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WO2018178397A1 - Acides aminés n-alkylés et oligopeptides, leurs utilisations et leurs procédés de production - Google Patents

Acides aminés n-alkylés et oligopeptides, leurs utilisations et leurs procédés de production Download PDF

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WO2018178397A1
WO2018178397A1 PCT/EP2018/058488 EP2018058488W WO2018178397A1 WO 2018178397 A1 WO2018178397 A1 WO 2018178397A1 EP 2018058488 W EP2018058488 W EP 2018058488W WO 2018178397 A1 WO2018178397 A1 WO 2018178397A1
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alkyl
amino acid
aryl
alcohol
nmr
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Katalin BARTA
Tao Yan
Bernard Lucas Feringa
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Rijksuniversiteit Groningen
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Rijksuniversiteit Groningen
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids

Definitions

  • N-alkylated amino acids and oligopeptides uses thereof and methods for providing them.
  • the invention relates to the synthesis of amphiphilic amino acid derivatives, in particular to N-alkylation of amino acids and oligopeptides by the direct alkylation of amines with alcohols. It also relates to the use of the N-alkylated products as surfactant.
  • N-alkyl amino acids Long-chain alkyl amino acid-based surfactants are known in the art, including N-alkyl amino acids, N-acyl amino acids, N-alkyl amino amides and alkyl amino acid esters (Infante et al., C. R. Chimie, 2004, 7, 583-592).
  • N-alkyl amino acids Long-chain alkyl amino acid-based surfactants are known in the art, including N-alkyl amino acids, N-acyl amino acids, N-alkyl amino amides and alkyl amino acid esters (Infante et al., C. R. Chimie, 2004, 7, 583-592).
  • the synthesis of N-alkyl amino acids is relatively demanding (Bordes and Holmberg, Advances in Colloid and Interface Science, 2015, 222, 79-91).
  • the traditional pathways including N-alkylation of amino acids with alkyl halides (Bordes et al., Journal of Colloid and Interface Science 2013, 411, 47
  • alcohols are abundant chemical reagents that can be derived from renewable resources through fermentation, depolymerization of lignocellulose (Barta and Ford, Acc. Chem. Res., 2014, 47, 1503-1512) as well as reduction of fatty acids contained in plants oil (Kreutzer, J. Am. Oil. Chem. Soc. 1984, 61, 343 - 348).
  • alcohols have been already used as reagent to alkylate amines in industrial scale, these known alkylation processes require harsh reaction conditions.
  • the present inventors set out to provide an improved method for the synthesis of N-alkylated amino acids which method is environmentally benign and preferably uses building blocks from renewable sources. In particular, they aimed at providing fully sustainable production of (novel) surfactants based on renewable resources i.e. amino acids and long chain alcohols that can be obtained from fatty acids.
  • the invention provides a method for the N-alkylation of an unprotected amino acid or the N-terminus of an oligopeptide substrate, comprising reacting said unprotected amino acid or oligopeptide substrate with an alcohol in the presence of a homogeneous transition metal catalyst.
  • the reported Fe- catalyst system used low or medium polarity solvents such as toluene and cyclopentyl methyl ether (CPME) in which unprotected amino acids are not soluble. Hence, selective N-alkylation of unprotected amino acids or oligopeptides according to the present invention could not have predicted.
  • CPME cyclopentyl methyl ether
  • Leonard et al. (Org. Process Res. Dev. 2015, 19, 1400-1410) describe the use of the "borrowing hydrogen strategy" in the synthesis of a number of pharmaceutically relevant intermediates, such as the alkylation of a protected amino acid ((S)-amino acid ester compound 29) using a diol.
  • the alkylation of a protected amino acid ((S)-amino acid ester compound 29) using a diol.
  • Leonard et al. does not relate to the N-alkylation of an unprotected amino acid.
  • the present inventors are the first to show direct N-alkylation of free ct-amino acids and simple peptides with a variety of alcohols using low loadings of a
  • the presented atom-economic transformation only results in water as byproduct, thereby significantly simplifying the purification procedure.
  • the reaction is highly selective, and most products were obtained in quantitative yield.
  • Reaction temperature as low as 60°C were used with several substrates.
  • the method is modular and allows for the use of a range of alcohol reaction partners leading to functionalized amino acids with modular properties such as low or high hydrophilicity.
  • the use of long chain alcohols and amino acids as only reaction partners to obtain mono-N-alkyl amino acids, especially with a molecular iron catalyst holds great potential for the fully sustainable production of completely bio-based surfactants.
  • the alkylation is performed in the presence of a Fe- or
  • Ru-based catalyst for use in the present invention include those according to one of the following Formula's A, B or C herein below.
  • Rl and R2 are independently selected from the group consisting of: alkyl, aryl, -CH 2 Ph and silyl moieties (e.g. TMS (trimethylsilyl), TBDMS (tertbutyldimethylsilyl), TIPS (triisopropylsilyl) or TBDPS
  • R3 and R4 are independently selected from the group consisting of:
  • L is selected from the group consisting of CO, acetonitrile phosphine, phosphite, phosphoramidite, primary or secondary amine, primary, secondary or tertiary alcohol,
  • X is O, NH or N-R where R is an alkyl or aryl, preferably X is O.
  • Rl and R2 are independently selected from the group consisting of: alkyl, aryl, -CH2PI1 and,
  • silyl moieties (e.g. TMS (trimethylsilyl), TBDMS (tertbutyldimethylsilyl), TIPS (triisopropylsilyl) or TBDPS (tertbutyldiphenylsilyl));
  • R3 and R4 are independently selected from the group consisting of:
  • L is selected from the group consisting of CO, acetonitrile phosphine, phosphite, phosphoramidite, primary or secondary amine, primary, secondary or tertiary alcohol,
  • X is O, NH or N-R6 where R6 is an alkyl or aryl, preferably X is
  • Rl and R2 are independently selected from the group consisting of: alkyl, aryl, -CH 2 Ph and silyl moieties (e.g. TMS [trimethylsilyl], TBDMS [tertbutyldimethylsilyl, TIPS [triisopropylsilyl] or TBDPS
  • R3 and R4 are independently selected from the group consisting of H, Alkyl (with broad range of substitution), silyl, Aryl (with broad range of substitution on the aromatic ring: e.g.
  • L is CO or acetonitrile.
  • L CO and catalyst activation is with MesNO, base or UV light.
  • L acetonitrile and catalyst activation is with heat
  • X is oxygen
  • Exemplary Fe-based catalysts for use in the present invention include
  • R H, CH 2 Ph, TBDMS,
  • the catalyst is of the formula:
  • a method of the invention involves direct N- alkylation catalyzed by a Ru catalyst.
  • Very suitable Ru catalysts for use in the present invention include those according to one of the following Formula's D:
  • Ri, R2, R3 and R 4 are independently selected from the group consisting of alkyl, aryl, -CH2PI , optionally with one or more substitution on the aromatic ring, preferably wherein Ri, R2, R3 and R 4 are (optionally substituted) aryl or -CH2PI1.
  • the Ru-based catalyst is of the formula D.
  • the catalyst is 1- hydroxytetraphenylcyclopentadienyl-(tetraphenyl-2,4-cyclopentadien-l-one)- ⁇ -hydrotetracarbonyldiruthenium(II) (Shvo catalyst) of the formula
  • a Ru-based catalyst may be prepared in situ from a Ru precursor consisting of RuCl3, Ru3(CO)i2, [Ru(p-cymene)Cl2)]2, Ru(acac (acetylacetonate) and a ligand which is a monodentate (e.g. triaryl or trialkyl phosphine), bidentate (dcpe, dppf, DPEphos, Duphos.. etc) or tridentate phosphine (triphos and its derivatives).
  • a monodentate e.g. triaryl or trialkyl phosphine
  • bidentate dcpe, dppf, DPEphos, Duphos.. etc
  • tridentate phosphine triphos and its derivatives.
  • an Fe catalyst may be prepared in situ from a Fe precursor consisting of Fe(CO) 5 , Fe 3 (CO)i 2 , Fe(BF 4 ) 2 *6H 2 0 [iron (II) tetrafluoroborate, hexahydrate] ; Fe(OTf)2 [Iron (II) trifluormethansulfonate] ; Fe(OAc)2 [iron (II) acetate]; FeCh; FeBr2 or iron salts with organic acids as anions and a ligand, consisting of monodentate, bidentate, tridentate, or tetradentate phosphines, N-heterocyclic carbenes or the combination thereof.
  • the li and is that of a PNP pincer type E and E' shown below.
  • R aryl, alkyl
  • R' aryl, alkyl, amino, alkoxyl.
  • KOH or KOtBu potassium tert- butoxide
  • a Ru-based catalyst yielded di-N-alkylated products.
  • a Fe-based catalyst could be used to specifically produce mono-N-alkylated products, e.g. by control of reaction conditions including reaction time and/or substrate ratio.
  • a method of the invention therefore also allows to selectively produce mono— or bis- alkylated products.
  • a method of the invention is broadly applicable to a diverse set of unprotected amino acids and small unprotected peptides.
  • Amino acids are biologically important organic compounds containing amine (-NH2) and carboxyl (-COOH) functional groups, along with a side-chain (R group) specific to each amino acid.
  • the key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen, though other elements are found in the side-chains of certain amino acids.
  • About 500 amino acids are known (though only 20 are based on the genetic code) and can be classified in many ways.
  • the invention involves the N-alkylation of a naturally occurring amino acid.
  • a naturally occurring amino acid is one of the 20 common ct-amino acids (Gly, Ala, Val, Leu, He, Ser, Thr, Asp, Asn, Lys, Glu, Gin, Arg, His, Phe, Cys, Trp, Tyr, Met, and Pro), and other amino acids that are natural products, such as norleucine, ethylglycine, ornithine, methylbutenyl-methylthreonine, and phenylglycine.
  • the amino acid or oligopeptide substrate used in the present invention comprises or consists of a- amino acids.
  • ⁇ - and ⁇ - amino acids were also found to be suitable substrates for N- alkylation.
  • the amino acid or oligopeptide substrate preferably consists of or comprises an amino acid residue having an uncharged or hydrophobic side chain.
  • the oligopeptide substrate consists of from two to eight amino acids, preferably two to five amino acids, more preferably wherein the oligopeptide is a dipeptide or a tripeptide.
  • the N-alkylationof Asp, Glu, His, Lys and Arg may be achieved through technical adaptation of the catalytic system, such us pH tuning e.g. involving the addition of an organic acid or base such as AcOH or Et3N).
  • pH tuning e.g. involving the addition of an organic acid or base such as AcOH or Et3N.
  • good results were obtained with all naturally occurring amino acids excluding acidic amino acids (Asp, Glu) and basic amino acids (His, Lys, Arg).
  • the unprotected amino acid/oligopeptide is or comprises a natural amino acid other than aspartic acid, glutamic acid, histidine and/or arginine residue(s).
  • the amino acid residue is selected from the group consisting of Ser, Thr, Cys, Met, Phe, Try, Ala, Gly, Pro, Val, Leu, He, Gin and Asn.
  • Preferred oligopeptides are those comprising or consisting of two or more residues selected from Ser, Thr, Cys, Met, Phe, Try, Ala, Gly, Pro, Val, Leu, He, Gin, Asn.
  • it is Gly-Ala, Ala- Gly, Gly-Gly, Leu-Gly, Ala-Leu, Leu-Gly-Gly, Ala-Gly-Ala, and the like.
  • any alcohol can be directly coupled to the amino acid or oligopeptide substrate.
  • alcohols containing a single reactive hydroxyl group are typically preferred, e.g. in the synthesis of surfactants, diols may also be used.
  • the alcohol is a fatty alcohol.
  • Fatty alcohols (or long-chain alcohols) are usually high-molecular-weight, straight-chain primary alcohols, but can also range from as few as 4-6 carbons to a typical medium chain length of C10-C20 to as many as 26-34 , derived from natural fats and oils. The precise chain length varies with the source.
  • Fatty alcohols usually have an even number of carbon atoms and a single alcohol group (-OH) attached to the terminal carbon. Some are unsaturated and some are branched.
  • ⁇ ⁇ typically between 6-18
  • Preferred alcohols for use in the present invention include C8-C18 fatty alcohols, more preferably saturated fatty C8-C18 alcohols. Synthetic fatty alcohols from industrial processes that use syngas and an appropriate catalyst for 'higher alcohol synthesis' can also be used.
  • the alcohol is an unsaturated long chain, primary alcohol.
  • many of them can be derived from natural triglycerides (such as sunflower, palm, cashew, rapeseed, coconut, almond, soy oil) or triglycerides or lipids derived from algae.
  • the chain can have 1, 2 or 3 double bonds.
  • the alcohol is a branched aliphatic alcohol, for instance of the formula
  • the alcohol is a long chain aliphatic diol without branching on the chain or a long chain aliphatic diol with branching of alkyl-or aryl substituents on the chain, or a long chain diol with
  • the diol is of the formula
  • alcohols derived from monolignols such as coniferyl, coumaryl and synapyl alcohol
  • phenol- alcohols derived from lignin depolymerization such as coniferyl, coumaryl and synapyl alcohol
  • the diol is of the formula
  • the alcohol is an optionally substituted linear, branched or aromatic C1-C6 alcohol.
  • the alcohol is selected from the group consisting of ethanol, isopropanol, 1-butanol, 2-chloroethanol, 2-butanol, cyclopropylmethanol, benzylalcohol and 4-chlorobenzyl alcohol.
  • the alcohol is derived from biomass or other renewable source.
  • Methods for obtaining (fatty) alcohols are known in the art.
  • US2012/0115195 discloses a method for the production of fatty alcohols from biomass, including cellulose, xylan, hemicellulose, lignin, mannan, and other materials commonly found in biomass.
  • Non-limiting examples of renewable sources include grasses (e.g., switchgrass, Miscanthus), rice hulls, bagasse, cotton, jute, hemp, flax, bamboo, sisal, abaca, straw, leaves, grass clippings, corn stover, corn cobs, distillers grains, legume plants, sorghum, sugar cane, sugar beet pulp, wood chips, sawdust, and biomass.
  • grasses e.g., switchgrass, Miscanthus
  • rice hulls bagasse, cotton, jute, hemp, flax, bamboo, sisal, abaca, straw, leaves, grass clippings, corn stover, corn cobs, distillers grains, legume plants, sorghum, sugar cane, sugar beet pulp, wood chips, sawdust, and biomass.
  • alcohols are abundant chemical reagents that can be derived from renewable resources through fermentation, depolymerization of lignocellulose (Barta and Ford, Acc. Chem. Res., 2014
  • reaction conditions for performing the N-alkylation method of the invention can be optimized using routine skills.
  • the conditions are relatively mild.
  • Suitable reaction temperatures are those up to about 110°C, preferably up to about 100°C, like 95°C, 90°C, 85°C or lower.
  • good yields could be obtained at a temperature of only up to 80°C, like about 70°C or even about 60°C.
  • Reaction times can vary e.g. depending on reaction temperature, solvent, catalyst and/or desired yields.
  • Typical incubation times are at least 12 hours, preferably at least 16 hours, like 18 or 20 hours, more preferably at least 24 hours.
  • the reaction is performed under an argon atmosphere.
  • 0.1 to about 1 mmol amino acid or oligopeptide substrate is reacted with about 2-6 ml alcohol.
  • CF3CH2OH typically 1 - 4 ml
  • Additional toluene or an other low polar solvent, e.g. THF, CPME
  • THF trifluoride
  • CPME low polar solvent
  • the catalyst is preferably used at about 0.5 to 5 mol%.
  • the Fe- based catalyst is used at about 4-5 mol%.
  • the Ru-based catalyst is preferably used at about 0.5-1 mol%.
  • a further embodiment of the invention relates to an N-alkylated amino acid or oligopeptide obtainable by a method according to the invention.
  • an N-alkylated amino acid or oligopeptide selected from the group consisting of the reaction products of Tables 1 to 6 shown herein below.
  • the invention provides an N- alkylated amino acid or oligopeptide selected from the group consisting of the compounds shown in Scheme 2 or 3.
  • Preferred ⁇ -alkylated amino acid or oligopeptide compounds e.g.
  • the invention provides a method for the synthesis of an amino acid based surfactant, preferably a long-chain N-alkyl amino acid, comprising the N-alkylation of an unprotected amino acid or the N-terminus of an oligopeptide substrate by reacting said unprotected amino acid or oligopeptide substrate with a long chain (fatty) alcohol in the presence of a homogeneous transition metal catalyst.
  • the method comprises mono-N-alkylation using a Fe-based catalyst as described herein above or in the Examples.
  • N-alkyl amino acid-based surfactants carry a positive charge at low pH, are zwitterionic at intermediate pH and negatively charged at high pH. This not only affects their physicochemical behavior, for instance their ability to adsorb at charged surfaces, but it also brings about a special feature with respect to self-assembly in bulk and at surfaces. Therefore, the invention also provides the use of an N-alkylated amino acid or oligopeptide
  • surfactants include compounds 3dk, 3gm, 3dj, 3gj, 3gn, 5ak, 5an and those shown in Scheme 3.
  • CF3CH2OH (>99.0%) was purchased from TCI without further purification.
  • Complex Cat la was synthesized according to T. Yan, B. L. Feringa, K. Barta ACS Catal., 2016, 6, 381-388.
  • Cat 2 was purchased from Strem. All other reagents were purchased from Sigma, TCI or Acros in reagent or higher grade and were used without further purification.
  • This example exemplifies direct N-alkylation of unprotected amino acids using proline (la) as exemplary substrate, ethanol (2a) as the alkylation reagent and Cat la as the catalyst (Table 1).
  • Table 1 Optimization of reaction conditions for direct N-ethylation of proline (la) or leucine (lb) with ethanol (2a).
  • Enantiomeric excess (ee) is a measurement of purity used for chiral substances. It reflects the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a single completely pure enantiomer has an ee of 100%. In this example the enantiomeric excess (ee) of the N-alkylation products was investigated (Scheme 1, Table 2).
  • Cat lb gave 3aa quantitative yield with 99.2 % ee retention, 3ba 45 % yield with 79.7 % ee retention (Table 2, entry 2 and 4).
  • Cat 2 gave both 3aa and 3ba quantitative yields as described, with retention of ee of 93.2 % and 98.5 %, respectively (Table 2, entry 1 and 3).
  • Phenylalanine (Id) was selected to react with 2a, catalyzed by both Cat lb and Cat 2 for further comparison.
  • Cat lb gave 3da 55 % yield with 72.0 % ee retention, and Cat 2 gave 3da quantitative yield with 97.2 % ee retention (Table 2, entry 7 and 8).
  • Cat 2 was chosen for the further investigation.
  • EXAMPLE 3 N-alkylation using a secondary alcohol.
  • N-alkylated amino acids are widely used in surfactants, among which N-alkylated amino acids are not well studied because they are relatively difficult to be synthetized9.
  • 1- nonanol (2j) was selected to react with Id and lg.
  • Di-alkylated compounds 3dj and 3gj were selectively obtained with good to excellent yields of 75 % and 91 %, respectively (Table 4, entry 9 and 13).
  • the reaction also readily proceeded with 1-dodecanol (In) and lg as substrate, obtaining the corresponding product 3gn in an excellent yield of 92 % (Table 4, entry 17).
  • Table 6 Direct synthesis of amphiphiles through iron catalyzed N- alkylation of free amino acid (1) with fatty alcohols (2).
  • Table 6 Direct synthesis of amphiphiles through iron catalyzed N- alkylation of free amino acid (1) with fatty alcohols (2).
  • N-ethyl-proline (3aa) Synthesized according to General procedure.
  • N,N-di-ethyl-valine (3ca) Synthesized according to General procedure. Quantitative yield has been obtained according to crude H NMR. ⁇ NMR (400 MHz, D 2 0) ⁇ 3.45 - 3.52 (m, 1H) 3.05 - 3.35 (m, 4H), 2.22 - 2.40 (m, 1H), 1.15 - 1.40 (m, 6H), 0.99 - 1.10 (m, 3H), 0.86 - 0.99 (m, 3H) 13 C NMR (100 MHz, D 2 0) ⁇ 174.31, 74.85, 49.85, 45.30, 28.02, 22.22, 18.81, 11.73, 9.62. HRMS (APCI+, m/z): calculated for C9H20NO2 [M+H]+: 174.14886; found: 174.14879.
  • N,N-di-ethyl-phenylalanine (3da) Synthesized according to General procedure. Quantitative yield has been obtained according to crude H NMR. ⁇ NMR (400 MHz, D 2 0) ⁇ 7.12 - 7.43 (m, 5H), 3.80 - 3.93 (m, 1H), 3.08 - 3.40 (m, 4H), 2.98 - 3.31 (m, 2H), 1.17 - 1.33 (m, 6H). 13 C NMR (100 MHz, D 2 0) ⁇ 172.37, 135.44, 129.06, 128.80, 127.28, 67.81, 45.70 (br.s), 33.44, 8.42 (br.s). HRMS (APCI+, m/z): calculated for Ci 3 Hi 8 N0 2 [M-H]-: 220.13321 found: 220.13433.
  • N,N-di-ethyl-serine (3ea) Synthesized according to General procedure.
  • N 6 -acetyl-N 2 ,N 2 -di-ethyl-lysine (3ha) Synthesized according to General procedure. N 6 -acetyl-lysine (0.094 g, 0.50 mmol) affords 3ha (0.090 g, 75% yield). White solid was obtained after column chromatography (S1O2,
  • N-isopropyl-proline (3ab) Synthesized according to General procedure.
  • N-isopropyl-phenylalanine (3db) Synthesized according to General procedure. Quantitative yield has been obtained according to crude H NMR. ⁇ NMR (400 MHz, D 2 0) ⁇ 6.87 - 7.24 (m, 5H), 3.24 - 3.34 (m, 1H), 2.71 - 2.80 (m, 1H), 2.45 - 2.65 (m, 2H), 0.74 - 0.93 (m, 6H). 13 C NMR (100 MHz, D 2 0) ⁇ 181.45, 137.84, 129.08, 128.33, 126.40, 62.55, 45.96, 39.09, 22.57, 19.72.
  • HRMS (APCI+, m/z): calculated for Ci 2 Hi 8 N0 2 [M+H]+:
  • N-isopropyl-valine (3cb) Synthesized according to General procedure.
  • N-isopropyl-alanine (3fb) Synthesized according to General procedure. Quantitative yield has been obtained according to crude H NMR. ⁇ NMR (400 MHz, D 2 0) ⁇ 3.71 - 3.80 (m, 1H), 3.38 - 3.50 (m, 1H), 1.42 - 1.53 (m, 3H), 1.26 - 1.37 (m, 6H). 13 C NMR (100 MHz, D 2 0) ⁇ 177.76, 57.76, 52.17, 21.17, 20.71, 18.14. HRMS (APCI+, m/z): calculated for C 6 Hi 4 N02 [M+H]+: 132.10191; found: 132.10181.
  • N-n-butyl-proline (3ae) Synthesized according to General procedure.
  • N-cyclopropylmethyl-proline (3fb) Synthesized according to General procedure. Proline (0.058 g, 0.50 mmol) affords 3fb (0.046 g, 55% yield). White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 80:20 to 80:20).
  • N-(2-chloroethyl)-proline (3ag) Synthesized according to General procedure. Proline (0.058 g, 0.50 mmol) affords 3ag (0.063 g, 71% yield). White solid was obtained after crystallization in MeOH/Et 2 0. ⁇ NMR (400 MHz, D 2 0) ⁇ 4.45 - 4.65 (m, 3H), 3.76 - 3.93 (m, 2H), 3.33 - 3.54 (m, 2H), 2.38 - 2.55 (m, 1H), 2.15 - 2.32 (m, 1H), 1.97 - 2.14 (m, 2H).
  • N-benzyl-proline (3ah) Synthesized according to General procedure. Proline (0.019 g, 0.20 mmol) affords 3ah (0.028 g, 68% yield). White solid was obtained after crystallization in Et 2 0. ⁇ NMR (400 MHz, CDC1 3 ) ⁇ 9.33 (br.s, 1H), 7.28 - 7.52 (m, 5H), 4.11 - 4.37 (m, 2H), 3.74 - 3.90 (m, 1H), 3.59 - 3.74 (m, 1H), 2.78 - 2.94 (m, 1H), 2.17 - 2.38 (m, 2H), 1.79 - 2.08 (m, 2H).
  • N-(4-chloro-benzyl)-proline (3ai) Synthesized according to General procedure. Proline (0.058 g, 0.50 mmol) affords 3ai (0.098 g, 82% yield).
  • N,N-(di-n-butyl)-phenylalanine (3de) Synthesized according to General procedure. Phenylalanine (0.083 g, 0.50 mmol) affords 3de (0.116 g, 84% yield). White solid was obtained after column chromatography (Si0 2 ,
  • N,N-(di-n-nonyl)-phenylalanine (3dj) Synthesized according to General procedure. Phenylalanine (0.083 g, 0.50 mmol) affords 3dj (0.147 g, 75% yield). White solid was obtained after column chromatography (S1O2, Pentane/EtOAc 50:50 to 0:100, then EtOH/MeOH 90/10). H NMR (400 MHz, CDCI3) ⁇ 8.68 (br.s, 1H), 7.13 - 7.31 (m, 5H).
  • N,N-di-(5-hydroxypentyl)-phenylalanine (3dk) Synthesized according to General procedure. Phenylalanine (0.083 g, 0.50 mmol) affords 3dk (0.059 g, 35% yield). White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 50:50 to 30:70).
  • N,N-di-n-nonyl-glycine (3gj) Synthesized according to General procedure. Glycine (0.038 g, 0.50 mmol) affords 3gj (0.149 g, 91% yield). White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 90:10 to 70:30). ⁇ NMR (400 MHz, CDCI3) ⁇ 8.78 (br.s, 1H), 3.48 (s, 2H), 2.95 - 3.15 (m, 4H), 1.52 - 1.75 (m, 4H), 1.03 - 1.42 (m, 24H), 0.65 - 0.95 (m, 6H).
  • N-2-butyl-glycine (3gl) Synthesized according to General procedure.
  • N,N-di-(n-pentyl)-glycine (3gm): Synthesized according to General procedure. Glycine (0.038 g, 0.50 mmol) affords 3gm (0.097 g, 90% yield). White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 90:10 to 70:30). ⁇ NMR (400 MHz, D 2 0) ⁇ 3.68 (s, 2H), 3.05 - 3.25 (m, 4H), 1.56 - 1.80 (m, 4H), 1.20 - 1.40 (m, 8H), 0.75 - 1.00 (m, 6H).
  • N-n-pentyl-glycine (3gm') Synthesized according to General procedure. Glycine (0.038 g, 0.50 mmol) affords 3gm' (0.033 g, 46% yield). White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 60:40 to 30:70). ⁇ NMR (400 MHz, D 2 0) ⁇ 3.57 (s, 2H), 2.91 - 3.13 (m, 2H), 1.54 - 1.80 (m, 2H), 1.20 - 1.46 (m, 4H), 0.75 - 0.99 (m, 3H).
  • N,N-di-n-dodecyl-glycine (3gn) Synthesized according to General procedure. Glycine (0.038 g, 0.50 mmol) affords 3gn (0.189 g, 92% yield). White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 90:10 to 70:30). ⁇ NMR (400 MHz, CDCI3) ⁇ 8.36 (br.s, 1H), 3.49 (s, 2H), 2.95 - 3.15 (m, 4H), 1.52 - 1.75 (m, 4H), 1.03 - 1.42 (m, 36H), 0.75 - 0.95 (m, 6H).
  • N-dodecyl-glycine (3gn') Synthesized according to General procedure. Glycine (0.038 g, 0.50 mmol) affords 3gn' (0.066 g, 54% yield). White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 70:30 to 40:60). ⁇ NMR (400 MHz, KOH, D 2 0) ⁇ 3.00 - 3.20 (m, 2H), 2.38 - 2.58 (m, 2H), 1.36 - 1.57 (m, 2H), 1.12 - 1.35 (m, 18H), 0.73 - 0.90 (m, 3H).
  • N-nonyl-glycine (3gj') Synthesized according to General procedure. Glycine (0.038 g, 0.50 mmol) affords 3gj' (0.052 g, 51% yield). White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 70:30 to 40:60). ⁇ NMR (400 MHz, KOH, D 2 0) ⁇ 2.90 - 3.18 (m, 2H), 2.30 - 2.56 (m, 2H), 1.28 - 1.55 (m, 2H), 1.02 - 1.38 (m, 12H), 0.65 - 0.91 (m, 3H).
  • N-decyl-glycine (3go') Synthesized according to General procedure. Glycine (0.038 g, 0.50 mmol) affords 3go' (0.075 g, 69% yield). White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 70:30 to 50:50). ⁇ NMR (400 MHz, KOH, D 2 0) ⁇ 3.00 - 3.15 (m, 2H), 2.36 - 2.58 (m, 2H), 1.36 - 1.54 (m, 2H), 1.05 - 1.35 (m, 14H), 0.73 - 0.90 (m, 3H).
  • N-dodecyl-alanine (3gn') Synthesized according to General procedure. Alanine (0.045 g, 0.50 mmol) affords 3gn' (0.063 g, 49% yield). White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 70:30 to
  • N-nonyl-proline (3aj) Synthesized according to General procedure. Proline (0.053 g, 0.50 mmol) affords 3aj (0.063 g, 52% yield). White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 90:10 to 50:50).
  • N,N-di-ethyl-glycyl-alanine (5aa) Synthesized according to General procedure. Quantitative yield has been obtained according to crude H NMR. ⁇ NMR (400 MHz, D 2 0) ⁇ 4.08 - 4.22 (m, 1H), 3.88 - 4.03 (m, 2H), 3.17 - 3.31 (m, 4H), 1.30 - 1.36 (m, 3H), 1.21 - 1.30 (m, 6H). 13 C NMR (100 MHz, D 2 0) ⁇ 179.44, 164.77, 53.19, 51.17, 49.43, 16.92, 8.30. HRMS (APCI+, m/z): calculated for C9H19N2O3 [M+H]+: 203.13902; found: 203.13895.
  • N,N-di-(5-hydroxy-pentyl)-glycyl-alanine (0.073 g, 0.50 mmol) affords 5ak (0.036 g, 36% yield).
  • White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 60:40 to 30:70).
  • ⁇ NMR 400 MHz, D 2 0) ⁇ 4.15 - 4.23 (m, 1H), 3.55 - 3.67 (m, 4H), 3.19 - 3.34 (m, 2H,), 2.52 - 2.71 (m, 4H), 1.47 - 1.66 (m, 8H), 1.28 - 1.44 (m, 7H).
  • 13 C NMR (100 MHz, D 2 0) ⁇ 182.21,
  • N,N-di-ethyl-glycyl-alanine (5ba) Synthesized according to General procedure. Leucyl-glycyl- glycine (0.123 g, 0.50 mmol) affords 5ba (0.101 g, 67% yield). White solid was obtained after column chromatography (S1O2, EtOAc/MeOH 60:40 to 30:70).

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Abstract

L'invention concerne la synthèse de dérivés amphiphiles d'acides aminés, en particulier un procédé de N-alkylation d'un acide aminé non protégé ou de l'extrémité N-terminale d'un substrat oligopeptidique, comprenant la réaction dudit acide aminé non protégé ou du substrat oligopeptidique avec un alcool, par exemple un alcool gras, en présence d'un catalyseur de métal de transition homogène.
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CN109593044A (zh) * 2018-12-06 2019-04-09 盐城工学院 一种烷基脂肪酸胺及其制备方法
CN115215814A (zh) * 2022-09-06 2022-10-21 河南师范大学 异恶唑烷类化合物的合成方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109593044A (zh) * 2018-12-06 2019-04-09 盐城工学院 一种烷基脂肪酸胺及其制备方法
CN115215814A (zh) * 2022-09-06 2022-10-21 河南师范大学 异恶唑烷类化合物的合成方法

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