Tethered radical

J. C. Lopez, A. M. Gomez, and B. Fraser-Reid, Silicon-tethered radical cyclization and intramolecular Diels-Alder strategies are combined to provide a ready route to highly functionalized decalins, J. Chem. Soc. Chem. Comtmm. p. 762 (1993). 

Since the leakage factor can be easily calculated from Ti relaxation data, and ys/y is constant, that only leaves the determination of smax before the coupling factor can be directly accessed. For solutions of radicals where Heisenberg exchange is prominent, Emax must be measured as a function of concentration and extrapolated to infinite concentration where smax 26,50 pQr jmmobilized or tethered radicals, nitrogen nuclear spin relaxation effectively mixes the hyperfine states in virtually all cases (small peptides may be an exception) and smax 1 can safely be assumed. 56 Alternately, the determination of smax can be avoided... 

Eq. 3.21 shows the introduction of a hydroxymethyl group at the (3-position of allylic alcohol with the silicon-tethered radical approach developed by Stork [78-83]. Allyl silyl ether (64) was first prepared by the treatment of allylic alcohol (63) with dimethylbromomethylsiliyl chloride, and subsequently treated with Bu3SnH/AIBN, and finally treated with hydrogen peroxide in the presence of KF, to give a 1,3-diol derivative (66), as shown in eq. 3.21. 

Scheme 13 Silicon-tethered radical addition approach to chiral amines...

In the case of vinyl radical cyclizations of 49E , the intermediate silacycle could be oxidized under Tamao conditions to afford ketone 51 (2) [124], The consequence is an umpolung installation of an acetyl group, with the vinyl radical serving as an acyl anion equivalent, further expanding the synthetic potential of the Si-tethered radical additions. 

Scheme 14 Stereocontrol in 5-exo silicon-tethered radical addition...

The radical addition to 1-alkenyl or 1-alkynylboronic esters or amides took place extremely smoothly because the boron atom stabilizes the resulting ct-radical intermediates. Bu3SnH and PhSH predominated the trans-addition products 287 in the addition to 1-alkynylboronic amides at 90 °G, whereas Bu3SnH and Ph2Ph produced the m-addition products 288 at 0°C (>98% Equation (82)).455 Intramolecular addition to 1-alkenylboronic esters has been demonstrated in boron-tethered radical cyclization that provided 1,3- or 1,4-alkanediols 290 via oxidative workup (Equation (83)).456 Inter- and intramolecular additions of alkyl radical457 and sulfonyl radical458 have also been studied. 

An efficient synthesis of adenophostin (55a) analogues (55b-f) from d-xylose has been reported." The C-glycosidic analogue of adenophostin A and its uracil congener (56a,b) have also been prepared via a temporary silicon-tethered radical coupling reaction as the key step. ... 

Scheme 5.3.4 Intramolecular C-Glycosidations with Tethered Radical Acceptors...

As a natural extension to the utility of silicon tethered radical acceptors for the preparation of C-glycosides, Xin, et al.,27 applied this technology to the preparation of a C-maltose derivative. This example, centering around the preparation of a C-disaccharide, will be discussed in detail in Chapter 8. 

One way to reduce the unfavorable entropic barrier would be to use tethered radicals designed to trap H2 and take advantage of the low enthalpy of activation for dinuclear addition. One system investigated was the fulvalene complex76 shown in Equation 10.58. 

A highly general procedure relies on the use of a silicon tethered radical cyclization process to provide for introduction of a hydroxymethyl substituent using the Tamao conditions.33 38 Pioneered by Nishiyama39 the synthesis of regioisomeric diols, as in 33, from readily available ally silyl ethers, such as 31, was achieved via radical cyclization and oxidization. The predominance of the 5-exo cyclization is further demonstrated by the formation of 36 by this same process. 

The preparation of branched-chain sugars by intramolecular C-C bond formation is based on the tether approach. The radical donor may either be generated on a tether and cyclize onto an unsaturated sugar acceptor or, alternatively, the radical donor can be generated on the sugar template which cyclizes onto a tethered radical acceptor. 

Scheme 16. Synthesis of branched-chain sugars by intramolecular tethered radical addition to unsaturated carbohydrates...

Scheme 17. Preparation of branched-chain sugars via serial radical reactions initiated by tethered radical addition to unsaturated sugars...

Controlled radical cyclization directly onto a ring junction is less easy. Lejeune and Lallemand envisaged that a tethered radical cyclization of a (bromomethyl)dimethylsilyl ether onto an allylic double bond could be used to incorporate a hydroxymethyl functionality into an angular position at the ring junction of a decalin system [53]. This would then provide an interesting entry into a variety of natural products containing this skeletal functionality, such as the insect antifeedant clerodin 132 (Scheme 10-45). 

Scheme 10-45 A silyl-tethered radical cyclization could be used to incorporate angular hydroxymethyl functionality at a ring junction.

In most cases the radical generated after cyclization is quenched by H-abstraction. However, another possibility is to utilize the cyclized radical in another C-C bond-forming event. Fraser-Reid and co-workers utilized a silyl-tethered radical cyclization of the (L)-rhamnal-derived silyl ether 142 to generate the anomerically. stabilized radical 143, which could be trapped in the presence of an excess of acrylonitrile to generate acetate 144 after tether cleavage and peracetylation (Scheme 10-48) [55a]. This reaction sequence occurred with complete regio- and stereoselectivity. The same group has also used an acetal tether (vide infra) to effect similar transformations [55 b, 56]. 

Scheme 10-47 Crimmins and O Mahony used a silicon-tethered radical cyclization in a synthesis of talaromycin A.

---