Radical reactions stereocontrol

The N,0- and N,S-heterocyclic fused ring products 47 were also synthesized under radical chain conditions (Reaction 53). Ketene acetals 46 readily underwent stereocontrolled aryl radical cyclizations on treatment with (TMSlsSiH under standard conditions to afford the central six-membered rings.The tertiary N,0- and N,S-radicals formed on aryl radical reaction at the ketene-N,X(X = O, S)-acetal double bond appear to have reasonable stability. The stereoselectivity in hydrogen abstractions by these intermediate radicals from (TMSlsSiH was investigated and found to provide higher selectivities than BusSnH. 

The conversion of carbohydrate derivatives into functionalized cyclohexanes and cyclopentanes has recently been reviewed [95]. The key step is the formation of carbon-carbon bonds, and different approaches have been used for this purpose. Radical reactions have in the last decade been recognized as valuable in this context [96] since the regio- and stereocontrol may frequently be predictable [97]. 

Our approach was to use the unsaturated bromodeoxylactones in an intramolecular radical reaction, since these compounds possess both the radical precursor and the radical trap within the same molecule. Thus, reacting the unsaturated bromodeoxyheptonolactone 20 (Scheme 14) with tributyltin hydride and a radical initiator, the bicyclic lactone 65 a was obtained in a quantitative yield within 1 h. The stereocontrol in the reaction was determined by the structure of the product, since the compound obtained has two fused cyclopentane rings which can only be cis anellated. The radical A, which is the intermediate, was trapped by the tin hydride. The stereochemistry of the newly formed chiral center is determined by the configuration at C-4 in the educt 20 [45]. 

The conformational barriers in acyclic radicals are smaller than those in closed-shell acycles, with the barrier to rotation in the ethyl radical on the order of tenths of a kilocalorie per mole. The barriers increase for heteroatom-substituted radicals, such as the hydroxymethyl radical, which has a rotational barrier of 5 kcal/mol. Radicals that are conjugated with a n system, such as allyl, benzyl, and radicals adjacent to a carbonyl group, have barriers to rotation on the order of 10 kcal/mol. Such barriers can lead to rotational rate constants that are smaller than the rate constants of competing radical reactions, as was demonstrated with a-amide radicals, and this type of effect permits acyclic stereocontrol in some cases. "... 

Stereocontrol of free radical reactions has proven to be possible, as in the example shown (equation 95), and is widely exploited. The use of chiral auxiliaries as illustrated has proved to have a wide application. 

Until recently, stereocontrolled radical reactions had not been properly investigated. This field has witnessed a rapid growth during the past few years.74 We (in collaboration with... 

Radical reactions of this type do not affect the stereochemistry in the rest of the halide molecule. This is nicely illustrated in the synthesis of malyngolide688, in which the key step is the radical addition of an iodide to an excess of alkene. The reaction occurs in 70% yield and takes place in the presence of catalytic quantities of chlorotributyltin, with sodium borohydride in ethanol (equation 104). Aspects of the stereocontrol of acyclic radical reactions have been reviewed recently668. 

Applications of controlled radical reactions - including oxidation - deal almost exclusively with C=C double bonds. Indeed, a multitude of examples have been reported for the selective transformation of this functional group. Contrasting with this situation, only a very limited number of selective ( stereocontrolled ) radical reactions involving sp3-hybridized C-H bonds are known. Particularly useful functionalizations along these lines include the hydroxylation and the acyloxylation of alkyl chains. The reason for their limited success is of course due to the high stability of the C-H bond compared with that of the olefinic C=C unit most electrophilic reagents which readily add to unsaturated substrates are not able to oxidize a C-H bond. 

The contribution of the transition state position is usually not discussed as a main factor in controlling the stereochemistry of a radical reaction. However, its importance was recently raised in several publications. Moreover, the reactivity-selectivity principle proposed by Giese to rationalize the influence of the radical trap on the stereochemical outcome of 2-substituted cyclopentyl radicals [39] could also be considered as an influence of the transition state position (Scheme 15) in early transition states (reactive olefins such as fumarodinitrile) the reagent is far away from the radical center and the face discrimination is low. With less reactive olefins such as styrene, a later transition state is occurring and the product stability starts to influence the stereoehemical outcome. Therefore, the most stable trans di-substituted cyclopentanes are produced with a higher degree of stereocontrol. 

Scheme 11. Acyclic stereocontrol in radical reactions Lewis acid and chiral auxiliaries...

An investigation into the preparation of n = 2 telomers was successful in showing that the ACT strategy with templates of type 14 is a viable means for producing isotactic 1,3 stereocenters as exemplified in the production of 16 (n=2) (Scheme 8-5). The oxazolidine unit has documented success as a stereocontrol element in acyclic radical reactions [35-37], and thus its incorporation into this template provides, in effect, a chiral auxiliary to control the configuration of new stereogenic centers formed in the sequence. 

The third approach involves a short, elegant, free radical reaction of the 3 -deoxy-3 -iodo-5 -0-tritylthymidine 49 with hexamethylditin, t-butylisonitrile and azobisisobutyronitrile to give stereoselectively CNT 31. This synthetic pathway allows the stereocontrolled synthesis of CNT 31 in four steps and 22% overall yield from thymidine [79]. 

By the mid-1960s, ionic and radical reactions were well studied and their mechanisms largely understood. There were a number of reactions that did not fit into either of these categories. One example is the Diels-Alder reaction, identified in the 1930s. This reaction is notable for its stereocontrol, implying a highly ordered transition state and a concerted mechanism. Another example, electrocyclic ring closure, was identified by R. B. Woodward in his work on the synthesis of vitamin Bj. These reactions and others like them were called no-mechanism reactions. 

The reaction of P-H bonds with unsaturated substrates often proceeds without a metal catalyst [2]. In addition, add or base-catalyzed [3] as well as radical reactions [4] have been reported and extensively reviewed. Metal[Pg.143]

Barton, D.H.R., Bero, S.D., Quinclet-Sire, B., and Samadi, M., New synthesis of sugar, nucleoside and a-amino acid phosphonates. Tetrahedron, 48,1627,1992 Barton, D.H.R., G ro, S.D., Quinclet-Sire, B., and Samadi, M., Stereocontrolled radical reactions in carbohydrate and nucleoside chemistry, Tetrahedron Assym., 5, 2123, 1994. 

Sihi MP, JiJG. Acychc stereocontrol in radical reactions p-selectivity with oxazolidi-none auxiliaries. Angew Chem Int Ed. 1996 35 190-192. 

Sihi MP, Ji JG. Acyclic stereocontrol in radical reactions. Diastereoselective radical addition/allylation of N-propenoyloxazolidinone. J Org Chem. 1996 61 6090-6091. 

The radical chemistry of organotins is overwhelmed by the tin hydride chemistry. In the past decades, the knowledge of kinetic parameters authorized the expeditious construction of complex molecules by using cascade radical reaction based on BujSn" methodology. Moreover, these strategies also offered an excellent dia-stereocontrol, especially for the construction of polycyclic skeletons. These synthetic applications of BujSnH, which will not be covered in this chapter, were reviewed in recent years [279]. In addition to the tin hydride chemistry, there are several applications of organotins in radical syntheses involving mainly allylstan-... 

---