Clean, high-yield preparation of S,S and R,S amino acid isosteres
View Patent ↗The present invention provides compounds and methods that can be used to convert the intermediate halomethyl ketones (HMKs), e.g., chloromethyl ketones, to the corresponding S,S- and R,S-diastereomers. More particularly, the present invention provides: (1) reduction methods; (2) inversion methods; and (3) methods involving the epoxidation of alkenes. Using the various methods of the present invention, the R,S-epoxide and the intermediary compounds can be prepared reliably, in high yields and in high purity.
1. A method for preparing an R,S-epoxide compound having the following general formula:
said method comprising:
(a) contacting an S,S-halomethyl sulfonyl (S,S-HMS) compound having the following general formula:
with a carbamate-forming acetate containing a sufficient leaving group to form a cyclic carbamate having the following general formula:
and
(b) contacting said cyclic carbamate with an alkali metal base to form said R,S-epoxide;
wherein:
R 1 is an amino acid side chain;
R 2 is a blocking group;
R 3 is a member selected from the group consisting of arylsulfonyls and alkylsulfonyls; and
X 1 is a leaving group.
2. The method in accordance with claim 1 , wherein R 3 is a member selected from the group consisting of methylsulfonyl and toluenesulfonyl.
3. The method in accordance with claim 1 , wherein said carbamate-forming acetate is a member selected from the group consisting of sodium trichloroacetate, potassium trichloroacetate, tetrabutylammonium trichloroacetate, sodium tribromoacetate, potassium tribromoacetate sodium trifluoroacetate and potassium trifluoroacetate.
4. The method in accordance with claim 1 , wherein said carbamate-forming acetate is sodium trichloroacetate.
5. The method in accordance with claim 1 , wherein step (a) is carried out in toluene.
6. The method in accordance with claim 1 , wherein said alkali metal base is a member selected from the group consisting of NaOH, KOH, LiOH, NaOCH 3 , NaOCH 2 CH 3 and KOtBu.
7. The method in accordance with claim 1 , wherein said sufficient leaving group is selected from the group consisting of trichlormethyl, tribromomethyl and trifluoromethyl.
8. The method in accordance with claim 1 , wherein R 1 is a member selected from the group consisting of a side chain from any of the naturally occurring amino acids and amino acids mimetics; R 2 is a blocking group selected from the group consisting of BOC, MOC and CBZ; and X 1 is a leaving group selected from the group consisting of Cl, Br and F.
9. The method in accordance with claim 8 , wherein R 1 is a side chain from any of the naturally occurring amino acids.
10. The method in accordance with claim 1 , wherein R 1 is a member selected from the group consisting of a benzyl, a substituted benzyl, an S-phenyl, an alkyl and a para-nitrobenzene.
11. The method in accordance with claim 10 , wherein R 1 is benzyl.
12. The method in accordance with claim 8 , wherein R 2 is BOC.
13. The method in accordance with claim 1 , wherein X 1 is a chloro or bromo group.
14. The method in accordance with claim 1 , wherein R 1 is benzyl; R 2 is BOC; R 3 is methylsulfonyl; and X 1 is a bromo or chloro group.