A direct intramolecular asymmetric catalytic aldol cyclodehydration of meso-3,4-disubstituted-1,6-dialdehydes
Graphical Abstract
Introduction
In recent years the synthesis of carbocyclic nucleoside analogues has been the subject of great interest, due to their wide range of biological activity profiles.1, 2, 3, 4 In the same time, these compounds are chemically and enzymatically more stable than the corresponding nucleosides, according to the absence of a typical glucoside bond in their molecules.5 The role of the methylene group in the carbocycle as a bioisostere of oxygen is justified by the observed antiviral and antitumor efficacies of some natural carbocyclic nucleosides, such as Arystomicin6 and Neplanocin A,7 as well as synthetic ones, as Carbovir8, 9, 10 and Abacavir.11, 12, 13, 14 The latter shows great anti-HIV activity and therefore, it is used clinically to treat AIDS and AIDS-related complex.
As precursors of the carbocyclic moieties of compounds like nucleosides, carbohydrates and many other products of biological importance, cyclopentanoids play a fundamental role in synthetic organic chemistry. Among the broad range of organic transformations for the five-membered ring construction, the aldol condensation is an exceptionally useful C–C bond-forming reaction.15, 16, 17 Its catalytic asymmetric variant is a strategic one both in chemistry and in biology, where it presents a critical biological transformation in the context of metabolism. The enzymatic reactions, catalysed by Type I aldolases, which accept hydrophobic organic substrates, utilise an enamine mechanism.18 The aldolase antibodies synthesis and application in aldol reactions,19, 20, 21, 22, 23, 24 as well as their chemical oversimplified versions, have received considerable attention in recent years. Proline-catalysed asymmetric intramolecular condensation of dicarbonyl compounds, well known as Hajos–Parris–Eder–Sauer–Wiecher reaction, was discovered in the 1970s,25, 26, 27, 28, 29 and afterward widely exploited both in its intermolecular30, 31, 32, 33, 34, 35, 36, 37 and intramolecular38, 39, 40, 41, 42, 43, 44, 45, 46 variants. This reaction involves an enamine intermediate, with the C–C bond formation as the rate determining step and the stereodifferentiation occurring in this step, before dehydration. In the case of the Robinson annulating reaction it was found45 that while proline, as well as a number of similar chiral compounds, like hydroxy proline, azetidine carboxylic acid etc., catalyse both steps of the transformation, the chiral amines tested catalyse the annulation but not the dehydration. It was suggested that chiral compounds containing a secondary amine of pyrrolidine type and a carboxylate functionality are the most efficient catalysts and that the carboxylic acid functionality appears to be the key to the dehydration step.
The asymmetric aldol reactions of diketones and ketoaldehydes are widely investigated, while the condensation of dialdehydes, well known in its non-chiral version reaction, is much less studied. To the best of our knowledge, the only paper on this subject reports the direct intramolecular asymmetric catalytic aldol condensation of dialdehydes on the case of proline-catalysed cyclisation of heptanedials.46 The corresponding hydroxy cyclohexanecarbaldehydes are isolated with stereocontrol at the carbons, bearing the hydroxyl and carbaldehyde functionalities, while no dehydration products are detected, like in the most part of the cases of six-membered ring formation. In contrast, the direct catalytic intramolecular cross-aldol cyclisation of 1,6 dialdehydes, a widely exploited non-chiral transformation in the synthesis of a broad range of biologically active products,47, 48, 49, 50, 51, 52, 53, 54, 55 leads to dehydration products in general, the corresponding cyclopentenecarbaldehydes. However, the asymmetric variant, requiring an asymmetricity to be induced at the β-carbon in respect to the aldehyde, is still unknown.
As a part of our study on the cyclopentanoid synthesis, an asymmetric version of the direct intramolecular catalytic aldol cyclodehydration of meso-3,4-disubstituted-1,6-dialdehydes, leading to the corresponding cyclopentene carbaldehydes, is presented herein.
Section snippets
Results and discussion
The meso-3,4-disubstituted-1,6-dialdehydes were readily obtained by olefin oxidation of a series of differently meso-4,5-disubstituted cyclohexenes, applying ozonolysis and subsequent dimethyl sulphide (DMS) reductive work-up. Their asymmetric aldol cyclodehydration was conducted at ambient temperature in a time scale of 18–20 h, using different groups of compounds as catalysts (Scheme 1). In our previous work56 several alkenes were tested in a non-chiral transformation. Among them the cyclic
Conclusions
A first direct intramolecular asymmetric catalytic aldol cyclodehydration of 1,6-dialdehydes to the corresponding cyclopentene carbaldehydes was accomplished. Variable conversion was observed with dialdehyde 2, having amide substituents, while in the case of acetonide protected diol 5, the transformation was rather slow in general and without inducing substantial selectivity. Among the broad range of the catalysts tested, it appears that for the substrates studied some hydroxy amino acids, like
Experimental
All reagents and the most part of the catalysts were purchased from Aldrich and Fluka and were used without any further purification. The chiral phosphites were prepared in the laboratory.59 The amino alcohols, shown in Figure 1, were synthesised from (S)-(+)-alaninol, (S)-(−)-phenylalaninol, (S)-(+)-leucinol and (S)-(+)-valinol by azomethyne formation with benzaldehyde, acetaldehyde and acetone and subsequent LiAlH4 reduction, following standard procedures. The dichloromethane was dried over P2
Acknowledgements
We thank Fundação para a Ciência e Tecnologia and FEDER (Ref. SFRH/BPD/5531/2001) for the financial support. We also thank Dr. Eurico Cabrita for supplying us with samples of the chiral phosphites.
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