Alcohol 47 was attached to the silyl-modified support 46 in the presence of imidazole. The trimethoxytrityl group (TMT) of 48 was cleaved off using formic acid in DCM. The loading was estimated by spectroscopic quantitation of the released TMT-cation and was in a range of 0.35-0.45 mmol/g.The first element of diversity was introduced by a Suzuki crosscoupling. This step was followed by Dess-Martin oxidation to afford intermediate 49. Diversity was introduced again in the next step by the addition of a vinyl cuprate. Reduction of the keto function of 50 is performed by L-Selectride. The cleavage from the support can be carried out before or after this reduction to yield 51 or 52, respectively. Alternatively, the cleavage can be performed with a 2 mM solution of TBAF in DCM for 5 h, followed by treatment with water.
Recently, details were published of the new silyl linker 53 for the attachment of alcohols , This attachment was reported to proceed directly in the presence of a Rh-catalyst (Scheme 24). Thus, a transfer of 53 into the corresponding silyl chloride as in a previously published example of the same authors could be omitted , Linker 53 allowed also for the attachment of ketones via hydrosilylation. Cleavage of the final product proceeded as in the application of linker 46 by HF/pyridine/THF with MeOSiMe3 as scavenger.
Procedure: Direct loading of primary alcohol to polystyrene diethyl silane  To a solution of 1.7 mg Rh-catalyst in a 10 mL round-bottomed flask under argon was added 200 mg of resin 53. Then 66 mg of (S)-(-)-1-(2-methoxybenzoyl)-2-pyrrolidine in ethanol were added, and the reaction mixture was stirred at rt for 3 h.The mixture was then filtered and the resin washed with DCM (three times), toluene (twice)THF/water (1:1, twice), andTHF (three times).
Treatment with AcOH/THF/water (6:6:1) at 50° C for 4 h. released the alcohol from the support. The filtrate was concentrated to obtain the alcohol in a yield of 99.3 % (GC).
Alcohols can be immobilized directly as p-alkoxybenzylethers on Wang resins. The latter are stable to a variety of reaction conditions, and the final compounds are cleaved by mild acid treatment . As a further alternative, alcohols can also be linked to a solid support by a trityl linker . Release of the alcohol proceeds with 1 N HC1 at rt.
A 9-phenylfluoren-9-yl-based linker can also be used for the attachment of alcohols. This linker shows an improved acid stability compared with the trityl linker. The linker was applied to the synthesis of a peptide alcohol ,
An additional linker 54 for the immobilization of alcohols on solid support was published recently . The linker is activated with N-iodosuccinimide for the attachment of the alcohol. The alcohol is released by the action of penicillin amidase or by mild acid treatment, as outlined in Scheme 25. The yield of the enzymatic cleavage (25-50 %) is strongly dependent on the resin used.
188.8.131.52.4 Serine-Based Linker for Phenols
This linker unit, when coupled to an amine-modified support as in 55, is stable towards acids such as TFA as well as towards bases. The phenol can be released by fluoride ions . The driving force for the cleavage is the intramolecular formation of the oxazolidinone ring system 56 (Scheme 26).
The application of the linker was demonstrated in connection with Pictet-Spengler cy-clizations and Knoevenagel reactions. In a preliminary example it was also demonstrated that the linker might also be useful for alcohols.
Was this article helpful?