Ring structure intramolecular cycloadditions

Zero-valent, nickel-mediated intramolecular enyne metathesis is also an effective method for the synthesis of functionalized ring structures. Oxidative cycloaddition of enynes having an electron-withdrawing group on the alkenyl group generates nickelacyclopentene intermediates that... 

Intramolecular cycloadditions of substrates with a cleavable tether have also been realized. Thus esters (37a-37d) provided the structurally interesting tricyclic lactones (38-43). It is interesting to note that the cyclododecenyl system (w = 7) proceeded at room temperature whereas all others required refluxing dioxane. In each case, the stereoselectivity with respect to the tether was excellent. As expected, the cyclohexenyl (n=l) and cycloheptenyl (n = 2) gave the syn adducts (38) and (39) almost exclusively. On the other hand, the cyclooctenyl (n = 3) and cyclododecenyl (n = 7) systems favored the anti adducts (41) and (42) instead. The formation of the endocyclic isomer (39, n=l) in the cyclohexenyl case can be explained by the isomerization of the initial adduct (44), which can not cyclize due to ring-strain, to the other 7t-allyl-Pd intermediate (45) which then ring-closes to (39) (Scheme 2.13) [20]. While the yields may not be spectacular, it is still remarkable that these reactions proceeded as well as they did since the substrates do contain another allylic ester moiety which is known to undergo ionization in the presence of the same palladium catalyst. 

An intramolecular cycloaddition also occurred with 3-ylidenepiperazine-2,5-diones such as 124 or 125, obtained by Wittig-Horner-Emmons reaction from phosphonate 121 and aldehydes 122 or 123, respectively. The products of the Diels-Alder reaction are the bridged bicyclo[2.2.2]diazaoctane rings 126 and 127 that have been found in biologically active secondary metabolite such as VM55599 and brevianamide A. The different type of structures employed in this case requires a chemoselective reaction in order to produce the expected products as single diastereoisomers after 20 days (Scheme 18) <2001JOC3984>. 

Application to both Type I and Type II intramolecular Diels-Alder cycloaddition has also met with appreciable success, the most efficient catalyst for these reactions being imidazolidinone 21 (Scheme 7) [51, 52]. The power of the inttamolecular Diels-Alder reaction to produce complex carbocyclic ring structures from achiral precursors has frequently been exploited in synthesis to prepare a number of natural products via biomimetic routes. It is likely that the ability to accelerate these reactions using iminium ion catalysis will see significant application in the future. 

The intramolecular cycloadditions of cychc nitronates have received much more attention. The cyclic nitronate structure provides three basic modes of intramolecular cycloaddition (Fig. 2.15). Attachment of the tether to the C(3) position of the nitronate results in the formation of a sprro system (sprro mode). However, if the tether is appended to the C(4) position of the nitronate, the dipolar cycloaddition yields a fused ring system (fused mode). Finally, if the tether is attached at any other point of the cyclic nitronate, the cycloadducts obtained will consist of bicyclic structures (bridged mode). 

A number of intramolecular cycloadditions of alkene-tethered nitrile oxides, where the double bond forms part of a ring, have been used for the synthesis of fused carbocyclic structures (18,74,266-271). The cycloadditions afford the cis-fused bicyclic products, and this stereochemical outcome does not depend on the substituents on the alkene or on the carbon chain. When cyclic olefins were used, the configuration of the products found could be rationalized in terms of the transition states described in Scheme 6.49 (18,74,266-271). In the transition state leading to the cis-fused heterocycle, the dipole is more easily aligned with the dipolarophile if the nitrile oxide adds to the face of the cycloolefin in which the tethering chain resides. In the trans transition state, considerable nonbonded interactions and strain would have to be overcome in order to achieve good parallel alignment of the dipole and dipolarophile (74,266). 

Intramolecular cycloadditions of alkenyl-substituted nitrile oxides produce bicyclic isoxazolines. When monocyclic olehns are used, tricyclic structures are obtained. This approach was pioneered by both Kozikowski s and Curran s groups. A typical case involves the cycloaddition of nitro compound 191 [mixture of diastereomers derived from pentenose pyranoside 190], which produced a diaster-eomeric mixture of isoxazolines that contain cis-fused rings (i.e., 192) in near quantitative yield (326) (Scheme 6.85). Further elaboration of this mixture led to epoxycyclopentano-isoxazoline 193, which was then converted to the aldol product in the usual manner. The hydrogenation proceeded well only when rhodium on alumina was used as the catalyst, giving the required p-hydroxyketone 194. This... 

Intramolecular cycloaddition reactions have been performed on the furan-containing indoles 143, to provide an efficient route to numerous derivatives of the tetracyclic ring system 144, a structural motif of Aspidosperma and Strychnos alkaloids <02OL4643>. 

Finally, the intramolecular cycloaddition methodology also provides access to heterocyclic systems when methylenecyclopropanes with heteroatom-containing side chains are employed. However, as shown above, very complex structural requirements are deary operable. For example, methyl 4-[(l-methyl-2-methylenecyclopropyl)methoxy]but-2-ynoate only yields a complex product mixture mainly containing conjugated dienes (arising from a ring cleavage/ -elimination sequence) upon attempted palladium(0)-catalyzed cycloisomerization. ... 

The Diels-Alder reaction of tetrazine 14.3 with Ceo followed by intramolecular cycloaddition and loss of N2 results in the insertion of a C2-unit into the Cgo cage. In structure 14.3, the two carbon atoms marked with the pink dots are those that are eventually incorporated into the 52 cage. Figure 14.9 shows the structure of the product, C62(C6H4-4-Me)2, and confirms the presence of a 4-membered ring surrounded by four 6-membered rings. 

Catalytic carbonylative [4-Hl]cycloaddition is also considered to be a type of carbonylation with ruthenium catalysts via the intramolecular flve-membered ring structure. The substrates are a,p-unsaturated imines. A p,y-unsaturated y-lactam is prepared in a high yield by reaction with carbon monoxide at 180 °C for 20 h in the presence of Ru3(CO)i2 [99]. Representative reactions and their reaction mechanisms are shown in Eq. (7.49) and Scheme 7.13, respectively [99]. 

Polycyclic aromatic compounds, such as naphthalene and anthracene, are weU known to participate in Diels-Alder and related transformations as these reactions typically result in loss of aromaticity in only one of several arene rings [38]. Such cycloadditions are rarely observed in simpler monocyclic arenes. Several examples of intramolecular [3+2] cycloaddition between an arene and an attached nitrile oxide moiety have been reported [39]. Additionally, 4+2 cycloadditions (also intramolecular) between phenyl groups and attached aUenes have been examined [40]. Allene substrates can be conveniently genwated by base-induced isomerization of alkynyl amides under conditions also suitable for cycloaddition, thweby affording a one-pot method to convert substrates such as 42 to tricyclic products 43 (Schane 15.16) [41]. Elaboration of 43 and structurally related... 

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