Oxime resins

Belitsky, J.M., D. H. Nguyen, N. R. WuRTZ, and P. B. Dervan. Solid-phase synthesis of DNA binding polyamides on oxime resin. Bioorg. Med. Chem. 2002,... 

Depending on the reaction temperature and reaction time, tetrahydroisoquinoline 357 afforded different mixtures of 1,2,3,4,11,11 a-hcxahydro-6//-pyrazino[ 1,2-3]isoquinolines 358-361 and tetracyclic compound 362 (Scheme 30) <2005JA16796>. Each of the individual diastereoisomers 358-361 could be transformed into the compound 362. z7r-3//,4a//-3-Phcnylpcrhydropyra/ino[ 1,2-7]isoquinoline-l,4-dione was prepared via automated parallel solid-phase synthesis on Kaiser oxime resin <1998BML2369>. l,2,3,5,6,7-Hexahydropyrido[l,2,3-r/f ]quinoxaline-2,5-dionc was obtained by catalytic hydrogenation of ethyl 3-(2-oxo-l,2,3,4-tetrahydro-5-quinoxalinyl)acrylate in the presence of TsOH over 5% Pd/C catalyst under 40 psi of hydrogen <1996JME4654>. 

FIGURE 5.19 Approaches for synthesis of protected peptides using acid-sensitive protectors. For (A) the last residue is incorporated as the Cbz-derivative. (B) The chain is assembled on a substituted oxime resin,44 starting at the penultimate residue. The chain is then detached from the resin by displacement by the carboxy-terminal residue of the target peptide, which may be a free (terf-butylammonium salt) or carboxy-substituted residue. (C) An alternative for producing acids by use of the oxime resin is transesterfication of the peptide with A-hydroxypiperidine, followed by reduction to remove the piperidino substituent. 

JT Lobl, L Maggiore. Convenient synthesis of C-terminal peptide analogues by aminolysis of oxime resin-linked protected peptides. J Org Chem 53, 1979, 1988. 

JC Hendrix, JT Jarrett, ST Anisfield, PT Lansbury. Studies related to a convergent fragment-coupling approach to peptide synthesis using the Kaiser oxime resin. J Org Chem 57, 3414, 1992. 

N Voyer, A Lavoie, M Pinette, J Bernier. A convenient solid phase preparation of peptide subtituted amides, (oxime resin) Tetrahedron Lett 35, 355, 1994. 

Scheme 22 Solid-phase synthesis of the biotinylated, farnesylated tetrapeptide (59) using the Kaiser benzophenone oxime resin.

Five novel RGD peptides 81 containing either one or twice furanoid SAAs 80 were recently synthesized via an efficient solid-phase strategy based on Kaiser s oxime resin 71d (Scheme 43). 

Sulfahydantoins 87 and 88 are analogues of hydantoins and provide heterocyclic scaffolds with a great potential for the construction of bioactive compounds. A total of 28 derivatives, with crude purity generally higher than 85%, were prepared by parallel synthesis using an oxime resin as a solid support (Scheme 46) . The results constitute the first report of successful Mitsunobu reactions and reductive alkylations on the oxime resin. 

A very interesting approach to the solid-supported synthesis of hydroxamic acids was developed by Golebiowski and Klopfenstein . It employs an oxime resin (Kaiser resin) 171d and, unlike all previouxsly reported methods, allows the use of acid-labile protecting... 

Nevertheless, the direct nucleophilic displacement of support-bound carboxylates to prepare hydroxamates presents some limitations. For example, O-tert-butyldimethylsilyl-protected hydroxylamine displaces common acids from oxime resin however, further treatment with trifluoroacetic acid (TFA) is necessary to remove completely the silyl... 

Thouin and Lubell have overcome some of these issues by exposing oxime resin-bound(acyl)amino acids 197-200 to a solution of anhydrous hydroxylamine in 1 6 MeOH CHCI3 (Scheme 87). Enantiopure hydroxamates, possessing a variety of functional groups, are isolated by simple evaporation of volatile solvents. 

Due to the vast numbers and rapidity of novel developments in solid-phase synthesis over the past ten years, a number of reports currently found in the literature deal with solid-phase syntheses of lanthionine peptides. There are at least two different approaches to synthesize lanthionine peptides in which the sulfide bond links amino acid halves that are not direct neighbors within the peptide chain (Scheme 10). One obvious approach, method A, is based on the coupling of a preformed, orthogonally protected lanthionine monomer to the N-terminus of a peptide oxime resin. 48 This is then followed by acid-catalyzed cyclization and simultaneous release from the resin during amide bond formation with the C-terminal carboxy group via the peptide cyclization method on oxime resin (see Section 6.73.2.2). The alternative approach is lanthionine formation after peptide synthesis from amino acid derivatives, such as serine and cysteine (method B). 

Scheme 11 Synthesis of a Lanthionine Peptide via Solid-Phase Peptide Synthesis and Final Cleavage from Kaiser Oxime Resin 481...

Among the electrophilic handles proposed for head-to-tail and side-chain-to-tail cyclization of peptides on solid support by intrachain aminolysis with concurrent detachment of the product from the resin in the protected form (see Section 6.8.3.1.3), generally the oxime resin (also called Kaiser resin)1364 365 and a thioester resin[363l are recommended (see Scheme 14). In addition to the classical head-to-tail cyclization,[3431 the oxime resin is used for side-chain cyclizations as well as for the synthesis of multicyclic peptides vide infra). Due to its dual functions, the oxime resin can be employed only with Boc/Bzl chemistry it is not compatible with Fmoc/tBu chemistry where the basic N -deprotection leads to free amino groups and thus to premature cyclization reactions. To avoid this premature cleavage of the... 

The synthesis of type I bicyclic peptides is the most simple as the two side-chain-to-side-chain cyclizations can be performed successively on the assembled peptide or more appropriately by condensation of the two monocyclic segments preferably in solution. As shown in Scheme 23 (path A), for the synthesis of suitably protected monocyclic peptides, side-chain attachment of Asp or Glu residues to the oxime resin is proposed,[436,43T which leads to the desired cyclization and release of the protected segments as Pac or preferably as A1 es-tersJ396 These are C-terminally deprotected, when required, and then assembled in solution into bi- or polycyclic peptides of type I. 

A high yielding synthesis of anthranil from 2-nitrobenZaldehyde makes use of zinc and allyl bromide as the reducing agent. The method has also been used for the preparation of 3-substituted anthranils from 2-nitrophenyl ketones <99H(51)1921>. A solid phase synthesis of 3-aminobenzisoxazoles 15 is based on the displacement of fluoride from 2-fluorobenzonitriles by the Kaiser oxime resin and subsequent hydrolysis of the C=N bond <99JOC4547>. A synthesis of 3-(2-dialkylaminoethyl)benzisoxazoles from oximes of 2-hydroxyphenyl ketones has also been described <99H(51)2139>. ... 

SPPS on oxime resin couplings DCC, HOBt, DMF deprotection 25% TFA/CH2CI2... 

On the other hand, pyrenyl-L-alanine 184 has also been used as a conformational probe in the characterization of an artificial 4-a-helix bundle protein.11,121 The 53-residue peptide 186 incorporating one residue of 184 in each of two different helical segments was synthesized by solid-phase synthesis using a segment condensation strategy and the oxime resin. Boc-pyrenyl-L-alanine 191 was coupled just like any other amino acid by the BOP/HOBt method in DMF. CD and fluorescence studies demonstrated that the two pyrene groups were in close proximity forming an excimer complex, which is possible only when the polypeptide chain folds into a 4-a-helix bundle structure. 

Scheme 2 Synthesis of Side-Chain-Protected Peptides Employing the Oxime Resin,2l...

---