Nitronate structures intermolecular cycloadditions

It has long been recognized that nitrone cycloadditions may allow access to spirocyclic ring systems. Such systems are inherently difficult to synthesize by conventional methods, yet are a structural component of a number of biologically active natural materials. Two common strategies have emerged for spirocycle generation from exocyclic or endocyclic nitrones (Scheme 1.45). In the exocyclic version, the carbon atom (arrowed) of the nitrone C=N double bond of dipole 209 carries a cyclic substitutent and thus an intermolecular cycloaddition reaction will... 

Stereoselectivity of l S-Dipolar Cydoaddition. The stereoselectivity of the intermolecular cycloaddition of an acyclic nitrone to an alkene is difficult to predict, and wotdd appear to be susceptible to minor structural changes in either component (13). The chiral 2,2-dimethyl-l,3-dioxolan-4-yl nitrone showed only modest astereoface selectivity in its addition to methyl crotonate (14). However, the more hindered tetramethyl-l,3-dioxolan-4-yl nitrone was more selective. 

C(3a)/C(4) relationship arises from the dipolarophile approach proximal to C(4) substituent on the corresponding nitronate (Scheme 16.32). Only two- and three-atom tethered substrates have been studied in these cycloadditions. The two-atom tether leads to the fra/i5-C(3)/C(3a) relationship because it can only fold endo- during the [3 + 2] cycloaddition. However, the three-atom tether is flexible enough to react via the ejto-transition structure and to provide the cis-C (3)/C(3a) relationship. As always, the dipolarophile configuration is preserved as the relationship between C(2) and C(3) in the nitroso acetal. Unlike the double intermolecular cycloadditions or the spiro mode, the trans—trans or cis—trans relationship is established between the substiments at C(3),... 

Cyclopentyl isoxazolidine cycloadduct 324 was prepared by intramolecular nitrone cycloaddition by Baldwin et al. (280,281,352,353) as part of studies toward a total synthesis of pretazettine (Scheme 1.69). Related adducts have been prepared elsewhere (354—356) including fluorine-substituted carbocycles (357) and the adducts prepared by lOAC by Shipman and co-workers (333,334) who demonstrated their potential as a route to aminocyclopentitols (Scheme 1.66, Section 1.11.2). Such bicyclic structures have been prepared in rather unique intermolecular fashion by Chandrasekhar and co-workers (357a) from the cycloaddition of C,N-diphenyl nitrone to fulvene (325). 

Scheme 10.7 gives some other examples of 1,3-DPCA reactions. Entries 1 to 3 are typical intermolecular 1,3-DPCA. The 1,3-dipoles in each instance are isolatable compounds. Entries 4 and 5 are intramolecular nitrone cycloadditions. The product from Entry 5 was used in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxyl group is ensured by the structure of the isoxazoline from which it is formed. 

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. 

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