Nitronate structures intramolecular cycloadditions

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

Regiospecilic intramolecular cycloadditions of nitrones to sulfur-substituted dienes, with 3-sulfolene precursors, has been realized (Scheme 2.217). The stereochemical outcome of these reactions is affected by the structure of the substituent (sulfide or sulfone) in the diene and by the chain length connecting the diene and nitrone (a) and (b) (see Scheme 2.211). The bicyclic products obtained from these reactions have been converted to interesting heterocyclic compounds (709). 

The intramolecular cycloadditions of cychc nitronates have received much more attention. The cyclic nitronate structure provides three basic modes of intramolecular cycloaddition (Fig. 2.15). Attachment of the tether to the C(3) position of the nitronate results in the formation of a sprro system (sprro mode). However, if the tether is appended to the C(4) position of the nitronate, the dipolar cycloaddition yields a fused ring system (fused mode). Finally, if the tether is attached at any other point of the cyclic nitronate, the cycloadducts obtained will consist of bicyclic structures (bridged mode). 

Intramolecular cycloaddition of fV-benzyl-substituted 3-O-allylhexose nitrones furnishes chiral oxepane derivatives. The regioselectivity of the cycloaddition depends on several factors such as (1) the structural nature of the nitrone, (2) substitution and stereochemistry at 3-C of the carbohydrate backbone, and (3) substitution at the terminus of the O-allyl moiety. A mixture of an oxepane and a pyran is formed in the intramolecular oxime olefin cycloaddition of a 3-O-allyl carbohydrate-derived oxime <2003T4623>. The highly stereoselective synthesis of oxepanes proceeds by intramolecular nitrone cycloaddition reactions on sugar-derived methallyl ethers <2003TA3899>. 

Intramolecular cycloadditions via nitrones as intermediates are generally highly stereoselective processes that are used to generate a number of stereocenters in a complex molecule3-5-6-8- 8. The intrinsic rigidity of the transition structures enhances the stereocontrol exerted by steric and stereoelectronic factors (see Section A.2.3.5.). Tor more recent examples of intramolecular cycloadditions via nitrones, see references 337-354. 

The structure-reactivity relationship between a 19-Me- and 19-nor-5,10-seco-steroid has been investigated using lOOC and intramolecular nitrone cycloaddition taking into account various stereochemical aspects (Schemes 27 and 28) [67]. The E-19-nor-5,10-seco-ketone 255 a, on treatment with hydroxylamine hydrochloride (R = H), undergoes lOOC via 256a to a single isoxazolidine 257... 

As mentioned above (66, 393), (see Scheme 3.150) silylation followed by intramolecular enantioselective cycloaddition with five-membered cyclic nitronates, containing the hydroxyl group at C-4, can produce chiral polycyclic structures (293), which are direct precursors of chiral hydroxyamino acids (294) and aminopolyols (295) (Scheme 3.179). 

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). 

If the alkene is already joined on to the nitrone by a covalent bond so that the dipolar cycloaddition is an intramolecular reaction, one particular outcome may be dictated by the impossibility of the alternatives. Here is a simple case where an allyl group is joined to the same ring as in the previous example. The product has a beautifiiUy symmetrical cage structure and the mechanism shows the only way in which the iryolecule can fold up to allow a 1,3-dipolar cycloaddition to occur. 

Werner, K. M., De los Santos, J. M., Weinreb, S. M., Shang, M. A Convergent Stereoselective Synthesis of the Putative Structure of the Marine Alkaloid Lepadiformine via an Intramolecular Nitrone/1,3-Diene Dipolar Cycloaddition. J. Org. Chem. 1999, 64, 686-687. 

These intramolecular C-4-alkenyl nitrone cycloaddition reactions afford m-fused products with complete endo stereoselection. The induced stereoselection is also high and may be rationalized by the assumption that the transition structures with the bulkier substituent(s) at the stereocentcr(s) in a pseudo-equatorial position are favored over those with these groups in the pseudo-axial position. In conformationally mobile acyclic systems this generally results in a trans arrangement between the preexisting stereocenter and the newly formed stereocenter. This tendency seems compelling for x-substituted nitrones. In cyclic systems steric factors dictate the stereochemical outcome of the reaction. 

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