1. Field of the Invention
This invention relates to enantiomeric chiral compounds and a process for their stereoselective preparation. In another aspect this invention relates to enantiomerically enhanced or pure chiral cyclopentadiene ligands and compounds and a stereoselective process for their making by the creation of a chiral center at the carbon 6 position of a prochiral fulvene compound by hydride transfer. In yet another aspect, this invention relates to enantiomeric chiral Group III B - VIII B (the chemical Groups herein are as referenced to the Periodic Table of Elements, CRC Handbook of Chemistry and Physics, 68th ed. 1987-1988) organometallic complexes and a process for their stereoselective preparation.
2. Description of the Prior Art
Stereochemistry refers to the three-dimensional spatial configurations of molecules. Stereoisomers are compounds which have identical chemical constitution, but differ as to the orientation of the atoms or groups in three dimensional space. Stereoisomers fall into one of two broad classes: optical isomers and geometric (cis-trans) isomers. Enantiomers are one type of optically active three-dimensional isomers that are mirror image structures, which form as the result of the presence of one or more asymmetric or chiral centers. These mirror image forms compare to each other structurally as do the right and left hands when the chiral carbon atoms, C*, are lined up. For example, in the enantiomeric forms of glyceraldehyde, the two structures are mirror images of each other and cannot be made to coincide: ##STR1## There are several different nomenclature used in to refer to enantiomers: R/S; +/-; and d/1.
Pairs of stereoisomers differ so little in structure, and hence in physical properties, that they are generally differentiated by the use of a polarimeter, which measures the amount of rotation the compound imparts to polarized light as it passes through the compound. Yet despite the close similarity, one isomer of a pair may serve as a nourishing food, or as an antibiotic, or as a powerful heart stimulant, and the other isomer may be useless or even harmful. One of the most difficult problems in the preparation of compounds is the control of stereochemistry, and in particular the preparation of enantiomerically pure compounds. One of the most dramatic examples of the importance of chirality control was the use of the drug thalidomide, which was manufactured and sold as a racemic mixture (mixture4of the optical isomers wherein the mixture is optically inactive). One optical isomer produced the desired therapeutic effect, while the enantiomer, which was assumed to be pharmacologically inert, led to fetal deformities.
Chiral catalytic complexes could be utilized to facilitate enantioselective transformations. For example the enantioselective hydrogenation of acetamidocinnamic acid is catalyzed by the presence of a chiral rhodium catalyst. Transition metal organometallic complexes have long been used to catalyze chemical reactions. Recently transition metal complexes incorporating chiral chelating diphosphine ligands have been successfully utilized to effect enantioselective hydrogenations. However, the stereo-differentiating ability of these complexes can suffer due to the lability of phosphine ligands.
The tremendous potential of utilizing chiral organometallic complexes to carry out enantioselective transformations is hindered by the lack of readily available enantiomerically enhanced (that is, an excess of one of the enantiomers) or pure organometallic complexes, and enantiomerically enhanced or pure ligands or compounds from which to make enantiomerically enhanced or pure organometallic complexes.
Chiral cyclopentadienes are considered to be a suitable starting point for making enantiomeric organometallic complexes, however, only a small number of chiral cyclopentadienes are known and only a few of them are enantiomerically enhanced or pure. Generally, synthesis of chiral compounds from achiral reactants typically will yield the racemic modification or mixture. The enantiomers must then be separated (resolved) by special methods that are very difficult and yield less than desired results. A method that would produce an excess of the desired enanthomer could rely less on resolution techniques than a process that produced a racemic or essentially racemic mixture. There have been other attempts to develop enantiomerically enhanced or pure cyclopentadienyl ligands or compounds that have focused on preparing chiral cyclopentadienyl ligands from inexpensive naturally occurring enantiomerically enhanced or pure compounds. Unfortunately many of these routes require several synthetic steps to transform a naturally occurring starting material into a cyclopentadienyl derivative.
The addition of nucleophiles to fulvenes has proven to be a successful route for the preparation of substituted cyclopentadienyl ligands. Generally, a fulvene of the following general formula that is disubstituted at the 6 position: ##STR2## is reacted with a nucleophile R" selected from H, CH.sub.3 and C.sub.6 H.sub.5, CH.sub.2 P(C.sub.6 H.sub.5).sub.2, to yield the following substituted cyclopentadienyl ligand: ##STR3## wherein R is selected from CH.sub.3 and C.sub.6 H.sub.5, and R' is selected from H, CH.sub.3 and C.sub.6 H.sub.5. While the carbon 6 may potentially be a chiral center, the cyclopentadienyl ligand product will be a racemic modification or mixture. Furthermore, the scope of this reaction has been generally limited because the reaction of fulvene derivatives with heteroatom based nucleophiles has been found to lead to deprotonation rather than nucleophilic addition.
Therefore, the need exists in the art for an efficient, simple process for producing from fulvene compounds di-substituted at the 6 position, enantiomerically enhanced or pure cyclopentadienyl derivatives which could then be made into enantiomerically enhanced or pure organometallic compounds, without an undue amount of synthetic steps, and without having to rely entirely on resolution techniques.
USPTO Backgrounds
USPTO Backgrounds