Method for cleaving protecting groups and organic compounds from supports

Abstract

The present invention relates to a method for cleaving protecting groups from organic compound and cleaving organic compounds from a support, the method comprising subjecting the organic compound or the organic compound coupled to a support via a linker to a composition comprising: i) at least a Lewis acid, ii) at least a Brønsted acid, and optionally iii) at least a solvent. Also encompassed is a composition and several methods for cleaving protecting groups and / or linkers comprising the application of the composition.

Description

[0001] Method for cleaving protecting groups and organic compounds from supports Field of the Invention The present invention relates to a method comprising the application of a composition comprising at least a Lewis acid, at least a Brønsted acid, and optionally at least a solvent, the composition capable of cleaving protecting groups from an organic compound and cleaving off an organic compound from a support. The composition is also capable of simultaneously deprotecting the organic compound and cleaving the organic compound from a support. Background The Fmoc / t-Bu (fluorenylmethyloxycarbonyl / tert-butyl) variant of Merrifield’s solid- phase peptide synthesis (SPPS) is currently the standard methodology for the synthesis of a wide range of peptides from R&D to manufacturing on industrial scales. To this end, upon assembling of a peptide on a resin by Fmoc / t-Bu SPPS, the target compound is typically cleaved off the polymer support while also removing side chain protecting groups. Specifically, as in Fmoc / t-Bu SPPS the peptides are typically attached to polymer supports via acid labile linkers while side chains of heteroatom containing amino acids are also protected by acid labile protecting groups, the standard approach to cleave the target peptides off the resins while removing side chain protecting groups is by the action of a suitable acid. Most notably, trifluoroacetic acid (TFA) in the presence of various additives (so-called scavengers) is nowadays used as practically the only means of cleaving peptides of the resins and removing side chain protecting groups, while as a means of isolating the crude peptides after TFA cleavage, precipitation with ethereal solvents is typically employed (F. Dick, In Peptide Synthesis Protocols; M. W. Pennington, B. M. Dunn, Eds.; Humana Press: Totowa, NJ, 1995; 63, C. A. Guy and G. B. Fields, Methods Enzymol., 1997, 289, 67). Notably, as during the TFA cleavage various side reactions which decrease purity of the target peptide may occur, TFA cleavages of peptide resins accessed by Fmoc / t- Bu SPPS are typically extensively optimized with regards to which scavengers are used (D. S. King, C. G. Fields and G. B. Fields, Int. J. Pept. Protein Res., 1990, 36, 255) as well as the composition of the ‘’cleavage cocktail’’ and process parameters such as reaction time and temperature (J. Wang, A. Niemoeller and S. Viswanath, Chem. Eng. J., 2023, 476, 146928). Nevertheless, despite the broad utilization of TFA as a universal peptide synthesis reagent owing to its high usage rate in peptide resin cleavages, TFA is by the OECD classified as a per- and polyfluorinated substance (PFAS) as TFA contains a perfluorinated methyl group (R. Kai, Org. Process Res. Dev. 2023, 27, 1421, N. D. Tyrrell, Org. Process Res. Dev., 2023, 27, 1422). Hence, there is an increased pressure in the market to produce commercial peptides in the absence of PFAS. Moreover, TFA is highly corrosive posing a significant hazard to the workers utilizing this chemical, not least in the context of large-scale peptide manufacturing where kg amounts of TFA are routinely utilized to cleave quantities of peptide resins necessary to produce sufficient amounts of synthetic peptide products, most notably for the therapeutic and cosmetic peptide markets. Furthermore, peptides cleaved off peptide resin are typically isolated by precipitation with highly flammable ethers such as diethyl ether (DEE), diisopropylether (DIE) and methyl tert-butyl ether (MTBE) (B. G. de la Torre and D. Andreu, J. Pept. Sci., 2008, 14, 360), which also poses a safety hazard by potentially containing varying amounts of peroxides while isolating ether precipitated crude peptides can be hampered for example by cumbersome filtrations. Considering the above noted disadvantages of using TFA for peptide resin cleavages and employing ethereal precipitations for crude peptide isolations, alternative methods for peptide resin cleavages – crude peptide isolations are needed. Palladino and Stetsenko discloses hydrochloric acid (HCl) in trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP) to cleave specific side chain protecting groups and linkers used in SPPS (P. Palladino and D. A. Stetsenko, Org. Lett., 2012, 14, 6346, D. Stetsenko and P. Palladino, WO 2014 / 033466 A1, 2014, D. A. Stetsenko, V. S. Apukhtina, B. P. Chelobanov and P. Palladino, Russ. J. Bioorganic Chem, 2016, 42, 143). Also, Srivastava (WO 2007 / 130275) discloses a method for cleaving a peptide from a support using hydrochloric acid together with trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP). Vinayagam et al (2024) discloses the cleavage of benzyloxycarbonyl (Cbz) from amines by a Lewis acid or a Brønsted acid in hexafluoroisopropanol (HFIP). Although the above presented methodologies of cleaving side chain protecting groups and / or linkers do not comprise the application of TFA they all rely on the usage of fluorinated alcohols like TFE and HFIP also classified as PFAS. Moreover, low concentration HCl in subcritical water has been used to cleave peptides off Wang and RAM resins using microwave irradiation (A. Rees, WO 2015 / 028599, 2015), albeit this methodology has only been demonstrated for the cleavage of single amino acids while from the practical standpoint, the harsh cleavage conditions (>100 °C) constitute a significant concern as well. Giri et al (2017) presents ferric chloride (FeCl3) mediated side chain modification of aspartic acid- and glutamic acid containing peptides on a solid support. Tert-butyl (tBu) is used as the protecting group for the side chain carboxylic group of aspartic acid or glutamic acid. tBu is cleaved by the application of a Lewis acid, specifically FeCl3, in a suitable solvent such as dichloromethane (DCM). After cleavage of tBu modification of the carboxylic function is accomplished. Giri et al (2020) discloses the application of FeCl3 in a suitable solution for removal of the Boc group from amino acids and peptides in solution and solid phase. Peptides bound to a solid phase are cleaved off by the usual TFA-containing deprotection cocktail. The Giri papers do not disclose the combined usage of both a Lewis acid and a Brønsted acid. Sen et. al. (2016) discloses avenues for the synthesis of phthalocyanine derivatives such as tetrakis [(2-formylphenoxy)-phthalocyanine, tetrakis [(2-formylphenoxy)- phthalocyaninato]nickel(II) via hydrolysis of acetal-substituted phthalocyanine in tetrahydrofuran (THF) mediated by acetic acid and FeCl3. Acetal hydrolysis is initiated by the protonation of the oxygen of the acetal (dioxolan moiety) and proceeds through multiple reactions with water and acid (hydronium ion) until the aldehyde is formed. The presence of water and acid is crucial for driving the conversion of the acetal to aldehyde. Water is present in the form of water coordinated to FeCl3 as FeCl36H2O (ferric chloride hexahydrate). One objective of the present invention is the provision of a cleavage composition not comprising PFAS for cleaving linkers and / or protecting groups. One objective is the replacement of PFAS containing compositions for global deprotection of a polypeptide coupled to a solid support. One objective is the reduction or avoidance of using per- and polyfluoroalkyl substances in the synthesis of peptides. A further objective is to facilitate post cleavage workup by omitting the use of ethereal solvents for precipitating / isolating a peptide. One objective is the avoidance of compounds comprising carbon-fluorine bonds when cleaving an organic compound such as a polypeptide from a support. Summary of the Invention The invention relates to a method / process for cleaving protecting groups of organic compounds coupled to a support and / or cleaving organic compounds from a support by the application of at least one Lewis acid, at least one Brønsted acid, and optionally at least one solvent. Also encompassed is a composition comprising at least a Lewis acid and at least a Brønsted acid and optional at least a solvent for use to cleave protecting groups and organic compounds from supports. A further aspect relates to the use of a composition comprising at least a Lewis acid, at least a Brønsted acid, and optionally at least a solvent for simultaneous cleaving protecting groups of an organic compound coupled to a support and cleaving that organic compound from a support coupled to the support suitably by a linker. Thus, the composition comprising at least a Lewis acid and at least a Brønsted acid is capable of cleaving protecting groups of organic compounds. The composition also cleaves an organic compound coupled to a support. The organic compound is usually coupled to a support by a moiety / linker facilitating cleavage. Hence, the composition comprising at least a Lewis acid and at least a Brønsted acid can cleave the organic compound from the linker. The combination of a Lewis acid and Brønsted acid can effectively be applied in multistep organic synthesis where protecting groups are used for temporary modify reactive functional groups. Protecting groups prevent unwanted side reactions and enable selected reactivity and can be selectively introduced under mild conditions, are stable under the planned reaction conditions, are easily removable without affecting other functional groups and may be chosen to be compatible with other protecting groups (orthogonality). Protecting groups are specifically relevant in peptide synthesis, oligonucleotide synthesis, glycosylation reactions, synthesis of natural products and asymmetric synthesis. The application of a Lewis and Brønsted acid is particularly useful in multistep organic synthesis where the organic compound is coupled to a support, i.e. solid phase synthesis. Solid-phase synthesis involves anchoring the starting molecule to an insoluble polymeric support, typically resin beads, simplifying purification and sequential synthetic coupling (transformation). The starting molecule is usually coupled to the support by a molecule configured to be cleaved under defined conductions (pH, acid, base, etc.) often referred to as a linker. The combination of at least a Lewis acid and at least a Brønsted acid is also capable of cleaving an organic compound which is coupled to a support, such as an insoluble, non-degradable polymeric solid support. The organic compound is preferably coupled to a support by a linker. One particularly useful application of the combination of at least a Lewis acid and at least a Brønsted acid is in solid phase peptide synthesis. More specifically, the combination of at least a Lewis and at least a Brønsted acid is specifically attractive for cleaving off a polypeptide from a solid support and concurrently also deprotecting the polypeptide (commonly referred to as global deprotection). The combination of at least a Lewis acid and at least a Brønsted acid cleaves off a polypeptide from a support in high yield, effectively comparable to or even surpassing the properties of trifluoracetic acid (TFA) which currently is the golden standard in SPPS. One aspect of the invention relates to a method for cleaving bonds in (of) an organic compound comprising protecting groups coupled to a support, the method comprising subjecting the organic compound to i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent under conditions where the content of water is below about 100 equiv. (based on organic compound). One aspect of the invention relates to a method for cleaving bonds in (of) an organic compound, such as an organic compound coupled to a support (organic compound comprising at least one protection group), where the (cleavable) bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups, and between the organic compound and the linker coupled to a support, the method comprising: a) subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension comprising the organic compound; and b) maintaining the solution or suspension comprising the organic compound at a temperature and duration thereby forming a partially and / or fully deprotected organic compound coupled to the support and / or forming a partially and / or fully deprotected organic compound not coupled to the support. An aspect relates to a method for cleaving bonds in (of) an organic compound, such as an organic compound coupled to a support, where the (cleavable) bonds are located between the organic compound and protecting groups, the method comprising a) subjecting / mixing / treating the organic compound to / with a composition comprising: i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent thereby forming a solution or suspension; and b) maintaining the solution or suspension at a temperature and duration for forming a partially and / or fully deprotected organic compound. An aspect relates to a method for cleaving protecting groups from an organic compound, such as an organic compound coupled to a support, comprising protecting groups, comprising a) subjecting / mixing / treating the organic compound comprising protecting groups to / with a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent thereby forming a solution or suspension; and b) maintaining the solution or suspension at a temperature and duration for forming a partially and / or fully deprotected organic compound. An aspect of the invention relates to a method for cleaving bonds in (of) an organic compound, such as an organic compound coupled to a support, where the (cleavable) bonds are located between the organic compound and the protecting groups, and between the organic compound and the linker coupled to a support the method comprising: a) subjecting / mixing / treating the organic compound to / with a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent thereby forming a solution or suspension; and b) maintaining the solution or suspension at a temperature and duration for forming a partially and / or fully deprotected organic compound coupled to the support, and / or forming a partially and / or fully deprotected organic compound not couped to the support. An aspect relates to a method for cleaving protecting groups from an organic compound comprising protecting groups, the organic compound coupled to a support by a linker, the method comprising: a) subjecting / mixing / treating the support to / with a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent thereby forming a solution or suspension; and b) maintaining the suspension at a temperature and duration for forming a partially and / or fully deprotected organic compound coupled to the support, and / or a partially and / or fully deprotected organic compound not coupled to the support. An aspect relates to a composition for cleaving bonds in (of) an organic compound, such as an organic compound coupled to a support, where the (cleavable) bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compound and the linker coupled to a support, the composition comprising: i) at least one Lewis acid; ii) at least one Brønsted acid, and optionally iii) at least one organic solvent. An aspect relates to the use of a composition for cleaving bonds in an organic compound, such as an organic compound coupled to a support, where the (cleavable) bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compound and the linker coupled to a support, the composition comprising: i) at least one Lewis acid; ii) at least one Brønsted acid, and optionally iii) at least one organic solvent. An aspect relates to a method for the synthesis of a polypeptide comprising providing a support comprising a linker, consecutively coupling ^-amine protected amino acids, such as Fmoc- ^-amine protected amino acids, optionally comprising a side chain protecting group, thereby forming a polypeptide coupled to the support comprising side chain protecting groups; wherein the method further comprises a) subjecting / mixing / treating the support comprising the polypeptide to / with a composition comprising: i) at least a Lewis acid, ii) at least a Brønsted acid), and optionally iii) at least an organic solvent; and b) maintaining the suspension at a temperature and duration for forming a partially and / or fully deprotected polypeptide coupled to the support, and / or a partially and / or fully polypeptide compound not coupled to the support. A further aspect relates to a method for cleaving bonds in an organic compound, such as an organic compound coupled to a support, where the (cleavable) bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups, and between the organic compound and the linker coupled to a support, the method comprising: a) subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension comprising the organic compound; b) maintaining the solution or suspension comprising the organic compound at a temperature and duration thereby forming a partially and / or fully deprotected crude organic compound coupled to the support and / or forming a partially and / or fully deprotected organic compound not coupled to the support; and further adding a solution containing a suitable salt thereby adjusting the pH of the solution or suspension. A further aspect relates to a method for the removal or reduction of residual metals, the method comprising cleaving bonds in an organic compound, such as an organic compound coupled to a support, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups, and between the organic compounds and the linker coupled to a support, the method comprising: a) subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension comprising the organic compound; b) maintaining the solution or suspension at a temperature and duration thereby forming a partially and / or fully deprotected organic compound and / or a partially and / or fully deprotected organic compound coupled to the support comprising residual metals; the method further comprising the removal or reduction of residual metals from the solution or suspension comprising partially and / or fully deprotected crude organic compound by either one of: a) i) trapping / capturing the organic compound on an support ii) eluting residual metals iii) eluting the organic compound; or b) i) trapping / capturing residual metals on a suitable insoluble support ii) eluting the organic compound; or c) separating the metals trapped on the support from the organic compound by the means of filtration. A further aspect relates to the removal or reduction of residual metals, the method comprising cleaving bonds in an organic compound, such as an organic compound coupled to a support, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compounds and the linker coupled to a support, the method comprising: a) subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension comprising the organic compound; b) maintaining the solution or suspension at a temperature and duration thereby forming a partially and / or fully deprotected organic compound and / or a partially and / or fully deprotected organic compound coupled to the support comprising residual metals; the method further comprising: i), filter off the spent resin and any insolubles and remove the volatiles in vacuo; ii) precipitate the residual material in suitable (anti)solvent(s) in which the metals are adequately soluble; and iii) isolate the peptide by filtration and / or drying. Still a further aspect relates to a method for cleaving bonds in a polypeptide A, where the bonds are: A) between the polypeptide and protecting groups; B) between the polypeptide and a linker coupled to a support; or C) between the polypeptide and the protecting groups, and between the polypeptide and the linker coupled to a support; and where the polypeptide comprises at least one protected sulfhydryl containing amino acid, such as Cys, HCys or Pen, and the polypeptide is coupled to a support by a linker, the method comprising: a) subjecting the polypeptide coupled to a support to / with a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, and optionally in the presence of a polypeptide B comprising at least one protected sulfhydryl containing amino acid thereby forming a solution or suspension; b) maintaining the solution or suspension at a temperature and duration thereby forming a partially or fully deprotected sulfur containing polypeptide not coupled to the support, the sulfur containing polypeptide selected from: i) a polypeptide homodimer comprising two residues of polypeptides A connected by at least one moiety comprising a disulfide group; ii) a cyclic residue of polypeptide A wherein the at least two amino comprising sulfhydryl groups are connected by a moiety comprising a disulfide group ; or iii) a polypeptide heterodimer comprising polypeptide A and polypeptide B connected by at least one moiety comprising a disulfide group. A further aspect relates to a method comprising providing an organic compound comprising protecting groups coupled to a support by a linker, the method comprising the steps: a) treating the organic compound coupled to the support with a composition comprising: I) at least one Lewis acid, and II) and at least one organic solvent, thereby cleaving at least some of the protecting groups, forming a partially deprotected polypeptide coupled to the support; b) removing the deprotected protecting groups from step a); and c) treating the partially deprotected polypeptide coupled to the support from step a) with a composition comprising: i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one organic solvent, thereby cleaving the rest of the protecting groups and cleaving the polypeptide from the support thereby forming a solution / suspension of a (fully) deprotected crude organic compound. According to one aspect the support is a soluble or solid support. According to one aspect the support is a solid support. According to an aspect, the organic compound is coupled to a support, preferably with a linker. According to an aspect the composition comprising a Lewis and a Brønsted acid is a composition in liquid form such as a solution or suspension. The composition comprising a Lewis and a Brønsted acid is preferably an aqueous composition. According to one aspect, the organic compound is a polypeptide. According to one aspect, the protecting groups are side chain protecting groups and N-terminal and C-terminal protecting groups of polypeptides. According to one aspect, the side chain protecting groups are acid-labile side chain groups and the linker is an acid labile linker. According to an aspect the organic compound is not a phthalocyanine derivative, such as tetrakis [(2-(1,3-Dioxolan-2-Yl)Phenoxy)-Phthalocyanine and Tetrakis [(2-(1,3- Dioxolan-2-Yl)Phenoxy)-Phthalocyaninato] Nickel(II). According to an aspect the water content during bond cleavage mediated by a Lewis acid and a Brønsted acid should be kept at a very low. Preferably, the water content during the method of cleaving bonds mediated by a Lewis acid and a Brønsted acid is below about 100 equiv, below about 95 equiv, below about 90 equiv, below about 85 equiv, below about 80 equiv, below about 70, below about 60, below about 50 equiv. In terms of ppm the water content is preferably below about 30000 ppm, below about 25000 ppm, below about 22000 ppm, below about 20000 ppm, below about 15000 ppm, below about 10000 ppm, below about 5000, below about 1000 ppm. According to an aspect, a compound comprising bonds between carbon atoms and halogen atoms, specifically compounds comprising bonds between carbon atoms and fluorine atoms, is not present during the procedure of cleaving bonds, i.e. cleaving protecting groups and cleaving an organic compound form a support. According to an aspect, the cleaved bonds (covalent bonds) are situated between the organic compound and protecting groups and between the organic compound and a support. By cleaving the bonds, protecting groups are cleaved and the organic compound is cleaved from the support. Hence, invention may also be framed as a method for cleaving protecting groups (at least one protecting group) from an organic compound and / or cleaving an organic compound coupled to a support from the support. Thus, the invention (and also aspects / embodiments presented herein) can be formulated as: A method for cleaving any one of: at least a protecting group from an organic compound and cleaving an organic compound coupled to a support from said support, the method comprising subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, where the cleavage is conducted with a water content of below about 100 equiv. (based on organic compound). The method is preferably applied to liquid phase organic synthesis and solid phase organic synthesis. The method of preferably applied to solid phase peptide synthesis. Definitions Protecting groups A protecting group is a compound / moiety covalently coupled to a reactive group such as amine / amide, guanidinium, imidazole, indole, phenol, hydroxyl, carboxylic acid, carboxylate, alcohol, thiol, sulfhydryl, amide / amino. According to an embodiment, the protection group is an acid labile protecting group. As the name suggests, an acid labile protecting group is cleaved / removed at acid / acidic conditions and / or in the presence of certain compounds under acid / acidic conditions. Exemplified protecting groups are: tert-butyl [t-butyl] (tBu), Trityl (Trt), 2,4 dimethoxybenzyl (Dmb), 2,2,4,6,7-Pentamethyl-2,3 dihydrobenzofuran-5-sulfonly (Pbf), 9-xanthenyl (Xan), benzyloxymethyl (Bom), tert-butyldimethylsilyl (TBDMS), p- methylbenzyl (Meb), Mpe, Acetamidomethyl (Acm), tert-butyloxycarbonyl (Boc), Mtr (methoxytrimethylbenzene sulfonyl), Pmc (2,2,5,7,8-pentamethyl-chroman-6-sulfonyl chloride), OtBu, Mtt, StBu, Alloc, Mbh (4,4-dimethyloxybenzhydryl), Tmob (2,4,6- trimethoxybenzyl), Mmt (4-methoxytrityl), Ompe (O-3-methyl-pent-3-yl), Dmcp (1- cyclopropyl-1-methylethyl) and STmp (2,4,6-trimethoxyphenylthio). Protecting groups are used in peptide synthesis, such as solid phase peptide synthesis, and liquid phase peptide synthesis, oligonucleotide synthesis, glycosylation reactions, asymmetric synthesis and synthesis of natural products. Amino acid side chain protecting groups A side chain protecting group is a protecting group protecting a reactive chemical moiety of an amino acid side chain. Reactive chemical moieties of amino acids include amines (e.g. Lys, Orn, Dab, Dap), amides (e.g. Asn, Gln) hydroxyl groups (e.g. Ser, Thr, Tyr), carboxylic acid groups (e.g. Asp, Glu), thiol (e.g. Cys, HCys, Pen), imidazole (His), indole (Trp), and guanidino group (Arg). The above exemplified protecting groups are advantageously used for protecting amino acid side chains and N- and C- terminals. Any acid labile protecting group disclosed in Chem. Rev.2009, 109, 2455 is herein incorporated by reference and may be cleaved by the method of the present invention. Support The support can be either a soluble or solid support. A soluble support can be used for the synthesis of organic precursor molecules (fragments) in liquid phase, by the stepwise coupling of organic moieties to a soluble support (tag or anchoring compound). A soluble support can be applied in liquid phase peptide synthesis for the synthesis of different polypeptide fragments which are eventually cleaved from the soluble support and coupled in liquid phase to provide the target polypeptide (tag-assisted liquid peptide synthesis). The support may also be a solid support for deployment in solid phase organic synthesis, such as solid phase peptide synthesis. According to an embodiment, the support is a solid support. According to an embodiment, the support is a polymeric support, such as a non- dissolvable, non-degradable, solid polymeric support. Solid support A solid support is a support used in solid phase organic synthesis such as solid phase peptide synthesis (SPPS). A solid support is preferably an insoluble (non-dissolvable) and / or non-degradable support in the solvent systems implemented during bond cleavage and preferably during the recurrent synthesis of subunits for forming the target organic compound (such as a polypeptide or oligonucleotide). Polystyrene (PS) is abundantly used as a solid support and typically has the function of the core matrix of a solid support. Usually, the PS is cross-linked with e.g. divinylbenzene (DVB). Other solid supports include supports comprising core matrices of polyacrylate, polyamides such as polyacrylamide (PEGA) and polyethylene glycol. Core matrices may be functionalized with polymers such as polyethylene glycol (PEG), e.g. polystyrene (PS) polyethylene glycol (PEG) based supports. The PS-PEG supports have a PS core matrix to which PEG is grafted (TentaGel®, NovaGel, AmphiSphere, OctaGel). Some supports have a core matrix (backbone) only comprising e.g. PEG (NovaPEG, ChemMatrix). Additional supports include poly-ε-lysine based supports such as poly- ε-lysine cross-linked with sebacic acid (SpheriTide) or polyacrylamide (Amino Li) based supports¨. Linker A linker is a chemical moiety positioned between the organic compound (e.g. amino acid, oligo peptide, polypeptide, peptide) and a solid support the linker configured to be cleavable under defined conditions thereby facilitating the cleavage of the organic compound from the support. According to an embodiment, the linker is an acid-labile linker liable to cleavage under acid / acidic conditions. The organic compound, such as a polypeptide, is usually coupled to the linker by the α-carboxyl or α-alcanol. The cleavage is typically initiated in the C-terminal carboxylic acid, C-terminal carboxamide or C-terminal primary alcohol. The polypeptide may also be coupled to the support via an amino acid side chain (including a linker). According to an embodiment, the linker is selected from acid labile linkers such as Wang ([4-(hydroxymethyl)phenoxymethyl]) linker, 2CT (2-chlorotrityl) linker, 2-CT- COOH (2-(chloro)-4’-carboxy-triphenyl methanol) linker, Trt (trityl) linker, Trt-COOH (trityl carboxyl) linker, Rink (amide) (4-(((9-fluorenylmethoxycarbonyl)amino) (2,4- dimethoxyphenyl)methyl)phenoxy)acetic acid) linker, Ramage (RMG) ((R,S)-2- { [5- (9- fluorenylmethyloxycarbonylamino)-dibenzo [a,d]cycloheptane-2-yl]oxy}-acetic acid) linker, Pal (5-[4-(9-fluorenylmethoxycarbonyl)aminomethyl-3,5-dimethoxyphenoxy]- pentanoic acid) linker, Sieber (9- (9-fluorenylmethyloxycarbonylamino)-9H-xanthen-3- yl-oxymethyl) linker, SASRIN (4-Hydroxymethyl-3-methoxyphenoxyacetic acid) linker, HMPA (hydroxymethylphenoxyacetic acid) linker, DHP (dihydropyranyl) linker, 4-MBH (4-methylbenzhydryl) linker or base / nucleophile labile linkers such as HMBA (hydroxymethylbenzoyl) linker, HZB (hydrazinobenzoyl) linker and MeDbz (o- amino(methyl)aniline) / MeNBz (acyl-N′-methylacylurea) linker Further linkers which can be applied for coupling organic compounds to a support are linkers for the formation of peptide alcohol, i.e. linkers converting the C-terminus of a polypeptide to comprise an alcohol. A suitable linker can be formed by reacting a Wang or PEG-HMP (polyethylene glycol hydroxymethylphenyl) functionalized core matrix, such as polystyrene, with trichloroacetonitrile (in DCM) to form a trichloroacetamide / trichloroacetimidate resin. Further linkers for formation of peptide alcohols are dihydropyran functionalized resins. Additional linker modified supports (resins) which can be used for coupling organic compounds to a support are: Fmoc-NH-N=Pyv-AMS resin, Fmoc-NH-NH-2CT resin, Fmoc-AA-ol-Rink amide PS resin, Fmoc-AA-ol-Ramage-PS resin, Fmoc-AA-ol-Sieber PS resin, Wang trichloro-acetimidate resin, Hemisuccinate AMS resin, and Fmoc-AA- ol 2CT resin ix) pipecolic PS resin. Linkers disclosed by the following documents: Ferrer-Gago et al, Chem. Eur. J.2020, 26, 379 – 383; Ferreo-Gago and Koh, ChemPlusChem 2020, 85, 641–652; Bird and Dawson, Peptide Science vol 114, issue 5, sept 2022; Chelushkin et al, Tetrahedron Letters 56 (2015) 619–622, are hereby all incorporated by reference. Also, acid labile, TFA-cleavable linkers presented in Albericio et al Chem. Rev.2009, 109, 2455 are also incorporated herein by reference. According to one embodiment, the linker is selected form Wang linker, Ramage linker, Rink (amide) linker, Pal linker, Sieber linker, trityl linker, CTC linker, 4-MBH linker and SASRIN. Lewis acid A Lewis acid is a chemical species containing an empty electron orbital capable of accepting an electron pair. According to an embodiment, the Lewis acid is in oxidation state +II and +III. According to an embodiment, the Lewis acid is in oxidation state +III. According to an embodiment, the Lewis acid is in oxidation state +III with the proviso that the Lewis acid does not contain fluorine atoms. According to an embodiment, the Lewis acid is in oxidation state +II and +III and selected from metal containing compounds. According to an embodiment, the Lewis acid in oxidation state +II and +III and selected from (metal) halides, (metal) acetates and (metal) acetylacetonates. According to an embodiment, the Lewis acid is in oxidation state +II and +III and selected from metal halides, metal acetates and metal acetylacetonate with the proviso that the Lewis acid does not contain fluorine atoms. According to an embodiment, the Lewis acid does not contain carbon-fluorine bonds, fluorine atoms or charged fluorine atoms. According to an embodiment, the metal / metalloid atom of a Lewis acid is selected from vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), boron (B), aluminium (Al). According to an embodiment, the metal atom of a Lewis acid is selected from iron (Fe), manganese (Mn), and aluminium (Al). According to an embodiment, the Lewis acid is in oxidation state +II and / or +III and selected from compounds of formula MXy, where y is 2 or 3; M is selected from V, Cr, Mn, Fe, Co, Ni, Cu, Zn, B, and Al; and X is selected from F, Cl, Br, I, acetate and acetylacetonate, preferably X is selected from Cl, Br, I, acetate and acetylacetonate. According to an embodiment, the Lewis acid is in oxidation state +III and selected from compounds of formula MX3, where M is selected from V, Cr, Mn, Fe, Co, Ni, Cu, Zn, B, and Al; and X is selected from F, Cl, Br, and I, preferably X is selected from Cl, Br, I, acetate and acetylacetonate According to an embodiment, the metal atom of a Lewis acid is selected from iron FeX3 (oxidation state +III) where X is selected from Cl, Br, and I. According to an embodiment, the Lewis acid is selected from the following compounds: a) Lewis acids in oxidation state +III selected from compounds of formula MX3, where M is selected from V, Cr, Mn, Fe, Co, Ni, Cu, Zn, B, and Al; and X is selected from Cl, Br and acetylacetonate; and / or b) Lewis acids in oxidation state +II selected from compounds of formula MX2 , where M is selected from V, Cr, Mn, Fe, Co, Ni, Co, Zn, B, and Al; and X is selected from acetate. According to an embodiment, the Lewis acid is selected from compounds of formula M(OAc)z where z is 2, and M is selected from V, Cr, Mn, Fe, Co, Ni, Cu, Zn, B, and Al. According to an embodiment, the Lewis acid is selected from iron (III) chloride (FeCl3), iron (III) fluoride (FeF3), iron (III) bromide (FeBr3), iron (III) iodide (FeI3), iron (II) acetate (Fe(OAc)2) and iron (III) acetylacetonate (Fe(acac)3). According to an embodiment, the Lewis acid is selected from iron (III) chloride (FeCl3), iron (III) fluoride (FeF3), iron (III) bromide (FeBr3), iron (III) iodide (FeI3), and iron (II) acetate (Fe(OAc)2). According to an embodiment the Lewis acid is selected from iron (III) (FeCl3) chloride, iron (II) acetate (Fe(OAc)2) and iron (III) acetylacetonate (Fe(acac)3). According to an embodiment the Lewis acid is selected from iron (III) (FeCl3) chloride, and iron (II) acetate (Fe(OAc)2). According to an embodiment, the Lewis acid is iron (II) acetate (Fe(OAc)2). According to an embodiment, the Lewis acid is FeCl3. Lewis acids also include any hydrated form of any of the Lewis acids disclosed herein such as hydrates of FeCl3 exemplified by FeCl32 H2O, FeCl32.5 H2O, FeCl33.5 H2O but not including FeCl36 H2O. Also contemplated in the composition for cleaving bonds are mixtures of two or more Lewis acids. Brønsted acid A Brønsted acid as used herein is a compound capable of donating protons, i.e. hydrogen ions. According to an embodiment, the Brønsted acid does not contain carbon-fluorine bonds, fluorine atoms or charged fluorine atoms. According to an embodiment the Brønsted acid as a pKa (water) of below about 7.0, 6.0, preferably below about 5.5, or 5,0. If the Brønsted acid has more than one acidic proton the pKa value relates to the most acidic proton. According to an embodiment, the Brønsted acid is selected from carboxylic acids, hydrogen halides of formula H-Z where Z is selected from Cl, Br and I, sulphonic acids, sulfuric acid, and phosphoric acid. According to an embodiment, the Brønsted acid is selected from formic acid; compounds with the formula X3C-COOH where X is selected from H, Cl, Br and I; hydrobromic acid (HBr); hydrochloric acid (HCl); sulfuric acid (H2SO4): phosphoric acid (H3PO4), methanesulfonic acid (MsOH); toluenesulfonic acid (TsOH); and Camphorsulfonic acid (CsOH). According to an embodiment, the Brønsted acid is selected from formic acid (FA), acetic acid (AcOH), trichloracetic acid (TCA), tribromoracetic acid (TBA), triiodoacetic acid (TIA), hydrobromic acid (HBr), hydrochloric acid (HCl), sulfuric acid (H2SO4), phosphoric acid (H3PO4), methanesulfonic acid (MsOH), toluenesulfonic acid (TsOH), Camphorsulfonic acid (CsOH). According to an embodiment, the Brønsted acid is selected from formic acid (FA), acetic acid (AcOH), trichloracetic acid (TCA), trichloracetic acid (TBA), triiodoacetic acid (TIA), methanesulfonic acid (MsOH), toluenesulfonic acid (TsOH), Camphorsulfonic acid (CsOH), hydrobromic acid (HBr), hydrochloric acid (HCl). According to an embodiment, the Brønsted acid is selected from FA, acetic acid (AcOH), trichloracetic acid (TCA), trbromoacetic acid (TBA), triiodoacetic acid (TIA), hydrobromic acid (HBr), and hydrochloric acid (HCl). According to an embodiment, the Brønsted acid is selected from acetic acid (AcOH), trichloracetic acid (TCA), tribromoracetic acid (TBA), triiodoacetic acid (TIA) and HCl According to an embodiment, the Brønsted acid is selected from acetic acid (AcOH), trichloracetic acid (TCA), tribromoracetic acid (TBA), and HCl According to an embodiment, the Brønsted acid is selected from acetic acid (AcOH) and hydrochloric acid (HCl). According to an embodiment, the Brønsted acid is hydrochloric acid (HCl). Also contemplated in the composition are mixtures of two or more Brønsted acids. The Lewis acid and Bronsted acid can be added in any order or be added as a composition to the organic compound coupled to a support. Scavenger A scavenger is a species / compound that has the ability to suppress reactions reducing the yield and / or purity of the final organic compound. Useful scavengers include silanes such as TES (triethylsilane), TIS (triisopropylsilane); aromatic compounds such as anisole, phenol, cresol, indole, 2-methylindole; thioethers such as dimethylsulfide, thioanisole; and thiols such as ethanedithiol, dithiothreitol, 3,6-dioxa-1,8-octanedithiol and 1,4-benzenedimethanethiol. Water in small amounts and typically below 5 vol% and functioning as a scavenger may be used if the water does not interfere with the cleavage of bonds mediated by a Lewis acid and a Brønsted acid. Water may be added after the Lewis acid and a Brønsted acid mediated bond cleavage. Organic compound The term organic compound embraces any organic compound, preferably organic compounds chemically assembled by the recurrent coupling of subunits. Such subunits can be amino acids, such as natural and synthetic or otherwise modified amino acids, nucleotides, or any other subunits for assembling the target organic compound. Thus, organic compounds cover peptides, polypeptides, proteins, oligonucleotides, peptidomietics and any other organic compound comprising protecting groups cleavable by the composition of the present invention. A polypeptide as defined herein comprises at least two amino acids up to at least 500 amino acids or more. The term polypeptide also embraces short proteins. Examples of short proteins are glutathione, LIL proteins, Trp-cage, and insulin. The organic compound preferably comprises protecting groups. Equivalent Equivalent or equiv. relates to the organic compound. Short description of figures Figure 1: LC-MS chromatogram for Aib-ACP obtained from Table 22, entry 1 cleavage of Aib-ACP RMG AMS resin (full view). Figure 2: LC-MS chromatogram for for Aib-ACP obtained from Table 22, entry 1 cleavage of Aib-ACP RMG AMS resin (zoom-in). Figure 3: Mass spectrum [M+H]+ of the main peak in the Aib-ACP obtained from Table 22, entry 1 cleavage of Aib-ACP RMG AMS resin, calcd, 1090.59; found, 1090.50. Figure 4: LC-MS chromatogram for Aib-ACP obtained from Table 22, entry 29 cleavage of Aib-ACP RMG AMS resin (full view). Figure 5: LC-MS chromatogram for for Aib-ACP obtained from Table 22, entry 29 cleavage of Aib-ACP RMG AMS resin (zoom-in). Figure 6: LC-MS chromatogram for Aib-ACP obtained from Table 22, entry 30 cleavage of Aib-ACP RMG AMS resin (full view). Figure 7: LC-MS chromatogram for Aib-ACP obtained from Table 22, entry 30 cleavage of Aib-ACP RMG AMS resin (zoom-in). Figure 8: Mass spectrum ^M+H^+of the main peak in the Aib-ACP obtained from Table 22, entry 30 cleavage of Aib-ACP RMG AMS resin, calcd, 1090.59; found, 1090.59. Figure 9: LC-MS chromatogram for degarelix obtained from Table 23, entry 1 cleavage of degarelix-RAM AMS resin (full view). Figure 10: LC-MS chromatogram for degarelix obtained from Table 23, entry 1 cleavage of degarelix-RAM AMS resin (zoom-in). Figure 11: Mass spectrum [M+H]+ of the main peak in the degarelix obtained from Table 23, entry 1 cleavage of degarelix-RAM AMS resin, calcd (z=+2), 816.38; found, 816.18. Figure 12: LC-MS chromatogram for degarelix obtained from Table 23, entry 2 cleavage of degarelix-RAM AMS resin (full view). Figure 13: LC-MS chromatogram for degarelix obtained from Table 23, entry 2 cleavage of degarelix-RAM AMS resin (zoom-in). Figure 14: Mass spectrum [M+H]+ of the main peak in the degarelix obtained from Table 23, entry 2 cleavage of degarelix-RAM AMS resin, calcd (z=+2), 816.38; found 815.94. Figure 15: LC-MS overlay of degarelix crudes from TFA and FeCl3 and HCl cleavages from example 24. Figure 16: LC-MS overlay of degarelix crudes from TFA and FeCl3 and HCl cleavages from example 24 (zoom-in). Figure 17: LC-MS chromatogram for (Fmoc-Cys-OH)2 obtained from Scheme SX1 cleavage of Fmoc-Cys(Trt)-Wang resin after 0.5 h (full view). Figure 18: LC-MS chromatogram for (Fmoc-Cys-OH)2 obtained from Scheme SX1 cleavage of Fmoc-Cys(Trt)-Wang resin after 0.5 h (zoom-in). Figure 19: HPLC overlay of fractions from desalting of crude Aib-ACP from TFA cleavage of Aib-ACP peptide resin. From bottom to top: i) fraction 1, (load); ii) fraction 2, 0.1% AcOH in 10% MeCN; iii) fraction 3, 0.1% AcOH in 20% MeCN (isolated); iv) fraction 4, 0.1% AcOH in 30% MeCN. Figure 20: HPLC overlay of fractions from desalting of crude Aib-ACP from FeCl3 / HCl cleavage of Aib-ACP peptide resin. From bottom to top: i) fraction 1, (load); ii) fraction 2, 0.1% AcOH in 10% MeCN; iii) fraction 3, 0.1% AcOH in 20% MeCN (isolated); iv) fraction 4, 0.1% AcOH in 30% MeCN. Figure 21: Overlay of HPLC-MS chromatograms of desalted and lyophilized Aib-ACP (2 mg mL-1 in AcOH / MeCN / H2O (10:40:50)) from a TFA cleavage of Aib-ACP peptide resin (lower) and from a FeCl3 / HCl cleavage of Aib-ACP peptide resin (upper), full view. Figure 22: Overlay of HPLC-MS chromatograms of desalted and lyophilized Aib-ACP (2 mg mL-1 in AcOH / MeCN / H2O (10:40:50) from a TFA cleavage of Aib-ACP peptide resin (graph having lower major peak between 10,25 and 10,50) and from a FeCl3 / HCl cleavage of Aib-ACP peptide resin (graph having upper major peak between 10,25 and 10,50), zoom-in. Figure 23: Mass spectrum [M+H]+ of the main peak in the desalted Aib-ACP from TFA cleavage of Aib-ACP peptide resin (Figure 15), calcd.1090.59; found 1090.66. Figure 24: Mass spectrum [M+H]+ of the main peak in the desalted Aib-ACP from FeCl3 / HCl cleavage of Aib-ACP peptide resin (Figure 15), calcd. 1090.59; found 1090.68. Figure 25: Schematic representation of an oxidative BA – LA cleavage of a sulfhydryl containing organic molecule exemplified by a sulfhydryl containing peptide. Examples of different modes of sulfhydryl functionalization occurring concurrently with the cleavage: a) formation of a peptide homodimer; b) formation of a cyclic peptide; c) formation of a peptide heterodimer. Figures 26 to 33 illustrate chromatograms from examples 26 to 29. In examples 26-29 the implication of the presence of water during bond cleavage is analyzed. The chromatograms of figures 26 to 33 illustrate the analysis of the solution obtained after global deprotection and cleavage of Boc-Val-Gln(Trt)-Aib-Aib-Ile-Asp(Ot-Bu)-Tyr(t- Bu)-Ile-Asn(Trt)-Gly – RMG resin under the conditions set out in tables 28 to 31. Figures 26 and 27 illustrate the chromatograms obtained from the cleavage solutions obtained under the conditions of entries 1 to 5 of table 29. Figure 27 illustrates the chromatograms of figure 26 in higher resolution within the time frame of from about 6 to about 14 minutes. Figures 28 and 29 illustrate the chromatograms obtained from the cleavage solutions obtained under the conditions of entries 1 to 6 of table 30. Figure 29 illustrates the chromatograms of figure 28 in higher resolution within the time frame of from about 6 to about 14 minutes. Figures 30 and 31 illustrate the chromatograms obtained from the cleavage solutions obtained under the conditions of entries 1 to 11 of table 31. Figure 31 illustrates the chromatograms of figure 30 in higher resolution within the time frame of from about 6 to about 14 minutes. Figures 32 and 33 illustrate the chromatograms obtained from the cleavage solutions obtained under the conditions of entries 1 to 10 of table 32. Figure 33 illustrates the chromatograms of figure 32 in higher resolution within the time frame of from about 8 to about 13 minutes. Further disclosure of the invention The application of protecting groups is an important concept in organic synthesis whereby selected functional groups are temporarily blocked. In synthesis protocols comprising the recurrent coupling of moieties (sub-units), such as natural, synthetic and modified natural amino acids, it is often important to protect functional groups which are prone to react under the reaction condition during coupling of the moieties. Protecting groups are applied both in liquid phase organic synthesis and solid phase organic synthesis. In liquid and solid phase organic synthesis comprising the recurrent coupling of equivalent molecules (moieties), such as amino acids, it is often important to protect certain functional groups of the molecules to ensure the formation of the target organic compound. Also, once an organic compound comprising all desired sub-units is formed the organic compound typically needs to be cleaved from the support. Furthermore, the protecting groups of the organic compound must also be cleaved. In many instances, and for efficiency, it is preferred to implement a procedure simultaneously cleaving the protecting groups and cleaving the organic compound from the support thereby forming a crude target organic compound in solution or suspension. In accordance with the invention, it has been found that a composition comprising at least one Lewis acid, at least one Brønsted acid, and optionally at least one suitable solvent is capable of cleaving protecting groups of organic compounds and cleaving the organic compound from a support. The composition is capable of cleaving protecting groups from organic compounds in solution not coupled to a support. Should the organic compound comprising protecting groups be coupled to a support with a linker the composition is capable of cleaving both the protecting groups and cleaving the linker, thereby cleaving off the organic compound from the support and providing a deprotected organic compound in solution / suspension, i.e. global deprotection. Thus, the composition of the invention is capable of cleaving bonds in(of) an organic compound, such as an organic compound coupled to a support, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups, and between the organic compound and the linker coupled to a support. The term “cleaving a bond between” should be understood to be equivalent to cleaving any protecting group from an organic compound and cleaving an organic compound from a support should the organic compound be coupled to a support. “Cleaving a bond” may impart any chemical activities such as transformations / reactions eventually leading to the cleavage of a protecting group form an organic compound and cleavage of an organic compound from a support. “Cleaving a bond” may impart the cleavage of any number of bonds necessary for cleaving protecting groups and cleaving the organic compound from a support. Should the organic compound be coupled to a support a linker is preferably positioned between the organic compound and the support for facilitating the cleavage of the organic compound form the support. The cleavage of bonds between an organic compound and a linker coupled to a support imparts chemical activities such as transformations / reactions eventually leading to an organic compound cleaved form the support. It has been shown that the composition of the invention can successfully cleave a variety of amino acid side chain protecting groups and C-terminal and / or N-terminal protecting groups of a polypeptide and linkers coupling a polypeptide to a support such as a support for solid and liquid phase synthesis, a soluble or non-soluble support. The application of at least a Lewis and at least a Brønsted acid can be implemented in a liquid phase peptide synthesis scheme (LPPS) or solid phase peptide synthesis (SPPS) scheme. In a liquid phase peptide synthesis scheme the organic compound is usually coupled via a linker to a soluble support. Such soluble support may be referred to as a tag (or anchor). By the implementation of suitable amino acid protecting strategies peptide fragments can be synthesized on the soluble support (tag) and the tag-coupled peptide fragment can be subjected to the composition of the present invention, thereby forming peptide fragments which in subsequent steps can be coupled to generate a target polypeptide. The composition of the present invention is further preferably implemented in solid phase peptide synthesis (SPPS) schemes and particularly after the target polypeptide is formed but still coupled to a solid support with some or all the side chain protecting groups and N-terminal and C-terminal protecting group present. The invention is applicable to a variety of SPPS strategies including Fmoc SPPS and ISPPS (Inverse peptide synthesis) where the peptides are assembled in the N to C direction (Liu et al, 2024). Examples of protecting groups which may be cleaved by the present invention: In general, all protecting groups cleavable with TFA are also cleavable with the composition of the invention. Amino acids with side chain amine (Lys): Boc, Mtt (4-methyltrityl), Mmt (4- methoxytrityl) Amino acids with side chain comprising carboxylic acid (Asp, Glu): tBu, Trt, Dmb, PhiPr (phenylisopropyl), OtBu Amino acids with side chain comprising guanidinium (Arg, Harg): Pbf, Mtr, Pmc, Mis, Boc2 Amino acids with side chain comprising amide (Asn, Gln): Xan (9-Xanthenyl), Trt, Mtt, Mbh, Tmob Amino acids with side chain comprising imidazole (His): Trt, Boc, Mtt, Mmt, 2-CT Amino acids with side chain indole (Trp): For (formyl), Boc, Trt, Mmt Amino acids with hydroxyl side chain (Ser, Thr, Tyr, hydroxyproline): TBDMS (tert- butyldimethylsilyl), Trt, tBu, and corresponding pseudoproline (4-carboxyoxazolidines) Amino acids with thiol side chain (Cys, HCys, Pen): Meb (p-methylbenzyl), (acetamidomethyl), Trt, Thp, Mmt, tBu, StBu, and corresponding pseudoproline (thiazolidine) Composition Certain combinations of Lewis acids and Brønsted acids are capable of cleaving protecting groups from an organic compound and / or cleaving an organic compound from a support without a further solvent. In certain embodiments, the Brønsted acid as well as the Lewis acid can also serve as a solvent. In certain embodiments, the presence of an organic solvent (in addition to the Brønsted acid and Lewis acid) is beneficial. The composition is typically provided in liquid form such as a solution or suspension. The compounds of the composition such as Lewis acid, a Brønsted acid, and optional solvent and any other compound class such as scavengers also encompasses two or more Lewis acids, Brønsted acids, optional solvents and compounds of other compounds classes (e.g. scavengers) respectively. The compounds of the composition may be added separately in any order or in the form of a pre-formed solution or suspension to the organic compound or support to which the organic compound is bound. According to an embodiment, either the Lewis acid or the Brønsted acid may be added to one step without being removed, and subsequently either the Lewis acid or the Brønsted acid, is then added. Thus, the combination of Lewis acid and the Brønsted acid is achieved following the step where either a Lewis acid or a Brønsted acid is added. When the Lewis acid, Brønsted acid and optional organic solvent are added to the organic compound or support a solution or suspension is formed. According to an embodiment, the solution or suspension comprising an organic compound has a content of water of below about 100 equiv, below about 95 equiv, below about 90 equiv, below about 85 equiv, below about 80 equiv, below about 70, below about 60, below about 50 equiv. In terms of ppm the water content is preferably below about 30000 ppm, below about 25000 ppm, below about 22000 ppm, below about 20000 ppm, below about 15000 ppm, below about 10000 ppm, below about 5000, below about 1000 ppm. According to an embodiment, the solution or suspension or general reaction conditions during bond cleavage is essentially free from water. Essentially free means that the solution or suspension (or media) where bonds are cleaved has a water content less than about 100 equiv. or less than about 85 equiv. According to an embodiment, the composition comprising the organic compound, preferably coupled to a support, and a Lewis acid and a Brønsted acid is essentially free from fluorine atoms or compounds comprising fluorine atoms including PFAS (Per- and polyfluoroalkyl substances). By essentially free in the context of fluorine atoms / compounds comprising fluorine atoms is understood a level which is under any national and international threshold. The Lewis acid is typically present in the solution or suspension in an amount of from about 0,001; 0,01; 0,1; 0,5; 1 equiv, based on organic compound. The upper amount of Lewis acid depends on the circumstances and may range up to about 100 equiv. The Lewis acid may be added in an amount of from 1 up to about 100 equiv, from about 1 up to about 50 equiv. The lower end point can be about 0,001; 0,01; 0,1; 1, 2, 3, 4 or 5 eq. The upper end point can be about 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 50 eq. Suitable ranges can be formed by combining any of the lower end points with any of the upper end points. The Brønsted acid may be present in an amount of from 0,001; 0,01; 0,1; 0,5; 1 up to about 1000 equiv (based on organic compound), such as from about 20 up to about 700 equiv, preferably from about 50 up to about 500 equiv. The lower end point can be about 0,001, 0,01, 0,1, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 eq. The upper end point can be about 100, 150, 200, 250, 300, 350, 400, 450 or 500 eq. Suitable ranges can be formed by combining any of the lower end points with any of the upper end points. The Lewis acid and Brønsted acid may also be present in catalytic amounts. According to an embodiment the Brønsted acid is present in a higher amount than the Lewis acid such from about 1:2 up to about 1:100 (based on equiv). The Lewis acid and the Brønsted acid may be present in approximately equimolar amounts (+-50 mol%). An optional scavenger may be present in the composition from about 0,1, 1, 2 or 3 % (w / v) up to about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 % (w / v). Thiol scavengers, and more specifically dithiol scavengers may vary in amounts of from 2 to 20% (w / v), preferably from 5 to 10 % (w / v). Specifically, for deprotection of oxidation prone AA(PG) side chains such as Trp(Boc), Cys(Trt / Mmt) and His(Trt), use of dithiol scavengers such as DTT is particularly advantageous for attaining target products in suitable yield and purity. The amount of scavenger is the total amount of scavengers. Some preferred compositions: A composition comprising a Lewis acid selected from FeCl3; a Brønsted acid selected from AcOH and HCl; and a solvent selected from DMC and MeCN preferably DMC. Solvent The solvent is preferably an organic solvent such as a water miscible organic solvent. According to an embodiment, the solvent is an aprotic organic solvent. According to an embodiment, the solvent is an aprotic organic solvent not containing any one of the following chemical functions: amide function, thionyl group, and carbon- fluorine bonds. An aprotic solvent is a solvent not containing acidic protons and lacking hydroxyl and amine groups. According to an embodiment, the solvent does not contain fluorine atoms. According to an embodiment, the solvent does not contain carbon-fluorine bonds. Dimethylformamide (DMF) is a representative solvent having an amide function. Dimethyl sulfoxide (DMSO) is a representative solvent with a thionyl group. HFIP (hexafluoro-2-propanol) is a representative solvent containing carbon-fluorine bonds. According to an embodiment, the organic solvent is selected from acetonitrile (MeCN), dichloromethane (DCM), alkyl acetates such as ethyl acetate (EtOAc), dioxane, 1,3 dioxolane (DOL), tetrahydrofuran (THF), tetrahydropyran (THP), 2- methyltetrahydrofuran (2-MeTHF), 4-methyltetrahydropyran (4-MeTHP), toluene (Tol), anisole (Ani), 1,2-dimethoxybenzene (1,2-DMB), 1,3-dimethoxybenzene (1,3-DMB), n- hexane (Hex), n-heptane (Hep), petroleum ether (PE), cyclopentylmethyl ether (CPME), tert-Butylmethylether (TBME), dipropyleneglycol, dimethylether (DMM), dimethyl carbonate (DMC), diethyl carbonate (DEC), propylene carbonate (PC), dimethyl isosorbide (DMI), gammavalerolactone (GVL). According to an embodiment, the organic solvent is selected from acetonitrile (MeCN), dichloromethane (DCM), ethyl acetate (EtOAc), dioxane, 1,3 dioxolane (DOL), tetrahydrofuran (THF), tetrahydropyran (THP), 2-methyltetrahydrofuran (2-MeTHF), 4- methyltetrahydropyran (4-MeTHP), toluene (Tol), anisole (Ani), 1,2-dimethoxybenzene (1,2-DMB), 1,3-dimethoxybenzene (1,3-DMB), n-hexane (Hex), n-heptane (Hep), petroleum ether (PE), cyclopentylmethyl ether (CPME), tert-Butylmethylether (TBME), dipropyleneglycol dimethylether (DMM), dimethyl carbonate (DMC), diethyl carbonate (DEC), dimethyl isosorbide (DMI), and gammavalerolactone (GVL). According to an embodiment, the solvent is selected from acetonitrile (MeCN), dichloromethane (DCM), ethyl acetate (EtOAc), dioxane, tetrahydrofuran (THF), tetrahydropyran (THP), 2-methyltetrahydrofuran (2-MeTHF), 4-methyltetrahydropyran (4-MeTHP), dimethyl carbonate (DMC), 1,3 dioxolane (DOL), and toluene. According to an embodiment the solvent is DMC. Protic organic solvents should be avoided as well as water during the cleavage of bonds using a Lewis acid and a Brønsted acid. Water in any form such as free water or water coordinated to e.g. Lewis acids should be kept at a very low level. Preferably, the water content during the method of cleaving bonds mediated by a Lewis acid and a Brønsted acid is below about 100 equiv, below about 95 equiv, below about 90 equiv, below abour 85 equiv, below about 80 equiv, below about 70, below about 60, below about 50 equiv. In terms of ppm the water content is preferably below about 30000 ppm, below about 25000 ppm, below about 22000 ppm, below about 20000 ppm, below about 15000 ppm, below about 10000 ppm, below about 5000, below about 1000 ppm. According to an embodiment, the solvent is capable of dissolving the Lewis acid or the adduct(s) formed from Lewis acid(s) and Brønsted acid(s). Some preferred reaction conditions for bond cleavage: The application of FeCl3 and a Brønsted acid selected from AcOH and / or HCl; and DMC as solvent. The temperature during bond cleavage may, range of from about rt (room temperature) up to about 70°C. In many instances the conversion and chemo selectivity tend to increase when the temperature during the presence of the composition is increased. According to an embodiment the temperature is at least about 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 42°C, 44°C, 45°C. According to an embodiment the temperature is not above about 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C. A range of temperature can be may by combining any of the lower temperatures from 30°C to 45°C with any of the higher temperatures from 50°C to 65°C. The duration of the presence of the composition (duration of bond cleavage) may be from about 10, 15, 20, 25, 30, 35, 40, 45, 50 minutes up to several hours such as up to about 1, 2, 3, 4, 5 hours. Depending on the Lewis acid / Brønsted acid system the duration of bond cleavage may vary. Preferably, the duration of the bond cleavage (the method of cleaving bonds) is less than about 3 hours, less than 1,5 hours, less than 1 hour, less than about 45 minutes. A further aspect relates to a method comprising providing a peptide fragment comprising protecting groups (protected peptide fragment) coupled to a support by a linker, the method comprising the steps: a) subjecting the peptide fragment coupled to the support with a composition comprising: I) at least a Lewis acid, and II) at least a solvent, and optionally III) at least a scavenger; thereby cleaving the peptide fragment from the support without cleaving any protecting groups forming a protected peptide fragment in a solution or suspension; b) optionally removing (such as by filtration) the Lewis acid from the solution or suspension comprising the peptide fragment forming a solution or suspension depleted in Lewis acid; c) adding suitable coupling agents to the solution or suspension from step a) or optionally to the solution or suspension depleted in Lewis acid from step b) comprising the protected peptide fragment thereby coupling two protected peptide fragments forming a protected polypeptide in the solution or suspension; and d) adding at least a Brønsted acid and optionally a Lewis acid to the solution or suspension from step c) comprising the protected polypeptide thereby forming a partially or fully deprotected polypeptide in the solution or suspension. In this aspect comprising the selective cleavage of a peptide fragment from a solid while keeping all protecting groups by the application of a composition of a Lewis acid and a solvent, the linker is suitably quite sensitive to cleavage by a Lewis acid. Preferably, the linker is highly acid-labile (acid sensitive) readily cleaved by a composition of a Lewis acid and a solvent, such as 2-CT and Sieber linkers. After cleaving the peptide fragment from the support two or more peptide fragments are coupled by the formation of an amide bond by the addition of suitable coupling agent to the solution or suspension. In one embodiment the Lewis acid is not removed after step a) and is consequently still present during step b). In one embodiment the Lewis acid is removed in step b). In this case, after coupling of the peptide fragments, a Brønsted acid and a Lewis acid, and an optional solvent, is added to total deprotection. The steps described in a) and c) can be repeated, thereby increasing the length of protected polypeptide. Finally, the fully assembled polypeptide obtained by a series of a) and c) cleavage and peptide coupling process steps respectively is deprotected by the addition of a Brønsted acid or the addition of both a Brønsted acid and a Lewis acid in d). The completion of the peptide coupling in step c) is preferably controlled by suitable analytical methods (Kaiser test, etc.). Suitable coupling agents can be selected from diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), tert-butylethylcarbodiimide (TBEC), 1-Ethyl-3-(3- dimethylaminopropyl)carbodiimidaliphatic e (EDCxHCl) (optionally in the presence of coupling additives such as 1-Hydroxybenzotriazole (HOBt), 6-Chloro-1- hydroxybenzotriazole (Cl-HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt), 2- Hydroxypyridine-N-oxide (HOPO), ethyl cyanohydroxyiminoacetate (Oxyma), Oxyma- B, N-Hydroxysuccinimide (HOSu), N-Hydroxy-5-norbornene-2,3-dicarboxylic acid imide (HONB), Hexafluorophosphate benzotriazole tetramethyl uronium (HBTU), O- (Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate [O-[ N,N,N′,N′- Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate ] (TBTU), O- [(Ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HOTU), O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N′- tetramethyluronium tetrafluoroborate (TOTU), O-(1H-6-chlorobenzotriazole-1-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), O-(6-Chlorobenzotriazol-1- yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TCTU), 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), O-(7-Azabenzotriazole-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), 1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino- carbenium hexafluorophosphate (COMU), 1- [(Dimethylamino)(morpholino)methylene]-1H-[1,2,3]triazolo[4,5-b]pyridine-1-ium 3- oxide hexafluorophosphate (HDMA), HDMB, 6-chloro-1- ((dimethylamino)(morpholino)-methylene)-1H-benzotriazolium (HDMC), Benzotriazol- 1-yloxytris(dimethylamino)phosphonium hexafluorophosphateC (BOP), (Benzotriazol- 1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), [Ethyl cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphosphonium hexafluorophosphate (PyOxim), 6-Chloro-benzotriazole-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyClock), N,N,N′,N′-Tetramethylchloroformamidinium Hexafluorophosphate (TCFH), N-(chloro(morpholino)methylene)-N- methylmethanaminium hexafluorophosphate (DMCH), Chlorotripyrrolidinophosphonium hexafluorophosphate (Pyclop), tetramethylfluoroformamidinium hexafluorophosphate (TFFH), tetramethylammonium trifluoromethanethiolate ((Me4N)SCF3), 2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 2,4-Dichloro-6-methoxy-1,3,5-triazine (DCMT), 4-(4,6-Dimethoxy-1,3,5- triazin-2-yl)-4-methylmorpholinium chloride (DMTMMCl), 4-(4,6-Dimethoxy-1,3,5- triazin-2-yl)-4-methylmorpholinium tetrafluoroborate (DMTMMBF4) and 2-(4,6- dimethoxy-1,3,5-triazinyl)trialkylammonium salts (DMT-Ams). In step c) a Brønsted acid is added to the solution or suspension, and optionally a solvent and / or a scavenger. The addition of a Brønsted acid forms a composition of a Lewis acid and a Brønsted acid capable of fully deprotecting the polypeptide thereby generating a crude polypeptide for further work-up A still further aspect relates to a method comprising providing a polypeptide comprising protecting groups coupled to a support by an acid stable linker such as a base-labile linker, the method comprising the steps: a) subjecting the polypeptide coupled to the support with a composition comprising: I) at least a Lewis acid, at least a Brønsted acid; and optionally III) at least a solvent, forming a solution or suspension; b) maintaining the solution or suspension at a temperature and duration thereby cleaving all protecting groups forming a solution or suspension comprising a fully deprotected polypeptide coupled to the support; and c) cleaving the fully deprotected polypeptide from the support by the addition of a base or nucleophile to the solution or suspension comprising a fully deprotected polypeptide coupled to the support, thereby forming a solution or suspension comprising a fully deprotected polypeptide not couped to the support. Acid stable (base-labile linkers) linkers include HMBA (hydroxymethylbenzoyl) linker, HZB (hydrazinobenzoyl) linker and MeDbz (o-amino(methyl)aniline) / MeNBz (acyl-N′- methylacylurea) linker’’ A further aspect of the invention relates to a method for generating polypeptides comprising at least a disulfide group, said disulfide group linking two peptide subunits together, the peptide subunits being identical or different, or, said disulfide group linking two amino acids comprising each a sulfhydryl group present on the same polypeptide. For every pair of sulfhydryl group a further disulfide group can be formed either on the same polypeptide or between identical or different peptide subunits. These polypeptides are generated ‘in situ’ when cleaving and deprotecting a polypeptide comprising at least one sulfhydryl group from a support with a composition comprising at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent. The polypeptide coupled to a support with a linker typically comprises protecting groups blocking e.g. reactive groups of amino acid side chains including at least one sulfhydryl group. The application of a composition comprising at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, deprotects the polypeptide while also cleaving the polypeptide from the support, and concomitantly also facilitates the formation of a disulfide group from any pair of sulfhydryl groups, present on the same polypeptide or present on each of identical or two different polypeptides. The coupling of two different polypeptides by a disulfide group can be accomplished by the provision of a polypeptide A comprising at least one protected sulfhydryl containing amino acid coupled via a linker to a support, subjecting the polypeptide A coupled to a support to / with a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, in the presence of a polypeptide B comprising at least one protected sulfhydryl containing amino acid, thereby cleaving polypeptide A from the support and further deprotecting polypeptide A and polypeptide B thereby forming a polypeptide C1 comprising polypeptide A and polypeptide B, said polypeptides A and B linked by a disulfide group and / or a polypeptide C2 comprising two polypeptides A said polypeptides A linked by a disulfide group and / or a polypeptide C3 comprising two polypeptides B said polypeptides B linked by a disulfide group. Thus, a further aspect related to a method comprising providing an organic compound A comprising at least one amino acid, said amino acid comprising a sulfhydryl moiety such as Cys, HCys or Pen, said organic compound A being coupled via a linker to a support, the method comprising: a) subjecting the organic compound coupled to a support to / with a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, and optionally in the presence of an organic compound B comprising at least one amino acid, said amino acid comprising a sulfhydryl moiety thereby forming a solution or suspension; b) maintaining the solution or suspension at a temperature and duration thereby forming a deprotected organic compound A and optionally deprotected organic compound B and forming an organic compound comprising at least one disulfide group selected from: i) an organic compound C1 formed from organic compound A and comprising a bridge comprising a disulfide group said bridge connecting the two amino acids which previously had sulfhydryl moieties; and / or ii) an organic compound C2 comprising organic compound A and organic compound B, said organic molecules A and B linked by at least a moiety comprising a disulfide group; and / or iii) an organic compound C3 comprising two organic compounds A said organic compounds A linked by at least a moiety comprising a disulfide group; and / or iv) an organic compound C4 comprising two organic molecules B said organic molecules B linked by at least one moiety comprising a disulfide group. According to an embodiment, the organic compound cleaved from the solid support, a crude organic compound, is isolated by precipitation with a suitable ether solvent such as diethyl ether, MTBE, diisopropylether, 2-MeTHF, 4-MTHP, CPME, n-hep, n-hex, and PE. Preferably, volatile compounds are evaporated prior to isolation of the crude organic compounds. The crude organic compound may also be isolated, preferably without the application of ethereal organic compounds, by adding an aqueous solution containing a suitable salt which adjusts the pH. An adjustment of the pH appreciably increases the stability of the target organic compound. A suitable salt contained in the aqueous solution can be e.g. ammonium acetate, ammonium carbonate or ammonium phosphate of suitable concentrations. Thus, one aspect relates to a method comprising providing an organic compound comprising protecting groups, the organic compound coupled to a solid support by a linker, the method comprising: a) subjecting / mixing / treating the organic compound to / with a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a suspension; b) maintaining the suspension at a temperature and duration thereby forming a partially or fully deprotected crude organic compound; and further adding an aqueous solution containing a suitable salt there by adjusting the pH of the suspension. According to an embodiment, the crude organic compound obtained following cleavage from the solid support is dissolved in an aqueous solution, the solution preferably comprising a cosolvent selected from MeCN, EtOH and iPrOH (isopropanol) and mixtures thereof. According to an embodiment, process related impurities from a solution comprising the crude organic compound after cleavage are separated by preparatory liquid chromatography. Process related impurities include acid related species. Useful preparatory liquid chromatography includes affinity chromatography, chromatographic separation based on hydrophobicity such as RPLC (reverse phase liquid chromatography), and chromatographic separation based on charge such as ion exchange chromatography (IEX). A further aspect relates to a method for the synthesis of a polypeptide comprising providing a solid support comprising a linker, consecutively coupling Fmoc ^-amine protected amino acids optionally comprising an acid labile side chain protecting group, thereby forming a polypeptide coupled to the solid support comprising side chain protecting groups; wherein the method further comprises a cleavage step comprising subjecting / mixing the solid support comprising the polypeptide with a cleavage composition comprising: i) a Lewis acid, ii) a Brønsted acid, and optionally iii) an organic solvent. An Fmoc ^-amine protected amino acids is added to the peptide chain during each coupling cycle. The Fmoc protecting group is readily cleavable by application of an amine such as piperidine under basic conditions enabling the use of acid labile side chain protecting groups. If the ^-amine of the last amino acid is protected with an acid labile protecting groups, such as Boc, the acid labile ^-amine protecting group may be cleaved when the polypeptide is cleaved off the solid support thereby dispensing an extra cleavage step. During the cleavage step preferably all protecting groups of the organic compound, such as polypeptide, are cleaved as well as the linker providing a fully deprotected crude organic compound, e.g. a polypeptide. The Lewis acid is preferably a metal containing compound (or a mixture of one or more Lewis acids), such as ferric chloride (FeCl3). When using a Lewis acid (and a Brønsted acid) for cleavage of protecting groups of organic compounds and / or cleaving the organic compound from a support residual metals will be present in the solution of the comprising the target organic compound. Thus, it is beneficial to remove the residual metals from the solution of the target organic compound. Residual metal(s) are preferably removed or reduced from the solution comprising the target organic compound by either one of a) comprising i) trapping / capturing the peptide on a polymer support ii) eluting any metal constituents iii) eluting the peptide; or b) comprising i) trapping / capturing any metal constituents on a suitable polymer support ii) eluting the target organic compound or c) separating the metals trapped on the support from peptides by the means of filtration. Alternatively, the residual metals, typically stemming from the Lewis acid(s) used in the cleavage can be advantageously removed after cleavage by a method comprising: i), filter off the spent resin and any insolubles and remove the volatiles in vacuo; ii) precipitate the residual material in suitable (anti)solvent(s) in which the metals are adequately soluble; and iii) isolate the peptide by filtration and / or drying. Thus, one aspect relates to a method for the removal or reduction of residual metals, the method comprising providing an organic compound comprising protecting groups, the organic compound coupled to a support by a linker, the method comprising: a) subjecting / mixing / treating the organic compound to / with a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension; b) maintaining the solution or suspension at a temperature and duration thereby forming a solution or suspension of partially and / or fully deprotected crude organic compound comprising residual metals; the method further comprising either one of: a) i) trapping / capturing the peptide on a polymer support; ii) eluting any metal constituents iii) eluting the peptide; or b) comprising i) trapping / capturing any metal constituents on a suitable polymer support ii) eluting the target organic compound; or c) separating the metals trapped on the support from peptides by the means of filtration. A further aspect relates to a method for the removal or reduction of residual metals, the method comprising providing an organic compound comprising protecting groups, the organic compound coupled to a solid support by a linker, the method comprising: a) subjecting / mixing / treating the organic compound to / with a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension; b) maintaining the solution or suspension at a temperature and duration thereby forming a solution or suspension of partially or fully deprotected crude organic compound comprising residual metals; the method further comprising: i), filter off the spent solid support and any insolubles and removal of volatiles in vacuo; ii) precipitate the residual material in suitable (anti)solvent(s) in which the metals are adequately soluble; and iii) isolate the peptide by filtration and / or drying. An antisolvent is typically a liquid organic compound, or a mixture of such compounds in which the target organic molecule, typically a peptide, is poorly soluble and precipitates, enabling its isolation e.g. by filtration or centrifugation; common ''antisolvents' used in SPPS include, diethyl ether, MTBE, DIPE, heptane, hexane, cyclohexane, petroleum ether (all boiling ranges), CPME, 2-MeTHF, 4-MTHP; alternatively for highly hydrophobic organic molecule substrates (for example polypeptide chains consisiting predominantly of hydrophobic AAs), water or suitable aqueous solutions may serve as ''antisolvents'' as well.

[0002] FURTHER EMBODIMENTS 1. A method for cleaving bonds in (of) an organic compound coupled to a support, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups between the organic compound and the linker coupled to a support the method comprising: a) subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension comprising the organic compound; b) maintaining the solution or suspension comprising the organic compound at a temperature and duration thereby forming a partially and / or fully deprotected organic compound coupled to the support and / or forming a partially and / or fully deprotected organic compound not coupled to the support. 2. The method according to claim 1, wherein the content of water is below about 100 equiv, preferably below about 95 equiv. such as below about 90 equiv. or below about 85 equiv. 3. The method according to claim 1 or 2, wherein the support is selected from soluble and solid supports. 4. The method according to claim 1, wherein the support is a solid support. 5. The method according to any one of the preceding claims, wherein the organic compound is a polypeptide. 6. The method according to any one of the preceding claims, wherein the protecting groups are acid-labile protecting groups, and the linker is an acid-labile linker. 7. The method according to any one of the preceding claims, wherein the Lewis acid is in oxidation states +II and +III. 8. The method according to claim 1, wherein the Lewis acid is in oxidation state +II and +III and selected from compounds of formula MXy, where y is 2 or 3; M is selected from V, Cr, Mn, Fe, Co, Ni, Cu, Zn, B, and Al; and X is selected from F, Cl, Br, I, acetate and acetylacetonate. 9. The method according to claim 1, wherein the Lewis acid is in oxidation state +III and selected from compounds of formula MX3; M is selected from V, Cr, Mn, Fe, Co, Ni, Cu, Zn, B, and Al; and X is selected from F, Cl, Br, and I. 10. The method according to any one of the preceding claims, wherein the Brønsted acid does not contain fluorine atoms. 11. The method according to any one of the preceding claims, wherein the Brønsted acid has a pKa (in water) below about 7.0, preferably below about 6.0. 12. The method according to claim 1, wherein the composition is essentially free from fluorine atoms. 13. The method according to any one of the preceding claims, wherein the Brønsted acid is selected from carboxylic acids, hydrogen halides of formula H-Z where Z i.s selected from Cl, Br and I, sulphonic acids, sulfuric acid, and phosphoric acid. 14. The method according to any one of the preceding claims, wherein the Brønsted acid is selected from formic acid; compounds with the formula X3C-COOH where X is selected from H, Cl, Br and I; hydrobromic acid (HBr); hydrochloric acid (HCl); sulfuric acid (H2SO4): phosphoric acid (H3PO4), methanesulfonic acid (MsOH); toluenesulfonic acid (TsOH); and Camphorsulfonic acid (CsOH). 15. The method according to any one of the preceding claims, wherein the Brønsted acid is selected from acetic acid (AcOH), trichloracetic acid (TCA), tribromoracetic acid (TBA), triiodoacetic acid (TIA), hydrobromic acid (HBr), and hydrochloric acid (HCl). 16. The method according to any one of the preceding claims, wherein the solvent is an aprotic organic solvent not containing any one of: amide function, thionyl group, and carbon-fluorine bonds. 17. The method according to any one of the preceding claims, wherein the solvent is selected from acetonitrile (MeCN), dichloromethane (DCM), alkyl acetates such as ethyl acetate (EtOAc), dioxane, 1,3 dioxolane (DOL), tetrahydrofuran (THF), tetrahydropyran (THP), 2-methyltetrahydrofuran (2-MeTHF), 4-methyltetrahydropyran (4-MeTHP), toluene (Tol), anisole (Ani), 1,2-dimethoxybenzene (1,2-DMB), 1,3- dimethoxybenzene (1,3-DMB), n-hexane (Hex), n-heptane (Hep), petroleum ether (PE), cyclopentylmethyl ether (CPME), tert-Butylmethylether (TBME), dipropyleneglycol dimethylether (DMM), dimethyl carbonate (DMC), diethyl carbonate (DEC), propylene carbonate (PC), dimethyl isosorbide (DMI), and gammavalerolactone (GVL). 18. The method according to any one of the proceeding claims, wherein the solvent is selected from acetonitrile (MeCN), dichloromethane (DCM), ethyl acetate (EtOAc), dioxane, tetrahydrofuran (THF), tetrahydropyran (THP), 2-methyltetrahydrofuran (2- MeTHF), 4-methyltetrahydropyran (4-MeTHP), dimethyl carbonate (DMC), 1,3 dioxolane (DOL), and toluene. 19. The method according to any one of the preceding claims, wherein the temperature during cleavage is in the range from about 30°C up to about 70°C, preferably from about 30°C up to about 60°C, such as from about 35°C up to about 50°C. 20. The method according to any one of the preceding claims, wherein the linker is an acid labile linker selected from the linker is selected from acid labile linkers such as Wang ([4-(hydroxymethyl)phenoxymethyl]) linker, 2CT (2-chlorotrityl) linker, 2-CT- COOH (2-chloro)-4’-carboxy-triphenyl methanol) linker, Trt (trityl) linker, Trt-COOH (trityl carboxyl) linker, Rink (amide) (4-(((9-fluorenylmethoxycarbonyl)amino) (2,4- dimethoxyphenyl)methyl)phenoxy)acetic acid) linker, Ramage (RMG) ((R,S)-2- { [5- (9-fluorenylmethyloxycarbonylamino)-dibenzo [a,d]cycloheptane-2-yl]oxy}-acetic acid) linker, Pal (5-[4-(9-fluorenylmethoxycarbonyl)aminomethyl-3,5- dimethoxyphenoxy]-pentanoic acid) linker, Sieber (9- (9- fluorenylmethyloxycarbonylamino)-9H-xanthen-3-yl-oxymethyl) linker, SASRIN (4- Hydroxymethyl-3-methoxyphenoxyacetic acid) linker, HMPA (hydroxymethylphenoxyacetic acid) linker, DHP (dihydropyranyl) linker, 4-MBH (4- methylbenzhydryl) linker or base / nucleophile labile linkers such as HMBA (hydroxymethylbenzoyl) linker, HZB (hydrazinobenzoyl) linker and MeDbz (o- amino(methyl)aniline) / MeNBz (acyl-N′-methylacylurea) linker. 21. The method according to any one of the preceding claims, wherein the acid labile linker is selected from Wang linker, CTC linker, trityl linker, Rink amide linker, Ramage linker, Pal linker, Sieber linker, and SASRIN linker. 22. A composition for cleaving bonds in an organic compound, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compound and the linker coupled to a support, the composition comprising: i) at least one Lewis acid; ii) at least one Brønsted acid, and optionally iii) at least an organic aprotic solvent. 23. Use of a composition for cleaving bonds in an organic compound coupled to a support, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compound and the linker coupled to a support, the composition comprising: i) at least one Lewis acid; ii) at least one Brønsted acid, and optionally iii) at least an organic aprotic solvent. 24. A method for the synthesis of a polypeptide comprising providing a solid support comprising a linker, consecutively coupling ^-amine protected amino acids, such as Fmoc ^-amine protected amino acids, optionally comprising a side chain protecting group, thereby forming a polypeptide coupled to the solid support comprising side chain protecting groups; wherein the method further comprises: a) subjecting the solid support comprising the polypeptide to / with a composition comprising: i) at least one Lewis acid, ii) at least one Brønsted acid), and optionally iii) at least one solvent; and b) maintaining the suspension at a temperature and duration for forming a partially and / or fully deprotected polypeptide coupled to the support, and / or a partially and / or fully polypeptide compound not coupled to the support. 25. A method for cleaving bonds in an organic compound, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compound and the linker coupled to a support, the method comprising: a) subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension comprising the organic compound; b) maintaining the solution or suspension comprising the organic compound at a temperature and duration thereby forming a partially and / or fully deprotected crude organic compound coupled to the support and / or forming a partially and / or fully deprotected crude organic compound not coupled to the support; and further adding an aqueous solution containing a suitable salt there by adjusting the pH of the solution or suspension. 26. The method according to claim 25, wherein the salt is selected from ammonium acetate, ammonium carbonate or ammonium phosphate or mixtures thereof. 27. A method for the removal or reduction of residual metals, the method comprising cleaving bonds in / of an organic compound coupled to a support, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compounds and the linker coupled to a support, the method comprising: a) subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension comprising the organic compound; b) maintaining the solution or suspension at a temperature and duration thereby forming a partially and / or fully deprotected organic compound and / or a partially and / or fully deprotected organic compound coupled to the support comprising residual metals; the method further comprising either one of: a) i) trapping / capturing the organic compound on an insoluble support ii) eluting residual metals iii) eluting the organic compound; or b) i) trapping / capturing residual metals on a suitable insoluble support ii) eluting the organic compound; or c) separating the metals trapped on the support from the organic compound by the means of filtration. 28. A method for the removal or reduction of residual metals, the method comprising cleaving bonds in an organic compound coupled to a support, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compounds and the linker coupled to a support, the method comprising: a) subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension comprising the organic compound; b) maintaining the solution or suspension at a temperature and duration thereby forming a partially and / or fully deprotected organic compound and / or a partially and / or fully deprotected organic compound coupled to the support comprising residual metals; the method further comprising: i), filter off the spent resin and any insolubles and remove the volatiles in vacuo; ii) precipitate the residual material in suitable (anti)solvent(s) in which the metals are adequately soluble; and iii) isolate the peptide by filtration and / or drying. 29. A method comprising providing a peptide fragment comprising protecting groups (protected peptide fragment) coupled to a support by a linker, the method comprising the steps: a) subjecting the peptide fragment coupled to the support with a composition comprising: I) at least a Lewis acid, and II) at least a solvent, and optionally III) at least a scavenger; thereby cleaving the peptide fragment from the support without cleaving any protecting groups forming a protected peptide fragment in a solution or suspension; b) optionally removing the Lewis acid from the solution or suspension comprising the peptide fragment forming a solution or suspension depleted in Lewis acid; c) adding suitable coupling agents to the solution or suspension from step a) or optionally to the solution or suspension depleted in Lewis acid from step b) comprising the protected peptide fragment thereby coupling two protected peptide fragments forming a protected polypeptide in the solution or suspension; and d) adding at least a Brønsted acid and optionally a Lewis acid to the solution or suspension from step c) comprising the protected polypeptide thereby forming a partially or fully deprotected polypeptide in the solution or suspension. 30. A method comprising providing a polypeptide comprising protecting groups coupled to a support by an acid stable linker such as a base-labile linker, the method comprising the steps: a) subjecting the polypeptide coupled to the support with a composition comprising: I) at least a Lewis acid, II) at least a Brønsted acid; and optionally III) at least a solvent, forming a solution or suspension; b) maintaining the solution or suspension at a temperature and duration thereby cleaving all protecting groups forming a solution or suspension comprising a fully deprotected polypeptide coupled to the support; and c) cleaving the fully deprotected polypeptide from the support by the addition of a base or nucleophile to the solution or suspension comprising a fully deprotected polypeptide coupled to the support, thereby forming a solution or suspension comprising a fully deprotected polypeptide not couped to the support. 31. A method comprising providing an organic compound A comprising at least one amino acid, said amino acid comprising a sulfhydryl moiety such as Cys, HCys or Pen, said organic compound A being coupled via a linker to a support, the method comprising: a) subjecting the organic compound coupled to a support to / with a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, and optionally in the presence of an organic compound B comprising at least one amino acid, said amino acid comprising a sulfhydryl moiety thereby forming a solution or suspension; b) maintaining the solution or suspension at a temperature and duration thereby forming a deprotected organic compound A and optionally deprotected organic compound B and forming an organic compound comprising at least one disulfide group selected from: i) an organic compound C1 formed from organic compound A and comprising a bridge comprising a disulfide group said bridge connecting the two amino acids which previously had sulfhydryl moieties; and / or ii) an organic compound C2 comprising organic compound A and organic compound B, said organic molecules A and B linked by at least a moiety comprising a disulfide group; and / or iii) an organic compound C3 comprising two organic compounds A said organic compounds A linked by at least a moiety comprising a disulfide group; and / or iv) an organic compound C4 comprising two organic molecules B said organic molecules B linked by at least one moiety comprising a disulfide group. EXAMPLES Abbreviations: TFA: trifluoro acetic acid MeCN: acetonitrile EtOAc: ethylacetate DCM: dichloromethane FA: formic acid AcOH: acetic acid TCA: trichloroacetic acid TBA: tribromoacetic acid DMSO: dimethyl sulfoxide DMC: dimethyl carbonate PC: propylene carbonate DOL: 1,3-dioxolane 2-MeTHF: 1-methyltetrahydrofuran 4-MeTHP: 4-methyltetrahydropyran THP: tetrahydropyran DIEA: N,N-diisopropylethylamine TIS: triisopropylsilane If not stated otherwise all ratios are volume related (v / v). Examples 1 to 7 investigate the cleavage of Fmoc-Leu-Wang resin from the resin under different conditions such as type of Lewis acid, type of Brønsted acid, type of solvent, reaction duration and temperature. The cleavage of the amino acid from the resin is illustrated as follows: Fm Loo ac d-L ine gu 0-W .3a mn mg o re l / s gin General Synthetic Protocol for examples 1 to 7 A hemolysis tube (product type) was charged with 83.3 mg of Fmoc-Leu-Wang resin (0.025 mmol). The compounds (Lewis acid and / or Brønsted acid) and optional solvents were added to the hemolysis tube. The tube was capped, and the reaction mixture was stirred with a magnetic stirrer (Heidolph model) at 250 rpm for a duration and time as specified in the examples. The temperature was either room temperature (RT approx. 20-22 °C) or 40 °C (water bath). The reaction was monitored at different time points by extracting 5 µL aliquots from the mixture. The aliquots were diluted into 1 mL of H2O / MeCN (7:3) and analyzed by HPLC-MS. The conversion of all the cleavages were determined based on calibration curves using corresponding area of the amount of Fmoc-Leu-OH released at 220 nm. LC-MS analyses were performed on a ThermoFischer HPLC Vanquish™ Core equiped with a DAD detector coupled with an ThermoFischer ISQ-EM in a positive electrospray mode (ESI). HPLC conditions: SunFire C18, 2.5µm, 4.6x75mm column, FA / H2O (0.1:100, A), FA / MeCN (0.1:100 B) as buffers, 5% B to 95% B over 9 min gradient, flow of 1.0 mL / min, detection at 220 nm and column temperature 25 °C. Example 1 Lewis acid Screening In this example different Lewis acids were evaluated without the presence of a Brønsted acid and in conjunction with MeCN as a solvent at RT and 40°C. The respective Lewis acid (5 equiv, 0.125 mmol) was dissolved in the respective solvent (1 mL). The resulting solution was added in a hemolysis tube containing 83.3 mg of Fmoc-Leu-Wang resin (0.025 mmol). The tube was capped, and the reaction mixture was stirred with a magnetic stirrer (Heidolph model) at 250 rpm for a duration and time as specified in the examples. The temperature was either RT (approx.20- 22°C) or 40 °C (water bath). The reaction was monitored at different time points by extracting 5 µL aliquots from the mixture. The aliquots were diluted into 1 mL of H2O / MeCN, (7:3) and analyzed by HPLC-MS. The conversion of all the cleavages were determined based on calibration curves using corresponding area of the amount of Fmoc-Leu-OH released at 220 nm. Table 1: Results Lewis acid screening Entry Lewis Acid (equiv) Solvent Temp. (°C) Conversion (%)11h 4h > 20 h 1 MgI2 (5equiv) MeCN rt 0 % 0 % 0 % 2 MgI2(5equiv) MeCN 40 °C 0 % 0 % 0 % 3 FeBr2(5equiv) MeCN rt 0 % 0 % NA 4 FeBr2 (5equiv) MeCN 40 °C 0 % 0 % NA 5 FeI2 (5equiv) MeCN rt 0 % 0 % 1 % 6 FeI2 (5equiv) MeCN 40 °C 1 % 5 % 15 % 7 AlCl3 (5equiv) MeCN rt 1 % 1 % NA 8 AlCl3 (5equiv) MeCN 40 °C 4 % 11 % NA 9 FeCl3 (5equiv) MeCN rt 3 % 14 % 46 % 10 FeCl3 (5equiv) MeCN 40 °C 33 % 49 % 56 % 11 FeCl3 (5equiv) MeCN / H2O (1 / 1) rt 0 % 0 % 0 % 12 FeCl3(5equiv) MeCN / H2O (1 / 1) 40 °C 0 % 0 % 0 % 13 FeCl36H2O (5equiv) MeCN rt 0 % 0 % 1 % 14 FeCl36H2O (5equiv) MeCN 40 °C 1 % 7 % 38 % 15 FeBr3 (5equiv) MeCN rt 1 % 4 % NA 16 FeBr3 (5equiv) MeCN 40 °C 16 % 44 % NA1Determined by HPLC (220 nm) quantifying the amount of Fmoc-Leu-OH released into reaction mixture based on calibration study Example 2 Brønsted Acid Screening In this example different Brønsted acids were evaluated in the absence of a Lewis acid and with the solvent MeCN at RT and 40°C. Synthetic protocol: The respective Brønsted acid (70 equiv, 1.75 mmol) was dissolved in the respective solvent (1 mL). The resulting solution was added in a hemolysis tube containing 83.3 mg of Fmoc-Leu-Wang resin (0.025 mmol). The tube was capped, and the reaction mixture was stirred with a magnetic stirrer (Heidolph model) at 250 rpm for a duration and time as specified in the examples. The temperature was either RT or 40 °C (water bath). The reaction was monitored at different time points by extracting 5 µL aliquots from the mixture. The aliquots were diluted into 1 mL of H2O / MeCN, (7:3) and analyzed by HPLC-MS. The conversion of all the cleavages were determined based on calibration curves using corresponding area of the amount of Fmoc-Leu-OH released at 220 nm. Table 2: Results Brønsted Acid Screening Entry Brønsted Acid pKa (Predicted)1Solvent Temp. (°C) C2(equiv) onversion (%) 1h 4h > 20 h 1 FA (70equiv) 3.74±0.10 MeCN rt 0 % 0 % 0 % 2 FA (70equiv) 3.74±0.10 MeCN 40 °C 0 % 0 % 0 % 3 AcOH (70equiv) 4.79±0.10 MeCN rt 0 % 0 % 0 % 4 AcOH (70equiv) 4.79±0.10 MeCN 40 °C 0 % 0 % 0 % 5 TCA (40equiv) 0.09±0.18 MeCN rt 0 % 0 % NA 6 TCA (70equiv) 0.09±0.18 MeCN rt 0 % 1 % 2 % 7 TCA (70equiv) 0.09±0.18 MeCN 40 °C 1 % 6 % 29 % 8 TCA (80equiv) 0.09±0.18 MeCN rt 0 % 1 % 3 % 9 TBA (70equiv) 0.22±0.10 MeCN rt 0 % 0 % 2 % 10 TBA (70equiv) 0.22±0.10 MeCN 40 °C 2 % 6 % 27 % 11 H3PO4 (70equiv) 1.97±0.10 MeCN rt 0 % 0 % 0 % 12 H3PO4 (70equiv) 1.97±0.10 MeCN 40 °C 0 % 0 % 0 %1Data from Scifinder;2Determined by HPLC (220 nm) quantifying the amount of Fmoc-Leu-OH released into reaction mixturebased on calibration study Abbreviations: FA = Formic Acid; TCA = TriChloroacetic Acid; TBA = TriBromoacetic Acid Example 3 Combination of Lewis and Brønsted Acid In this example different combinations of Lewis acids and Brønsted acids were evaluated in MeCN at RT and 40°C. Synthetic Protocol: The respective Lewis acid (5 equiv, 0.125 mmol) was dissolved in the respective solvent (1 mL) and then the Brønsted acid was added (70 equiv, 1.75 mmol). The resulting solution was added in a hemolysis tube containing 83.3 mg of Fmoc-Leu- Wang resin (0.025 mmol). The tube was capped, and the reaction mixture was stirred with a magnetic stirrer (Heidolph model) at 250 rpm for a duration and time as specified in the examples. The temperature was either RT or 40 °C (water bath). The reaction was monitored at different time points by extracting 5 µL aliquots from the mixture. The aliquots were diluted into 1 mL of H2O / MeCN, (7:3) and analyzed by HPLC-MS. The conversion of all the cleavages was determined based on calibration curves using corresponding area of the amount of Fmoc-Leu-OH released at 220 nm. Table 3: Results combination of Lewis and Brønsted Acid Entry Lewis Acid Brønsted Acid Solvent Temp. (°C) Conversion (%)1 2 MgI2 (5equiv) AcOH (70equiv) MeCN 40 °C 0 % 0 % 1 % 3 FeBr2 (5equiv) AcOH (70equiv) MeCN rt 0 % 0 % NA 4 FeBr2 (5equiv) AcOH (70equiv) MeCN 40 °C 0 % 0 % NA 5 FeI2 (5equiv) AcOH (70equiv) MeCN rt 0 % 0 % 0 % 6 FeI2(5equiv) AcOH (70equiv) MeCN 40 °C 0 % 1 % 4 % 7 AlCl3 (5equiv) AcOH (70equiv) MeCN rt 10 % 39 % NA 8 AlCl3 (5equiv) AcOH (70equiv) MeCN 40 °C 57 % 88 % NA 9 FeCl3 (5equiv) FA (70equiv) MeCN rt 9 % 23 % 56 % 10 FeCl3(5equiv) FA (70equiv) MeCN 40 °C 34 % 60 % 72 % 11 FeCl3(5equiv) AcOH (70equiv) MeCN rt 24% 52 % 75 % 38 % 50 % 72 % 58 % 65 % NA 12 FeCl3 (5equiv) AcOH (70equiv) MeCN 40 °C 91 % 65 % 68 % 13 FeCl3(5equiv) TCA (70equiv) MeCN rt 68 % 67 % 71 % 14 FeCl3 (5equiv) TCA (70equiv) MeCN 40 °C 67 % 67 % 72 % 15 FeCl3 (5equiv) TBA (70equiv) MeCN rt 64 % 64 % 64 % 16 FeCl3 (5equiv) TBA (70equiv) MeCN 40 °C 66 % 67 % 61 % MeCN / H2O 17 FeCl3 (5equiv) AcOH (70equiv) rt 0 % 0 % 0 % (1 / 1) MeCN / H2O 18 FeCl3 (5equiv) AcOH (70equiv) 40 °C 0 % 0 % 0 % (1 / 1) FeCl36H2O 19 AcOH (70equiv) MeCN rt 0 % 1 % 11 % (5equiv) FeCl 6H O 20 3 2 AcOH (70equiv) MeCN 40 °C 12 % 49 % 86 % (5equiv) 21 FeBr3(5equiv) AcOH (70equiv) MeCN rt 4 % 13 % NA 22 FeBr3 (5equiv) AcOH (70equiv) MeCN 40 °C 33 % 51 % NA 23 FeCl3 (5equiv) H3PO4 (70equiv) MeCN rt 0 % 0 % 1 % 24 FeCl3 (5equiv) H3PO4 (70equiv) MeCN 40 °C 0 % 3 % 24 %1Determined by HPLC (220 nm) quantifying the amount of Fmoc-Leu-OH released into reaction mixturebased on calibration study Abbreviations: FA = Formic Acid; TCA = TriChloroacetic Acid; TBA = TriBromoacetic Acid Example 4 Impact on equivalency of acetic acid (AcOH) In this example the equivalency of acetic acid to amino acid was evaluated by a composition of FeCl3 and AcOH with or without solvent being MeCN. Synthetic protocol: FeCl3 (5 equiv, 0.125 mmol) was dissolved in MeCN and AcOH was added at a volume to reach the targeted equivalence (140 and 350 eq) at a total volume of 1 mL. For entry 5 and 6 FeCl3 (5 equiv, 0.125 mmol) was dissolved in AcOH without addition of MeCN giving 700 equiv of AcOH. The resulting solution was added in a hemolysis tube containing 83.3 mg of Fmoc-Leu-Wang resin (0.025 mmol). The tube was capped, and the reaction mixture was stirred with a magnetic stirrer (Heidolph model) at 250 rpm for a duration and time as specified in the examples. The temperature was either RT or 40 °C (water bath). The reaction was monitored at different time points by extracting 5 µL aliquots from the mixture. The aliquots were diluted into 1 mL of H2O / MeCN, (7:3) and analyzed by HPLC-MS. The conversion of all the cleavages was determined based on calibration curves using corresponding area of the amount of Fmoc-Leu-OH released at 220 nm. Table 4: Impact on equivalency of acetic acid (AcOH) Entry Lewis Acid Brønsted Acid Temp. (equiv) (equiv) Solvent (°C) 1 FeCl3 (5equiv) AcOH (140equiv) MeCN rt 2 FeCl3(5equiv) AcOH (140equiv) MeCN 40 °C 80 % 85 % 84 % 3 FeCl3 (5equiv) AcOH (350equiv) MeCN rt 13 % 62 % 95 % 4 FeCl3 (5equiv) AcOH (350equiv) MeCN 40 °C 80 % 96 % 98 % 5 FeCl3 (5equiv) AcOH (700equiv) NA rt 1 % 10 % 32 % 6 FeCl3 (5equiv) AcOH (700equiv) NA 40 °C 32 % 54 % 66 %1Determined by HPLC (220 nm) quantifying the amount of Fmoc-Leu-OH released into reaction mixturebased on calibration study Example 5 Impact of solvents and binary mixtures In this example various solvents were evaluated at RT and 40°C for compositions of FeCl3 and AcOH. Synthetic protocol: FeCl3 (5 equiv, 0.125 mmol) was dissolved in 900 µL of the respective solvent and subsequently AcOH (70 equiv, 1.75 mmol) was added to obtain 1 mL of solvent. The resulting solution was added in a hemolysis tube containing 83.3 mg of Fmoc-Leu- Wang resin (0.025 mmol). The tube was capped, and the reaction mixture was stirred with a magnetic stirrer (Heidolph model) at 250 rpm for a duration and time as specified in the examples. The temperature was either RT or 40 °C (water bath). The reaction was monitored at different time points by extracting 5 µL aliquots from the mixture. The aliquots were diluted into 1 mL of H2O / MeCN, (7:3) and analyzed by HPLC-MS. The conversion of all the cleavages was determined based on calibration curves using corresponding area of the amount of Fmoc-Leu-OH released at 220 nm. Table 5: Impact of solvents and binary mixtures 2 FeCl3 (5equiv) AcOH (70equiv) DMSO 40 °C 0 % 0 % 0 % 3 FeCl3 (5equiv) AcOH (70equiv) EtOAc rt 89 % 89 % 90 % 4 FeCl3 (5equiv) AcOH (70equiv) EtOAc 40 °C 85 % 84 % 76 % 5 FeCl3 (5equiv) AcOH (70equiv) EtOH rt 0 % 0 % 0 % 6 FeCl3 (5equiv) AcOH (70equiv) EtOH 40 °C 0 % 0 % 0 % 7 FeCl3 (5equiv) AcOH (70equiv) DMF rt 0 % 0 % 0 % 8 FeCl3 (5equiv) AcOH (70equiv) DMF 40 °C 0 % 0 % 0 % 9 FeCl3 (5equiv) AcOH (70equiv) Toluene rt > 98 % > 98 % > 98 % 10 FeCl3(5equiv) AcOH (70equiv) Toluene 40 °C 97 % 94 % > 98 % 11 FeCl3(5equiv) AcOH (70equiv) DCM rt > 98 % > 98 % > 98 % 12 FeCl3 (5equiv) AcOH (70equiv) DCM 40 °C 94 % > 98 % > 98 % Dimethyl 13 FeCl3(5equiv) AcOH (70equiv) carbonate rt 86 % 95 % 79 % (DMC) Dimethyl 14 FeCl3 (5equiv) AcOH (70equiv) carbonate 40 °C 81 % 99 % 81 % (DMC) Propylene 15 FeCl3 (5equiv) AcOH (70equiv) carbonate rt 0 % 0 % 0 % (PC) Propylene 16 FeCl3 (5equiv) AcOH (70equiv) carbonate 40 °C 1 % 4 % 12 % (PC) 3 1,3-Dioxolane 17 FeCl (5equiv) AcOH (70equiv) rt 10 % 11 % 3 % (DOL) 1,3-Dioxolane 18 FeCl (5equiv) 40 °C 16 % 4 % 2 19 FeCl (5equiv) rt 21 % 48 % 83 uran 2- 3 Methyltetrahydrof 20 FeCl (5equiv) AcOH (70equiv) 40 °C 73 % 83 % 93 % uran Methyltetrahydro 23 FeCl3 (5equiv) AcOH (70equiv) rt 46 % 88 % 89 % pyran (4-MeTHP) 4- Methyltetrahydro 24 FeCl3 (5equiv) AcOH (70equiv) 40 °C 85 % 91 % > 98 % pyran (4-MeTHP)1Determined by HPLC (220 nm) quantifying the amount of Fmoc-Leu-OH released into reaction mixturebased oncalibration studyExample 6 Use of HCl as Brønsted acid In this example hydrochloric acid as Brønsted acid was evaluated with and without FeCl3 with different solvents. Additionally, only FeCl3 was evaluated in combination with dioxane as solvent. Further, FeCl3 in combination with acetic acid was evaluated in combination with MeCN and the solvent mixture MeCN and dioxane at a volume ratio of 1:1. Synthesis protocol: In entries 1 to 4 concentrated hydrochloric acid (37 vol%) was used. In the rest of the entries, hydrochloric acid was provided as a 4M solution in dioxane. For Entry 1 to 8: The respective Brønsted acid (70 equiv, 1.75 mmol) was dissolved in the respective solvent to obtain a total volume of 1 mL. The resulting solution was added in a hemolysis tube containing 83.3 mg of Fmoc-Leu-Wang resin (0.025 mmol). The tube was capped, and the reaction mixture was stirred with a magnetic stirrer (Heidolph model) at 250 rpm for a duration and time as specified in the examples. The temperature was either RT or 40 °C (water bath). The reaction was monitored at different time points by extracting 5 µL aliquots from the mixture. The aliquots were diluted into 1 mL of H2O / MeCN, (7:3) and analyzed by HPLC-MS. The conversion of all the cleavages were determined based on calibration curves using corresponding area of the amount of Fmoc-Leu-OH released at 220 nm. For Entry 9 to 20: FeCl3 (5 equiv, 0.125 mmol) was dissolved in respective solvent and subsequently AcOH or HCl 4M in Dioxane (70 equiv, 1.75 mmol) was added to obtain a total volume of 1 mL. The resulting solution was added in a hemolysis tube containing 83.3 mg of Fmoc-Leu-Wang resin (0.025 mmol). The tube was capped, and the reaction mixture was stirred with a magnetic stirrer (Heidolph model) at 250 rpm for a duration and time as specified in the examples. The temperature was either RT or 40 °C (water bath). The reaction was monitored at different time points by extracting 5 µL aliquots from the mixture. The aliquots were diluted into 1 mL of H2O / MeCN, (7:3) and analyzed by HPLC-MS. The conversion of all the cleavages were determined based on calibration curves using corresponding area of the amount of Fmoc-Leu-OH released at 220 nm.Table 6: Results use of HCl as Brønsted acidEntry Lewis Acid Brønsted Acid Solvent Temp. Conversion (%)1 1 HCl 37 % (70equiv) Dioxane rt 0 % 1 % 8 % 2 HCl 37 % (70equiv) Dioxane 40 °C 2 % 8 % 36 % 3 HCl 37 % (70equiv) MeCN rt 0 % 0 % 4 % 4 HCl 37 % (70equiv) MeCN 40 °C 3 % 10 % 25 % 5 HCl 4 M (70equiv) Dioxane rt 1 % 6 % 35 % 6 HCl 4 M (70equiv) Dioxane 40 °C 7 % 29 % 80 % 7 HCl 4 M (70equiv) MeCN rt 44 % 81 % 94 % 8 HCl 4 M (70equiv) MeCN 40 °C 87 % 93 % 97 % 9 FeCl3 (5equiv) Dioxane rt 2 % 13 % 47 % 10 FeCl3 (5equiv) Dioxane 40 °C 14 % 47 % 71 % 11 FeCl3 (5equiv) AcOH (70equiv) Dioxane rt 74 % 79 % 86 % 12 FeCl3 (5equiv) AcOH (70equiv) Dioxane 40 °C 84 % 76 % 90 % 17 FeCl3 (5equiv) HCl 4 M (70equiv) Dioxane rt 60 % 78 % 81 % 18 FeCl3 (5equiv) HCl 4 M (70equiv) Dioxane 40 °C 85 % 87 % 64 % 19 FeCl3 (5equiv) HCl 4 M (140equiv) NA rt 75 % 92 % 91 % 20 FeCl3 (5equiv) HCl 4 M (140equiv) NA 40 °C 95 % 92 % 67 %1Determined by HPLC (220 nm) quantifying the amount of Fmoc-Leu-OH released into reaction mixturebased on calibration study Example 7 In the following example different Lewis acids were evaluated in presence of either HCl or acetic acid as Brønsted acid with MeCN as solvent at RT and 40°C. Synthetic protocol: The respective Lewis acid (5 equiv, 0.125 mmol) was dissolved in MeCN and subsequently AcOH or HCl 4M in Dioxane (70 equiv, 1.75 mmol) was added to obtain 1 mL of solvent. The resulting solution was added in a hemolysis tube containing 83.3 mg of Fmoc-Leu-Wang resin (0.025 mmol). The tube was capped, and the reaction mixture was stirred with a magnetic stirrer (Heidolph model) at 250 rpm for a duration and time as specified in the examples. The temperature was either RT or 40 °C (water bath). The reaction was monitored at different time points by extracting 5 µL aliquots from the mixture. The aliquots were diluted into 1 mL of H2O / MeCN, (7:3) and analyzed by HPLC-MS. The conversion of all the cleavages was determined based on calibration curves using corresponding area of the amount of Fmoc-Leu-OH released at 220 nm. Table 7: Screening of Lewis acids in presence of either HCl or acetic acid as Brønsted acid with MeCN as solvent. Entry Lewis Acid (equiv) Brønsted Acid Solvent Temp. Conversion (%)1 2 FeCl2 (5equiv) NA MeCN 40 °C 0 % 0 % 0 % 3 FeCl2(5equiv) AcOH (70equiv) MeCN rt 0 % 0 % 0 % 4 FeCl2(5equiv) AcOH (70equiv) MeCN 40 °C 0 % 0 % 4 % 5 FeCl2 (5equiv) HCl 4 M (70equiv) MeCN rt 86 % > 98 % 90 % 6 FeCl2 (5equiv) HCl 4 M (70equiv) MeCN 40 °C 84 % > 98 % 99 % 7 Fe(OAc)2 (5equiv) NA MeCN rt 0 % 0 % 0 % 8 Fe(OAc)2(5equiv) NA MeCN 40 °C 0 % 0 % 0 % 9 Fe(OAc)2 (5equiv) AcOH (70equiv) MeCN rt 0 % 0 % 0 % 10 Fe(OAc)2 (5equiv) AcOH (70equiv) MeCN 40 °C 0 % 0 % 0 % 11 Fe(OAc)2 (5equiv) HCl 4 M (70equiv) MeCN rt > 98 % > 98 % > 98 % 12 Fe(OAc)2 (5equiv) HCl 4 M (70equiv) MeCN 40 °C > 98 % > 98 % NA Mn(OAc) 142NA MeCN 40 °C 0 % 0 % 0 % 4H2O(5equiv) Mn(OAc) 15 2 AcOH (70equiv) MeCN rt 0 % 0 % 0 % 4H2O(5equiv) Mn(OAc)2 16 AcOH (70equiv) MeCN 40 °C 0 % 0 % 0 % 4H2O(5equiv) Mn(OAc)2 17 HCl 4 M (70equiv) MeCN rt 26 % 47 % 90 % 4H2O(5equiv) Mn(OAc) 1822HCl 4 M (70equiv) MeCN 40 °C 98 % > 98 % > 98 % 4H O(5equiv)1Determined by HPLC (220 nm) quantifying the amount of Fmoc-Leu-OH released into reaction mixturebased calibration study Example 8 Cleavages of Fmoc-Leu-HMPA resin Experimental: a) Synthesis of Fmoc-Leu-HMPA resin (4-(Hydroxymethyl)phenoxyaceamidomethyl polystyrene).4.0 g of 0.59M aminomethylstyrene (AMS) resin (2.36 mmol) was added to a fritted syringe. The resin was swollen in 30 mL DMF for 1 h at rt and drained. Then, 2.44 g of Fmoc-Leu-HMPA-OH (4.72 mmol, 2.0 equiv), 670 mg Oxyma (4.72 mmol, 2.0 equiv), and 732 µL tert-butyl-ethylcarbodiimide (TBEC) (4.72 mmol, 2.0 equiv) in 25 mL of DMF were added to the swollen resin, the syringe was sealed and the resulting slurry was shaken at 45 °C for 30 min upon which the syringe was drained. The drained polymer was washed with 3 x 30 mL DMF, 3 x 30 mL i-PrOH (isopropyl alcohol) and dried to constant weight which gave 6.3 g of Fmoc-Leu HMPA AMS resin. Fmoc content of the resin was determined as previously reported (Green Chem.2019, 21, 2594) to be 0.35 M i.e.2.21 mmol of the target resin was obtained b) Cleavages of Fmoc-Leu-HMPA resin. 100 mg of Fmoc-Leu-HMPA AMS resin (0.35M, 0.035 mmol) was weighed into a 2 mL fritted syringe. Next, reagents and solvent used in the cleavage were added to the syringe, the syringe was sealed and shaken (400 rpm) on an IKA® KS basic 130 apparatus (Green Chem.2019, 21, 2594, Figure S4) at the stated temperature for the stated time (table 8). R1: TFA / TIS (95:5), 1 mL, rt R2: 5 equiv (28.8 mg) FeCl3 in DCM, 1 mL, rt R3: 5 equiv FeCl3 in MeCN, 1 mL, rt R4: MeCN / AcOH (9:1), 1 mL, rt R5: 5 equiv FeCl3 in MeCN / AcOH (9:1), 1 mL, rt R6: 5 equiv FeCl3 in MeCN / AcOH (9:1), 1 mL, 40 °C For all reactions, 50 µL aliquots of the reaction mixtures were taken out at 1 h and 4 h. These aliquots were added to 1.0 mL MeCN and analyzed by HPLC. The yields of all the cleavages were determined using 1.0 mg mL-1Fmoc-Leu-OH in MeCN as the reference standard as follows: first, the concentration of Fmoc-Leu-OH in all diluted aliquots of all the reaction mixtures were determined using the 1.0 mg mL-1Fmoc-Leu- OH as the reference. Next, the amount of Fmoc-Leu-OH released from the resin was calculated and based on the known mol amount the starting Fmoc-Leu-HMPA resin, the yields of Fmoc-Leu-OH for all cleavages were determined. HPLC analyses were carried out on an Agilent 1100 system using following conditions: Waters XSelect Peptide CSH130 C18 XP 2.5µ 4.6x150mm column, TFA / H2O (0.1:100, A), TFA / MeCN (0.1:100 B) as buffers, 5% B to 90% B over 10 min gradient, flow of 0.6 mL min-1, detection at 220 nm and column temperature 30 °C. Table 8: Cleavage of Fmoc-Leu-HMPA AMS resin under different conditions 1Entry Conditions TemperatureYield (%)1 TFA / TIS (95:5) rt 50.125 equiv FeCl3in DCMrt 2.135 equiv FeCl3in MeCNrt <0.14 AcOH / MeCN (1:9) rt <0.155 equiv FeCl3in AcOH / MeCN (1:9)rt 17.865 equiv FeCl3in AcOH / MeCN (1:9)40 °C 98>1 Determined by HPLC (220 nm) quantifying the amount of Fmoc-Leu-OH released into solution using a sample of Fmoc-Leu-OH as a reference standard. Example 9 Cleavages of Fmoc-Leu RAM resin Experimental: a) Synthesis of Fmoc-Leu-RAM resin. 2.0 g of 0.66M Fmoc-RAM AMS resin (rink amide resin) (1.32 mmol) was added to a fritted syringe. The resin was swollen in 15 mL DMF for 1 h at rt and drained. Then, the resin was shaken with 15 mL 4- methylpiperidine (10% v / v) in DMF for 30 min at 45 °C and drained. The resin was washed with 5 x 10 mL DMF and to the washed resin was added 0.96 g of Fmoc-Leu- OH (2.64 mmol, 2.0 equiv), 375 mg Oxyma (2.64 mmol, 2.0 equiv), and 409 µL TBEC (2.64 mmol, 2.0 equiv) in 15 mL of DMF were added to the swollen resin, the syringe was sealed and the resulting slurry was shaken at 45 °C for 30 min upon which the syringe was drained. The drained polymer was washed with 3 x 30 mL DMF, 3 x 30 mL i-PrOH and dried to constant weight which gave 2.225 g of Fmoc-Leu RAM resin. Fmoc content of the resin was determined as previously reported (Green Chem.2019, 21, 2594) to be 0.59M i.e.1.31 mmol of the target resin was obtained. b) Cleavages of Fmoc-Leu-RAM resin.100 mg of Fmoc-Leu-RAM resin (0.59M, 0.059 mmol) was weighed into a 2 mL fritted syringe. Next, reagents and solvent used in the cleavage were added to the syringe, the syringe was sealed and shaken (400 rpm) on an IKA® KS basic 130 apparatus (Green Chem. 2019, 21, 2594, Figure S4) at the stated temperature for the stated time according to Table 9. For all reactions, 50 µL aliquots of the reaction mixtures were taken out at 2 h. These aliquots were added to 0.95 mL MeCN and analyzed by LC-MS. The yields of all the cleavages were determined using 10.0 mg Fmoc-Leu-OH which was treated with 1.0 mL TFA / DCM / TIS / H2O (45:45:5:5) for 2 h and diluted with MeCN to 10.0 mL. The concentration of Fmoc-Leu-NH2 in the aliquots of the reaction mixtures of the cleavages of Fmoc-Leu-RAM resin were determined using the Fmoc-Leu-OH as the reference, assuming that the UV absorbances for the Fmoc-Leu-OH reference and the Fmoc-Leu-NH2 cleaved off Fmoc-Leu RAM resin are comparable. Next, the amount of Fmoc-Leu-NH2 released from the resin was calculated and based on the known mol amount the starting Fmoc-Leu-RAM resin, the yields of Fmoc-Leu-NH2 for all cleavages were determined. LC-MS analyses were performed on a Thermoscientific MSQ Plus in a positive mode (ESI) coupled with Dionex UltiMate 3000. HPLC conditions: Waters XSelect Peptide CSH130 C18 XP 2.5µ 4.6x150mm column, TFA / H2O (0.1:100, A), TFA / MeCN (0.1:100 B) as buffers, 10% B to 90% B over 15 min gradient, flow of 0.6 mL / min, detection at 294 nm and column temperature 30 °C. Table 9. Cleavage of Fmoc-Leu-RAM resin under different conditions Yield of Fmoc-Leu-NH Entry Conditions Temperature 2 (%)11 TFA / DCM / TIS / H2O (45:45:5:5) rt 77.0 2 TFA / DCM / H2O (50:45:5) rt 87.2 3 0.59 mmol FeCl3 / 1.18 mmol HCl in DMC 45 ^C 93.6 4 0.59 mmol FeCl3 / 1.18 mmol HCl / 5%TIS in DMC45 ^C88.1 5 0.59 mmol FeCl3 / 2.36 mmol AcOH in DMC 45 ^C >99 0.59 mmol FeCl3 / 2.36 mmol AcOH / 5%TIS in 6 C 4 >99 DM 5 ^C 1 Determined by LC-MS (294 nm) quantifying the amount of Fmoc-Leu-NH2 released into solution using a sample of Fmoc-Leu-OH as a reference standard. In the following series of examples 10 to 20 the cleavage of Fmoc protected amino acids coupled to a Wang resin (Fmoc-AA(PG)-Wang resins) and cleavage of amino acid protecting groups (PG) were evaluated. Experimental: (examples 10 to 20): a) Syntheses of Fmoc-AA(PG) Wang resins. These syntheses were carried out according to a previously described protocol (Tetrahedron Lett.2008, 49, 2907). Thus, for each synthesis, 2.0 g of 0.60M Wang resin (Wang resin: p-Alkoxy-benzyl alcohol polymer-bound, p-Alkoxybenzyl alcohol resin, [4-(Hydroxymethyl) phenoxymethyl] polystyrene) (1.20 mmol) was added to a fritted syringe. The resins were swollen in 15 mL DCM for 1 h at rt and drained. Then, the resin was shaken with 15 mL 0.25M PBr3 in DCM for 60 min at rt and drained. All resins were then washed with 5 x 10 mL DCM and 5 x 10 mL DMF and to the washed resins were then added 2.4 mmol (2.0 equiv) of Fmoc-AA(PG)-OH and DIEA (2.4 mmol, 2.0 equiv) in 12 mL of DMF, the syringes were sealed, and the resulting slurries were shaken at rt for 16 h upon which the syringes were drained. The drained Fmoc-AA(PG)-Wang polymers was washed with 3 x 20 mL DMF, 3 x 20 mL i-PrOH and dried to constant weight. Fmoc contents of all the resins were determined as previously reported (Green Chem. 2019, 21, 2594) furnishing following amounts of Fmoc-AA(PG) Wang resins i) 2572.0 mg of 0.33M Fmoc-Arg(Pbf) Wang resin, 0.85 mmol ii) 2824.1 mg of 0.30M Fmoc-Asn(Trt) Wang resin, 0.83 mmol iii) 2654.5 mg of 0.33M Fmoc-Trp(Boc) Wang resin, 0.87 mmol iv) 2693.2 mg of 0.29M Fmoc-His(Trt) Wang resin, 0.77 mmol v) 2924.8 mg of 0.28M Fmoc-Cys(Trt) Wang resin, 0.81 mmol vi) 2560.7 mg of 0.31M Fmoc-Tyr(t-Bu) Wang resin, 0.79 mmol vii) 2467.0 mg of 0.33M Fmoc-Ser(t-Bu) Wang resin, 0.82 mmol viii) 2527.1 mg of 0.31M Fmoc-Lys(Boc) Wang resin, 0.77 mmol ix) 2820.0 mg of 0.27M Fmoc-Lys(Trt) Wang resin, 0.75 mmol x) 2478.8 mg of 0.33M Fmoc-Glu(Ot-Bu) Wang resin, 0.82 mmol b) Cleavages of Fmoc-AA(PG) Wang resins.100 mg of a Fmoc-AA(PG) Wang resin was weighed into a 2 mL fritted syringe. Next, reagents and solvents used in the cleavage as stated in Tables 10–20 were added to the syringe. For the cleavages carried out in a TFA cocktail, TIS, water and DCM were added first, followed by TFA. For the cleavages carried out in TFA-free cocktails, the Lewis acids were added first, followed by adding a solvent and, if used scavenger(s) were added. A Brønsted acid was added as the last reagent. The syringe was sealed and shaken (400 rpm) on an IKA® KS basic 130 apparatus (Green Chem. 2019, 21, 2594, Figure S4) at the temperatures stated in Tables 10-20. For all reactions, 50 µL aliquots of the reaction mixtures were taken out at the times stated in Tables 10–20. These aliquots were added to 0.95 mL MeCN and analyzed by LC-MS. The yields of all Fmoc-AA-OH products obtained in all cleavages were determined using 10.0 mg Fmoc-AA(PG)-OH as references, which were treated with 1.0 mL TFA / DCM / TIS / H2O (45:45:5:5) [v / v] for 2 h and diluted with MeCN to 10.0 mL to furnish samples of Fmoc-AA-OH references. The concentrations of Fmoc-AA-OH product in the aliquots of the reaction mixtures of the cleavages of Fmoc-AA(PG) Wang resins were determined using the Fmoc-AA-OH references released from the Fmoc-AA(PG)-OH materials. Next, the amounts of Fmoc- AA-OHs released from the resins were calculated and based on the known amount of the starting Fmoc-AA(PG) Wang starting resins, the yields of Fmoc-AA-OHs for all cleavages depicted in Tables 10-20 were determined. LC-MS analyses were performed on a Thermoscientific MSQ Plus in a positive mode (ESI) coupled with Dionex UltiMate 3000. HPLC conditions: Waters XSelect Peptide CSH130 C18 XP 2.5µ 4.6x150mm column, TFA / H2O (0.1:100, A), TFA / MeCN (0.1:100 B) as buffers, 10% B to 90% B over 15 min gradient, flow of 0.6 mL min-1, detection at 294 nm, column temperature 30 °C and inj. volume 5.0 µL. Examples 10 Cleavage of Fmoc-Arg(Pbf)-Wang resin under different conditions Table 10. Cleavage of Fmoc-Arg(Pbf)-Wang resin under different conditions Fmoc- Fmoc- Cleavage Lewis Brønsted Arg- Arg- Entry time Temperature Cleavage medium acid acid OH OH (min) (mmol) (mmol) yield purity (%)a(%) TFA / DCM / TIS / H2O 1 120 rt no 96.8 93.0 (45:45:5:5) FeCl3 HCl 2 30 45 °C DMC (0.59) (1.18)b22.2 75.4cFeCl3HCl 30 45 °C DMCb21.6 82.2 (0.59) (1.18) FeCl3 AcOH 30 45 °C DMC 13.6 55.6 (0.59) (2.36) c FeCl3 AcOH 30 45 °C DMC 8.9 41.0 (0.59) (2.36) FeCl 5 °C DMC3HCl 30 4cb68.6 83.9 (0.59) (1.18) FeCl3 HCl 120 45 °C DMCcb56.6 66.3 (0.59) (1.18) c FeCl3 AcOH 30 45 °C DMC 29.5 38.1 (0.59) (2.36) c FeCl3AcOH 120 45 °C DMC 59.7 74.0 (0.59) (2.36) FeCl3 AcOH 30 45 °C noc0.7 10.8 (0.59) (16.61) FeCl3AcOH 120 45 °C noc2.1 59.3 (0.59) (16.61) c Fe(acac) 30 45 °C DMC (0.59)0.0 0.0 Fe(a 120 45 °C DMCccac)3 HCl (0.59) (1.18)b0.0 0.0Fe(acac)3AcOH 30 45 °C noc(0.59) (16.61)0.0 0.0Fe(acac) Ac 120 45 °C noc3 OH (0.59) (16.61)0.0 0.0c FeCl3 AcOH 30 45 °C DMC 21.8 33.0 (0.59) (2.36) c FeCl3AcOH 120 45 °C DMC 60.7 77.8 (0.59) (2.36) d FeCl3 AcOH 30 45 °C DMC 32.0 40.8 (0.59) (2.36) d FeCl3 AcOH 120 45 °C DMC 62.9 80.1 (0.59) (2.36) FeCl3AcOH 30 45 °C DMCc23.6 33.5 (0.59) (4.72) FeCl3 AcOH 120 45 °C DMCc53.8 77.7 (0.59) (4.72) e FeCl3 AcOH 30 45 °C DMC 11.6 16.2 (0.59) (2.36) e FeCl3 AcOH 120 45 °C DMC 30.1 40.3 (0.59) (2.36)cFeCl3AcOH 24 30 45 °C DMC 23.4 30.2 (0.59) (2.36) c FeCl3 AcOH 25 60 45 °C DMC 38.4 49.8 (0.59) (2.36) c FeCl3 AcOH 26 30 50 °C DMC 31.8 43.4 (0.59) (2.36) c FeCl3AcOH 27 60 50 °C DMC 47.9 64.0 (0.59) (2.36) FeCl3 AcOH 28 30 55 °C DMCc35.7 48.0 (0.59) (2.36) c FeCl3 AcOH 29 60 55 °C DMC 53.6 69.3 (0.59) (2.36) c FeCl3AcOH 30 30 60 °C DMC 35.4 49.6 (0.59) (2.36) c FeCl3 AcOH 31 60 60 °C DMC 51.2 69.5 (0.59) (2.36) c FeCl3AcOH 32 30 60 °C DMC 68.3 97.1 (0.59) (0.59) FeCl DMC 3 AcOH 33 60 60 °Cc79.9 97.4 (0.59) (0.59) c FeCl3 HCl 34 30 45 °C DMCb61.5 78.7 (0.59) (0,59) FeCl °C DMC3HCl 35 120 45cb64.7 80.8 (0.59) (0,59) c FeCl3 HCl 36 30 45 °C DMCb45.4 56.7 (0.59) (0,39) c FeCl3 HCl 37 120 45 °C DMCb62.5 81.7 (0.59) (0,39) FeCl3HCl 38 30 55 °C DMCc61.1 90.4 (0.59) (0,59)bFeCl HCl 39 120 55 °C DMCc3 b 32.8 56.7 (0.59) (0,59) c FeCl3 HCl 40 30 55 °C DMCb62.2 83.9 (0.59) (0,39) c FeCl3HCl 41 120 55 °C DMC 82.9 74.5 (0.59) (0,39)ba Determined by LC-MS (294 nm) quantifying the amount of Fmoc-Arg-OH released into solution using a sample of Fmoc-Arg-OH as a reference standard;b4M HCl in dioxane was used;cTIS (5% (v / v) of total volume) used as a scavenger;dTIS (10% (v / v) of total volume) used as a scavenger;eTIS (5% (v / v) of total volume) and BDMT (5% w / v) used as scavengers. Example 11 Cleavages of Fmoc-Asn(Trt)-Wang resin Table 11. Cleavage of Fmoc-Asn(Trt)-Wang resin under different conditions Fmoc- Fmoc- Brønsted Cleavage Temperat FeCl3 Asn-OH Asn-OH Entry Cleavage medium acid time (min) ure (mmol) yield purity (mmol) (%)a(%) TFA / DCM / TIS / H t 2O 1 120 r no 84.7 99.4 (45:45:5:5) 2 30 45 °C DMCcHCl 0.59 (1.18)b76.5 87.6c HCl 3 120 45 °C DMC 0.59 (1.18)b66.0 71.1 0 45 °C DMCcHCl 4 3 0.59 (0.59)b95.5 96.1HC 5 120 45 °C DMCcl 0.59 (0.59)b95.1 85.4c AcOH 6 30 55 °C DMC 0.59 85.5 99.3 (0.59) 7 120 55 °C DMCcAcOH 0.59 (0.59)86.7 96.0a Determined by LC-MS (294 nm) quantifying the amount of Fmoc-Asn-OH released into solution using a sample of Fmoc-Asn-OH as a reference standard;b4M HCl in dioxane was used;cTIS (5% (v / v) of total volume) used as a scavenger.

[0003] Example 12 Cleavages of Fmoc-Trp(Boc)-Wang resin Table 12. Cleavage of Fmoc-Trp(Boc)-Wang resin under different conditions Fmoc- Fmoc- Cleavage Brønsted TIS DTT Trp- Trp- Temper mmol Entry time Cleavage medium acid (% (% OH OH ature FeCl3 (min) (mmol) v / v) w / v) yield purity (%)a(%) TFA / DCM / TIS / H2O 1 120 rt no 5.0 no 76.2 96.9 (45:45:5:5) 2 30 45 °C DMC 0.59 HCl (1.18)b5.0 no 52.1 64.6 3 120 45 °C DMC 0.59 HCl (1.18)b5.0 no 45.3 54.1 4 30 45 °C DMC 0.59 HCl (0.59)b5.0 no 40.1 54.3 5 120 45 °C DMC 0.59 HCl (0.59)b5.0 no 38.6 63.7 AcOH 6 30 55 °C DMC 0.59 5.0 no 7.2 74.7 (0.59) AcOH 7 120 55 °C DMC 0.59 5.0 no 5.4 13.1 (0.59) 8 30 45 °C DMC 0.30 HCl (0.30)b2.5 no 31.7 75.8 9 120 45 °C DMC 0.30 HCl (0.30)b2.5 no 25.0 64.7 10 30 45 °C DMC 0.30 HCl (0.30)b2.5 5.0 73.5 91.0 11 120 45 °C DMC 0.30 HCl (0.30)b2.5 5.0 60.1 75.1 12 15 45 °C DMC 0.30 HCl (0.30)b2.5 2.5 85.6 93.8 13 60 45 °C DMC 0.30 HCl (0.30)b2.5 2.5 75.9 85.4 14 15 45 °C DMC 0.30 HCl (0.30)b2.5 5.0 84.7 95.4 15 60 45 °C DMC 0.30 HCl (0.30)b2.5 5.0 73.0 87.6 16 15 45 °C DMC 0.30 HCl (0.30)b5.0 5.0 82.4 95.5 17 60 45 °C DMC 0.30 HCl (0.30)b5.0 5.0 78.5 88.6 18 15 45 °C DMC 0.30 HCl (0.30)b5.0 10.0 82.5 96.5 19 60 45 °C DMC 0.30 HCl (0.30)b5.0 10.0 78.2 91.6 a Determined by LC-MS (294 nm) quantifying the amount of Fmoc-Trp-OH released into solution using a sample of Fmoc-Trp-OH as a reference standard;b4M HCl in dioxane was used. Example 13 Cleavages of Fmoc-His(Trt)-Wang resin Table 13. Cleavage of Fmoc-His(Trt)-Wang resin under different conditions Fmoc- Fmoc- Brønsted TIS DTT Cleavage Tempe Cleavage mmol His-OH His-OH Entry acid ( % (% time (min) rature medium FeCl3 yield purity (mmol) v / v) w / v) (%)a(%) TFA / DCM / 1 120 rt TIS / H2O no no 5.0 no 86.0 98.5 (45:45:5:5) 2 30 45 °C DMC 0.59 5.0 no 34.3 35.0 3 120 45 °C DMC 0.59 5.0 no 53.1 44.3 HCl 4 30 45 °C DMC 0.59b5.0 no 32.1 30.0 (0.59) HCl 5 120 45 °C DMC 0.59b5.0 no 47.2 50.7 (0.59) AcOH 6 30 55 °C DMC 0.59 5.0 no 70.1 63.2 (0.59) AcOH 7 120 55 °C DMC 0.59 5.0 no 71.5 84.2 (0.59) AcOH 8 30 55 °C DMC 0.30 2.5 no 48.2 60.3 (0.30) AcOH 9 120 55 °C DMC 0.30 2.5 no 66.8 81.0 10 180 55 °C DMC 0.30 AcOH 2.5 no 83.1 88.0 (0.30) AcOH 11 30 55 °C DMC 0.30 2.5 5.0 42.9 54.8 (0.30) AcOH 12 120 55 °C DMC 0.30 2.5 5.0 65.2 81.4 (0.30) AcOH 13 180 55 °C DMC 0.30 2.5 5.0 81.4 91.0 (0.30) a Determined by LC-MS (294 nm) quantifying the amount of Fmoc-His-OH released into solution using a sample of Fmoc-His-OH as a reference standard;b4M HCl in dioxane was used. Example 14 Cleavages of Fmoc-Cys(Trt)-Wang resin Table 14. Cleavage of Fmoc-Cys(Trt)-Wang resin under different conditions Fmoc Fmoc- Cleavage Brønsted -Cys- Cys- Entry time Temperature Cleavage mmol acid Scavenger OH OH medium FeCl3 (%w / v) (min) (mmol) yield purity (%)a(%) TFA / DCM / TIS / 1 120 rt no no no 40.5 90.9 H2O (1:1) 2 30 45 °C DMCc0.59 HCl (1.18)bno 0.0 0.030 45 °C DMCcAcOH 0.30 (0.30)no 0.0 0.04 120 45 °C DMCcAcOH 0.30 (0.30)no 0.0 0.0AcOH 5 30 45 °C DMCc0.30 5.0 (DTT) 42.1 70.7 (0.30) c AcOH 6 120 45 °C DMC 0.30 5.0 (DTT) 49.2 68.2 (0.30) c AcOH 7 30 45 °C DMC 0.30 10.0 (DTT) 44.0 78.2 (0.30) c AcOH 8 120 45 °C DMC 0.30 10.0 (DTT) 54.7 76.0 (0.30) c AcOH 9 30 45 °C DMC 0.30 5.0 (DITU) 0.0 0.0 (0.30) c AcOH 10 120 DMC 0.30 5.0 (DITU) 0.0 0.0 (0.30) a Determined by LC-MS (294 nm) quantifying the amount of Fmoc-Cys-OH released into solution using a sample of Fmoc-Cys-OH as a reference standard;b4M HCl in dioxane was used;cTIS (5% (v / v) of total volume) used as a scavenger. Example 15 Cleavages of Fmoc-Tyr(t-Bu)-Wang resin Table 15. Cleavage of Fmoc-Tyr(t-Bu)-Wang resin under different conditions Cleavage Brønsted Fmoc- Fmoc- mmol Entry time Temperature Cleavage medium acid Tyr-OH Tyr-OH FeCl3 (min) (mmol) yield (%)apurity (%) TFA / DCM / TIS / H2O 1 120 rt no no 84.8 99.4 (45:45:5:5) 2 30 45 °C DMCc0.59 HCl (1.18)b51.9 67.9 3 120 45 °C DMCc0.59 HCl (1.18)b21.5 33.7 4 30 45 °C DMCc0.59 HCl (0.59)b54.7 76.2 5 60 45 °C DMCc0.59 HCl (0.59)b52.6 67.9 AcOH 6 30 55 °C DMCc0.59 (0.59 43.1 96.1 mmol) AcOH 7 60 55 °C DMCc0.59 (0.5957.2 91.7mmol) a Determined by LC-MS (294 nm) quantifying the amount of Fmoc-Tyr-OH released into solution using a sample of Fmoc-Tyr-OH as a reference standard;b4M HCl in dioxane was used;cTIS (5% (v / v) of total volume) used as a scavenger.

[0004] Example 16 Cleavages of Fmoc-Ser(t-Bu)-Wang resin Table 16. Cleavage of Fmoc-Ser(t-Bu)-Wang resin under different conditions Fmoc- Fmoc- Brønsted Ser- Ser- Cleavage mmol Entry Temperature Cleavage medium acid OH OH time (min) FeCl3 (mmol) yield purity (%)a(%) 85.1 93.3 58.6 64.8 3 120 45 °C DMCcHCl 0.59 (1.18)b9.8 13.3c HCl 4 30 45 °C DMC 0.59 (0.59)b83.6 83.7HCl 5 60 45 °C DMCc0.59b75.4 79.0 (0.59) 6 30 55 °C DMCcAcOH 0.59 (0.59)82.4 95.27 60 55 °C DMCcAcOH 0.59 (0.59)85.0 93.3a Determined by LC-MS (294 nm) quantifying the amount of Fmoc-Ser-OH released into solution using a sample of Fmoc-Ser-OH as a reference standard;b4M HCl in dioxane was used;cTIS (5% (v / v) of total volume) used as a scavenger. Example 17 Cleavages of Fmoc-Lys(Boc)-Wang resin Table 17. Cleavage of Fmoc-Lys(Boc)-Wang resin under different conditions Fmoc- Fmoc- Cleavage Brønsted Lys-OH Entry time Temperature Cleavage medium acid FeCl yiel min) 3 d ( (mmol) (%)a(%) TFA / DCM / TIS / H2O 1 120 rt no no 74.1 93.3 (45:45:5:5) 2 30 45 °C DMCc0.5975.9 88.9 3 120 45 °C DMCc0.5955.1 61.4 4 30 45 °C DMCc0.59 77.6 91.0 5 60 45 °C DMCc0.59 71.0 86.1 c AcOH 6 30 55 °C DMC 0.59 >98 98.1 (0.59) AcOH 7 60 55 °C DMCc0.59 >98 97.2 (0.59) a Determined by LC-MS (294 nm) quantifying the amount of Fmoc-Lys-OH released into solution using a sample of Fmoc-Lys-OH as a reference standard;b4M HCl in dioxane was used;cTIS (5% (v / v) of totalvolume) used as a scavenger. Example 18 Cleavages of Fmoc-Lys(Trt)-Wang resin Table 18. Cleavage of Fmoc-Lys(Trt)-Wang resin under different conditions Fmoc- Cleavage Brønsted Fmoc- Entry time Temperature Cleavage medium acid Lys-OH FeC (min) l3 (mmol) purity (%) TFA / DCM / TIS / H2O 1 120 rt no no 95.3 99.5 (45:45:5:5) 2 30 45 °C DMCc0.69.1 3 120 45 °C DMCc0.59 65.7 64.6 4 30 45 °C DMCcHCl 0.59 (0.59)b65.5 70.960 45 °C DMCc0.5981.8 c AcOH 6 30 55 °C DMC 0.59 90.2 95.7 (0.59) 0 55 °C DMCcAcOH 7 6 0.59 (0.59)91.9 99.1a Determined by LC-MS (294 nm) quantifying the amount of Fmoc-Lys-OH released into solution using a sample of Fmoc-Lys-OH as a reference standard;b4M HCl in dioxane was used;cTIS (5% (v / v) of total volume) used as a scavenger. Example 19 Table 19. Cleavage of Fmoc-Ser(t-Bu)-Wang resin under different conditions Fmoc- Fmoc- Brønsted Glu- Glu- Cleavage mmol Entry time (min) Temperature Cleavage medium FeCl acid OH OH 3 (mmol) yield purity (%)a(%) TFA / DCM / TIS / H O 1 120 rt 2 no >98 99.8 (45:45:5:5) c HCl 2 30 45 °C DMC 0.59b67.7 69.3 (1.18) 3 120 45 °C DMCc0.59 36.6 32.9 4 30 45 °C DMCc0.5994.8 80.3 c AcOH 5 30 55 °C DMC 0.59 (0.59)72.5 97.36 60 55 °C DMCcAcOH 0.59 (0.59)>98 94.8a Determined by LC-MS (294 nm) quantifying the amount of Fmoc-Glu-OH released into solution using a sample of Fmoc-Glu-OH as a reference standard;b4M HCl in dioxane was used;cTIS (5% (v / v) of total volume) used as a scavenger. Example 20 Cleavages of Fmoc-Glu(OtBu)-Wang resin Table 20. Cleavage of Fmoc-Ser(t-Bu)-Wang resin under different conditions Fmoc- Fmoc- Brønsted Glu- Glu- Cleavage mmol Entry Temperature Cleavage medium acid OH OH time (min) FeCl3 (mmol) yield purity (%)a(%) TFA / DCM / TIS / H2O 1 120 rt no no >98 99.8 (45:45:5:5) 5 30 55 °C DMCcAcOH 0.59 (0.59)72.5 97.36 60 55 °C DMCcAcOH 0.59 (0.59)>98 94.8a Determined by LC-MS (294 nm) quantifying the amount of Fmoc-Glu-OH released into solution using a sample of Fmoc-Glu-OH as a reference standard;b4M HCl in dioxane was used;cTIS (5% (v / v) of totalvolume) used as a scavenger. Example 21 Cleavage of Fmoc-Cys(Trt) Wang resin forming (Fmoc-Cys-OH)2 Scheme SX1. Cleavage of Fmoc-Cys(Trt)-Wang resin by FeCl3 / AcOH in DMC / TIS forming (Fmoc-Cys-OH)2 Experimental: 100 mg of 0.28M Fmoc-Cys(Trt) Wang resin (0.028 mmol) was weighed into a 2 mL fritted syringe. Next, 48.6 mg (0.30 mmol) FeCl3, 933 µL DMC, 50 µL TIS and 17.2 µL (0.30 mmol) AcOH were added, the syringe was sealed and shaken (400 rpm) on an IKA® KS basic 130 apparatus (Green Chem.2019, 21, 2594, Figure S4) at 45 ^C and 50 µL aliquots of the reaction mixture were taken out 0.5 h and 1.0 h, respectively. These aliquots were added to 0.95 mL MeCN and analyzed by LC-MS. The yield of (Fmoc-Cys-OH)2 obtained 0.5 h and 1.0 h respectively was determined using 10.0 mg Fmoc-Cys(Trt)-OH as a reference, which was treated with 1.0 mL TFA / DCM / TIS / H2O (45:45:5:5) for 2 h and diluted with MeCN to 10.0 mL to furnish a sample of an Fmoc- Cys-OH (Figure 11). As the Fmoc-Cys-OH reference has one Fmoc group and the (Fmoc-Cys-OH)2 product has two, it was assumed that the amount of (Fmoc-Cys-OH)2 was half of what the determination using Fmoc-Cys-OH as the reference would indicate. The concentrations of (Fmoc-Cys-OH)2 product in the aliquots of the reaction mixtures were thus determined using the Fmoc-Cys-OH reference released from the Fmoc-Cys(Trt)-OH material. Next, the amounts of (Fmoc-Cys-OH)2 released from the resin after 0.5 h and 1.0 h were calculated. Based on the known amount of the starting Fmoc-Cys(Trt) Wang starting resin, the yields of (Fmoc-Cys-OH)2 for the cleavage depicted in Scheme SX1 were determined as 13.3% (0.5 h) and 13.6% (1.0 h). LC-MS analyses were performed on a Thermoscientific MSQ Plus in a positive mode (ESI) coupled with Dionex UltiMate 3000. HPLC conditions: Waters XSelect Peptide CSH130 C18 XP 2.5µ 4.6x150mm column, TFA / H2O (0.1:100, A), TFA / MeCN (0.1:100 B) as buffers, 10% B to 90% B over 15 min gradient, flow of 0.6 mL min-1, detection at 294 nm, column temperature 30 ^C and inj. volume 5.0 µL. Example 22 Global deprotection and cleavage from resin of Boc-Val-Gln(Trt)-Aib-Aib-Ile-Asp(Ot- Bu)-Tyr(t-Bu)-Ile-Asn(Trt)-Gly – RMG resin forming H-Val-Gln-Aib-Aib-Ile-Asp-Tyr-Ile- Asn-Gly-NH2 (Aib-ACP) under different conditions as set out in tables 22 and 26 to 31. Experimental: a) Synthesis of Aib-ACP RMG AMS resin. The Aib-ACP RMG AMS resin synthesized in Green Chem.2019, 21, 5990 was used. Thus, the synthesis commenced with 37.04 g of 0.27 M Fmoc-RMG AMS resin (10 mmol) and furnished 51.24 of the final, dried Aib-ACP RMG resin, meaning that the theoretically attainable amount of Aib-ACP which could be cleaved off the Aib-ACP RMG resin was 0.195 mmol g-1. b) Cleavages of Aib-ACP RMG resin. All cleavages were carried out using 500 mg, 0.098 mmol of the Aib-ACP RMG resin. The resin was weighed into a 10 mL fritted syringe. Next, reagents and solvents used in the cleavage as stated in tables 22 and 26 to 31 were added to the syringe. For the cleavage carried out in TFA cocktail, TIS and water were added first, followed by TFA. For the cleavages carried out in TFA-free cocktails, the Lewis acids were added first, followed by adding a solvent and, if used, scavenger(s) were added. A Brønsted acid was added as the last reagent. In all cases, the total volume of solvents and liquid reagents was 10 mL g-1Aib-ACP RMG resin. The syringes were sealed and shaken (400 rpm) on an IKA® KS basic 130 apparatus (Green Chem.2019, 21, 2594, Figure S4) at the temperatures stated in tables 22 and 26 to 31. Upon completion of all cleavages the reaction mixtures were diluted (1:20) with 2M NH4OAc in MeCN / H2O (1:9) and analyzed by LC-MS. The yields of all Aib- ACP products were determined relative to the cleavage in TFA / TIS / H2O (92.5:5.0:2.5; v / v / v) which gave Aib-ACP in 84% yield (Green Chem.2019, 21, 5990). Thus, for each cleavage Aib-ACP RMG resin cleavage, LC-MS area of the product (in mAu x min) was determined, and the cleavage yield was calculated vs the TFA / TIS / H2O (92.5:5.0:2.5) cleavage, which was taken to be 84%. LC-MS analyses were performed on a Thermoscientific MSQ Plus in a positive mode (ESI) coupled with Dionex UltiMate 3000. HPLC conditions: Waters XSelect Peptide CSH130 C18 XP 2.5µ 4.6x150mm column, TFA / H2O (0.1:100, A), TFA / MeCN (0.1:100 B) as buffers, 10% B to 90% B over 15 min gradient, flow of 0.6 mL min-1, detection at 220 nm, column temperature 30 °C and inj. volume 5.0 µL. Table 22. Cleavage of Aib-ACP RMG resin under different conditions Aib- Cleavage Lewis acid Brønsted ACP Aib-ACP medium (equiv) acid (equiv) yield purity (%) (%)aTFA / TIS / H2O 1 2.0 rt no no 84.0 74.4 (92.5:5:2.5) 2 16.0 rt DMC FeCl2 (5.0) HCl (70.0)b3.0 23.3 3 4 5 16.0 rt DMC FeCl3 (5.0) HCl (70.0)b20.2 53.9 6 16.0 rt DMC n.a. HCl (70.0)b4.5 14.7 7 0.5 45 °C DMC FeCl3 (15.0) n.a. 0.2 4.2 8 0.5 45 °C DMC FeCl3 (5.0) HCl (70.0)b6.1 34.6 9 0.5 45 °C DMCcFeCl3 (5.0) HCl (70.0)b13.6 45.3 10 0.5 45 °C DMC FeCl3 (15.0) HCl (70.0)b60.7 65.5 11 0.5 45 °C MeCN FeCl3 (15.0) HCl (70.0)b59.0 52.1 AcOH 12 0.5 45 °C DMC FeCl3 (15.0) (70.0)66.4 43.313 0.5 45 °C MeCN FeCl3 (15.0) AcOH (70.0)6.7 6.7Fe(acac)3 14 0.5 45 °C DMC HCl (70.0)b64.3 55.3 (15.0) Fe(acac)3 15 0.5 45 °C MeCN HCl (70.0)b52.5 40.6 (15.0) Fe(acac)3 16 0.5 45 °C MeCN HCl (70.0)b61.6 56.2 (30.0) Fe(acac)3 17 2.0 45 °C MeCN HCl (70.0)b50.3 54.7 (30.0) Fe(acac) 18 0.5 45 °C DMC 3 AcOH (30.0) (70.0)0.0 0.0Fe(acac) AcO 19 0.5 45 °C MeCN 3 H (30.0) (70.0)0.0 0.020 2.0 45 °C MeCN FeCl3(15.0) HCl (70.0)b43.2 42.6 21 0.5 45 °C MeCNcFeCl3 (15.0) HCl (70.0)b52.8 49.1 22 2.0 45 °C MeCNcFeCl3 (15.0) HCl (70.0)b40.2 42.9 23 0.5 45 °C MeCNdFeCl3 (15.0) HCl (70.0)b56.8 45.0 24 2.0 45 °C MeCNdFeCl3 (15.0) HCl (70.0)b41.4 38.1 25 0.5 45 °C DMC FeCl3 (30.0) HCl (70.0)b62.3 63.7 26 0.5 45 °C DMCcFeCl3 (30.0) HCl (70.0)b68.6 61.1 27 0.5 45 °C DMCcFeCl3 (7.5) HCl (70.0)b11.4 54.1 28 0.5 45 °C DMC FeCl3 (30.0) HCl (30.0)b70.9 61.3 29 0.5 45 °C DMC FeCl3 (30.0) HCl (20.0)b80.0 66.3 AcOH 30 0.5 45 °C DMC FeCl3 (30.0) (140.0)79.3 68,7AcOH 31 0.5 45 °C DMC FeCl3 (30.0) 79.9 68.0 (70.0) AcOH 32 0.5 45 °C DMC FeCl3 (30.0) (30.0)65.7 64.9a Determined by LC-MS (220 nm) quantifying the amount of Aib-ACP released into solution using a sample of Aib-ACP released off AiB ACP RMG AMS resin using entry 1 cleavage conditions (Green Chem.2019, 21, 5990) as a reference standard;b4M HCl in dioxane was used;cTIS (5% (v / v) of total volume) used as a scavenger;dTIS (10% (v / v) of total volume) used as a scavenger. Table 23 presents the significant peaks of the chromatogram depicted in figure 1. Peak no.21 is Aib- ACP. Table 23. Area% for integrated peaks in Aib-ACP obtained from Table 22, entry 1 cleavage of Aib-ACP RMG AMS resin (chromatogram of figure 1). Peak no. Ret.time (min) Height (mAU) area (%) (mAU*min) 1 5.933 0.53 0.1931 3.34 2 6.063 0.13 0.0481 1.19 3 6.113 0.13 0.0480 1.21 4 6.373 0.06 0.0209 0.69 5 6.420 0.07 0.0264 0.83 6 6.477 0.36 0.1321 2.44 7 6.560 0.10 0.0377 1.12 8 6.673 0.61 0.2221 5.20 9 6.743 2.34 0.8515 15.29 10 6.830 0.79 0.2863 6.49 11 7.060 0.61 0.2216 5.81 12 7.113 1.09 0.3977 9.37 13 7.207 0.95 0.3459 5.21 14 7.287 0.27 0.0985 2.27 15 7.377 0.46 0.1654 3.89 16 7.477 1.07 0.3874 8.98 17 7.580 0.77 0.2802 7.16 18 7.630 0.39 0.1425 3.16 19 7.710 1.99 0.7224 9.40 20 7.800 0.86 0.3132 8.08 21 7.870 74.38 27.0325 615.46 22 8.007 1.43 0.5213 11.82 23 8.080 0.27 0.0990 2.50 24 8.213 1.98 0.7210 17.12 25 8.260 0.49 0.1775 4.97 26 8.317 0.30 0.1078 2.45 27 8.437 1.71 0.6225 13.06 28 8.657 0.35 0.1275 1.96 29 8.833 0.16 0.0589 1.10 30 8.940 0.23 0.0829 1.80 31 9.110 0.55 0.2010 4.07 32 9.220 0.41 0.1481 3.86 33 9.330 0.06 0.0217 0.57 34 9.427 0.13 0.0455 1.28 35 9.573 0.52 0.1875 4.03 36 10.373 3.44 1.2493 17.66 Sum 100.00 36.3453 804.82 Table 24 presents the significant peaks of the chromatogram depicted in Figure 2. Peak no. 15 is Aib-ACP. Table 24. Area% for integrated peaks in Aib-ACP obtained from Table 22, entry 29 cleavage of Aib-ACP RMG AMS resin (chromatogram of Figure 2). Area Peak no. Ret.time (min) area (%) (mAU*min) Height (mAU) 1 6.660 1.02 0.3965 10.17 2 6.727 2.20 0.8541 15.33 3 6.817 0.57 0.2210 5.53 4 7.043 0.43 0.1682 4.78 5 7.097 0.75 0.2918 7.30 6 7.193 0.81 0.3152 5.06 7 7.277 0.22 0.0860 2.29 8 7.363 0.26 0.0991 2.56 9 7.463 0.86 0.3326 7.85 10 7.563 0.58 0.2254 5.87 11 7.620 0.30 0.1168 2.80 12 7.693 1.14 0.4445 9.23 13 7.727 0.70 0.2724 7.19 14 7.787 0.58 0.2243 6.45 15 7.857 66.29 25.7514 581.52 16 7.993 1.13 0.4397 10.55 17 8.060 0.28 0.1069 2.63 18 8.203 2.76 1.0736 16.85 19 8.423 2.84 1.1049 23.18 20 8.820 0.27 0.1055 2.38 21 9.087 0.71 0.2754 4.82 22 9.210 0.36 0.1413 3.58 23 9.560 4.20 1.6326 38.35 24 10.350 6.38 2.4779 34.67 25 11.327 0.68 0.2632 2.68 26 11.607 3.16 1.2263 29.04 27 11.870 0.51 0.1987 2.79 Sum 100.00 38.8454 845.45 Table 25. Area% for integrated peaks in Aib-ACP obtained from Table 22, entry 30 cleavage of Aib-ACP RMG AMS resin. Area Peak no. Ret.time (min) Height (mAU) area (%) (mAU*min) 1 6.673 0.90 0.3332 8.49 2 6.743 2.15 0.8005 14.81 3 6.830 0.53 0.1980 4.95 4 7.060 0.37 0.1388 3.97 5 7.113 0.74 0.2768 7.65 6 7.210 0.61 0.2251 4.46 7 7.293 0.20 0.0750 2.41 8 7.380 0.17 0.0616 1.83 9 7.480 0.79 0.2939 6.98 10 7.583 0.65 0.2407 6.09 11 7.640 0.33 0.1235 2.90 12 7.710 1.88 0.6976 9.26 13 7.803 0.64 0.2395 6.18 14 7.873 68.65 25.5141 579.76 15 8.010 1.36 0.5069 11.74 16 8.090 0.26 0.0969 2.18 17 8.217 3.55 1.3183 17.44 18 8.430 5.18 1.9252 43.20 19 8.543 0.46 0.1693 5.30 20 8.660 0.23 0.0847 2.06 21 8.830 0.28 0.1052 2.73 22 9.113 0.66 0.2453 4.40 23 9.223 0.30 0.1119 3.39 24 9.577 2.72 1.0097 23.99 25 10.380 6.39 2.3748 34.93 Sum 100.00 37.1664 811.10

[0005] Example 23 Deprotection and cleavage from resin of Ac-D-2Nal-D-Phe(4Cl)-D-3Pal-Ser(tBu)- 4Aph(L-Hor)-D-4Aph(Cbm)-Leu-Lys(iPr,Boc)-Pro-D-Ala-RAM AMS resin to form Ac- D-2Nal-D-Phe(4Cl)-D-3Pal-Ser-4Aph(L-Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala- NH2 (degarelix). Experimental: a) Synthesis of degarelix RAM AMS resin. The degarelix RAM AMS resin was synthesized according to a previously disclosed protocol (WO 2010 / 121835) commencing with 4.872 kg of 1.95M AMS resin (9.5 mol) which upon loading of the Rink amide linker (Fmoc-RAM-OH) gave 8.5 mol of Fmoc-RAM AMS resin. Upon completing the synthesis, 26.504 kg of the final, dried degarelix RAM AMS resin was obtained, meaning that the theoretically attainable amount of degarelix which could be cleaved off the degarelix RAM AMS resin was 0.320 mmol g-1. b) Cleavages of degarelix RAM AMS resin. All cleavages were carried out using 100 mg, 0.032 mmol of the degarelix RAM AMS resin. The resin was weighed into a 2 mL fritted syringe and then reagents and solvents used in the cleavage as stated in Table X were added to the syringe. For the cleavages carried out in TFA-free cocktails, the Lewis acids were added first, followed by adding a solvent and, if used, scavenger(s) were added. A Brønsted acid was added as the last reagent. In all cases, the total volume of solvents and liquid reagents was 10 mL g-1 degarelix RAM AMS resin. The syringes were sealed and shaken (400 rpm) on an IKA® KS basic 130 apparatus (Green Chem.2019, 21, 2594, Figure S4) at the temperatures stated in Table 23. Upon completion of all cleavages, the reaction mixtures were diluted (1:6.6) with 2M NH4OAc in AcOH / EtOH / H2O (15:15:70) and analyzed by LC-MS. The yields of all degarelix products were determined using a sample of degarelix API as a reference standard (Figures 9 and 10). LC-MS analyses were performed on a Thermoscientific MSQ Plus in a positive mode (ESI) coupled with Dionex UltiMate 3000. HPLC conditions: Waters XSelect Peptide CSH130 C18 XP 2.5µ 4.6x150mm column, TFA / H2O (0.1:100, A), TFA / MeCN (0.1:100 B) as buffers, 10% B to 90% B over 15 min gradient, flow of 0.6 mL min-1, detection at 220 nm, column temperature 30 °C and inj. volume 1.0 µL. Table 26. Cleavage of degarelix-RAM resin under different conditions Ac-D-2Nal-D-Phe(4Cl)-D-3Pal-Ser-4Aph(L-Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2 (degarelix)Cleavage Cleavage Lewis acid Brønsted degarelix degarelix Entry time Temperature medium (equiv) acid (equiv) yield (%)apurity (%) (min) 1 120 rt TFA no no 71.5 95.3 2 30 45 °C DMC FeCl3 (18.4) HCl (36.8)b69.2 89.1 3 120 45 °C DMC FeCl3 (18.4) HCl (36.8)b60.4 71.7 4 30 45 °C DMC FeCl3 (18.4) no 0.9 81.8 5 30 45 °C DMC no HCl (36.8)b0.2 45.5 6 30 45 °C MeCN FeCl3 (18.4) HCl (36.8)b66.7 79.8 7 30 45 °C acetone HCl (36.8)b51.7 8 30 45 °C DMC HCl (36.8)b0.2 31.3 9 30 45 °C DMC AcOH (73.6) 34.7 94.2 AcOH 10 30 45 °C no FeCl3 (18.4) 29.2 88.3 (545.4) 11 10 45 °C DMC FeCl3 (18.4) HCl (36.8)b24.2 93.2 12 20 45 °C DMC FeCl3 (18.4) HCl (36.8)b52.6 91.8 13 60 45 °C DMC FeCl3 (18.4) AcOH (73.6) 32.9 92.9 14 120 45 °C DMC FeCl3 (18.4) AcOH (73.6) 61.7 91.2 15 15 45 °C DMC FeCl3 (18.4) HCl (36.8)b50.4 93.1 16 15 45 °C DMCcFeCl3 (18.4) HCl (36.8)b33.1 92.7 17 20 45 °C DMC FeCl3 (18.4) HCl (18.4)b37.7 95.3 18 20 45 °C DMC FeCl3 (9.2) HCl (36.8)b36.1 93.7 19 30 45 °C DMC FeCl3 (18.4) HCl (18.4)b60.6 94.3 20 30 45 °C DMC FeCl3 (18.4) HCl (12.2)b6.7 90.5 21 30 55 °C DMC FeCl3 (18.4) HCl (18.4)b65.1 91.8 22 30 55 °C DMC FeCl3 (18.4) HCl (12.2)b59.7 94.0 23 30 55 °C DMC FeCl3 (18.4) AcOH (18.4) 17.4 92.2 a Determined by LC-MS (220 nm) quantifying the amount of degarelix released into solution using a sample of degarelix API as a reference standard;b4M HCl in dioxane was used;cTIS (10% (v / v) of total volume) used as a scavenger. Example 24 Assessment of TFA vs a BA-LA cleavage of a GMP batch of degarelix peptide resin on 100 mg resin scale (RAM amide AM resin: 2-{[(R,S)-5-(9- Fluorenylmethyloxycarbonyl-amino)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2- yl]oxy}acetyl-AM resin. The protected degarelix peptide coupled to the RAM amide AM resin was cleaved using the following protocols: I: neat TFA, 2h rt neat TFA, 2h rt (entry 1 in Table 26) II: 18.4 equiv FeCl3 / 12.2 equiv HCl in DMC, 0.5h, 55 ^C (BA-LA protocol, entry 22 in Table 26) All degarelix cleavages were diluted (1:6.6) with 2M NH4OAc in AcOH / EtOH / H2O (15:15:70). Example 25 Desalting of Aib-ACP crudes and determination of residual Fe content. Samples of crude Aib-ACP cleaved off Aib-ACP resin by TFA cleavage cocktail (Table 22, entry 1) and by FeCl3 / HCl (Table 22, entry 28) followed by neutralization with 2M NH4OAc in 10% MeCN (100 mL) were diluted with 200 mL 0.1% AcOH. The resulting solutions were applied onto a 10 g pad of Amberchrom CG161M resin (fraction 1, load). The peptides were then eluted using i) 0.1% AcOH in 10% MeCN (200 mL, fraction 2); ii) 0.1% AcOH in 20% MeCN (200 mL, fraction 3); iii) 0.1% AcOH in 30% MeCN (200 mL, fraction 4). For Aib-ACP cleaved both by TFA (Figure 19) and by FeCl3 / HCl (Figure 20), most of the peptide was eluted in fraction 3. Most MeCN from fraction 3 of TFA cleaved and FeCl3 / HCl cleaved Aib-ACP was removed on a rotary evaporator under reduced pressure. The desalted material was then isolated by lyophilization on a Christ Alpha 2-4 LSC basic lyophilizer furnishing 13.5 mg of Aib-ACP for the material from the TFA cleavage and 12.1 mg for the material from FeCl3 / HCl cleavage, in both case as an off white solid. The LC-MS analysis of the desalted and lyophilized Aib-ACP materials revealed comparable purity for Aib-ACP from the TFA cleavage (83.15%, Table 26) and the FeCl3 / HCl cleavage (82.04%, Table 27) respectively and the molecular weight of Aib-ACP as the main product in these lyophilized materials was confirmed by MS analysis (Figures 23 and 24). For the desalted and lyophilized Aib- ACP materials stemming from TFA and FeCl3 / HCl cleavages of Aib-ACP RMG AMS resin the Fe content was determined by elemental analysis using inductively coupled plasma – sector field mass spectrometry (ICP-SFMS) with following results: i) Aib-ACP from TFA cleavage: 5.32 ppm Fe ii) Aib-ACP from FeCl3 / HCl cleavage: 81.8 ppm Fe iii) blank sample: <0.2 ppm Fe Determination of the efficiency of Fe removal from crude Aib-ACP obtained by FeCl3 / HCl cleavage of Aib-ACP resin was calculated as follows: 238.4 mg FeCl3 was used in the cleavage and taking into account molecular weight of FeCl3 [162.204] and the atomic weight of Fe [55.85], the amount of Fe used in the cleavage was 100.71 mg. Considering that i) the content of Fe in the isolated peptide as determined by ICP- SFMS was 81.8 ppm ii) the amount of isolated Aib-ACP was 12.1 mg means that 0.00098978 mg (0.00818%) of Fe from the cleavage was left in the lyophilized product. This means that the efficiency of Fe removal by desalting on the Amberchrom resin was 99.99182%. Table 27. Area% for integrated peaks in Fig.21 / 22 (black / lower graph fig.21). Peak Ret.time Rel. Area Height no. (min) (mAU*min) (mAU) 1 7.353 0.09 0.0558 1.64 2 7.450 0.64 0.4086 10.02 3 7.550 0.27 0.1710 4.76 4 7.603 0.38 0.2398 5.47 5 7.677 0.86 0.5465 11.63 6 7.713 0.70 0.4451 11.55 7 7.770 0.91 0.5776 16.65 8 7.837 83.15 52.8510 1174.66 9 7.977 1.83 1.1641 25.80 10 8.047 0.32 0.2050 5.11 11 8.180 3.14 1.9978 45.16 12 8.230 0.77 0.4914 12.93 13 8.280 0.43 0.2709 6.51 14 8.407 2.80 1.7805 38.59 15 8.620 0.35 0.2222 4.24 16 8.803 0.24 0.1520 3.02 17 8.893 0.05 0.0308 1.03 18 9.073 1.24 0.7876 13.36 19 9.187 0.05 0.0317 1.02 20 9.537 0.15 0.0943 2.48 21 10.350 1.63 1.0370 11.91 Sum 100.00 63.5607 1407.54 Table 28. Area% for integrated peaks in Fig.21 / 22 (blue / upper graph fig 21). Peak Ret.time Rel. Area Height no. (min) (mAU*min) (mAU) 1 5.123 1.23 0.7706 8.75 2 5.530 0.63 0.3938 7.13 3 6.993 0.15 0.0911 1.87 4 7.100 0.26 0.1650 4.66 5 7.293 0.10 0.0642 1.70 6 7.457 1.23 0.7707 15.49 7 7.560 0.13 0.0816 3.05 8 7.620 0.18 0.1098 3.27 9 7.727 1.58 0.9892 11.76 10 7.783 0.78 0.4849 13.61 11 7.850 82.04 51.2145 1152.28 12 7.987 1.41 0.8774 23.75 13 8.060 0.32 0.2011 6.72 14 8.170 0.77 0.4830 19.10 15 8.193 2.22 1.3829 33.67 16 8.290 0.45 0.2809 3.30 17 8.413 1.76 1.0987 22.71 18 8.633 0.35 0.2205 4.85 19 8.807 0.25 0.1576 2.39 20 9.090 0.78 0.4868 9.08 21 9.353 0.32 0.2017 2.54 22 9.557 0.15 0.0938 1.82 23 9.640 0.10 0.0612 0.99 24 9.823 0.30 0.1869 3.16 25 10.120 0.12 0.0727 0.91 26 10.363 1.70 1.0635 15.16 27 10.603 0.27 0.1670 0.96 28 11.090 0.24 0.1475 2.33 29 12.037 0.17 0.1072 1.57 Sum 100.00 62.4258 1378.57 In the following examples 26 to 29 the impact of water was investigated regarding the TFA-fee FeCl3 / AcOH induced global deprotection and cleavage of Boc-Val-Gln(Trt)- Aib-Aib-Ile-Asp(Ot-Bu)-Tyr(t-Bu)-Ile-Asn(Trt)-Gly – RMG resin forming H-Val-Gln-Aib- Aib-Ile-Asp-Tyr-Ile-Asn-Gly-NH2 (Aib-ACP) under the conditions as set out in tables 26 to 31. The analysis procedures of examples 26 to 29 were identical to those outlined in example 22. Reaction conditions of examples 26 to 29 were also very close to those of example 22 with the difference that water in varying amounts was present as set out in tables 29, 30 and 31. In example 26 specifically anhydrous FeCl3 was compared to FeCl36 H2O (table 28). Furthermore, in example 27 (entries 5 and 6) FeCl36 H2O without addition of separate water was compared to anhydrous FeCl3 with the addition of 180 equiv of water corresponding to the water content of FeCl36 H2O. Both reactions failed to yield Aib- ACP suggesting that it does not matter if water is coordinated to FeCl3 or added separately in the same amount to anhydrous FeCl3. Cleavage conditions with TFA and analytical conditions examples 26-29: Org Lett, 2024, SI page 283 / 575, table S362.

[0006] Example 26 FeCl3 anhydrous versus hydrate form (FeCl36 H2O) and reaction time Table 29 FeCl3 anhydrous versus hydrate form and reaction time Cleavage Cleavage Lewis acid Brønsted Yield Entry TemperatureaPurity (%) time medium equiv acid equiv (%) TFA / TIS / H2O 1 2 h rt NA NA 84 %174 %1(92.5 / 5 / 2.5) 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 86 % 61 % 2 3 4 h 40-45 °C DMC FeCl3 (30) AcOH (70) 30 % 23 % FeCl3 4 0.5 h 40-45 °C DMC AcOH (70) 0 % NA 6H2O (30) FeCl3 5 4 h 40-45 °C DMC AcOH (70) 7 % 10 % 6H2O (30) a Determined by LC-MS (220 nm) quantifying the amount of Aib-ACP released into solution using a sample of Aib-ACP released off AiB ACP RMG AMS resin using entry 1 cleavage conditions (Green Chem.2019, 21, 5990) as a reference standard Figures 26 and 27 illustrate the chromatograms from entries 1 to 5 (bottom to top). Figure 27 is the zoomed part of the chromatogram of figure 26 between 6 and 14 minutes. Example 27 Equimolar water addition either with regard to FeCl3, AcOH or FeCl36 H2O. Table 30 Equimolar water addition Cleavage Entry Temperature Cleavage medium Lewis acid (equiv) time TFA / TIS / H2O 1 2 h rt NA (92.5 / 5 / 2.5) 2 0.5 h 40-45 °C DMC FeCl3 (30) 3 0.5 h 40-45 °C DMC FeCl3 (30) 4 0.5 h 40-45 °C DMC FeCl3 (30) 5 0.5 h 40-45 °C DMC FeCl3 (30) 6 0.5 h 40-45 °C DMC FeCl36H2O (30) Table 30 cont. Brønsted acid Water content Aib-ACP yield Aib-ACP purity Entry (equiv) (equiv) (%)a(%) 1 NA NA 84 % 74 % 2 AcOH (70) NA 86 % 61 % 3 AcOH (70) H2O (30) 90 % 49 % 4 AcOH (70) H2O (70) 42 % 26 % 5 AcOH (70) H2O (180) 0 % NA 6 AcOH (70) NA 0 % NA a Determined by LC-MS (220 nm) quantifying the amount of Aib-ACP released into solution using a sample of Aib-ACP released off AiB ACP RMG AMS resin using entry 1 cleavage conditions (GreenChem. 2019, 21, 5990) as a reference standardFigures 28 and 29 illustrate the chromatograms from entries 1 to 6 (bottom to top). Figure 29 is the zoomed part of the chromatogram of figure 27 between 6 and 14 minutes. Example 28 Impact of water during TFA-free deprotection and cleavage from resin for water contents from zero (entry 2) to 85 eq. (entry 11). The resin bound Aib-ACP peptide had Trt as side chain protecting groups. At an increased water content, not only was the peptide cleavage reduced but also the ability of the FeCl3 / AcOH cleavage composition to deprotect the Trt side chain protecting groups. Evidently, the content of Trt side chain protected (non-deprotected) Aib-ACP increased with increased water content. Table 31 Cleavage Lewis acid Brønsted acid Entry Cleavage time Temp. medium equiv equiv TFA / TIS / H2O 1 2 h rt NA NA (92.5 / 5 / 2.5) 2 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 3 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 4 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 5 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 6 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 7 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 8 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 9 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 10 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 11 0.5 h 40-45 °C DMC FeCl3(30) AcOH (70) Table 31 cont. Water content Aib-ACP Yield Aib-ACP Peptide+Trt equiv (ppm) (%)aPurity (%) Purity (%) 1 NA 84 %174 %10.12 % 2 NA 93 % 62 % 0.44 % H2O 3 100 % 61 % 0.47 % 0.5 (176 ppm) H2O 4 91 % 60 % 0.31 % 1 (352 ppm) H2O 5 97 % 60 % 0.22 % 5 (1758 ppm) H2O 6 94 % 58 % 7.54 % 10 (3517 ppm) H2O 7 93 % 55 % 13.77 % 20 (7034 ppm) H2O 8 92 % 50 % 19.38 % 30 (10550 ppm) H2O 9 68 % 34 % 37.07 % 60 (21101 ppm) H2O 10 54 % 26 % 44.58 % 70 (24617 ppm) H2O 11 41 % 24 % 44.13 % 85 (29893 ppm) a Determined by LC-MS (220 nm) quantifying the amount of Aib-ACP released into solution using a sample of Aib-ACP released off AiB ACP RMG AMS resin using entry 1 cleavage conditions (GreenChem. 2019, 21, 5990) as a reference standardFigures 30 and 31 illustrate the chromatograms from entries 1 to 11 (bottom to top). Figure 31 is the zoomed part of the chromatogram of figure 30 between 8 and 13 minutes. Example 29 Impact of water during TFA-free deprotection and cleavage from resin of water contents from 70 eq (entry 3) to 200 eq (entry 10). Table 32 Cleavage Cleavage Lewis acid Brønsted acid Entry Temp. time medium equiv equiv TFA / TIS / H2O 1 2 h rt NA NA (92.5 / 5 / 2.5) 2 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 3 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 4 2 h 40-45 °C DMC FeCl3 (30) AcOH (70) 5 0.5 h 40-45 °C DMC FeCl3(30) AcOH (70) 6 0.5 h 40-45 °C DMC FeCl3(30) AcOH (70) 7 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) 8 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) FeCl3 9 0.5 h 40-45 °C DMC AcOH (70) 6H2O (30) 10 0.5 h 40-45 °C DMC FeCl3 (30) AcOH (70) Table 32 cont. Water Aib-ACP Aib-ACP Impurity 2 Impurity 3 Peptide+Trt Entry content Yield a Purity (%) purity (%) purity (%) Purity (%) equiv (%) 1 NA 84 %174 %11.20 % 0.43 % 0.12 % 2 NA 93 % 62 % 5.88 % 3.69 % 0.44 % 3 H2O (70) 30 % 22 % 1.53 % 0.08 % 43.09 % 4 H2O (70) 75 % 40 % 7.27 % 0.15 % 24.08 % 5 H2O (85) 16 % 17 % 1.37 % 0.08 % 39.20 % 6 H2O (100) 7 % 12 % 1.00 % NA 35.97 % 7 H2O (150) 0 % 1 % NA NA 16.14 % 8 H2O (180) 0 % NA NA NA 7.36 % 9 NA 0 % NA NA NA 7.90 % 10 H2O (200) 0 % NA NA NA 4.53 % a Determined by LC-MS (220 nm) quantifying the amount of Aib-ACP released into solution using a sample of Aib-ACP released off AiB ACP RMG AMS resin using entry 1 cleavage conditions (GreenChem. 2019, 21, 5990) as a reference standardFigures 32 and 33 illustrate the chromatograms from entries 1 to 10 (bottom to top). Figure 31 is the zoomed part of the chromatogram of figure 30 between 8 and 13 minutes. -------------------------------

Claims

1 1. A method for cleaving bonds in (of) an organic compound coupled to a support, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups between the organic compound and the linker coupled to a support the method comprising: a) subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension comprising the organic compound; b) maintaining the solution or suspension comprising the organic compound at a temperature and duration thereby forming a partially and / or fully deprotected organic compound coupled to the support and / or forming a partially and / or fully deprotected organic compound not coupled to the support.

2. The method according to claim 1, wherein the content of water is below about 100 equiv, preferably below about 95 equiv. such as below about 90 equiv. or below about 85 equiv.

3. The method according to claim 1 or 2, wherein the support is selected from soluble and solid supports.

4. The method according to claim 1, wherein the support is a solid support.

5. The method according to any one of the preceding claims, wherein the organic compound is a polypeptide.

6. The method according to any one of the preceding claims, wherein the protecting groups are acid-labile protecting groups, and the linker is an acid-labile linker.

7. The method according to any one of the preceding claims, wherein the Lewis acid is in oxidation states +II and +III.

8. The method according to claim 1, wherein the Lewis acid is in oxidation state +II and +III and selected from compounds of formula MXy,where y is 2 or 3; M is selected from V, Cr, Mn, Fe, Co, Ni, Cu, Zn, B, and Al; and X is selected from F, Cl, Br, I, acetate and acetylacetonate.

9. The method according to claim 1, wherein the Lewis acid is in oxidation state +III and selected from compounds of formula MX3; M is selected from V, Cr, Mn, Fe, Co, Ni, Cu, Zn, B, and Al; and X is selected from F, Cl, Br, and I.2 10. The method according to any one of the preceding claims, wherein the Brønsted acid does not contain fluorine atoms.

11. The method according to any one of the preceding claims, wherein the Brønsted acid has a pKa (in water) below about 7.0, preferably below about 6.

0.

12. The method according to claim 1, wherein the composition is essentially free from fluorine atoms.

13. The method according to any one of the preceding claims, wherein the Brønsted acid is selected from carboxylic acids, hydrogen halides of formula H-Z where Z is selected from Cl, Br and I, sulphonic acids, sulfuric acid, and phosphoric acid.

14. The method according to any one of the preceding claims, wherein the Brønsted acid is selected from formic acid; compounds with the formula X3C-COOH where X is selected from H, Cl, Br and I; hydrobromic acid (HBr); hydrochloric acid (HCl); sulfuric acid (H2SO4): phosphoric acid (H3PO4), methanesulfonic acid (MsOH); toluenesulfonic acid (TsOH); and Camphorsulfonic acid (CsOH).

15. The method according to any one of the preceding claims, wherein the Brønsted acid is selected from acetic acid (AcOH), trichloracetic acid (TCA), tribromoracetic acid (TBA), triiodoacetic acid (TIA), hydrobromic acid (HBr), and hydrochloric acid (HCl).

16. The method according to any one of the preceding claims, wherein the solvent is an aprotic organic solvent not containing any one of: amide function, thionyl group, and carbon-fluorine bonds.

17. The method according to any one of the preceding claims, wherein the solvent is selected from acetonitrile (MeCN), dichloromethane (DCM), alkyl acetates such as ethyl acetate (EtOAc), dioxane, 1,3 dioxolane (DOL), tetrahydrofuran (THF), tetrahydropyran (THP), 2-methyltetrahydrofuran (2-MeTHF), 4-methyltetrahydropyran (4-MeTHP), toluene (Tol), anisole (Ani), 1,2-dimethoxybenzene (1,2-DMB), 1,3- dimethoxybenzene (1,3-DMB), n-hexane (Hex), n-heptane (Hep), petroleum ether (PE), cyclopentylmethyl ether (CPME), tert-Butylmethylether (TBME), dipropyleneglycol dimethylether (DMM), dimethyl carbonate (DMC), diethyl carbonate (DEC), propylene carbonate (PC), dimethyl isosorbide (DMI), and gammavalerolactone (GVL).3 18. The method according to any one of the proceeding claims, wherein the solvent is selected from acetonitrile (MeCN), dichloromethane (DCM), ethyl acetate (EtOAc), dioxane, tetrahydrofuran (THF), tetrahydropyran (THP), 2-methyltetrahydrofuran (2- MeTHF), 4-methyltetrahydropyran (4-MeTHP), dimethyl carbonate (DMC), 1,3 dioxolane (DOL), and toluene.

19. The method according to any one of the preceding claims, wherein the temperature during cleavage is in the range from about 30°C up to about 70°C, preferably from about 30°C up to about 60°C, such as from about 35°C up to about 50°C.

20. The method according to any one of the preceding claims, wherein the linker is an acid labile linker selected from the linker is selected from acid labile linkers such as Wang ([4-(hydroxymethyl)phenoxymethyl]) linker, 2CT (2-chlorotrityl) linker, 2-CT- COOH (2-chloro)-4’-carboxy-triphenyl methanol) linker, Trt (trityl) linker, Trt-COOH (trityl carboxyl) linker, Rink (amide) (4-(((9-fluorenylmethoxycarbonyl)amino) (2,4- dimethoxyphenyl)methyl)phenoxy)acetic acid) linker, Ramage (RMG) ((R,S)-2- { [5- (9-fluorenylmethyloxycarbonylamino)-dibenzo [a,d]cycloheptane-2-yl]oxy}-acetic acid) linker, Pal (5-[4-(9-fluorenylmethoxycarbonyl)aminomethyl-3,5- dimethoxyphenoxy]-pentanoic acid) linker, Sieber (9- (9- fluorenylmethyloxycarbonylamino)-9H-xanthen-3-yl-oxymethyl) linker, SASRIN (4- Hydroxymethyl-3-methoxyphenoxyacetic acid) linker, HMPA (hydroxymethylphenoxyacetic acid) linker, DHP (dihydropyranyl) linker, 4-MBH (4- methylbenzhydryl) linker or base / nucleophile labile linkers such as HMBA (hydroxymethylbenzoyl) linker, HZB (hydrazinobenzoyl) linker and MeDbz (o- amino(methyl)aniline) / MeNBz (acyl-N′-methylacylurea) linker.

21. The method according to any one of the preceding claims, wherein the acid labile linker is selected from Wang linker, CTC linker, trityl linker, Rink amide linker, Ramage linker, Pal linker, Sieber linker, and SASRIN linker.

22. A composition for cleaving bonds in an organic compound, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compound and the linker coupled to a support, the composition comprising:4 i) at least one Lewis acid; ii) at least one Brønsted acid, and optionally iii) at least an organic aprotic solvent.

23. Use of a composition for cleaving bonds in an organic compound coupled to a support, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compound and the linker coupled to a support, the composition comprising: i) at least one Lewis acid; ii) at least one Brønsted acid, and optionally iii) at least an organic aprotic solvent.

24. A method for the synthesis of a polypeptide comprising providing a solid support comprising a linker, consecutively coupling α-amine protected amino acids, such as Fmoc α-amine protected amino acids, optionally comprising a side chain protecting group, thereby forming a polypeptide coupled to the solid support comprising side chain protecting groups; wherein the method further comprises: a) subjecting the solid support comprising the polypeptide to / with a composition comprising: i) at least one Lewis acid, ii) at least one Brønsted acid), and optionally iii) at least one solvent; and b) maintaining the suspension at a temperature and duration for forming a partially and / or fully deprotected polypeptide coupled to the support, and / or a partially and / or fully polypeptide compound not coupled to the support.

25. A method for cleaving bonds in an organic compound, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compound and the linker coupled to a support, the method comprising: a) subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension comprising the organic compound; b) maintaining the solution or suspension comprising the organic compound at a temperature and duration thereby forming a partially and / or fully deprotected crude organic compound coupled to the support and / or forming a partially and / or fully deprotected crude organic compound not coupled to the support; and further adding5 an aqueous solution containing a suitable salt there by adjusting the pH of the solution or suspension.

26. The method according to claim 25, wherein the salt is selected from ammonium acetate, ammonium carbonate or ammonium phosphate or mixtures thereof.

27. A method for the removal or reduction of residual metals, the method comprising cleaving bonds in / of an organic compound coupled to a support, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compounds and the linker coupled to a support, the method comprising: a) subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension comprising the organic compound; b) maintaining the solution or suspension at a temperature and duration thereby forming a partially and / or fully deprotected organic compound and / or a partially and / or fully deprotected organic compound coupled to the support comprising residual metals; the method further comprising either one of: a) i) trapping / capturing the organic compound on an insoluble support ii) eluting residual metals iii) eluting the organic compound; or b) i) trapping / capturing residual metals on a suitable insoluble support ii) eluting the organic compound; or c) separating the metals trapped on the support from the organic compound by the means of filtration.

28. A method for the removal or reduction of residual metals, the method comprising cleaving bonds in an organic compound coupled to a support, where the bonds are located: A) between the organic compound and protecting groups; B) between the organic compound and a linker coupled to a support; or C) between the organic compound and the protecting groups and between the organic compounds and the linker coupled to a support, the method comprising: a) subjecting the organic compound to a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, thereby forming a solution or suspension comprising the organic compound;6 b) maintaining the solution or suspension at a temperature and duration thereby forming a partially and / or fully deprotected organic compound and / or a partially and / or fully deprotected organic compound coupled to the support comprising residual metals; the method further comprising: i), filter off the spent resin and any insolubles and remove the volatiles in vacuo; ii) precipitate the residual material in suitable (anti)solvent(s) in which the metals are adequately soluble; and iii) isolate the peptide by filtration and / or drying.

29. A method comprising providing a peptide fragment comprising protecting groups (protected peptide fragment) coupled to a support by a linker, the method comprising the steps: a) subjecting the peptide fragment coupled to the support with a composition comprising: I) at least a Lewis acid, and II) at least a solvent, and optionally III) at least a scavenger; thereby cleaving the peptide fragment from the support without cleaving any protecting groups forming a protected peptide fragment in a solution or suspension; b) optionally removing the Lewis acid from the solution or suspension comprising the peptide fragment forming a solution or suspension depleted in Lewis acid; c) adding suitable coupling agents to the solution or suspension from step a) or optionally to the solution or suspension depleted in Lewis acid from step b) comprising the protected peptide fragment thereby coupling two protected peptide fragments forming a protected polypeptide in the solution or suspension; and d) adding at least a Brønsted acid and optionally a Lewis acid to the solution or suspension from step c) comprising the protected polypeptide thereby forming a partially or fully deprotected polypeptide in the solution or suspension.

30. A method comprising providing a polypeptide comprising protecting groups coupled to a support by an acid stable linker such as a base-labile linker, the method comprising the steps: a) subjecting the polypeptide coupled to the support with a composition comprising: I) at least a Lewis acid, II) at least a Brønsted acid; and optionally III) at least a solvent, forming a solution or suspension;7 b) maintaining the solution or suspension at a temperature and duration thereby cleaving all protecting groups forming a solution or suspension comprising a fully deprotected polypeptide coupled to the support; and c) cleaving the fully deprotected polypeptide from the support by the addition of a base or nucleophile to the solution or suspension comprising a fully deprotected polypeptide coupled to the support, thereby forming a solution or suspension comprising a fully deprotected polypeptide not couped to the support.

31. A method comprising providing an organic compound A comprising at least one amino acid, said amino acid comprising a sulfhydryl moiety such as Cys, HCys or Pen, said organic compound A being coupled via a linker to a support, the method comprising: a) subjecting the organic compound coupled to a support to / with a composition comprising i) at least one Lewis acid, ii) at least one Brønsted acid, and optionally iii) at least one solvent, and optionally in the presence of an organic compound B comprising at least one amino acid, said amino acid comprising a sulfhydryl moiety thereby forming a solution or suspension; b) maintaining the solution or suspension at a temperature and duration thereby forming a deprotected organic compound A and optionally deprotected organic compound B and forming an organic compound comprising at least one disulfide group selected from: i) an organic compound C1 formed from organic compound A and comprising a bridge comprising a disulfide group said bridge connecting the two amino acids which previously had sulfhydryl moieties; and / or ii) an organic compound C2 comprising organic compound A and organic compound B, said organic molecules A and B linked by at least a moiety comprising a disulfide group; and / or iii) an organic compound C3 comprising two organic compounds A said organic compounds A linked by at least a moiety comprising a disulfide group; and / or iv) an organic compound C4 comprising two organic molecules B said organic molecules B linked by at least one moiety comprising a disulfide group. ------------

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