Stereoselective radical carbocyclization

Hanessian, S. and Ninkovic, S. (1996) Stereoselective synthesis of ( )-a-kainic acid and (-l-)-a-allokainic acid via trimethylstannyl-mediated radical carbocyclization and oxidative destannylation. /. Otg. Chem., 61, 5418-5424. 

Free-radical cyclizations using ethyl radicals generated by EtsB/air system or stannyl radicals systems provide a range of carbocyclic and heterocyclic hydroxylamines (equation 77). Stereoselectivity in these reactions is variable but can be semiquaUtatively predicted by Beckwith-Houk models . Depending on the substitution pattern of the emerging cyclic system, stereoselectivity can be very high, especially in fused polycyclic systems (equation... 

Matsugi, M. et al. Highly Stereoselective Synthesis of Carbocycles via a Radical Addition Reaction Using 2,2 -Azobis(2,4-dimethyl-4-methoxyvaleronitrile) [V-70LJ. 2.1 1999 [149]... 

The formation of ring systems by the anionic cyclization of olefinic alkyl, aryl and vinyl-lithiums is an interesting synthetic transformation that provides a regiospecific and highly stereoselective route to five-membered carbocycles and heterocycles99. Most importantly, it is possible to functionalize the initially formed cyclization product by a tandem reaction with electrophiles, a reaction that is not generally possible in the case of radical cyclizations. 

Kilburn has extensively studied radical cascades centered on the use of methylenecyclopropane derivatives. An addition-fragmentation process ap-parented to pathway c opened new routes for the synthesis of carbocycles. In a recent work, a Sml2-promoted cascade of propargyl ether 73 has been used to give bicyclic ether 78 with good diastereoselectivity (Scheme 24), thus providing a short route to the monoterpenoid paeonilactone B. The observed stereoselectivity in the 74 75 cyclization step was shown to be critically dependent on the presence of HMPA [84]. 

M. Matsugi, K. Gotanda, C. Ohira, M. Suemura, A. Sano, and Y. Kita, Stereoselective synthesis of carbocycles via a radical addition reaction using 2,2 -azobis(2,4-dimethyl-4-methoxyvaleronitrile), J. Org. Chem., 64 (1999) 6928-6930. 

A related carbocycle is synthesized starting from carbohydrate precursors. The radicals are generated via Barton deoxygenation of the intermediate 5-heptenolsiei. The effect of 1-, 2-, 3-and 4-substituents on the stereoselectivity of the cyclization reaction has also been described 17-18. The formation of the 1,5-m-product is rationalized by the Beckwith modelThe 4,5-configuration of the main product is tram and is explained by the influence of allylic strain. 

The stereoselectivity in hydrogen-abstraction reactions of carbohydrate radicals differs from the reactions of mono- or disubstituted carbocyclic radicals in some characteristic ways. Generally, the ring oxygen atom leads to pronounced higher axial attack if located next to the radical center. At the same time, it has been observed that some of these carbohydrate C-l radicals prefer a twist boat to a chair conformation44 4b. Furthermore, the large number of substituents present simultaneously make the conformational analysis of axial and equatorial transition states more difficult. 

In this article we provide a broad overview of the application of radical methods in carbohydrate chemistry, including typical examples classified by the type of bond formed. The factors controlling the stereoselectivity of inter- and intramolecular C-C bond formation are now well understood and have been exploited in the synthesis of C-glycosides [2]. Intramolecular C C bond formation using carbohydrate-based chiral templates also provides a powerful route to branched-chain sugars [3] and carbocycles [4]. Finally, we include synthetically useful processes involving key carbon-heteroatom and C-H bond formation. 

Careful experiments using deuterated substrate 55 by Kakinuma and Eguchi revealed that (1) the Perrier carbocyclization of 55 involved no retro-aldol process and was thus an irreversible reaction and (2) the overall cyclization reaction was nonstereoselective with respect to the C-6 methylene site fScheme 12.15). Based on the results of complete stereochemical scrambling at C-6 in cyclized product 57, Kakinuma and Eguchi proposed the presence of radical intermediate 56. They also suggested that the cyclization might be a radical process, although this model could not explain the stereoselectivity at C-5. 

Oxime ethers derived from hydroxy aldehydes, upon conversion to their phenyl thionocarbonate esters, undergo radical cyclizations resulting in the formation of carbocycles. For example, an oxime ether obtained from D-glucose is converted into its phenyl thionocarbonate ester at C-5 and, upon heating in benzene in the presence of tributyltin hydride, affords cyclopentanes in 93% yield as a 62 38 mixture of two diastereomers (eq 7). In general, only low to modest stereoselectivity between the newly formed stereocenters is observed in a number of substrates examined. 

Stereoselective [3-r 2]-cycloadditions of trimethylenemethane equivalents provide an effective route to substituted five-membered carbocycles not otherwise easily prepared [38-41], Trimethylenemethane diradicals have commonly been accessed from bicyclic diazenes such as 127 not otherwise easily prepared [38, 102], Little showcased that with substrate 129, incorporating an embedded stereocenter, tricyclopentanoid 132 was formed with high yield and diastereoselectivity (dr=99 l. Scheme 18.22) [103], The predominant formation of diastereomer 132 was attributed to a kinetically controlled trapping of the energetically favored intermediate radical 130, in which A] 3 interactions involving the silyloxy substituent are minimized. 

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