Nitroalkenes cycloadditions with

High-pressnre promoted cycloadditions of nitroalkenes and enol ethers eliminate the nse of Lewis acids fEq 8 106 "Thus, even sterically hmdered nitroalkenes react with 2,3-thhydro-furan to give the exo cyclic nitronates stereoselecdvely without using Lewis acids... 

The introduction of heterodienes has extended the synthetic versatility of cycloaddition reactions in organic synthesis.150 Denmark and coworkers have developed the use of nitroalkenes as dienes in [4+2] cycloaddition. Nitroalkenes react with simple alkenes in the presence of SnCl4 as a promoter. For example, the reaction of nitrocyclohexene with cyclopentene gives three products. The major product is awh-isomer, which arises from an exo approach of cyclopentene toward nitrocyclohexene (see Eq. 8.94).151... 

The simplest nitroalkene, nitroethene, undergoes Lewis acid-promoted [4+2] cycloaddition with chiral vinyl ethers to give cyclic nitronates with high diastereoselectivity. The resulting cyclic nitronates react with deficient alkenes to effect a face-selective [3+2] cycloaddition. A remote acetal center controls the stereochemistry of [3+2] cycloaddition. This strategy is applied to synthesis of the pyrrolizidine alkaloids (+)-macronecine and (+)-petasinecine (Scheme 8.33).165... 

Di- and trisubstituted nitroalkenes tethered to dipolarophiles (unsaturated esters, nitriles) undergo tandem [4+2]/[3+2] cycloadditions with 2,3-dimethyl-2-butene or butyl vinyl ether in the presence of Lewis acids (Eq. 8.112). For the dimethylene tether, the E-configuration of the dipolarophile is preferred, and the products arise selectively from a syn-endo pathway.177... 

The extremely high selectivity for tandem cycloaddition, the ease of manipulation of the nitroso acetals, and the release of the vinyl ether appendage in the hydrogenolytic cleavage constitute ideal features for asymmetric modifications of the cycloadditions with chiral vinyl ethers. As discussed in Section 8.3.2.1 (Inter [4+2]/inter [3+2] cycloadditions of nitroalkenes), the stereochemical course depends on the Lewis acids. The results are summarized in Scheme 8.38.179 The high levels and complementary selectivity with three chiral vinyl ethers and two kinds of Lewis acids (Ti- and Al-based Lewis acids) are presented in this scheme. 

Despite the lack of success in the attempts at intramolecular cycloaddition with substrates 83 and 91, a moderately promising outcome was observed for the nitroalkene substrate (98, Scheme 1.10c). Heating a dilute solution of oxido-pyridinium betaine 98 in toluene to 120 °C produced a 20 % conversion to a 4 1 mixture of two cycloadducts (110 and 112), in which the major cycloadduct was identified as 110. While initially very encouraging, it became apparent that the dipolar cycloaddition reaction proceeded to no greater than 20 % conversion, an outcome independent of choice of reaction solvent. Further investigation, however, revealed that the reaction had reached thermodynamic equilibrium at 20 % conversion, a fact verified by resubmission of the purified major cycloadduct 110 to the reaction conditions to reestablish the same equilibrium mixture at 20 % conversion. 

Synthesis of Six-membered Cyclic Nitronates by the [4 + 2]-cycloaddi-tion Reaction The [4 + 2]-cycloaddition reaction of conjugated nitroalkenes (42) with olefins (43) is the most powerful and widely used method for the synthesis of six-membered cyclic nitronates (35) (Scheme 3.38). 

The behavior of complexes of nitroalkenes (42) with LA toward conjugated dienes is yet another factor underlying the role of these complexes. Conjugated nitroalkenes (42) are considered as active dienophiles in classical Diels-Alder reactions (104, 105). On the contrary, in the presence of SnCl4, nitroalkenes (42) react with cyclopentadiene and 1,3-cyclohexadiene exclusively at one double bond (103). Therefore, it is highly probable that the 42 + 43 cycloaddition proceeds by a nonconcerted mechanism in the presence of LA (see Scheme 3.40). 

Initially, a complex of nitroalkene (42) with LA (A) is reversibly formed. The efficient concentration of the latter is determined by the reaction conditions and the nature of heterodiene (42) and LA. This complex acts as a Michael substrate and adds alkene (43) to give bipolar adduct B, which undergoes cycliza-tion to give cationic intermediate C. The latter eliminates LA to yield target nitronate (35). In the case of nonconcerted cycloaddition, ionic intermediate B can undergo different isomerization reactions, some of which are considered below. The stereoselectivity of the process depends on the reactive conformation... 

In this approach, the SENA skeleton is assembled from nitroalkene (42) and nucleophile 56.With the exception of two examples (entries 1 and 2 in Table 3.2), the reaction does not stop at SENA 51, which either undergoes intramolecular cyclization through [3 + 2]-cycloaddition to give fused heterocycles (as a rule after elimination of trimethylsilanol) (198-200) or is involved in [3+ 2]-cycloaddition with specially added methyl vinyl ketone or methyl acrylate to form (after elimination of silanol) substituted isoxazolines in rather high yields (201). 

The asymmetric tandem cycloaddition of the chiral carbohydrate nitroalkene (35) with ethyl vinyl ether involves the initial formation of the nitronate (36) which reacts exclusively with electron-withdrawing alkenes by 3 -I- 2-cycloaddition to yield chiral bicycles (37) and (38) (Scheme 12). ... 

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 Lewis acid-promoted tandem inter[4 + 2]/intra[3 + 2]-cycloaddition of the (fumaroyloxy)nitroalkene (124) with the chiral /i-silylvinyl ether (125) is the key step in the total synthesis of (+)-crotanecine (126), the necine base of a number of pyrrolizidine alkaloids (Scheme 46).237 The tandem inter[4 + 2]/intra[3 + 2]-cycload-ditions of nitroalkenes (127) with dipolarophiles attached to the /f-carbon of a vinyl ether (128) provides a method of asymmetric synthesis of highly functionalized aminocyclopentanes (129) (Scheme 47).238 trans-2-( 1 -Methyl-phenylethyl)cyclohex-anol has been developed as a new auxiliary in tandem 4 + 2/3 + 2-cycloadditions of nitroalkenes.239 The scope and limitations of the bridged mode tandem inter-[4 + 2]/intra[3 + 2]-cycloadditions involving simple penta-1,4-dienes are described in detail.240 A tandem intermolecular/intramolecular Diels-Alder cycloaddition was successfiilly used to synthesize a B/C cA-fused taxane nucleus (130) in 50% overall... 

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. 

Chiral (Z)-l-(alkylsulfinyl)-2-nitroalkenes underwent Lewis acid-promoted Diels-Alder reactions, with complete control of the diastereoselectivity as well as endo selectivity, to yield single cycloadducts.114 Enantiopure (-)-trans-benzo[d ]dithi-ine-S.S -dioxide underwent Diels-Alder cycloadditions with a series of cyclic dienes, affording adducts with diastereoselectivities ranging from fair to high.113... 

The oxidation of the alcohol was performed with supported perruthenate (8.48, Fig. 8.46) to produce clean aldehydes 8.91 after filtration. The Henry reaction was performed in the presence of a commercially available, supported strong base 8.92 and an excess of volatile nitroalkenes, giving clean nitroalcohols 8.93 after filtration and evaporation. The reaction mixtures from the trifluoroacetylation/elimina-tion steps were purified with commercially available amino PS resin 8.58 to scavenge the trifluoroacetates and with acidic ion-exchange resin 8.76 to remove the TEA-derived salts. Again, the nitrostyrenes 8.94 were obtained cleanly after filtration and evaporation. Cycloaddition with isocyanoacetate was promoted by the commercially available, supported guanidine base 8.95, while the subsequent N-alkylation of the pyrroles 8.96 was performed with an excess of halide in the presence of the commercially available, supported phosphazene 8.97. In this case, the excess halide was removed by treatment with supported 8.58, and filtra-... 

Macrocyclization of an unsaturated nitrile oxide (10, 309).1 Reaction of the co-nitroalkene 1 with p-chlorophenyl isocyanate results in a nitrile oxide intermediate that undergoes an intramolecular [3 + 2] cycloaddition to give 2. The yield is considerably higher than that obtained by oxidation of the corresponding unsaturated oxime. The product is converted in several steps to the may tans inoid 3. 

Carbamoyl nitroso dienophiles, derived from chiral pyrrolidines, have been generated and their reactivity with cyclohexa-diene investigated. Using (—)-fra/w-2,5-dimethylpyirolidine as the auxiliary, the [4 + 2] cycloadduct is isolated in 82% yield and with 98% diastereomeric excess (eq 10). Similarly, chiral ynamine dienophiles have been utilized in asymmetric [4 + 2] cycloadditions with a,p-unsaturated nitroalkenes to afford cyclic nitronic esters. The resulting esters subsequently undergo a rapid [1,31-rearrangement to afford chiral cyclic nitrones in moderate yield and high diastereoselectivity (eq 11)-... 

Synthesis of Substituted Pyrrolidines. A cycloaddition/red-uction sequence between nitroalkenes and vinyl ethers derived from DCP, i.e., 2 can effect the enantioselective synthesis of substituted pyrrolidines. 2-Substituted 1-nitroalkenes undergo highly efficient and diastereoselective Lewis-acid-promoted [4 + 2] cycloaddition with DCP-derived vinyl ethers to afford cyclic ni-tronates 5 in high yields. Subsequent reduction with Pt02 (7.5 mol%), under 160 psi of H2 at room temperature for 24 h, affords the optically active 3-substituted pyrrolidines (6) (71-97%, both as the free base and V-protected derivatives), and the chiral auxiliary 1 (eq 3). 

Dienophiles substituted with appropriate heteroatoms may offer a number of advantages such as (1) provide dienophilic equivalents of C-—C and moieties which do not undergo [4 + 2] cycloadditions to 1,3-dienes because of low (e.g. isolated alkenes, alkynes, allenes) or different reactivities (e.g. ketenes) (2) enhance or invert the regiochemistry of the Diels-Alder process (3) permit facile removal of the activating and/or regiocontrolling group after cycloaddition with or without introduction of further functionalities. The use of nitroalkenes as dienophiles demonstrates these issues most strikingly. 

Denmark and Marcin showed that 2,2-disubstituted 1-nitroalkenes undergo facile MAD-promoted [4 -r 2] cycloaddition with n-butyl vinyl ether in toluene at 0 °C to give cyclic nitronates as anomeric mixtures in good yield [173]. This method is a promising route to the stereoselective synthesis of disubstituted pyrrolidines and can thus be applied to the synthesis of the biologically active pyrrolidine alkaloid, mesembrine (Sch. 134). 

The in situ generation of TV-vinyl-AT-cyclohexylnitrosonium cations from the corresponding a-chloro nitrone, e.g., AT-(2-chloroethylidene)cy-clohexylamine N-oxide (25), and their subsequent [4+ + 2] cycloaddition with electron-rich, neutral, or selected electron-deficient dienophiles have been extensively investigated (Scheme 9-1X).173-175 The intermediate im-inium salts which are derived from the regio- and stereoselective [4+ + 2] cycloadditions are not generally isolated but are subjected to the useful transformations illustrated in Scheme 9-IX. The intramolecular [4+ + 2] cycloadditions of vinylnitrosonium cations and nitroalkenes have been detailed.176... 

The stereochemical limits of this type of domino reaction were also studied [8j. When l-phenyl-2-nitropropene 15b was used, the only product isolated was nitronate (16b). Nitroalkene 15b failed to react as a dipolarophile in the second cycloaddition with nitronate 16b, under even more extreme conditions (15 kbar, 50 °C, 96 h, Scheme 9.17). However, nitronate 16b reacted with y -nitrostyrene (15a) at 15 kbar, RT within 72 h completely regio- and stereoselectively producing the bicyclic nitroso acetal 49. 

Denmark and Cottell combined a novel silicon-tethered cycloaddition with a later oxidation for the synthesis of (+)-l-epiaustraline.42 Treatment of the nitroalkene with MAPh,... 

Nitroalkenes have found some use as dienes in the Diels-Alder reaction. The nitroalkene is electron-dehcient and therefore reacts best with electron-rich dienophiles such as enol ethers. Good yields of the cycloadduct can be obtained by using a Lewis acid catalyst such as SnCU or TiCl2(0 Pr)2 at low temperature. For example, cycloaddition with cyclopentene gave the nitronate 69 in high yield (3.56). ° The nitronate cycloadducts can undergo a variety of different transformations, such as a subsequent 1,3-dipolar cycloaddition with an alkene (see Section 3.4). 

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