Synthesis of grossularines-1 and analogs thereof and method of use
In one embodiment of the present invention, a synthesis of grossularine-1 and N,N-didesmethylgrossularine-1 2 and analogs thereof based on a novel oxidative dimerization-electrocyclization sequence of 2-amino-4-(3-indolyl)imidazoles derived from oxotryptamine 3 is described.
1. A method of synthesizing grossularine-1
comprising:
condensing oxotryptamine
and dimethylcynanmide in the absence of air to produce 2-dimethylamino-4-(3-indolyl)imidazole
(R=Me) as an HCl salt;
exposing 2-dimethylamino-4-(3-indolyl)imidazole
(R=Me) HCl salt to an ammonia saturated methanol solution in air to produce α-carboline imine
and exposing α-carboline imine
to hydrolysis conditions to produce grossularine-1
(R=Me).
2. A method of synthesizing N,N-didesmethylgrossularine-1
(R=H) comprising:
condensing oxotryptamine
and cynanmide in the absence of air to produce 2-amino-4-(3-indolyl)imidazole
(R=H);
exposing 2-amino-4-(3-indolyl)imidazole
(R=H) to an ammonia saturated methanol solution in air to produce imine
and
exposing imine
to hydrolysis conditions to produce N,N-didesmethylgrossularine-1
(R=H).
3. A compound selected from the group consisting of 2-dimethylamino-4-(3-indolyl)imidazole
(R=Me), 2-amino-4-(3-indolyl)imidazole
(R=H) dimer
dimer
α-carboline mine
and imine
4. A method of synthesis comprising:
(1) reacting a first compound
with a second compound
wherein
and
R is hydrogen, and wherein W, X, Y, and Z are each selected from the group consisting of hydrogen, alkyl, halogen, aryl, OR′, or SR′ wherein R′ is hydrogen, alkyl or aryl, to form a third compound having the formula:
and/or a fourth compound having the formula:
(2) hydrolyzing the fourth compound to form:
5. The method of claim 4 wherein reaction step (1) is performed in the presence of a methanol and ammonia solution.
6. The method of claim 4 wherein reaction step (1) is performed in the presence of a methanol solution substantially saturated with ammonia.
7. A method of synthesis comprising:
(1) reacting a first compound
with a second compound
wherein
and
R is alkyl or aryl, and wherein W, X, Y, and Z are each selected from the group consisting of hydrogen, alkyl, halogen, aryl, OR′, or SR′, wherein R′ is hydrogen, alkyl or aryl, to form a third compound having the formula:
and/or a fourth compound having the formula:
(2) hydrolyzing the fourth compound to form:
8. The method of claim 7 wherein reaction step (1) is performed in the presence of a methanol and ammonia solution.
9. The method of claim 7 wherein reaction step (1) is performed in the presence of a methanol solution substantially saturated with ammonia.
10. A method of synthesis comprising:
(1) reacting a first compound
with a second compound
wherein
and
R is hydrogen, and wherein W, X, Y, and Z are each selected from the group consisting of hydrogen, alkyl, halogen, aryl, OR′, or SR′, wherein R′ is hydrogen, alkyl or aryl, to form a third compound having the formula:
and/or a fourth compound having the formula:
11. The method of claim 10 wherein reaction step (1) is performed in the presence of a methanol and ammonia solution.
12. The method of claim 10 wherein reaction step (1) is performed in the presence of a methanol solution substantially saturated with ammonia.
13. A method of synthesis comprising:
(1) reacting a first compound
with a second compound
wherein
and
R is alkyl or aryl, and wherein W, X, Y, and Z are each selected from the group consisting of hydrogen, alkyl, halogen, aryl, OR′, or SR′, wherein R′ is hydrogen, alkyl or aryl, to form a third compound having the formula:
and/or a fourth compound having the formula:
14. The method of claim 13 wherein reaction step (1) is performed in the presence of a methanol and ammonia solution.
15. The method of claim 13 wherein reaction step (1) is performed in the presence of a methanol solution substantially saturated with ammonia.
16. A compound selected from the group consisting of N,N-diethyl-pre-grossulariine-1
N,N-diethyl-grossularine-1
piperidinyl-pre-grossularine-1
piperidinyl-grossularine-1