Esterification of polymer-supported hydroxyl groups using the Mitsunobu reaction

Abstract

Resin-bound hydroxyl groups were esterified by N-protected amino acids using triphenylphosphine and diethyl azodicarboxylate (Mitsunobu reaction) in tetrahydrofuran or dimethylformamide. The typical reaction time was 1 h and the yield for different amino acids varied from 65 to 100%. No racemization was detected in model peptides.

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“…In the search for a general epimerization‐free anchoring system, treatment of the polymer‐supported β‐amino alcohol 3 c with Fmoc‐( L or D )‐Cys(Trt)‐OH in a Mitsunobu reaction33 afforded compounds 4 c and 4 d , respectively, in enantiomerically pure form (Figure 1). This esterification system is reported to lead to a low level of substitution34 but to preserve chiral integrity 35. As expected, epimerization was not detected (by HPLC of compounds 7 c and 7 d , formed from 4 c and 4 d by removal from the resin and cleavage of the tert ‐butyl ether and trityl thioether; Figure 1).…”

An Fmoc Compatible, O to S Shift-Mediated Procedure for the Preparation of C-Terminal Thioester Peptides

“…These conditions, however, gave poor results in the case of the C-terminal β-branched residue Val. In the course of investigating an alternative method for coupling Val, use of the Mitsunobo reaction − was shown to give dramatically improved yields (Supporting Information Figure S2). The efficiency of the Mitsunobu coupling method was then assessed for all naturally occurring amino acids with the exception of Cys.…”

The “One-Bead-One-Compound” Combinatorial Library Method

“…Numerous organic reactions useful for solid-phase combinatorial chemistry have been reported in the literature. These include reductive alkylation; ,,, Mitsunobu etherification − and esterification; carbon−carbon bond-forming reactions such as Horner/Wittig, , Grignard, Heck, , Stille, ,− and Suzuki reactions; ,− Michael addition; and amide reduction. , One should be able to use these reactions in the design of heterogeneous libraries.…”