A Method for Selective N-Boc Deprotection on Wang Resin

Abstract

A simple, inexpensive and efficient method for the selective cleavage of N-Boc protecting group under acidic conditions on high load Wang resin is described. This method employs the use of concd sulfuric acid in 1,4-dioxan and provides an efficient process for the complete Boc deprotection with minimal loss of substrate through cleavage from resin. Solid phase organic synthesis (SPOS) has been widely applied for preparing small organic molecule libraries for screening purposes. 1 More recently, the scale-up of a variety of solid phase syntheses using a high load (4 mmol/ g) Merrifield resin has been reported. 2 Consequently, the approach of using high load resins in solid phase chemistry for the preparation of the initial quantities of drug substance required for pre-clinical toxicological studies is now feasible. This not only requires that all steps are chemically efficient (conversion and isolated yield) but also imposes cost limitations on the use of certain reagents.In general, the use of N-Boc protection strategies for solid phase synthesis is currently limited to acid stable resins with the initial step in the synthesis being the direct attachment of substrate to Merrifield resin. However, the forcing conditions required to cleave the product from the resin limits the nature of compounds that can be prepared using this strategy. The alternative approach is to use orthogonal base sensitive protecting groups such as Fmoc in association with modified resins such as Wang and 2-chlorotrityl, which allow the use of milder resin cleavage conditions such as 50% TFA in dichloromethane (DCM). 3,4 However, on larger scales the cost associated with the use of Fmoc protected monomers can become prohibitive. In this letter we describe a simple method of N-Boc deprotection, which is compatible with Wang resin.Recently we wished to prepare the dipeptide (4) and opted to follow a SPOS strategy using high load Merrifield derived Wang resin, Scheme 1. Although there are a number of methods available for N-Boc deprotection on solid support, 5 including the use of TMSOTf/Lutidine, 6 TMSCl/ Phenol, 7 , silicon tetrachloride, 8,9 aluminium chloride 10 and dilute aqueous HCl in organic solvents, 11,12 we encountered difficulties in the selective removal of a N-Boc group without appreciable loss of substrate through cleavage from the resin. For example, using TMSOTf/2,6-lutidine, at least two treatments with fresh reagents were necessary and even then the reaction was incomplete giving rise to other unidentified impurities. Similarly, whilst the use of TMSCl/Phenol for the selective removal of the Boc protection appeared to work well on small scale (1-5g), the results were inconsistent and at times gave as much as 20-25% loss of product from cleavage of the resin. Attempts to enhance this protocol through the use of fresh TMSCl (to minimise the presence of residual HCl) or TMSCl pre-treated with sodium carbonate and high purity phenol (>99%) failed to give more consistent results. Furthermore, attempts to increase selectivity by u...

The Use of Tin(IV) Chloride for Mild and Selective Boc Deprotection on TFA Cleavable Rink-Amide MBHA Resin

“…The Fmoc-Lys(Boc)-resin loading results, along with the decreased yield obtained for the model peptide and the resin-bound Fmoc-phenylalanine loading results, 10 agree with previous studies, [1][2][3] suggesting that the extent of cleavage from the resin may vary depending on steric factors related to the resin. The steric hindrance around the peptide-resin amide bond may also vary slightly from one C-terminal amino acid to another.…”

“…In addition, the urethane moiety presumably reacts faster and is more susceptible to the SnCl 4 acidolysis. It should be noted that our HPLC and mass spectrometric results for the model peptide, as well Analyzing our results alongside previous studies [1][2][3][4] of Boc deprotection on acid-sensitive resins, we recommend individual optimization of the deprotection conditions. An example of such optimization has been described by Boeglin et al 4 By optimizing the previously described methods for Rink 1 and Wang 3 resins using TMSOTf and a tertiary base, they obtained appropriate conditions for selective Boc deprotection on acid-labile FMPB-AM resin with minimum loss of material from the resin.…”

“…Recently, we wanted to selectively remove the Boc protecting group from TFA-sensitive Rink-amide MBHA resin, without removal of substrate from the resin. Few reagents have been introduced for such Boc deprotection on acid-sensitive resins, [1][2][3][4] however, to the best of our knowledge, attempts to remove Boc groups from acid-sensitive resins have always resulted in some cleavage from the resin. In addition, reagents described in the literature to perform such Boc deprotections have not been used for the removal of Boc groups from compounds bound to Rinkamide MBHA resin.…”

8 Natural polymers—chemistry

“…137 Guanidinylation of the ornithine side chain amino functions with an N-Boc-NЈ-Ts-protected amidinopyrazole yields arginine containing peptides. 138 Concentrated sulfuric acid in 1,4-dioxane affords an inexpensive and efficient method for the removal of the N-Boc protection on a high load Wang resin, 139 and a dimethyl ether-poly(hydrogen fluoride) complex has been shown to cleave peptides efficiently from Merrifield resins. 140 Microarrays containing thousands of short peptides per cm 2 have been prepared by parallel synthesis on 3-aminopropylsilanized glass, using photolithography and photogenerated acid in the deprotection step of the otherwise conventional Bocprotocol.…”

2 Synthetic methods : Part (iii) Protecting groups

“…A method that is selective for N-Boc deprotection even for substrates immobilized on resins via the acid labile Wang linker is concentrated H 2 SO 4 in 1,4dioxane (1:9). 120 In stark contrast, the use of 4 M HCl in CH 2 Cl 2 resulted in complete cleavage of the Wang linker, with Boc groups remaining largely intact. Nitrolytic deprotection of N-Boc groups using HNO 3 (3.5 equiv.)…”