Transannular Diels-Alder cycloaddition

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... 

In the development of a new strategy using Claisen-Ireland ring contraction of large ring lactone followed by transannular Diels-Alder cycloaddition, Roush [119] prepared the tetraene diester 490 through a Claisen-Johnson rearrangement (Scheme 6.76). 

Debenzoyltashironin, a densely functionalized polycyclic natural product that induces neurite outgrowth in fetal rat cortical neurons, was synthesized by Danishefsky and co-workers using a biomimetic synthetic route. As shown in Scheme 20.4, the cyclic quinone monoketal 10 was formed by oxidative dearomatization of 9 followed by intramolecular O-cyclization. The transannular Diels-Alder cycloaddition was observed during this process. However, a 4-minute microwave irradiation was needed to complete the reaction to give 11 in 65% yield. It is remarkable that such a complex polycyclic ring system was assembled in two steps. Incorporation of a trisubstituted allene as the dieno-phile of 9 was important because the transannular Diels-Alder reaction did not proceed when an alkene dienophile... 

Two diastereomers (1 1.4 disfavor 17) were formed from the Diels-Alder reaction because of a lack of facial selectivity even though the reaction was completely endo-selective. Desilylation of 17 followed by direct oxidation with iodosylbenzene gave bisquinone 19, which underwent the transannular Diels-Alder cycloaddition at room temperature over a period of 40 hours to give longithorone A in 90% yield. 

The Diels-Alder cycloaddition of 1,2-dimcthylcnc 2.n]mclacyclophancs (83) with DMAD followed by aromatization (84) and photoinduced transannular cycliza-tion produced phenanthrene-anellated polycyclic aromatic hydrocarbons (85) (Scheme... 

The intramolecular Diels-Alder cyclization of cyclohexadiene-l,2-dicarboxylic anhydride-derived diester-tethered triene (86) produces the cycloadducts in a ratio of 7 1 (Scheme 31). The intramolecular Diels-Alder reactions of amino acid-derived trienes (87) yield cycloaddition products (88) and (89) which are mainly cw-fused and derived from the exo-transition states (Scheme 32). A key reaction in the synthesis of the natural product momilactone A is the transannular Diels-Alder cyclization of the trans-trans-cis alkene (90) to the trans-syn-trans tricycle (91) (Scheme 33). The Diels-Alder cycloaddition of 1 l-oxapentacyclo[6,5,2,2 0 0 ]-heptadeca-4,14,16-triene-4,5-dicarboxylic anhydride (92) with cyclopentadiene proceeds with 5yn-facial selectivity to produce syn,endo and syn,exo cycloadducts (93) and (94)... 

AMI, B3LYP/6-31G //AMl, and B3LYP/6-31G computational studies have been used to investigate the molecular mechanism of the domino cycloadditions between DMAD and naphthalino- and anthraceno-furanophanes. The transannular Diels-Alder reaction of the furanophane (143) successfully produced the desired isomer (144), a key intermediate in the total synthesis of the diterpenoid chatancin (Scheme 55). ... 

In 2003, Deslongchamps and coworkers reported an elegant synthesis of (+)-chatancin (112) in 17 steps involving a biomimetic transannular cycloaddition (Scheme 8.18) [48]. Although there are no evidences of in vivo transannular Diels-Alder (TADA) reaction in cembranoids, Deslongchamps hypothesized that 112 could be obtained from a macrocyclic pyranophane such as 116a. To verify... 

Since the publication of CHEC-II(1996) <1996CHEC-II(6)1>, in which thermally induced [4+2] cycloadditions have been reviewed, significant progress has been realized in this strategy, especially for the synthesis of polycyclic heterocycles. Cyclophanes 12 containing pyridazine and indole units were used for the synthesis of pentacyclic compounds 13 via a thermally induced transannular inverse-electron-demand Diels-Alder reaction (Equation 2) <20020L127, 2002AGE3261>. 

Generation of the highly strained tricyclic 91 (Sch. 18) can be accomplished by transannular photo-[4+2] cycloaddition of 1,3,6-cyclo-octatrience 90 by direct (unsensitized) irradiation, albeit in modest yield [60]. Structures such as 91 can, however, be unstable toward a thermal retro-Diels-Alder reaction [61]. 

Such syntheses take advantage of transannular intramolecular hetero Diels-Alder reactions [426], another impressive example is the diene transmissive hetero Diels-Alder reaction of the thioketone 5-14. The diene 5-15 formed by this cycloaddition underwent a second Diels-Alder reaction with N-phenyl-maleimide to yield the fused polycycle 5-16 as single diastereomer (Fig. 5-5) [427]. 

This idea is presented more formally in Scheme 5 with the thought that five of the six rings of the target molecule and seven of its stereocenters (as expressed in 34) could arise from a polyunsaturated precursor (30) through a series of two cycloaddition reactions and a macrocyclization event. For instance, if 30 initially participated in a Type I intramolecular Diels—Alder reaction with endo selectivity to afford 32, a subsequent intramolecular condensation of the Knoe-venagel type could then provide 33, a substrate poised for an intramolecular transannular hetero-Diels—Alder reaction between its electron-poor enone system and the proximal trisubstituted double... 

Since its initial discovery in 1928," the Diels-Alder reaction has become one of the most powerful transformations at the disposal of organic chemists and has found applications in countless occasions. This popularity of the Diels-Alder reaction stems from its ability to stereospecifically generate a six-membered ring through the formation of two new CT-bonds, one 7t-bond, and up to four stereocenters in one concerted cycloaddition. The Diels-Alder reaction is well suited for transannular applications because the dienes and dienophiles can be easily incorporated into macrocyclic precursors and the reaction can be accelerated by catalysts or by heating alone. In addition, the macrocyclic environment provides both enthalpic and entropic activation for reactions that may not readily occur under intermolecular or other intramolecular settings. This allows for efficient generation of complex polycyclic compounds from relatively simple macrocyclic substrates. ... 

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