Nitroalkene 1 + 2 / cycloadditions

The majority of asymmetric dipolar cycloadditions have been investigated in the context of the tandem [4 + 2]/[3 + 2]-nitroalkene cycloaddition. The chiral nitronate is prepared by using either a chiral nitroalkene, vinyl ether, or Lewis acid in the hrst cycloaddition. The acetal center at C(6) of the nitronate provides important steric and electronic effects that control the subsequent dipolar cycloaddition. Subsequently, in the cycloadditions of the chiral nitroalkenes 281 and 284, the dipolarophile approaches from the side distal to that of the substituent at C(4) and the acetal center at C(6) (Eq. 2.27 and Table 2.53) (90,215). 

The dipolar cycloaddition of nitronates has been applied to the synthesis of several natural products in the context of the tandem [4+2] / [3 + 2] nitroalkene cycloaddition process. All of these syntheses have focused on the construction of pyrrolidine, pyrrolizidine, and indolizidine alkaloids. For example, the synthesis of ( )-hastanecine (316), a necine alkaloid, involves the elaboration of a p-benzoy-loxynitroalkene 311 via [4 + 2] cycloaddition with a chiral vinyl ether (312) in the presence of a titanium based Lewis acid, to provide the nitronate 313 with high diastereo- and facial selectivity (Scheme 2.30) (69). The dipolar cycloaddition of... 

The photochemical reaction of tetranitromethane with aromatic compounds leads in low yields to 1,3,2-dioxazoles, as products of the nitroalkene cycloaddition of the trinitromethyl intermediate <1995ACS482, 1996ACS29, 1996ACS735>. The cycloaddition products 22a and 22b (0.2-1.8%) were isolated from 1,3-dimethylnaphthalene <1995ACS482>, compound 23a (20%) from 1,2,3-trimethylbenzene <1996ACS29>, and compound 23b (3%) from 1,2,3,4-tetramethylbenzene <1996ACS735>. The structure of all these compounds has been proved by single crystal X-ray analysis (see Section 6.02.3.1). 

If nitroalkenes are employed as heterodienes in hetero Diels-Alder reactions instead of nitrosoalkenes, cyclic nitrones are formed. These cycloadducts undergo numerous subsequent reactions, and especially the combination of this hetero Diels-Alder reaction with a 1,3-dipolar cycloaddition is an extremely powerful tool for the synthesis of polycyclic alkaloids. This domino [4+ 2]/[3+ 2] cycloaddition chemistry has been comprehensively reviewed by Denmark and Thorarensen very recently, and this review also covers many hetero Diels-Alder reactions of nitroalkenes being not part of this sequential transformation [5]. Therefore the present article will focus on some selected examples which might highlight the advanced state of the art concerning stereocontrol of these reactions. On the other hand, an insight shall be given into the multitude of polycyclic structures accessible by means of nitroalkene cycloaddition chemistry. 

Novel stereoselectivity in tandem inter[4+2]/intra[3+2] nitroalkene cycloaddition... 

The size of the Lewis acid also influences the stereoselectivity of the [4-1-2] nitroalkene cycloaddition. Thus, trimethylaluminum is one of the smaller Lewis acids that promote the cycloaddition (R" = Me, Figure 16.1) and subsequently the reaction may proceed via the en /o-transition structure. The preference for the endb-transition structure can be rationalized by the stabilizing effect of secondary orbital interactions [67]. Alternatively, the bulkier derivatives of aluminum, such as ATPh (R is a bulky phenol) can be used to direct the [4 + 2] step toward the less crowded exotransition structure [67]. 

Although electron-rich dienophUes are the most reactive, unactivated alkenes also can participate in the [4 + 2] cycloaddition of nitroalkenes. An example of one of the slowest reported nitroalkene cycloadditions is provided in Scheme 16.10b [81]. The dienophile 42 contains a terminal double bond and the reaction takes 3 days at 15 °C to provide nitronate 43, albeit still in very good yield. 

The strongly nucleophilic enamines are among the first reported dienophiles for nitroalkene cycloadditions [85]. Thus, nitroalkene 51 undergoes thermal [4 + 2] cycloaddition with enamine 52 to provide nitronate 53 (Scheme 16.11) [86]. 

Unlike the regioselectivity of the [4 + 2] nitroalkene cycloaddition, the exo-Zendo-selectivity is less consistent. Thus, cyclohexadiene (45) reacts with a disubstimted... 

Transformations on the Periphery of Nitroso Acetals Without Cleavage of N—O Bonds The tandem nitroalkene cycloaddition is more synthetically useful because... 

An intermolecular [4 + 2] nitroalkene cycloaddition can be followed by an intramolecular [3 + 2] cycloaddition of the formed nitronate intermediate. As illustrated in Figure 16.7, two variants of such a process are possible, depending on whether the dipolarophile is attached to the nitroalkene or the dienophile. The former has been studied more extensively and is described in the following section. 

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. 

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