Stereochemistry Diels-Alder cycloadditions

According to frontier molecular orbital theory (FMO), the reactivity, regio-chemistry and stereochemistry of the Diels-Alder reaction are controlled by the suprafacial in phase interaction of the highest occupied molecular orbital (HOMO) of one component and the lowest unoccupied molecular orbital (LUMO) of the other. [17e, 41-43, 64] These orbitals are the closest in energy Scheme 1.14 illustrates the two dominant orbital interactions of a symmetry-allowed Diels-Alder cycloaddition. 

The non-preservation of cis stereochemistry of dienophiles 24 and 26 in the adducts 25 and 27 is due to a cis-trans photoisomerization of the double bond and to the concerted suprafacial Diels-Alder cycloaddition of diene to the ground state of trans dienophiles. 

Posner G. H., Bull D. S. Recent Advances in Control of Absolute Stereochemistry in Diels-Alder Cycloadditions of 2-Pyrones Recent Res. Dev. Org. Chem. 1997 1 259-271... 

Horton D., Koh D., Takagi Y., Usui T. Diels-Alder Cycloaddition to Unsatnrated Sugars. Stereocontrol As a Ennetion of Stmeture and Stereochemistry ACS Symp. Ser. 1992 494 66-80... 

Effect of Choice of Geometry on Relative Energies of Regio and Stereochemistry of Diels-Alder Cycloadditions of Substituted Cyclopentadienes with Acrylonitrile/ 6-31G Model... 

To demonstrate the feasibility of Diels-Alder cycloaddition using y-pyrones as dienophiles,47 50 the reaction of 3-cyanochromone 31 with diene 32 in toluene proceeded at 200 °C in a sealed tube for 72 h to give the desired cycloadduct 33 in 80% yield [Scheme 6] without observing any inverse electron demand [4 + 2] cycloadducts.51 However, the endo exo ratio was only 1.3 1 as determined by ]H NMR with the stereochemistry assigned using nOe experiments. 

Stable disilenes generally do not undergo Diels-Alder cycloaddition with conjugated dienes16, but the reaction is well known in the cases of more reactive disilene derivatives8. The stereochemistry of the reaction has not been widely studied, but isolated examples such as those shown in equations 86-88 show that the reaction proceeds with retention of the original stereochemistry of both the diene (equation 88)161 and the disilene (equations 86 and 87)162. Reaction of tetrakis(trimethylsilyl)disilene (35) with 1,3-buta-diene in solution yields the expected Diels-Alder adduct 116 (equation 89)68. 

Pradilla et al. [140] have recently produced a nice paper showing that enan-tiopure hydroxy 2-p-tolylsulfinyl butadienes 158 (Scheme 78) undergo a highly face-selective Diels-Alder cycloaddition with AT-phenyl maleimide and phenyl-triazolidine dione, presumably controlled by the chiral sulfur atom (dienophile approach from the upper face of diene). Complementary 7r-facial selectivity (dienophile approach from the bottom face of diene) is displayed by related enantiopure sulfonyldienes 158 (Scheme 78). The authors suggest that the behavior of 158 is a consequence of the predominant influence of the chiral sulfur with respect to the hydroxylic carbon (the only chiral center in 158 ) on the stereochemical course of the cycloadditions. According to their explanation, dienes will adopt conformations similar to those depicted in Scheme 78, with the chiral centers employing their stereochemistry to maximum effect due to 1,3-allylic strain (which is considered as the main directing effect of these cycload-... 

Total simple diastereoselectivity is observed in the hetero-Diels-Alder cycloaddition of nitro-soarencs to 1,3-dienes leading to the corresponding 3,6-dihydro-2//-l, 2-oxazines. A number of acyclic 1,4-disubstituted dienes have been reacted with nitrosoarenes, but the stereochemistry of the adduct 1 has not been assigned 6 s. 

The intramolecular variant of the hetero-Diels-Alder cycloaddition is attractive since it allows the stereochemistry of the products to be controlled at four centers or even more, if substituents in the bridging chain are considered. Following the experimental procedures devised for inter-molecular cycloaddition, a number of bicyclic and polycyclic systems have been prepared with the... 

Alves, C. N., Romero, O. A. S., Da Silva, A. B. F. Theoretical study on the stereochemistry of intramolecular hetero Diels-Alder cycloaddition reactions of azoalkenes. Int. J. Quantum Chem. 2003, 95, 133-136. 

The cyclobutene ring first opens in an electrocyclic reaction 152. This must be conrotatory as it is a four electron process but there is no stereochemistry at this stage. Then an intramolecular Diels-Alder cycloaddition 153 closes the new six-membered ring. This is a particularly favourable reaction as the formation of the alkene completes a benzene ring. It would not be possible to prepare such an unstable diene so a tandem process is necessary. 

Diene (14) reacted with a series of aldehydes under BFj-OEt2 catalysis in CH2CI2 to give predominantly trans products (Table 10).31 32 Aldol-type products, such as p-hydroxy enones, are isolated (along with dihydropyrones) from the reaction mixtures. Using TFA as a catalyst, the p-hydroxy enones are, as previously described, converted into dihydropyrones. The stereoselectivity of these reactions is consistent with a Mukaiyama-aldol reaction rather than a Diels-Alder cycloaddition. The stereochemistry of the p hydroxy enones is also consistent with the observation that the (Z)-alkoxysilane reacts with the aldehyde in an extended transition state to give anti (threo) aldol products (Scheme 16). In the cases using ZnCh or lanthanide ions as catalysts aldol products have not been detected. 

An important strategy for achieving substrate control is the use of chiral auxiliaries, which are structures incorporated into reactants for the purpose of influencing the stereochemistry. Two of the most widely used systems are oxazolidinones " derived from amino acids and sultams derived from camphorsulfonic acid. These groups are most often used as carboxylic acid amides. They can control facial stereoselectivity in reactions such as enolate alkylation, aldol addition, and Diels-Alder cycloadditions, among others. The substituents on the chiral auxiliary determine the preferred direction of approach. 

Thioketones of various types are readily available and are well documented as effective dienophiles. Representative thioketone cycloadditions are listed in Table 5-1. In general, it appears that thioketones usually add to most dienes in high yield at exceptionally low temperatures to afford stable adducts, although some of these adducts tend to undergo retro-Diels-Alder reactions. - Very little has been done toward establishing the regiochemical selectivity of thioketone additions to unsymmetrical 1,3-dienes, and the few such entries in Table 5-1 indicate that mixtures were obtained. The exo/endo stereochemistry of [4 + 2] cycloadditions with unsymmetrical thioketones has not been probed to date. It has been reported that Diels-Alder cycloadditions of thioketones can also be pho-tochemically induced. 

Nucleophilic ring opening of the lactone ring in bicycloadducts of type 5 leads directly to tetrasubstituted cyclohexenes in which the relative stereochemistry of all four contiguous stereocenters is established. Thus, pyrones provide attractive synthetic equivalents to acyclic dienes of type 6 which may be difficult to prepare as pure geometrical isomers and which in many cases do not lead via Diels-Alder cycloaddition to the desired stereochemical relationships. The application of [4+2] cycloaddition reactions of 2-pyrones to synthesizing functionalized cyclohexenes was the partial subject of a 1994 review. ... 

From the above survey of results the synthetic potential of the oxazinolactam intermediate 46 in hand, we envisaged to synthesize monomorine I (62) which constitutes of an extension of the methodology based on intramolecular nitroso Diels-Alder cycloaddition. The relative stereochemistry of this substance, isolated as one of the trail pheromones from Pharaoh ants (Monomorium pharaonis L.) (ref. 19), has been determined its relative stereochemistry by nonstereoselective synthesis (ref. 20). More recently, a stereospecific synthesis of racemic 62 (ref. 21) and a chiral synthesis of the (-)-enantiomer of natural 62 (ref. 22) were reported. 

Q 10. Predict the [4 + 2] Diels—Alder cycloaddition product with the right stereochemistry. 

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