Cascade reactions transannular cyclization

The second one-pot cascade reaction was used to complete the synthesis of the natural product from acid 69. Reduction of the two azide groups of 69 produced the highly polar diamine 70, which was treated with EDC and HOBt to induce an intramolecular lactam cyclization and deliver the macro-palau amine 71. When the crude reaction mixture of 71 was heated in TEA, compound 72, proceeding through amidine tautomer 71, elicited the key transannular cyclization and delivered the palau amine in 17% overall yield from 69. The outcome stereochemistry was all in the control of the stereocenters within the substrate. 

Other attempts to promote radical DA reactions were pursued, notably to open an entry into steroidal structures. An interesting case is the radical cyclization of ynone 153 in order to prepare tetracyclic ketone 155 through a 13-e rfo-dig macrocyclization-radical tandem transannular DA cascade. The unique resulting tetracyclic compound 158, displays a completely different structure with two contiguous quaternary sp carbons and two conjugated enone moieties (Scheme 42),... 

Hollingworth, G. J., Pattenden, G. and Schulz, D. J. (1995) Cascade Radical Cyclization-Fragmentation-Transannular-Ring Expansion Reactions Involving Oximes. A New Approach to Synthesis of Angular Triquinanes, Aust. J. Chem. 48, 381-399. 

Interestingly, placement of the (bromomethyl)dimethyl-silylether to the other propargylic position of the macrocycle (i.e., 121, Scheme 20.32) led to a transannular radical reaction cascade to give a single diastereomeric 4-6-5 tricyclic 126, which was converted to 127 by the Tamao oxidation in 47% yield over two steps. The high chemo-selectivity of the radical reaction of the primary radical 122 toward the 5-exo-dig versus 5-exo-trig cyclization was also notable for the mixed allylic and propargylic (bromo-methyl)dimethylsilyl ether 121 (Scheme 20.32). 

A tandem macrocyclization/transannular radical cyclization of iodopolyene 134 was employed by Pattenden and co-workers for synthesis of ( )-estrone. The radical reaction cascade involved the 5-endo-trig cyclization of 134 to form the cyclopropylmethyl radical 136 (Scheme 20.34), which underwent opening of the... 

A transannular Michael reaction cascade with both (E,Z)- and ( , )-macrocyclic-1,7-bis-enones (307) has been reported to afford triyclic products (308) with excellent diastereoselectivity. By contrast, (Z,E)- and (Z,Z)-macrocyclic lactones failed to cyclize, apparently due to an unfavourable geometry. 

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