Asymmetric synthesis of peptides

1. A process for the production of a compound of formula (Ic):

comprising reaction of a compound of formula (VII)

with a compound of formula (III)

HY—R 7   (III)

wherein X is O, S, or NR 8 , where R 8 is C 1-16 alkyl, C 6-12 aryl or hydrogen;

Y is O, S or NH;

R 2 is independently selected from a C 1-10 branched or straight chain alkyl group, C 5-12 heteroaryl group or C 6-12 aryl group, optionally substituted with OR 13 , SR 13 , N(R 13 ) 2 , CO 2 R 13 , CON(R 13 ) 2 , SO 2 R 12 , SO 3 R 12 , phenyl, imidazolyl, indolyl, hydroxyphenyl or NR 13 C(═NR 13 )N(R 13 ) 2 ;

wherein each R 1′ is independently hydrogen or as defined from R 1 below;

R 14 is —[CO—C(R 1′ )(R 9 )—N(R 10 )] m —(R 11 );

R 12 is hydrogen, C 1-6 alkyl, C 6-12 aryl or N(R 13 ) 2 , wherein each occurrence of R 13 is independently hydrogen, C 1-6 alkyl or C 6-12 aryl,

each R 9 and R 10 is independently hydrogen or a group as defined for R 1′ ;

or R 9 and R 10 can together form a 4 to 7 membered ring, optionally substituted with OR 13 , SR 13 , N(R 13 ) 2 , CO 2 R 13 , CON(R 13 ) 2 , C 1-10 alkyl or C 6-12 aryl,

wherein said ring can be fully, partially or unsaturated, and wherein the ring may contain one or more heteroatoms selected from O, S or N;

R 11 is hydrogen or an amino protecting group, wherein the amino protecting group is a benzyloxycarbonyl group, a t-butoxycarbonyl group, a 2-(4-biphenylyl)-isopropoxycarbonyl group, a fluorenylmethoxycarbonyl group, a triphenylmethyl group or a 2-nitrophenylsulphenyl group;

R 5 is a C 5-12 aryl, C 5-12 heteroaryl or C 1-8 branched or straight chain alkyl optionally substituted with OR 13 , SR 13 , N(R 13 ) 2 , CO 2 R 13 , CON(R 13 ) 2 , phenyl, imidazolyl, indolyl, hydroxyphenyl or NR 13 C(═NR 13 )N(R 13 ) 2 or a linker for attachment of formula (VII) to a resin, wherein the linker is OR 13 , N(R 13 ) 2 , CO 2 R 13 or SR 13 , or an alkyl group having 1 to 4 carbons or a C 6-12 aryl group, said alkyl and aryl groups being optionally substituted with OR 13 , N(R 13 ) 2 , CO 2 R 13 or SR 13 ;

R 6 is hydrogen or

wherein R 5 and X are as defined above;

R 7 is a group

or is independently selected from a C 1-10 branched or straight chain alkyl group or a C 6-12 aryl group, optionally substituted with OR 13 , SR 13 , N(R 13 ) 2 , CO 2 R 13 , CON(R 13 ) 2 , SO 2 R 12 , SO 3 R 12 , phenyl, imidazolyl, indolyl, hydroxyphenyl or NR 13 C(═NR 13 )N(R 13 ) 2 or wherein R 7 and Y together form a 4 to 7 membered ring, optionally substituted with OR 13 , SR 13 , N(R 13 ) 2 , CO 2 R 13 , CON(R 13 ) 2 , SO 2 R 12 , SO 3 R 12 , phenyl, imidazolyl, indolyl, hydroxyphenyl or NR 13 C(═NR 13 )N(R 13 ) 2 , wherein said ring can be fully, partially or unsaturated, and wherein the ring may contain one or more heteroatoms in addition to Y, selected from O, S or N; wherein R 1 is independently selected from a C 1-10 branched or straight chain alkyl group, C 5-12 heteroaryl group or C 6-12 aryl group optionally substituted with OR 13 , SR 13 , N(R 13 ) 2 , CO 2 R 13 , CON(R 13 ) 2 , SO 2 R 12 , SO 3 R 12 , phenyl, imidazolyl, indolyl, hydroxyphenyl or NR 13 C(═NR 13 )N(R 13 ) 2 ;

R 4 is a carboxyl protecting group or hydrogen, wherein the carboxyl protecting group is methyl, ethyl, benzyl, t-butyl or phenyl;

n is 1, 2 or 3, and m is a value selected from 1-100.

2. The process as claimed in claim 1 wherein R 1 and R 2 are independently selected from C 1 alkyl optionally substituted with OH, SH, CO 2 H, CONH 2 , phenyl, imidazolyl, indolyl or hydroxyphenyl; C 2 alkyl optionally substituted with OH, CO 2 H, CONH 2 or SCH 3 ; C 3 alkyl NHC(═NH)NH 2 or C 4 alkyl optionally substituted with NH 2 .

3. The process as claimed in claim 1 wherein R 5 is a linked resin and the process is carried out on solid phase.

4. The process as claimed in claim 1 wherein the process is carried out in solution.

5. The process as claimed in claim 1 , further comprising replacement of the R 6 group with hydrogen to form a compound of formula (Ic):

wherein X, Y, R 2 , R 7 and R 14 are as defined above in claim 1 , and wherein R 6 is hydrogen.

6. The process as claimed in claim 1 wherein the production of a compound of formula (Ic) occurs without epimerization.

7. The process as claimed in claim 1 , wherein the production of a compound of formula (Ic) comprises

(a) converting an amine of formula (IV)

to form a compound of formula (VII) via peptide bond formation; and

(b) reacting the compound of formula (VII)

with a compound of formula (III).

8. The process of claim 7 , wherein the formation of a compound of formula (VII) occurs by reaction of one or more compounds of formula (V)

Z—CO—R 3   (V)

in a stepwise manner,

wherein R 3 is as defined for R 2 or is hydrogen,

or a group

or a group —C(R 1′ )(R 9 )—N(R 10 )(R 11 );

Z is hydroxide, halide or azide;

R 4′ is as defined for R 4 ;

and wherein Y, R 1′ , R 4 , R 9 , R 10 and R 11 are as defined above in claim 1 .

9. The process as claimed in claim 7 , wherein the production of a compound of formula (Ic) occurs without epimerization.

10. The process as claimed in claim 7 , wherein R 5 is a linked resin and the process is carried out on solid phase.

11. The process as claimed in claim 7 , wherein the process is carried out in solution.