Basics Discovered by Otto Paul Hermann Diels and Kurt Alder in 1928; awarded the Nobel prize in chemistry in 1950. The LUMO of the dienophile reacts with the HOMO of the diene in a [4+2] cycloaddition. For more information, see Z/N p 421-432. Steric Effects Electronic Effects Regioselectivity Electron-rich dienes paired with electron-poor dienophiles result in high selectivity for the "ortho products." One way to think about pairing the diene/dienophile is to consider resonance structures in which the alkenes have charge separation. Note: there is no actual charge separation, but it can help explain the regiochemistry. For practice, convince yourself the the following reaction yields the product shown. Rate of reactivity: diene Rate of reactivity: dienophile Stereochemistry The stereochemistry of the diene and dienophile is translated to the cyclohexene product. In short, the geometry of the alkenes (cis/trans) is directly related to the syn/anti relationship observed in the product. Dienophile Diene In this example, the diene can react with the dienophile in two ways: the exo or endo approach. Endo approach is preferred due to the secondary overlap of pi-orbitals. Another way to look at the transition state is to draw a double Newman projection. Top/Bottom Approach If the dienophile can approach the diene from the top or bottom face, enantiomers are formed. High Endo Selectivity Controlling the Diels-Alder reaction to select for the endo product relies on changing the HOMO and/or LUMO of the system. Cyclic dienophiles Common examples are quinone and maleic anhydride. Electron-neutral cyclopentadiene paired with electron-poor dienophiles gives a mix of endo and exo products. Electron-rich Dienes If an electron-rich diene is paired with an electron-poor dieneophile, the reaction undergoes cycloaddition with excellent endo selectivity. Adding electron density into the diene's molecular orbitals raises the HOMO. Electron-poor Dienophiles Adding a Lewis acid further depletes the dienophile of its electron density, thereby lowering the LUMO. Here, we see an electron-rich, cyclic diene paired with an electron-poor dienophile. Heating the reaction gives poor endo/exo selectivity. However, upon addition of a Lewis acid (AlCl 3 ), the reaction can proceed at low temperature and th endo product is highly favored. Intramolecular Diels-Alder: the rules are breakable Two types of connectivity for intramolecular Diels-Alder reactions exist: Type I - a linear connection where the dienophile is attached (at length) at position 1 of the diene; or Type II - a branched connection where the dienophile is attached (at length) at position 2 of the diene. Type I results in a fused bicyclic ring system. Type II results in a bridged bicyclic ring system. Intramolecular Diels-Alder reactions can be found in a number of total syntheses ( Angew. Chem., Int. Ed. 2002 , 41 , 1668-1698 ). For an example of a Type II Diels-Alder reaction in practice, see Angew. Chem., Int. Ed. 2001 , 40 , 820-849. Asymmetric Diels-Alder Substrates with bulky substituents will affect the diastereoselectivity of a Diels-Alder reaction by limiting the approach of the diene/dienophile pair. Here, we see the preferred endo product that minimizes steric interactions with the phenyl substituent ( Synthesis 2002 , 2457-2463 ). Chiral Auxiliaries Incorporating a chiral auxiliary and Lewis acid can lead to facial control of the cycloaddition by blocking one face of the dienophile. Examples of oxazolidinones with R 2 AlCl can be found here: J. Am. Chem. Soc. 1988 , 110 , 1238-1256 (shown below); J. Am. Chem. Soc. 1987 , 109 , 1186-1194 (IMDA, Type I); J. Am. Chem. Soc. 1984 , 106 , 4261-4263 (IMDA, Type I); Angew. Chem., Int. Ed. 2002 , 41 , 1650-1667 (review); CAC '99 1177. Chiral Catalysis Chiral catalysts have also been shown to control the enantioselectivity of a Diels-Alder reaction. Oxazolidinone/oxazoline The achiral oxazolidinone below relies on a chiral BOX ligand and coordination of a copper catalyst ( J. Am. Chem. Soc. 1993 , 115 , 6460-6461 ). Iminium Catalyzed Iminium formation blocks one face of the dienophile so that approach of the diene results in endo selectivity and good to high enantioselectivity ( J. Am. Chem. Soc. 2000 , 122 , 4243-4244 ). Proline derived Imidazolidinone derived Application to a Total Synthesis of dl -Estrone A cobalt-mediated alkyne cyclization undergoes a ring closing and re-opening to set up a Type I Diels-Alder reaction ( J. Am. Chem. Soc. 1980 , 102 , 5253-5261 ). Application to a Total Synthesis of dl -Pumiliotoxin C L. E. Overman published a stereospecific synthesis of pumiliotoxin in 1977 as a racemic mixture. The following year, his group published a second iteration of the same core, but with a much shorter overall synthesis ( Te trahedron Lett. 1977 , 18 , 1253-1256 ; J. Am. Chem. Soc. 1978 , 100 , 5179-5185 ). Retrosynthetic analysis of the cis-decalin core suggests six possible disconnections. Considering all possible diene/dienophile pairs, disconnection #3 displays all favorable attributes: electron-rich diene, electron-poor dienophile, and endo selectivity to provide the desired stereochemistry of the product. The forward synthesis showcases a Curtius rearrangement to build the requisite carbamate protected diene. Susequent addition of crotonaldehyde and heat results in the cyclohexene core, which can undergo a Horner-Wadsworth-Emmons reaction and reduction to give an advanced intermediate. Deproection and reductive amination provides the natural product in 3 steps and 50% overall yield.