CATALYST FOR MANUFACTURING AMIDE COMPOUND, AND METHOD FOR MANUFACTURING AMIDE COMPOUND

Abstract

The present invention provides a catalyst containing a Brønsted acid as a novel means capable of producing an amide compound by highly stereoselectively and/or highly efficiently causing an amidation reaction in a variety of substrates having a carboxylic ester group and an amino group.

Claims

1. A catalyst for amide reaction between a carboxylic acid ester group and an amino group, said catalyst comprising a Brønsted acid.

2. The catalyst according to claim 1, wherein the Brønsted acid is selected from the group consisting of compounds with pKa values of 6.0 or less.

3. The catalyst according to claim 1 or 2, wherein the Brønsted acid is selected from the group consisting of aliphatic or aromatic hydrocarbons having one or more carboxyl groups.

4. 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 amide reaction between the compound represented by general formula (1-1) and the compound represented by general formula (1-2) in the presence of a Brønsted acid according to any one of claims 1 to 3. ##STR00123## In general formula (1-1), R.sup.10 represents a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents, and 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. ##STR00124## 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. ##STR00125## 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.

5. A method of producing, from a compound represented by general formula (2-1), an amide compound represented by general formula (2-2), comprising: causing intramolecular amide reaction in the compound represented by general formula (2-1) in the presence of a Brønsted acid according to any one of claims 1 to 3. ##STR00126## In general formula (2-1), R.sup.20 represents a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents, and 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. ##STR00127## In general formula (2-2), each symbol represents the same definition as that of the same symbol in general formula (2-1) above.

6. 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 amide reaction between the compound represented by general formula (3-1) and the compound represented by general formula (3-2) in the presence of a Brønsted acid according to any one of claims 1 to 3. ##STR00128## In general formula (3-1), R.sup.30 represents a monovalent hydrocarbon group or heterocyclic group that may have one or more substituents, and 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. ##STR00129## 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. ##STR00130## 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.

7. The method according to any one of claims 4 to 6, wherein R.sup.10 in general formula (1-1), R.sup.20 in general formula (2-1), or R.sup.30 in general formula (3-1) is a monovalent aromatic group or heterocyclic group which may have one or more substituents.

8. The method according to any one of claims 3 to 7, wherein the reaction is carried out as a batch reaction or a flow reaction.

Description

EXAMPLES

[0221] 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.

[0222] Amide compounds were produced by the production method according to the present invention, in a manner described in each of the following examples.

[0223] In the following examples, unless otherwise stated, diastereomeric (dr) and enantiomeric (er) ratios are calculated by .sup.1H-NMR analysis (measuring instrument: JEOL 4 00SS, measurement conditions: 400 MH z, solvent: CDCl.sub.3 or High performance liquid chromatography (HPLC) analysis using a DAICEL chiral column (measuring instrument: JEOL 400SS, measurement conditions: 400 MHz, solvent: CDCl.sup.3) or HPLC analysis (measuring instrument: Shimadzu SPD-M20A) using DAICEL chiral column. The dr and er values in the text are rounded off to one decimal place.

[0224] In the following examples, the reactant compound with a carboxylic ester group subject to the amidation reaction may be referred to as “Reactant Compound 1” and the reactant compound with an amino group subject to the amidation reaction as “Reactant Compound 2.”

Example Group A: Amidation Reactions Using Various BrøNsted Acids

*General Synthesis Procedure A:

[0225] ##STR00017##

[0226] Under argon atmosphere, in a glove box, a heat-dried 5.0-mL screw-cap vial containing a stirrer (samarium-cobalt) was charged with Boc-L-Ala-OMe as Reactant Compound 1 and L-Ala-Ot-Bu as Reactant Compound 2 at ratios of Reactant Compound 1=1.0 mmol and Reactant Compound 2=2.0 mmol. 20 mol % of one of various acidic compounds was then added to the vial, and the reaction mixture was stirred vigorously at 70° C. for 72 hours in a preheated oil bath under nitrogen atmosphere, then the reaction was cooled to ambient temperature. The reaction mixture was diluted with CHCl.sub.3 (3.0 mL) and pipetted into a transferred to a silica gel column, and the used vial and pipette were washed with CHCl.sub.3 (12.0 mL). The used vial and pipette were washed with CHCl.sub.3 (12.0 mL). The reaction mixture was purified by flash column chromatography (using 0 to 60% AcOEt in hexane as mobile phase) to thereby afford the target compound Boc-L-Ala-L-Ala-Ot-Bu as a colorless liquid.

*Example A1: Reaction Using Acetic Acid

[0227] ##STR00018##

[0228] The reaction was carried out in accordance with General synthesis procedure A using acetic acid (pKa=4.79, Mw=60.05) as the acidic compound to thereby afford the target compound. Yield: 69%, dr=96.2:3.8.

*Example A2: Reaction Using Propionic Acid

[0229] ##STR00019##

[0230] The reaction was carried out in accordance with General synthesis procedure A using propionic acid (pKa=4.79, Mw=74.08) as the acidic compound to thereby afford the target compound. Yield: 70%, dr=95.0:4.9.

*Example A3: Reaction Using Butanoic Acid

[0231] ##STR00020##

[0232] The reaction was carried out in accordance with General synthesis procedure A using butanoic acid (pKa=4.76, Mw=88.11) as the acidic compound to thereby afford the target compound. Yield: 69%, dr=95.0:5.0.

*Example A4: Reaction Using Valeric Acid

[0233] ##STR00021##

[0234] The reaction was carried out in accordance with General synthesis procedure A using valeric acid (pKa=4.78, Mw=102.13) as the acidic compound to thereby afford the target compound. Yield: 75%, dr=95.5:4.5.

*Example A5: Reaction Using Caproic Acid

[0235] ##STR00022##

[0236] The reaction was carried out in accordance with General synthesis procedure A using caproic acid (pKa=4.78, Mw=116.13) as the acidic compound to thereby afford the target compound. Yield: 64%, dr=96.5:3.5.

*Example A6: Reaction Using Thioacetic Acid

[0237] ##STR00023##

[0238] The reaction was carried out in accordance with General synthesis procedure A using thioacetic acid (pKa=3.95, Mw=76.11) as the acidic compound to thereby afford the target compound. Yield: 63%, dr=91.7:8.3.

*Example A7: Reaction Using Formic Acid

[0239] ##STR00024##

[0240] The reaction was carried out in accordance with General synthesis procedure A using formic acid (pKa=3.74, Mw=46.03) as the acidic compound to thereby afford the target compound. Yield: 28%, dr=94.5:5.5.

*Example A8: Reaction Using Trichlorolic Acid

[0241] ##STR00025##

[0242] The reaction was carried out in accordance with General synthesis procedure A using trichlorolic acid (pKa=0.009, Mw=46.03) as the acidic compound to thereby afford the target compound. Yield: 43%, dr=98.1:6.1.

*Example A9: Reaction Using Trifluoroacetic Acid

[0243] ##STR00026##

[0244] The reaction was carried out in accordance with General synthesis procedure A using trifluoroacetic acid (pKa=0.05, Mw=46.03) as the acidic compound to thereby afford the target compound. Yield: 31%, dr=93.6:6.4.

*Example A10: Reaction Using Ammonium Acetate

[0245] ##STR00027##

[0246] The reaction was carried out in accordance with General synthesis procedure A using ammonium acetate (pKa=9.9, Mw=77.08) as the acidic compound to thereby afford the target compound. Yield: 62%, dr=96.3:3.7.

*Example A11: Reaction Using Isobutyric Acid

[0247] ##STR00028##

[0248] The reaction was carried out in accordance with General synthesis procedure A using isobutyric acid (pKa=4.85, Mw=88.11) as the acidic compound to thereby afford the target compound. Yield: 80%, dr=95.6:4.4.

*Example A12: Reaction Using Pivalic Acid

[0249] ##STR00029##

[0250] The reaction was carried out in accordance with General synthesis procedure A using pivalic acid (pKa=4.94, Mw=102.132) as the acidic compound to thereby afford the target compound. Yield: 85%, dr=95.0:5.0.

*Example A13: Reaction Using Diisopropylacetic Acid

[0251] ##STR00030##

[0252] The reaction was carried out in accordance with General synthesis procedure A using diisopropylacetic acid (pKa=4.74, Mw=144.21) as the acidic compound to thereby afford the target compound. Yield: 79%, dr=93.1:6.9.

*Example A14: Reaction using 2-tert-butyl-3,3-dimethylbutanoic acid

[0253] ##STR00031##

[0254] The reaction was carried out in accordance with General synthesis procedure A using 2-tert-butyl-3,3-dimethylbutanoic acid (pKa=4.83, Mw=172.26) as the acidic compound to thereby afford the target compound. Yield: 69%, dr=90.6:9.4.

*Example A15: Reaction Using Oxalic Acid

[0255] ##STR00032##

[0256] The reaction was carried out in accordance with General synthesis procedure A using oxalic acid (pKa=1.38, Mw=90.03) as the acidic compound to thereby afford the target compound. Yield: 13%, dr=98.6:1.4.

*Example A16: Reaction Using Malonic Acid

[0257] ##STR00033##

[0258] The reaction was carried out in accordance with General synthesis procedure A using malonic acid (pKa=2.92, Mw=104.06) as the acidic compound to thereby afford the target compound. Yield: 55%, dr=94.7:5.3.

*Example A17: Reaction Using Succinic Acid

[0259] ##STR00034##

[0260] The reaction was carried out in accordance with General synthesis procedure A using succinic acid (pKa=4.24, Mw=118.09) as the acidic compound to thereby afford the target compound. Yield: 63%, dr=94.6:5.4.

*Example A18: Reaction Using L-Malic Acid

[0261] ##STR00035##

[0262] The reaction was carried out in accordance with General synthesis procedure A using L-malic acid (pKa=3.61, Mw=134.09) as the acidic compound to thereby afford the target compound. Yield: 18%, dr=97.8:2.2.

*Example A19: Reaction Using Adipic Acid

[0263] ##STR00036##

[0264] The reaction was carried out in accordance with General synthesis procedure A using adipic acid (pKa=4.39, Mw=146.14) as the acidic compound to thereby afford the target compound. Yield: 70%, dr=95.9:4.1.

*Example A20: Reaction Using Fumaric Acid

[0265] ##STR00037##

[0266] The reaction was carried out in accordance with General synthesis procedure A using fumaric acid (pKa=3.15, Mw=116.07) as the acidic compound to thereby afford the target compound. Yield: 15%, dr=98.7:1.3.

*Example A21: Reaction Using Lactic Acid

[0267] ##STR00038##

[0268] The reaction was carried out in accordance with General synthesis procedure A using lactic acid (pKa=3.91, Mw=90.08) as the acidic compound to thereby afford the target compound. Yield: 36%, dr=93.9:6.1.

*Example A21(a): Reaction Using L-Lactic Acid

[0269] ##STR00039##

[0270] The reaction was carried out in accordance with General synthesis procedure A using L-lactic acid (pKa=3.91, Mw=90.08) as the acidic compound to thereby afford the target compound. Yield: 42%, dr=94.4:5.6.

*Example A21(b): Reaction Using D-Lactic Acid

[0271] ##STR00040##

[0272] The reaction was carried out in accordance with General synthesis procedure A using D-lactic acid (pKa=3.91, Mw=90.08) as the acidic compound to thereby afford the target compound. Yield: 41%, dr=94.0:6.0.

*Example A22: Reaction Using L-Tartaric Acid

[0273] ##STR00041##

[0274] The reaction was carried out in accordance with General synthesis procedure A using L-tartaric acid (pKa=3.07, Mw=150.09) as the acidic compound to thereby afford the target compound. Yield: 9%, dr=99.1:0.9.

*Example A23: Reaction Using Maleic Acid

[0275] ##STR00042##

[0276] The reaction was carried out in accordance with General synthesis procedure A using maleic acid (pKa=2.39, Mw=116.07) as the acidic compound to thereby afford the target compound. Yield: 44%, dr=94.9:5,1.

*Example A24: Reaction Using Citric Acid

[0277] ##STR00043##

[0278] The reaction was carried out in accordance with General synthesis procedure A using citric acid (pKa=2.93, Mw=192.12) as the acidic compound to thereby afford the target compound. Yield: 11%, dr=95.3:4.7.

*Example A25: Reaction Using Lactic Acid Methyl

[0279] ##STR00044##

[0280] The reaction was carried out in accordance with General synthesis procedure A using lactic acid methyl (pKa=13.07, Mw=104.10) as the acidic compound to thereby afford the target compound. Yield: 20%, dr=94.1:5.9.

*Example A26: Reaction Using Ethyl Lactate

[0281] ##STR00045##

[0282] The reaction was carried out in accordance with General synthesis procedure A using ethyl lactate (pKa=13.21, Mw=118.13) as the acidic compound to thereby afford the target compound. Yield: 15%, dr=98.3:1.7.

*Example A27: Reaction Using Trichloroacetic Acid

[0283] ##STR00046##

[0284] The reaction was carried out in accordance with General synthesis procedure A using trichloroacetic acid (pKa=0.09, Mw=163.39) as the acidic compound to thereby afford the target compound. Yield: 39%, dr=98.5:1.5.

*Example A28: Reaction Using Bromoacetic Acid

[0285] ##STR00047##

[0286] The reaction was carried out in accordance with General synthesis procedure A using bromoacetic acid (pKa=2.73, Mw=138.85) as the acidic compound to thereby afford the target compound. Yield: 40%, dr=91.7:8.3.

*Example A29: Reaction Using 1-Adamantane Carboxylic Acid

[0287] ##STR00048##

[0288] The reaction was carried out in accordance with General synthesis procedure A using 1-adamantane carboxylic acid (pKa=4.86, Mw=180.24) as the acidic compound to thereby afford the target compound. Yield: 54%, dr=97.2:2.8.

*Example A30: Reaction Using (+)-10-Camphorsulfonic Acid

[0289] ##STR00049##

[0290] The reaction was carried out in accordance with General synthesis procedure A using (+)-10-camphorsulfonic acid (pKa=1.17, Mw=232.30) as the acidic compound to thereby afford the target compound. Yield: 21%, dr=81.2:18.8.

*Example A31: Reaction Using Benzoic Acid

[0291] ##STR00050##

[0292] The reaction was carried out in accordance with General synthesis procedure A using benzoic acid (pKa=4.20, Mw=46.03) as the acidic compound to thereby afford the target compound. Yield: 56%, dr=95.5:4.5.

*Example A32: Reaction Using 2,6-Dimethylbenzoic Acid

[0293] ##STR00051##

[0294] The reaction was carried out in accordance with General synthesis procedure A using 2,6-dimethylbenzoic acid (pKa=3.56, Mw=150.17) as the acidic compound to thereby afford the target compound. Yield: 62%, dr=94.4:5.6.

*Example A33: Reaction Using 2,4,6-Trimethylbenzoic Acid

[0295] ##STR00052##

[0296] The reaction was carried out in accordance with General synthesis procedure A using 2,4,6-trimethylbenzoic acid (pKa=3.85, Mw=164.20) as the acidic compound to thereby afford the target compound. Yield: 72%, dr=94.9:5.1.

*Example A34: Reaction Using 2,6-Diisopropylbenzoic Acid

[0297] ##STR00053##

[0298] The reaction was carried out in accordance with General synthesis procedure A using 2,6-diisopropylbenzoic acid (pKa=3.08, Mw=206.28) as the acidic compound to thereby afford the target compound. Yield: 69%, dr=92.9:7.1.

*Example A35: Reaction Using 2,6-Di-Tert-Butylbenzoic Acid

[0299] ##STR00054##

[0300] The reaction was carried out in accordance with General synthesis procedure A using 2,6-di-tert-butylbenzoic acid (pKa=2.86, Mw=234.34) as the acidic compound to thereby afford the target compound. Yield: 87%, dr=84.7:15.3.

*Example A36: Reaction Using 2,4,6-Triisopropylbenzoic Acid

[0301] ##STR00055##

[0302] The reaction was carried out in accordance with General synthesis procedure A using 2,4,6-triisopropylbenzoic acid (pKa=3.06, Mw=248.36) as the acidic compound to thereby afford the target compound. Yield: 68%, dr=94.6:5.4.

*Example A37: Reaction Using 2,6-Dimethoxy Benzoic Acid

[0303] ##STR00056##

[0304] The reaction was carried out in accordance with General synthesis procedure A using 2,6-dimethoxy benzoic acid (pKa=3.98, Mw=182.17) as the acidic compound to thereby afford the target compound. Yield: 43%, dr=97.6:2.4.

*Example A38: Reaction Using Phthalic Acid

[0305] ##STR00057##

[0306] The reaction was carried out in accordance with General synthesis procedure A using phthalic acid (pKa=2.95, Mw=166.13) as the acidic compound to thereby afford the target compound. Yield: 27%, dr=92.8:7.2.

*Example A39: Reaction Using Isophthalic Acid

[0307] ##STR00058##

[0308] The reaction was carried out in accordance with General synthesis procedure A using isophthalic acid (pKa=3.53, Mw=166.13) as the acidic compound to thereby afford the target compound. Yield: 75%, dr=94.9:5.1.

*Example A40: Reaction Using 1,2-Phenylene Diacetate

[0309] ##STR00059##

[0310] The reaction was carried out in accordance with General synthesis procedure A using 1,2-phenylene diacetate (pKa=3.90, Mw=194.18) as the acidic compound to thereby afford the target compound. Yield: 35%, dr=95.1:4.9.

*Example A41: Reaction Using Pyromellitic Acid

[0311] ##STR00060##

[0312] The reaction was carried out in accordance with General synthesis procedure A using pyromellitic acid (pKa=1.87, Mw=254.15) as the acidic compound to thereby afford the target compound. Yield: 5%, dr=94.8:5.2.

*Example A42: Reaction Using L-Proline

[0313] ##STR00061##

[0314] The reaction was carried out in accordance with General synthesis procedure A using L-proline (pKa=2.35, Mw=115.13) as the acidic compound to thereby afford the target compound. Yield: 15%, dr=98.5:1.5.

*Example A43: Reaction Using Proline Tetrazole

[0315] ##STR00062##

[0316] The reaction was carried out in accordance with General synthesis procedure A using proline tetrazole (pKa=3.77, Mw=139.16) as the acidic compound to thereby afford the target compound. Yield: 13%, dr=98.1:1.7.

*Example A44: Reaction using (S)-2-(1H-tetrazol-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0317] ##STR00063##

[0318] The reaction was carried out in accordance with General synthesis procedure A using (S)-2-(1H-tetrazol-5-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (pKa=4.66, Mw=239.27) as the acidic compound to thereby afford the target compound. Yield: 47%, dr=91.5:8.5.

*Example A45: Reaction using 1,1′-binaphthyl-2,2′-dicarboxylic acid

[0319] ##STR00064##

[0320] The reaction was carried out in accordance with General synthesis procedure A using 1,1′-binaphthyl-2,2′-dicarboxylic acid (pKa=3.66, Mw=342.34) as the acidic compound to thereby afford the target compound. Yield: 22%, dr=98.5:1.5.

*Example A46: Reaction Using Phenol

[0321] ##STR00065##

[0322] The reaction was carried out in accordance with General synthesis procedure A using phenol (pKa=9.86, Mw=94.11) as the acidic compound to thereby afford the target compound. Yield: 15%, dr=98.7:1.3.

*Example A47: Reaction Using Benzenethiol

[0323] ##STR00066##

[0324] The reaction was carried out in accordance with General synthesis procedure A using benzenethiol (pKa=6.61, Mw=110.18) as the acidic compound to thereby afford the target compound. Yield: 20%, dr=93.7:6.3.

*Example A48: Reaction Using Catechol

[0325] ##STR00067##

[0326] The reaction was carried out in accordance with General synthesis procedure A using catechol (pKa=9.50, Mw=110.11) as the acidic compound to thereby afford the target compound. Yield: 37%, dr=98.0:2.0.

*Example A49: Reaction Using 4-Nitrophenol

[0327] ##STR00068##

[0328] The reaction was carried out in accordance with General synthesis procedure A using 4-nitrophenol (pKa=7.23, Mw=139.11) as the acidic compound to thereby afford the target compound. Yield: 54%, dr=91.1:8.9.

*Example A50: Reaction Using 4-Methoxyphenol

[0329] ##STR00069##

[0330] The reaction was carried out in accordance with General synthesis procedure A using 4-methoxyphenol (pKa=10.40, Mw=124.14) as the acidic compound to thereby afford the target compound. Yield: 15%, dr=99.1:0.9.

*Example A51: Reaction Using p-Toluene Boronic Acid

[0331] ##STR00070##

[0332] The reaction was carried out in accordance with General synthesis procedure A using p-toluene boronic acid (pKa=8.84, Mw=135.96) as the acidic compound to thereby afford the target compound. Yield: 15%, dr=98.4:1.6.

*Example A52: Reaction Using 4-Methoxyphenylboronic Acid

[0333] ##STR00071##

[0334] The reaction was carried out in accordance with General synthesis procedure A using 4-methoxyphenylboronic acid (pKa=8.96, Mw=151.96) as the acidic compound to thereby afford the target compound. Yield: 17%, dr=98.5:1.4.

*Example A53: Reaction Using 2,4,6-Trimethylphenol

[0335] ##STR00072##

[0336] The reaction was carried out in accordance with General synthesis procedure A using 2,4,6-trimethylphenol (pKa=10.97, Mw=136.19) as the acidic compound to thereby afford the target compound. Yield: 11%, dr=99.1:0.9.

*Example A54: Reaction Using 2,6-Di-Tert-Butyl-4-Methylphenol

[0337] ##STR00073##

[0338] The reaction was carried out in accordance with General synthesis procedure A using 2,6-di-tert-butyl-4-methylphenol (pKa=12.76, Mw=220.35) as the acidic compound to thereby afford the target compound. Yield: 11%, dr=98.6:1.4.

*Example A55: Reaction using N-(2,6-dimethylphenyl)-1,1,1-trifluoromethanesulfonamide

[0339] ##STR00074##

[0340] The reaction was carried out in accordance with General synthesis procedure A using N-(2,6-dimethylphenyl)-1,1,1-trifluoromethanesulfonamide (pKa=4.76, Mw=253.24) as the acidic compound to thereby afford the target compound. Yield: 19%, dr=97.4:2.6.

*Example A56: Reaction using N-[2,6-bis(1-methylethyl)phenyl]-1,1,1-trifluoromethanesulfonamide

[0341] ##STR00075##

[0342] The reaction was carried out in accordance with General synthesis procedure A using N-[2,6-bis(1-methylethyl)phenyl]-1,1,1-trifluoromethanesulfonamide (pKa=4.67, Mw=309.35) as the acidic compound to thereby afford the target compound. Yield: 18%, dr=91.5:8.5.

*Example A57: Reaction using 4-methylphenylsulfonic acid anhydride

[0343] ##STR00076##

[0344] The reaction was carried out in accordance with General synthesis procedure A using 4-methylphenylsulfonic acid anhydride (pKa=1.361, Mw=326.39) as the acidic compound to thereby afford the target compound. Yield: 18%, dr=94.9:5.1.

*Example A58: Reaction Using Methanesulfonic Acid

[0345] ##STR00077##

[0346] The reaction was carried out in accordance with General synthesis procedure A using methanesulfonic acid (pKa=1.75, Mw=96.11) as the acidic compound to thereby afford the target compound. Yield: 21%, dr=94.0:6.0.

*Example A59: Reaction Using Tert-Butyldimethylsilanol

[0347] ##STR00078##

[0348] The reaction was carried out in accordance with General synthesis procedure A using tert-butyldimethylsilanol (pKa=15.37, Mw=132.28) as the acidic compound to thereby afford the target compound. Yield: 9%, dr=99.0:1.0.

*Example A60: Reaction Using Triphenylsilanol

[0349] ##STR00079##

[0350] The reaction was carried out in accordance with General synthesis procedure A using triphenylsilanol (pKa=13.39, Mw=276.40) as the acidic compound to thereby afford the target compound. Yield: 12%, dr=99.3:0.7.

*Example A61: Reaction using 2,2,2-trifluoroethanol

[0351] ##STR00080##

[0352] The reaction was carried out in accordance with General synthesis procedure A using 2,2,2-trifluoroethanol (pKa=12.46, Mw=100.04) as the acidic compound to thereby afford the target compound. Yield: 16%, dr=98.0:2.0.

Example Group B: Amidation Reactions Using Various Reactant Compound 1

*General Synthesis Procedure B:

[0353] ##STR00081##

[0354] Under argon atmosphere, in a glove box, a heat-dried 5.0-mL screw-cap vial containing a stirrer (samarium-cobalt) was charged with PG-AA-OMe (where AA refers to an amino acid and PG refers to a protective group of the amino group of the amino acid AA) as Reactant Compound 1 and L-Ala-Ot-Bu as Reactant Compound 2 at ratios satisfying any one of Conditions [a] to [c] below. In addition, pivalic acid (102.1 mg, 1.0 mmol) is added as the Brønsted acid, the reaction mixture was stirred vigorously at 70° C. for 72 hours in a preheated oil bath under nitrogen atmosphere, then the reaction was cooled to ambient temperature. The reaction mixture was diluted with CHCl.sub.3 (3.0 mL) and pipetted into a transferred to a silica gel column, and the used vial and pipette were washed with CHCl.sub.3 (12.0 mL). The used vial and pipette were washed with CHC.sub.3 (12.0 mL). The reaction mixture was purified by flash column chromatography (using 0 to 60% AcOEt in hexane as mobile phase) to thereby afford the title compound of each Example.

*Condition [a]: Reactant Compound 1=1.0 mmol, Reactant Compound 2=2.0 mmol.
*Condition [b]: Reactant Compound 1=1.0 mmol, Reactant Compound 2=1.0 mmol.
*Condition [c]: Reactant Compound 1=2.0 mmol, Reactant Compound 2=1.0 mmol.

[0355] Among the values of yield, er, and dr in this Example Group, the values marked with * were measured by HPLC analysis, and those marked with ** were by .sup.1H-NMR analysis.

*Example B1: Synthesis of Boc-Gly-L-Ala-Ot-Bu

[0356] ##STR00082##

[0357] The reaction was carried out in accordance with General synthesis procedure B using Boc-Gly-OMe as Reactant Compound 1 to thereby afford the title compound Boc-Gly-L-Ala-Ot-Bu as colorless liquid.

*Condition [a]: Yield>99%, er=96:4.
*Condition [b]: Yield 83%, er=93:7.
*Condition [c]: Yield 93%, er=91:9.

*Example B2: Synthesis of Boc-L-Ala-L-Ala-Ot-Bu

[0358] ##STR00083##

[0359] The reaction was carried out in accordance with General synthesis procedure B using Boc-L-Ala-OMe as Reactant Compound 1 to thereby afford the title compound Boc-L-Ala-L-Ala-Ot-Bu as colorless liquid.

*Condition [a]: Yield 93%, dr=90:10.
*Condition [b]: Yield 61%, dr=85:15.
*Condition [c]: Yield 84%, dr=85:15.

*Example B3: Synthesis of Boc-L-Leu-L-Ala-Ot-Bu

[0360] ##STR00084##

[0361] The reaction was carried out in accordance with General synthesis procedure B using Boc-L-Leu-OMe as Reactant Compound 1 to thereby afford the title compound Boc-L-Leu-L-Ala-Ot-Bu as white solid.

*Condition [a]: Yield 86%, dr=92:8.
*Condition [b]: Yield 56%, dr=87:13.
*Condition [c]: Yield 54%, dr=84:16.

*Example B3′: Synthesis of Cbz-L-Leu-L-Ala-Ot-Bu

[0362] ##STR00085##

[0363] The reaction was carried out in accordance with General synthesis procedure B using Cbz-L-Leu-OMe as Reactant Compound 1 to thereby afford the title compound Cbz-L-Leu-L-Ala-Ot-Bu as white solid.

*Condition [a]: Yield 74%, dr=95:5.
*Condition [b]: Yield 56%, dr=87:13.
*Condition [c]: Yield 65%, dr=90:10.

*Example B4: Synthesis of Boc-L-Ile-L-Ala-Ot-Bu

[0364] ##STR00086##

[0365] The reaction was carried out in accordance with General synthesis procedure B using Boc-L-Ile-OMe as Reactant Compound 1 to thereby afford the title compound Boc-L-Ile-L-Ala-Ot-Bu as white solid.

*Condition [a]: Yield 25%, dr=82:18.
*Condition [b]: Yield 21%, dr=84:16.
*Condition [c]: Yield 22%, dr=87:13.

*Example B5: Synthesis of Boc-L-Val-L-Ala-Ot-Bu

[0366] ##STR00087##

[0367] The reaction was carried out in accordance with General synthesis procedure B using Boc-L-Val-OMe as Reactant Compound 1 to thereby afford the title compound Boc-L-Val-L-Ala-Ot-Bu as white solid.

*Condition [a]: Yield 22%, dr=89:11.
*Condition [b]: Yield 20%, dr=72:28.
*Condition [c]: Yield 12%, dr=>95:1.

*Example B6: Synthesis of Boc-L-Phe-L-Ala-Ot-Bu

[0368] ##STR00088##

[0369] The reaction was carried out in accordance with General synthesis procedure B using Boc-L-Phe-OMe as Reactant Compound 1 to thereby afford the title compound Boc-L-Phe-L-Ala-Ot-Bu as white solid.

*Condition [a]: Yield 79%, dr=92:8.
*Condition [b]: Yield 51%, dr=93:7.
*Condition [c]: Yield 63%, dr=92:8.

*Example B7: Synthesis of Boc-L-Trp-L-Ala-Ot-Bu

[0370] ##STR00089##

[0371] The reaction was carried out in accordance with General synthesis procedure B using Boc-L-Trp-OMe as Reactant Compound 1 to thereby afford the title compound Boc-L-Trp-L-Ala-Ot-Bu as colorless liquid.

*Condition [a]: Yield 56%, dr=89:11.
*Condition [b]: Yield 15%, dr=71:29.
*Condition [c]: Yield 17%, dr=72:28.

*Example B8: Synthesis of Boc-L-Thr-L-Ala-Ot-Bu

[0372] ##STR00090##

[0373] The reaction was carried out in accordance with General synthesis procedure B using Boc-L-Thr-OMe as Reactant Compound 1 to thereby afford the title compound Boc-L-Thr-L-Ala-Ot-Bu as colorless liquid.

*Condition [a]: Yield 72%, dr=80:20.
*Condition [b]: Yield 41%, dr=72:28.
*Condition [c]: Yield 32%, dr=76:24.

*Example B9: Synthesis of Cbz-L-Met-L-Ala-Ot-Bu

[0374] ##STR00091##

[0375] The reaction was carried out in accordance with General synthesis procedure B using Cbz-L-Met-OMe as Reactant Compound 1 to thereby afford the title compound Cbz-L-Met-L-Ala-Ot-Bu as white solid.

*Condition [a]: Yield 81%, dr=90:10.
*Condition [b]: Yield 51%, dr=94:6.
*Condition [c]: Yield 60%, dr=86:14.

*Example B10: Synthesis of Boc-L-Pro-L-Ala-Ot-Bu

[0376] ##STR00092##

[0377] The reaction was carried out in accordance with General synthesis procedure B using Boc-L-Pro-OMe as Reactant Compound 1 to thereby afford the title compound Boc-L-Pro-L-Ala-Ot-Bu as white solid.

*Condition [a]: Yield 51%, dr=92:8.
*Condition [b]: Yield 55%, dr=84:16.
*Condition [c]: Yield 55%, dr=83:17.

Example Group C: Amidation Reactions Various Reactant Compounds 2

*General Synthesis Procedure C:

[0378] ##STR00093##

[0379] Under argon atmosphere, in a glove box, a heat-dried 5.0-mL screw-cap vial containing a stirrer (samarium-cobalt) was charged with Boc-L-Ala-Ot-Bu as Reactant Compound 1 and AA-Ot-Bu (where AA refers to an amino acid) as Reactant Compound 2 at ratios satisfying any one of Conditions [a] to [c] below. In addition, pivalic acid (102.1 mg, 1.0 mmol) was added as the Brønsted acid, and the reaction mixture was stirred vigorously at 70° C. for 72 hours in a preheated oil bath under nitrogen atmosphere, then the reaction was cooled to ambient temperature. The reaction mixture was diluted with CHCl.sub.3 (3.0 mL) and pipetted into a transferred to a silica gel column, and the used vial and pipette were washed with CHCl.sub.3 (12.0 mL). The used vial and pipette were washed with CHCl.sub.3 (12.0 mL). The reaction mixture was purified by flash column chromatography (using 0 to 60% AcOEt in hexane as mobile phase) to thereby afford the title compound of each Example.

*Condition [a]: Reactant Compound 1=1.0 mmol, Reactant Compound 2=2.0 mmol.
*Condition [b]: Reactant Compound 1=1.0 mmol, Reactant Compound 2=1.0 mmol.
*Condition [c]: Reactant Compound 1=2.0 mmol, Reactant Compound 2=1.0 mmol.

[0380] Among the values of yield, er, and dr in this Example Group, the values marked with * were measured by HPLC analysis, and those marked with ** were by .sup.1H-NMR analysis.

*Example C1: Synthesis of Boc-L-Ala-Gly-Ot-Bu Synthesis of

[0381] ##STR00094##

[0382] The reaction was carried out in accordance with General synthesis procedure C using Gly-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-Gly-Ot-Bu as colorless liquid.

*Condition [a]: Yield 90%, er=>99:1.
*Condition [b]: Yield 55%, er=>99:1.
*Condition [c]: Yield 77%, er=>99:1.

*Example C2: Synthesis of Boc-L-Ala-L-Ala-Ot-Bu

[0383] ##STR00095##

[0384] The reaction was carried out in accordance with General synthesis procedure C using L-Ala-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-L-Ala-Ot-Bu as white solid.

*Condition [a]: Yield 90%, dr=90:10.
*Condition [b]: Yield 74%, dr=86:14.
*Condition [c]: Yield 66%, dr=85:15.

*Example C3: Synthesis of Boc-L-Ala-L-Leu-Ot-Bu

[0385] ##STR00096##

[0386] The reaction was carried out in accordance with General synthesis procedure C using L-Leu-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-L-Leu-Ot-Bu as colorless liquid.

*Condition [a]: Yield>99%, dr=94:6.
*Condition [b]: Yield 95%, dr=87:13.
*Condition [c]: Yield>99%, dr=91:9.

*Example C4: Synthesis of Boc-L-Ala-L-Ile-Ot-Bu

[0387] ##STR00097##

[0388] The reaction was carried out in accordance with General synthesis procedure C using L-Ile-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-L-Ile-Ot-Bu as colorless liquid.

*Condition [a]: Yield 69%, dr=>95:1.
*Condition [b]: Yield 63%, dr=>95:1.
*Condition [c]: Yield 95%, dr=>95:1.

*Example C5: Synthesis of Boc-L-Ala-L-Val-Ot-Bu

[0389] ##STR00098##

[0390] The reaction was carried out in accordance with General synthesis procedure C using L-Val-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-L-Val-Ot-Bu as colorless liquid.

*Condition [a]: Yield 99%, dr=>99:1.
*Condition [b]: Yield 70%, dr=>99:1.
*Condition [c]: Yield 78%, dr=>99:1.

*Example C5′: Synthesis of Boc-L-Ala-D-Val-Ot-Bu

[0391] ##STR00099##

[0392] The reaction was carried out in accordance with General synthesis procedure C using D-Val-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-D-Val-Ot-Bu as colorless liquid.

*Condition [a]: Yield 84%, dr=97:3.

*Example C6: Synthesis of Boc-L-Ala-L-Phg-Ot-Bu

[0393] ##STR00100##

[0394] The reaction was carried out in accordance with General synthesis procedure C using L-Phg-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-L-Phg-Ot-Bu as white solid.

*Condition [a]: Yield 53%, dr=55:45.
*Condition [b]: Yield 48%, dr=53:47.
*Condition [c]: Yield 85%, dr=55:45.

*Example C7: Synthesis of Boc-L-Ala-L-Phe-Ot-Bu

[0395] ##STR00101##

[0396] The reaction was carried out in accordance with General synthesis procedure C using L-Phe-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-L-Phe-Ot-Bu as white solid.

*Condition [a]: Yield 89%, dr=91:9.
*Condition [b]: Yield 77%, dr=86:14.
*Condition [c]: Yield 83%, dr=86:14.

*Example C8: Synthesis of Boc-L-Ala-L-Trp-Ot-Bu

[0397] ##STR00102##

[0398] The reaction was carried out in accordance with General synthesis procedure C using L-Trp-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-L-Trp-Ot-Bu as colorless liquid.

*Condition [a]: Yield 51%, dr=>95:1.
*Condition [b]: Yield 39%, dr=>95:1.
*Condition [c]: Yield 54%, dr=>95:1.

*Example C9: Synthesis of Boc-L-Ala-L-Thr(t-Bu)-Ot-Bu

[0399] ##STR00103##

[0400] The reaction was carried out in accordance with General synthesis procedure C using L-Thr(t-Bu)-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-L-Thr(t-Bu)-Ot-Bu as colorless liquid.

*Condition [a]: Yield 98%, dr=>95:1.
*Condition [b]: Yield 86%, dr=>95:1.
*Condition [c]: Yield 45%, dr=>95:1.

*Example C10: Synthesis of Boc-L-Ala-L-Met-Ot-Bu

[0401] ##STR00104##

[0402] The reaction was carried out in accordance with General synthesis procedure C using L-Met-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-L-Met-Ot-Bu as colorless liquid.

*Condition [a]: Yield 89%, dr=90:10.
*Condition [b]: Yield 70%, dr=88:12.
*Condition [c]: Yield 95%, dr=87:13.

*Example C11: Synthesis of Boc-L-Ala-L-Lys(Cbz)-Ot-Bu

[0403] ##STR00105##

[0404] The reaction was carried out in accordance with General synthesis procedure C using L-Lys(Cbz)-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-L-Lys(Cbz)-Ot-Bu as white solid.

*Condition [a]: Yield 87%, dr=>95:1.
*Condition [b]: Yield 87%, dr=>95:1.
*Condition [c]: Yield 83%, dr=>95:1.

*Example C12: Synthesis of Boc-L-Ala-L-Pro-Ot-Bu

[0405] ##STR00106##

[0406] The reaction was carried out in accordance with General synthesis procedure C using L-Pro-Ot-Bu as Reactant Compound 2 to thereby afford the title compound Boc-L-Ala-L-Pro-Ot-Bu as colorless liquid.

*Condition [a]: Yield 32%, dr=99:1.
*Condition [b]: Yield 19%, dr=93:7.
*Condition [c]: Yield 25%, dr=99:1.

Example Group D: Amidation Reactions Using Reactant Compounds 1 Having Various Protective Groups PGs

*General Synthesis Procedure D:

[0407] ##STR00107##

[0408] Under argon atmosphere, in a glove box, a heat-dried 5.0-mL screw-cap vial containing a stirrer (samarium-cobalt) was charged with PG-L-Ala-OMe (where PG refers to a protective group of the amino group of L-Ala) as Reactant Compound 1 and L-Ala-Ot-Bu as Reactant Compound 2 at ratios of Reactant Compound 1=1.0 mmol and Reactant Compound 2=2.0 mmol. In addition, pivalic acid was added as the Brønsted acid at a ratio satisfying any one of Condition [a] or [b], and the reaction mixture was stirred vigorously at 70° C. for 72 hours in a preheated oil bath under nitrogen atmosphere, then the reaction was cooled to ambient temperature. The reaction mixture was diluted with CHCl.sub.3 (3.0 mL) and pipetted into a transferred to a silica gel column, and the used vial and pipette were washed with CHCl.sub.3 (12.0 mL). The used vial and pipette were washed with CHCl.sub.3 (12.0 mL). The reaction mixture was purified by flash column chromatography (using 0 to 60% AcOEt in hexane as mobile phase) to thereby afford the title compound of each Example.

*Condition [a]: pivalic acid=100 mol %.
*Condition [b]: pivalic acid=50 mol %.

*Example D1: Synthesis of Boc-L-Ala-L-Ala-Ot-Bu

[0409] The reaction was carried out in accordance with General synthesis procedure C using Boc-L-Ala-OMe as Reactant Compound 1 to thereby afford the title compound Boc-L-Ala-L-Ala-Ot-Bu as colorless liquid.

*Condition [a]: Yield>99%, dr=95:5.
*Condition [b]: Yield>99%, dr=95:5.

*Example D2: Synthesis of Cbz-L-Ala-L-Ala-Ot-Bu

[0410] The reaction was carried out in accordance with General synthesis procedure C using Cbz-L-Ala-OMe as Reactant Compound 1 to thereby afford the title compound Cbz-L-Ala-L-Ala-Ot-Bu as white solid.

*Condition [a]: Yield 83%, dr=93:7.
*Condition [b]: Yield 83%, dr=95:5.

*Example D3: Synthesis of Bz-L-Ala-L-Ala-Ot-Bu

[0411] The reaction was carried out in accordance with General synthesis procedure C using Bz-L-Ala-OMe as Reactant Compound 1 to thereby afford the title compound Bz-L-Ala-L-Ala-Ot-Bu as white solid.

*Condition [a]: Yield 95%, dr=95:5.
*Condition [b]: Yield 97%, dr=95:5.

*Example D4: Synthesis of Bn-L-Ala-L-Ala-Ot-Bu

[0412] The reaction was carried out in accordance with General synthesis procedure C using Bn-L-Ala-OMe as Reactant Compound 1 to thereby afford the title compound Bn-L-Ala-L-Ala-Ot-Bu as white solid.

*Condition [a]: Yield 83%, dr=>95:5.
*Condition [b]: Yield 83%, dr=>95:5.

*Example D5: Synthesis of H-L-Ala-L-Ala-Ot-Bu

[0413] The reaction was carried out in accordance with General synthesis procedure C using H-L-Ala-OMe with no protective group as Reactant Compound 1 to thereby afford the title compound H-L-Ala-L-Ala-Ot-Bu as colorless liquid.

*Condition [a]: Yield 16%, dr=>95:5.

Example Group E: Amidation Reactions Using Reactant Compounds 1 Having Carboxylic Acid Groups Esterified with Aromatic or Heterocyclic Moiety

*Example E1: Synthesis of Boc-L-Ala-L-Ala-Ot-Bu via Boc-Ala-OPh

(Step E1-1) Synthesis of Boc-Ala-OPh

[0414] ##STR00108##

[0415] Under argon atmosphere, in a glove box, a heat-dried 5.0-mL screw-cap vial containing a stirrer (samarium-cobalt) was charged with Boc-L-Ala-OH (CAS No.: 15761-38-3, 946.1 mg, 5.0 mmol) and Ph-OH (470 mg, 5.0 mmol). This mixture was then combined with N,N′-dicyclohexyl carbodiimide (DCC) (1.135 g, 5.5 mmol) and N,N-dimethyl-4-amino pyridine (4-DMAP) (670 mg, 5.5 mmol), and then dissolved into dried DCM(10 mL, 0.5M). The reaction mixture was stirred vigorously at room temperatures for 3 hours under argon atmosphere. The reaction was monitored by TLC analysis, and upon completion of the reaction, the reaction mixture was diluted with DCM, and then purified by flash column chromatography (using 0 to 30% AcOEt in hexane as mobile phase) to thereby afford the title compound Boc-Ala-OPh as white solid.

(Step E1-2) Synthesis of Boc-L-Ala-L-Ala-Ot-Bu from Boc-Ala-OPh

[0416] ##STR00109##

[0417] Under argon atmosphere, in a glove box, a heat-dried 5.0-mL screw-cap vial containing a stirrer (samarium-cobalt) was charged with Boc-L-Ala-OPh prepared in (Step E-1) (265.0 mg, 1.0 mmol) as Reactant Compound 1, L-Ala-Ot-Bu (290.4 mg, 2.0 mmol) as Reactant Compound 2, and pivalic acid (102.1 mg, 1.0 mmol) as the Brønsted acid, and the mixture was dissolved into dried CHCl.sub.3 (0.5 mL, 2M). The resulting mixture was stirred vigorously at room temperatures for 0.5 hours under nitrogen atmosphere. The reaction mixture was diluted with CHCl.sub.3 (3.0 mL) and pipetted into a transferred to a silica gel column, and the used vial and pipette were washed with CHCl.sub.3 (12.0 mL). The used vial and pipette were washed with CHCl.sub.3 (12.0 mL). The reaction mixture was then purified by flash column chromatography (using 0 to 60% AcOEt in hexane as mobile phase) to thereby afford the title compound Boc-L-Ala-L-Ala-Ot-Bu as colorless liquid. Yield: >99%, dr>99:1.

*Example E2: Synthesis of Boc-L-Ala-L-Ala-Ot-Bu via Boc-Ala-ONp

[0418] ##STR00110##

[0419] The reaction was carried out in accordance with the procedure mentioned above except that Boc-L-Ala-OPh was changed to Boc-L-Ala-ONp (CAS No. 2483-49-0, 310.3 mg, 1.0 mmol) to thereby afford the title compound Boc-L-Ala-L-Ala-Ot-Bu as colorless liquid. Yield: >99%, dr>99:1.

*Example E3: Synthesis of Boc-L-Ala-L-Ala-Ot-Bu via Boc-Ala-OSu

[0420] ##STR00111##

[0421] The reaction was carried out in accordance with the procedure mentioned above except that Boc-L-Ala-OPh was changed to Boc-L-Ala-OSu (CAS No. 3392-05-0, 286.3 mg, 1.0 mmol) to thereby afford the title compound Boc-L-Ala-L-Ala-Ot-Bu as colorless liquid. Yield: >99%, dr>99:1.

*Example E4: Synthesis of Boc-L-Ala-L-Phg-Ot-Bu via Boc-Ala-OPh

[0422] ##STR00112##

[0423] The reaction was carried out in accordance with the procedure mentioned above except that L-Ala-Ot-Bu was changed to L-Phg-Ot-Bu (CAS No. 53934-78-4, 414.6 mg, 2.0 mmol) to thereby afford the title compound Boc-L-Ala-L-Phg-Ot-Bu as white solid. Yield: 98%, dr>99:1.

*Example E5: Synthesis of Boc-L-Ala-L-Phg-Ot-Bu via Boc-Ala-OPh

[0424] ##STR00113##

[0425] The reaction was carried out in accordance with the procedure mentioned above except that Boc-L-Ala-OPh was changed to Boc-L-Ala-ONp (CAS No. 2483-49-0, 310.3 mg, 1.0 mmol) and L-Ala-Ot-Bu was changed to L-Phg-Ot-Bu (CAS No. 53934-78-4, 414 mg, 2.0 mmol) to thereby afford the title compound Boc-L-Ala-L-Phg-Ot-Bu as white solid. Yield: >99%, dr>99:1.

*Example E6: Synthesis of Cbz-L-Ala-L-Ala-Ot-Bu via Cbz-Ala-OPh

(Step E6-1) Synthesis of Cbz-Ala-OPh

[0426] ##STR00114##

[0427] The reaction was carried out in accordance with the procedure in (Step E1-1) above except that Boc-L-Ala-OH was changed to Cbz-L-Ala-OH (CAS No.: 1142-20-7, 1.116 g, 5.0 mmol) to thereby afford the title compound Cbz-Ala-OPh as white solid.

(Step E6-2) Synthesis of Cbz-L-Ala-L-Ala-Ot-Bu from Cbz-Ala-OPh

[0428] ##STR00115##

[0429] The reaction was carried out in accordance with the procedure in (Step E1-2) except that Boc-L-Ala-OPh was changed to Cbz-L-Ala-OPh prepared in (Step E6-1) (299.3 mg, 1.0 mmol) and the reaction time was changed from 0.5 hours to 1.5 hours to thereby afford the title compound Cbz-L-Ala-L-Ala-Ot-Bu as white solid. Yield: >99%, dr>99:1.

*Example E7: Synthesis of Cbz-L-Ala-L-Ala-Ot-Bu via Cbz-Ala-O(4-BrPh)

(Step E7-1) Synthesis of Cbz-Ala-bromophenol

[0430] ##STR00116##

[0431] The reaction was carried out in accordance with the procedure in (Step E1-1) above except that Boc-L-Ala-OH was changed to Cbz-L-Ala-OH (CAS No.: 1142-20-7, 1.116 g, 5.0 mmol), Ph-OH was changed to 4-bromophenol (1.038 g, 6.0 mmol), and the dried DCM was changed to dried EtOAc (50 mL, 0.1M) to thereby afford the title compound Cbz-Ala-O(4-BrPh) as white solid.

(Step E7-2) Synthesis of Cbz-L-Ala-L-Ala-Ot-Bu from Cbz-Ala-O(4-BrPh)

[0432] ##STR00117##

[0433] The reaction was carried out in accordance with the procedure in (step E1-2) above except that Boc-L-Ala-OPh was changed to Cbz-Ala-O(4-BrPh) prepared in (Step E7-1) (378.2 mg, 1.0 mmol) and the reaction time was changed from 0.5 hours to 1.5 hours to thereby afford the title compound Cbz-L-Ala-L-Ala-Ot-Bu as white solid. Yield: >99%, dr>99:1.

*Example E8: Synthesis of Cbz-L-Ala-L-Ala-Ot-Bu via Cbz-Ala-O(2-MePh)

(Step E8-1) Synthesis of Cbz-Ala-O(2-MePh)

[0434] ##STR00118##

[0435] The reaction was carried out in accordance with the procedure in (Step E1-1) above except that Boc-L-Ala-OH was changed to Cbz-L-Ala-OH (CAS No.: 1142-20-7, 1.116 g, 5.0 mmol), Ph-OH was changed to 2-methylphenol (648.8 mg, 6.0 mmol), and dried DCM was changed to dried EtOAc (50 mL, 0.1M) to thereby afford the title compound Cbz-Ala-O(2-MePh) as white solid.

(Step E8-2) Synthesis of Cbz-L-Ala-L-Ala-Ot-Bu from Cbz-Ala-O(2-MePh)

[0436] ##STR00119##

[0437] The reaction was carried out in accordance with the procedure in (Step E1-2) above except that Boc-L-Ala-OPh was changed to Cbz-Ala-O(2-MePh) prepared in (step E8-1) (313.4 mg, 1.0 mmol), and the reaction time was changed from 0.5 hours to 1.5 hours to thereby afford the title compound Cbz-L-Ala-L-Ala-Ot-Bu as white solid. Yield: 83%, dr>99:1.

*Example E9: Synthesis of Fmoc-L-Ala-L-Ala-Ot-Bu via Fmoc-Ala-OPh

(Step E9-1) Synthesis of Fmoc-Ala-OPh

[0438] ##STR00120##

[0439] Under argon atmosphere, in a glove box, a heat-dried 5.0-mL screw-cap vial containing a stirrer (samarium-cobalt) was charged with Fmoc-L-Ala-OH (CAS No.: 35661-39-3, 1.556 g, 5.0 mmol) and Ph-OH (470 mg, 5.0 mmol). The mixture was then combined with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (water-soluble carbodiimide hydrochloride, WSCDHCl) (1.245 g, 6.5 mmol) and 1-hydroxy benzotriazole (HoBt) (859 mg, 6.5 mmol), and was dissolved into dried DCM (25 mL, 0.2M). Triethyl amine (Et.sub.3N) (1.7 mL, 12.5 mmol) was dropped into the resulting solution. The mixture was stirred vigorously under argon atmosphere at −5° C. for 3 hours. The reaction was monitored by TLC analysis, and upon completion of the reaction, the reaction mixture was diluted with DCM. The reaction mixture was then purified by flash column chromatography (using 0 to 40% AcOEt in hexane as mobile phase) to thereby afford the title compound Fmoc-Ala-OPh as white solid.

(Step E9-2) Synthesis of Fmoc-L-Ala-L-Ala-Ot-Bu from Fmoc-Ala-OPh

[0440] ##STR00121##

[0441] The reaction was carried out in accordance with the procedure mentioned above except that Boc-L-Ala-OPh was changed to Fmoc-Ala-OPh prepared in (step E9-1) (387.4 mg, 1.0 mmol), the amount of CHCl.sub.3 used was changed from 1.5 mL to 3.0 mL, and the reaction time was changed from 0.5 hours to 2 hours to thereby afford the title compound Fmoc-L-Ala-L-Ala-Ot-Bu as white solid. Yield: >99%, dr: 99:1.

*Example E10: Synthesis of Boc-L-Ala-L-Ala-L-Ala-Ot-Bu (tripeptide) via Boc-L-Ala-OPh

[0442] ##STR00122##

[0443] Under argon atmosphere, in a glove box, a heat-dried 5.0-mL screw-cap vial containing a stirrer (samarium-cobalt) was charged with Boc-L-Ala-OPh as Reactant Compound 1 and L-Ala-L-Ala-Ot-Bu as Reactant Compound 2 at ratios satisfying any of Condition [a] or [b] below. In addition, pivalic acid (51.1 mg, 0.5 mmol) was added as the Brønsted acid, and the mixture was dissolved into dried CHCl.sub.3 (0.5 mL, 1M). The resulting mixture was stirred vigorously under nitrogen atmosphere at room temperatures for 0.5 hours, and the reaction mixture was diluted with CHCl.sub.3 (3.0 mL) and pipetted into a transferred to a silica gel column, and the used vial and pipette were washed with CHCl.sub.3 (12.0 mL). The used vial and pipette were washed with CHCl.sub.3 (12.0 mL). The reaction mixture was then purified by flash column chromatography (using 0 to 100% AcOEt in hexane as mobile phase) to thereby afford the title compound Boc-L-Ala-L-Ala-L-Ala-Ot-Bu as white solid.

*Condition [a]: Reactant Compound 1=0.5 mmol, Reactant Compound 2=0.5 mmol.

[0444] The yield was 26% and dr was 99:1 under this condition.

*Condition [b]: Reactant Compound 1=1.0 mmol, Reactant Compound 2=0.5 mmol.

[0445] The yield was 40% and dr was 98:2 under this condition.