Tandem radical strategy

Scheme 8. Stork s tandem radical cyclization/trapping strategy for the synthesis of (+)-prostaglan-din F2a (45).

On the basis of the examples addressed thus far, it is clear that radical reactions can accomplish manifold transformations in organic synthesis. One of the outstanding achievements of synthetic radical chemistry is the development of synthetic strategies based on controlled, tandem radical cyclizations. The efficiency of such strategies is exemplified in the substantial and elegant synthetic work of D. P. Curran and his group.54 The remainder of this chapter will address the concise total syntheses of ( )-hirsutene [( )-1]55 and ( )-A9(12)-capnellene [( )-2]56 by the Curran group. 

Hirsutene (1) and A9(,2,-capnellcnc (2), the parent members of the hirsutane and capnellane families of triquinane natural products, respectively, are isomeric molecules that possess four contiguous stereogenic centers, one of which is quaternary. The linearly fused tricyclopentanoid frameworks of compounds 1 and 2 are obviously very similar, differing only with respect to the positions of the three methyl groups. An asset of Curran s tandem radical cyclization strategy is that it provides a unified entry into a wide variety of linear condensed cyclopentanoid natural products. As a result, it is possible to devise nearly identical retrosynthetic pathways for these structurally related molecules. 

The key features of Curran s productive and elegant tandem radical cyclization strategy are illustrated in a retrosynthetic analysis for hirsutene (1) (see Scheme 27). The final synthetic event was projected to be an intermolecular transfer of a hydrogen atom from tri-rc-butyltin hydride to the transitory tricyclic vinyl radical 131. The latter can then be traced to bicyclic tertiary radical 132 and thence to monocyclic primary radical 133 through successive hex-5-enyl-like radical cyclizations. It was anticipated that the initial radical 133 could be generated through the abstraction of the iodine atom from... 

From an exhaustive retrosynthetic analysis and from the experimental work performed by Curran [29] [32], it was clear that the synthesis of modhephene required an elaborate strategy. In the first place, the tandem radical cyclisation should be conducted individually rather than just in one step since it allows more flexibility. In the second place, Curran s observation that the precursor of modhephene (54) could be the olefmic exocyclic derivative 55 allows the application of a series of heuristic principles already familiar to us, which greatly simplifies the retrosynthetic analysis and leads to diquinane and, finally, through a second radical retroannulation to the very simple cyclopentanone derivative (Scheme 7.24). 

Finally, although a practical total synthesis of a naturally occurring indole alkaloid using a tandem radical cyclization strategy has yet to be demonstrated this strategy has shown great potential as a powerful tool in indole synthesis. 

The presence of a quaternary carbon atom is frequently encountered in sesquiterpene natural products and it often creates a synthetic challenge when two or more quaternary carbon atoms are present contiguously. The synthetic strategies for the construction of quaternary carbon centers involve sigmatropic rearrangements/ intramolecular cycloaddition/ and the reaction of tertiary carbon nucleophiles with a carbon electrophile. Recently, radical cyclization strategies turned out to be very effective for this purpose. For example, Srikrishna utilized the radical cyclization reaction to prepare tricyclo[6.2.1.0 - ]undecane system, which is present in several sesquiterpenes such as zizaenes and prelacinanes, and Chen demonstrated that a tandem radical cyclization approach is an efficient method for constructing the two quaternary carbon centers in the cedrene skeleton. ... 

The potential of sequential radical addition as a powerful method to achieve the formation of five-membered rings was fully realized in the tandem radical cyclization strategy devised by Curran for the synthesis of triquinanes. In the case of linearly fused triquinanes, such as hirsutene 90 (Scheme 3.40), this strategy implies the retrosynthetic disconnection of the tricyclic framework by the application of two sequential radical cyclization transforms at rings A and... 

Another strategy involving tandem radical reactions that offers an advantage of multiple carbon-carbon bond formation in a single operation in the aqueous medium tandem construction of carbon-carbon bonds has been widely being studied by Naito and co-workers (Scheme 7.12). The indium-mediated tandem... 

Sato determined that the use of Lewis acid was advantageous for tandem radical addition/reduction reactions in terms of both yield and selectivity [25]. As shown in Scheme 8, Lewis acid promoted the addition of the butyl radical to the a,fi-unsaturated ester, which in turn led to the formation of chelated transition state N. The improved selectivity was likely the result of a tighter complexation between the hydroxyl and carbonyl functions of the substrate and the aluminum atom. Nagano and collaborators used the same strategy with y-methoxy-a-methylenecarboxylic esters [26]. The use of La(fod)3 delivered a very good ratio of anti isomer in that reaction involving 1,3-asymmetric induction and a 7-membered cyclic transition state, illustrated by O in Scheme 8. 

Parker KA, Fokas D (1992) Convergent synthesis of (-1-/—)-dihydroisocodeine in 11 steps by the tandem radical cyclization strategy - a formal total synthesis of (- -/—)-morphine. J Am Chem Soc 114 9688-9689... 

Lizos D, Tripoli R, Murphy JA (2001) A novel and economical route to (-i-/—)-horsfiline using an aryl iodoazide tandem radical cyciisation strategy. Chem Conunun (Cambridge, UK) 2732-2733... 

In another strategy, the tricycUc ring has been formed in a single step from a benzene derivative by tandem radical cycUzations to yield methyl 1-acetyl-2,3,9,10-tetrahydrolysergate as an example [44]. 

The previously described tandem radical cycllzation strategy has... 

Parker, K. A. Fokas, D. "Convergent Synthesis of d/-Dihydroisocodeine in 11 Steps by the Tandem Radical Cyclization Strategy. A Formal Total Synthesis of d/-Morphine" J. Am. Chem. Soc. 1992, 114, 9688-9689. 

The radical cyclization of jS-alkoxyacrylates also offers an attractive approach to the formation of 2,6-c/i-tetrahydropyrans [50, 51], A noteworthy strategy was demonstrated by the Lee group in the first total synthesis of lasonolide A [52, 53], Lee and coworkers illustrated the tandem radical cyclization of a,)S-alkoxyacrylate... 

A different strategy has been applied in our work, that emphasizes the importance of DNA stability on hole transfer within double-stranded DNA. This work is based on determination of the overall yield of oxidized nucleosides that arise from the conversion of initially generated purine and pyrimidine radical cations within DNA exposed to two-photon UVC laser pulses. On the one hand, this work benefits from the excellent current knowledge of chemical reactions involving the radical cations of DNA bases, and on the other hand, from major analytical improvements that include recent availability of the powerful technique of high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (CLHP-ESI-MS/MS) [16-18]. 

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