Tandem intramolecular nitroalkene

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... 

SCHEME 16.76 Tandem intramolecular-[4 + 2]/intermolecular-[3 + 2] cycloadditions of allene-containing nitroalkenes. 

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. 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

Intramolecular [3+ 2]-cycloaddition of six-membered cyclic nitronates was extensively studied by Prof. Denmark and coworkers for the tandem [4 + 2] [3 + 2] -cycloaddition reactions of nitroalkenes. Detailed considerations of this problem were summarized in two reviews (394a, b). Most data were comprehensively discussed in Reference 394b. It is unnecessary to repeat this information however, it is worthwhile to briefly review the available data. 

As a consequence of the complimentary electron demand of the nitroalkene and the product nitronate, there exists the possibility of a one-pot, tandem reaction. In this case, the nitroalkene will react preferentially with the electron-rich alkene to produce an intermediate nitronate. This nitronate can then react with a second alkene bearing an electron-withdrawing substituent. Therefore subjection of the nitroalkene 210 to both ethyl vinyl ether and acrylonitrile provides only the nitroso acetal 211 in moderate yield (Eq. 20) (70). Moreover, this also allows the possibility of intramolecular variants of the process. 

Cyclic alkyl nitronates may be used in tandem [4+2]/[3+2] cycloadditions of nitroalkanes, and this reaction has been extensively studied by Denmark et al. (64,333-335). In recent work, they developed the silicon-tethered heterodiene-alkene 219 (Scheme 12.63). Steric hindrance and the fact that both the nitroalkene and the a,p-unsaturated ester in 219 are electron deficient renders the possibility of self-condensation. Instead, 219 reacts with the electron-rich chiral vinyl ether 220 in the presence of the catalyst 224 to form the intermediate chiral nitronate 221. The tandem reaction proceeds from 221 with an intramolecular 1,3-dipolar cycloaddition to form 222 with 93% de. Further synthetic steps led to the formation of ( )-detoxinine 223 (333). A similar type of tandem reaction has also been applied by Chattopadhyaya and co-workers (336), using 2, 3 -dideoxy-3 -nitro-2, 3 -didehydrothymidine as the starting material (336). 

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... 

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. 

Scheme 2.43 Tandem Michael/intramolecular alkylation sequence between bro-momalonate and nitroalkenes catalysed by a preformed diamine nickel catalyst.

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]. 

Once we understand flie regio- and stereochemistry of the [3+2] cycloaddition reactions involving nitronates, the formulation of the tandem process proposed in Part 2 is not difficult. The starting compounds are a nitroalkene 7 (tethered to an a,P-unsaturated ester) and 2,3-dimethyl-2-butene 8, a simple unactivated alkene. The fragments of flie starting materials can be easily recognized in the structure of the reaction product 9, as indicated in Scheme 22.7. The nitroalkene skeleton has been drawn in red and the 2,3-dimethyl-2-butene in blue. Discoimection of bonds a and b in 9 leads back to nitronate intermediate 13. Disconnection of c and d bonds in 13 leads back to nitroalkene 7 and 2,3-dimethyl-2-butene 8 (Scheme 22.7). The overall reaction could be interpreted as a tandem intermolecular [4+2]/ intramolecular [3+2] cycloaddition. Next we will formulate the process step by step. 

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 ... 

Intramolecular [4+2] cycloadditions of nitroalkenes Reactivity and selectivity in [4+2] cycloadditions of nitroalkenes without Lewis acid activation Nitronates as dipoles in [3+2] cycloadditions Chemistry of nitroso acetals Definition of different variants of the tandem [4+2]/[3+2] cycloadditions of nitroalkenes... 

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. 

Selectivity in the Spiro Mode Intramolecular [3+2] Cycloadditions of Nitronates Placement of the tether at C(3)-position of the nitronate provides access to spiro mode dipolar cycloadditions (Scheme 16.31). Such nitronates are prepared by [4 + 2] cycloadditions of nitroalkenes bearing a dipolarophile attached at the a-carbon. Only (3-unsubstituted nitroalkenes of this type have been used for the tandem cycloadditions. As a consequence of their high electrophi-licity and low stability, such nitroalkenes have been prepared by nitromercuration. 

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... 

The Fused Mode Cycloaddition The fused mode of the tandem intermolecular-[4- -2]/intramolecular-[3 + 2] cycloaddition of nitroalkenes is the most extensively studied of all the variants. Figure 16.10 correlates the configuration of the nitroso acetal product with the requirements for the configuration of the starting materials. If present, the substituents at C(4), C(5), and C(6) are established during the inter-molecular [4 + 2] cycloaddition as outlined earlier. The trans... 

As illustrated in Figure 16.7, an intramolecular [4 + 2] nitroalkene cycloaddition can be followed by an intermolecular [3 + 2] cycloaddition of the formed nitronate intermediate. This variant of the tandem cycloaddition has not been extensively studied and only two reports can be found. Moreover, the resulting nitroso acetals have not been subjected to further transformations such as hydrogenolysis. 

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. 

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