Catalyst – solid sorbent – or support therefor: product or process – Catalyst or precursor therefor – Organic compound containing
Reexamination Certificate
1999-10-22
2003-08-05
Bell, Mark L. (Department: 1755)
Catalyst, solid sorbent, or support therefor: product or process
Catalyst or precursor therefor
Organic compound containing
C502S150000, C502S167000, C502S169000, C502S170000, C502S171000, C502S200000, C502S202000
Reexamination Certificate
active
06602817
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the fields of organic synthesis, asymmetric synthesis, catalysis, combinatorial catalysis, organoboron chemistry, combinatorial chemistry and medicinal chemistry. More specifically, the invention relates to methods for preparing chiral amine or amino alcohols used to prepare chiral reagents or catalysts which can be used for the synthesis of many other molecules.
BACKGROUND OF THE INVENTION
Although many chiral reagents or catalysts containing chiral amine or amino alcohol ligands and their methods of synthesis are known, these often have limited effectiveness giving products with high enantiomeric excess (%ee) only in certain cases. Most synthetic routes to chiral amines or amino alcohols proceed with low or mixed stereoselectivity, involve multiple steps, allow only limited types of substituents, or require highly reactive organometallics that involve cumbersome experimental conditions and necessitate additional protection-deprotection steps.
Rather than rely on the identification of a globally effective catalyst system, the present invention allows the facile construction of stereochemically pure amine or amino alcohol ligands that are subsequently used to form chiral reagents or catalysts. These can be prepared either individually or as combinatorial libraries and can be used to easily identify the most suitable catalyst for a given transformation.
A key feature of the present invention is the construction of amine or amino alcohol ligands in one or two steps and in high enantiomeric and diastereomeric purity.
SUMMARY OF THE INVENTION
This invention relates to a practical and effective method for the stereocontrolled synthesis of amines or amino alcohols for the preparation of a large variety of chiral catalysts for asymmetric synthesis. This process involves the one-step combination of certain organoboron derivatives, including organoboronic acids, organoboronates and organoborates with primary or secondary amines and certain carbonyl derivatives, such as &agr;-keto acids, &agr;-hydroxy aldehydes or carbohydrates. This process constitutes a three-component reaction and is suitable for the rapid generation of combinatorial libraries of amine or amino alcohols. These products can be converted to chiral reagents or catalysts via a subsequent reaction with an appropriate reagent, which can be present as a fourth component or can be used in a follow-up step.
The synthetic procedure is quite simple and works in a variety of solvents, including water, ethanol, dichloromethane and toluene. Product isolation is often very simple and can give fairly pure products without the need for chromatography or distillation. Of special significance is the fact that this process generates new C—C bonds with very high stereoselectivity (up to more than 99% de and 99% ee) when certain chiral components are used in the reaction. Due to its operational simplicity and the fact that no hazardous chemicals or special precautions are required, this invention is suitable for the practical and convenient synthesis of many types of amine or amino alcohol ligands, including stereochemically pure derivatives. These molecules can then serve as components of chiral reagents or catalysts which are useful for the synthesis of a variety of chiral organic molecules. In this manner, this invention is useful for the preparation of various chemicals, pharmaceuticals and agrochemicals.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Definitions:
An organoboron derivative, as defined herein, comprises a compound having a boron atom connected to at least one alkyl, allyl, alkenyl, aryl, allenyl or alkynyl group.
Alkyl groups of the present invention include straight-chained, branched and cyclic alkyl radicals containing up to about 20 carbons. Suitable alkyl groups may be saturated or unsaturated. Further, an alkyl may also be substituted one or more times on one or more carbons with substituents selected from the group consisting of C1-C6 alkyl, C3-C6 heterocycle, aryl, halo, hydroxy, amino, alkoxy and sulfonyl. Additionally, an alkyl group may contain up to 10 heteroatoms or heteroatom substituents. Suitable heteroatoms include nitrogen, oxygen, sulfur and phosphorous.
Aryl groups of the present invention include aryl radicals which may contain up to 10 heteroatoms. An aryl group may also be optionally substituted one or more times with an aryl group or a lower alkyl group and it may be also fused to other aryl or cycloalkyl rings. Suitable aryl groups include, for example, phenyl, naphthyl, tolyl, imidazolyl, pyridyl, pyrroyl, thienyl, pyrimidyl, thiazolyl and furyl groups.
The term “combinatorial library” as used herein refers to a set of compounds that are made by the same process, by varying one or more of the reagents. Combinatorial libraries may be made as mixtures of compounds, or as individual pure compounds, generally depending on the methods used for identifying active compounds. Where the active compound may be easily identified and distinguished from other compounds present by physical and/or chemical characteristics, it may be preferred to provide the library as a large mixture of compounds. Large combinatorial libraries may also be prepared by massively parallel synthesis of individual compounds, in which case compounds are typically identified by their position within an array. Intermediate between these two strategies is “deconvolution”, in which the library is prepared as a set of sub-pools, each having a known element and a random element. For example, using the process of the invention each sub-pool might be prepared from only a single amine (where each sub-pool contains a different amine), but a mixture of different carbonyl derivatives (or organoboron reagents). When a sub-pool is identified as having desired activity, it is resynthesized as a set of individual compounds (each compound having been present in the original active sub-pool), and tested again to identify the compounds responsible for the activity of the sub-pool.
The term “Metal” means any metal, metal derivative, or metal substitute useful for performing the a reaction in order to synthesize a reagant or catalyst. Examples include, but are not limited to B, Li, Mg, Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Mo, Ru, Rh, Pd, Ag, Re, Os, Ir, Pt, La, Ce and Yb.
General Description:
The first step of this invention involves a novel synthesis of a chiral amine or amino alcohol ligand and the second step involves the conversion of this amine or amino alcohol to a chiral reagent or catalyst.
The first step is based on the use of organoboron compounds in a C—C bond forming reaction where the electrophile is derived from a carbonyl and an amine and the product is a new substituted amine. There are many variations of this methodology involving different organoboron, carbonyl and amine components. For the purpose of illustration the following variations are described here.
Synthesis of Chiral Amines:
One aspect of the invention is a process for generating chiral amine derivatives of formula (1) or a combinatorial library of molecules of formula (1), by combining compounds (2), (3) and (4):
where R
1
and R
2
are each independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, acyl, carboxy, carboxamido, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, and —YR, where Y is selected from the group consisting of —O—, —NR
a
—, —S—, —SO—, and —SO
2
—, and R and R
a
are each independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and acyl, or R
1
and R
2
together form a methylene bridge of 2 to 20 carbon atoms; and where R
3
and R
4
are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl; aryl, and heteroaryl; and where R
5
is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl; R
6
, R
7
Bell Mark L.
Pasterczyk J.
University of Southern California
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