Linker Marshall

Scheme 12.11 Microwave-assisted aminolysis (Marshall linker).

The successful assembly of organic compounds on a solid support represents only part of the challenge in SPOS. After completion of synthetic sequence, the compounds must be cleaved from linkers attached to polymer by a chemical or photochemical reaction, for example, treatment of a polymer-bound compound with acids, bases, nucleophiles, redox reagents, and even photons. Acid-labile linker and amine-cleavable Marshall linker are two major classes of hnkers used in combinatorial synthesis. 

The Marshall Unker [23] has been widely used to synthesize compounds that can be cleaved by primary and secondary amines to afford the corresponding amides. Marshall linker was used in the synthesis of three or more diversity-site hbraries because it allowed the addition of one more diversity element at the cleavage step. While the original reported linker [23] involved the oxidation of the Unker before cleavage, the efficient release of the resin-bound compounds using nucleophiles from the unoxidized linker has been reported [16, 24]. Similarly to the acid-labile linkers, the kinetics of the cleavage reaction and time required for this reaction directly affect the synthesis efficiency, purity and yield of the final products. A cleavage study was carried out on seven resin-bound thiophenol esters (34—40) on Marshall Unker with 3 amines (41-43) (Scheme 12.11 and Tab. 12.4). 

Marshall linker 34 was esterilied with the BOC-meroquinene scaffold 33 (Scheme 1.8). Cycloaddition of nitrile oxides 36 with the solid-supported terminal alkene 35 gave isoxazolines 37. The regiochemistry of addition was expected to give predominantly the structure in which the... 

Fang, L. et al.. Kinetics study of amine cleavage reactions of various resin-bound thiophenol esters from Marshall linker, J. Comb. Chem., 4, 362, 2002. 

In an alternative approach to the synthesis of dihydrobenzopyran libraries, the dihydrobenzopy-ranone core was synthesized by Breitenbucher and Hui in solution via acylation of p-hydroxyben-zoic acid (171) and subsequent condensation with a ketone or aldehyde (Figure ll.Sl). After coupling of carboxylic add 172 to the Marshall linker, the carbonyl of the dihydrobenzopyranone... 

According to Marshall [23] and Beech [26], the oxidation of the thiophenol linker would increase the reaction rate. To study this effect, the linker in resin (35) was oxidized to sulfone/sulfoxide using mCPBA. Cleavage reaction of resin (35) -OX with n-butylamine went to completion in less than 4 min (Fig. 12.20), compared with 24 h needed for this resin under the same conditions without oxidation. The rate constant was determined to be 0.0179, which was a 580-fold increase compared with the unoxidized form. This result indicated that a linker oxidation was preferred for high yield when the products will not be affected by oxidation conditions. 

McKeown, S.C. Watson, S.P. Carr, R.A.E. Marshall, P.A. Photolabile Carbamate Based Dual Linker Analytical Construct for Facile Monitoring of Solid Phase Chemistry TLC for Solid Phase Tetrahedron Lett. 40, 2407-2410 (1999). 

Scheme 16.4 Sulfide safety-catch linker by Marshall et al.

The first reported solid-phase synthesis of head-to-tail cyclic peptides was based on the intramolecular aminolysis of resin-bound o-nitrophenyl esters. The cyclization proceeds concurrently to cleave the peptide from the resin, after deprotection and neutralization of the AT-terminal residue (Scheme 2A). Accordingly, Fridkin et al. [3] reported the preparation of several simple, unhindered cyclopeptides, such as cyc/o(Ala-Gly-Ala-Ala). Similarly, Flanigan and Marshall [4] obtained activation of the resin-bound peptide ester, after elongation of the peptide chain, by oxidation of the 4-(methyl-thio)phenyl (MTP) linker to a sulfonyl ester. Subsquent deblocking of the A-terminal residue and intramolecular condensation yielded the desired cyclic peptide. However, this method was found not to be suitable for the synthesis of longer and more hindered cyclic peptides [5]. 

Pavia s linker unit exploits amide or urea bond formation with concomitant displacement of the solid support, which is by far the most common approach for achieving cyclative cleavage. The first example of such an approach was Marshall s preparation of cyclic dipeptides, as shown in Table 1.3, Entry 1. Besides this, such classical cyclization C—N bond forming reactions have been used to prepare ambitious synthetic targets using SPOS,... 

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