Clean, high-yield preparation of S,S and R,S amino acid isosteres
AssigneeAerojet Fine Chemicals LLC
InventorsAslam A. Malik, Todd E. Clement, Hasan Palandoken, James Robinson, III, Joy A. Stringer
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Abstract
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.
Claims36
A method for preparing an R,S-epoxide compound having the following general formula:
- said method comprising:
- reducing a halomethyl ketone (HMK) compound having the following general formula:
- with a non-chelating, bulky reducing agent to form an R,S-halomethyl alcohol (R,S-HMA) compound having the following general formula:
- and
- contacting said R,S-HMA compound of Formula II with an alkali metal base to form said R,S-epoxide compound;
- wherein:
- R1 is an amino acid side chain;
- R2 is a blocking group;
- and
- X1 is a leaving group.
The method in accordance with 1, wherein said non-chelating, bulky reducing agent is a member selected from the group consisting of lithium aluminum t-butoxyhydride (LATBH) and sodium tris-t-butoxyborohydride (STBH).
A method for preparing an R,S-epoxide compound having the following general formula:
- said method comprising:
- (a) reducing a halomethyl ketone (HMK) compound having the following general formula:
- with a reducing agent to form an S,S-halomethyl alcohol (S,S-HMA) compound having the following general formula:
- (b) contacting said S,S-HMA compound of Formula II with a member selected from the group consisting of arylsulfonyl halides and alkylsulfonyl halides in the presence of an amine to form an S,S-halomethyl sulfonyl (S,S-HMS) compound having the following general formula:
- (c) contacting said S,S-HMS compound of Formula III with an acetate in the presence of a phase transfer catalyst and water to form an R,S-halomethyl acetate (R,S-HMAc) compound having the following general formula:
- and (d) contacting said R,S-HMAc compound of Formula IV with an alkali metal base to form said R,S-epoxide;
- wherein:
- R1 is an amino acid side chain;
- R2 is a blocking group;
- R3 is a member selected from the group consisting of arylsulfonyls and alkylsulfonyls;
- R4 is an acyl group;
- and
- X1 is a leaving group.
Dependencies are inferred from the claim text.