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US 8,558,017 B2Granted
Ruthenium (II) catalysts for use in stereoselective cyclopropanations
AssigneeVanda Pharmaceuticals Inc.
InventorsDavid E. Pereira, Wade Aumiller, Raymond Dagger
Life of this patent
Estimating the term…
Abstract
Chiral ruthenium catalysts comprising salen and alkenyl ligands are provided for stereoselective cyclopropanation, and methods of cyclopropanation are provided. The chiral ruthenium catalyst is prepared in situ by combining an alkenyl ligand, a deprotonated chiral salen ligand, and a ruthenium (II) metal. A preferred catalyst is prepared in situ by combining 2,3-dihydro-4-venylbenzofuran,deprotonated 1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butyl-salicylidene) and RuCl2(p-cymene)]2.
Claims16
A method of stereoselective cyclopropanation comprising the step of:
- combining a carbene precursor and an alkenyl substrate in the presence of a chiral catalyst to form a cyclopropyl product, the chiral catalyst is prepared in situ by the step of:
- combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal;
- wherein the alkenyl ligand is of formula (I):
- where R5 is selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, C5-10 heteroaryl, C3-10 heterocycle;
- and
- where R6 is selected from the group consisting of hydrogen, and C1-8 alkyl;
- and
- where R5 and R6 together with the atoms to which they are attached may form a carbocyclic ring;
- wherein the deprotonated chiral ligand is of formula (III):
- where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsbstituted C3-10 heterocyclyl, substituted or unsubstituted C5-10 heteroaryl;
- where R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl and substituted or unsubstituted arylalkyl;
- where R3 and R4 together with the atoms to which they are attached may form a ring;
- and
- wherein M1 and M2 are each a counterion independently selected from the group consisting of Group I metal ions and Group II metal ions.
11 more elements
A method of stereoselective cyclopropanation consisting of the steps of:
- combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal to form a chiral catalyst in situ;
- wherein the alkenyl ligand is of formula (I):
- where R5 is selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, C5-10 heteroaryl, C3-10 heterocycle;
- and
- where R6 is selected from the group consisting of hydrogen, and C1-8 alkyl;
- and
- where R5 and R6 together with the atoms to which they are attached may form a carbocyclic ring;
- wherein the deprotonated chiral ligand is of formula (III):
- where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C5-10 heteroaryl;
- where R3 and R4 are each independently selected from the group consisting of subsituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl and substituted or unsubstituted arylalkyl;
- where R3 and R4 together with the atoms to which they are attached may form a ring;
- and
- where M1 and M2 are each a counterion independently selected from the group consisting of Group I metal ions and Group II metal ions;
- and
- combining a carbene precursor and an alkenyl substrate in the presence of the chiral catalyst to form a cyclopropyl product.
12 more elements
In the stereoselective cyclopropanation of a carbene precursor and an alkenyl substrate with a chiral catalyst of the formulae (V) or (VI):
- where R5 is selected from the group consisting of hydrogen, C1-5 alkyl, C6-10 aryl, C5-10 heteroaryl, C3-10 heterocycle;
- and
- where R6 is selected from the group consisting of hydrogen and C1-8 alkyl;
- and
- where R5 and R6 together with the atoms to which they are attached may form a carbocyclic ring;
- where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C5-10 heteroaryl;
- where R3 and R4 are each independently selected from the group consisting of substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl and substituted or unsubstituted arylalkyl;
- where R3 and R4 together with the atoms to which they are attached may form a ring;
- and
- where M1 and M2 are each a counterion independently selected from the group consisting of Group I metal ions and Group II metal ions;
- the improvement comprising generating the chiral catalyst in situ.
8 more elements
A catalyst for stereoselective reactions prepared by the step of combining an alkenyl ligand and a deprotonated chiral ligand in the presence of a ruthenium (II) metal;
- wherein the alkenyl ligand is of formula (I):
- where R5 is selected from the group consisting of hydrogen, C1-8 alkyl, C6-10 aryl, C5-10 heteroaryl, C3-10 heterocycle;
- and
- where R6 is selected from the group consisting of hydrogen, and C1-8 alkyl;
- and
- where R5 and R6 together with the atoms to which they are attached may form a carbocyclic ring;
- wherein the deprotonated chiral ligand is of formula (III):
- where R1 and R2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C5-10 heteroaryl;
- where R3 and R4 are each independently selected from the group consisting of subsituted or unsubstituted C1-8 alkyl, substituted or unsubstituted C3-8 cycloalkyl, C1-10 alkoxy, C1-12 alkylamino, substituted or unsubstituted C3-10 heterocyclyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C5-10 heteroaryl and substituted or unsubstituted arylalkyl;
- where R3 and R4 together with the atoms to which they are attached may form a ring;
- and
- where M1 and M2 are each a counterion independently selected from the group consisting of Group I metal ions and Group II metal ions.
9 more elements
Dependencies are inferred from the claim text.