Tandem radical cyclizations

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

Scheme 15. Tandem radical cyclizations in Chen s synthesis of ( )-A2-8-epicedrene [( )-84].

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... 

Scheme 29. Synthesis of ( )-hirsutene [( )-1] by tandem radical cyclizations.

From 152, the synthesis of the tandem radical cyclization precursor 155 only requires a few manipulations of the two side chains. 

Radical cyclizations of tetrahydropyridine scaffolds have been used to access diverse skeletal frameworks.An example of tandem radical cyclizations with two C-C bond formation is shown in Reaction (82). Treatment... 

The following molecules have been synthesized by radical cyclization and tandem radical cyclizations. Identify the bond or bonds that could be formed by radical cyclizations and suggest an appropriate reactant and reaction conditions that would lead to the specified products. 

Tandem radical cyclizations of suitably substituted /V-aryl thiocarbamates, thioamides and thioureas have been induced by exposure to 4 equiv. of tnj(trimethylsilyl)silane (TTMSH (TMS)3SiH), 1 equiv. of 2,2 -azo-/h.v-isobu-tyronitrile (AIBN as a radical initiator) and UV light to provide furoquinolines, isofuroquinolines, cyclopentaquinolines, indoloquinolines and related ring systems (Scheme 31).58... 

Several methods based on radical cyclizations have been developed and applied to the synthesis of the fully saturated system. An example (Scheme 11) is provided by the tandem radical cyclization of properly substituted imines 33 obtained from tu-benzeneselenylamines and aldehydes <1995TL5623>. 

Scheme 28 explains the stereochemical outcome from the tandem radical cyclization in the presence of the [Yb(Ph-pybox)(OTf)3] (pybox = 2,6-bis(2-oxazolin-2-yl)pyridine). The ytterbium complex 107 is shown in an octahedral geometry (with one triflate still bound to the metal) where re-face cyclization is favored due to the steric interactions of the substrate and the ligand s phenyl groups. The 6-endo cyclization takes place via a chair-like transition state to yield a tertiary radical 108 followed by a ring flip and... 

The Kolbe electrolysis has also been used to initiate tandem radical cyclization reactions [21]. Recently, Matzeit and Schafer reported that these reactions could be used to construct angularly fused tricyclic ring skeletons (Scheme 8) [22]. The reaction led to the formation of three new C-C bonds. In addition to the desired tricyclic product, the reaction formed a pair of products having the... 

For chemical routes to tandem radical cyclization reaction see Curran DP, Kuo SC (1987) Tetrahedron 43 5653, as well as reference 17c. 

The tandem radical cyclization of tetrayne (97) and its derivatives has been performed to generate the polycyclic pyran (98) via a biradical intermediate.238 The cycloaddition reaction of a biradical species (or diyl) and a multiply bonded species (the diylophile)239 has been observed with unique allene diylophiles.240 The short-lived biradical fonned by the irradiation of the diazene (99) is trapped by an allene diester to form a second biradical species (100). Intramolecular cyclization occurs such that all steric interactions are minimized and so enforces stereocontrol in the formation of the cycloadduct (101) see Scheme 14. A paper reports the rearrangement of 2-vinyhnethylenecyclopropane (102) to 3-methylcyclopentene (103) via the triplet biradical (104), which has been characterized for the first tune by IR spectroscopy.241... 

Pseudocopsinine (215) was isolated from Vinca erecta. Parsons et al. devised a concise synthesis of the pseudocopsinine framework 214 utilizing a 5-exo/5-exo double tandem radical cyclization [83-84]. The cyclization precursor 213 was readily accessible via a [3 + 2] nitrone cyclization. As depicted in Scheme 40, reaction between the pyrrolidine aldehyde 210 ando-... 

Scheme 40. Synthesis of a model for pseudocopsinine via a 5-exol5-exo double tandem radical cyclization...

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 diastereospecific synthesis of novel [3.6.6.4.7]-fused pentacyclic /3-lactams via a novel 6-exo-trig,7-endo- %-tandem radical cyclization has been reported. The use of this method for the construction of a polycyclic system fused to an azetidin-2-one template has been very little exploited. The mixture of /3-lactams 509 and 510 (R = -f 4 I—Cl C. -Cl I—Cl ICH3) in their racemic forms on treatment with tributyltin hydride gave diastereomeric mixtures of tetracyclic 511 and 512 in the same ratio as in the starting materials (Equation 84) <2003TL1827>. 

Tandem radical cyclization/cross-coupling 2 Low-valent Fe 2.1.3... 

Tandem Radical Cyclization/Cross-Coupling or Heck Reactions... 

Tandem Radical 5-exo Cyclization/Heck Reactions or Tandem Radical Cyclization/Allylic Substitution Reactions... 

Oshima s group reported the first example of a tandem radical cyclization/intermo-lecular Heck reaction in 2002 (Fig. 60) [289]. Iodoacetaldehyde allyl acetal 242a was treated with styrene 243, catalytic amounts of CoCl2(dpph), and trimethylsi-lylmethylmagnesium chloride 224 as a stoichiometric reducing agent. 4-Cinnamyl-butyrolactol 244 was isolated in 50% yield (cf. Fig. 54). 

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