Chemistry of hydrocarbon compounds – Unsaturated compound synthesis – By alkyl transfer – e.g. – disproportionation – etc.
Reexamination Certificate
1998-07-13
2002-02-12
Griffin, Walter D. (Department: 1764)
Chemistry of hydrocarbon compounds
Unsaturated compound synthesis
By alkyl transfer, e.g., disproportionation, etc.
C585S645000, C585S646000, C585S940000, C549S429000, C549S507000, C549S001000, C549S009000, C549S010000, C549S013000, C549S029000, C549S200000, C549S214000
Reexamination Certificate
active
06346652
ABSTRACT:
FIELD OF INVENTION
The present invention relates generally to organometallic catalysts, and more specifically to the catalytic conversion of a racemic mixture of dienes to a cyclic olefin by a ring-closing metathesis (RCM) reaction. The present invention also provides a method for converting achiral or meso substrates into at least one enantiomer of a product through reactions referred to as a catalytic, enantioselective desymmetrization reactions.
BACKGROUND OF THE INVENTION
The formation of carbon—carbon bonds remains among the most important reactions in synthetic organic chemistry. Consequently, the development of transition metal catalyzed carbon—carbon bond formation represented a significant advance in organic synthesis. One reaction involving transition metal catalyzed carbon—carbon formation is olefin metathesis. Olefin metathesis can be defined conceptually as a mutual exchange of alkylidene units between two olefins involving both the formation and cleavage of carbon—carbon double bonds. Transition metal ion catalysts allow this reaction to proceed in a facile manner through a [2+2] cycloaddition between an M═C center and a carbon—carbon double bond. When two olefin groups are located on the same molecule and are subjected to olefin metathesis conditions, a ring-closing metathesis (RCM) reaction can occur in which a series of olefin metathesis reactions produce a cyclic olefin. Ring-closing metathesis is most facile for 5-7 membered ring systems because of the low ring strain afforded by these compounds. Ruthenium and molybdenum alkylidene complexes have proven capable of ring closing dienes having a variety of functional groups.
RCM reactions are generally plagued by undesirable reactions that compete with ring formation, such as acyclic diene metathesis and ring opening metathesis. The former reaction involves polymer formation through the metathesis of terminal dienes whereas the latter reaction comprises metathesis reactions of the ring-closed cyclic olefin. These competing reactions can be circumvented, for example, by performing the reactions under dilute conditions, optimizing ring sizes and utilizing hindered olefin substrates. The latter strategy is also useful for directing the initial reaction of the metal alkylidene towards one olefinic site in a diene over the other olefinic group.
The development of asymmetric ring closing metathesis has considerable potential as a powerful synthetic tool for the preparation of ring structures of defined stereosymmetry. For example, a logical application of asymmetric RCM is the synthesis of natural products which contain varying sizes of ring systems having pendant functional groups of specific stereosymmetry. U.S. Pat. No. 5,516,953 discloses a process for the preparation of optically active cycloolefins catalyzed by molybdenum and tungsten complexes. This process requires that substrate be initially isolated as an optically active diene. Olefin metathesis is catalyzed by molybdenum and tungsten halide or oxide complexes that may also contain alkoxide or amido ligands. In some instances, a tin, lead, aluminum, magnesium or zinc complex cocatalyst may be required.
U.S. Pat. No. 4,654,462 describes a process for olefin metathesis by a tungsten complex containing two phenoxy groups, a halogen atom, an alkyl radical and a carbene. Stereoselectivity is reported sufficient to control cis/trans isomerization in the metathesis of pure cis or trans olefins.
Only recently, the first report of an asymmetric RCM reaction involving the interaction of a chiral catalyst with a racemic substrate mixture was reported by Grubbs et al.
J. Am. Chem. Soc
. 1996, 118, 2499
, Organometallics
1996, 15, 1865. A racemic diene substrate was added to a molybdenum alkylidene amido catalyst containing a dialkoxide ligand. At various conversion levels of the starting mixture, the enantiomeric excess of the unreacted diene mixture was analyzed, resulting in enantiomeric excess values of up to 48%. The enantiomeric excess of the ring-closed product was not reported. It was proposed that the dialkoxide had a rigid structure suitable to promote the transfer of asymmetry.
There remains a fundamental need for the synthesis of optically pure products by using asymmetric ring-closing metathesis reactions. In a recent review article, Blechert et al. discuss the state of the art relating to asymmetric RCM reactions, maintaining that “In light of the e.e. [enantiomeric excess] values obtained to date, synthetic applications of this process are currently not envisioned.”
Angew. Chem., Int. Ed. Engl
. 1997, 36, 2036. Asymmetric processes only begin to show promise industrially when achieving enantiomeric excess values of at least 80%.
Another class of reactions that further advances the field of asymmetric synthesis is enantioselective desymmetrization reactions. The desymmetrization process involves converting achiral or meso substrates, i.e. substrates having a plane of symmetry, into a molecule having a stereocenter. If the desymmetrization reaction can be carried out enantioselectively, then one enantiomer is produced selectively in high enantiomeric excesses. In particular, desymmetrization reactions involving carbon-carbon bond formation have great potential in the pharmaceutical industry and in natural products synthesis, and only a limited number of examples have been reported in the literature. In Trost et al., palladium-catalyzed cyclization reactions yield chiral products having enantiomeric excesses of no more than 90%. Higher enantiomeric excess values can be obtained but only in the presence of added triethylamine.
J. Org. Chem
. 1998, 63, 1339-1341. In Mikami et al., carbon—carbon bond formation is effected between two substrates in an enantioselective fashion in the presence of a chiral titanium complex.
J. Am. Chem. Soc
. 1992, 114, 6566-6568. The field of asymmetric synthesis, however, remains wide open to increase the variety of desymmetrization reaction types and to improve synthetic conditions such as lower catalyst loadings, increased yields and conversions and decreased reaction times.
It remains a challenge to design a metal catalyst that can catalytically generate compounds having stereocenters while achieving high enantioselectivity.
SUMMARY OF THE INVENTION
In one illustrative embodiment of the present invention, a composition is provided having the structure:
The composition has a chiral dialkoxide ligand, denoted by
wherein the dialkoxide is of at least 80% optical purity.
reaction site is of sufficient shape specificity, defined in part by the dialkoxide of sufficient rigidity and a M═N—R
1
site to cause a mixture of two enantiomeric olefins to react with an M═C center of the
reaction site at different rates. The reaction is an olefin metathesis reaction and the product has at least a 50% enantiomeric excess of one enantiomer present in the original mixture. M is a metal ion, preferably molybdenum or tungsten.
In one embodiment of the invention, the group of atoms defining the shortest chemical bond pathway linking the oxygen atoms in
contains at least four atoms. In another illustrative embodiment of the present invention,
comprises the structure:
The chiral dialkoxide transfers asymmetry to the composition such that the composition is at least 80% optically pure.
In another embodiment of the present invention, a method is provided wherein a diene mixture of enantiomers is reacted with the M═C center of the above-mentioned composition. The method involves allowing a first enantiomer of the mixture to metathesize at M to an extent greater than a second enantiomer to form a product that has an enantiomeric excess of at least 50%. The metathesizing step occurs catalytically.
One aspect of the invention provides a method which includes a step of adding the racemic diene mixture to produce a ring-closed metathesis compound having an enantiomeric excess of at least 50% at 50% conversion of the diene mixture. Moreover, the enantiomeric excess of an enantiomer in the unreacted di
Hoveyda Amir H.
Schrock Richard R.
Griffin Walter D.
Massachusetts Institute of Technology
Wolf Greenfield & Sacks P.C.
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