WO1995026975A1 - Groupes alkyle ramifies, acycliques et apliphatiques en tant que constituants de groupes protecteurs lies a des chaines laterales de fractions aminoacides et leur utilisation dans la preparation de structures de peptides, de polypeptides ou de proteines - Google Patents

Groupes alkyle ramifies, acycliques et apliphatiques en tant que constituants de groupes protecteurs lies a des chaines laterales de fractions aminoacides et leur utilisation dans la preparation de structures de peptides, de polypeptides ou de proteines Download PDF

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Publication number
WO1995026975A1
WO1995026975A1 PCT/SE1995/000337 SE9500337W WO9526975A1 WO 1995026975 A1 WO1995026975 A1 WO 1995026975A1 SE 9500337 W SE9500337 W SE 9500337W WO 9526975 A1 WO9526975 A1 WO 9526975A1
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group
amino
protective
protective groups
acid
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PCT/SE1995/000337
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WO1995026975A9 (fr
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Anders UNDÉN
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Unden Anders
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C07K1/064—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for omega-amino or -guanidino functions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/061—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups
    • C07K1/063—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using protecting groups for alpha-amino functions
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • Acyclic aliphatic branched alkyl groups as constituents of protective groups bound to side chains of amino-acid moieties, and their use in the preparation of peptide, polypeptide or protein structures.
  • the present invention relates to protective groups bound to side chains of amino-acid moieties, and their use in the preparation of peptide, polypeptide or protein structures.
  • the protective groups of the invention comprise acyclic aliphatic branched alkyl groups.
  • the first group of problems may result from the fact that the protective groups of the side chains employed in the synthesis are not sufficiently stable under the reaction conditions used during the synthesis, that the protective groups do not give sufficient protection against a side reaction, or that the removal of the protective groups give rise to specific side reactions.
  • sequence dependent The second group of problems is usually referred to as "sequence dependent" and is suggested to arise from the association of the peptide chain into non- covalently linked aggregates.
  • sequence dependent In the synthesis of a polypeptide or protein in homogenous solution these problems will be reflected in low solubility of the polypeptide, whereas in solid-phase peptide synthesis aggregation will result in lower reaction rates in the coupling of protected amino acid or lower reaction rates in the deprotection of the temporary N ⁇ protective group.
  • Chemical peptide synthesis is commonly carried out with either of two strategies, namely using the acid labile te/t-butyloxycarbonyl (Boc) or the base labile 9-fluorenylmethoxycarbonyl (Fmoc) group, respectively. These different strategies will require different protective groups on the side chains of the amino acids. These two strategies will in the following text be referred to as
  • the ⁇ -COOH group of aspartic acid is during the synthesis according to Boc chemistry commonly protected with benzyl or cyclohexyl esters. Tarn et al reported in Tetrahedron Letters, 1979, No 42, pages 4033-4036, that the cyclohexyl protecting group was superior to the benzyl ester as protection against base-catalyzed aspartimide formation, and that a 24 hour treatment with triethylamine still gave rise to 14% aspartimide when protecting the ⁇ - COOH as a cyclohexylester. Similar results were obtained by Nicolas et al in Tetrahedron Letters, 1989, vol. 30, pages 497-500.
  • the side chain of histidine contains two heterocyclic nitrogens, one of which is usually protected during solid-phase peptide synthesis. It is well known in the art that the ⁇ -nitrogen in the imidazole nucleus can give rise to racemization by abstracting the C ⁇ hydrogen when the COOH group is activated. In order to avoid this reaction, either electron-withdrawing groups has to be introduced at the ⁇ -nitrogen, or a protective group has to be introduced at the ⁇ -nitrogen. In the latter case the protective group does not have to be electron-withdrawing. Colombo et al discussed in J.Chem. Soc. Perk. Trans.
  • the benzyloxymethyl (Bom) is a protective group on the ⁇ -nitrogen in Boc chemistry.
  • This protective group can give rise to formaldehyde during the splitting off by acid, leading to the formation of several side products as shown by Mitchell et al in Int. J. Peptide Protein Res., 1990, 36, pages 350-355.
  • the trityl group is widely used in Fmoc chemistry but the trityl group is not a , is not strongly electron-withdrawing protective group, and it is therefore not surprising that Harding et al showed on poster P025 at the 23rd European
  • Aromatic protective groups such as benzyl ester, ethers or carbamates, Cycloalkanes such as the cyclohexyl and cyclopentyl esters suggested as protective groups for aspartic and glutamic acid in Boc chemistry, and; ( _The simple tertiary acyclic tert-butyl group in the form of ester, carbamate or ethers in Fmoc chemistry.
  • acyclic aliphatic protective groups has not prior to the present invention been considered to have any advantages in peptide synthesis. This is reflected in the fact that this type of protective groups has not been employed as protective groups for the side chains of amino acids.
  • the present invention provides new protective groups bound to side chains of amino-acid moieties which do not have the disadvantages of the hitherto used protected derivatives in peptide synthesis.
  • Protective groups bound to the side chains of amino-acid moieties which groups are composed of acyclic saturated branched hydrocarbons with between 6 - 18 carbon atoms are more flexible than analogous cyclic structures.
  • Protective groups of this type are able to protect the protected polypeptide chain or protein chain from side reactions during the synthesis.
  • the new protective groups according to the invention have properties superior to protective groups previously reported. They are more stable during the synthesis or protects from modification to a significantly greater extent than previously reported comparable protective groups. They can be introduced into the peptide chain by standard procedures and can be cleaved with standard procedures for peptide synthesis.
  • the present invention is directed to a protective group bound to a side chain of an amino-acid moiety , which group is an aliphatic acyclic branched alkyl group protecting a thiol, hydroxyl, or carboxyl group or an aliphatic acyclic branched alkoxycarbonyl group protecting an amino group or heterocyclic nitrogen, wherein the alkyl and alkoxy entities have from 6 to 18 carbon atoms and have at least two identical alkyl chains.
  • amino-acid moiety may in the present invention be a protected or deprotected form of an amino acid, a resin-bound amino-acid ,or an amino- acid residue forming part of a peptide, polypeptide or protein.
  • the amino-acid moiety may be protected so that the N ⁇ amino group is protected by a tert-butyloxycarbonyl group or 9-fluorenyl-methoxy-carbonyl group or benzyloxycarbonyl group, and the optionally modified carboxyl group is (i) present as an unmodified COOH group, (ii) modified by a protecting group (iii) modified by an activating group, or (iv) bound to the linker of a resin.
  • the branched alkyl or 8 alkoxy entity has no more than two identical alkyl chains.
  • the branched alkyl or alkoxy entity has three alkyl chains, at least two of which are identical.
  • the amino-acid moiety derives from an amino acid which is selected from the group consisting of histidine, tryptophan, tyrosine and lysine, and said protecting group is an alkoxycarbonyl group.
  • the amino-acid moiety derives from an amino acid which is selected from the group consisting of cysteine, serine, threonine, aspartic acid and glutamic acid and said protecting group is an alkyl group.
  • the alkyl entity of the protective group has 7 carbon atoms.
  • the alkyl entity of the protective group has 9 carbon atoms.
  • Another aspect of the invention is directed to the use of a protective group bound to a side chain of an amino-acid moiety in the synthesis of peptides, polypeptides and proteins.
  • the aliphatic acyclic branched alkyl entities of the protective groups bound to side chains of amino-acid moieties according to the invention may form side-chain protected amino acids which, when used in peptide synthesis, have properties superior to currently used protective groups for side chains of amino acids.
  • a protective group of the invention generally has larger flexibility than a cyclic aliphatic protective group or a protective group of aromatic character such as a benzyl ester.
  • alkyl protective groups bound to the side chains can be used as protective groups in two chemical forms: 1. Alkyl groups where the alkyl entities are linked directly to the side chain of the amino acid. These include protective groups for the side chains of Ser, Thr and Cys (ethers) and Asp, Glu (esters)
  • alkyl group-O-CO- amino-acid side chain alkyl group-O-CO- amino-acid side chain.
  • protecive groups can be constructed from these principles.
  • the histidine and tyrosine derivatives of III and V are new innovative nucleophile resistant protected derivatives where the protective group is stable to trifluoroacetic acid but readily cleaved with hydrogen fluoride (Boc chemistry).
  • similar use of the derivatives IV and VI will provide nucleophile resistant but trifluoroacetic acid labile protective groups for histidine in Fmoc chemistry.
  • these protective groups suppress racemization, are cleaved by anhydrous acid and is not known to form any other harmful side products during the cleavage than the alkyl carbocation.
  • alkoxycarbonyl groups such as 2,4-dimethyl-3-pentyloxycarbonyl and 2,6- dimethyl-4-heptyloxycarbonyl groups in structural formulae (2) above can be used as nucleophile resistant, hydrogen fluoride cleavable protective groups. See comparative example 3 below.
  • Protection of the thiolgroup of cysteine in the form of tertiary thioether by sterically hindered tertiary S-alkyl groups can reduce the rate of S-tert butylation of cysteine forming a sulphonium salt derivative during the removal of the Boc group in Boc chemistry.
  • the present invention can be be applied with a large number of different hydrocabons but the general idea is that they should not contain any cyclic hydrocarbon as these will provide less serical hindrance and flexibility.
  • Displayed below are the structural formulae (3) comprising examples of alkyl entities of protective groups according to the invention.
  • Fig 1 shows the effect of treatment of the model peptide: Boc-Lys(2CIZ)-
  • Aspartyl peptide indicate the the unmodified product Lys-Tyr-Asp-Gly-Phe-NH2.
  • FIG. 2 shows the effect of treatment of the model peptide: Boc-Lys(2CIZ)- Tyr(2BrZ)-Asp(Xpp)-Gly-Phe, linked to a p-methylbenzhydryl-amine resin with 20% piperidine in dimethylformamide for fourteen hours followed by cleavage of the protected peptide-resin with liquid hydrogen fluoride and chromatographical analysis of the product on a reversed phase HPLC column using a gradient of 80% acetonitrile 20% water.
  • Xpp indicated different protective groups on the ⁇ -COOH group of aspartic acid.
  • Tertiary alcohols can be synthesized by well established procedures from alkyl halides and ketones by using the Grignard reaction. A description of such procedures can be found in Vogel ' s textbook of practical organic chemistry, fifth edition, Furniss, B.S., Hannaford, A.J., Smith, P.W., Tatchell A.R., 1991 , ISBN 0-582-46236-3, Longman Scientific & Technical, pages 538-539.
  • 2,6-dimethyl-4-heptanol is added 1.2 equivalents of phosgene (1.98 M solution in toluene). The solution is stirred at room temperature for 6 hours.
  • Residual phosgene is removed by passing a stream of dry nitrogen through the solution.
  • Residual phosgene is removed by passing a stream of dry nitrogen through the solution.
  • activation of a tertiary alcohol can be achieved by preparing the fluoroformates of said alcohol.
  • a procedure for the preparation of fluoroformates of a tertiary alcohol, which is used to introduce super acid labile N -protective groups for use in peptide syntheses, is described by Voelter and M ⁇ ller in Leibigs Ann. Chem. ,1983, pages 248- 260.
  • N ⁇ -Boc-Histidine is dissolved in dimethyl sulphoxide and two equivalents of diisopropylethylamine is added.
  • the solution is stirred for 10 minutes at room temperature.
  • the reaction mixture is added to a twenty times larger volyme of ethyl acetate and washed with an equal volyme of water containing two equivalents of acetic acid.
  • the aqueous phase is discarded and the ethyl acetate phase is washed once with water.
  • the ethyl acetate phase is dried over magnesium sulphate, filtered and concentarated by evaporation. Aliquotes of the resulting oil is dissolved in a mixture of acetonitrile and water containing 0.1 % trifluroacetic acid and purified by High Performance Liquid Chromatography (HPLC) using a reversed phase column.
  • HPLC High Performance Liquid Chromatography
  • the resulting oil is re dissolved in ethyl acetate and is washed with 0.1 M HCI (3 times), 0.1 M sodium hydrogen carbonate (3 times) and saturated sodium chloride solution (3 times).
  • the ethyl acetate solution was dried with MgS0 4 , filtered and an equal volume of hexane was added. This solution was filtered through a funnel containing silica to remove remaining traces of dicyclohexylurea followed by evaporation of the solvents.
  • the resulting oil was re dissolved in ethanol, followed by evaporation of the solvent in order to remove residual ethyl acetate. This procedure was repeated twice.
  • One equivalent of the intermediate product obtained in example 7 was dissolved in ethanol and a hydrogenating catalyst, 5% palladium on charcoal, was added.
  • the said catalyst was added in an amount of 1 part by weight per 20 parts by weight of the starting material.
  • the reaction mixture is flushed by nitrogen and hydrogen gas is bubbled through the said mixture for 4 hours.
  • the reaction mixture is flushed by nitrogen, transferred to a centrifugation tube and centrifuged so that the catalyst is obtained as a pellet at the bottom of the centrifugation tube.
  • the supernatant is collected, the solvent is removed by evaporation, the resulting oil is re dissolved in ethyl acetate, and the product is shaken into an aqueous solution of sodium bicarbonate.
  • the chloroformates were prepared according to example 3.
  • One equivalent Boc-Tyr-OH was dissolved in acetonitrile, 1.1 equivalent N,N diisopropyl-ethyl amine was added followed by 1 equivalent benzyl bromide. After 24 hours, the solvent was evaporated, the resulting oil taken up in ethyl acetate and washed with 1 N HCI (3 times) followed by water (3 times) .
  • the product was shaken into a water solution of 1.1 equivalent NaOH, followed by acidification with solid citric acid and the Boc-Tyr-OBzl was taken up in ethyl acetate.
  • the product was crystallised from ethyl acetate and hexane.
  • the polypeptide of the sequences stated above was prepared by solid phase peptide synthesis using conventional Boc chemistry.
  • a p- methylbenzhydrylamine resin containing 1 equivalent of amino groups was washed with 2x5% N,N-diisopropylethylamine in methylene chloride and washed 4 times with methylene chloride. After these washes the resin was resuspended in a small volyme of methylene chloride.
  • the first Boc amino acid was activated by mixing 1 equivalent of Boc amino acid, 1.1 equivalents of N-hydroxybenzotriazole and 1 equivalent of dicyclohexylcarbodiimide in N,N-dimethylformamide (DMF).
  • a peptide of the following sequence was synthesized: Boc- Lys(2-CI-Z)-Tyr(2BrZ)- Asp(Xpp)-Gly-Phe-MBHA, where Xpp denotes the aspartic acid protective groups studied, and MBHA the p-methylbenzhydryl amine resin. Xpp can be cyclohexyl or 2,4-dimethyl-3-pentyl.
  • the protected peptide resin was treated with 20% piperidine in DMF for 4 hours, cleaved in liquid hydrogen fluoride and the purity of the product assayed by HPLC using a reversed phase column. The elution profiles from these experiments are shown in fig .1. A.
  • the benzyl and cyclohexyl esters are standard protective groups in Boc chemistry for aspartic acid.
  • the benzyl ester was not included in the study as it is well known that this type of protection results in even higher levels of aspartimide under these reaction conditions.
  • the main product in B denoted aspartyl peptide is the correct product as indicated by plasma desorbtion mass spectrometry and reference peptides prepared without piperidine treatment.
  • Boc group These Boc-His(Xpp)OH amino acid derivatives, where Xpp denotes the protective groups A-C in table 1 , was coupled with the BOP reagent.
  • the peptides were treated with 20 % piperidine in DMF, the peptides cleaved from the resins by trifluoroacetic acid and the ratio between peptides with protective group on the histidine residue and peptides were the protective group has been removed by the action of piperidine was recorded by analysing the HPLC elution profiles and identification of the products by plasma desorbtion mass spectrometry. For comparison the stability of the N i - 2- adamantyl and N im -1-adamantyl derivatives of histidine as reported by
  • the 2-Br benzyloxycarbonyl protective group is the standard protective group for the phenolic OH group of tyrosine in Boc chemistry , but that this protective group has some disadvantages in terms of nucleophile sensitivity.
  • this protective group has some disadvantages in terms of nucleophile sensitivity.
  • the peptide resin was treated with 20% piperidine in DMF, cleaved with trifluoroacetic acid and the products analysed and purified as described in the comparative example 2 above.
  • trifluoroacetic acid cleaves all protective groups except the histidine protective groups, the relative amount of nucleophile cleaved protective groups can be recorded.

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Abstract

L'invention concerne un groupe protecteur lié à une chaîne latérale d'une fraction aminoacide et qui est un groupe alkyle ramifié, acyclique et aliphatique protégeant un groupe thiol, hydroxyle ou carboxyle ou un groupe alcoxycarbonyle ramifié, acyclique et aliphatique protégeant un groupe amino ou un azote hétérocyclique, les entités alkyle et alcoxy possédant de 6 à 18 atomes de carbone et au moins deux chaînes alkyle identiques. L'invention concerne, de plus, l'utilisation d'un tel groupe protecteur lié à une chaîne latérale d'une fraction aminoacide dans la synthèse de peptides, de polypeptides, et de protéines.
PCT/SE1995/000337 1994-03-30 1995-03-30 Groupes alkyle ramifies, acycliques et apliphatiques en tant que constituants de groupes protecteurs lies a des chaines laterales de fractions aminoacides et leur utilisation dans la preparation de structures de peptides, de polypeptides ou de proteines WO1995026975A1 (fr)

Applications Claiming Priority (2)

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SE9401079-0 1994-03-30
SE9401079A SE9401079L (sv) 1994-03-30 1994-03-30 Nya derivat av asparaginsyra och glutaminsyra som är skyddade på sidokedjans karboxylsyragrupp form av estrar som försvårar aspartimidbildning vid fastfassyntes av peptider

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WO1995026975A9 WO1995026975A9 (fr) 1995-12-07

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2886531A1 (fr) 2013-12-19 2015-06-24 Merck Patent GmbH Dérivés d'acide aspartique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2387943A1 (fr) * 1977-04-22 1978-11-17 Takeda Chemical Industries Ltd Nouveaux groupes protecteurs pour proteger les groupes o-amino des acides amines et des peptides et acides amines et peptides ainsi proteges
EP0056274A1 (fr) * 1981-01-14 1982-07-21 Takeda Chemical Industries, Ltd. Dérivés de l'indole et procédé de préparation de peptides
EP0264063A2 (fr) * 1986-10-09 1988-04-20 Shin-Etsu Chemical Co., Ltd. Réactif pour enlever les groupes de protection dans la synthèse peptidique
EP0562659A1 (fr) * 1992-03-20 1993-09-29 SOLVAY (Société Anonyme) Procédé de synthèse peptidique et nouveaux intermédiaires de synthèse

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2387943A1 (fr) * 1977-04-22 1978-11-17 Takeda Chemical Industries Ltd Nouveaux groupes protecteurs pour proteger les groupes o-amino des acides amines et des peptides et acides amines et peptides ainsi proteges
EP0056274A1 (fr) * 1981-01-14 1982-07-21 Takeda Chemical Industries, Ltd. Dérivés de l'indole et procédé de préparation de peptides
EP0264063A2 (fr) * 1986-10-09 1988-04-20 Shin-Etsu Chemical Co., Ltd. Réactif pour enlever les groupes de protection dans la synthèse peptidique
EP0562659A1 (fr) * 1992-03-20 1993-09-29 SOLVAY (Société Anonyme) Procédé de synthèse peptidique et nouveaux intermédiaires de synthèse

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 74, No. 5, 2 August 1971, (Columbus, Ohio, USA), SAKAKIBARA, SHUMPEI et al., "New Protective Group Suitable for Masking Specific Amino Groups During Peptide Synthesis", pages 31958, The Abstract No. 31954w; & BULL. CHEM. SOC. JAP., 1970, 43 (10), 3322. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2886531A1 (fr) 2013-12-19 2015-06-24 Merck Patent GmbH Dérivés d'acide aspartique

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