Intramolecular Diels-Alder Cycloaddition

Intramolecular Diels-Alder Cycloaddition

The basic Diels-Alder reaction is the reaction between a diene and a dienophile to form a cyclic ring structure through the formation of new double bond and two new sigma bonds. The reaction was discovered in 1928 by Otto Paul Hermann Diels and his former student, Kurt Alder. The two German chemists made the discovery while studying the formation of complex organic compounds at the University of Kiel. The reaction became such a vital part of organic chemistry that the pair received the Nobel Prize in Chemistry in 1950.

In the Intramolecular Diels-Alder Cycloaddition reaction, the diene and the dienophile are part of one compound. Again, the reaction leads to the formation of one new double bond and two new sigma bonds, but this time the ultimate product is a fused cyclic ring.

Two Modes of Addition

Two basic modes of addition are possible in the Intramolecular Diels-Alder Cycloaddtion reaction and each leads to the formation of a different product, a fused product or a bridged product.The mode of addition that is to take place is dependent upon the carbons to which the alkyl chain is attached. [ 1M.Nantz, G. Zweifel. Modern Organic Synthesis an Introduction. W.H. 2 Freeman and Company, 2007, pg 429-430 ]

The following are examples of fused addition products. Fused addition greatly predominates over bridged addition, so much so that an example of this sort could not be found.

Endo and Exo Products

It is possible for both endo and exo products to be formed in this reaction. Recall that the endo product is the one in which the substituent points toward the double bond and the exo product is the one in which the substituent points away from the double bond. [ P.Y Bruice. Organic Chemistry. Pearson Education, Inc. 2007 ]

Here are some examples of endo and exo products formed through Intramolecular Diels-Alder Cycloaddition reactions.

The endo product is formed when the substituent is pointing towards where the new double bond will be. And the exo product is formed when the substituent is pointing away from where the new double bond will be.

Diastereoselectivity

Intramolecular Diels-Alder Cycloaddtion reactions tend to be very stereoselective, but the diastereoselectivity can be improved through the addition of lewis acid catalysts.

In the previous example, the first reaction without using a lewis acid lead to a 90% yield of a 62:38 cis:trans product. Upon the addition of a lewis acid, the same reaction was found to lead to a 100% yield of 100:0 product. In the second reaction, the addition of a lewis acid produced 100% of the endo product, while running the reaction with no lewis acid resulted in a 60:40 ratio of endo:exo product.

Activating Groups

Electron withdrawing groups have been found to reduce the temperature at which an Intramolecular Diels-Adler Cycloaddition reaction must be carried out.

The starting compounds used in these two reactions are very similar. The significant difference lies in the fact that compound 1 has a carbonyl attached to it that is absent in compound 2. The presence of this carbonyl allows for the reaction to take place at 0°C while the absence of it requires the reaction to be carried out at 160°C.

Applications

Intramolecular Diels-Alder cycloaddition is extremely useful for the formation of naturally occurring polycyclic rings. The reaction provides ready access to polycyclic compounds with a great deal of stereoselectivity. The following are several useful drugs whose complete synthesis have been accomplished using the intramolecular Diels-Alder reaction.

olanapyrone A

Solanapyrone A is an inhibitor of mammalian DNA polymerase β and λ, repair type DNA polymerase. The compound was isolated from the phytopathogenic fungi Alternaria solani, the cause of “early blight” in tomato and potato plants. The drug is being look as an anit-cancer medication. [B. Lygo, M. Bhatia, J.W.B Cooke, D.J Hirst. Synthesis of (+/-)- solanapyrones A and B. Tetrahedron Letters, 2003]

Salvinorin A

Isolated from the hallucinogenic sage, Salvia Divinorum. Salvinorin A is a potent and selective κ-opioid receptor. The compound has potential uses in psychotherapuetic treatments and Alzheimer’s treatment. [ A.C Burns, C.J Forsyth. Intramolecular Diels-Alder/Tsuji Allylation Assembly of the Functionalized trans-Decalin of Salvinorin A. Organic Letters, Vol.10, No.1 2008, pg 97-100 ]

Himbacine

Himbacine is a potent Potent muscarinic receptor antagonist, Isolated from the bark of Galbulimima baccata, a type of magnolia tree. The drug is a promising lead in Alzheimer’s disease research. [ S. Chackalamannil, R.J Davies, Y. Wang, et al. Total Synthesis of (+)- Himbacine and (+)-Himbeline. J.Org.Chem, 64, 1999, pg 1932-1940 ]

References


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