Cycloaddition, Double intramolecular

The tandem double intramolecular 4 + 3/3 + 2-cycloaddition of the nitroalkene (10) produced the nitroso acetal (11) in 77% yield. Further functional group manipulations allowed for the conversion to the partial core (12) of the complex polycyclic alkaloid daphnilactone B in high yield (Scheme 3).6 The tandem intramolecular 4 + 2/3 + 2-cycloaddition cascade of 1,3,4-oxadiazoles (13) to polycyclic adducts (14) was investigated by considering the tethered initiating dienophile, the tethered dipolarophile, the 1,3,4-oxadiazole C(2) and C(5) substituents, the tether lengths and sites, and the central heterocycle (Scheme 4).7... 

A one-pot, double intramolecular 1,3-dipolar cycloaddition reaction of azomethine ylides was developed by reaction of 4 equiv of an O-allyl salicyl-adehyde with a fluorous amino ester under microwave heating to generate a novel hexacyclic ring system 13 that contains seven stererocenters (Scheme 15) [45]. 

Fenestranes are compounds of theoretical interest in which the central carbon atom undergoes severe planarization distortion. Reactions sequences involving double intramolecular Pauson-Khand reactions of ene-diynes, or intramolecular Pauson-Khand of dienynes followed by photochemical [2 + 2] cycloaddition, successfully lead to [5.5.5.5]- or [4.5.5.5]fenestrane, respectively [42], For instance, compound 37 was obtained from ene-diyne 36 in moderate yield as a single all-czs stereoisomer [43] (Scheme 18). 

Tandem double intramolecular [4- -2]/[3- -2] cycloadditions were performed using nitroalkenes tethered to both the dienophile and the dipolarophile. For example, the [4-1-2] cycloaddition of the linear triene 544 was promoted by SnCU to afford a 3 2 mixture of545 and 546 rapidly. The intramolecular [34-2] cycloaddition was taken to completion by stirring the mixture in toluene at room temperature, and the polycyclic nitroso acetal 546 was then isolated as a single diastereoisomer in 87% overall yield (Scheme 128) <2003JOC8015>. 

S. E. Denmark, R. Y. Baiazitov, S. T. Nguyen, Tandem double intramolecular [4+2]/ [3+2] cycloadditions of nitroalkenes construction of the pentacyclic core structure of daphnilactone B, Tetrahedron 65 (2009) 6535-6548. 

Double intramolecular [2 + 2 + 2] cycloaddition enabled long helicene synthesis. A racemic anthra[ll]helicene was prepared via the cobalt-mediated double intramolecular [2 + 2 + 2] cycloaddition of a me.yo-hexayne followed by acetic acid elimination and dehydrogenation (Scheme 10.5) [8]. 

Recently, as shown in Scheme 6.155, Denmark and Baiazitov reported that tandem double-intramolecular [4 + 2]/[3 + 2] cycloadditions of nitroalkene gave e%o-folded product in good yield with excellent stereoselectivity [183]. 

The tandem double intramolecular [4 + 2]/[3 + 2] cycloadditions of 1,3,4-oxadiazoles developed by Boger and coworkers (Scheme 16.1) are also well represented. In this process, a 1,3,4-oxadiazole acts as an electron-poor heterodiene and engages in an inverse-electron-demand [4 + 2] cycloaddition. This step is followed by a retro-[3 + 2] cycloaddition that generates a dipole, reacting further via a [3 + 2] cycloaddition step. This cycloaddition has been used as the key step in the total syntheses of several Vinca alkaloids. Only tandem cascade cycloadditions of this type have been reported. 

Asymmetric induction can be also accomplished through the use of a chirally modified nitro olefin. Sugar-based nitroalkenes participate in thermal [4 + 2] cycloaddition to form enantiomerically pure nitronates [55,97]. Alternatively, diastereoselective cycloadditions are possible with chiral nitroalkenes as illustrated on Scheme 16.15 [47]. The tandem double intramolecular cycloaddition of enantiopure nitro-alkene 62 containing a single stereogenic center provides nitroso acetal 63 with high diastereoselectivity (relative to the existing center) in moderate yield. The product is isolated as a mixture of isomers that is formed due to epimerization of the intermediate nitronate (not shown) and used toward total synthesis of daphnilactone B. 

The tandem cycloaddition of nitroalkene 394 (Scheme 16.77) produces a tetracyclic nitroso acetal 397 with up to six new stereogenic centers in just two steps. Hydrogenolysis reveals a bicyclic amino diol 398, which may react further, for example, forming tetracyclic lactam 399. AU of the six newly formed stereogenic centers may potentially remain in the hydrogenolysis products, such as 398. It is this dramatic increase in complexity that makes the tandem, double-intramolecular nitroalkene cycloaddition so attractive. 

The earliest substrates for the tandem double intramolecular cycloadditions involved a,p-unsaturated nitrile... 

C(6) Tethered Dipolarophile Tandem, double-intramolecular cycloadditions of nitroalkenes in which the dipolarophile is attached to the C(5) or C(6)-carbon of dienophile has been more extensively studied. For example, a series of nitroalkenes has been prepared wherein the dipolarophile is attached to the C(6)-carbon 411a-c (Scheme 16.79)... 

SCHEME 16.79 Tandem, double intramolecular cycloadditions of nitroaUcenes with C(6)-tethered dipolarophile and hydrogenolysis of the resulting nitroso acetals. 

C(5) Tethered Dipolarophile The last of the known variants of the tandem, double-intramolecular cycloaddition differs by the point of attachment of the dipolarophile in... 

Tandem, Double-Intramolecular Cycloaddition Toward the Synthesis of Daphnilactone B The structure of amide 420 resembles the core of the naturally occurring alkaloid daphnilactone B 421 (Figure 16.15) [165]. The B/C/D ring system of 421 is clearly present in 420. The total or even partial synthesis [46, 47, 83a, 147, 148] of such a complex alkaloid would demonstrate the power of the tandem, double-intramolecular cycloaddition of nitroalkenes for creating polycyclic natural products in a stereocontroUed fashion. 

The model studies demonstrated that an exo-(tether)-[4-1-2] cycloaddition on the a-unsubstimted nitroalkene, and the construction of the piperidine ring are possible. In the next stage of the synthesis the elements needed to create rings A, D, E, and F were installed in a suitable precursor. Thus, enantiopure nitroalkene (S)-165 (prepared as a 5/1 mixture of nitroalkene isomers, Scheme 16.83) [47, 147] undergoes tandem, double-intramolecular [4 + 2]/[3- -2] cycloaddition in the presence of SnCLj to provide an inseparable mixture of nitroso acetals 167. Assuming that the substrate does not isomerize prior to the [4 + 2] cycloaddition, the reaction proceeds via the cnt/o-(tether)-transi-tion stmcture. Calculations suggest that the reaction is... 

SCHEME 16.83 Construction of the core of daphnilactone B by tandem, double-intramolecular cycloaddition of nitroalkene (5)-165. 

The tandem, double intramolecular cycloadditions are highly stereoselective. Only one isomer forms and the dienophile... 

SCHEME 16.102 Stereoselectivity of the double intramolecular tandem cycloaddition of 1,3,4-oxadiazoles. 

The Influence of the Tether Length on Reactivity in Tandem, Double Intramolecular [4+2]/[3+2] Cycloadditions of 1,3,4-Oxadiazole For the syntheses of Aspi-dosperma alkaloids, a four-atom tether to the dienophile is required to form the six-membered lactam 500a... 

The tandem, double intramolecular cycloadditions of 1,3,4-oxadiazoles has also been used for the syntheses of several other pentacyclic Aspidosperma alkaloids (+)-fendleridine (also known as aspidoalbidine 520, Scheme 16.110), (+)-ace-tylaspidoalbidine 521 (Scheme 16.110), (—)-aspidospermine,... 

The tandem cycloaddition of nitroalkenes is a very complex process consisting of a number of elementary reactions. Multiple bonds, stereogenic centers, and rings are created. The connection between the starting materials and the final product is often not obvious. To simplify the retrosynthetic analysis, summary charts (e.g.. Figure 16.8) for most of the modes of the tandem cycloaddition of nitroalkenes were provided. Illustrations of how these charts can be used for retrosynthetic analysis (e.g.. Scheme 16.54) were also provided. For the most complex modes, such as double intramolecular cycloadditions, a similar chart would be too complex and of limited utility because of the myriad of theoretically possible tether lengths and placements. Moreover, only a handful of variants have been realized in practice. 

The need for the high reaction temperature has been a major obstacle in developing the tandem cycloadditions of 1,3,4-oxadiazoles. As a consequence, chemoselectivity of such processes is poor. Successfiil activafion of the [4 + 2] step in such a tandem process using high pressure or Lewis acids is unknown. Only highly symmetrical products could be prepared until recently via double intermolecular and itner-[4 + 2]/intra-[3 + 2] variants. The chemoselectivity of a double intramolecular variant of the tandem process is not plagued by these limitations and it has been employed in the syntheses of Vinca alkaloids and their analogs. 

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