Radical Transannular Cascades

Winkler and Sridar investigated the transannular radical reaction cascade of 1,5-cyclooctadienes (i.e., 103 and 110) for synthesis of linear triquinanes (Schemes 20.29 and 20.30). The substituents were found to exert subtle... 

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... 

SCHEME 20.36. The total synthesis of 7,8-epoxy-4-basmen-6-one by a transannular radical reaction cascade. 

Preparation of an oestrone analogue has been made by treatment of a polyene iodide with (TMS)3SiH via a radical cascade involving a 13-endo macrocyclization followed by successive opening of a cyclopropane ring and a 6-exo/5-exo transannular cyclization (equation 52)104. 

In all these cases, we dealt with precursors bearing a ring, which generally serves as a template or as a radical acceptor. Many excellent reviews and book chapters have covered radical tandem reactions [5]. Herein, we will focus on two distinct approaches to radical cascades. The chapter will be devoted to the construction of polycyclic structures (at least 3 rings). We will deal with two distinct approaches the first one focussing on the use of acyelic precursors, the second one based on transannular processes. 

On the other hand, in the last ten years, many groups have explored different elegant radical cascade strategies implying one or more transannular cyclization(s) to reach polycyclic frameworks of natural products [43]. 

From the literature, we can highlight four distinct strategies aiming at the construction of tricyclic or tetracyclic frameworks, based on cascade radical combinations of (C) intra - one (or two) transannular processes, (D) transannular - intra processes, (E) macrocyclization - two transannular processes, (F) two (or three) transannular processes inside a macrocycle (illustration of each strategy is shown on Scheme 29). 

In the area of stereodefined sesquiterpenic triquinane construction, radical cascades involving one transannular cyclization from cyclooctanyl or cyclooctenyl radicals proved to be very efficient and reliable strategies. 

Surprisingly few examples in this category of nine-membered ring radicals are devoted to the synthesis of polycyclic frameworks through a radical cascade involving transannular closures. We have previously mentioned the capacity of the car-yophyllene radical to cyclize transannularly (Scheme 28), but this example of a unique radical cyclization step was not applied in cascade strategies [45]. 

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),... 

Radicals constitute another type of reactive intermediate that have found considerable use in synthesizing seven-membered rings. Pat-tenden provides a rather remarkable example of the way this process can be incorporated into a macrocyclization-transannulation cascade to prepare polycycles. Tributyltin hydride generates a radical intermediate which, upon macromolecular ring closure and two subsequent transannular processes, provides a tricyclic product (Eq. 8)." Aside... 

The group of Boger described the total synthesis of kopsinine, a member of the Aspidosperma alkaloids, using their landmark [4 + 2]/[3 + 2] cycloaddition cascade for the conversion of 44 to 45 (Scheme 16). An unusual Sml2-promoted transannular cyclisation of xanthate 46, formed the bicyclo[2,2,2]octane moiety and provided the highly compact core of the natural product 48 as a single diastereoisomer. Although 48 is the least stable diastereoisomer, its formation is consistent with a radical cyclisation mechanism followed by kinetic protonation of the samarium enolate 47 formed after a second electron transfer. 

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. 

Dhimane AL, Ai ssa C, Malacria M. Transannular radical cascade as an approach to the diastereoselective synthesis of linear triquinane. Angew. Chem. Int. Ed. 2002 41 3284-3287. 

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