Domino Knoevenagel hetero Diels-Alder reactions of sugar derived δ , ε-unsaturated aldehydes

δ,ε-Unsaturated aldehydes prepared from D-glucose and D-ribose served as suitable substrates in intramolecular domino Knoevenagel hetero Diels-Alder reactions with N,N-dimethylbarbituric acid yielding polyhydroxylated carbocycle-dihydropyran fused ring systems.


Introduction
6] Tietze and his co-workers [2][3][4][7][8] extensively studied and exploited this particularly simple way to construct fused heterocycles, usually in a stereoselective manner. Othr groups also thoroughly employed this key sequence in their synthetic efforts.[9][10][11][12][13] Prompted by our continuing interest in building carbocycles from carbohydrates 14 we decided to explore the possibility of preparing novel carbocyclic derivatives through the intramolecular DKHDA approach following the retrosynthetic itinerary depicted in Scheme 1.According to this, a polyhydroxylated carbocycle-dihydropyran fused ring system 1 could be obtained applying a Knoevenagel condensation of δ,ε-unsaturated aldehydes 3 with appropriate 1,3-dicarbonyl components to form intermediates 2, followed by an intramolecular hetero Diels-Alder cycloaddition reaction.In turn, aldehydes 3 could be synthesized from an hexose or a pentose.

Results and Discussion
To investigate the feasibility of our plan we chose to perform our reactions with three extensively studied 1,3-dicarbonyl compounds: N,N-dimethylbarbituric acid, 4, Meldrum's acid, 5, and dimedone, 6, (Figure 1) are readily available symmetrical reagents, which were often employed in DKHDA reactions with good results.The required δ,ε-unsaturated aldehydes 8 (Scheme 2) and 14 (Scheme 3) were prepared from the corresponding iodide 7 and alcohol 13, respectively, and used without isolation in the domino reactions.Precursors 7 and 13 are derivatives of D-glucose and D-ribose; easily accessible following well established procedures.14e Tietze's general protocol 8d which involves catalysis of ethylenediamine diacetate (EDDA) and the presence of a dehydrating agent was followed using initially the most reactive of the 1,3dicarbonyl compounds shown in Figure 1, barbituric acid derivative 4. Reactions were found to proceed smoothly under refluxing conditions in acetonitrile with both sugar derived candidates affording the desired cycloadducts in average overall yields from iodide 7 and alcohol 13 (Scheme 2 and Scheme 3).
Careful investigation of the reaction mixture obtained from the monosubstituted olefin 8 revealed the presence of three products (Scheme 2).The minor one was easily separated from the other two isomers using column chromatography and was found to be the regioisomeric product with the bridged structure of 12.The other two products (diastereoisomers 10 and 11), formed almost in equimolar quantities, were subsequently separated on PTLC.
A mixture of products was also obtained from the domino reaction of the 1,2-disubstituted olefin 14 through the Knoevenagel intermediate 15 (Scheme 3).This mixture was actually found to contain the major product 16 along with two unidentified products (most likely diasteroisomers) in less than 5% of the total amount.The presence of the unknown compounds could be easily detected in the 1 H NMR spectra where two extra couples of singlets were observed in the area of N-methyl groups (δ 3.49, 3.47 and 3.15, 3.13).However, all chromatographic efforts to obtain pure samples of the major product and the possible diasteroisomers were proved futile.Assignment of the stereochemistry of all products isolated was made with the aid of COESY and NOESY experiments.For the case of aldehyde 8 the transition states of the intramolecular hetero Diels-Alder (HDA) reaction were studied in order to explain our findings (Scheme 4).
Although there is a detailed and systematic investigation dealing with the stereochemistry of six-membered fused systems, very few efforts targeted the question of which is the stereochemical outcome of reactions leading to five-membered analogous systems.1b,2,7,9 It seems that stereochemistry of C-2 (sugar numbering) plays a crucial role in which of the transition states will dominate.Thus, cis-product 10 could derive either from the exo-Z-syn (1) or the endo-E-syn (1) approach.Formation of the diastereoisomeric cis-product 17 is highly disfavored since in the exo-Z-syn (2) or endo-E-syn (2) transition states approach of C-2 substituent with the nonreacting carbonyl group becomes important.The same steric hindrance prevents the formation of trans-product 18, whereas 11 was obtained in appreciable yield probably because of the lesser interaction between the H-2 and the non-reacting carbonyl group.The possibility of an endo-Z- anti transitional state was ruled out due to inability of the diene and dienophile to approach. 2nalogously, the exclusive formation of the regioisomeric bridged product 12 is justified accepting an exo-Z-syn approach.However, the small size of the carbon chain between the alkene and hetero diene moieties does not allow the formation of 12 in high yield.
Substrate 15 exhibits a similar behavior but we speculate that cis-product 16 derives exclusively from the corresponding exo-Z-syn transitional state since the endo-E-syn is prohibited by the rigidity the acetonide ring imposes.Proximity of the same ring with the benzyloxymethyl substituent of the double bond seems to disfavor the exo-E-anti approach, which will allow the formation of a trans-diastereoisomer.
In contrast to the results obtained with N,N-dimethylbarbituric acid, Meldrum's acid, 5, failed to give cycloaddition products with δ,ε-unsaturated aldehydes 8 and 14.Both substrates led, upon heating in acetonitrile, to highly complicated mixtures, which were found solely to consist of decomposition products instead to the desired ones.These unexpected findings are not in accordance with the results reported by Tietze 2,7 and Takano 9 where domino reactions with Meldrum's acid easily took place.
Interestingly, we were able to isolate the Knoevenagel condensation product 19 when the reaction between 8 and 5 was performed at ambient temperature (Scheme 5).This intermediate was purified and used in thermal or catalyzed reactions in order to achieve cycloaddition to 20.However, none of the conditions employed e.g.heating in acetonitrile or isopropyl alcohol 9c and Lewis acid catalysis 11 (with MgBr 2 , Et 2 AlCl, BF 3 .OEt 2 , ZnCl 2 and SnCl 4 ) in a variety of solvents gave better results.To the best of our knowledge, this is the first Meldrum's acid system, which undoubtedly gives the Knoevenagel condensation and fails to give the intramolecular cycloaddition.Reactions with dimedone, 6, were also investigated.Lower reactivity for this 1,3-dicarbonyl component was expected and was indeed observed since all reactions run gave no cycloaddition products.In fact, similar results were obtained by Vasella's group 15 when DKHDA reaction of 8 to 6 was attempted leading to a double addition of dimedone to the unsaturated aldehyde.

Conclusions
The intramolecular domino Knoevenagel hetero Diels-Alder reaction could be used as an exceptional approach towards the preparation of fused polyhydroxylated carbocycles in an easy and efficient way.Our initial goal was to demonstrate the feasibility of this plan.Systematic study of the rules governing the stereochemical outcome of these reactions with different substrates and employment of products derived from simple 1,3-dicarbonyl components in synthetic schemes leading to other equally interesting products, through the appropriate transformations (e.g. from N,N-dimethylbarbituric acid 8m ), will be certainly part of our research program.

Experimental Section
General Procedures.All reactions were carried out under a nitrogen atmosphere with dry and freshly distilled solvents under anhydrous conditions.Yields refer to chromatographically and spectroscopically homogeneous materials, unless otherwise stated.Column chromatography was performed on silica gel (Kieselgel 60, 70-230 mesh).Preparative thin layer chromatography (PTLC) was performed on 0.25 mm E. Merck silica gel plates (60F-254).R f values were measured using the indicated eluent on silica gel plates (60F-254) using UV light or p- anisaldehyde solution for visualization.HRMS were recorded on a VG ZAB-ZSE mass spectrometer under FAB conditions with NBA as the matrix. 1 H NMR spectra were recorded at 300 or 600 MHz on a Bruker 300 AM or a Bruker DRX-600 spectrometer, respectively. 13C NMR spectra were recorded at 75 MHz on a Bruker 300 AM spectrometer.All NMR experiments were carried out using tetramethylsilane as an internal standard.IR spectra were recorded on a Perkin Elmer 297 instrument.Optical rotations were measured at 25 o C on an A. Krüss P3000 Automatic Digital Polarimeter.