Bicyclic ring systems, alkylative cyclization

When the acetonide and the bicyclic ring system are removed, as in the substrate triene 33, it becomes apparent that the origin of the stereoselectivity lies in the influence of the remote alkyl substituents. Cyclization of the hexatriene 33 (R1 = Et R2 = CH3), a substrate that retains the substitution pattern of those described previously (i.e., 27 and 30), affords the same sense and degree of selectivity [d.r. (34/35) 4 1]. The isomeric substrate 33 (R1 = CH3 R2 = Et). a substrate in which the alkyl substituents are reversed, affords a 1 1 mixture of diastereomers. 

The 3-azido- 1,2,4-triazoles (230) exist in the azide form rather than the triazolotetrazole form.481-484 These compounds were obtained by cyclization of the hydrazonyl bromides (229, R = H) and by treating the 3-hydrazinotriazole (233) with nitrous acid482 (Scheme 26). The former reaction involves a preferential ring interconversion of tetrazole to triazble and presumably could be included in the general classification of Eq. (37) An alkyl substituent located in the tetrazole moiety appears to have a stabilizing influence on the triazolotetrazole ring system, since the bicyclic compounds (232), not azides (231), were obtained when the... 

With dienone 43 in hand, the cyclization-methylation sequence was carried out, providing bicyclic lactone 44 in 64% yield (Scheme 17). A single diastereomer was isolated from this reaction. Once again, an NOE experiment confirmed the cw-fused ring system, but an NOE interaction was not observed between the C6-H and the C9 methyl group. Again, the literature precedents for alkylations in similar systems,and our presumed model for diastereo-selection, mitigated our concerns about this result. Furthermore, the absence of an NOE does not confirm molecular structure. 

Additional substrates could easily be prepared in situ by reaction with NaSCN with the corresponding alkyl halide or appropriately activated alcohol, e.g., 51. The 6-5 fused ring system could be formed, as exemplified in the conversion of 51 into 52 via displacement followed by cyclization. The 5-5 ring system formed in excellent yield as well while, the 7-5-fused ring system did not react to form the desired bicyclic tetrazole. Other high-boiling, aprotic solvents e.g., DMSO) have been reported for promoting the intramolecular... 

This TiCU-promoted allene cycloaddition has also been extended to the synthesis of five-membered ring heterocycles. In this case, increasing the steric shielding about the silicon atom seems to improve the cyclization process by suppressing the unproductive desilylative alkylation. For example, 1,3-di-methyl(r-butyldimethylsilyl)allene (39) reacts smoothly with cyclohexanecarbaldehyde to give in high yield the dihydtofuran predominantly as one stereoisomer (equation 31). Similar reaction with an N-acyl-iminium ion precursor (40) produces the pyrrolizidine system as a mixture of bicyclic isomers (equation... 

The regioselectivity in diene addition reactions can also be influenced by ring strain effects in cyclization reactions. The regioselectivity is highly predictable in those cases, in which addition to the preferred diene center forms the preferred ring size. Thus, the cyclization of radical 15 proceeds readily to form the ct s-disubstituted cyclopentyhnethyl radical 16 with high selectivity. Similarly, cyclization of 17 affords exclusively bicyclic radical 18, in which the additional cyclopentane ring has been formed by addition to the terminal position of the butadiene subunit. This preference for 5-exo cyclizations onto dienes is not even dismpted by substiments at the C1 or C4 positions of the diene system, as seen for radical 19, which cyclizes to 20 (equation lO). This is in contrast to alkyl radical cyclizations to alkenes, in which major amounts of 6-endo cyclization is observed for 5-substituted systems. ... 

Among the very few reported possibilities offered by transannular cycle contraction of cyclododecenyl radicals to construct 9,5-, 8,6- or 7,7-bicyclic systems, the radical tandem approach to the taxanes planned by Pattenden, from the substituted A-ring precursor 134, introduces a new conceptual strategy, described as E in Scheme 29. First, a 12-e Jo-dig macrocyclization involving alkyl radical 135 occurs easily on the triple bond of the ynone moiety. The produced vinyl radical (major conformer is presented) 136 cyclizes in a 6- n-endo)-exol - n-exo)-endo transannular manner to assemble the unusual tricyclo[9.3.1.0 ]pentadecane framework 137 as a 6 1 ratio of diastereomers (Scheme 38) [55]. 

The methods most frequently used to synthesize these compounds are [6 + 0(a)] cyclizations. Ring closures may take place via intramolecular alkylation, condensation, or nucleophilic substitution. The starting materials for the cyclizations in the case of pyrazino-oxazines are always pyrazine derivatives. Only a few representatives of these systems have been prepared. Pyrimido-oxazines are the most explored group of compounds. In the bicyclic series, cyclizations have been carried out in most cases from pyrimidine intermediates and only rarely from morpholino intermediates. For the preparation of benzo-fused derivatives, both benzoxazine and quinazoline intermediates have been used. Pyrazino-oxazines represent a small group of compounds. For cyclizations, both pyrazino and oxazino intermediates have been used. There are many lactone structures among these compounds. For their preparation, the usual methods of lactone formation have been applied. 

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