Stereoselective methods, catalysts and intermediates for the synthesis of (−)-Nutlin-3 and related compounds
The present invention provides methods and intermediates are provided for the preparation of (−)-Nutlin-3. Methods and intermediates are also provided for the enantioselective addition of aryl nitromethanes to aldimines. Bis(amidine) catalysts for the use in these and other reactions are also provided.
1. A method for the preparation of a compound of Formula III comprising reacting a compound of Formula I:
with a compound of Formula II:
in the presence of a catalyst to make a compound of Formula III:
wherein:
both are p-chlorophenyl; and
R 1 is hydrogen, trimethylsilyl, Boc, Fmoc, Cbzacetyl, trifluoroacetyl, benzyl, triphenylmethyl or p-toluenesulfonyl.
2. The method of claim 1 , wherein the catalyst is a bis(amidine) and wherein the bis(amidine) is further defined as:
wherein Ar 3 and Ar 4 are each independently heteroaryl (C≦20) or substituted heteroaryl (C≦20) , provided that at least one of Ar 3 and Ar 4 comprise at least one nitrogen atom.
3. The method of claim 2 , wherein the bis(amidine) is:
4. The method of claim 2 , wherein the bis(amidine) is:
wherein R 3 , R 4 and R 5 are each independently:
hydrogen, hydroxy, halo, amino, nitro, or cyano or thio; or
alkyl (C≦6) , acyl (C≦6) , alkoxy (C≦6) , acyloxy (C≦6) , alkylamino (C≦6) , dialkylamino (C≦6) , Amido (C≦6) , or a substituted version of any of these groups.
5. The method of claim 1 , wherein one optical isomer of the compound of formula III is made with a diastereomeric ratio (dr) greater than 10:1 and an enantiomer excess (ee) greater than 85% and wherein the optical isomer has the formula IIIa:
wherein:
both are p-chlorophenyl; and
R 1 is hydrogen, trimethylsilyl , Boc, Fmoc, Cbzacetyl, trifluoroacetyl, benzyl, triphenylmethyl or p-toluenesulfonyl.
6. The method of claim 5 , wherein the dr is from 12:1 to 100:1.
7. The method of claim 5 , wherein the ee is from 90% to 99%.
8. A compound of the formula:
wherein:
both are p-chlorophenyl; and
R 1 is hydrogen, trimethylsilyl, Boc, Fmoc, Cbzacetyl, trifluoroacetyl, benzyl, triphenylmethyl or p-toluenesulfonyl.
9. The compound of claim 8 , wherein R 1 is H.
10. A composition comprising a compound of claim 8 , wherein one stereoisomer of the compound of formula III is present with a diastereomeric ratio (dr) from about 10:1 to about 100:1 and an enantiomer excess (ee) from 85% to 100%.
11. The compound of claim 8 , which is a stereoisomer of the formula IIIa:
wherein:
both are p-chlorophenyl; and
R 1 is Boc, Fmoc, Cbzacetyl, trifluoroacetyl, benzyl, triphenylmethyl or p-toluenesulfonyl.
12. The composition of claim 10 , wherein the ee is 90% to 99%.
13. The compound of claim 8 , wherein R 1 is Boc.
14. The compound of claim 8 further defined as: