SILANE-CONTAINING CONDENSED CYCLIC DIPEPTIDE COMPOUND, PRODUCTION METHOD THEREFOR, AND METHOD FOR PRODUCING POLYPEPTIDE COMPOUND USING SAME

Abstract

The present invention provides, as a novel compound that can be utilized for efficient synthesis or the like of a polypeptide comprising various amino acids, a silane-containing condensed cyclic dipeptide compound represented by formula (A).

##STR00001##

In formula (A), each of R.sup.11, R.sup.12, R.sup.13, R.sup.21, and R.sup.22 independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, or a thiol group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group that may have one or more substituents; and each of R.sup.a1 and R.sup.a2 independently represents a monovalent aliphatic hydrocarbon group or aromatic hydrocarbon group that may have one or more substituents

Claims

1. A silane-containing fused ring dipeptide compound represented by formula (A) ##STR00075## wherein, in formula (A), R.sup.11, R.sup.12, R.sup.13, R.sup.21, and R.sup.22 represent, independently of each other, a hydrogen atom, halogen atom, hydroxyl group, carboxyl group, nitro group, cyano group, or thiol group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group that may have one or more substituents, and R.sup.a1 and R.sup.a2 represent, independently of each other, a monovalent aliphatic hydrocarbon group or aromatic hydrocarbon group that may have one or more substituents.

2. A method for producing a silane-containing fused ring dipeptide compound according to claim 1, comprising: (i) causing a reaction between a first silane compound represented by formula (S1) and a second silane compound represented by formula (S2) in the presence of an amino acid represented by formula (R1); and (ii) adding an amino acid ester represented by formula (R2) to the reactant from step (i) to cause a further reaction, thereby preparing the a silane-containing fused ring dipeptide compound represented by formula (A); ##STR00076## wherein, in formula (S1), R.sup.a1 and R.sup.a2 each represents the same definition as in formula (A), and X.sup.1 and X.sup.2 represent, independently of each other, a halogen atom; ##STR00077## wherein, in formula (S2), R.sup.b1, R.sup.b2, and R.sup.b3 represent, independently of each other, a hydrogen atom or halogen atom, or a monovalent aliphatic hydrocarbon group or aromatic hydrocarbon group that may have one or more substituents, and Z represents a 5- to 10-membered heterocyclic group that contain at least one nitrogen atom as a ring-constituting atom and that may have one or more substituents; ##STR00078## wherein, in formula (R1), R.sup.11, R.sup.12, and R.sup.13 represent, independently of each other, the same definition as in formula (A); ##STR00079## wherein, in formula (R2), R.sup.21 and R.sup.22, independently of each other, each represent the same definition as in formula (A), and PG.sup.b represents a protecting group for a carboxyl group.

3. The method according to claim 2, wherein the reaction system in step (i) also contains a base and/or wherein the reaction system in step (ii) also contains a Lewis acid catalyst.

4. A method for producing a polypeptide compound using a silane-containing fused ring dipeptide compound according to claim 1, comprising: causing a reaction between a silane-containing fused ring dipeptide compound represented by formula (A), a protected amino acid or protected peptide compound represented by formula (R3), and an amino acid ester or peptide ester compound represented by formula (R4) to thereby produce a polypeptide compound represented by formula (P1); ##STR00080## wherein, in formula (R3), PG.sup.a represents a protecting group for an amino group, R.sup.31 and R.sup.32 represent, independently of each other, a hydrogen atom, halogen atom, hydroxyl group, carboxyl group, nitro group, cyano group, or thiol group, or an amino group, monovalent aliphatic hydrocarbon group, monovalent aromatic hydrocarbon group, or monovalent heterocyclic group that may have one or more substituents, R.sup.33 represents a hydrogen atom, carboxyl group, hydroxyl group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group that may have one or more substituents and that 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.31 and A.sup.32 represent, independently of each other, a divalent aliphatic hydrocarbon group containing 1 to 3 carbon atoms that may have one or more substituents, p31 and p32 represent, independently of each other, 0 or 1, 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; ##STR00081## wherein, in formula (R4), PG.sup.b represents a protecting group for a carboxyl group, R.sup.41 and R.sup.42 represent, independently of each other, a hydrogen atom, halogen atom, hydroxyl group, carboxyl group, nitro group, cyano group, or thiol group, or an amino group, monovalent aliphatic hydrocarbon group, monovalent aromatic hydrocarbon group, or monovalent heterocyclic group that may have one or more substituents, R.sup.43 represents a hydrogen atom, carboxyl group, hydroxyl group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group that may have one or more substituents and that may be bound to the nitrogen atom via a linking group, or R.sup.41 and R.sup.43 may be bound to each other to form, together with the carbon atom to which R.sup.41 binds and the nitrogen atom to which R.sup.43 binds, a hetero ring that may have one or more substituents, A.sup.41 and A.sup.42 represent, independently of each other, a divalent aliphatic hydrocarbon group containing 1 to 3 carbon atoms that may have one or more substituents, p41 and p42 represent, independently of each other, 0 or 1, 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; ##STR00082## wherein, in formula (P1), R.sup.11, R.sup.12, R.sup.13, R.sup.21, and R.sup.22 each represent the same definition as in formula (A), PG.sup.a, R.sup.31, R.sup.32, R.sup.33, A.sup.31, A.sup.32, p31, p32, and m each represent the same definition as in formula (R3), and PG.sup.b, R.sup.41, R.sup.42, R.sup.43, A.sup.41, A.sup.42, p41, p42, and n each represent the same definition as in formula (R4).

5. The method according to claim 4, comprising the steps of: (i) causing a reaction between the silane-containing fused ring dipeptide compound represented by formula (A) and the protected amino acid or protected peptide compound represented by formula (R3); and (ii) causing a further reaction between the reactant from step (i) and the amino acid ester or peptide ester compound represented by formula (R4) to thereby prepare the polypeptide compound of formula (P1).

6. The method according to claim 4, comprising the steps of: (i) causing a reaction between the silane-containing fused ring dipeptide compound represented by formula (A) and the amino acid ester or peptide ester compound represented by formula (R4); and (ii) causing a further reaction between the reactant from step (i) and the protected amino acid or protected peptide represented by formula (R3) to thereby prepare the polypeptide compound of formula (P1).

7. The method according to claim 5, wherein the reaction system in step (i) and/or (ii) contains a base and/or a condensing agent.

8. The method according to claim 4, further comprising the step of deprotecting the amino-protecting group PG.sup.a and/or the carboxyl-protecting group PG.sup.b in the polypeptide compound of formula (P1).

9. A method of producing a polypeptide compound using a silane-containing fused ring dipeptide compound according to claim 1, comprising: causing reactions among a silane-containing fused ring dipeptide compound represented by formula (A1), a silane-containing fused ring dipeptide compound represented by formula (A2), a protected amino acid or protected peptide compound represented by formula (R3), and an amino acid ester or peptide ester compound represented by formula (R4) to thereby prepare a polypeptide compound represented by formula (P2); ##STR00083## wherein, in formula (A1), R.sup.111, R.sup.112, R.sup.113, R.sup.121, and R.sup.122 represent, independently of each other, a hydrogen atom, halogen atom, hydroxyl group, carboxyl group, nitro group, cyano group, or thiol group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group that may have one or more substituents, and R.sup.a11 and R.sup.a12 represent, independently of each other, a linear or cyclic aliphatic hydrocarbon group that may have one or more substituents; ##STR00084## wherein, in formula (A2), R.sup.211, R.sup.212, R.sup.213, R.sup.221, and R.sup.222 represent, independently of each other, a hydrogen atom, halogen atom, hydroxyl group, carboxyl group, nitro group, cyano group, or thiol group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group that may have one or more substituents, and R.sup.a21 and R.sup.a22 represent, independently of each other, a linear or cyclic aliphatic hydrocarbon group that may have one or more substituents; ##STR00085## wherein, in formula (R3), PG.sup.a represents a protecting group for an amino group, R.sup.31 and R.sup.32 represent, independently of each other, a hydrogen atom, halogen atom, hydroxyl group, carboxyl group, nitro group, cyano group, or thiol group, or an amino group, monovalent aliphatic hydrocarbon group, monovalent aromatic hydrocarbon group, or monovalent heterocyclic group that may have one or more substituents, or R.sup.31 and R.sup.32 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.32 binds, a hetero ring that may have one or more substituents, R.sup.33 represents a hydrogen atom, carboxyl group, hydroxyl group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group that may have one or more substituents and that may be bound to the nitrogen atom via a linking group, A.sup.31 and A.sup.32 represent, independently of each other, a divalent aliphatic hydrocarbon group containing 1 to 3 carbon atoms that may have one or more substituents, p31 and p32 represent, independently of each other, 0 or 1, and m represents an integer of equal to or greater than 1 and corresponds 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; ##STR00086## wherein, in formula (R4), PG.sup.b represents a protecting group for a carboxyl group, R.sup.41 and R.sup.42 represent, independently of each other, a hydrogen atom, halogen atom, hydroxyl group, carboxyl group, nitro group, cyano group, or thiol group, or an amino group, monovalent aliphatic hydrocarbon group, monovalent aromatic hydrocarbon group, or monovalent heterocyclic group that may have one or more substituents, or R.sup.41 and R.sup.42 may be bound to each other to form, together with the carbon atom to which R.sup.41 binds and the nitrogen atom to which R.sup.42 binds, a hetero ring that may have one or more substituents, R.sup.43 represents a hydrogen atom, carboxyl group, hydroxyl group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group that may have one or more substituents and that may be bound to the nitrogen atom via a linking group, A.sup.41 and A.sup.42 represent, independently of each other, a divalent aliphatic hydrocarbon group containing 1 to 3 carbon atoms that may have one or more substituents, p41 and p42 represent, independently of each other, 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; ##STR00087## wherein, in formula (P2), R.sup.111, R.sup.112, R.sup.113, R.sup.121, and R.sup.122 each represents the same definition as in formula (A1), R.sup.211, R.sup.212, R.sup.213, R.sup.221, and R.sup.222 each the formula (A2) represents the same definition as in the formula (A1), PG.sup.a, R.sup.31, R.sup.32, R.sup.33, A.sup.31, A.sup.32, p31, p32, and m each represent the same definition as in formula (R3), and PG.sup.b, R.sup.41, R.sup.42, R.sup.43, A.sup.41, A.sup.42, p41, p42, and n each represent the same definition as in formula (R4).

10. The method according to claim 9, comprising the steps of: (i) causing a reaction between the silane-containing fused ring dipeptide compound represented by formula (A1) compound and the protected amino acid or protected peptide compound represented by formula (R3); (ii) causing a further reaction between the reactant from step (i) and the silane-containing fused ring dipeptide compound represented by formula (A2); and (iii) causing a further reaction between the reactant from step (ii) and the amino acid ester or peptide ester compound represented by formula (R4) to thereby prepare the polypeptide compound of formula (P1).

11. The method according to claim 9, comprising the steps of: (i) causing a reaction between the silane-containing fused ring dipeptide compound represented by formula (A2) and the amino acid ester or peptide ester compound represented by formula (R4); (ii) causing a further reaction between the reactant from step (i) and the silane-containing fused ring dipeptide compound represented by formula (A1); and (iii) causing a further reaction between the reactant from step (ii) and the protected amino acid or protected peptide compound represented by formula (R3) to thereby prepare the polypeptide compound of formula (P1).

12. The method according to claim 10, wherein the reaction system in step (i) and/or (ii) and/or (iii) contains a base and/or a condensing agent.

13. The method according to claim 9, further comprising the step of deprotecting the amino-protecting group PG.sup.a and/or the carboxyl-protecting group PG.sup.b in the polypeptide compound of formula (P2).

14. The method according to claim 6, wherein the reaction system in step (i) and/or (ii) contains a base and/or a condensing agent.

15. The method according to claim 11, wherein the reaction system in step (i) and/or (ii) and/or (iii) contains a base and/or a condensing agent.

Description

EXAMPLES

[0457] 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. Amino acids described below that have optical isomers shall refer to the L-form, unless otherwise specified.

Example Group I: Preparation of Fused Ring Dipeptide Compounds

[0458] General Synthesis Procedure I(1):

##STR00027##

[0459] A test tube with a volume of 16 mL is charged with a stirrer bar, a non-protected amino acid (2 equivalents), silyl dichloride (2 equivalents), trimethylsilylimidazole (TMS-IM, 146.7 ?L, 4 equivalents), and triethylamine (70 ?L, 2 equivalents), as well as dichloromethane (DCM), and the mixture is agitated at room temperature for one hour. The test tube is then placed in a glove box, and tantalum ethoxide (6.5 ?L, 10 mol %) and amino acid tert-butyl ester (0.25 mmol) are added to the mixture, which is agitated at room temperature or at 50? C. for 24 hours. After reaction, the mixture is diluted with chloroform (4.50 mL), and the product is isolated by silica gel column chromatography to obtain the target compound.

[0460] General Synthesis Procedure I(2):

##STR00028##

[0461] A test tube with a volume of 16 mL is charged with a stirrer bar, a non-protected amino acid (2 equivalents), silyl dichloride (2 equivalents), trimethylsilyl imidazole (TMS-IM, 146.7 ?L, 4 equivalents), and triethyl amine (70 ?L, 2 equivalents), as well as dichloromethane (DCM), and the mixture is agitated at room temperature for one hour. The test tube is then placed in a glove box, and an amino acid cumyl ester (0.25 mmol) is added to the mixture, which is agitated at room temperature for 24 hours (without using a Lewis acid catalyst such as tantalum ethoxide). After reaction, the mixture is diluted with chloroform (4.50 mL), and the product is isolated by silica gel column chromatography to obtain the target compound.

[0462] The amino acid cumyl esters used in the reaction can be synthesized by the following procedure, referring to, e.g., Roesner et al, Chem. Sci., 2019, 10:2465-2472. A test tube is charged with 2-phenyl-2-propanol (2.2 equivalents) and sodium hydroxide (0.5 equivalents), as well as diethyl ether, and the mixture is agitated at 0? C. to at room temperature for one hour to cause a reaction. Trichloroacetonitrile (2 equivalents) is then added to the test tube, and the mixture is agitated at 0? C. to at room temperature for 3 hours to cause a further reaction. After filtering out the solids with diethyl ether on filter paper, the solvent is removed under reduced pressure. Then, the mixture is combined with 1 equivalent of a Fmoc-protected amino acid, which is derived from the amino acid corresponding to the desired amino acid cumyl ester by protecting the amino group with a Fmoc group, and reacted in dichloromethane at room temperature overnight with stirring to obtain a Fmoc-protected amino acid cumyl ester. Finally, diethylamine (2 equivalents) is added to the mixture to cause a reaction in dichloromethane at room temperature for 1 hour to deprotect the Fmoc group to obtain the desired amino acid cumyl ester.

Example I(1): Synthesis of Using Fused Ring Dipeptide Compound Si(Me).SUB.2.-Phe-Ala-

[0463] ##STR00029##

[0464] According to General Synthesis Procedure I (1), L-phenylalanine (82.6 mg, 0.500 mmol), dimethyl dichlorosilane (59.8 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (4/1), whereby the title compound was obtained as white solid with a yield of 86% (62.8 mg). The diastereomer ratio was >17:1.

Example I(2): Synthesis of Using Fused Ring Dipeptide Compound Si(Me,pH)-Phe-Ala-

[0465] ##STR00030##

[0466] According to General Synthesis Procedure I (1), L-phenylalanine (82.6 mg, 0.500 mmol), dichloromethylphenyl silane (80.5 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (4/1), whereby the title compound was obtained as white solid with a yield of 48% (42.5 mg). The diastereomer ratio was >20:1.

Example I(3): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Phe-Ala-

[0467] ##STR00031##

[0468] According to General Synthesis Procedure I (1), L-phenylalanine (82.6 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (4/1), whereby the title compound was obtained as white solid with a yield of 91% (77.4 mg). The diastereomer ratio was >20:1.

Example I(4): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Val-Ala-

[0469] ##STR00032##

[0470] According to General Synthesis Procedure I (1), L-valine (58.6 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol) and L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at 50? C. for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (3/2), whereby the title compound was obtained as white solid with a yield of 83% (76.4 mg). The diastereomer ratio was >20:1.

Example I(5): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ile-Ala-

[0471] ##STR00033##

[0472] According to General Synthesis Procedure I (1), L-isoleucine (65.6 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at 50? C. for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (1/1), whereby the title compound was obtained as white solid with a yield of 76% (72.6 mg). The diastereomer ratio was >20:1.

Example I(6): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Leu-Ala-

[0473] ##STR00034##

[0474] According to General Synthesis Procedure I (1), L-leucine (65.6 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at 50? C. for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (1/1), whereby the title compound was obtained as white solid with a yield of 85% (81.2 mg). The diastereomer ratio was >20:1.

Example I(7): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ser(t-Bu)-Ala-

[0475] ##STR00035##

[0476] According to General Synthesis Procedure I (1), O-tert-butyl-L-serine (80.6 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (3/2), whereby the title compound was obtained as white solid with a yield of 92% (94.8 mg). The diastereomer ratio was >20:1.

Example I(8): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Thr(t-Bu)-Ala-

[0477] ##STR00036##

[0478] According to General Synthesis Procedure I (1), O-tert-butyl-L-threonine (87.6 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (3/2), whereby the title compound was obtained as white solid with a yield of 91% (97.0 mg). The diastereomer ratio was >20:1.

Example I(9): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Met-Ala-

[0479] ##STR00037##

[0480] According to General Synthesis Procedure I (1), L-methionine (74.6 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at 50? C. for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (3/2), whereby the title compound was obtained as white solid with a yield of 92% (92.0 mg). The diastereomer ratio was >20:1.

Example I(10): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Lys(Boc)-Ala-

[0481] ##STR00038##

[0482] According to General Synthesis Procedure I (1), NE-Boc-L-lysine (123 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (3/2), whereby the title compound was obtained as white solid with a yield of 88% (109 mg). The diastereomer ratio was >20:1.

Example I(11): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Tyr(t-Bu)-Ala-

[0483] ##STR00039##

[0484] According to General Synthesis Procedure I (1), O-tert-butyl-L-tyrosine (119 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (1/1), whereby the title compound was obtained as white solid with a yield of 90% (110 mg). The diastereomer ratio was >20:1.

Example I(12): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Trp(Boc)-Ala-

[0485] ##STR00040##

[0486] According to General Synthesis Procedure I (1), N.sup.1Boc-L-tryptophan (152 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (1/1), whereby the title compound was obtained as white solid with a yield of 81% (112 mg). The diastereomer ratio was >20:1.

Example I(13): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Asp(t-Bu)-Ala-

[0487] ##STR00041##

[0488] According to General Synthesis Procedure I (1), L-aspartic acid 4-tert-butyl (94.6 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (1/1), whereby the title compound was obtained as white solid with a yield of 95% (105 mg). The diastereomer ratio was >20:1.

Example I(14): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Glu(t-Bu)-Ala-

[0489] ##STR00042##

[0490] According to General Synthesis Procedure I (1), L-glutamic acid 5-tert-butyl (102 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (1/1), whereby the title compound was obtained as white solid with a yield of 93% (105 mg). The diastereomer ratio was >20:1.

Example I(15): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Aib-Gly-

[0491] ##STR00043##

[0492] According to General Synthesis Procedure I (1), 2-amino isobutyric acid (51.6 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), glycine tert-butyl ester (32.8 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (1/1), whereby the title compound was obtained as colorless solid with a yield of 84% (71.4 mg).

Example I(16): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Val-

[0493] ##STR00044##

[0494] According to General Synthesis Procedure I (1), L-alanine (44.5 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-valine tert-butyl ester (43.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (1/1), whereby the title compound was obtained as white solid with a yield of 81% (74.6 mg). The diastereomer ratio was >20:1.

Example I(17): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ser(t-Bu)-

[0495] ##STR00045##

[0496] According to General Synthesis Procedure I (1), L-alanine (44.5 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), O-tert-butyl-L-serine tert-butyl ester (54.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (3/2), whereby the title compound was obtained as white solid with a yield of 91% (93.8 mg). The diastereomer ratio was >20:1.

Example I(18): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Thr(t-Bu)-

[0497] ##STR00046##

[0498] According to General Synthesis Procedure I (1), L-alanine (44.5 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), O-tert-butyl-L-threonine tert-butyl ester (57.8 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (2/1), whereby the title compound was obtained as white solid with a yield of 90% (95.9 mg). The diastereomer ratio was >20:1.

Example I(19): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Met-

[0499] ##STR00047##

[0500] According to General Synthesis Procedure I (1), L-alanine (44.5 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-methionine tert-butyl ester (51.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (3/2), whereby the title compound was obtained as white solid with a yield of 93% (93.0 mg). The diastereomer ratio was >20:1.

Example I(20): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Lys(Boc)-

[0501] ##STR00048##

[0502] According to General Synthesis Procedure I (1), L-alanine (44.5 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), NE-Boc-L-lysine tert-butyl ester (75.6 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (2/1), whereby the title compound was obtained as white solid with a yield of 87% (108 mg). The diastereomer ratio was >20:1.

Example I(21): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Glu(t-Bu)-

[0503] ##STR00049##

[0504] According to General Synthesis Procedure I (1), L-alanine (44.5 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-glutamic acid di tert-butyl ester (64.8 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (3/2), whereby the title compound was obtained as white solid with a yield of 93% (106 mg). The diastereomer ratio was >20:1.

Example I(22): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-MeAla-Ala-

[0505] ##STR00050##

[0506] According to General Synthesis Procedure I (1), N-methyl-L-alanine (51.6 mg, 0.500 mmol), dimethyl dichlorosilane (59.8 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), L-alanine tert-butyl ester (36.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate, whereby the title compound was obtained as white solid with a yield of 84% (48.3 mg). The diastereomer ratio was >20:1.

Example I(23): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Phe-(1)

[0507] ##STR00051##

[0508] According to General Synthesis Procedure I (1), L-alanine (44.5 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), phenylalanine tert-butyl ester (55.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate, whereby the title compound was obtained as white solid with a yield of 91% (94.6 mg). The diastereomer ratio was approximately 4:1.

Example I(24): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Phe-(2)

[0509] ##STR00052##

[0510] In accordance with General Synthesis Procedure I(2), L-alanine (44.5 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and phenylalanine cumyl ester (70.8 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate, whereby the title compound was obtained as white solid with a yield of 93% (96.8 mg). The diastereomer ratio was >20:1.

Example I(25): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Tyr(t-Bu)-

[0511] ##STR00053##

[0512] In accordance with General Synthesis Procedure I(2), L-alanine (44.5 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and (tert-butyl)tyrosine cumyl ester (88.8 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate, whereby the title compound was obtained as white solid with a yield of 95% (116 mg). The diastereomer ratio was >20:1.

Example I(26): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Phg-

[0513] ##STR00054##

[0514] In accordance with General Synthesis Procedure I(2), L-alanine (44.5 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and phenylglycine cumyl ester (67.3 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate, whereby the title compound was obtained as white solid with a yield of 97% (97.5 mg). The diastereomer ratio was >20:1.

Example I(27): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Cys(Trt)-(1)

[0515] ##STR00055##

[0516] According to General Synthesis Procedure I (1), L-alanine (44.5 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and tantalum ethoxide (6.5 ?L, 0.0250 mmol), S-trityl cysteine tert-butyl ester (105 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate, whereby the title compound was obtained as white solid with a yield of 85% (131 mg). The diastereomer ratio was approximately 4:1.

Example I(28): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Cys(Trt)-(2)

[0517] ##STR00056##

[0518] In accordance with General Synthesis Procedure I(2), L-alanine (44.5 mg, 0.500 mmol), dichlorodiphenyl silane (104 ?L, 0.500 mmol), TMS-IM (147 ?L, 1.00 mmol) and triethyl amine (70.0 ?L, 0.500 mmol) were agitated in DCM for one hour. The test tube was then transferred into the glove box, and S-trityl cysteine cumyl ester (120 mg, 0.250 mmol) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate, whereby the title compound was obtained as white solid with a yield of 91% (140 mg). The diastereomer ratio was >20:1.

Referential Example Group: Reactions of Fused Ring Dipeptide Compounds and Aryl Compounds

Referential Example (1): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala- and Reaction with Benzyl Bromide

[0519] ##STR00057##

[0520] A test tube with a volume of 20 mL was charged with a stirrer bar, a fused ring dipeptide compound (0.25 mmol), TBAF (1 mol/Lin THF) (750 ?L, 3.0 equivalents) and benzyl bromide (89 ?L, 3.0 equivalents), and THF, and the mixture was agitated at room temperature for 24 hours. After the reaction, the mixture was diluted with chloroform (4.50 mL), and the product was isolated by silica gel column chromatography, whereby the target compound was obtained.

Referential Example (2): Synthesis of Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala- and Reaction with Benzyl Amine

[0521] ##STR00058##

[0522] A test tube with a volume of 20 mL was charged with a stirrer bar, a fused ring dipeptide compound (0.25 mmol), methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxyde (MABR: in THF 1 mol/L) (25 ?L, 10 mol %), TMS-OTf (67.7 ?L, 1.5 equivalents) and benzyl amine (55 ?L, 2.0 equivalents), as well as acetonitrile, and the mixture was agitated at 90? C. After 24 hours, TBAF (1 mol/L in THF) (250 ?L, 1.0 equivalents) was added to the mixture, which was agitated for 3 hours at room temperature. After the reaction, the mixture was diluted with chloroform (4.50 mL), and the product was isolated by silica gel column chromatography, whereby the target compound was obtained.

Example Group II: Synthesis of Tetra/Penta/Hexapeptides Using Fused Ring Dipeptide Compounds

[0523] General Synthesis Procedure II(1):

##STR00059##

[0524] A test tube with a volume of 20 mL is charged with a stirrer bar, a fused ring dipeptide compound (0.25 mmol), TBAF (1 mol/L in THF) (375 ?L, 1.5 equivalents), wscHCl (95.9 mg.2 equivalents), HOBt (67.6 mg, 2 equivalents), and N-protected amino acid (1.1 equivalents) as well as DCM, and the mixture is agitated at room temperature overnight. Thereafter, amino acid tert-butyl ester (3 equivalents), wscHCl (95.9 mg.2 equivalents), HOBt (67.6 mg, 2 equivalents), triethyl amine (53 ?L, 1.5 equivalents) and DCM (1.00 mL) are added to the test tube, and the mixture is agitated at room temperature for 24 hours. After the reaction, the mixture is diluted with chloroform (4.50 mL), and the product is isolated by silica gel column chromatography, whereby the target compound is obtained.

[0525] General Synthesis Procedure II(2):

##STR00060##

[0526] A test tube with a volume of 20 mL was charged with a stirrer bar, a fused ring dipeptide compound (0.25 mmol), trimethylsilyl trifluoromethanesulfonate (TMS-OTf) (1 mol/L in THF) (67.8 ?L, 1.5 equivalents), methyl aluminum bis(4-bromo-2,6-di-tert-butylphenoxyde (MABR)hexane solution (12.5 ?L, 10 mol %), and an amino acid tert-butyl ester (2 equivalents), as well as acetonitrile (MeCN), and the mixture is heated at 80? C. and agitated for 24 hours. Thereafter, the mixture in the test tube is combined with an amino acid whose amino group has been protected with a Fmoc group and whose carboxyl group has been converted into a carbonyl chloride group (2 equivalents) and TBAF (1 mol/L in THF) (500 ?L, 2 equivalents), and agitated at room temperature overnight. After the reaction, the mixture is diluted with chloroform (4.50 mL), and the product is isolated by silica gel column chromatography, whereby the target compound is obtained.

Example II(1): Synthesis of Tetrapeptide Cbz-Ala-Ala-Ala-Ala-Ot-Bu Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala-

[0527] ##STR00061##

[0528] According to General Synthesis Procedure II(1), fused ring dipeptide compound Si(Ph).sub.2-L-Ala-L-Ala-(85.0 mg, 0.250 mmol), Cbz-alanine (61.4 mg, 0.275 mmol), TBAF (1 mol/L in THF) (375 ?L, 0.375 mmol), wscHCl (95.9 mg.0.500 mmol), and HOBt (67.6 mg, 0.500 mmol) in THF were agitated under nitrogen atmosphere overnight at room temperature. Thereafter, alanine tert-butyl ester (109 mg, 0.750 mmol), wscHCl (95.9 mg.0.500 mmol), HOBt (67.6 mg, 0.500 mmol), triethyl amine (52.4 ?L, 0.375 mmol), and DCM (1 mL) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate, whereby the title compound was obtained as white solid with a yield of 82% (101 mg).

Example II(2): Synthesis of Tetrapeptide Fmoc-Ala-Ala-Ala-Ala-Ot-Bu Using Fused Ring Dipeptide Si(pH).SUB.2.-Ala-Ala-

[0529] ##STR00062##

[0530] According to General Synthesis Procedure II(1), fused ring dipeptide compound Si(Ph).sub.2-L-Ala-L-Ala-(85.0 mg, 0.250 mmol), Fmoc-alanine (85.6 mg, 0.275 mmol), TBAF (1 mol/L in THF) (375 ?L, 0.375 mmol), wscHCl (95.9 mg.0.500 mmol), and HOBt (67.6 mg, 0.500 mmol) in THF were agitated under nitrogen atmosphere overnight at room temperature. Thereafter, alanine tert-butyl ester (109 mg, 0.750 mmol), wscHCl (95.9 mg.0.500 mmol), HOBt (67.6 mg, 0.500 mmol), triethyl amine (52.4 ?L, 0.375 mmol), and DCM (1 mL) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate, whereby the title compound was obtained as white solid with a yield of 81% (118 mg).

Example II(3): Synthesis of Tetrapeptide Cbz-Ser(t-Bu)-Ala-Ala-Ala-Ot-Bu Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala-

[0531] ##STR00063##

[0532] According to General Synthesis Procedure II(1), fused ring dipeptide compound Si(Ph).sub.2-L-Ala-L-Ala-(85.0 mg, 0.250 mmol), Cbz-O-tert-butyl serine (81.2 mg, 0.275 mmol), TBAF (1 mol/L in THF) (375 ?L, 0.375 mmol), wscHCl (95.9 mg.0.500 mmol), and HOBt (67.6 mg, 0.500 mmol) in THF were agitated under nitrogen atmosphere overnight at room temperature. Thereafter, alanine tert-butyl ester (109 mg, 0.750 mmol), wscHCl (95.9 mg.0.500 mmol), HOBt (67.6 mg, 0.500 mmol), triethyl amine (52.4 ?L, 0.375 mmol), and DCM (1 mL) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (9/1), whereby the title compound was obtained as colorless solid with a yield of 77% (109 mg).

Example II(4): Synthesis of Tetrapeptide Cbz-Met-Ala-Ala-Ala-Ot-Bu Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala-

[0533] ##STR00064##

[0534] According to General Synthesis Procedure II(1), fused ring dipeptide compound Si(Ph).sub.2-L-Ala-L-Ala-(85.0 mg, 0.250 mmol), Cbz-methionine (77.9 mg, 0.275 mmol), TBAF (1 mol/L in THF) (375 ?L, 0.375 mmol), wscHCl (95.9 mg.0.500 mmol), and HOBt (67.6 mg, 0.500 mmol) in THF were agitated under nitrogen atmosphere overnight at room temperature. Thereafter, alanine tert-butyl ester (109 mg, 0.750 mmol), wscHCl (95.9 mg.0.500 mmol), HOBt (67.6 mg, 0.500 mmol), triethyl amine (52.4 ?L, 0.375 mmol), and DCM (1 mL) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (9/1), whereby the title compound was obtained as colorless solid with a yield of 68% (93.9 mg).

Example II(5): Synthesis of Tetrapeptide Cbz-Lys(Boc)-Ala-Ala-Ala-Ot-Bu Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala-

[0535] ##STR00065##

[0536] According to General Synthesis Procedure II(1), fused ring dipeptide compound Si(Ph).sub.2-L-Ala-L-Ala-(85.0 mg, 0.250 mmol), Na-Cbz-NE-Boc-lysine (105 mg, 0.275 mmol), TBAF (1 mol/L in THF) (375 ?L, 0.375 mmol), wscHCl (95.9 mg.0.500 mmol), and HOBt (67.6 mg, 0.500 mmol) in THF were agitated under nitrogen atmosphere overnight at room temperature. Thereafter, alanine tert-butyl ester (109 mg, 0.750 mmol), wscHCl (95.9 mg.0.500 mmol), HOBt (67.6 mg, 0.500 mmol), triethyl amine (52.4 ?L, 0.375 mmol), and DCM (1 mL) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (9/1), whereby the title compound was obtained as colorless solid with a yield of 81% (131 mg).

Example II(6): Synthesis of Tetrapeptide Cbz-Trp(Boc)-Ala-Ala-Ala-Ot-Bu Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala-

[0537] ##STR00066##

[0538] According to General Synthesis Procedure II(1), fused ring dipeptide compound Si(Ph).sub.2-L-Ala-L-Ala-(85.0 mg, 0.250 mmol), N.sup.a-Cbz-N.sup.in-Boc-tryptophan (171 mg, 0.275 mmol), TBAF (1 mol/L in THF) (375 ?L, 0.375 mmol), wscHCl (95.9 mg.0.500 mmol), and HOBt (67.6 mg, 0.500 mmol) in THF were agitated under nitrogen atmosphere overnight at room temperature. Thereafter, alanine tert-butyl ester (109 mg, 0.750 mmol), wscHCl (95.9 mg.0.500 mmol), HOBt (67.6 mg, 0.500 mmol), triethyl amine (52.4 ?L, 0.375 mmol), and DCM (1 mL) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (3/1), whereby the title compound was obtained as colorless solid with a yield of 68% (120 mg).

Example II(7): Synthesis of Tetrapeptide Cbz-Ala-Ala-Ala-Met-Ot-Bu Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala-

[0539] ##STR00067##

[0540] According to General Synthesis Procedure II(1), fused ring dipeptide compound Si(Ph).sub.2-L-Ala-L-Ala- (85.0 mg, 0.250 mmol), Cbz-alanine (61.4 mg, 0.275 mmol), TBAF (1 mol/L in THF) (375 ?L, 0.375 mmol), wscHCl (95.9 mg.0.500 mmol), and HOBt (67.6 mg, 0.500 mmol) in THF were agitated under nitrogen atmosphere overnight at room temperature. Thereafter, methionine tert-butyl ester (154 mg, 0.750 mmol), wscHCl (95.9 mg.0.500 mmol), HOBt (67.6 mg, 0.500 mmol), triethyl amine (52.4 ?L, 0.375 mmol), and DCM (1 mL) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (17/3), whereby the title compound was obtained as colorless solid with a yield of 61% (84.2 mg).

Example II(8): Synthesis of Tetrapeptide Cbz-Ala-Ala-Ala-Glu(t-Bu)-Ot-Bu Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala-

[0541] ##STR00068##

[0542] According to General Synthesis Procedure II(1), fused ring dipeptide compound Si(Ph).sub.2-L-Ala-L-Ala-(85.0 mg, 0.250 mmol), Cbz-alanine (61.4 mg, 0.275 mmol), TBAF (1 mol/L in THF) (375 ?L, 0.375 mmol), wscHCl (95.9 mg.0.500 mmol), and HOBt (67.6 mg, 0.500 mmol) in THF were agitated under nitrogen atmosphere overnight at room temperature. Thereafter, glutamic acid di tert-butyl ester (194 mg, 0.750 mmol), wscHCl (95.9 mg.0.500 mmol), HOBt (67.6 mg, 0.500 mmol), triethyl amine (52.4 ?L, 0.375 mmol), and DCM (1 mL) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with ethyl acetate/hexane (9/1), whereby the title compound was obtained as colorless solid with a yield of 61% (92.5 mg).

Example II(9): Synthesis of Pentapeptide Cbz-Aib-Gly-Ala-Ala-Ala-Ot-Bu Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala-

[0543] ##STR00069##

[0544] According to General Synthesis Procedure II(1), fused ring dipeptide compound Si(Ph).sub.2-L-Ala-L-Ala-(85.0 mg, 0.250 mmol), Cbz-Aib-Gly-OH (80.8 mg, 0.275 mmol), TBAF (1 mol/L in THF) (375 ?L, 0.375 mmol), wscHCl (95.9 mg.0.500 mmol), and HOBt (67.6 mg, 0.500 mmol) in THF were agitated under nitrogen atmosphere overnight at room temperature. Thereafter, alanine tert-butyl ester (109 mg, 0.750 mmol), wscHCl (95.9 mg.0.500 mmol), HOBt (67.6 mg, 0.500 mmol), triethyl amine (52.4 ?L, 0.375 mmol), and DCM (1 mL) were added to the mixture, which was agitated at room temperature for 24 hours. After the reaction, the product was isolated by column chromatography with methanol/chloroform (1/10), whereby the title compound was obtained as colorless solid with a yield of 55% (77.5 mg).

Example II(10): Synthesis of Tetrapeptide Fmoc-Ala-Ala-Ala-Ala-O-t-Bu Using Fused Ring Dipeptide Compound Si(Me,pH)-Ala-Ala-

[0545] ##STR00070##

[0546] According to General Synthesis Procedure II(2), fused ring dipeptide compound Si(Me,Ph)-L-Ala-L-Ala-(85.0 mg, 0.250 mmol), TMS-OTf) (1 mol/L in THF) (67.8 ?L, 1.5 equivalents), hexane solution of MABR (12.5 ?L, 10 mol %), and L-Ala-O-tBu (72.6 mg, 0.500 mmol) were mixed in acetonitrile (MeCN), and heated at 80? C. and agitated for 24 hours. Thereafter, Fmoc-L-Ala-COCl (165 mg, 0.500 mmol) and TBAF (1 mol/L in THF) (500 ?L, 2 equivalents) were added to the mixture in the test tube, and the mixture was agitated at room temperature overnight. After the reaction, the mixture was diluted with chloroform (4.50 mL), and the product isolated by silica gel column chromatography, whereby the title compound was obtained as colorless solid with a yield of 61% (88.5 mg).

Example II(11): Synthesis of Tetrapeptide Fmoc-Val-Ala-Ala-Ala-O-t-Bu Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala-

[0547] ##STR00071##

[0548] According to General Synthesis Procedure II(2), fused ring dipeptide compound Si(Me,Ph)-L-Ala-L-Ala-(85.0 mg, 0.250 mmol), TMS-OTf) (1 mol/L in THF) (67.8 ?L, 1.5 equivalents), hexane solution of MABR (12.5 ?L, 10 mol %), and L-Ala-O-tBu (72.6 mg, 0.500 mmol) were mixed in acetonitrile (MeCN), and heated at 80? C. and agitated for 24 hours. Thereafter, Fmoc-L-Val-COCl (179 mg, 0.500 mmol) and TBAF (1 mol/L in THF) (500 ?L, 2 equivalents) were added to the test tube, and the mixture was agitated at room temperature overnight. After the reaction, the mixture was diluted with chloroform (4.50 mL), and the product isolated by silica gel column chromatography, whereby the title compound was obtained as colorless solid with a yield of 53% (80.6 mg).

Example II(12): Synthesis of Tetrapeptide Fmoc-Met-Ala-Ala-Ala-O-t-Bu Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala-

[0549] ##STR00072##

[0550] According to General Synthesis Procedure II(2), fused ring dipeptide compound Si(Me,Ph)-L-Ala-L-Ala-(85.0 mg, 0.250 mmol), TMS-OTf) (1 mol/L in THF) (67.8 ?L, 1.5 equivalents), hexane solution of MABR (12.5 ?L, 10 mol %), and L-Ala-O-tBu (72.6 mg, 0.500 mmol) were mixed in acetonitrile (MeCN), and heated at 80? C. and agitated for 24 hours. Thereafter, Fmoc-L-Met-COCl (195 mg, 0.500 mmol) and TBAF (1 mol/L in THF) (500 ?L, 2 equivalents) were added to the test tube, and the mixture was agitated at room temperature overnight. After the reaction, the mixture was diluted with chloroform (4.50 mL), and the product isolated by silica gel column chromatography, whereby the title compound was obtained as colorless solid with a yield of 62% (99.2 mg).

Example II(13): Synthesis of Tetrapeptide Cbz-Lys(Boc)-Ala-Ala-Ala-O-t-Bu Using Fused Ring Dipeptide Compound Si(pH).SUB.2.-Ala-Ala-

[0551] ##STR00073##

[0552] A test tube with a volume of 20 mL was charged with a stirrer bar, fused ring dipeptide compound Si(Me,Ph)-L-Ala-L-Ala- (85.0 mg, 0.250 mmol), TMS-OTf) (1 mol/L in THF) (67.8 ?L, 1.5 equivalents), hexane solution of MABR (12.5 ?L, 10 mol %), and L-Ala-O-tBu (72.6 mg, 0.500 mmol) were mixed in acetonitrile (MeCN), and heated at 80? C. and agitated for 24 hours. Thereafter, Cbz-Lys(Boc)-OH (190 mg, 0.500 mmol), wscHCl (95.9 mg.0.500 mmol), HOBt (67.6 mg, 0.500 mmol), and TBAF (1 mol/L in THF) (500 ?L, 0.500 mmol) were added to the test tube, and the mixture was agitated at room temperature overnight. After the reaction, the mixture was diluted with chloroform (4.50 mL), and the product isolated by silica gel column chromatography, whereby the title compound was obtained as colorless solid with a yield of 59% (95.8 mg).

Example II(14): Synthesis of Hexapeptide Cbz-Ala-Met-Ala-Ser(t-Bu)-Ala-Ala-O-t-Bu Using Fused Ring Dipeptide Compounds Si(pH).SUB.2.-Met-Ala- and Si(pH).SUB.2.-Ser(t-Bu)-Ala-

[0553] ##STR00074##

[0554] A two-pronged eggplant flask with a volume of 30 mL was charged with a stirrer bar, fused ring dipeptide compound Si(Ph).sub.2-L-Met-L-Ala-(100 mg, 0.250 mmol), TBAF (1 mol/L in THF) (375 ?L, 1.5 equivalents), wscHCl (95.9 mg, 2 equivalents), HOBt (67.6 mg, 2 equivalents) and Cbz-ALANINE (61.4 mg, 0.275 mmol), as well as DCM, and agitated at room temperature overnight. To the resulting solution, fused ring dipeptide compound Si(Ph).sub.2-L-Ser(t-Bu)-L-Ala- (113 mg, 1.1 equivalents), TBAF (1 mol/L in THF) (375 ?L, 1.5 equivalents), wscHCl (95.9 mg.2 equivalents), HOBt (67.6 mg, 2 equivalents) and DCM (1.00 mL) were added, and the mixture was agitated under nitrogen atmosphere at room temperature. After 24 hours, alanine tert-butyl ester (145 mg, 4 equivalents), wscHCl (95.9 mg.2 equivalents), HOBt (67.6 mg, 2 equivalents), triethyl amine (53 ?L, 1.5 equivalents) and DCM (1 mL) were added to the flask, and agitated at room temperature for 24 hours. After the reaction, the mixture was diluted with chloroform (4.50 mL), and the product was isolated by silica gel column chromatography with methanol/chloroform (1/10), whereby the target hexapeptide was obtained with a yield of 32% (50.5 mg).