Nitroalkene tandem 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... 

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. 

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]. 

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. 

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)... 

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. 

SCHEME 16.80 Tandem, double-intramolecular cycloadditions of nitroalkenes with C(5)-tethered dipolarophile and hydrogenolysis of the resulting nitroso acetals. 

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 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. 

If we have a look to the structures of compounds 10,11 and 12 we will find some similarities with the tandem process we have just discussed. First, bicyclic isoxa-zolines 11-12 have been obtained through an intramolecular cyclization process. Second, the skeleton of the starting material is easily reeognizable in the final products, although some bonds have changed. The nitro group has been modified and the double bond that was plaeed at the end of the ehain has disappeared (bonds in red) but new C=N and C-C bonds have been incorporated (bonds in blue) (Scheme 22.10). However, all the reaetions we have discussed previously have in common a nitroalkene as starting material. Where is the nitroalkene in this case ... 

As for any tandem cycloaddition sequence, four different permutations arise from the pairwise combinations of intermolecular and intramolecular events in each step (Figure 16.7). The double intermolecular variant involves three independent reaction partoers. The intra-[4 + 2]/inter-[3 + 2] variant requires that the dienophile, but not the dipolarophile, is connected to the nitroalkene. This variant and the next two variants can create additional complexity by adjusting the length and point of attachment of the tether to... 

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