Diels-Alder Transannular

Deslongchamps P. Transannular Diels-Alder Reaction on Macrocycles a General Strategy for the Synthesis of Polycyclic Compounds A Idrichimica Acta 199124 43-56... 

Deslongchamps and coworkers [26] used a combination of a transannular Diels-Alder cycloaddition and an intramolecular aldol reaction in the synthesis of the unnatural enantiomer of a derivative of the (+)-aphidicolin (4-74), which is a diterpe-noic tetraol isolated from the fungus Cephalosporium aphidicolia. This compound is an inhibitor of DNA polymerase, and is also known to act against the herpes simplex type I virus. In addition, it slows down eukaryotic cell proliferation, which makes it an interesting target as an anticancer agent... 

Scheme 6/1.48. Domino Stille/transannular-Diels-Alder reaction.

En route to the total synthesis oftashironin (7-114a) and the debenzoylated compound 7-114b, which shows an interesting promotion of neurite growth, Danishefsky and coworkers have developed a domino oxidative dearomatization/trans-annular Diels-Alder reaction [54]. In this line, treatment of 7-115 with phenyl-iodine(III) diacetate (PIDA) led to an intermediate 7-116, which immediately underwent a transannular Diels-Alder reaction to furnish the complex cycloadducts 7-117 in good yields (Scheme 7.31). 

Scheme 7.36. Domino oxidation/twofold transannular-Diels-Alder reaction in the total synthesis of FR182877 (7-133).

The thermally and Lewis acid-promoted transannular Diels-Alder reactions have proven to be a powerful tool for the synthesis of steroids and other natural products [24]. A research team led by Takamura, Arimoto, and Uemura utilized this reaction to assemble the polycyclic skeleton of nakiterpiosin (1) [25]. Heating macrolide 39 at 160 °C gave 40 and 41 as a mixture of diastereomers in good yields. 

Toro, A. Nowak, P. Deslongchamps, P. (2000) Transannular Diels-Alder aitiy into stemodanes first asymmetric total synthesis of (+)-maritimol. J. Am. Chem. Soc., 122,4526-7. 

An enantioselective biomimetic synthesis of longithorone A was accomplished on the basis of proposed biosynthesis. " The syntheses of two [12]-paracyclophanes 105 and 107 are realized by applying ene-yne metatheses macrocyclization to 104 and 106, which are synthesized from the common substrate 103. Longtholone A is constructed using intermolecular and transannular Diels-Alder reactions followed by oxidation (Scheme 40). 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

An interesting and rare example of inverse electron demand transannular Diels-Alder reaction of the furanophane 65 was employed for the synthesis of the chatancin core as depicted in Equation (45) <2003JOC6847>. The diastereoselectivity of this reaction was controlled by the macrocyclic conformation of 65 in the protic reaction medium. 

The first asymmetric total synthesis of (+)-maritimol, a diterpenoid natural product that possesses a unique tetracyclic stemodane framework was accomplished by P. Deslongchamps. To introduce the C12 stereocenter, the Enders SAMP/RAMP hydrazone alkylation was used. This stereocenter played a crucial role in controlling the diastereoselectivity of the key transannular Diels-Alder reaction later in the synthesis. The required SAMP hydrazone was formed under standard conditions using catalytic p-toluenesulfonic acid. Subsequent protection of the free alcohol as a f-butyidiphenylsilyl ether, deprotonation of the hydrazone with LDA and alkylation provided the product in high yield and excellent diastereoselectivity. The hydrazone was converted to the corresponding nitrile by oxidation with magnesium monoperoxyphthalate. 

The key steps in the first total synthesis of (+)-momilactone A by P. Deslongchamps et al. were a highly diastereoselective transannular DIels-Alder cycloadditlon and the Prdvost reaction The 3-ketolactone moiety was installed by first treating the tricyclic alkene with A/-bromo acetamide and silver acetate to obtain the trans bromoacetate with excellent diastereoselectivlty. The cIs stereochemistry of the lactone was achieved a few steps later by the intramolecular nucleophilic displacement of the bromide with the carboxylate ion on the adjacent six-membered ring. 

Studies toward the biomimetic total synthesis of (+)-chatancin were conducted by P. Deslongchamps et al. The authors planned to use a transannular Diels-Alder reaction of a pyranophane intermediate as the key ring forming step. The cyclic dienedione precursor for this transformation was prepared using the Prins reaction on a substrate derived from trans-trans farnesol. 

The scalable total synthesis of the cytotoxic natural product (+)-FR182877 was accomplished in the laboratory of E.J. Sorensen.The key steps of the synthetis were an intramolecular Tsuji-Trost allylation to prepare the 19-membered macrocyclic pentaene followed by a double transannular DIels-Alder cycloadditlon to obtain the desired pentacyclic structure. The allylic carbonate was exposed to 10 mol% of the Pd-catalyst under high dilution conditions in THF. The new bond between Cl and Cl 9 was formed with complete diastereoselectivity and in good yield, although the configuration at Cl 9 was not determined. 

Marsault, E., Toro, A., Nowak, P., Deslongchamps, P. The transannular Diels-Alder strategy applications to total synthesis. Tetrahedron 2001,57,4243 260. 

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