Selenium linkers

Selenium linkers show reactivities comparable to those of sulfur hnkers but selenium has several advantages due to the weaker C-Se bond, hi addition to that, selenium can often be oxidized faster than sulfur and selenium linkers 

The first synthetic examinations of seleniiun hnkers were conducted on resins that were either synthesized via polymerization ofp-vinylphenylselenol or by modification of bromopolystyrene with K2Se [317]. 

Selenium-based linkers 590 can also be synthesized from polystyrene via lithiation and subsequent addition of dimethyldiselenide to the polymer support. Reaction of bromine gives selenenyl bromide that can be reduced to the lithium selenium resin in the presence of liBH4 that is alkylated subsequently [318]. Other approaches include the addition of former synthesized selenium-containing building blocks to the resin, for example, the hnker systems generated by Elofsson et al. [319] and Nakamura et al. [320,321]. 

In a very simple manner, starting from Merrifield resin, reaction with KSeCN forms a resin-bound methylselenocyanate that can be alkylated to give immobihzed compound 591 [322]. 

Beyond these general possible cleavage reactions, there are other possibilities to cleave from selenium-containing resins that should be mentioned 

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Scheme 3.2 Solid-phase semi synthesis of Vancomycin (48) based on a new selenium linker [123, 124].

The selenium linker has been used as starting point for a library of natural products and medicinal relevant molecules by Nicolaou et al. (Scheme 3.29) [295,... 

The selenium linker 1.45 (103), obtained from Merrifield resin and potassium selenocyanate, was treated according to oxyselenylation conditions to give a supported selenolactone. Oxidative deseleny lation (m-CPB A, DCM, rt) produced the unsaturated lactone in good yield and purity. An expansion of this chemistry, including several SP transformations prior to the cleavage, is mentioned in the original paper (103). 

Nicolaou [44-47] has pioneered the use of selenium linkers in soUd-phase synthesis. A selenium linker [44,45], cleaved under radical conditions, has been utilized in a cyclative-capture strategy for the soUd-phase synthesis of indolines (Scheme 61). Treatment of o-allylanihnes with selenenyl bromide resin in the presence of a Lewis acid results in cyclative-capture to give immobilized indoline 240. Further functionalization was then carried out prior... 

Scheme 61 Radical cleavage of a selenium linker by Nicolaou [44,45]...

Scheme 63 Selenium linker cleavage in the absence of a radical quench by Nicolaou [45]...

Scheme 64 Selenium linker cleavage in the synthesis of 2-deoxyglycosides by Nicolaou [46]...

Scheme 65 Selenium linker cleavage in an approach to everinomicin 13,384-1 by Nico-laou [47]...

Scheme 66 Selenium linker cleavage, carbonylation and cyclization by Engman [48]...

Scheme 68 Cleavage of a chiral selenium linker by Wirth [50]...

Scheme 16.26 Selenium linker yielding alkanes or alkenes by Nicolaou et at.

SCHEME 1.3 Benzopyrans synthesized on solid support utilizing a novel selenium linker and IRORI radiofrequency tags, MacroKan technologies, and the NanoKan system. 

A selenium linker has been used in the preparation of various nitrogen-containing heterocycles. Cycloaddition of nitrile oxides to resin-bound alkynes gave resin-bound isoxazoles (Scheme 11.41). a-AIkylation of the resin-bound cycloadducts with halides under basic conditions gave additional diversity for the products. Traceless oxidative cleavage of the isoxazoles was achieved via the elimination of the resin with hydrogen peroxide. The diversity of the products was still expanded with a second cascade of 1,3-dipolar cycloadditions to alkenes attached to the resin. 

Scheme 11.41. Solid-phase synthesis of isoxazoles with a traceless selenium linker.

Selenium linker systems tend to be oxidized in the presence of reagents like mCPBA or H2O2 and their cleavage properties are similar to those of sulfur linkers. Two general possible pathways to release compoimds from the selenium hnker systems 597 are responsible for a lot of fimctionahties that can be formed successfully from those linkers (Scheme 87). On the one hand. 

Scheme 88 demonstrates the compatibility of selenium linker systems with reductive, eliminative and nucleophilic conditions. The linker has been synthesized from polystyrene 604 via lithiation and quenching with dimethyld-iselenide 605 as mentioned above. Reaction to terminal alkenes 610 is performed via an oxidation-elimination process, induced by the addition of H2O2. Alkyl compound 609 is released using radical chemistry with a combination of AIBN and n-BusSnH [323]. 

Scheme 89 Multifunctional cleavage from selenium linkers...

The addition of nucleophiles to the cr-center of the selenium linker has been described by several groups among them Nicolaou et aL who investigated the formation of several spiro compounds 624 upon cleavage from solid supports [327] (Scheme 91). Crucial for these transformations are heteroatom-nucleophiles which can attack the released compoimds after sel-eniiun linker oxidation and elimination. Following the above-mentioned and similar routes, Nicolaou et aL synthesized diverse orthoesters and aUylic orthoesters [328]. 

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