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.
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
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.
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.
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.
Common examples are quinone and maleic anhydride.
Electron-neutral cyclopentadiene paired with electron-poor dienophiles gives a mix of endo and exo products.
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.
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 (AlCl3), 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.
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).
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 R2AlCl 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 catalysts have also been shown to control the enantioselectivity of a Diels-Alder reaction.
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 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).
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 (Tetrahedron 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.