mmetric benzene-bridged aminosulfoximine ligand.

As practiced in the preceding syntheses by Evans and Nishiyama and Yamamura, the A-ring fragment 43 is formed through substrate-directed vinylogous aldol reaction of the Brassard-type diene 19 and the chiral aldehyde 42, which is prepared using Brown s protocols for enantioselective allylation [53], followed by hydroxy-directed nnn-diastereoselective reduction of the C3 ketone (Me4NB(OAc)3H) [41],... 

A Lewis acid-catalyzed vinylogous Mukaiyama aldol reaction between 2-trialkylsilyloxyfurans and a-substituted ketones proceeded diastereoselectively... 

Here the hapten (Scheme 2) is a 13-diketone, which incorporates structural features of both reactants - ketone donor and aldehyde acceptor (see below, Scheme 3) - in the aldol reaction of interest. In favorable cases the hapten reacts with the primary amino-group of a lysine residue in the complementary-determining region of an antibody to form a Schiffbase 5, which readily tautomerises to the more stable vinylogous amide 6. 

Antibodies produced by this procedure were screened for their ability to react with the hapten to form the vinylogous amide 6, which has a convenient UV chromophore near 318nm, clear of the main protein absorption. Two antibodies selected in this way catalysed the expected aldol reaction of acetone with aldehyde 7 by way of the enamine 8 (Scheme 3) the remainder did not. These two effective aldolase mimics have been studied in some detail, and a crystal structure is available for (a Fab fragment of) one of them.126,281... 

Recent Advances in Vinylogous Aldol Reactions and Their Applications in the Syntheses of Natural Products... 

Keywords Vinylogous Aldol reaction Lewis acid Callipeltoside... 

Herein we will focus on the recent development of vinylogous [1] aldol reactions and their application in the synthesis of natural products [2-5]. In particular the synthesis of unsaturated esters through the vinylogous Mukaiyama aldol reaction is of great interest, since it provides rapid access to larger carbon frameworks and allows for a wide variety of transformations of the double bond (dihydroxylation, epoxidation, cuprate addition etc.). 

Scheme 3 Vinylogous aldol reaction based on Sato s method...

Fig.l Possible transition states in the vinylogous aldol reaction of 8 with benzaldehyde... 

These first examples of the catalytic asymmetric aldol reaction not only provided first results that could be utilized for such transformations but also highlighted the problems that had to be overcome in further elaborations of this general method. It was shown that truly catalytic systems were required to perform an enantioselective and diastereoselective vinylogous aldol reaction, and it became obvious that y-substituted dienolates that serve as propionate-acetate equivalents provide an additional challenge for diastereoselective additions. To date, the latter problem has only been solved for diastereoselective additions under Lewis acid catalysis (vide infra) (Scheme 4, Table 3). 

Scheme 4 Vinylogous aldol reaction with dienolate 8...

Scheme 6 Vinylogous aldol reactions with different catalyst loading...

Scheme 8 Vinylogous aldol reaction using Carreira s catalyst Table 7 Reactions of various aldehydes with Carreira s catalyst (R-19)...

In order to demonstrate the efficiency and applicability of their method, Car-reira et al. described the synthesis of the C1-C13 polyol segment of amphotericin (Fig. 2). The vinylogous aldol reaction was utilized twice, during the... 

Table 9 Vinylogous aldol reactions using enolate and aldehyde activation ...

Scheme 17 Vinylogous aldol reaction with y-substituted ketene acetal 40 using Carreira s catalyst...

Table 10 Vinylogous aldol reaction of 40 with different aldehydes...

Scheme 18 Vinylogous aldol reactions with chiral aldehyde 44...

Based on the same strategy, Denmark and coworkers developed a vinylogous aldol reaction using enolate activation with a catalyst derived from SiCl4 and dimeric phosphoramide 47 [24,25]. This strategy relies on the observation that not all Lewis acid - Lewis base interactions diminish the Lewis acidity [26-28]. Due to the formation of a pentacoordinated silicon cation (48), both the enolate and the substrate can be assembled in a closed transition state, giving rise to the observed high selectivities (Scheme 19) [29,30]. 

---