Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2002-07-01
2004-08-31
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S467000, C548S316400
Reexamination Certificate
active
06784323
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to catalysis of enantioselective reactions, and more particularly relates to the use of chiral organic compounds as catalysts for a variety of reactions involving &agr;,&bgr;-unsaturated aldehydes as reactants.
BACKGROUND
Ancillary (or “spectator”) ligand-metal coordination complexes (e.g., organometallic complexes) and compositions are useful as catalysts, stoichiometric reagents and therapeutic agents. The ancillary ligand contains functional groups that bind to one or more metal centers and remain associated therewith, providing an opportunity to modify the steric, electronic and chemical properties of the active sites of the complex, i.e., the metal centers.
Unfortunately, many organometallic reagents are expensive and depending on their catalytic activity may not be commercially viable. Moreover, many organometallic complexes are useful only for very specific chemical reactions and do not have broad utility as catalysts for a variety of different types of reactions. This problem may be emphasized for the catalysis of reactions leading to chiral molecules, particularly the conversion of either chiral or a chiral molecules via enantioselective catalysis to provide a chiral product.
Over the last 30 years enantioselective catalysis has become one of the most important frontiers in exploratory organic synthetic research. In the pharmaceutical industry and other industries, the use of pure enantiomeric molecules is often important for safety and efficacy. Thus, in the production of pharmaceuticals, use of catalysts or reagents that preferentially produce one enantiomer of a molecule relative to another enantiomer is particularly advantageous. Unfortunately, the catalysts that produce such enantiomers are typically organometallic complexes that are specific for a particular reaction. In addition, there is no way to predict with any reasonable accuracy which enantiomer will result. Examples of organometallic catalysts used to prepare chiral materials include BINOL-based complexes (Mikami et al. (1994)
J. Am. Chem. Soc
. 116:2812; Kobayashi et al. (1994)
J. Am. Chem. Soc
. 116:4083; Mikami et al. (1989)
J. Am. Chem. Soc
. 111:1940; Mikami et al. (1994)
J. Am. Chem. Soc
. 116:4077; Keck et al. (1993)
J. Am. Chem. Soc
. 115:8467; Keck et al. (1995)
J. Am. Chem. Soc
. 117:2363), BINAP-based complexes (Miyashita et al. (1980)
J. Am. Chem. Soc
. 102:7932; Miyashita et al. (1984)
Tetrahedron
40:1245; Takaya et al. (1986)
J. Org. Chem
. 51:629; Takaya et al. (1988)
Org. Synth
. 67:20; Cai et al. (1995)
Tetrahedron Lett
. 36:7991), DUPHOS complexes (Burk et al. (1990)
Organometallics
9:2653; Burk et al. (1993)
J. Am. Chem. Soc
115:10125; Burk et al. (1992)
J. Am. Chem. Soc
. 114:6266; Burk et al. (1995)
J. Am. Chem. Soc
. 117:9375); salen-based complexes (i.e., organometallic complexes containing the N,N-bis(3,5-di-t-butylsalicylidene)-1,2-cyclohexane-diamino ligand; see, e.g., Li et al. (1993)
J. Am. Chem. Soc
115:5326, and Evans et al. (1993)
Tetrahedron Lett
. 34:7027), and bisoxazoline-containing compounds (Evans et al. (1993)
J. Am. Chem. Soc
. 115:6460; Evans et al. (1997)
J. Am. Chem. Soc
. 119:7893; Evans et al. (1996)
Tetrahedron Lett
. 37:7481; Corey et al. (1992)
Tetrahedron Lett
. 33:6807; Gothelfet al. (1996)
J. Org. Chem
. 61:346).
Despite the observed need and relatively few, narrow solutions, relatively few asymmetric transformations have been reported which employ organic molecules as reaction catalysts. There is tremendous potential for academic, economic and environmental benefit should versatile, chiral organic catalysts be developed. Only a few researchers have disclosed organic catalysts useful for preparing chiral materials. See, e.g.,
Asymmetric Catalysis in Organic Synthesis
, Noyori, R., Ed. (New York: Wiley, 1994) and
Asymmetric Synthesis
, Ojima, I., Ed. (New York: VCH, 1993), and references cited therein. Also see Yang et al. (1998)
J. Am. Chem. Soc
. 120(24):5943-5952, who disclose the use of a dioxirane to catalyze enantioselective epoxidation, Shi et al. (1995)
J. Chem. Research
(S):46-47 (
J. Chem. Research
(M): 0401-0411), who disclose preparation of chiral quaternary ammonium salts stated to be useful as chiral phase-transfer catalysts by reaction of (R)-(+)-2,2-bis(bromomethyl)-6,6-dinitrobiphenyl and (R)-(+)-2,2-bis(bromomethyl)-1,1-binaphthyl with cyclic amines such as pyrrolidine, piperidine and 4-hydroxypiperidine. International Patent Publication No. WO 92/02505 to Castelijns also discloses use of a secondary amine in a catalytic transformation, i.e., in conversion of an unsaturated imine to a pyridine product, by reaction with an aldehyde or ketone.
Recently, however, certain organic catalysts have been disclosed as generally useful in a variety of enantioselective transformations, by lowering the LUMO (lowest unoccupied molecular orbital) of a reactant to facilitate reaction thereof. The organic catalysts are acid addition salts of nonmetallic compounds containing a Group 15 or Group 16 heteroatom, e.g., chiral amines, exemplified by the imidazolidinone salt (5S)-5-benzyl-2,2,3-trimethylimidazolidin-4-one hydrochloride (I)
while exemplary reactants are &agr;,&bgr;-unsaturated carbonyl compounds, including &agr;,&bgr;-unsaturated aldehydes as well as &agr;,&bgr;-unsaturated ketones. Such catalysts and reactions are described in U.S. Pat. No. 6,307,057 to MacMillan and U.S. Pat. No. 6,369,243 to MacMillan et al., which disclose the utility of (I) and other chiral amine salts in catalyzing a variety of reactions, including cycloaddition reactions, 1,4 nucleophile conjugate addition reactions, 1,4 radical addition reactions, organometallic insertion reactions, and ene reactions.
The use of catalyst (I) in the LUMO-lowering activation of &agr;,&bgr;-unsaturated aldehydes, in particular, has been reported by Ahrendt et al. (2000)
J. Am. Chem. Soc
. 122:4243-4244, Jen et al. (2000)
J. Am. Chem. Soc
. 122:9874-9875, and Paras et al. (2001)
J. Am. Chem. Soc
. 123:4370-4371. The reaction proceeds via the reversible formation of an iminium ion intermediate, which can be in one of two enantiomeric configurations. Using propenal as a reactant and (I) as the catalyst, the possible iminium ion intermediates A and B are formed (Equation 1):
Upon further reaction, e.g., with cyclopentadiene in a Diels-Alder reaction, each intermediate results in a different enantiomeric product. That is, intermediate A gives rise to an exo product, while intermediate B results in the endo product (Equation 2):
While imidazolidinone salt (I) and other chiral amines described in the foregoing references are quite valuable as enantioselective organic catalysts, there is a continuing need for nonmetallic catalysts that exhibit even higher levels of enantioselectivity across a diverse range of carbon-carbon bond forming reactions involving &agr;,&bgr;-unsaturated carbonyl compounds as reactants. An ideal catalyst would be inexpensive and straightforward to synthesize, compatible with aerobic conditions, and provide for efficient reaction rates, good control over the geometry of the iminium ion intermediate, and high levels of enantiofacial discrimination. The invention is, in part, directed to such novel catalysts.
The invention is also directed to use of the novel catalysts in the alkylation of indoles and other bicyclic and polycyclic molecules containing at least one N-heterocyclic ring. With the commercial success of chiral pharmaceuticals has come an increasing demand for enantioselective methods to access structural motifs of established value in medicinal chemistry, and the indole structure has become widely identified as a “privileged pharmacophore” with implementation in over 40 medicinal agents of diverse therapeutic action. See Kleeman et al.,
Pharmaceutical Substances
4
th
Ed.; Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. Thieme: Stuttgart, New York, 2001. Surprisingly, however, asymmetric entry to indolic architecture has been largely restricted to either the derivatiz
California Institute of Technology
Reed Dianne E.
Reed & Eberle LLP
Richter Johann
Warzel Mark L.
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