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 intermmediate 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-halomethyl alcohol (R,S-HMA) compound having the following general formula:
said method comprising:
reducing a halomethyl ketone (HMK) compound having the following general formula:
with lithium aluminum t-butoxyhydride (LATBH) to form said R,S-HMA compound;
wherein:
R 1 is an amino acid side chain;
R 2 is a blocking group; and
X 1 is a leaving group, wherein said leaving group is a halo group;
wherein:
the reduction is carried out in diethyl ether.
2. The method in accordance with claim 1 , wherein R 1 is a member selected from the group consisting of a benzyl group, an S-phenyl group, an alkyl group and para-nitrobenzene.
3. The method in accordance with claim 1 , wherein X 1 is chloro or bromo.
4. The method in accordance with claim 1 , wherein R 2 is a blocking group selected from the group consisting of BOC, MOC and CBZ.
5. The method in accordance with claim 1 , wherein the reduction is carried out at a temperature ranging from about −30° C. to about 25° C.
6. The method in accordance with claim 1 , wherein the reduction is carried out at a temperature ranging from about −5° C. to about 5° C.
7. A method for preparing an R,S-halomethyl alcohol (R,S-HMA) compound having the following general formula:
said method comprising:
reducing a halomethyl ketone (HMK) compound having the following general formula:
with a reducing agent selected from the group consisting of sodium cyanoborohydride, cerium chloride/sodium borohydride, potassium tri-sec-butylborohydride (K-Selectride®), potassium trisamylborohydride (KS-Selectride®) and (+)-B-chlorodiisopinocampheylborane ((+)-Dip Chloride™) to form said R,S-HMA compound;
wherein:
an amino acid side chain;
R 2 is a blocking group; and
X 1 is a leaving group, wherein said leaving group is a halo group.
8. A method for isolating an R,S-halomethyl alcohol (R,S-HMA) from a mixture of R,S- and S,S-HMAs, said method comprising:
combining the mixture of R,S- and S,S-HMAs with hexane and heating to a temperature ranging from 50° C. to about 60° C. to produce a hexane extractant, wherein said R,S-HMA has the following general formula:
wherein said S,S-HMA has the following general formula:
cooling said hexane extractant to a temperature ranging from about 0° C. to about 10° C., filtering said hexane extractant to form a first retentate and recovering said first retentate;
combining said first retentate with hexane to form a hexane solution, heating said hexane solution to a temperature ranging from about 50° C. to about 60° C., and cooling said hexane solution to a temperature ranging from about 30° C. to about 40° C. to produce a suspension; and
filtering said suspension to form a second retentate and recovering said second retentate, wherein said R,S-HMA is present in said second retentate.