Radical reactions strategy

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. 

Synthetic strategies based on multistep radical reactions have steadily grown in popularity with time. The knowledge of radical reactivity has increased to such a level as to aid in making the necessary predictions for performing sequential transformations.Silanes, and in particular (TMSlsSiH, as mediators have contributed substantially in this area, with interesting results in terms of reactivity and stereoselectivity. ... 

Another effective radical cascade strategy started from bromomethyldi-methylsilyl propargyl ethers. " The synthesis of functionalized cyclopenta-none 108 was achieved as a single diastereomer, starting from the reduction of bromoderivative 107 in the presence of (TMSlaSiH (Reaction 83). When different substituents are used in the skeleton, as in compound 109, a completely different reaction pattern resulted (Reaction 84). 

Instead of simply using two radical reactions in a domino process, the combination of three and more radical C-C- or C-N-bond forming radical transformations is also possible. This makes this methodology one of the most powerful procedures in the synthesis of complex molecules starting from simple substrates [77]. During the years, several strategies have been developed, and these are depicted in Scheme 3.50. The strategies can be classified as three types ... 

Because reductive cleavage of aliphatic nitro compounds with Bu3SnH proceeds via alkyl radicals, nitro compounds are also used as precursors to alkyl radicals. Reactions using nitro compounds may have some advantages over other ones, since aliphatic nitro compounds are available from various sources. For example, the sequence of the Michael additions of nitro compounds provides an excellent method for the construction of quaternary carbon compounds (Eq. 7.79).126 Newkome has used this strategy for the construction of dendritic polymers (Eq. 7.80).127... 

This radical cyclization strategy was utilized for the synthesis of the smaller fragment silyl ether 54 as well (Scheme 8). Evans aldol reaction of the boron eno-late derived from ent-32 with aldehyde 33, samarium(III)-mediated imide methyl ester conversion, and protecting group exchange led to tosylate 51. Elaboration of 51 to ketone 53 was achieved under the conditions used for construction of the second tetrahydrofuran moiety of 49 from 46. A highly diastereoselective reduc-... 

In practice, it was found that whereas the synthesis of hirsutene according to the dual strategy met with success under thermal conditions, but at temperatures as high as 580 °C, under photochemical conditions it afforded the unnatural cis, syn, cis configuration of some intermediates which then need further elaboration. Although the transformations 44 — 43a and 45. — 43a by a [2 + 2] -cycloaddition and a vinylcyclopropane rearrangement, respectively, may involve intermediates with a more or less biradical character, they are not typical radical reactions such as the ones we are considering here. 

The strategies and symbolism developed by Curran for radical reactions [29] parallel, in some way, all that we have learned about polar or ionic reactions. 

A new free-radical carbonylation strategy, employing S -phenyl chlorothioformates and alkyl halides, has been developed. Reaction with (Eu3Sn)2 furnishes the corresponding S -phenyl esters in moderate yields (Scheme 30). 

The general concepts of stereoselectivity in radical reactions have been illustrated in a number of recent books. Readers are referred to those books for a thorough treatment [1,2]. The following sections deal with a collection of applications where silanes act as mediators for smooth and selective radical strategies, based on consecutive reactions. 

The increasing popularity of radical reactions is certainly due to the so-called tandem or cascade reaction , i.e., the ability of forming and breaking several bonds in a one-pot procedure. Again, the concepts of disciplined processes and predictability are applied in these successful strategies, which show the elegance and power of the synthetic plan based on radical reactions. 

In both reactions the intermediate glycosyl radicals are trapped from the a-face y hydrogen atom donors. Thus, by taking advantage of the stereoelectronic and conformational effects of hexopyranosyl radicals, these strategies enable the production ol p glycosides. 

Chapter 24 Strategy XI Radical Reactions in Synthesis FGA and its Reverse. 

This reaction - the benzoin condensation17 - is the nearest we have come to realising the simplest strategy of acyl anion and carbonyl electrophile in one step. One important group of reactions that make 1,2-difunctionalised compounds is the subject of the next chapter on radical reactions. A more modem version of this reaction, not needing cyanide, is described in chapter 39. 

A similar cyclization strategy has been used for the synthesis of a key methylcarbapenem intermediate 10 [95SL915], The note worthy aspect of this work is the establishment of three contiguous chiral centers during the radical reaction. 

The simple piperidine alkaloid coniine (for selected asymmetric syntheses of coniine see [22, 81-85]) offered a preliminary test case for hybrid radical-ionic annulation in alkaloid synthesis. From butyraldehyde hydrazone and 4-chloro-iodobutane (Scheme 4), manganese-mediated photolysis afforded the acyclic adduct in 66% yield (dr 95 5) the cyclization did not occur in situ [69, 70]. Nevertheless, Finkelstein conditions afforded the piperidine, and reductive removal of the auxiliary afforded coniine in 34% overall yield for four steps. This reaction sequence enables a direct comparison between radical- and carbanion-based syntheses using the same retrosynthetic disconnection an alternative carbanion approach required nine to ten steps [81, 85]. The potential for improved efficiency through novel radical addition strategies becomes quite evident in such comparisons where multifunctional precursors are employed. 

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