Silyl ether tethers

The one-electron oxidation of enol silyl ether donor (as described above) generates a paramagnetic cation radical of greatly enhanced homolytic and electrophilic reactivity. It is the unique dual reactivity of enol silyl ether cation radicals that provides the rich chemistry exploitable for organic synthesis. For example, Snider and coworkers42 showed the facile homolytic capture of the cation radical moiety by a tethered olefinic group in a citronellal derivative to a novel multicyclic derivative from an acyclic precursor (Scheme 8). 

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. 

Catalytic alcoholysis of silanes by a variety of transition metal based catalysts is a useful method to form silyl ethers under mild conditions (Scheme 19). The process is atom-economical hydrogen gas is the only byproduct. This mild method has not been fully exploited for the preparation of unsymmetrical bis-alkoxysilanes. A catalytic synthesis using silicon alcoholysis would circumvent the need of bases (and the attendant formation of protic byproducts), and eliminate the need for excess silicon dichlorides in the first silyl ether formation. We sought catalytic methods that would ultimately allow formation of chiral tethers that are asymmetric at the silicon center (Scheme 20). Our method, once developed, should be easily transferable for use with high-value synthetic intermediates in a complex target-oriented synthesis therefore, it will be necessary to evaluate the scope and limitation of our new method. 

Despite the development of various intermolecular radical addition methods, those studies have rarely accommodated additional functionality, our discovery of the manganese-mediated photolysis conditions notwithstanding. Prior to that discovery, we began to elaborate an alternative strategy which employs temporary tethers ([115, 116] reviews of silicon-tethered reactions [117-120]) (silyl ether or acetal linkages) linking radical and acceptor. In this scenario the C-C bond is constructed via cyclization, in which internal conformational constraints can control diaster-eoselectivity. The tether itself would be converted to useful functionality upon cleavage, and once the tether is cleaved the net result may be considered as formal acyclic stereocontrol. ... 

One silicon tethered example that is unique in its selectivity is the cinnamyl tethered silyl enol ether shown in Sch. 17. Unlike all of the other silyl tethered examples, this compound gives a photoadduct that is the result of a cross 2+2. However, it is the product expected if the cycloaddition is a stepwise process involving radical intermediates. It is also the product expected if the reaction pathway is controlled by 7i-stacking. 

The opposite sequence is described with alkynyl silyloxy-tethered enynes. A cascade CM-RCM reaction proceeds in the presence of a second generation ruthenium carbene to give cyclic siloxanes. The initial CM is directed to occur on the alkyne by employing sterically hindered substituted alkenes tethered to the alkyne via a silyl ether group [24] (Scheme 11). 

In the second example the diazene possesses a four-carbon tether with two stereogenic centers. The major product can be viewed as arising via a pathway where the tether coils to resemble a chair form of cyclohexane with the methyl, silyl ether and tive-membered ring occupying pseudoequatorial positions. Iliat the observed stereospecificity is due to the preference for the substituents to orient themselves... 

Another intramolecular approach to C-linked disaccharides has been described by Skrydstrup and Beau [116] using 2-pyridyl sulfones to generate anomeric radicals. Tethering sulfone 280 with chlorosilane 279 provides silyl ether 281 (O Scheme 60). 

The enol silyl ether (56) undergoes a photoinduced reaction in the presence of chloranil to give cyclohexenone and the adduct (57) and the currently available evidence suggests that the reaction proceeds by electron transfer to the photo-activated chloranil to give (56) A photophysical study has appeared of the chromophore-quencher compounds [Au(CCPh)(L )] (L = 10-[(diphenylphosphi-no)methyl]anthracene) and [Au(CCPh)(L )]BPh4 (L = l-[2-(diphenylphosphin-oxy)ethyl]pyridinium], 1 -[2-(diphenylphosphinoxy)ethyl]-4-methyl pyridinium, 1 -[2-(diphenylphosphinoxy)ethyl]-4-tert-butylpyridinium, and 1 -[2-(diphenylpho-sphinoxy)ethyl]triethylammonium in which the Au(CCPh) chromophore is linked by a flexible tether to the acceptors. 

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. 

Conversion of aldehydes to ketones via cyanohydrin derivatives tethers) by alkylation or Michael addition also used with silyl ethers, diafcylarrtnonitrites (see also Stetter reaction). 

We also attached three steroid substrates to an iodophenyl template in 16 (Scheme 6-7) using a tris-silyl ether link, and saw that the template could direct selective radical-relay chlorination to all three tethered substrate species in the same work we reported a similar finding when a thiophene ring was the triply tethered template [49]. Thus the sulfur atom of thiophene can perform radical relay. In these triple catalytic functionalizations, the more reactive sulfuryl chloride was the preferred reagent. 

The importance of the tether in enabling such high stereo- and regiocontrol was further exemplified upon investigation of the analogous intermolecular reaction [6 a, d]. Exposing silyl ethers 6 (diene) and 7 (dienophile) to similar reaction conditions provided a mixture of all four possible regio- and stereoisomers in the ratio 3 2 2 1 (Scheme 10-2). 

The use of silyl acetals as tethering groups in the IMDA reaction is often hampered by the relatively poor yields observed in the formation of unsymmetrical systems. However, the preparation of the triene precursors can be facilitated if only one of the r-systems is linked through a silyl ether connection, while its reacting partner is attached directly to the silicon tether [9]. 

Dialkylvinylsilyl halides are readily prepared, for example, by hydrosilylation of acetylenes indeed, the most simple dimethyl- and diphenylvinylsilyl chlorides are now commercially available. Substitution of the halide with the appropriate hydroxydiene then generates the desired triene precursor. Vinyl silyl ethers are also much more stable than silyl acetals, especially towards hydrolysis nevertheless, a number of mild methods are still available for subsequent removal of the tether. 

Scheme 10-5 A short tether ensures complete regio- and stereocontrol with vinyl silyl ethers Subsequent tether cleavage is also readily achieved.

The following discussion on the application of the temporary connection to radical cyclizations will be divided into five sections. In the first, a silyl ether is used as the tether in which one of the alkyl groups attached to the silicon possesses the radical precursor (usually a halogen). In the second section, it is the radical acceptor which is introduced on silyl ether formation. The third section concerns the use of silyl acetals as a temporary connection and in the fourth other templating strategies which do not fall into any of the aforementioned areas will be discussed. The final section is a discussion of the use of some of these strategies in C-glycosylation. 

---