Bromoacetal resin

Tripeptides with N-terminal anthranilic acid part were used as starting materials in the solid-phase synthesis carried out on TentaGel resin to prepare 1,4,11,1 l -tetrahydro-2//-pyrazino[2,l-3]quinazoline-3,6-diones with various N-l and N-3 substituents <2003EPP1471066>. Tandem cyclization from [6+0] atom fragments took place in the solid-phase synthesis of 143 from 142. Intermediate 141 was built on bromoacetal resin (Scheme 17) <1998JOC3162>. 

In the first step, a resin-bound secondary amine is acylated with bromoacetic acid, in the presence of N,N-diisopropylcarbodiimide. Acylation of secondary amines is difficult, especially when coupHng an amino acid with a bulky side chain. The sub-monomer method, on the other hand, is facilitated by the use of bromoacetic acid, which is a very reactive acylating agent Activated bromoacetic acid is bis-reactive, in that it acylates by reacting with a nucleophile at the carbonyl carbon, or it can alkylate by reacting with a nucleophile at the neighboring ah-phatic carbon. Because acylation is approximately 1000 times faster than alkylation, acylation is exclusively observed. 

Coupling of bromoacetic acid To a stirred soln of bromoacetic acid (10 equiv) in CH2C12 (maximum concentration 0.3 M) were added bromoacetyl bromide (8 equiv) and DIPEA (20 equiv). The mixture was added to amino-peptide-resin and shaken for 10 min with the resin followed by washing with CH2C12. 

The linker 36 was prepared on pMeBHA resin using Fmoc chemistry. After the tetrapeptide was synthesized, the Fmoc group was removed by piperidine/NMP (1 4) for 20 min and the Boc group was removed by TFA/CH2C12 (1 1) for 20 min followed by neutralization with DIPEA/NMP (1 19). Fmoc-p-Ala-OH and bromoacetic acid were then condensed stepwise to the peptide-resin. Completion of each reaction was monitored by the ninhydrin test. The peptide-resin was treated with TFA/3-cresol/TfOH (9 1 1 v/v) for 1 h at rt. Subsequently, H20 was added to the mixture with cooling and the mixture was washed with pentane (2 x ) followed by Et20 (2 x ). The aqueous soln was applied to RP-HPLC, and the purified peptide analyzed by FAB-MS m/z 1067.0 Da [M + H]+ (calcd 1067.2 Da). 

Dissolve bromoacetic acid (10 eq, relative to resin loading) and DIC (11 eq) in minimal amount of DMF. Add this solution to the resin. 

An acidic resin can be made by the polymerization of 4-vinylpyridine initiated by AIBN and heat followed by treatment of the polymer with bromoacetate. Explain what is happening and give a representative part structure of the acidic resin. 

The use of a C-enriched building block anchored to a resin makes the gel-phase spectrum selective for the appearance of the new C signal, and the enrichment allows much shorter acquisition times (133, 134) a real-time kinetic was reported for the alkylation of amines with C-enriched bromoacetic acid (135). An example from our laboratories (136) shows the formation of a cyanohydrin on SP is monitored by C-enriched gel-phase NMR using C-benzaldehyde. The appearance of the cyanohydrin signal (63.2 ppm) and its increase at different reaction times is easily monitored by comparison with the constant signals of the solvent (deuterated benzene, 133-126 ppm. Fig. 1.19, spectra A-D). A major drawback of this technique is the cost and the limited availability of C-enriched building blocks, which currently severely limits its application. 

Solid-phase synthesis has also been used to make peptoids, some examples of which are shown in Fig. 2.4. Compounds of general structure 2.8, where the amino acid side chain is on the nitrogen, have been prepared either by the corresponding Fmoc-protected N-aUcylated glycines (33) or, in an improved method, via treatment of a resin-bound secondary amine with bromoacetic acid to produce the first peptoid building block, which is then elaborated via iteration of the procedure (34). Other modified P-peptoid structures such as 2.9 with repeating P-amino propionic units have been prepared by acylation of a resin-bound amine with acriloyl chloride followed by Michael addition of a primary amine. The cycle is repeated to build up the polymer... 

Following chain assembly of the desired peptide to produce 0.25 mmol of iV -Boc-peptide-resin, the Boc group was removed by treatment with neat TFA (10 mL) for 2 x Imin. The TFA was drained and the resin was flow-washed for 40 s with DMF. The resin was then neutralized with 10% DIPEA/DMF (10 mL) for 1 min, followed by a 10 s DMF flow wash. Bromoacetic acid (2.0 mmol) was dissolved in CH2Q2 (2mL) at 0°C and DIG (1.0 mmol) was added and activated for 10 min in an ice bath. This mixture was added to the neutralized peptide-resin (swollen in DMF) and coupled for 20 min. The peptide was cleaved as described above. 

Resin-supported a-bromoacetic acid 1125 undergoes amine displacement, urea formation, and intramolecular cyclization to afford 3-aminohydantoins 1126. A diverse set of 3-aminohydantoins with different substituents at the 1-position was readily prepared (Scheme 272) <2000TL1165>. 

Scheme 16 shows a synthesis of regioisomeric 2,6-diketopiperazines 59. Wang-resin-linked bromoacetic add 56 was reacted with 4-nitrobenzyl esters of amino... 

Goff and Zuckermann [51] reported the synthesis of 2-oxopiperazine 16 by intramolecular Michael addition on the solid phase. The coupling of resin-bound unsaturated dipeptoids with a variety of Fmoc-L-amino acids, N,N -diisopropylcarbodiimide (DIPCDI), and 1-hydroxybenzotriazole (HOBt) affords tripeptoids, which after treatment with 20% piperidine in DMF, were acylated with benzoyl chloride-EtaN in 1,2-dichloroethane. Following treatment with 95% TFA in H2O, a diastereomeric ratio of monoketopiperazines 16 was obtained (Fig. 8). Rather than benzoyl chloride, phenylisocyanate or bromoacetic acid and an amine could be used. 

The access to peptoids was simplified with the solid-phase submonomer approach (Scheme 21) reported by Zuckerman et al. [56]. As shown in Scheme 21, the first step consists of acylation of the resin-bound amine with bromoacetic acid and DIC as the coupling agent, and in a second step, the side chain is introduced by nucleophilic substitution of the halide with an excess of a primary amine. This method, which allows the preparation of a wide variety of oligomers, has been applied successfully to the generation of diverse combinatorial peptoid libraries [50]. Furthermore, A-hlkyl glycine residues containing peptide or peptoid-peptide hybrids can be read-... 

Peptoid oligomers are synthesized on a Rink amide resin (50 /Ltmol scale) to avoid diketopiperazine formation. In order to suppress the formation of diketopiperazine during the synthesis of peptoids with a C-terminal carboxylic group, one can use the 2-chloro tritylchloride resin [155]. Following Fmoc removal, the resin is bromoacylated by successively adding a solution of bromoacetic acid (83 mg, 600 tmol, 12 equiv.) in DMF (830 fiL) and 200 fiL of DIG (103 /xL, 660 tmol, 13 equiv.) in DMF (170 >L) to the resin. The reaction mixture is shaken for 30 min at room temperature. A double coupling is performed systematically. The resin is then filtered and washed three times with 2 mL of DMF. The nucleophilic substitution step... 

Approach C is based on a-bromoacetic acid as key building block and starts from Rink-amine. After coupling of a-bromoacetic acid yielding 25, followed by nucleophilic displacement with an amine, polymer-bound derivative 22 is obtained. Repetition of this cycle of events and cleavage from the resin gives rise to peptoid 20. 

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