Intramolecular radical approach

Zoretic, P.A., Zhang, Y, and Ribeiro, A.A., An intramolecular radical approach to angular electro-phores in polycyclic systems, Tetrahedron Lett., 37, 1751, 1996. 

The aldol reaction is one of the most important reactions in synthetic organic chemistry. Many traditional ionic routes are currently available for diastereo- and enantioselective aldol reaction [97-99]. In contrast to highly basic ionic processes, development of radical methods for preparation of aldols using neutral conditions is attractive [100-102]. With the exception of intramolecular cyclization reactions, radical approaches towards aldol products remain largely unexplored [103-109]. 

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]. 

Hudlicky and co-workers reported a stepwise radical cyclization approach for the preparation of the complete morphinan ring skeleton 216 (Fig. 5.52). One of the key steps involves the intramolecular radical cyclization of cyclohexenyl... 

A good deal of effort has been devoted to the preparation of derivatives of the cyclohepta[cd]indole and bicyclo[4.3.1]decane ring systems, that can be considered related to the ABC and CD ring systems of welwistatin, respectively, but much of this work cannot be translated easily to methods relevant to welwistatin synthesis. For instance, many successful approaches to the cyclohepta[cd] indole system are based on intramolecular radical cycliza-tions [12] or Heck reactions [13]. In many published examples, a substituent at the indole C-2 avoids the competing reaction at this position, but this device renders the reaction products inadequate to achieve the oxindole struc-... 

A radical approach to cyclization is offered by the intramolecular homolytic substitution (ShO reaction at a silicon center. Reaction of phenyl bromoacetate with a stannylated silyl homoallyl ether under atom transfer conditions provides cyclic alkoxysilanes (Equation (119)).2... 

Our Total Synthesis (Part I) Construction of the A/B Ring System Highlighted by an Intramolecular Radical-Induced Carbocyclization Approach... 

Schmalz has reported on the intramolecular radical cyclization of (arene)Cr(CO)3 complexes (Scheme 10). Whilst most of the products from these reactions were transformed into aromatics, dearomatized products can potentially be accessed via this new and appealing approach [32-34]. 

In the first example, the electronic requirements were investigated with similar outcomes. The final yields of cyclised 34a-c were calculated over two steps, so radical precursors 33a-c were not isolated. However, the cyclised to reduced ratio was in favour of the former. In the second example, an asymmetric synthesis of azaindolines 37a and 37b was successfully achieved by radical cyclisation of enantiomerically pure 36a and 36b. The neutral conditions used preserve the stereogenic centre, demonstrating the potential of this approach. Banerjee (02JCS(P1)1769) reported a study of an intramolecular radical addition of a 2-p37ridyl radical from 38 onto a double bond to produce the tricyclic products 39-41 (Scheme 9). 

Caddick S, Aboutayab K, West R (1993) An intramolecular radical cyclization approach to fused [1,2-a] indoles. Synlett 231-232... 

The radical approach for C-C bond formation is a popular method within organic chemistry. The use of radical chemistry in carbohydrate synthesis has certain advantages. Firstly the reaction conditions are very mild and tolerant of a range of functional and protecting groups. Anomeric radicals are also stable towards elimination and epimerisation. Most significantly, the chemistry required to incorporate an appropriate substituent at C-1, employed in the initial homolytic cleavage step, is common within carbohydrate chemistry. The use of such radical techniques can be subdivided into two classes, intermolecular and intramolecular reactions. 

Macrocyclization has benefitted from a variety of approaches, of which intramolecular radical l,4-addition °, Pd-catalyzed diyne cy-cloisomerization and syntheses via sulfonium ylids and ketoketenes are notable. Tandem methodologies are also in vogue, one of which illustrates the theme of transient generation of a reactive enone function. For highly condensed systems, routes via transient formation of dipoles (cf. Synth. Meth. 44, 489) are fast developing as are serial radical approaches (example s. Synth. Meth. 44, 972). However, for a general overview of current cycliza-tion techniques a recent review is worthy of note. ... 

The application of intramolecular radical cyclisations in synthetic organic chemistry is a valuable approach to obtain important synthetic targets such as natural product precursors and biologically active substances. The use of carbohydrate starting materials in this field is no exception to this because of their well-defined stereochemistry, highly functionalised nature and availability. 

Zoretic PA, Wang M, Zhang Y, Shen Z, Ribeiro AA. Total synthesis of fi(,/-isospongiadiol an intramolecular radical cascade approach to furanoditerpenes. J. Org. Chem. 1996 61(5) 1806-1813. 

In the synthesis of molecules without functional groups the application of the usual polar synthetic reactions may be cumbersome, since the final elimination of hetero atoms can be difficult. Two solutions for this problem have been given in the previous sections, namely alkylation with nucleophilic carbanions and alkenylation with ylides. Another direct approach is to combine radical synthons in a non-polar reaction. Carbon radicals are. however, inherently short-lived and tend to undergo complex secondary reactions. Escheirmoser s principle (p. 34f) again provides a way out. If one connects both carbon atoms via a metal atom which (i) forms and stabilizes the carbon radicals and (ii) can be easily eliminated, the intermolecular reaction is made intramolecular, and good yields may be obtained. 

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