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Diels-Alder Reaction

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    22895
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    Basics

    Discovered by Otto Paul Hermann Diels and Kurt Alder in 1928; awarded the Nobel prize in chemistry in 1950.

    00_basics_reaction.png

    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.

    00_basics_MO diagram.png

    Steric Effects

    01a_basics_diene isomers.png

    01b_sterics_krel of rxn with maleic anhydride.png01c_sterics_sterics matter.png

    Electronic Effects

    02a_e effects_typical.png

    Regioselectivity

    Electron-rich dienes paired with electron-poor dienophiles result in high selectivity for the "ortho products."

    02b_electronics_regioselectivity.png

    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.

    02c_electronics_charge separation.png

    For practice, convince yourself the the following reaction yields the product shown.

    02d_electronics_convince yourself.png

    Rate of reactivity: diene

    02e_electronics_diene reactivity.png

    Rate of reactivity: dienophile

    02f_electronics_dienophile reactivity.png

    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

    03a_stereochem_dienophile.png

    Diene

    In this example, the diene can react with the dienophile in two ways: the exo or endo approach.

    03b_stereochem_endo_exo.png

    Endo approach is preferred due to the secondary overlap of pi-orbitals.

    03c_stereochem_endo_exo.png

    Another way to look at the transition state is to draw a double Newman projection.

    03e_stereochem_double Newman projection.png

    Top/Bottom Approach

    If the dienophile can approach the diene from the top or bottom face, enantiomers are formed.

    03e_stereochem_top_bottom_approach.png

    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.

    Screen Shot 2015-03-06 at 11.04.04 AM.png

    Electron-neutral cyclopentadiene paired with electron-poor dienophiles gives a mix of endo and exo products.

    04b_stereochem_cyclic dienes.png

    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.

    04c_stereochem_electron rich diene.png

    Electron-poor Dienophiles

    Adding a Lewis acid further depletes the dienophile of its electron density, thereby lowering the LUMO.

    04d_stereochem_Lewis acid MO diagram.png

    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.

    04e_stereochem_LA example.png

    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.

    04f_stereochem_intramolecular DA.png

    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).

    04g_stereochem_Syn '02 2457.png

    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 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.

    04h_stereochem_oxazolidinone.png

    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).

    04i_stereochem_BOX catalized.png

    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

    04j_stereochem_proline catalized.png

    Imidazolidinone derived

    04k_stereochem_imidazolidinone catalized.png

    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).

    05a_intramolecular_sterol.png

    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.

    05b_pumiliotoxin C_retorsynthesis.png

    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.

    05c_pumiliotoxin_disconnections.png

    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.

    05d_pumiliotoxin_total synthesis.png


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