Transannular 4 + 2-cycloaddition

The methodology can be utilized in the preparation of quite complex derivatives such as the bicyclic guanidine outlined in Equation (1). In this example, in a one-pot reaction, 2-(o-azidophenyl) ethylamine and an o-azidoaryl carbonyl compound react to form the corresponding imine which upon subsequent treatment with triphenylphosphine and an arylisocyanate affords the cyclic guanidine (29) in a consecutive aza-Wittig/(27t -b 2n) cycloaddition/transannular annelation reaction sequence. 

Isomers, Rearrangement Trans... s. a. Interdiange Transannular s. Cycloaddition, transannular. Ring closure, -Transesterification... 

Dell C. P. Cycloaddition in Synthesis Contemporary Organic Synthesis 1997 4 87 Keywords natural products, metal catalyzed, asymmetric reactions, Ionic reactions, transannular reactions, tethered reactions, tandem reactions, benzo-qulnones, quinodimethanes, hefero-Dlels-Alder reactions... 

The most widely exploited photochemical cycloadditions involve irradiation of dienes in which the two double bonds are fairly close and result in formation of polycyclic cage compounds. Some examples of alkene photocyclizations are given in Scheme 6.9. Entry 1 is a transannular cyclization. The preference for the observed product over tricyclo[4.2.0.02,5]octane does not seem to have been analyzed in detail. Entries 2, 3, and 4 involve photolysis in the presence of Cu03SCF3. Entries 5 and 6 are cases in which the double bonds are in close proximity and can cyclize to caged structures. 

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... 

Vamos M, Ozboya K, Kobayashi Y (2007) Synthesis of bicyclic pyroglutamic acid featuring the Ugi reaction and a unique stereoisomerization at the angular position by Grob fragmentation followed by a transannular ketene [2-1-2] cycloaddition reaction. Synlett 1595-1599. Kreye O, Westermann B, Wessjohann LA (2007) A stable, convertible isonitrile as a formic acid carbanion [-COOH] equivalent and its application in multicomponent reactions. S3mlett 20 3188-3192... 

Formation of cluster opened methano- and imino[60[fullerenes (fulleroids and azafUlleroids) Thermal [3+2]-cycloadditions ofdiazo compounds or azides leads to the formation of fulleropyrazolines or fullerotriazolines. Thermolysis of such adducts after extrusion of N2 affords as kinetic products the corresponding [5,6]-bridged methano and iminofullerenes with an intact 60 re-electron system and an open transannular bond (see Chapter 4) [88-91]. The corresponding [6,6]-bridged structures with 58 re-electrons and a closed transannular bond are formed only in traces. 

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>. 

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... 

Bicyclic 3a//-cyclopentene[8 annulcnc-l,4-(5//,9a//)-dioncs undergo three types of acid-induced transannular reactions (1) Michael addition (5-exo-trig or 6-exo-trig) leading to the tetracyclic diones, (2) 3 + 2-cycloaddition followed by a novel sequential skeletal rearrangement to 2-naphthalenone derivatives, (3) ipso-Friedel-Crafts alkylation accompanied by the rearomatization and the loss of water (Scheme 25). The factors that control the reaction mode of these transannular cyclizations are discussed... 

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]. 

Natural products containing six-membered rings are ubiquitous, therefore the following set of target molecules are limited to those containing eight-membered rings that would be accessible via [4+4] cycloadditions. Notably, 1,5-cyclo-octadienes 88 can be converted to bicyclo[3.3.0]octanes 201 transannular electrophilic [124] and radical cyclization (Sch. 44) [125]. 

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]. 

Transannular free radical 1,5-cycloadditions to 1,5-cyclooctadiene are equally prevalent, frequently cleaner, and capable of providing convenient access to bicyclo-[3.3.0]octyl derivatives.84-86 ... 

Intramolecular exocyclic transannular cycloaddition of TMM can provide a viable route to propel-lanes, such as the sesquiteipene modhephene (144). TTiis methodology is demonstrated in an efficient synthesis of a [3.3.3]propellane (145) (equation 149)." The methylenecycloprtqtane approach is preferred in this case because it works well with dialkyl-substimted systems. 

Several detailed investigations of transannular IMDA cycloadditions have appeared in recent years. This transformation promises to become an important synthetic method owing to the potential for the rapid efficient construction of complex polycyclic ring systems. Other potenti strategic benefits include increased reactivity due to diminished entropic requirements (AS ). This is nicely illustrated by the facile cyclization of (101) with a tetrasubstituted dienophile, compared with the unsuccessful IMDA reaction of (102) (Figure 27). Although the cyclization of (101) proceeds with only moderate diastereoselection, many other examples have been reported that exhibit outstanding selectivity, e.g. cyclization of (103). It is conceivable that conformational constraints imposed by the macrocyclic system may lead to improved IMDA stereoselectivity relative to conventional acyclic trienes, but this point has not yet been demonstrated in any published examples. 

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