Benzhydrylamine resins

BENZHYDRYLAMINE RESIN FOR SYNTHESIS OF PEPTIDE AMIDES USING BOC/BZL CHEMISTRY... 

A better, higher yielding approach for the preparation of templates attached to different peptides employs a combination of solid-phase and solution-phase couplings (Scheme ll).121 A peptide chain is synthesized on a low-loading benzhydrylamine resin and reacted with a bifunctional electrophile such as the bis(pentafluorophenyl) ester 4 (R1 = Pfp) (low resin... 

Scheme 4 shows another impressive example of intrinsic purification by cyclative cleavage structurally complex thiazolyl hydantoins were synthesized starting from N-protected amino acids bound to 6-aminohexanoic acid-derivatized benzhydrylamine resin 15. The conjugates 11 were transformed into thioureas 12, which in turn were treated with a-bromo ketones to produce thiazoles 13 on the solid phase. The hydantoins 14 were prepared in four further steps by cyclative cleavage as described above. At the end of this nine-step sequence, almost 20 products were obtained, with purities generally exceeding 95%. Cleavage conditions in this case involved the use of a mixture of dioxane/triethylamine at 60 °C for 6 h [5]. 

A solution phase chiral auxiliary for 1,3-dipolar cycloaddition of isomunchnones with vinyl ethers has been adapted for solid phase synthesis by attaching both enantiomers of the precursor a-hydroxyvaline to benzhydrylamine resin (Scheme 12.12) [13,19]. The auxiliary 22 was then functionalized by acylation and diazotiza-tion to provide diazoimide resin 23. Rhodium(II)-catalyzed nitrogen extrusion and cycloaddition in the presence of different vinyl ethers afforded, after detachment from the polymer, various bicydic molecules (24) in 49-65% yield and provided high degrees of selectivity (93-95% ee). 

Related resins 8e [349] and 8f [350] have been used in Suzuki coupling reactions cleavage was possible under conditions of lower acid concentration for 8f, attributable to anchimerically assisted ipso protonation by the amide carbonyl. Similar observations have been made concerning the conditions required to cleave this silane anchoring group from a linker that had been attached to benzhydrylamine resin [351]. 

For practical purposes, however, it is necessary to enhance the acid-sensitivity of this bond by the presence of a second benzene ring at the benzylic carbon atom. Benzhydrylamine resins indeed proved themselves in numerous syntheses of peptide amides... 

Tam, J. P., DiMarchi, R. D., and Merrifield, R. B. (1981) Design and synthesis of a multi-detachable benzhydrylamine resin for solid-phase peptide synthesis. Tetrahedron Lett. 22, 2851-2854. 

Hiral983 Hirao, A., Itsuno, S., Hattori, I., Yamaguchi, K., Naka-hama, S. and Yamazaki, N., New Method for the Preparation of Benzhydrylamine Resins, J. Chem. Soc., Chem. Commun., (1983) 25-26. 

Tam1985 Tam, J.P., A Gradative Deprotection Strategy for the Solid-Phase Synthesis of Peptide Amides Using p-(Acyloxy)benzhydrylamine Resin and the S 2 Deprotection Method, J. Org. Chem., 50 (1985) 5291-5298. 

With the piperidine carboxylic acid 42 and two related unhydroxylated amino acids (Boc-4-piperidine carboxylic acid and Boc-i -pipecolic acid) a small library was constructed on a 4-methyl benzhydrylamine resin by use of HATU activation in DMF-dichloromethane 1 1. 

Functionalized supports with amino groups such as benzhydrylamine (BHA) 26 [32] and 4-methylbenzhydrylamine (MBHA) 3 [3] provided C-terminal amides upon HF cleavage (Fig. 2). Polyalkoxyaminobenzyl and alkoxydiphenylamino resins such as PAL (5-(4-aminomethyl-3,5-dime-... 

FIGURE 5.16 Production of amides by cleavage of benzhydryl amides. Recognition that removal by acidolysis of benzhydryl protectors from carboxamides gave the amides (B) led to development of benzhydrylamine (BHA) resin (C).33 Treatment with HF of a peptide amide that has been assembled on a BHA resin using Boc/Bzl chemistry gives the peptide amide (D). Peptide amide is also obtainable by ammonolysis of the resin-bound benzyl ester (A), a reaction that is more efficient if gaseous NH3 is employed (see Section 8.3). 

Bio-beads consists of (1% cross-linked polystyrene with 1.25 mmol chloromethyl substitution per gram of dry resin respectively benzhydrylamine polymer (1% cross-linked polystyrene with 0.24 mmol NH2 per gram of dry resin, Bio-Rad Laboratories (Richmond, CA, USA). 

For the hydrolysis of peptides linked to resins, the release of the C-terminal amino acid is strongly dependent upon the type of resin and amino acid residue. For this purpose the use of propanoic acid/12M HC1 (1 1 )[6 is recommended. More studies, however, indicate hydrolysis with TFA/12M HC1 (1 3) at 160°C is more appropriate since quantitative release of the most stable Phe residue from benzhydrylamine- (BHA-), 4-methylbenzhydrylamine-(pMeBHA-), and 4-(hydroxymethyl)phenylacetamidomethyl-resins occurs in 20, 6, and 5 h, respectively, compared to the 30,18, and 18h required with propanoic acid/12M HC1 (1 1)) ... 

A much more useful approach is the cleavage of peptide-resins having a C-terminal amide bond to the solid support. The most common solid supports for the synthesis of peptide amides are benzhydrylamine derivatives,which liberate the peptide by acidolysis. Examples include the 4-methylbenzhydrylamine resin (pMeBHA resin, for the Boc/Bzl... 

The first supports bearing primary anodno groups including the aminomethyl-polystyrene [270], benzhydrylamine (BHA) [271], and p-methylbenzhydryl-amine (MBHA) [272,273] resins 7a (Table 7) were developed initially for the synthesis of peptide amides. Because the carbocations derived from resins 7a are not especially stabilized, cleavage requires the use of a strong acid such as TFMSA or treatment with HF and usually requires an amide... 

Early examples of the use of resin-bound amines for the solid synthesis of peptidyl amides involve the use of linkers such as benzhydrylamine or benzyl-amine. Following peptide assembly, these linkers require highly acidic (e.g. 

Resins incorporating benzyhydrol and benzhydrylamine groups. (P)—benzhydryl ester or benzhydryl-amide bond cleaved by mild acidolysis to give free peptide and peptide-amide, respectively... 

Carbamate linker systems (Fig. 9, [19,182-191]) are often produced by the transformation of an alcohol to a carbonate functionality. Afterwards, the carbonate can be reacted with amines and amide coupUng reagents to give carbamates. This strategy is for example used by Und n et al. [192] by the addition of 4-nitrophenylchloroformate (4-NPCF) to a 4-methyl-benzhydrylamine polystyrene (MBHA-PS)-based resin and further addition of an alkylamine. A similar sequence is conducted with a solid-supported hydroxy-functionality that is converted via phosgene addition into the chlo-roformate. Addition of amines then gives resin-bound carbamates [193]. 

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