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REACTION AGENT FOR AMIDE REACTIONS AND AMIDE COMPOUND PRODUCTION METHOD USING SAME

20230002422 · 2023-01-05

    Inventors

    Cpc classification

    International classification

    Abstract

    [Problem] To provide a novel means capable of generating highly stereoselective and/or highly efficient amidation reactions in a variety of substrates having a carboxyl group and an amino group, and capable of producing amide compounds.

    [Solution] A reaction agent for amide reactions between carboxyl groups and amino groups and including a silane compound indicated by general formula (A) and/or general formula (B).

    ##STR00001##

    (In general formulas (A) and (B), each substituent represents the definition described in the Claims.)

    Claims

    1. A reaction agent for amide reaction between a carboxyl group and an amino group, comprising at least one silane compound selected from compounds represented by general formulae (A) and (B). ##STR00182## In general formula (A), R.sup.a1 represents a monovalent hydrocarbon group substituted with one or more halogen atoms, R.sup.a2 represents a hydrogen atom or a 5- to 7-membered heterocyclic group that contains at least one nitrogen atom as a ring-constituting atom and may have one or more substituents, x represents an integer of 3 or 4, wherein x Rai's may be either identical to each other or different from each other, and y represents an integer of 1 or 0, provided that x+y=4 and that when y is 0, then R.sup.a2 is absent. ##STR00183## In general formula (B), R.sup.b1 and R.sup.b2, independently of each other, represent a hydrogen atom or an alkyl group or alkoxy group having 1 to 10 carbon atoms or an aryl group, aralkyl group, alkyl aryl group, aryloxy group, aralkyloxy group, or alkyl aryloxy group having 6 to 12 carbon atoms, wherein the alkyl, alkoxy, aryl, aralkyl, alkyl aryl, aryloxy, aralkyloxy, or alkyl aryloxy group may have one or more substituents, and Z.sup.b1 and Z.sup.b2, independently of each other, represent a 5- to 7-membered heterocyclic group that contains at least one nitrogen atom as a ring-constituting atom and may have one or more substituents.

    2. A method of producing, from a compound represented by general formula (1-1) and a compound represented by general formula (1-2), an amide compound represented by general formula (1-3), comprising: causing a reaction between the compound represented by general formula (1-1) and the compound represented by general formula (1-2) in the presence of a silane compound according to claim 1. ##STR00184## In general formula (1-1), R.sup.11 represents a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents or a monovalent group formed by linking, optionally via a linking group, two or more multivalent hydrocarbon and/or heterocyclic groups that each may have one or more substituents. ##STR00185## In general formula (1-2), R.sup.12 represents a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents or a monovalent group formed by linking, optionally via a linking group, two or more multivalent hydrocarbon and/or heterocyclic groups that each may have one or more substituents, and R.sup.13 represents a hydrogen atom, carboxyl group, or hydroxyl group, or a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents and may be bound to the nitrogen atom via a linking group, or R.sup.12 and R.sup.13 may be bound to each other to form, together with the nitrogen atom to which R.sup.12 and R.sup.13 bind, a hetero ring that may have one or more substituents. ##STR00186## In general formula (1-3), each symbol represents the same definition as that of the same symbol in general formulae (1-1) and (1-2) above.

    3. A method of producing, from a compound represented by general formula (2-1), an amide compound represented by general formula (2-2), comprising: causing an intramolecular reaction in the compound represented by general formula (2-1) in the presence of a silane compound according to claim 1. ##STR00187## In general formula (2-1), R.sup.21 represents a divalent hydrocarbon group or heterocyclic group that may have one or more substituents or a divalent group formed by linking, optionally via a linking group, two or more multivalent hydrocarbon and/or heterocyclic groups that each may have one or more substituents, and R.sup.22 represents a hydrogen atom, carboxyl group, or hydroxyl group, or a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents and may be bound to the nitrogen atom via a linking group, or R.sup.21 and R.sup.22 may be bound to each other to form, together with the nitrogen atom to which R.sup.21 and R.sup.22 bind, a hetero ring that may have one or more substituents. ##STR00188## In general formula (2-2), each symbol represents the same definition as that of the same symbol in general formula (2-1) above.

    4. A method of producing, from a compound represented by general formula (3-1) and a compound represented by general formula (3-2), an amide compound represented by general formula (3-3), comprising: causing a reaction between the compound represented by general formula (3-1) and the compound represented by general formula (3-2) in the presence of a silane compound according to claim 1. ##STR00189## In general formula (3-1), R.sup.31 and R.sup.32, independently of each other, represent a hydrogen atom, halogen atom, hydroxyl group, carboxyl group, nitro group, cyano group, thiol group, or, a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents and may be bound to the carbon atom via a linking group, and R.sup.33 represents a hydrogen atom, carboxyl group, hydroxyl group, or, a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents and may be bound to the nitrogen atom via a linking group, or R.sup.31 and R.sup.33 may be bound to each other to form, together with the carbon atom to which R.sup.31 binds and the nitrogen atom to which R.sup.33 binds, a hetero ring that may have one or more substituents, A.sup.1 and A.sup.2, independently of each other, represent a divalent aliphatic hydrocarbon group that may have one or more substituents having 1 to 3 carbon atoms, T.sup.1 represents a hydrogen atom or a monovalent substituent, p1 and p2, independently of each other, represent an integer of 0 or 1, and m represents an integer of equal to or greater than 1 corresponding to the number of the structure units parenthesized with [ ], provided that when m is equal to or greater than 2, then the two or more structure units in [ ] may be either identical to each other or different from each other. ##STR00190## In general formula (3-2), R.sup.34 and R.sup.35, independently of each other, represent a hydrogen atom, halogen atom, hydroxyl group, carboxyl group, nitro group, cyano group, thiol group, or, a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents and may be bound to the carbon atom via a linking group, R.sup.36 represents a hydrogen atom, carboxyl group, hydroxyl group, or, a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents and may be bound to the nitrogen atom via a linking group, R.sup.34 and R.sup.36 may be bound to each other to form, together with the carbon atom to which R.sup.34 binds and the nitrogen atom to which R.sup.36 binds, a hetero ring that may have one or more substituents, A.sup.3 and A.sup.4, independently of each other, represent a divalent aliphatic hydrocarbon group that may have one or more substituents having 1 to 3 carbon atoms, T.sup.2 represents a hydrogen atom or a monovalent substituent, p3 and p4, independently of each other, represent an integer of 0 or 1, and n represents an integer of equal to or greater than 1 corresponding to the number of the structure units parenthesized with [ ], provided that when n is equal to or greater than 2, then the two or more structure units in [ ] may be either identical to each other or different from each other. ##STR00191## In general formula (3-3), each symbol represents the same definition as that of the same symbol in general formulae (3-1) and (3-2) above.

    5. The method according to any one of claims 2 to 4, wherein the reaction is carried out in the presence of, in addition to the silane compound represented by general formula (A), a second silane compound which is different from the silane compound represented by general formula (A).

    6. The method according to claim 5, wherein the second silane compound is at least one compound selected from compounds represented by general formulae (C1) to (C4). ##STR00192## In general formulae (C1) to (C4), R.sup.c1 to R.sup.c3, independently of each other, represent a hydrogen atom or a linear- or branched-chain alkyl group or alkoxy group that contains 1 to 10 carbon atoms and may have one or more substituents, provided that 0 or 1 of R.sup.c1 to R.sup.c3 is a hydrogen atom, R.sup.c4 and R.sup.c5, independently of each other, represent a linear- or branched-chain alkyl group or alkoxy group that contains 1 to 10 carbon atoms and may have one or more substituents, Z.sup.c represents a 5- to 10-membered heterocyclic group that contains at least one nitrogen atom as a ring-constituting atom and may have one or more substituents, Y.sup.c represents a hydrogen atom or halogen group, R.sup.c6 represents a linear- or branched-chain alkyl group, alkoxy group, or alkyl carbonyl group that contains 1 to 10 carbon atoms and may have one or more substituents, and s represents an integer of 1 or 2, provided that when s is 2, then R.sup.c6 is absent.

    7. The method according to any one of claims 2 to 6, wherein the reaction is in the presence of an aminosilane catalyst.

    8. The method according to claim 7, wherein the aminosilane catalyst is at least one compound selected from compounds represented by general formula (D). ##STR00193## In general formula (D), R.sup.d1 to R.sup.d3, independently of each other, represent a hydrogen atom or a linear- or branched-chain alkyl group or alkoxy group that may have one or more substituents, provided that 0 or 1 of R.sup.d1 to R.sup.d3 is a hydrogen atom, and R.sup.d4 and R.sup.d5, independently of each other, represent a hydrogen atom or an alkyl group, aryl group, alkyl aryl group, or aryl alkyl group that may have one or more substituents, provided that 0 or 1 of R.sup.d4 and R.sup.d5 is a hydrogen atom.

    9. The method according to any one of claims 2 to 8, wherein the reaction is carried out in the presence of a Lewis acid catalyst.

    10. The method according to claim 9, wherein the Lewis acid catalyst is a metal compound containing at least one metal selected from the group consisting of titanium, zirconium, hafnium, tantalum, and niobium.

    11. The method according to any one of claims 2 to 10, wherein the reaction is carried out in the presence of a phosphorus compound.

    12. The method according to claim 11, wherein the phosphorus compound is either a phosphine compound or phosphate compound.

    13. The method according to any one of claims 2 to 12, wherein the reaction is carried out as a batch reaction or a flow reaction.

    Description

    EXAMPLES

    [0298] The present invention will be described in more detail below with reference to examples. However, the present invention should in no way be bound by the following examples, and can be implemented in any form within the scope that does not depart from the purpose of the invention.

    [0299] Amide compounds were produced by the production method according to the present invention, in a manner described in each of the following examples.

    [0300] In the following examples, unless otherwise stated, diastereomeric and enantiomeric ratios were determined by .sup.1H-NMR analysis (measuring instrument: JEOL 400SS, JEOL 400 MHz, solvent: CDCl3).

    Synthesis Example Group: Synthesis of Trialkoxy Silanes (Silane Compounds (A)

    [0301] *General synthesis procedure:

    ##STR00060##

    [0302] A two-necked round-bottom flask, heated and dried in a glove box under argon atmosphere, was equipped with a stirrer (samarium-cobalt), reflux cooler, and vacuum adapter. The flask was evacuated and refilled three times with nitrogen (N.sub.2) gas, then filled with dry dichloromethane (16 mL) and trichlorosilane (HSiCl.sub.3, 5.4 g, 40 mmol) and cooled to 0° C. in an ice bath. Next, the alcohol corresponding to the alkoxy group of the trialkoxysilane to be synthesized (ROH, 3.3 equivalents, 132 mmol) was added dropwise and stirred at room temperature for 1 hour, then heated to 50° C. and refluxed for 3 hours. After completion of the reaction, the solvent and unreacted alcohol were removed and distilled under reduced pressure and nitrogen (N.sub.2) gas atmosphere (70-80° C./30 mmHg), the desired trialkoxysilane (HSiR.sub.3) was obtained.

    [0303] In the reaction formula above, R represents a halogen substitution alkoxy group.

    *Synthesis Example 1: Synthesis of tris(2,2,2-trifluoroethoxy)silane

    [0304] ##STR00061##

    [0305] The reaction was carried out in accordance with the General Synthesis Procedure using 2,2,2-trifluoroethanol (CF.sub.3CH.sub.2OH) as an alcohol, followed by distillation at 70° C./30 mmHg, whereby the title compound tris(2,2,2-trifluoroethoxy)silane ((CF.sub.3CH.sub.2O).sub.3SiH) was isolated as colorless liquid. The yield was 75%.

    [0306] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 4.48 (s, 1H), 4.14 (q, 6H, J=8.3 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 123.6 (q, .sup.1J(C—F)=276 Hz), 61.3 (q, .sup.2J(C—F)=37 Hz); .sup.29Si NMR (80 MHz, CDCl.sub.3, 24° C.): −59.0.

    *Synthesis Example 2: Synthesis of tris((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)silane

    [0307] ##STR00062##

    [0308] The reaction was carried out in accordance with the General Synthesis Procedure using 1,1,1,3,3,3-hexafluoro-2-propanol ((CF.sub.3).sub.2CH.sub.2OH) as an alcohol, followed by distillation at 70° C./30 mmHg, whereby the title compound tris((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)silane (((CF.sub.3).sub.2CH.sub.2O).sub.3SiH) was isolated as colorless liquid. The yield was 60%.

    [0309] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 4.76 (s, 1H), 4.63-4.60 (m, 3H); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 120.6 (q, .sup.1J(C—F)=280 Hz), 70.3 (quin, .sup.2J(C—F)=35 Hz); .sup.29Si NMR (80 MHz, CDCl.sub.3, 24° C.): −62.8.

    *Synthesis Example 3: Synthesis of tris(2.2.2-trichloroethoxy)silane

    [0310] ##STR00063##

    [0311] The reaction was carried out in accordance with the General Synthesis Procedure using 2,2,2-trichloroethanol (CCl.sub.3CH.sub.2OH) as an alcohol, without being followed by distillation, whereby the title compound tris(2,2,2-trichloroethoxy)silane ((CCl.sub.3CH.sub.2O).sub.3SiH) was isolated as colorless liquid. The yield was 94%.

    [0312] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 4.80 (s, 1H), 4.42 (s, 6H); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 97.6, 75.7; .sup.29Si NMR (80 MHz, CDCl.sub.3, 24° C.): −61.3.

    *Synthesis Example 4: Synthesis of tris(2,2,3,3-tetrafluoropropoxy)silane

    [0313] ##STR00064##

    [0314] The reaction was carried out in accordance with the General Synthesis Procedure using 2,2,3,3-tetrafluoro-1-propanol (CF.sub.2HCF.sub.2CH.sub.2OH) as an alcohol, followed by distillation at 120° C./30 mmHg, whereby the title compound tris(2,2,3,3-tetrafluoropropoxy)silane ((CF.sub.2HCF.sub.2CH.sub.2O).sub.3SiH) was isolated as colorless liquid. The yield was 71%.

    [0315] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 6.02-5.75 (m, 3H), 4.44 (s, 1H), 4.20-4.13 (m, 6H); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 114.7 (tt, .sup.1J(C—F)=248 Hz, .sup.2J(C—F)=26.7 Hz), 109.4 (tt, .sup.1J(C—F)=214 Hz, .sup.2J(C—F)=31.4 Hz), 60.5 (t, .sup.2J(C—F)=29.5 Hz); .sup.29Si NMR (80 MHz, CDCl.sub.3, 24° C.): −57.9.

    Example Group A: Amidation Reaction Between Carbonic Acid Compound and Amino Compound Using Silane Compound (A)

    *Example a1: Synthesis of N-(4-methoxybenzyl)propionamide

    [0316] ##STR00065##

    [0317] A 5.0-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), propanoic acid (0.5 mmol, 1 equivalent), and 4-methoxybenzylamine (0.75 mmol, 1.5 mmol). This mixture was combined with HSi[OCH(CF.sub.3).sub.2].sub.3 (0.65 mmol, 1.3 equivalents) (generation of hydrogen gas was observed), and then mixed and dissolved in dry DCM (0.5 mL, 1M), and the vial was sealed. The vial was removed from the glove box and stirred vigorously for 6 hours at room temperature under an argon atmosphere. The progress of the reaction was monitored by TLC analysis. Once the reaction completed, and the reaction mixture diluted with CHCl.sub.3 (3.0 mL) and transferred by a pipette to a silica gel column, and the vial and pipette used were washed with CHCl.sub.3 (5.0 mL). The resulting reaction product was purified with flash column chromatography using 0 to 40% AcOEt in hexane, whereby N-(4-methoxybenzyl)propionamide was obtained as a white solid. The yield was 93%.

    *Example a2: Synthesis of N-benzyl-N-methyl propionamide

    [0318] ##STR00066##

    [0319] The reaction was carried out in the same manner as in Example a1 except that N-methyl benzylamine (0.75 mmol, 1.5 equivalents) was used instead of 4-methoxybenzylamine, whereby N-benzyl-N-methyl propionamide was obtained as a white solid. The yield was 91%.

    Example Group B: Intramolecular Amidation Reaction of Amino Carbonic Acid Compound Using Silane Compound (A)

    *Example b1: Synthesis of (S)-tert-butyl (2-oxoazepan-3-yl)carbamate

    [0320] ##STR00067##

    [0321] A 5.0-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), Boc-Lys-OH (0.5 mmol, 1 equivalent), and HSi(OCH.sub.2CF.sub.3).sub.3 (0.5 mmol, 1 equivalent), and then mixed and dissolved in dry DMSO (0.5 mL, 1M), and the vial was sealed. The vial was removed from the glove box, placed in an oil bath heated to 50° C., and then stirred vigorously for 24 hours. The progress of the reaction was monitored by TLC analysis. Once the reaction completed, and the reaction mixture diluted with CHCl.sub.3 (3.0 mL), and transferred by a pipette to a silica gel column. The vial and the pipette used were washed with CHCl.sub.3 (5.0 mL). The resulting reaction product was purified with flash column chromatography using 0 to 40% AcOEt in hexane, whereby (S)-tert-butyl (2-oxoazepan-3-yl)carbamate was obtained as a white solid. The yield was 95%.

    Example Group C: Amidation Reaction Between Two Amino Acid Compounds Using Silane Compound (A) (without Protective Group)

    *Example c1: Synthesis of H-L-Phe-L-Ala-Ot-Bu (1)

    [0322] ##STR00068##

    [0323] A 5-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), L-phenylalanine (H-L-Phe-OH, 82.6 mg, 0.5 mmol), tris(hexafluoroisopropoxy)silane (HSi(OCH(CF.sub.3).sub.2).sub.3, 530.2 mg, 1.0 mmol), and chloroform (0.5 mL), and sealed with a septum and a screw cap. The reaction vial was removed from the glove box, placed in an oil bath heated to 50° C., then stirred vigorously for 1 hour. The screw cap was removed, and use a microsyringe on top of the septum to remove the N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA, 12 0.7 mg, 0.5 mg, 0.5 mg (mmol) was added, capped with a screw cap, and stirred vigorously for 1 hour at room temperature. The screw cap was removed, N-tert-butyldimethylsilyl-N-methyl trifluoroacetamide (MTBSTFA, 120.7 mg, 0.5 mmol) was added through the septum using a microsyringe, and the vial was sealed with the screw cap again, and was stirred vigorously at room temperature for 1 hour. The screw cap was removed again, L-alanine-tert-butyl ester (H-L-Ala-Ot-Bu, 36.3 mg, 0.25 mmol) was added through the septum using a microsyringe, and the vial was sealed with the screw cap again, and stirred vigorously for 21 hours in an oil bath heated to 30° C. The reaction vial was removed from the oil bath and left to stand until it reached to room temperature, and the reaction mixture was diluted with a 1% methanol/chloroform mixture (3.0 mL), and the product was transferred to a previously prepared silica gel column (1% methanol/chloroform mixture) using a Pasteur pipette. This procedure was repeated three more times, and the screw cap, septum, and the Pasteur pipette used was washed with the same mixture. The reaction product was purified with silica gel column chromatography (1-5% methanol/chloroform mixture), whereby the desired dipeptide (H-L-Phe-L-Ala-Ot-Bu, 69.2 mg, 95%, >99:1dr) was obtained as a white solid.

    *Example c2: Synthesis of H-L-Phe-L-Ala-Ot-Bu (2)

    [0324] ##STR00069##

    [0325] A 5-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), L-phenylalanine (H-L-Phe-OH, 41.3 mg, 0.25 mmol), tris(hexafluoroisopropoxy)silane (HSi(OCH(CF.sub.3).sub.2).sub.3, 265.1 mg, 0.5 mmol), and chloroform (0.5 mL), and sealed with a septum and a screw cap. The reaction vial was removed from the glove box, placed in an oil bath heated to 50° C., and then stirred vigorously for 1 hours. The screw cap was removed, through the septum using a microsyringe N-tert-butyldimethylsilyl-N-methyl trifluoroacetamide (MTBSTFA, 60.3 mg, 0.25 mmol) was added, and the vial was sealed with the screw cap again, and was stirred vigorously at room temperature for 1 hour. The screw cap was removed again, through the septum using a microsyringe L-alanine-tert-butyl ester (H-L-Ala-Ot-Bu, 72.6 mg, 0.5 mmol) was added, and the vial was sealed with the screw cap again, in an oil bath heated to 30° C. stirred vigorously for 21 hours. The reaction vial was removed from the oil bath and left to stand until it reached to room temperature, and the reaction mixture was diluted with a 1% methanol/chloroform mixture (3.0 mL). and the product was transferred to a previously prepared silica gel column (1% methanol/chloroform mixture) using a Pasteur pipette. This procedure was repeated three more times, and the screw cap, septum, and the Pasteur pipette used was washed with the same mixture. The reaction product was purified with silica gel column chromatography (1-5% methanol/chloroform mixture), whereby the desired dipeptide (H-L-Phe-L-Ala-Ot-Bu. 72.7 mg, 99%, >99:1dr) was obtained as a white solid.

    *Example c3: Synthesis of H-L-Phe-L-Ser(t-Bu)-Ot-Bu

    [0326] ##STR00070##

    [0327] A 5-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), L-phenylalanine (H-L-Phe-OH, 82.6 mg, 0.5 mmol), tris(hexafluoroisopropoxy)silane (HSi(OCH(CF.sub.3).sub.2).sub.3, 530.2 mg, 1.0 mmol), and chloroform (0.5 mL), and sealed with a septum and a screw cap. The reaction vial was removed from the glove box, placed in an oil bath heated to 50° C., and then stirred vigorously for 1 hours. The screw cap was removed, through the septum using a microsyringe N-tert-butyldimethylsilyl-N-methyl trifluoroacetamide (MTBSTFA, 120.7 mg, 0.5 mmol) was added, and the vial was sealed with the screw cap again, and was stirred vigorously at room temperature for 1 hour. The screw cap was removed again, through the septum using a microsyringe L-serine-tert-butyl ester (H-L-Ser(t-Bu)-Ot-Bu, 54.3 mg, 0.25 mmol) was added, and the vial was sealed with the screw cap again, in an oil bath heated to 30° C. stirred vigorously for 21 hours. The reaction vial was removed from the oil bath and left to stand until it reached to room temperature, and the reaction mixture was diluted with a 1% methanol/chloroform mixture (3.0 mL), and the product was transferred to a previously prepared silica gel column (1% methanol/chloroform mixture) using a Pasteur pipette. This procedure was repeated three more times, and the screw cap, septum, and the Pasteur pipette used was washed with the same mixture. The reaction product was purified with silica gel column chromatography (1-5% methanol/chloroform mixture), whereby the desired dipeptide (H-L-Phe-L-Ser(t-Bu)-Ot-Bu, 73.6 mg, 81%, >99:1dr) was obtained as a colorless, gum-like compound.

    *Example c4: Synthesis of H-L-Phe-L-Val-Ot-Bu (1)

    [0328] ##STR00071##

    [0329] A 5-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), L-phenylalanine (H-L-Phe-OH, 82.6 mg, 0.5 mmol), tris(hexafluoroisopropoxy)silane (HSi(OCH(CF.sub.3).sub.2).sub.3, 530.2 mg, 1.0 mmol), and chloroform (0.5 mL), and sealed with a septum and a screw cap. The reaction vial was removed from the glove box, placed in an oil bath heated to 50° C., and then stirred vigorously for 1 hours. The screw cap was removed, through the septum using a microsyringe N-tert-butyldimethylsilyl-N-methyl trifluoroacetamide (MTBSTFA, 120.7 mg, 0.5 mmol) was added, and the vial was sealed with the screw cap again, and was stirred vigorously at room temperature for 1 hour. The screw cap was removed again, through the septum using a microsyringe L-valine-tert-butyl ester (H-L-Val-Ot-Bu, 43.3 mg, 0.25 mmol) was added, and the vial was sealed with the screw cap again, in an oil bath heated to 30° C. stirred vigorously for 21 hours. The reaction vial was removed from the oil bath and left to stand until it reached to room temperature, and the reaction mixture was diluted with a 1% methanol/chloroform mixture (3.0 mL), and the product was transferred to a previously prepared silica gel column (1% methanol/chloroform mixture) using a Pasteur pipette. This procedure was repeated three more times, and the screw cap, septum, and the Pasteur pipette used was washed with the same mixture. The reaction product was purified with silica gel column chromatography (1-5% methanol/chloroform mixture), whereby the desired dipeptide (H-L-Phe-L-Val-Ot-Bu, 28.0 mg, 35%, >99:1dr) was obtained as a colorless, gum-like compound.

    *Example c5: Synthesis of H-L-Phe-L-Val-Ot-Bu (2)

    [0330] ##STR00072##

    [0331] A 5-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), L-phenylalanine (H-L-Phe-OH, 41.3 mg, 0.25 mmol), tris(hexafluoroisopropoxy)silane (HSi(OCH(CF.sub.3).sub.2).sub.3, 265.1 mg, 0.5 mmol), and chloroform (0.5 mL), and sealed with a septum and a screw cap. The reaction vial was removed from the glove box, placed in an oil bath heated to 50° C., and then stirred vigorously for 1 hours. The screw cap was removed, through the septum using a microsyringe N-tert-butyldimethylsilyl-N-methyl trifluoroacetamide (MTBSTFA, 60.3 mg, 0.25 mmol) was added, and the vial was sealed with the screw cap again, and was stirred vigorously at room temperature for 1 hour. The screw cap was removed again, through the septum using a microsyringe L-valine-tert-butyl ester (H-L-Val-Ot-Bu, 86.6 mg, 0.5 mmol) was added, and the vial was sealed with the screw cap again, in an oil bath heated to 30° C. stirred vigorously for 21 hours. The reaction vial was removed from the oil bath and left to stand until it reached to room temperature, and the reaction mixture was diluted with a 1% methanol/chloroform mixture (3.0 mL), and the product was transferred to a previously prepared silica gel column (1% methanol/chloroform mixture) using a Pasteur pipette. This procedure was repeated three more times, and the screw cap, septum, and the Pasteur pipette used was washed with the same mixture. The reaction product was purified with silica gel column chromatography (1-5% methanol/chloroform mixture), whereby the desired dipeptide (H-L-Phe-L-Val-Ot-Bu, 69.3 mg, 87%, >99:1dr) was obtained as a colorless, gum-like compound.

    *Example c6: Synthesis of H-L-Ala-L-Ala-Ot-Bu (1)

    [0332] ##STR00073##

    [0333] A 5-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), L-alanine (H-L-Ala-OH, 44.5 mg, 0.5 mmol), tris(hexafluoroisopropoxy)silane (HSi(OCH(CF.sub.3).sub.2).sub.3, 265.1 mg, 0.5 mmol), and chloroform (0.5 mL), and sealed with a septum and a screw cap. The reaction vial was removed from the glove box, placed in an oil bath heated to 50° C., and then stirred vigorously for 1 hours. The screw cap was removed, through the septum using a microsyringe N-tert-butyldimethylsilyl-N-methyl trifluoroacetamide (MTBSTFA, 120.7 mg, 0.5 mmol) was added, and the vial was sealed with the screw cap again, and was stirred vigorously at room temperature for 1 hour. The screw cap was removed again, through the septum using a microsyringe L-alanine-tert-butyl ester (H-L-Ala-Ot-Bu, 36.3 mg, 0.25 mmol) was added, and the vial was sealed with the screw cap again, in an oil bath heated to 30° C. stirred vigorously for 21 hours. The reaction vial was removed from the oil bath and left to stand until it reached to room temperature, and the reaction mixture was diluted with a 1% methanol/chloroform mixture (3.0 mL), and the product was transferred to a previously prepared silica gel column (1% methanol/chloroform mixture) using a Pasteur pipette. This procedure was repeated three more times, and the screw cap, septum, and the Pasteur pipette used was washed with the same mixture. The reaction product was purified with silica gel column chromatography (5 to 30% methanol/chloroform mixture), whereby the desired dipeptide (H-L-Ala-L-Ala-Ot-Bu, 30.0 mg, 55%, >99:1dr) was obtained as a colorless, gum-like compound.

    *Example c7: Synthesis of H-L-Ala-L-Ala-Ot-Bu (2)

    [0334] ##STR00074##

    [0335] A 5-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), L-alanine (H-L-Ala-OH, 22.3 mg, 0.25 mmol), tris(hexafluoroisopropoxy)silane (HSi(OCH(CF.sub.3).sub.2).sub.3, 265.1 mg, 0.5 mmol), and sealed with a septum and a screw cap. The reaction vial was removed from the glove box, placed in an oil bath heated to 50° C., and then stirred vigorously for 1 hours. The screw cap was removed, through the septum using a microsyringe N-tert-butyldimethylsilyl-N-methyl trifluoroacetamide (MTBSTFA, 60.3 mg, 0.25 mmol) was added, and the vial was sealed with the screw cap again, and was stirred vigorously at room temperature for 1 hour. The screw cap was removed again, through the septum using a microsyringe L-alanine-tert-butyl ester (H-L-Ala-Ot-Bu, 54.5 mg, 0.375 mmol) was added, and the vial was sealed with the screw cap again, in an oil bath heated to 30° C. stirred vigorously for 21 hours. The reaction vial was removed from the oil bath and left to stand until it reached to room temperature, and the reaction mixture was diluted with a 1% methanol/chloroform mixture (3.0 mL), and the product was transferred to a previously prepared silica gel column (1% methanol/chloroform mixture) using a Pasteur pipette. This procedure was repeated three more times, and the screw cap, septum, and the Pasteur pipette used was washed with the same mixture. The reaction product was purified with silica gel column chromatography (5 to 30% methanol/chloroform mixture), whereby the desired dipeptide (H-L-Ala-L-Ala-Ot-Bu, 42.1 mg, 78%, >99:1dr) was obtained as a colorless, gum-like compound.

    *Example c8: Synthesis of H-L-Ile-L-Ala-Ot-Bu

    [0336] ##STR00075##

    [0337] A 5-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), L-custom-characterleucine (H-L-Ile-OH, 65.6 mg, 0.5 mmol), tris(hexafluoroisopropoxy)silane (HSi(OCH(CF.sub.3).sub.2).sub.3, 530.2 mg, 1.0 mmol), and chloroform (0.5 mL), and sealed with a septum and a screw cap. The reaction vial was removed from the glove box, placed in an oil bath heated to 50° C., and then stirred vigorously for 1 hours. The screw cap was removed, through the septum using a microsyringe N-tert-butyldimethylsilyl-N-methyl trifluoroacetamide (MTBSTFA, 120.7 mg, 0.5 mmol) was added, and the vial was sealed with the screw cap again, and was stirred vigorously at room temperature for 1 hour. The screw cap was removed again, through the septum using a microsyringe L-alanine-tert-butyl ester (H-L-Ala-Ot-Bu, 36.3 mg, 0.25 mmol) was added, and the vial was sealed with the screw cap again, in an oil bath heated to 30° C. stirred vigorously for 21 hours. The reaction vial was removed from the oil bath and left to stand until it reached to room temperature, and the reaction mixture was diluted with a 1% methanol/chloroform mixture (3.0 mL), and the product was transferred to a previously prepared silica gel column (1% methanol/chloroform mixture) using a Pasteur pipette. This procedure was repeated three more times, and the screw cap, septum, and the Pasteur pipette used was washed with the same mixture. silica gel column chromatography (1 to 10% methanol/chloroform mixture)custom-character the reaction product was purified, desired dipeptide (H-L-Ile-L-Ala-Ot-Bu, 23.0 mg, 36%, >99:1dr) was obtained as a colorless, gum-like compound.

    *Example c9: Synthesis of H-L-Phe-L-Ala-Ot-Bu

    [0338] ##STR00076##

    [0339] A 5-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), L-phenylalanine (H-L-Phe-OH, 82.6 mg, 0.5 mmol), tristrifluoroethoxy silane (HSi(OCH.sub.2CF.sub.3).sub.3, 358.8 mg, 1.0 mmol), and chloroform (0.5 mL), and sealed with a septum and a screw cap. The reaction vial was removed from the glove box, placed in an oil bath heated to 50° C., and then stirred vigorously for 1 hours. The screw cap was removed, through the septum using a microsyringe N-tert-butyldimethylsilyl-N-methyl trifluoroacetamide (MTBSTFA, 120.7 mg, 0.5 mmol) was added, and the vial was sealed with the screw cap again, in an oil bath heated to 50° C. stirred vigorously for 2 hours. The screw cap was removed again, through the septum using a microsyringe L-alanine-tert-butyl ester (H-L-Ala-Ot-Bu, 36.3 mg, 0.25 mmol) was added, and the vial was sealed with the screw cap again, and stirred vigorously at room temperature for 21 hours. The reaction vial was removed from the oil bath and left to stand until it reached to room temperature, and the reaction mixture was diluted with a 1% methanol/chloroform mixture (3.0 mL), and the product was transferred to a previously prepared silica gel column (1% methanol/chloroform mixture) using a Pasteur pipette. This procedure was repeated three more times, and the screw cap, septum, and the Pasteur pipette used was washed with the same mixture. The reaction product was purified with silica gel column chromatography (1-5% methanol/chloroform mixture), whereby the desired dipeptide (H-L-Phe-L-Ala-Ot-Bu, 26.2 mg, 36%, >99:1dr) was obtained as a white solid.

    Example Group D: Amidation Reactions Between Two Amino Acid Compounds Using Silane Compound (A) (with Protective Group)

    *General Synthesis Procedure:

    [0340] ##STR00077##

    [0341] A 5.0-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), a first amino acid AA.sup.1 with its terminal amino group protected (0.5 mmol, 1 equivalent), and a second amino acid AA.sup.2 with its terminal carboxyl group tert-butylated (0.75 mmol, 1.5 equivalents). This mixture was combined with tris(1,1,1,3,3,3-hexafluoroisopropoxy)silane (HSi[OCH(CF.sub.3).sub.2].sub.3, 0.65 mmol, 1.3 equivalents) (generation of hydrogen gas was observed), and then mixed and dissolved in dry DCM (0.5 mL, 1M), and the vial was sealed. The vial was removed from the glove box and stirred vigorously for 6 hours at room temperature under an argon atmosphere. The reaction was monitored with TLC analysis. Once the reaction completed, and the reaction mixture diluted with CHCl.sub.3 (3.0 mL), and transferred by a pipette to a silica gel column. The vial and pipette used were washed with CHCl.sub.3 (5.0 mL). The reaction mixture was purified with flash column chromatography using 10 to 100% AcOEt in hexane or 0 to 10% MeOH in CHCl.sub.3 as an eluate, whereby an analytically pure product was obtained. In the reaction formula above, R.sup.aa1 represents the side chain of the first amino acid AA.sup.1, R.sup.aa2 represents the side chain of the second amino acid AA.sup.2, and PG.sup.aa represents the terminal amino protective group of the first amino acid AA.sup.1.

    *Example d1: Synthesis of Boc-L-Ala-L-Ala-OtBu

    [0342] ##STR00078##

    [0343] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Ala-OtBu was isolated as colorless liquid. The yield was 97%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.48 (40% AcOEt in hexane); [α].sub.D.sup.25=−20.0 (c 1.40, CHCl.sub.3).

    *Example d2: Synthesis of Bzo-L-Ala-L-Ala-OtBu

    [0344] ##STR00079##

    [0345] The reaction was carried out in accordance with the General Synthesis Procedure, using Bzo-L-Ala as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Bzo-L-Ala-L-Ala-OtBu was isolated as a white solid. The yield was 98%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.60 (70% AcOEt in hexane).

    [0346] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.81-7.79 (m, 2H), 7.51-7.47 (m, 1H), 7.43-7.39 (m, 2H), 7.02 (br d, 1H, J=6.9 Hz), 6.84 (br d, 1H, J=5.9 Hz), 4.77 (quin, 1H, J=7.1 Hz), 4.44 (quin, 1H, J=7.1 Hz), 1.51 (d, 3H, J=6.9 Hz), 1.47 (s, 9H), 1.37 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.0, 171.8, 167.0, 133.9, 13.7, 128.6, 127.2, 82.0, 49.5, 48.9, 28.0, 19.2, 18.3.

    *Example d3: Synthesis of Boc-Gly-L-Ala-OtBu

    [0347] ##STR00080##

    [0348] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-Gly as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-Gly-L-Ala-OtBu was isolated as colorless liquid. The yield was 99%, and the diastereomer ratio was er>99:1.

    *Example d4: Synthesis of Boc-L-Val-L-Ala-OtBu

    [0349] ##STR00081##

    [0350] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Val as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Val-L-Ala-OtBu was isolated as a white solid. The yield was 80%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.68 (40% AcOEt in hexane); [α].sub.D.sup.25=−12.8 (c 1.01, CHCl.sub.3).

    [0351] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 6.40 (br s, 1H), 7.66 (br d, 1H, J=6.4 Hz), 4.44 (quin, 1H, J=7.1 Hz), 3.92 (br t, 1H, J=7.8 Hz), 2.16-2.09 (m, 1H), 1.45 (s, 9H), 1.43 (s, 9H), 1.36 (d, 3H, J=7.1 Hz), 0.96 (d, 3H, J=6.8 Hz), 0.90 (d, 3H, J=6.8 Hz); .sup.13C{.sup.1H}NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.0, 170.9, 155.9, 82.1, 79.9, 59.9, 48.7, 31.2, 28.4, 28.0, 19.3, 18.7, 17.7

    *Example d5: Synthesis of Boc-L-Ile-L-Ala-OtBu

    [0352] ##STR00082##

    [0353] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ile as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ile-L-Ala-OtBu was isolated as a white solid. The yield was 77%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.57 (40% AcOEt in hexane); [α].sub.D.sup.25=−12.6 (c 1.03, CHCl.sub.3).

    [0354] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 6.45 (br s, 1H), 5.08 (br s, 1H), 4.42 (quin, 1H, J=7.1 Hz), 3.94 (br t, 1H, J=7.1 Hz), 2.00-1.86 (m, 1H), 1.59-1.47 (m, 1H), 1.44 (s, 9H), 1.42 (s, 9H), 1.35 (d, 3H, J=7.1 Hz), 1.17-1.06 (m, 1H), 0.92 (d, 3H, J=6.8 Hz), 0.89 (t, 3H, J=7.5 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.9, 171.0, 155.8, 82.0, 79.9, 59.3, 48.7, 37.5, 28.4, 28.0, 24.8, 18.6, 15.6, 11.6.

    *Example d6: Synthesis of Boc-L-Leu-L-Ala-OtBu

    [0355] ##STR00083##

    [0356] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Leu as the first amino acid AA and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Leu-L-Ala-OtBu was isolated as a white solid. The yield was 79%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.66 (50% AcOEt in hexane); [α].sub.D.sup.25=+92.4 (c 1.06, CHCl.sub.3).

    [0357] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.36-7.30 (m, 5H), 6.31 (br d, 1H, J=6.6 Hz), 5.74 (br s, 1H), 5.12 (br s, 1H), 4.38 (quin, 1H, J=7.1 Hz), 1.40 (s, 9H), 1.38 (s, 9H), 1.37 (d, 3H, J=7.5 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.5, 169.4, 155.2, 138.2, 129.1, 128.4, 27.3, 82.2, 80.1, 58.7, 49.1, 28.4, 27.9, 18.6.

    *Example d7: Synthesis of Boc-L-Phe-L-Ala-OtBu

    [0358] ##STR00084##

    [0359] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Phe as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Phe-L-Ala-OtBu was isolated as a white solid. The yield was 96%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.68 (50% AcOEt in hexane); [α].sub.D.sup.25=+17.7 (c 1.07, CHCl.sub.3).

    [0360] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.28-7.18 (m, 5H), 6.44 (br d, 1H, J=6.4 Hz), 4.99 (br s, 1H), 4.40-4.33 (m, 2H), 3.11-3.02 (m, 2H), 1.43 (s, 9H), 1.40 (s, 9H), 1.31 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.7, 170.6, 155.4, 136.6, 129.5, 128.7, 127.0, 82.1, 80.2, 55.7, 48.8, 38.6, 28.3, 28.0, 18.7.

    *Example d8: Synthesis of Boc-L-Tyr(Bu)-L-Ala-OtBu

    [0361] ##STR00085##

    [0362] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Tyr(Bu) as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Tyr(.sup.tBu)-L-Ala-OtBu was isolated as a white solid. The yield was 93%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.65 (40% AcOEt in hexane).

    [0363] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.08 (d, 2H, J=8.5 Hz), 6.90 (d, 2H, J=8.2 Hz), 6.44 (br d, 1H, J=6.4 Hz), 4.95 (br s, 1H), 4.39-4.31 (m, 2H), 3.06-2.97 (m, 2H), 1.43 (s, 9H), 1.40 (s, 9H), 1.31 (s, 9H), 1.30 (d, 3H, J=7.7 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.7, 170.7, 155.4, 154.4, 131.4, 129.9, 124.3, 82.0, 80.1, 78.4, 55.7, 48.8, 37.8, 28.9, 28.3, 28.0, 18.6.

    *Example d9: Synthesis of Boc-L-Ser(Bu)-L-Ala-OtBu

    [0364] ##STR00086##

    [0365] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ser(.sup.tBu) as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ser(.sup.tBu)-L-Ala-OtBu was isolated as a white solid. The yield was 99%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.66 (40% AcOEt in hexane).

    [0366] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.28 (br s, 1H), 5.43 (br s, 1H), 4.41 (quin, 1H, J=7.1 Hz), 4.15 (br s, 1H), 3.78-3.76 (m, 1H), 3.38-3.34 (m, 1H), 1.45 (s, 9H), 1.45 (s, 9H), 1.35 (d, 3H, J=7.1 Hz), 1.19 (s, 9H); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.9, 170.1, 155.5, 81.8, 80.0, 74.0, 61.9, 54.3, 48.9, 28.4, 28.0, 27.4, 18.8.

    *Example d10: Synthesis of Boc-L-Thr(.SUP.t.Bu)-L-Ala-OtBu

    [0367] ##STR00087##

    [0368] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Thr(.sup.tBu) as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Thr(.sup.tBu)-L-Ala-OtBu was isolated as a white solid. The yield was 88%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.58 (40% AcOEt in hexane).

    [0369] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.52 (br d, 1H, J=6.0 Hz), 5.57 (br d, 1H, J=5.5 Hz), 4.42-4.32 (m, 1H), 4.12-4.06 (m, 2H), 1.44 (s, 9H), 1.43 (s, 9H), 1.34 (d, 3H, J=7.1 Hz), 1.23 (s, 9H), 1.08 (d, 3H, J=6.2 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.8, 169.7, 155.7, 81.8, 79.7, 75.1, 67.0, 58.6, 49.0, 28.46, 28.42, 28.0, 18.5, 17.7.

    *Example d11: Synthesis of Boc-L-Cys(Bzl)-L-Ala-OtBu

    [0370] ##STR00088##

    [0371] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Cys(Bzl) as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Cys(Bzl)-L-Ala-OtBu was isolated as a white solid. The yield was 92%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.64 (40% AcOEt in hexane).

    [0372] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.35-7.21 (m, 5H), 6.91 (br d, 1H, J=5.5 Hz), 5.36 (br s, 1H), 4.42 (quin, 1H, J=7.1 Hz), 4.27 (br s, 1H), 3.74 (s, 2H), 2.87 (dd, 1H, J=14.2, 5.8 Hz), 2.74 (dd, 1H, J=14.0, 6.6 Hz), 1.45 (s, 18H), 1.37 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H}NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.6, 170.0, 155.3, 137.9, 129.1, 128.6, 127.2, 82.1, 80.3, 53.7, 49.0, 36.5, 33.8, 28.3, 28.0, 18.6.

    *Example d12: Synthesis of Boc-L-Met-L-Ala-OtBu

    [0373] ##STR00089##

    [0374] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Met as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Met-L-Ala-OtBu was isolated as a white solid. The yield was 93%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.76 (40% AcOEt in hexane).

    [0375] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 6.63 (br d, 1H, J=7.3 Hz), 5.20 (br d, 1H, J=7.1 Hz), 4.42 (quin, 1H, J=7.1 Hz), 4.27 (q, 1H, J=6.7 Hz), 2.58 (t, 2H, J=7.3 Hz), 2.11 (s, 3H), 2.09-2.02 (m, 1H), 1.97-1.88 (m, 1H), 1.45 (s, 9H), 1.43 (s, 9H), 1.36 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.8, 170.9, 155.5, 82.0, 80.0, 53.3, 48.8, 32.0, 30.1, 28.4, 28.0, 18.4, 15.2.

    *Example d13: Synthesis of Boc-L-Asp(.SUP.t.Bu)-L-Ala-OtBu

    [0376] ##STR00090##

    [0377] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Asp(.sup.tBu) as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Asp(.sup.tBu)-L-Ala-OtBu was isolated as a white solid. The yield was 87%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.60 (40% AcOEt in hexane).

    [0378] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.02 (br d, 1H, J=6.0 Hz), 5.67 (br d, 1H, J=7.8 Hz), 4.43 (br s, 1H), 4.36 (quin, 1H, J=7.1 Hz), 2.87-2.83 (m, 1H), 2.56 (dd, 1H, J=17.0, 6.0 Hz), 1.427 (s, 9H), 1.423 (s, 9H), 1.41 (s, 9H), 1.32 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.7, 171.3, 170.3, 155.5, 81.9, 81.7, 80.3, 50.7, 48.9, 37.5, 28.3, 28.1, 28.0, 18.5.

    *Example d14: Synthesis of Boc-L-Glu(.SUP.t.Bu)-L-Ala-OtBu

    [0379] ##STR00091##

    [0380] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Glu(.sup.tBu) as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Glu(.sup.tBu)-L-Ala-OtBu was isolated as a white solid. The yield was 96%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.40 (40% AcOEt in hexane).

    [0381] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 6.81 (br s, 1H), 5.35 (br d, 1H, J=7.6 Hz), 4.37 (quin, 1H, J=7.1 Hz), 4.12-4.06 (m, 1H), 2.39-2.25 (m, 2H), 2.07-1.99 (m, 1H), 1.90-1.80 (m, 1H), 1.41 (s, 9H), 1.40 (s, 9H), 1.38 (s, 9H), 1.30 (d, 3H, J=7.3 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.7, 171.8, 171.1, 155.6, 81.9, 80.8, 79.9, 53.8, 48.8, 31.8, 28.3, 28.1, 28.07, 28.00, 18.4.

    *Example d15: Synthesis of Boc-L-Asn(trt)-L-Ala-OtBu

    [0382] ##STR00092##

    [0383] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Asn(trt) as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Asn(trt)-L-Ala-OtBu was isolated as a white solid. The yield was 74%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.55 (40% AcOEt in hexane).

    [0384] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.28-7.16 (m, 15H), 6.91 (br s, 1H), 6.19 (br d, 1H, J=7.3 Hz), 4.46-4.44 (m, 1H), 4.33 (quin, 1H, J=7.1 Hz), 3.09 (d, 1H, J=16.1 Hz), 2.69 (dd, 1H, J=15.5, 4.8 Hz), 1.45 (s, 9H), 1.43 (s, 9H), 1.27 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H}NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.5, 170.8, 170.6, 155.8, 144.4, 128.7, 128.0, 127.1, 81.8, 80.2, 70.8, 51.3, 49.1, 38.0, 28.4, 28.0, 18.3.

    *Example d16: Synthesis of Boc-L-Gln(trt)-L-Ala-OtBu

    [0385] ##STR00093##

    [0386] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Gln(trt) as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Gln(trt)-L-Ala-OtBu was isolated as a white solid. The yield was 77%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.23 (40% AcOEt in hexane).

    [0387] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.31-7.22 (m, 15H), 6.56 (br d, 1H, J=7.3 Hz), 5.42 (br d, 1H, J=5.7 Hz), 4.32 (quin, 1H, J=7.3 Hz), 4.02 (q, 1H, J=7.1 Hz), 2.48 (t, 2H, J=6.2 Hz), 2.06-1.91 (m, 2H), 1.43 (s, 18H), 1.28 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.9, 171.1, 155.8, 144.7, 128.8, 128.0, 127.0, 81.9, 79.9, 70.6, 53.4, 48.8, 33.6, 29.8, 28.4, 28.0, 18.0.

    *Example d17: Synthesis of Boc-L-Lys(Z)-L-Ala-OtBu

    [0388] ##STR00094##

    [0389] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Lys(Z) as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Lys(Z)-L-Ala-OtBu was isolated as a white solid. The yield was 93%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.31 (40% AcOEt in hexane).

    [0390] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.34-7.28 (m, 5H), 6.57 (br s, 1H), 5.18 (br s, 1H), 5.08 (s, 2H), 5.01 (br s, 1H), 4.41 (quin, 1H, J=7.1 Hz), 4.13-4.07 (m, 1H), 3.17 (t, 2H, J=6.0 Hz), 1.84-1.79 (m, 1H), 1.66-1.56 (m, 1H), 1.54-1.48 (m, 2H), 1.43 (s, 9H), 1.42 (s, 9H), 1.38-1.36 (m, 2H), 1.34 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.0, 171.5, 156.7, 136.7, 128.6, 128.2, 128.1, 82.1, 80.0, 66.7, 54.2, 48.7, 40.5, 32.2, 29.4, 28.4, 28.0, 22.4, 18.5.

    *Example d18: Synthesis of Boc-L-Arg(Z).SUB.2.-L-Ala-OtBu

    [0391] ##STR00095##

    [0392] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Arg(Z).sub.2 as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Arg(Z).sub.2-L-Ala-OtBu was isolated as a white solid. The yield was 69%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.42 (40% AcOEt in hexane).

    [0393] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 9.43 (br s, 1H), 9.27 (br s, 1H), 7.41-7.26 (m, 10H), 6.76 (br d, 1H, J=7.1 Hz), 5.48 (br d, 1H, J=8.0 Hz), 5.24 (s, 2H), 5.02-5.09 (m, 2H), 4.33 (quin, 1H, J=7.1 Hz), 4.24-4.22 (m, 1H), 4.09-4.02 (m, 1H), 3.94-3.88 (m, 1H), 1.81-1.57 (m, 4H), 1.42 (s, 18H), 1.19 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.7, 171.4, 163.8, 160.8, 155.9, 155.6, 136.9, 134.7, 128.98, 128.94, 128.5, 128.4, 127.94, 127.90, 81.7, 79.8, 69.0, 67.0, 53.9, 48.7, 44.2, 28.4, 28.0, 24.8, 18.1.

    *Example d19: Synthesis of Boc-L-His(Bzl)-L-Ala-OtBu

    [0394] ##STR00096##

    [0395] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-His(Bzl) as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-His(Bzl)-L-Ala-OtBu was isolated as a white solid. The yield was 91%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.42 (40% AcOEt in hexane).

    [0396] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.42 (br s, 1H), 7.36-7.28 (m, 3H), 7.17-7.12 (m, 3H), 6.71 (s, 1H), 6.18 (br s, 1H), 5.06-4.97 (m, 2H), 4.37-4.32 (m, 2H), 3.08 (d, 1H, J=12.1 Hz), 2.90 (dd, 1H, J=14.6, 6.0 Hz), 1.43 (s, 9H), 1.42 (s, 9H), 1.27 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.9, 171.1, 155.8, 138.6, 136.7, 136.0, 129.1, 128.4, 127.5, 117.3, 81.7, 79.8, 54.7, 51.0, 48.7, 30.3, 28.4, 28.0, 18.5.

    *Example d20: Synthesis of Boc-L-Trp-L-Ala-OtBu

    [0397] ##STR00097##

    [0398] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Trp as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Trp-L-Ala-OtBu was isolated as a white solid. The yield was 99%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.46 (40% AcOEt in hexane).

    [0399] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 8.30 (br d, 1H, J=17.1 Hz), 7.34 (d, 1H, J=7.8 Hz), 7.19-7.15 (m, 1H), 7.12-7.08 (m, 1H), 7.05 (br s, 1H), 6.45 (br s, 1H), 5.15 (br s, 1H), 4.44 (br s, 1H), 4.34-4.30 (m, 1H), 3.30 (br s, 1H), 3.18 (dd, 1H, J=14.4, 6.8 Hz), 1.40 (s, 18H), 1.24 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.7, 171.1, 155.5, 136.3, 127.6, 123.3, 122.3, 119.7, 119.0, 111.2, 110.6, 82.0, 80.1, 55.2, 48.8, 28.3, 28.0, 18.6.

    *Example d21: Synthesis of Boc-L-Pro-L-Ala-OtBu

    [0400] ##STR00098##

    [0401] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Pro as the first amino acid AA.sup.1 and L-Ala-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Pro-L-Ala-OtBu was isolated as a white solid. The yield was 99%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.33 (40% AcOEt in hexane).

    *Example d22: Synthesis of Boc-L-Ala-L-Gly-OtBu

    [0402] ##STR00099##

    [0403] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Gly-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Gly-OtBu was isolated as a white solid. The yield was 86%, and the diastereomer ratio was er>99:1.

    R.sub.f=0.21 (40% AcOEt in hexane).

    *Example d23: Synthesis of Boc-L-Ala-L-Val-OtBu

    [0404] ##STR00100##

    [0405] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Val-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Val-OtBu was isolated as a white solid. The yield was 86%, and the diastereomer ratio was er>99:1.

    R.sub.f=0.65 (40% AcOEt in hexane).

    [0406] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 6.55 (br d, 1H, J=8.0 Hz), 5.00 (br s, 1H), 4.42-3.39 (m, 1H), 4.18-4.16 (m, 1H), 2.17-2.13 (m, 1H), 1.47 (s, 9H), 1.43 (s, 9H), 1.35 (d, 3H, J=7.2 Hz), 0.91 (d, 3H, J=6.8 Hz), 0.89 (d, 3H, J=6.8 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.5, 170.9, 155.5, 82.0, 80.1, 57.4, 50.2, 31.5, 28.4, 28.1, 18.9, 18.0, 17.5.

    *Example d24: Synthesis of Boc-L-Ala-L-Ile-OtBu

    [0407] ##STR00101##

    [0408] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Ile-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Ile-OtBu was isolated as a white solid. The yield was 98%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.62 (40% AcOEt in hexane).

    [0409] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 6.58 (br d, 1H, J=7.7 Hz), 5.0 (br d, 1H, J=7.3 Hz), 4.44 (dd, 1H, J=8.6, 4.7 Hz), 4.16-4.08 (m, 1H), 1.91-1.81 (m, 1H), 1.45 (s, 9H), 1.43 (s, 9H), 1.34 (d, 3H, J=7.1 Hz), 1.29-1.36 (m, 2H), 0.93-0.97 (m, 6H); .sup.13C{.sup.1H}NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.2, 170.8, 155.5, 81.9, 80.0, 56.8, 50.1, 38.2, 28.4, 28.1, 25.2, 18.1, 15.4, 11.8.

    *Example d25: Synthesis of Boc-L-Ala-L-Leu-OtBu

    [0410] ##STR00102##

    [0411] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Leu-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Leu-OtBu was isolated as a white solid. The yield was 99%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.57 (40% AcOEt in hexane).

    [0412] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 6.55 (br s, 1H), 5.13 (br d, 1H, J=6.2 Hz), 4.46-4.41 (m, 1H), 4.16-4.5 (m, 1H), 1.60-1.44 (m, 3H), 1.42 (s, 9H), 1.40 (s, 9H), 1.32 (d, 3H, J=7.1 Hz), 0.89 (d, 6H, J=6.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.3, 172.0, 155.5, 81.8, 80.0, 51.4, 49.9, 41.8, 28.3, 28.0, 24.9, 22.9, 22.0, 18.3.

    *Example d26: Synthesis of Boc-L-Ala-L-Phg-OtBu

    [0413] ##STR00103##

    [0414] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Phg-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Phg-OtBu was isolated as a white solid. The yield was 95%, and the diastereomer ratio was dr=93.1:6.9.

    R.sub.f=0.63 (40% AcOEt in hexane).

    [0415] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.32-7.27 (m, 5H), 7.18 (br s, 1H), 5.41 (d, 1H, J=7.3 Hz), 5.00 (br s, 1H), 4.22 (br s, 1H), 1.41 (s, 9H), 1.38 (s, 9H), 1.34 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 171.8, 169.7, 155.5, 137.2, 128.8, 128.2, 127.0, 82.7, 80.2, 57.0, 50.0, 28.3, 27.9, 18.1.

    *Example d27: Synthesis of Boc-L-Ala-L-Phe-OtBu

    [0416] ##STR00104##

    [0417] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Phe-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Phe-OtBu was isolated as a white solid. The yield was 99%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.48 (40% AcOEt in hexane).

    *Example d28: Synthesis of Boc-L-Ala-L-Tyr(Bu)-OtBu

    [0418] ##STR00105##

    [0419] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Tyr(.sup.tBu)-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Tyr(.sup.tBu)-OtBu was isolated as a white solid. The yield was 94%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.48 (40% AcOEt in hexane).

    *Example d29: Synthesis of Boc-L-Ala-L-Ser(.SUP.t.Bu)-OtBu

    [0420] ##STR00106##

    [0421] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Ser(tBu)-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Ser(.sup.tBu)-OtBu was isolated as a white solid. The yield was 97%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.57 (40% AcOEt in hexane).

    [0422] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 6.60 (br d, 1H, J=6.4 Hz), 5.11 (br s, 1H), 4.54-4.52 (m, 1H), 4.19 (br s, 1H), 3.76 (dd, 1H, J=8.7, 3.0 Hz), 3.50 (dd, 1H, J=8.7, 2.7 Hz), 1.44 (s, 9H), 1.42 (s, 9H), 1.37 (d, 3H, J=7.0 Hz), 1.12 (s, 9H); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.3, 169.3, 155.2, 81.9, 79.8, 73.1, 62.1, 53.2, 50.1, 28.4, 28.1, 27.4, 19.1.

    *Example d30: Synthesis of Boc-L-Ala-L-Thr(.SUP.t.Bu)-OtBu

    [0423] ##STR00107##

    [0424] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Thr(.sup.tBu)-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Thr(.sup.tBu)-OtBu was isolated as a white solid. The yield was 95%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.63 (40% AcOEt in hexane).

    *Example d31: Synthesis of Boc-L-Ala-L-Cys(trt)-OtBu

    [0425] ##STR00108##

    [0426] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Cys(trt)-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Cys(trt)-OtBu was isolated as a white solid. The yield was 99%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.77 (40% AcOEt in hexane).

    [0427] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.39-7.36 (m, 6H, J=6.4 Hz), 7.28-7.24 (m, 6H), 7.22-7.18 (m, 3H), 6.45 (br d, 1H, J=6.1 Hz), 5.02 (br s, 1H), 4.45-4.41 (m, 1H), 4.13-4.05 (m, 1H), 2.60 (dd, 1H, J=12.1, 5.5 Hz), 2.53 (dd, 1H, J=12.0, 4.5 Hz), 1.43 (s, 9H), 1.41 (s, 9H), 1.33 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.1, 169.1, 155.3, 144.4, 129.6, 128.1, 126.9, 82.7, 80.1, 66.6, 51.7, 50.1, 34.0, 28.4, 28.0, 18.8.

    *Example d32: Synthesis of Boc-L-Ala-L-Met-OtBu

    [0428] ##STR00109##

    [0429] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Met-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Met-OtBu was isolated as a white solid. The yield was 99%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.54 (40% AcOEt in hexane).

    [0430] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 6.70 (br d, 1H, J=7.8 Hz), 5.00 (br s, 1H), 4.57-4.52 (m, 1H), 4.15-4.08 (m, 1H), 2.54-2.41 (m, 2H), 2.16-2.09 (m, 1H), 2.08 (s, 3H), 2.03-1.89 (m, 1H), 1.45 (s, 9H), 1.43 (s, 9H), 1.35 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.4, 170.8, 155.5, 82.5, 80.2, 52.2, 50.2, 32.1, 29.9, 28.4, 28.1, 18.3, 155.5.

    *Example d33: Synthesis of Boc-L-Ala-L-Asp(.SUP.t.Bu)-OtBu

    [0431] ##STR00110##

    [0432] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Asp(.sup.tBu)-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Asp(.sup.tBu)-OtBu was isolated as a white solid. The yield was 96%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.75 (40% AcOEt in hexane).

    [0433] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 6.83 (br d, 1H, J=8.0 Hz), 5.08 (br s, 1H), 4.65 (q, 1H, J=4.1 Hz), 4.17 (br s, 1H), 2.88 (dd, 1H, J=17.1, 4.3 Hz), 2.69 (dd, 1H, J=17.1, 4.3 Hz), 1.44 (s, 9H), 1.434 (s, 9H), 1.431 (s, 9H), 1.37 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.4, 170.4, 169.6, 155.2, 82.4, 81.7, 80.0, 50.2, 49.1, 37.4, 28.4, 28.1, 28.0, 19.1.

    *Example d34: Synthesis of Boc-L-Ala-L-Glu(.SUP.t.Bu)-OtBu

    [0434] ##STR00111##

    [0435] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Glu(.sup.tBu)-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Glu(.sup.tBu)-OtBu was isolated as a white solid. The yield was 99%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.67 (40% AcOEt in hexane).

    [0436] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 6.84 (br s, 1H), 5.24 (br d, 1H, J=6.0 Hz), 4.38 (td, 1H, J=8.2, 4.8 Hz), 4.12 (br s, 1H), 2.37-2.13 (m, 2H), 2.08-1.96 (m, 1H), 1.86-1.76 (m, 1H), 1.38 (s, 9H), 1.35 (s, 9H), 1.35 (s, 9H), 1.28 (d, 3H, J=7.1 Hz); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.5, 172.1, 170.8, 155.4, 82.1, 80.6, 79.8, 52.1, 50.0, 31.3, 28.3, 28.0, 27.9, 27.5, 18.4.

    *Example d35: Synthesis of Boc-L-Ala-L-Asn-OtBu

    [0437] ##STR00112##

    [0438] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Asn-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Asn-OtBu was isolated as a white solid. The yield was 99%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.25 (5% MeOH in CHCl.sub.3).

    *Example d36: Synthesis of Boc-L-Ala-L-Lys(Z)-OtBu

    [0439] ##STR00113##

    [0440] The reaction was carried out in accordance with the General Synthesis Procedure, using Boc-L-Ala as the first amino acid AA.sup.1 and L-Lys(Z)-OtBu as the second amino acid AA.sup.2, whereby the title compound Boc-L-Ala-L-Lys(Z)-OtBu was isolated as a white solid. The yield was 96%, and the diastereomer ratio was dr>99:1.

    R.sub.f=0.72 (70% AcOEt in hexane).

    [0441] .sup.1H NMR (400 MHz, CDCl.sub.3, 24° C.): δ 7.34-7.28 (m, 5H), 6.69 (br s, 1H), 5.11 (br s, 1H), 5.08 (s, 2H), 4.46-4.41 (m, 1H), 4.16-4.10 (m, 1H), 3.22-3.15 (m, 2H), 1.86-1.78 (m, 1H), 1.65-1.55 (m, 1H), 1.51-1.48 (m, 2H), 1.44 (s, 9H), 1.43 (s, 9H), 1.38-1.24 (m, 5H); .sup.13C{.sup.1H} NMR (100 MHz, CDCl.sub.3, 24° C.): δ 172.8, 171.2, 156.6, 155.6, 136.6, 128.5, 128.2, 128.1, 127.9, 82.0, 80.0, 66.6, 52.4, 50.0, 40.6, 32.0, 29.1, 28.4, 28.0, 22.1, 18.3.

    Example Group E: Synthesis of Boc-L-Ala-L-Asn-OtBu Via Amidation Reaction Using Silane Compound (A)

    *General Synthesis Procedure:

    [0442] ##STR00114##

    [0443] A 5.0-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), Boc-L-Ala(0.5 mmol, 1 equivalent), and L-Ala-OtBu. This mixture was combined with a silane compound (0.5 mmol, 1 equivalent) (generation of hydrogen gas was observed), and then mixed and dissolved in dry DCM (0.5 mL, 1M), and the vial was sealed. The vial was removed from the glove box and stirred vigorously under an argon atmosphere at room temperature for 24 hours. The reaction was monitored with TLC analysis. Once the reaction completed, the reaction mixture was diluted with CHCl.sub.3 (3.0 mL), and transferred by a pipette to a silica gel column. The vial and pipette used were washed with CHCl.sub.3 (5.0 mL). The reaction mixture was purified with flash column chromatography using 10 to 100% AcOEt in hexane or 0 to 10% MeOH in CHCl.sub.3 as an eluate, whereby the title compound Boc-L-Ala-L-Ala-OtBu was obtained.

    *Example e1: Synthesis Using Si[OCH.SUB.2.CF.SUB.3.].SUB.4

    [0444] The reaction was carried out in accordance with the General Synthesis Procedure except that L-Ala-OtBu was used in an amount of 1 equivalent (0.5 mmol), and tris(1,1,1,3,3,3-hexafluoroisopropoxy)silane (HSi[OCH(CF.sub.3).sub.2].sub.3) was used as a silane compound, whereby the title compound Boc-L-Ala-L-Ala-OtBu was obtained. The yield was 78%, and the diastereomer ratio was dr>99:1.

    *Example e2: Synthesis Using HSi[OCH.SUB.2.CF.SUB.2.CHF.SUB.2.].SUB.3

    [0445] The reaction was carried out in accordance with the General Synthesis Procedure except that L-Ala-OtBu was used in an amount of 1 equivalent (0.5 mmol), and tris(3,3,2,2-tetrafluoro n-propoxy)silane (HSi[OCH.sub.2CF.sub.2CHF.sub.2].sub.3) was used as a silane compound, whereby the title compound Boc-L-Ala-L-Ala-OtBu was obtained. The yield was 53%, and the diastereomer ratio was dr>99:1.

    *Example e3: Synthesis Using HSi[OCH.SUB.2.CCl.SUB.3.].SUB.3

    [0446] The reaction was carried out in accordance with the General Synthesis Procedure except that L-Ala-OtBu was used in an amount of 1 equivalent (0.5 mmol), and tris(2,2,2-trichloroethoxy)silane (HSi[OCH.sub.2CCl.sub.3].sub.3) was used as a silane compound, whereby the title compound Boc-L-Ala-L-Ala-OtBu was obtained. The yield was 53%, and the diastereomer ratio was dr>99:1.

    *Example e4: Synthesis Using HSi[OCH.SUB.2.CF.SUB.3.].SUB.3

    [0447] The reaction was carried out in accordance with the General Synthesis Procedure except that L-Ala-OtBu was used in an amount of 2 equivalents (0.5 mmol), and tris(2,2,2-trifluoroethoxy)silane (HSi[OCH.sub.2CF.sub.3].sub.3) was used as a silane compound, whereby the title compound Boc-L-Ala-L-Ala-OtBu was obtained. The yield was 53%, and the diastereomer ratio was dr>99:1.

    *Example e5: Synthesis Using Si[OCH.SUB.2.CF.SUB.3.].SUB.4

    [0448] The reaction was carried out in accordance with the General Synthesis Procedure except that L-Ala-OtBu was used in an amount of 2 equivalents (0.5 mmol), and tetrakis(2,2,2-trifluoroethoxy)silane (Si[OCH.sub.2CF.sub.3].sub.4) was used as a silane compound, whereby the title compound Boc-L-Ala-L-Ala-OtBu was obtained. The yield was 66%, and the diastereomer ratio was dr>99:1.

    *Example e6: Synthesis Using Si[OCH(CF.SUB.3.).SUB.2.].SUB.4

    [0449] The reaction was carried out in accordance with the General Synthesis Procedure except that L-Ala-OtBu was used in an amount of 2 equivalents (0.5 mmol), and tetrakis(1,1,1,3,3,3-hexafluoroisopropoxy)silane (Si[OCH(CF.sub.3).sub.2].sub.4) was used as a silane compound, whereby the title compound Boc-L-Ala-L-Ala-OtBu was obtained. The yield was 85%, and the diastereomer ratio was dr>99:1.

    Example Group F: Amidation Reaction Using Silane Compound (A) in the Presence of Tris(Haloalkoxy)Aminosilane Catalyst 1

    *Example f1: Synthesis of Boc-L-Ala-L-Ala-OtBu Via Amidation Reaction 1

    [0450] ##STR00115##

    [0451] In a glove box, a heat-dried 5.0-mL screw-cap vial was charged with a magnetic stirring rod (Sm—Co), benzylamine (53.6 mg, 0.50 mmol), DCM (0.50 mL), and HSi[OCH(CF.sub.3).sub.2].sub.3 (265.1 mg, 0.50 mmol), and the vial was sealed and removed from the glove box. The resulting mixture was stirred vigorously under an argon atmosphere at room temperature for 4 hours, whereby a catalyst solution containing BnNHSi[OCH(CF.sub.3).sub.2].sub.3 was prepared. In a glove box, a flame-dried 5.0 mL screw cap vial was charged with a mixture of the catalyst solution containing BnNHSi[OCH(CF.sub.3).sub.2].sub.3 (0.015 mL, 0.015 mmol), Boc-L-Ala-OH (94.6 mg, 0.50 mmol), DCM (0.50 mL), HSi[OCH(CF.sub.3).sub.2].sub.3 (265.1 mg, 0.50 mmol), and L-Ala-OtBu(72.6 mg, 0.50 mmol), and the vial was sealed and removed from the glove box. The resulting mixture was stirred vigorously under an argon atmosphere at room temperature for 6 hours, and the reaction mixture was diluted with CHCl.sub.3 (3.0 mL), and then transferred into a SiO.sub.2 column with a pipette. The vial and pipette used were washed with CHCl.sub.3 (12 mL). The reaction mixture was purified with flash column chromatography (20 to 100% AcOEt in hexane), whereby Boc-L-Ala-L-Ala-OtBu was isolated as a colorless liquid. The yield was 99% (156.9 mg), and the diastereomer ratio was dr>99:1.

    *Example f2: Synthesis of Boc-L-Ala-L-Ala-OtBu Via Amidation Reaction 2

    [0452] ##STR00116##

    [0453] In a glove box, a heat-dried 5.0-mL screw-cap vial was charged with a magnetic stirring rod (Sm—Co), benzylamine (53.6 mg, 0.50 mmol), DCM (0.50 mL), and HSi[OCH(CF.sub.3).sub.2].sub.3 (265.1 mg, 0.50 mmol), and the vial was sealed and removed from the glove box. The resulting mixture was stirred vigorously under an argon atmosphere at room temperature for 4 hours, whereby a catalyst solution containing BnNHSi[OCH(CF.sub.3).sub.2].sub.3 was prepared. A flame-dried 5.0 mL screw-cap vial was charged with ETFE septa, a magnetic stirring bar (Sm—Co), and Boc-L-Ala-OH (94.6 mg, 0.50 mmol). After replacing the air in the vial with nitrogen, L-Ala-OtBu (72.6 mg, 0.50 mmol), DCM (0.50 mL), HSi[OCH(CF.sub.3).sub.2].sub.3 (265.1 mg, 0.50 mmol), and the catalyst solution containing BnNHSi[OCH(CF.sub.3).sub.2].sub.3 (0.015 mL, 0.015 mmol) were put into the vial, which was then sealed with a screw cap. The resulting mixture was stirred vigorously under a nitrogen atmosphere at room temperature for 6 hours, and the reaction mixture was diluted with CHCl.sub.3 (3.0 mL), and transferred into SiO.sub.2 column with a pipette. The vial and pipette used were washed with CHCl.sub.3 (12 mL). The reaction mixture was purified with flash column chromatography (20 to 100% AcOEt in hexane), whereby the title compound Boc-L-Ala-L-Ala-OtBu was isolated as a colorless liquid. The yield was 98% (155.0 mg), and the diastereomer ratio was dr>99:1.

    *Example f3: Synthesis of Boc-L-Met-L-Ala-OtBu Via Amidation Reaction

    [0454] ##STR00117##

    [0455] The reaction was carried out in the same manner as in Example f1 except that Boc-L-Met-OH (124.7 mg, 0.50 mmol) was used instead of Boc-L-Ala-OH, and the mixing of the reaction solution was carried out at 40° C. for 12 h, whereby Boc-L-Met-L-Ala-OtBu was isolated as a colorless liquid. The yield was 94% (176.5 mg), and the diastereomer ratio was dr>99:1.

    *Example f4: Synthesis of Boc-L-Val-L-Ala-OtBu Via Amidation Reaction

    [0456] ##STR00118##

    [0457] The reaction was carried out in the same manner as in Example f1 except that Boc-L-Val-OH (108.6 mg, 0.50 mmol) was used instead of Boc-L-Ala-OH, the used amount of DCM was changed to 1.0 mL, and the mixing of the reaction solution was carried out at 40° C. for 12 h, whereby Boc-L-Val-L-Ala-OtBu was obtained as a white solid. The yield was 80% (137.1 mg), and the diastereomer ratio was dr>99:1.

    *Example f5: Synthesis of Fmoc-L-Ser(tBu)-L-Lys(Boc)-OBn Via Amidation Reaction

    [0458] ##STR00119##

    [0459] The reaction was carried out in the same manner as in Example f1 except that Fmoc-L-Ser(tBu)-OH (191.7 mg, 0.50 mmol) was used instead of Boc-L-Ala-OH, the used amount of DCM was changed to 1.0 mL, L-Lys(Boc)-OBn (168.2 mg, 0.50 mmol) was used instead of L-Ala-OtBu, and the mixing of the reaction solution was carried out at 40° C. for 12 h, whereby Fmoc-L-Ser(tBu)-L-Lys(Boc)-OBn was obtained as a white solid. The yield was 84% (295.8 mg), and the diastereomer ratio was dr>99:1.

    *Example f6: Synthesis of Boc-L-Ala-L-Val-OtBu Via Amidation Reaction

    [0460] ##STR00120##

    [0461] The reaction was carried out in the same manner as in Example f1 except that L-Val-OtBu (86.6 mg, 0.50 mmol) was used instead of L-Ala-OtBu, and the mixing of the reaction solution was carried out at 40° C. for 12 h, whereby Boc-L-Ala-L-Val-OtBu was obtained as a white solid. The yield was 94% (162.2 mg), and the diastereomer ratio was dr>99:1.

    *Example f7: Synthesis of Fmoc-L-Ar2(Boc).SUB.2.-L-Thr(tBu)-OtBu Via Amidation Reaction

    [0462] ##STR00121##

    [0463] The reaction was carried out in the same manner as in Example f1 except that Fmoc-L-Arg(Boc).sub.2-OH (298.3 mg (HPLC purity 92.4%), about 0.47 mmol. The main byproduct is Fmoc-L-Arg(Boc)-OH. Purchased from Watanabe Chemical Industry Co.) was used instead of Boc-L-Ala-OH, the used amount of DCM was changed to 1.0 mL, L-Thr(tBu)-OtBu(115.7 mg, 0.50 mmol) was used instead of L-Ala-OtBu, and the mixing of the reaction solution was carried out at 40° C. for 12 h, whereby Fmoc-L-Arg(Boc).sub.2-L-Thr(tBu)-OtBu was obtained as a white solid. The yield was about 81% (307.7 mg), and the diastereomer ratio was dr>99:1.

    Example Group G: Amidation Reactions Using Silane Compound (A) in the Presence of Tris(Haloalkoxyl)Aminosilane Catalyst 2

    [0464] ##STR00122##

    [0465] In a glove box, a flame-dried 5.0 mL screw-cap vial was charged with a mixture of 1 MDCM solution of each of various aminosilane catalysts shown in Tables 1 to 3 below (referred to as “Catalyst” in the reaction formula above and in Tables 1 to 3 below) (0.015 mL, 0.015 mmol), HSi[OCH(CF.sub.3).sub.2].sub.3 (265.1 mg, 0.50 mmol), Boc-L-Val-OH (108.6 mg, 0.50 mmol), L-Val-OtBu (86.6 mg, 0.50 mmol), and DCM (1.0 mL), and the vial was sealed and removed from the glove box. The resulting mixture was stirred vigorously under an argon atmosphere at room temperature for 6 hours, and the reaction mixture was diluted with CHCl.sub.3 (3.0 mL), and transferred into a SiO.sub.2 column with a pipette. The vial and pipette used were washed with CHCl.sub.3 (12 mL). The reaction mixture was purified with flash column chromatography (20 to 100% AcOEt in hexane), whereby the target compound Boc-L-Val-L-Val-OtBu was obtained. The yield and the diastereomer ratios of each target compound obtained for each of the various aminosilane catalysts used are shown in Tables 1 to 3 below.

    TABLE-US-00005 TABLE 1 Yield Diastereomer ratio Entry Aminosilane catalyst (%) d.r.  0 None 53 >99:1  1 [00123]embedded image 66 >99:1  2 [00124]embedded image 49 >99:1  3 [00125]embedded image 68 >99:1  4 [00126]embedded image 67 >99:1  5 [00127]embedded image 75 >99:1  6 [00128]embedded image 62 >99:1  7 [00129]embedded image 65 >99:1  8 [00130]embedded image 57 >99:1  9 [00131]embedded image 80 >99:1 10 [00132]embedded image    

    TABLE-US-00006 TABLE 2 Yield Diastereomer ratio Entry Aminosilane catalyst (%) d.r. 11 [00133]embedded image 65 >99:1 12 [00134]embedded image 58 >99:1 13 [00135]embedded image 49 >99:1 14 [00136]embedded image 71 >99:1 15 [00137]embedded image 61 >99:1 16 [00138]embedded image 66 >99:1 17 [00139]embedded image 70 >99:1 18 [00140]embedded image 71 >99:1 19 [00141]embedded image 73 >99:1 20 [00142]embedded image     21 [00143]embedded image 65 >99:1 22 [00144]embedded image 62 >99:1

    TABLE-US-00007 TABLE 3 yield Diastereomer ratio Entry Aminosilane catalyst (%) d.r. 23 [00145]embedded image 48 >99:1 24 [00146]embedded image 60 >99:1 25 [00147]embedded image 65 >99:1 26 [00148]embedded image 52 >99:1 27 [00149]embedded image 66 >99:1 28 [00150]embedded image 40 >99:1 29 [00151]embedded image 42 >99:1 30 [00152]embedded image 38 >99:1 31 [00153]embedded image 66 >99:1 32 [00154]embedded image 58 >99:1 33 [00155]embedded image 58 >99:1 34 [00156]embedded image 57 >99:1

    Example Group H: Amidation Reactions Using Silane Compound (A) in the Presence of Cesium Fluoride and Imidazole (without Protective Group)

    *Example h1: Synthesis of H-L-Phe-L-Ala-OtBu (in the Presence of Cesium Fluoride and Imidazole)

    [0466] ##STR00157##

    [0467] A 5-mL screw-cap vial heated and dried in a glove box was charged, under an argon atmosphere, with a stirrer (samarium-cobalt), L-phenylalanine (H-L-Phe-OH, 165.2 mg, 1.0 mmol), tris(hexafluoroisopropoxy)silane (HSi(OCH(CF.sub.3).sub.2).sub.3, 530.2 mg, 1.0 mmol), cesium fluoride (CsF, 10 mol %), imidazole (10 mol %), and chloroform (0.5 mL), and sealed with a septum and a screw cap. The reaction vial was removed from the glove box, placed in an oil bath heated to 30° C., and then stirred vigorously for 1 hours. The screw cap was removed, and N-tert-butyldimethylsilyl-N-methyl trifluoroacetamide (MTBSTFA, 120.7 mg, 0.5 mmol) was added through the septum using a microsyringe, and the vial was sealed with the screw cap again, in an oil bath heated to 30° C. stirred vigorously for 1 hours. The screw cap was removed again, through the septum using a microsyringe L-alanine-tert-butyl ester (H-L-Ala-Ot-Bu, 145.2 mg, 1.0 mmol) was added, and the vial was sealed with the screw cap again, in an oil bath heated to 30° C. stirred vigorously for 6 hours. The reaction vial was removed from the oil bath and left to stand until it reached to room temperature, and the reaction mixture was diluted with a 1% methanol/chloroform mixture (3.0 mL), and the product was transferred to a previously prepared silica gel column (1% methanol/chloroform mixture) using a Pasteur pipette. This procedure was repeated three more times, and the screw cap, septum, and the Pasteur pipette used was washed with the same mixture. The reaction product was purified with silica gel column chromatography (1-5% methanol/chloroform mixture), whereby the desired dipeptide (H-L-Phe-L-Ala-Ot-Bu, 97%, >99:1dr) was obtained as a white solid.

    *Reference Example h1: Synthesis of H-L-Phe-L-Ala-OtBu (in the Absence of Cesium Fluoride and Imidazole)

    [0468] ##STR00158##

    [0469] The synthesis was carried out in the same manner as in Example h1 except that cesium fluoride and imidazole were not used, and the heating time of the solution after the addition of H-L-Ala-Ot-Bu under stirring was changed from 6 hours to 12 hours, whereby the desired dipeptide (H-L-Phe-L-Ala-Ot-Bu, 99%, >99:1dr) was obtained as a white solid.

    *Example h2: Synthesis of H-L-Leu-L-Ala-OtBu (in the Presence of Cesium Fluoride and Imidazole)

    [0470] ##STR00159##

    [0471] The synthesis was carried out in the same manner as in Example h1 except that L-leucine (H-L-Leu-OH, 1.0 mmol) was used instead of L-phenylalanine, whereby the desired dipeptide (H-L-Leu-L-Ala-OtBu, 95%, >99:1dr) was obtained as a white solid.

    *Reference Example h2: Synthesis of H-L-Leu-L-Ala-OtBu (in the absence of cesium fluoride and imidazole)

    ##STR00160##

    [0472] The synthesis was carried out in the same manner as in Example h2 except that cesium fluoride and imidazole were not used, and the heating time of the solution after the addition of H-L-Ala-Ot-Bu under stirring was changed from 6 hours to 12 hours, whereby the desired dipeptide (H-L-Leu-L-Ala-Ot-Bu, 99%, >99:1dr) was obtained as a white solid.

    *Example h3: Synthesis of H-L-Ala-L-Ala-OtBu (in the Presence of Cesium Fluoride and Imidazole)

    [0473] ##STR00161##

    [0474] The synthesis was carried out in the same manner as in Example h1 except that L-alanine (H-L-Ala-OH, 1.0 mmol) was used instead of L-phenylalanine, the temperature of the first heating for 1 hours was changed from 30° C. to 50° C., and the heating time of the solution after the addition of H-L-Ala-Ot-Bu under stirring was changed from 6 hours to 12 hours, whereby the desired dipeptide (H-L-Ala-L-Ala-OtBu, 99%, >99:1dr) was obtained as a white solid.

    *Example h4: Synthesis of H-L-Met-L-Ala-OtBu (in the Presence of Cesium Fluoride and Imidazole)

    [0475] ##STR00162##

    [0476] The synthesis was carried out in the same manner as in Example h1 except that L-methionine (H-L-Met-OH, 1.0 mmol) was used instead of L-phenylalanine, and the heating time of the solution after the addition of H-L-Ala-Ot-Bu under stirring was changed from 6 hours to 12 hours, whereby the desired dipeptide (H-L-Met-L-Ala-OtBu, 99%, >99:1dr) was obtained as a white solid.

    Example Group I: Amidation Reactions Using Silane Compound (B) (1)

    [0477] The amide compounds were produced according to the method described in each of the following Example sections.

    [0478] In the following examples, unless otherwise stated, diastereomeric or enantiomeric ratios were determined with .sup.1H-NMR analysis (measuring instrument: JEOL 400SS, measuring condition: 400 MHz, solvent: CDCl.sub.3).

    *Example i1: Synthesis of H-Phe-Ala-Ot-Bu 1

    [0479] ##STR00163##

    [0480] A 12-mL test tube was charged with phenylalanine (H-Phe-OH, 0.25 mmol, 41.3 mg) and dimethylsilyldiimidazole (DMSDIM, 0.275 mmol, 52.8 mg) suspended in dichloromethane (DCM, 1 mL) in a glove box, and stirred under an argon atmosphere at room temperature. After one hour, Ta(OMe)s(12.5 μmol, 4.2 mg), trimethylsilylimidazole (TMSIM, 0.50 mmol, 73.4 μL) and alanine tert-butyl ester (0.75 mmol, 108.8 mg) was added in a glove box, and was stirred at room temperature for 24 hours. The product was diluted with chloroform (5 mL), and purified with silica gel chromatography (CHCl.sub.3:MeOH=100:1), whereby title dipeptide H-Phe-Ala-Ot-Bu was obtained. The resulting quantity was 67.2 mg, the yield was 92%, and the diastereomer ratios were dr>99:1. A trace of tripeptide H-Phe-Phe-Ala-Ot-Bu byproduct was observed.

    [0481] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.78 (br d, J=7.6 Hz, 1H, NH), 7.33-7.21 (m, 5H, PhH), 4.50-4.42 (quin, J=7.4 Hz, 1H, CHCH.sub.3), 3.62 (dd, J=3.9 Hz, 9.2 Hz, 1H, CH.sub.2PH), 3.22 (dd, J=3.9 Hz, 9.2 Hz, 1H, CH.sub.2PH), 2.72 (m, 1H, CHCH.sub.2), 1.59 (br s, 2H, NH.sub.2CHPh), 1.45 (s, 9H, C(CH.sub.3).sub.3), 1.36 (d, J=7.1 Hz, 3H, CHCH.sub.3). .sup.13C NMR (100 MHz, CDCl3): δ 173.8, 172.2, 137.7, 129.3, 128.6, 126.7, 81.8, 56.2, 48.2, 40.9, 27.9, 18.6.

    *Example i2: Synthesis of H-Phe-Ala-Ot-Bu 2

    [0482] ##STR00164##

    [0483] A 12-mL test tube was charged with phenylalanine (H-Phe-OH, 0.50 mmol, 82.6 mg), dimethylsilyldiimidazole (DMSDIM, 0.55 mmol, 105.6 mg) suspended in dichloromethane (DCM, 1 mL) in a glove box, and stirred under an argon atmosphere at room temperature. After one hour, 2,2′-bipyridine-6,6′-diol (25 μmol, 4.7 mg), trimethylsilylimidazole (TMSIM, 0.50 mmol, 73.4 μL) and alanine tert-butyl ester (H-Ala-OtBu, 0.25 mmol, 36.3 mg) was added in a glove box, and was stirred at room temperature for 24 hours. The product was diluted with chloroform (5 mL), and purified with silica gel chromatography (CHCl.sub.3:MeOH=100:1), whereby title dipeptide H-Phe-Ala-Ot-Bu was obtained. The resulting quantity was 62.8 mg, the yield was 86%, and the diastereomer ratios were dr96:4. A trace of tripeptide H-Phe-Phe-Ala-Ot-Bu byproduct was observed.

    *Example i3: Synthesis of H-Phe-Ala-Ot-Bu 3

    [0484] ##STR00165##

    [0485] A 5-mL vial was charged with phenylalanine (H-Phe-OH, 0.50 mmol, 82.6 mg), dimethylsilyldiimidazole (DMSDIM, 0.55 mmol, 105.6 mg) and tert-butyl dimethyl silane (tBuMe.sub.2SiH, 0.50 mmol, 82.1 μL) suspended in dichloromethane (DCM, 0.1 mL) in a glove box, and stirred under an argon atmosphere at room temperature. After one hour, alanine tert-butyl ester (H-Ala-OtBu, 0.25 mmol, 36.3 mg) was added in a glove box, and was stirred at room temperature for 24 hours. The product was diluted with chloroform (5 mL), and purified with silica gel chromatography (CHCl.sub.3:MeOH=100:1), whereby title dipeptide H-Phe-Ala-Ot-Bu was obtained. The resulting quantity was 54.1 mg, the yield was 74%, and the diastereomer ratios were dr>99:1. A trace of tripeptide H-Phe-Phe-Ala-Ot-Bu byproduct was observed.

    *Example i4: Synthesis of H-Phe-Ala-Ot-Bu 4

    [0486] ##STR00166##

    [0487] A 5-mL vial was charged with phenylalanine (H-Phe-OH, 0.50 mmol, 82.6 mg), dimethylsilyldiimidazole (DMSDIM, 0.55 mmol, 105.6 mg) and tert-butyl dimethyl silane (tBuMe.sub.2SiH, 0.50 mmol, 82.1 μL) suspended in dichloromethane (DCM, 0.1 mL) in a glove box, and stirred under an argon atmosphere at room temperature. After one hour, in a glove box 2,2′-bis(diphenyl phosphino)-1,1′-binaphthyl (BINAP, 12.5 μmol, 7.8 mg) and alanine tert-butyl ester (H-Ala-OtBu, 0.25 mmol, 36.3 mg) was added, and was stirred at room temperature for 24 hours. The product was diluted with chloroform (5 mL), and purified with silica gel chromatography (CHCl.sub.3:MeOH=100:1), whereby title dipeptide H-Phe-Ala-Ot-Bu was obtained. The resulting quantity was 52.6 mg, the yield was 72%, and the diastereomer ratios were dr>99:1. A trace of tripeptide H-Phe-Phe-Ala-Ot-Bu byproduct was observed.

    [Example Group J: Amidation Reactions Using Silane Compound (B) (2)]*General Synthesis Procedure

    [0488] ##STR00167##

    [0489] A 12-mL test tube was charged with a first amino acid AA.sup.1 (0.5 mmol, 1 equivalent) and dimethylsilyldiimidazole (DMSDIM, 0.5 mmol, 1 equivalent) and suspended in dichloromethane (DCM, 1 mL) in a glove box, and stirred under an argon atmosphere at room temperature. After one hour, Ta(OEt)s (10 mol %), trimethylsilylimidazole (TMSIM, 1.0 mmol, 2 equivalents), and L-Ala-OtBu (1.0 mmol, 2.0 equivalents) was added in a glove box, and was stirred at room temperature for 24 hours. The product was diluted with chloroform (5 mL), and purified with silica gel chromatography (CHCl.sub.3:MeOH=100:1), whereby an analytically pure product was obtained. In the reaction formula above, R.sup.1 represents the side chain of the first amino acid AA.sup.1.

    *Example j1: Synthesis of L-Phe-L-Ala-OtBu

    [0490] The reaction was carried out in accordance with the General Synthesis Procedure except that L-phenylalanine (L-Phe) was used as the first amino acid AA.sup.1, whereby the title compound L-Phe-L-Ala-OtBu was obtained. The yield was 95%, and the diastereomer ratio was dr>20:1.

    ##STR00168##

    *Example j2: Synthesis of L-Val-L-Ala-OtBu

    [0491] The reaction was carried out in accordance with the General Synthesis Procedure except that L-valine (L-Val) was used as the first amino acid AA.sup.1, and the reaction temperature was changed to 50° C., whereby the title compound L-Val-L-Ala-OtBu was obtained. The yield was 72%, and the diastereomer ratio was dr>20:1.

    ##STR00169##

    *Example j3: Synthesis of L-Ile-L-Ala-OtBu

    [0492] The reaction was carried out in accordance with the General Synthesis Procedure except that L-isoleucine (L-Ile) was used as the first amino acid AA.sup.1, and the reaction temperature was changed to 50° C., whereby the title compound L-Ile-L-Ala-OtBu was obtained. The yield was 78%, and the diastereomer ratio was dr>20:1.

    ##STR00170##

    *Example j4: Synthesis of L-Leu-L-Ala-OtBu

    [0493] The reaction was carried out in accordance with the General Synthesis Procedure except that L-leucine (L-Leu) was used as the first amino acid AA.sup.1, and the reaction temperature was changed to 50° C., whereby the title compound L-Leu-L-Ala-OtBu was obtained. The yield was 89%, and the diastereomer ratio was dr>20:1.

    ##STR00171##

    *Example j5: Synthesis of L-Met-L-Ala-OtBu

    [0494] The reaction was carried out in accordance with the General Synthesis Procedure except that L-methionine (L-Met) was used as the first amino acid AA.sup.1, whereby the title compound L-Met-L-Ala-OtBu was obtained. The yield was 86%, and the diastereomer ratio was dr>20:1.

    ##STR00172##

    *Example j6: Synthesis of Bn-L-Cys-L-Ala-OtBu

    [0495] The reaction was carried out in accordance with the General Synthesis Procedure except that benzyl-L-cysteine (Bn-L-Cys) was used as the first amino acid AA.sup.1, whereby the title compound Bn-L-Cys-L-Ala-OtBu was obtained. The yield was 56%, and the diastereomer ratio was dr>20:1.

    ##STR00173##

    *Example j7: Synthesis of Boc-L-Trp-L-Ala-OtBu

    [0496] The reaction was carried out in accordance with the General Synthesis Procedure except that L-tryptophan whose side chain's amino group was protected with a Boc group (Boc-L-Trp) was used as the first amino acid AA.sup.1, whereby the title compound Boc-L-Trp-L-Ala-OtBu was obtained. The yield was 91%, and the diastereomer ratio was dr>20:1.

    ##STR00174##

    *Example j8: Synthesis of tBuO-L-Tyr-L-Ala-OtBu

    [0497] The reaction was carried out in accordance with the General Synthesis Procedure except that L-tyrosine whose side chain's hydroxyl group was protected with a t-butyl group (tBuO-L-Tyr) was used as the first amino acid AA.sup.1, whereby the title compound tBuO-L-Tyr-L-Ala-OtBu was obtained. The yield was 90%, and the diastereomer ratio was dr>20:1.

    ##STR00175##

    *Example j9: Synthesis of tBuO-L-Ser-L-Ala-OtBu

    [0498] The reaction was carried out in accordance with the General Synthesis Procedure except that L-serine whose side chain's hydroxyl group was protected with a t-butyl group (tBuO-L-Ser) was used as the first amino acid AA.sup.1, whereby the title compound tBuO-L-Ser-L-Ala-OtBu was obtained. The yield was 71%, and the diastereomer ratio was dr>20:1.

    ##STR00176##

    *Example j10: Synthesis of tBuO-L-Thr-L-Ala-OtBu

    [0499] The reaction was carried out in accordance with the General Synthesis Procedure except that L-threonine whose side chain's hydroxyl group was protected with a t-butyl group (tBuO-L-Thr) was used as the first amino acid AA.sup.1, whereby the title compound tBuO-L-Thr-L-Ala-OtBu was obtained. The yield was 95%, and the diastereomer ratio was dr>20:1.

    ##STR00177##

    *Example j11: Synthesis of PG-L-Lys-L-Ala-OtBu

    [0500] The reaction was carried out in accordance with the General Synthesis Procedure except that L-lysine whose side chain's amino group was protected with a protective group PG (PG-L-Lys) was used as the first amino acid AA.sup.1, whereby the title compounds PG-L-Phe-L-Ala-OtBu were obtained. The protective group PG was changed from a Boc group, Cbz group, and Trt group. For Boc-L-Phe-L-Ala-OtBu, the yield was 53%, and the diastereomer ratio was dr>20:1; for Cbz-L-Phe-L-Ala-OtBu, the yield was 55%, and the diastereomer ratio was dr>20:1; and for Trt-L-Phe-L-Ala-OtBu, the yield was 71%, and the diastereomer ratio was dr>20:1.

    ##STR00178##

    *Example j12: Synthesis of tBuO-L-Glu-L-Ala-OtBu

    [0501] The reaction was carried out in accordance with the General Synthesis Procedure except that L-glutamic acid whose side chain's carbonic acid group was protected with a t-butyl group (tBuO-L-Glu) was used as the first amino acid AA.sup.1, whereby the title compound tBuO-L-Glu-L-Ala-OtBu was obtained. The yield was 88%, and the diastereomer ratio was dr>20:1.

    ##STR00179##

    *Example j13: Synthesis of tBuO-L-Asp-L-Ala-OtBu

    [0502] The reaction was carried out in accordance with the General Synthesis Procedure except that L-asparaginic acid whose side chain's carbonic acid group was protected with a t-butyl group (tBuO-L-Asp) was used as the first amino acid AA.sup.1, whereby the title compound tBuO-L-Asp-L-Ala-OtBu was obtained. The yield was 90%, and the diastereomer ratio was dr>20:1.

    ##STR00180##

    *Example 14: Synthesis of β-Ala-L-Ala-OtBu

    [0503] The reaction was carried out in accordance with the General Synthesis Procedure except that β-alanine (β-Ala) was used as the first amino acid AA.sup.1, whereby the title compound β-Ala-L-Ala-OtBu was obtained. The yield was 53%.

    ##STR00181##

    INDUSTRIAL APPLICABILITY

    [0504] The present invention can be widely used for the synthesis of amide compounds in various industrial fields, and therefore has high utility value.