Organic Chemistry Portal
Organic Chemistry Highlights

Monday, August 14, 2006
Douglass Taber
University of Delaware

New Dienes and Dienophiles for Intermolecular and Intramolecular Diels-Alder Cycloadditions

The Diels-Alder reaction is a powerful tool for the construction of substituted cyclohexenes. Erik J. Sorenson of Princeton University has developed (J. Am. Chem. Soc. 2005, 127, 8612. DOI: 10.1021/ja052383c) a class of hydrazinodienes, exemplified by 1. Lewis acid-mediated cycloaddition to give 3 proceeded smoothly. Protection of the aldehyde followed by sigmatropic loss of N2 led to the product 4. This new class of dienes opens access to cyclohexenes having substitution patterns that cannot be prepared by direct Diels-Alder addition.

Aromatics and heteroaromatics are potentially inexpensive dienes, as strategies can be developed for breaking up their aromaticity. Stoichiometric transition metal complexes have been used for this purpose, but this approach is seldom practical, because of the expense of the transition metal used. W.D. Harman of the University of Virginia has now shown (J. Am. Chem. Soc. 2005, 127, 10568. DOI: 10.1021/ja050143r) that the 1:1 complex 7 of 2,6-lutidine (5) and the inexpensive tris(pyrazolo)borate tungsten 6 serves as an effective Diels-Alder diene, adding acrylonitrile to deliver, after oxidative removal of the tungsten, the highly functionalized adduct 8.

One of the most important advances for the Diels-Alder reaction in recent years has been the development of effective enantioselective organocatalysts. To date, this work had focused onα-unsubstituted or α-haloacroleins. Kazuaki Ishihara of Nagoya University has now prepared (J. Am. Chem. Soc. 2005, 127, 10504. DOI: 10.1021/ja053368a) a family of triamine catalysts that are effective with α-acyloxy acroleins.

In a parallel development (Org. Lett. 2005, 7, 4515. DOI: 10.1021/ol051872e), Dimitris Georgiadis of the University of Athens has found that a Lewis acid effectively promotes the Diels-Alder cycloaddition of α-acetoxy acrolein 12 to sorbyl alcohol 13. This reaction is apparently intramolecular, with the Lewis acid linking the diene and the dienophile.

Enantiomerically-pure linkers can also be used to direct Diels-Alder cycloaddition. Takayuki Doi and Takashi Takahashi of the Tokyo Institute of Technology designed (Chem. Commun. 2005, 4908. DOI: 10.1039/b509156j) the dipeptide linker of 16 and 17. They observed that 16 cyclized with high diastereocontrol to 18, while 17 gave a ~ 1:1 mixture. These results were predicted qualitatively by computational analysis of the competing transition states.

The intramolecular Diels-Alder cycloaddition is a powerful tool for polycarbocyclic construction. The continuing work of Peter Metz of the Technische Universitšt Dresden (Angew. Chem. Int. Ed. 2005, 44, 6231. DOI: 10.1002/anie.200501511) demonstrates that the IDA is also an effective tool for the enantioselective construction of heterocycles. Alcohol 20 was prepared by enantioselective hydroboration. Formation of the sulfonate ester 22 led directly to the Diels-Alder adduct 23, which was brought to enantiomeric purity by recrystallization. Methyl lithium opening followed by oxidative cleavage and reductive cyclization delivered the hydroxy ester 25, a key intermediate in the total synthesis of pamamycin-621A.

D. F. Taber, Org. Chem. Highlights 2006, August 14.