Synthesis of chiral enaminones, their derivatives, and bioactivity studies thereof
This invention provides enantioenriched heterocyclic enaminone compounds with quaternary stereogenic centers and novel methods of preparing the compounds. Methods include the method for the preparation of a compound of formula (I): comprising treating a compound of formula (II): with a transition metal catalyst under alkylation conditions.
1. A method for the preparation of a compound of formula (I):
comprising treating a compound of formula (II):
with a transition metal catalyst under alkylation conditions, wherein, as valence and stability permit,
R 1 and R 2 are independently hydrogen or optionally substituted alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, or alkynyl; or
R 1 and R 2 are taken together to form an optionally substituted heterocyclic ring;
R 3 is substituted or unsubstituted hydrogen, alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, alkenyl, alkynyl, or halo;
R 4 is hydrogen, halogen, alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, alkenyl, or alkynyl;
R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are independently selected for each occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, arylalkoxy, heteroaralkyl, carbocyclylalkyl, and heterocyclylalkyl;
W is CR 13 R 13 , O, S, or NR 14 ;
R 13 is selected, independently for each occurrence, from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, arylalkoxy, heteroaralkyl, carbocyclylalkyl, and heterocyclylalkyl;
R 14 is independently selected for each occurrence from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, or alkynyl;
wherein R 2 and R 4 may combine with the atoms to which they are attached to form an optionally substituted 4-9 membered heterocyclic ring, R 4 and an occurrence of R 13 may combine with the carbons to which they are attached to form an optionally substituted 3-8 membered ring, R 4 and an occurrence of R 14 may combine with the atoms to which they are attached to form an optionally substituted 4-8 membered heterocyclic ring, two occurrences of R 13 may combine with the carbons to which they are attached to form a 3-8 membered ring, or an occurrence of R 13 and an occurrence of R 14 may combine with the atoms to which they are attached to form an optionally substituted 4-8 membered heterocyclic ring; and
n is an integer from 1-4.
2. The method of claim 1 , wherein R 5 ,R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each independently selected for each occurrence from hydrogen, halogen, cyano, alkyl, alkoxy, alkylthio, amide, amine, aryloxy, and arylalkoxy.
3. The method of claim 1 , wherein R 3 is selected from optionally substituted alkyl, aryl, aralkyl, haloalkyl, and hydroxyalkyl.
4. The method of claim 1 , wherein W at each occurrence is CR 13 R 13 and n is an integer from 1-3;and
wherein R 13 is selected, independently for each occurrence, from hydrogen, halogen, cyano, alkyl, alkoxy, alkylthio, amide, amine, aryloxy, and arylalkoxy.
5. The method of claim 1 , wherein R 1 and R 2 taken together form an optionally substituted heterocyclic ring.
6. The method of claim 1 , wherein the transition metal catalyst comprises a transition metal selected from palladium, nickel, and platinum.
7. The method of claim 6 , wherein the transition metal catalyst comprises Pd 2 (dba) 3 or Pd 2 (pmdba) 3 .
8. The method of claim 7 , wherein the transition metal catalyst is used in an amount from about 0.1 mol % to about 20 mol % total palladium relative to the compound of formula (II).
9. The method of claim 1 , wherein the transition metal catalyst further comprises an enantioenriched phosphine ligand.
10. The method of claim 9 , wherein the enantioenriched phosphine ligand is a phosphinooxazoline ligand.
11. The method of claim 10 , wherein the phosphinooxazoline ligand is selected from (S)—(CF 3 ) 3 -tBuPHOX and (S)-tBuPHOX.
12. The method of claim 10 , wherein the ligand is used in an amount selected from 0.25 mol % to about 25 mol % relative to the compound of formula (II).
13. The method of claim 1 , wherein the compound of formula (I) is enantioenriched.