Silyl radical cyclization

The importance of carbon-centred radical cyclizations in organic chemistry has been documented in the large number of papers published each year and numerous reviews and books dealing with this subject. In Chapter 7 the reader can find a collection of such processes mediated by organosilanes. The silicon-centred radical cyclizations have instead received very little attention, although there has been a growing interest in silicon-containing compounds from a synthetic point of view, due to their versatility and applicability to material science. As we shall see, this area of research is very active and some recent examples show the potentiality of silyl radical cyclization in the construction of complex molecules. 

Undoubtedly, further work will be necessary in order to get a solid background for silyl radical cyclizations. In particular, further investigations on the nature of the pendant alkenyl substituent as well as on the ring size and substituent effects on the silicon in the ring expansion can be expected in the future. 

In the total synthesis of talaromycin A, silylmethyl radical cyclization serves as a method for the stereoselective introduction of the 1,3-diol unit64. Starting from the corresponding alcohol, silylation, radical cyclization of the (bromomeihyl)dimethylsilyl eLher 4 and subsequent oxidative cleavage gives the desired product in 78% overall yield. 

An efficient two-step annelation of functionalized orthoesters with trimethyl-silyloxyfuran derivatives has been reported that produces bicyclo[3. .0]lactones. ° The reaction in Scheme 7 shows an example in which the initial condensation between silyl enol ether and orthoester is followed by the radical cyclization reaction under standard conditions. It is worth underlining the complete diastereocontrol in which three contiguous stereocenters are generated in one step with >95% stereoselectivity. 

Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two examples are shown in Reaction (80), where treatment of 100 with E3B, air, and (TMS)3SiH provided the tricycle 101 in excellent yields as a single diastereomer. Interestingly, the bulky silyl ether moiety is not required to achieve stereoselectivity in this process. 

An early - but mechanistically interesting - construction of a bicyclo[3.1.0]oxa-hexane by a domino radical cyclization was presented by Luh s group [50]. The addition of tributyl tin and AIBN to a solution of bromides 3-111 in refluxing benzene gave 3-114 as single diastereoisomers in acceptable yields via the intermediates 3-112 and 3-113 (Scheme 3.29). It is important that the cyclopropyl carbinyl radical intermediate has the correct stability and reactivity, which is achieved by the a-silyl substituent. 

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-... 

Scheme 19)." Homoallyloxysilanes gave a mixture of five- and six-membered rings, but the intermediate silyl radical underwent predominantly 6-endo cyclization. Pentenyloxysilane gave the 1-endo product only. The stereochemistry of these reactions was found to be determined by steric effects, even in the presence of chiral thiol catalysts. The structures of the radical intermediates were studied by EPR. 

It is worth mentioning that in a few cases the (3-elimination of the silyl radical from the a-silyl alkoxyl radical (47) with the formation of corresponding carbonyl derivative was observed [63,64]. Evidently the fate of a-silyl alkoxyl radical depends on the method of radical generation and/or the nature of the substrate. Two examples that delineate the potentialities of this rearrangements are reported in Reactions (5.33) and (5.34). In the former, the 5-exo cyclization of secondary alkyl radical on the carbonyl moiety followed by the radical Brook rearrangement afforded the cyclopentyl silyl ether [65], whereas Reaction (5.34) shows the treatment of an a-silyl alcohol with lead tetracetate to afford the mixed acetyl silyl acetal under mild conditions [63]. 

Early work was focused to establish the preference for exo- vs endo-mode of cyclization. However, the absence of an effective method for generation of alkyl and/or aryl substituted silyl radicals made this task difficult. The reaction of prototype alkanesilane I with thermally generated t-BuO radicals at 145 °C after 4 h afforded a 48 % yield of unreacted starting material and 19 % yield of a six-membered cyclic product (Scheme 6.1) [1]. Moreover, EPR studies of the same reaction recorded the spectra at temperatures between —30 and 0°C, which were identified as the superimposition of two species having allylic-type (2) and six-membered ring (3) structures, respectively [2]. At higher temperatures radical 2 predominates therefore, the low yield detected in the product studies could derive from the extensive t-BuO attack on the allylic hydrogens. 

Scheme 6.2 Preference for 6-endo-trig cyclization of silyl radicals...

The endo-mode of cyclization is found to be the preferred path also in the lower homologues. Reaction (6.2) shows the reactions of two silanes (8) with thermally generated t-BuO radicals to afford the five-membered ring in low yields via a 5-endo-trig cyclization [1], EPR spectra recorded from these two silanes with photogenerated t-BuO radicals are assigned to secondary alkyl radical intermediates formed by an intermolecular addition involving the expected silyl radical and the parent silane [2],... 

Allyloxysilanes (14) undergo radical chain cyclization in the presence of di-tert-butyl hyponitrite as radical initiator and thiol as a catalyst at ca 60 °C (Reaction 6.3) [5]. The thiol promotes the overall abstraction from the Si—H moiety as shown in Scheme 6.4 and the silyl radical undergoes a rapid 5-endo-trig cyclization. Indeed, EPR studies on the reaction of t-BuO radical with silanes 14 detected only spectra from the cyclized radicals even at — 100°C, which implies that the rate constants for cyclization are > 10 s at this temperature. 

Analogously silylated cyclohexadiene 25 having propargyl alcohol as a pendant was used in the radical intramolecular hydrosilylation followed by ionic ring opening to provide alcohol 26 in 55 % yield (Scheme 6.6) [6]. The cyclization of silyl radical 27 to radical 28 represents an example of a 5-endo-dig process. 

Sequences (or cascades) of radical reactions involving the 5-endo-trig cyclization of silyl radical to an allyloxy-type substituent as the key step have been developed and applied to the synthesis of natural products [7 11]. The concept and the sequence of radical reactions is outlined in Scheme 6.7. A radical of... 

Scheme 6.7 Sequential radical reactions including 5-endo-trig cyclization of silyl radical...

Extensive mechanistic investigation of the ring expansion 33 —> 34 was performed in order to differentiate between a ring-opening reaction to give a silyl radical 39 (path a), followed by the 6-endo cyclization, or a pentavalent silicon transition state 40 (path b). It was clearly demonstrated that the ring expansion proceeds via a pentavalent silicon transition state (Scheme 6.10) [16]. 

The chemoselective addition of silyl radical to the double bond of the (3-alkenyloxyenone derivative 24 was instead planned in Reaction (7.29) and accompanied by a 5-exo-trig radical cyclization leading to the diastereomeric cyclic ether products [40]. 

The radical-based strategy has invaded the field of A-containing heterocycles. Cyclizations mediated by silyl radicals have been introduced as the key step in the synthesis of alkaloids and pharmacologically active compounds, with many advantages both in terms of selectivity and bio-compatibility. Some of the most significant and innovative examples are described in this section. 

Silyl substituted carbon-centred radicals, which are produced when adding RsSi to unsaturated bonds can participate in consecutive reactions other than cyclization. A simple example is given in Reaction (7.66) where the adduct of silyl radical to (3-pinene rearranged by opening the four-membered ring prior to H atom transfer [33,77],... 

It was proposed that an initially generated silyl radical 3, by reaction of i-BuO radical and polysilane 2, attacks another silicon atom in the same backbone to give a cyclic polysilane that contains an acyclic chain and another silyl radical (Scheme 8.1) [12]. The last silyl radical can either cyclize or abstract a hydrogen atom from another macromolecule, thus propagating the chain degradation. The reaction in Scheme 8.1 is an example of intramolecular homolytic substitution (ShO, a class of reactions discussed in Chapter 6. 

P. Mayon and Y. Chapleur, Exclusive 6-endo radical cyclizations of a-silyl radicals derived from carbohydrate allylic silylethers, Tetrahedron Lett. 35 3703 (1994). 

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