Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-02-23
2001-04-03
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S253000, C549S018000, C549S028000, C549S419000
Reexamination Certificate
active
06211370
ABSTRACT:
BACKGROUND OF THE INVENTION
The demand for enantiomerically pure compounds has grown rapidly in recent years. One important use for such chiral, non-racemic compounds is as intermediates for synthesis in the pharmaceutical industry. For instance, it has become increasingly clear that enantiomerically pure drugs have many advantages over racemic drug mixtures. The advantages of enantiomerically pure compounds (reviewed in, e.g., Stinson, S. C.,
Chem Eng News,
Sep. 28, 1992, pp. 46-79) include fewer side effects and greater potency in many cases.
Traditional methods of organic synthesis have often been optimized for the production of racemic materials. The production of enantiomerically pure material has historically been achieved in one of two ways: the use of enantiomerically pure starting materials derived from natural sources (the so-called “chiral pool”); or the resolution of racemic mixtures by classical techniques. Each of these methods has serious drawbacks, however. The chiral pool is limited to compounds found in nature, so only certain structures and absolute configurations are readily available. Resolution of racemates often requires the use of resolving agents; this process may be inconvenient and is certain to be time-consuming. Furthermore, resolution often means that the undesired enantiomer is discarded, thereby wasting half of the material.
Cycloaddition reactions are powerful, frequently-exploited elements of the palette of transformations available to the synthetic organic chemist. There are numerous reasons for the importance of cycloaddition reactions, inter alia: 1) they are concerted reactions; 2) their products are significantly more complex than the required starting materials; 3) the relative simplicity and synthetic accessibility of the required starting materials; and 4) they are capable of generating a number of stereocenters in a single operation. The first of these points is tremendously important because concerted reactions transmit to their products in well-understood ways the stereochemical information contained in their starting materials.
The synthetic utility of cycloaddition reactions in which one of the reactants is a carbonyl group or analogue thereof—termed “Hetero”-cycloadditions —has been further expanded by progress in the development of asymmetric catalysts for these reactions. The Hetero-Diels-Alder reaction is perhaps the best example of a cycloaddition reaction whose utility has been has been augmented by research directed at the development of asymmetric catalysts (for a review, see: Danishefsky
Chemtracts: Organic Chemistry
1989, 273). Catalysts comprising a transition metal ion and a chiral, non-racemic ligand have been reported to render enantioselective various Hetero-Diels-Alder cycloadditions; these reactions gave products in good to excellent enantiomeric excess (for leading references, see: Danishefsky and DeNinno,
Angew. Chim., Intl. Ed. Engl.
1987, 26, 15-23; Corey and Loh,
J. Am. Chem. Soc.,
1991, 113, 8966-8967; Yamamoto et al.,
J. Org Chem.,
1992, 57, 1951-1952; Keck et al.,
J. Org Chem.,
1995, 60, 5998-5999; and Ghosh et al.,
Tetrahedron Lett.
1997, 38, 2427-2430).
The cyclohexene ring generated in a Diels-Alder reaction can be incorporated without further modification into biologically-active natural products, drug candidates, and pharmaceuticals. Additionally, the newly-formed cyclohexene ring may serve as a starting point for further synthetic transformations. For example, the A, B, and C rings of the steroid skeleton are functionalized cyclohexane rings; a number of routes to steriods based on the Diels-Alder reaction have been reported. The olefin in the cyclohexene derived from a Diels-Alder reaction can serve as a functional handle for subsequent transformations. The Diels-Alder reaction tolerates a wide range of “spectator” functionality—functionality not involved in, or affected by, the reaction conditions—which can serve as reactive sites in subsequent transformations. Finally, the so-called Hetero-Diels-Alder reaction provides access to unsaturated six-membered heterocycles.
SUMMARY OF THE INVENTION
In one aspect of the present invention, there is provided a process for enantioselective chemical synthesis which generally comprises reacting a diene and an aldehyde in the presence of a non-racemic chiral catalyst to produce a enantiomerically enriched dihydropyran product. The diene substrate comprises a 1,3-diene moiety, the dienophile comprises a single reactive &pgr;-abond, and the chiral catalyst comprises an asymmetric tetradentate or tridentate ligand complexed with a transition metal ion. In the instance of the tetradentate ligand, the catalyst complex has a rectangular planar or rectangular pyrimidal geometry. The tridentate ligand-metal complex has a trigonal pyrimidal or planar geometry. In a preferred embodiment, the ligand has at least one Schiff base nitrogen complexed with the metal core of the catalyst. In another preferred embodiment, the ligand provides at least one stereogenic center within two bonds of a ligand atom which coordinates the metal.
In general, the metal atom is a main group metal or transition metal from Groups 3-12 or from the lanthanide series, and is preferably not in its highest state of oxidation. For example, the metal can be a late transition metal, such as selected from the Group 5-12 transition metals. In certain embodiments, the metal atom is selected from the group consisting of Na, K, Rb, Mg, Ca, Sr, B, Al, Ga, In, Si, Ge, and Sn. In certain embodiments, the metal atom is selected from the group consisting of Co, Cr, Mn, V, Fe, Mo, W, Ru and Ni.
Exemplary diene substrates for the subject reaction include 1,3-dienes in which any or all of the heavy atoms comprising the backbone of said 1,3-diene are chosen from the set containing C, N, O, S, and P.
In preferred embodiments, the subject transformation can be represented as follows:
wherein
Y represents O, S, or NR
7
;
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
each independently represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or —(CH
2
)
m
—R
8
;
any two or more of the substituents R
1
, R
2
, R
3
, R
4
, R
5
and R
6
taken together may form a carbocylic or heterocyclic ring having from 4 to 8 atoms in the ring structure;
R
8
represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and
m is zero or an integer in the range of 1 to 8.
In certain embodiments, R
1
, R
2
, R
3
, and R
4
are chosen such that the substrate has a plane of symmetry.
Exemplary dienophile substrates for the subject reaction include aldehydes, ketones, esters, amides, carbonates, thioaldehydes, thioamides, thiocarbonates, lactones, lactams, thiollactones, thiolactams, imines, oximes, hydrazones, thionoesters, thioesters, dithioesters, thionolactones, thiolactones, dithiolactones, phosphorus ylides, thioketones, acid halides, anhydrides, imines, iminium ions, imines, oximes, oximes, hydrazones, nitroso-containing compounds, nitro-containing compounds, compounds containing a phosphorus-oxygen &pgr;-bond, and compounds containing a phosphorus-sulfur &pgr;-bond.
In a preferred embodiment, the method includes combining a diene, a dienophile, and a non-racemic chiral catalyst as described herein, and maintaining the combination under conditions appropriate for the chiral catalyst to catalyze an enantioselective cycloaddition reaction between the two substrates.
In certain embodiments, the chiral catalyst which is employed in the subject reaction is represented by the general formula:
wherein
Z
1
, Z
2
, Z
3
and Z
4
each represent a Lewis base;
the C
1
moiety, taken together with Z
1
, Z
3
and M, and the C
2
moiety, taken together with Z
2
, Z
4
and M, each, independently, form a heterocycle;
R
1
, R
2
, R′
1
and R′
2
each, independently, are absent or represent a covalent
Dossetter Alexander G.
Jacobsen Eric N.
Jamison Timothy F.
Schaus Scott E.
Foley Hoag & Eliot LLP
Gordon Dana M.
Harvard University
McKane Joseph K.
Solola Taofiq A.
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