Cho

OCH,

BAL Backbone Amide Linker

BAL Backbone Amide Linker

Scheme 16

FmocNH R2 63 MttNH

Scheme 16

Procedure

Linker attachment: An amino-functionalized polystyrene or PEG-polystyrene resin may be used as starting material. First, 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid (PALde-hyde) [83] (4 equiv.) and HATU [84] (4 equiv.) were dissolved in DMF, then DIEA (8 equiv.)

was added and, after 1 min of preactivation, this solution was added to the resin (1 equiv.). Coupling was allowed to proceed at 25° C for 2 h, at which time the Kaiser ninhydrin test [59] was negative.

General procedure: A mixture of amino acid methyl ester hydrochloride (10 equiv.) and NaBH3CN (10 equiv.) in DMF was added to the PALdehyde resin 61 (1 equiv.).The reaction was allowed to proceed for 1 h at 25° C, after which the resin was washed with DCM and MeOH, and finally dried.

The Fmoc-amino acid (10 equiv.), HATU (10 equiv.) and DIEA (20 equiv.) in DCM/DMF (9:1) were added to the aminoacyl ester resin 62 and allowed to react for 2 h at 25° C. After washing with DMF and DCM the coupling was repeated with fresh reagents, again for 2 h. The resulting resin 63 was washed with DMF and DCM , then treated with Ac20/DMF (1:9) for 20 min, and washed thoroughly with DMF.

Repeated treatments with 20 % piperidine in DMF (3 x 1 min, then 3x5 min) was followed by extensive washing with DMF (Kaiser ninhydrin test remains negative).The diketopiper-azine remains grafted on the support.

An optional alkylation of the unsubstituted amide bond may be carried out by the following steps under argon atmosphere in a screw-cap tube with aTeflon-lined cap, a sintered glass frit, a stopcock, and a jacket where acetone at -70° C circulates during metalation. Lithiated oxazolidinone inTHF was freshly prepared from 5-phenylmethyl-2-oxazolidinone (10 equiv.) plus 2.0 M n-BuLi in hexane (10 equiv.), then added to the diketopiperazine resin. After 90 min at-70° C, the alkylating agent (15 equiv.) was added, followed by DMF to reach a final solvent ratio ofTHF/DMF (7:3).The resin was allowed to warm to 25° C and after 5 h it was filtered and washed withTHF, thenTHF/H20 (1:1), again withTHF, and finally with DCM [1],

The trisubstituted diketopiperazine 64 was cleaved into solution withTFA/H20 (9:1) for 2 h and isolated from the eluate and the combined washes (using appropriate solvents to solubilize the product).

Diketopiperazine libraries prepared according to the scheme above are suitable for both on- and off-resin screening. The heterocycle formation occurs while the product is grafted on the solid support, whereas alternative schemes described in the literature [79,80] involve cy-clative cleavage, with ring formation leading to concomitant release of the product into solution.

The chemistry described was also successful for amino acid esters other than methyl esters. Ring formation rates and yields with methyl, ally], and benzyl esters were shown to be very similar.

3.4.11.2 Piperazine-diones by Acid Cyclative Cleavage. Method A including Reductive Alkylation

This method [79] was used for the preparation of a prototype combinatorial library of 1000 piperazine-diones. The key step of this experimental procedure resides in the reductive alkylation step with sodium triacetoxyborohydride, which was thoroughly validated for the solidphase reaction format.

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