AU2001234505A1 - Chemical transformation of substrates using nonmetallic, organic catalyst compositions - Google Patents

Description

CHEMICAL TRANSFORMATION OF SUBSTRATES USING NONMETALLIC, ORGANIC CATALYST COMPOSITIONS

TECHNICAL FIELD

The present invention relates to organic reagents and their use as catalysts for a variety of reactions. More particularly, this invention relates to the use of a heteroatom- containing activator and an acid as a catalyst composition for various bond-forming reactions. Even more particularly, this invention relates to the preparation of chiral products from either chiral or achiral starting materials using a heteroatom-containing activator and an acid as a catalytic composition of matter. The invention finds utility in the fields of organic synthesis, catalysis and chiral chemistry.

BACKGROUND ART 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 be 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 achiral 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. HI: 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), DUPHΟS 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)-l,2- cyclohexanediamino 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. 11_5:6460; 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; Gothelf et 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: NCH, 1993), and references cited therein. Also see Yang et al. (1998) J Am. Chem. Soc. 120(24V.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)- l,l'-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.

The aforementioned orgamc catalysts are not, however, useful in catalyzing a broad range of chemical transformations, but are specific for a particular reaction and thus have limited utility. There is accordingly a need in the art for organic catalysts that are versatile with respect to the types of reactions that can be catalyzed, are inexpensive to synthesize, and are readily capable of scale-up for commercialization. It is also desirable that such catalysts be capable of preparing chiral products from starting materials that may be either chiral or achiral in nature.

DISCLOSURE OF THE INVENTION

Accordingly, it is a primary object of the invention to address the aforementioned need in the art and provide methods, catalyst compositions and reaction systems for chemically transforming a substrate, wherein the catalyst composition is composed of nonmetallic components, is useful for catalyzing a wide variety of reactions and reaction types, is relatively inexpensive to synthesize, and is simple and straightforward to work with and scale up. Importantly, the catalyst composition may also contain a chiral component that enables enantioselective catalysis and synthesis of a chiral product.

It is another object of the invention to provide a process for catalytically transforming a compound containing a functional group to provide a product in which the functional group contains at least one newly formed covalent bond.

It is another object of the invention to provide such a process wherein the reaction is carried out in the presence of a catalyst composition composed of a heteroatom- containing activator and an acid.

It is still another object of the invention to provide such a process wherein the reaction is carried out in the presence of a catalyst composition composed of a salt of a heteroatom-containing activator and an acid. It is yet another object of the invention to provide a chemical reaction wherein an nonmetallic, organic catalyst composition lowers the LUMO (lowest unoccupied molecular orbital) of a substrate to facilitate reaction thereof.

It is a further object of the invention to provide such processes and reactions wherein the catalyst composition contains a chiral component.

It is still a further object of the invention to provide novel compounds in the form of a positively charged θ-,β-unsaturated imine.

It is an additional object of the invention to provide a catalyst composition composed of a heteroatom-containing activator and an acid. It is still an additional object of the invention to provide a reaction system composed of the aforementioned catalyst composition and a substrate such as an C-,β- unsaturated carbonyl compound.

Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.

Generally, the invention involves reaction of a first reactant containing a functional group typically having a π bond or an equivalent thereof (e.g., a σ bond having TC bond-type reactivity, as in cyclopropyl moieties) with a second reactant in the presence of a catalyst composition comprised of two catalyst precursors, a first precursor composed of a nonmetallic activator containing a Group 15 or Group 16 heteratom, and a second precursor composed of an acid, e.g., an inorganic acid, an organic acid, a Lewis acid, combinations thereof, or the like. Alternatively, the catalyst composition may be composed of a salt of a heteroatom-containing activator and an acid. By virtue of the interaction between the catalyst composition and the first reactant, the LUMO of the functional group of the first reactant is lowered relative to its initial state (i.e., prior to contact with the catalyst composition) and generally relative to the HOMO (highest occupied molecular orbital) of the second reactant as well. This LUMO-lowering in turn facilitates reaction of the functional group with the second reactant, enabling transformation of the first reactant by formation of new covalent bonds between the LUMO-lowered functional group and a second reactant (in either an intra- or intermolecular reaction). Suitable first reactants include, for example, C-,β-unsaturated carbonyl compounds such as CL, β -unsaturated ketones ' and X,β -unsaturated aldehydes.

The heteroatom-containing activator can be a chiral compound, i.e., chiral with respect to an axis, plane or center of asymmetry. For example, the heteroatom-containing activator may be a secondary amine, in which case the compound may be chiral with respect to an axis defined by the N-H bond of the amine moiety. Chiral activators may be designed to provide high enantioselectivity, such that a desired enantiomer can be synthesized in enantiomerically pure form.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 schematically illustrates a Diels- Alder reaction catalyzed using a catalyst composition of the invention.

Figure 2 schematically illustrates a cyclopropanation reaction catalyzed using a catalyst composition of the invention. Figure 3 schematically illustrates an epoxidation reaction catalyzed using a catalyst composition of the invention.

Figure 4 schematically illustrates an intramolecular [4+2] cycloaddition reaction catalyzed using a catalyst composition of the invention.

Figure 5 schematically illustrates a [3+2] cycloaddition reaction catalyzed using a catalyst composition of the invention.

Figure 6 schematically illustrates 1,4-conjugate addition of furan catalyzed using a catalyst composition of the invention.

Figure 7 schematically illustrates 1,4-conjugate addition of nitromethane catalyzed using a catalyst composition of the invention. Figure 8 schematically illustrates a Diels- Alder reaction between cyclopentadiene and an 0-,β-unsaturated carbonyl compound, wherein two possible enantiomeric products can result.

Figure 9 schematically illustrates a reaction catalyzed using a chiral secondary amine, wherein enantioselectivity of the process and chirality of the desired product can be controlled. Figure 10 is a flow chart illustrating a manufacturing method that may be used to implement the catalytic reactions of the invention.

MODES FOR CARRYING OUT THE INVENTION It is to be understood that unless otherwise indicated this invention is not limited to specific reactants, catalyst compositions (including heteroatom-containing activators and acids), or synthetic methods. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. For example, while the Diels-Alder reaction between a diene and dienophile is discussed throughout, the reaction is intended to be merely representative and not in any way limiting of the many types of reactions that can be catalyzed using the compositions and methods of the invention. As another example, while α,β-unsaturated ketones and aldehydes are frequent used to exemplify suitable "first reactants," such compounds, again, are merely illustrative and not limiting of the reactants with which the present compositions and methods can be used.

As used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, reference to reference to "a reagent" includes mixtures of reagents, "an acid" includes mixtures of acids, "a catalyst composition" includes mixtures of catalyst compositions, and the like.

In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.

The following definitions pertain to chemical structures, molecular segments and substituents: As used herein, the phrase "having the structure" is not intended to be limiting and is used in the same way that the term "comprising" is commonly used. The term "independently selected from the group consisting of is used herein to indicate that the recited elements, e.g., R groups or the like, can be identical or different (e.g., R¹, R², R³ and R⁴ in the structure of formula (II) may all be substituted alkyl groups, or R¹, R² and R⁴ may be hydrido and R³ may be methyl, etc.). "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, the phrase "optionally substituted hydrocarbyl" means that a hydrocarbyl moiety may or may not be substituted and that the description includes both unsubstituted hydrocarbyl and hydrocarbyl where there is substitution.

The term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, ..-propyl, isopropyl, «-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Generally, although again not necessarily, alkyl groups herein contain 1 to about 12 carbon atoms. The term "lower alkyl" intends an alkyl group of one to six carbon atoms, preferably one to four carbon atoms. "Substituted alkyl" refers to alkyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkyl" and "heteroalkyl" refer to alkyl in which at least one carbon atom is replaced with a heteroatom.

The term "alkenyl" as used herein refers to a branched or unbranched hydrocarbon group typically although not necessarily containing 2 to about 24 carbon atoms and at least one double bond, such as ethenyl, rø-propenyl, isopropenyl, τ?-butenyl, isobutenyl, octenyl, decenyl, and the like. Generally, although again not necessarily, alkenyl groups herein contain 2 to about 12 carbon atoms. The term "lower alkenyl" intends an alkenyl group of two to six carbon atoms, preferably two to four carbon atoms. "Substituted alkenyl" refers to alkenyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to alkenyl in which at least one carbon atom is replaced with a heteroatom. The term "alkynyl" as used herein refers to a branched or unbranched hydrocarbon group typically although not necessarily containing 2 to about 24 carbon atoms and at least one triple bond, such as efhynyl. /.-propynyl, isopropynyl, w-butynyl, isobutynyl, octynyl, decynyl, and the like. Generally, although again not necessarily, alkynyl groups herein contain 2 to about 12 carbon atoms. The term "lower alkynyl" intends an alkynyl group of two to six carbon atoms, preferably three or four carbon atoms. "Substituted alkynyl" refers to alkynyl substituted with one or more substituent groups, and the terms "heteroatom-containing alkynyl" and "heteroalkynyl" refer to alkynyl in which at least one carbon atom is replaced with a heteroatom.

The term "alkoxy" as used herein intends an alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy" group may be represented as -O-alkyl where alkyl is as defined above. A "lower alkoxy" group intends an alkoxy group containing one to six, more preferably one to four, carbon atoms.

Similarly, the term "alkyl thio" as used herein intends an alkyl group bound through a single, terminal thioether linkage; that is, an "alkyl thio" group may be represented as -S-alkyl where alkyl is as defined above. A "lower alkyl thio" group intends an alkyl thio group containing one to six, more preferably one to four, carbon atoms.

The term "allenyl" is used herein in the conventional sense to refer to a molecular segment having the structure -CH=C=CH₂. An "allenyl" group may be unsubstituted or substituted with one or more non-hydrogen substituents.

The term "aryl" as used herein, and unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, linked covalently, or linked to a common group such as a methylene or ethylene moiety. The common linking group may also be a carbonyl as in benzophenone, an oxygen atom as in diphenylether, or a nitrogen atom as in diphenylamine. Preferred aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like. In particular embodiments, aryl substituents have 1 to about 200 carbon atoms, typically 1 to about 50 carbon atoms, and preferably 1 to about 20 carbon atoms. "Substituted aryl" refers to an aryl moiety substituted with one or more substituent groups, and the terms "heteroatom- containing aryl" and "heteroaryl" refer to aryl in which at least one carbon atom is replaced with a heteroatom.

The term "aralkyl" refers to an alkyl group with an aryl substituent, and the term "aralkylene" refers to an alkylene group with an aryl substituent; the term "alkaryl" refers to an aryl group that has an alkyl substituent, and the term "alkarylene" refers to an arylene group with an alkyl substituent. The terms "halo" and "halogen" are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent. The terms "haloalkyl," "haloalkenyl" or "haloalkynyl" (or "halogenated alkyl," "halogenated alkenyl," or "halogenated alkynyl") refers to an alkyl, alkenyl or alkynyl group, respectively, in which at least one of the hydrogen atoms in the group has been replaced with a halogen atom.

The term "heteroatom-containing" as in a "heteroatom-containing hydrocarbyl group" refers to a molecule or molecular fragment in which one or more carbon atoms is replaced with an atom other carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon. Similarly, the term "heteroalkyl" refers to an alkyl substituent that is heteroatom-containing, the term "heterocyclic" refers to a cyclic substituent that is heteroatom-containing, the term "heteroaryl" refers to an aryl substituent that is heteroatom-containing, and the like. When the term "heteroatom-containing" appears prior to a list of possible heteroatom-containing groups, it is intended that the term apply to every member of that group. That is, the phrase "heteroatom-containing alkyl, alkenyl and alkynyl" is to be interpreted as "heteroatom- containing alkyl, heteroatom-containing alkenyl and heteroatom-containing alkynyl."

"Hydrocarbyl" refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, including branched or unbranched, saturated or unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like. The term "lower hydrocarbyl" intends a hydrocarbyl group of one to six carbon atoms, preferably one to four carbon atoms. The term "hydrocarbylene" intends a divalent hydrocarbyl moiety containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, including branched or unbranched, saturated or unsaturated species, or the like. The term "lower hydrocarbylene" intends a hydrocarbylene group of one to six carbon atoms, preferably one to four carbon atoms. "Substituted hydrocarbyl" refers to hydrocarbyl substituted with one or more substituent groups, and the terms "heteroatom-containing hydrocarbyl" and "heterohydrocarbyl" refer to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Similarly, "substituted hydrocarbylene" refers to hydrocarbylene substituted with one or more substituent groups, and the terms "heteroatom- containing hydrocarbylene" and "heterohydrocarbylene" refer to hydrocarbylene in which at least one carbon atom is replaced with a heteroatom. By "substituted" as in "substituted hydrocarbyl," "substituted hydrocarbylene,"

"substituted alkyl," "substituted alkenyl" and the like, as alluded to in some of the aforementioned definitions, is meant that in the hydrocarbyl, hydrocarbylene, alkyl, alkenyl or other moiety, at least one hydrogen atom bound to a carbon atom is replaced with one or more substituents that are functional groups such as hydroxyl, alkoxy, thio, amino, halo, silyl, and the like. When the term "substituted" appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group. That is, the phrase "substituted alkyl, alkenyl and alkynyl" is to be interpreted as "substituted alkyl, substituted alkenyl and substituted alkynyl." Similarly, "optionally substituted alkyl, alkenyl and alkynyl" is to be interpreted as "optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl." As used herein the term "silyl" refers to the -SiZ^Z³ radical, where each of Z¹,

Z², and Z³ is independently selected from the group consisting of hydrido and optionally substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, heterocyclic, alkoxy, aryloxy and amino.

As used herein, the term "phosphino" refers to the group -PZ'Z², where each of Z¹ and Z² is independently selected from the group consisting of hydrido and optionally substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, heterocyclic and amino.

The term "amino" is used herein to refer to the group -NZ'Z², where each of Z¹ and Z² is independently selected from the group consisting of hydrido and optionally substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl and heterocyclic. The term "thio" is used herein to refer to the group -SZ¹, where Z¹ is selected from the group consisting of hydrido and optionally substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl and heterocyclic.

The terms "LUMO" and "HOMO" (abbreviations for lowest unoccupied molecular orbital and highest occupied molecular orbital, respectively) refer to the frontier orbitals of two reactants (such as a diene and dienophile, in a Diels- Alder reaction), with the

LUMO referring to the vacant orbital of lowest energy, in a first reactant, and the HOMO referring to the orbital containing electrons of highest energy, in a second reactant. The present invention lowers the LUMO of a first reactant relative to its initial state, and generally relative to the HOMO of a second reactant, to facilitate reaction therewith. The term "chiral" refers to a structure that does not have an improper rotation axis (S_n), i.e., it belongs to point group C_n or D_n. Such molecules are thus chiral with respect to an axis, plane or center of asymmetry. Preferred "chiral" molecules herein are in enantiόmerically pure form, such that a particular chiral molecule represents at least about 95 wt.% of the composition in which it is contained, more preferably at least about 99 wt.% of that composition. The term "enantioselective" refers to a chemical reaction that preferentially results in one enantiomer relative to a second enantiomer, i.e., gives rise to a product of which a desired enantiomer represents at least about 50 wt.%. Preferably, in the enantioselective reactions herein, the desired enantiomer represents at least about 85 wt.% of the product, optimally at least about 95 wt.% of the product. The term "substrate" refers generally to a reactant, e.g., the "first reactant" herein or the "second reactant" herein.

As used herein all reference to the elements and groups of the Periodic Table of the Elements is to the version of the table published by the Handbook of Chemistry and Physics, CRC Press, 1995, which sets forth the new IUPAC system for numbering groups. In one embodiment, then, the invention provides a process for catalytically transforming a compound containing a functional group to provide a product in which the functional group contains at least one newly formed covalent bond. The starting material that is transformed is generally represented by the structure of formula (I)

wherein FG comprises the functional group, R¹ is hydrido, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl or silyl and is optionally covalently bound, directly or indirectly, to FG, and Q¹ and Q² are independently selected from the group consisting of OR¹, SR¹, N(R')₂, NR'(OR^]), NR^SR¹), and NR¹-N(R¹)₂, or Q¹ and Q² together form =Q in which Q is O, S, NR¹, N(OR'), N(SR') and N-N(R')₂. In some embodiments, it is preferred that =Q is other than =NR' or =N(OR^]). The process involves reacting this first reactant with a second reactant in the presence of a catalyst composition comprising a first catalyst precursor and a second catalyst precursor, wherein the first catalyst precursor is a heteroatom-containing activator and the second catalyst precursor is an acid. In structural formula (I), FG, Q^! and Q² are typically selected to enable formation of an intermediate in which the LUMO of the compound (particularly the LUMO of the functional group FG) is lowered relative to its initial state and generally relative to the HOMO of the second reactant as well. LUMO lowering in this way in turn enables reaction such that new covalent bonds are formed between the LUMO-lowered functional group FG and a second reactant (in either an intra- or intermolecular reaction). While not wishing to be bound by theory, it is proposed that formation of the intermediate involves replacement of the C-Q¹ and C-Q² (or C=Q) bonds with a covalent bond of that carbon atom to a heteroatom in the heteroatom-containing activator. Preferred first reactants are wherein Q' and Q² together form a carbonyl moiety =O and wherein FG contains a π bond between two atoms that are CL and β to the carbon atom bound to Q¹ and Q², e.g., FG may comprise A=B or A≡B wherein A is C or N, and B is N, C or O. For example, FG may comprise C=C, C=C=C, C≡C, C=N, C≡N, C=O or C=S. In such a case, the first reactant may be represented by the structural formula (la)

wherein A, B, R¹, Q¹ and Q² are as defined above, the dotted line represents an optional triple bond, and R², R³ and R⁴ are independently selected from the group consisting of hydrido, hydroxyl, sulfhydryl, amino, substituted amino, hydrocarbyl (e.g., alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), substituted hydrocarbyl (e.g., substituted alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), heteroatom-containing hydrocarbyl (e.g., heteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), substituted heteroatom-containing hydrocarbyl (e.g., substituted heteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), silyl and phosphino, or two or more of R¹, R², R³ and R⁴ are joined together in a ring structure, generally a five- or six-membered alicyclic or aromatic group (e.g., R³ and R⁴ may together form a cyclohexyl ring). Alternatively FG may contain a functional equivalent of a π bond such as a cyclopropyl or substituted cyclopropyl group, i.e., a group that has π bond-type reactivity.

In a preferred embodiment, the first reactant is an θ-,β-unsaturated carbonyl compound, generally an C-,β-unsaturated ketone or an C-,β-unsaturated aldehyde, and may be represented by the structure of formula (II)

in which R¹, R², R³ and R⁴ are as defined above. As may be seen in formula (II), the compound is an C_,β-unsaturated ketone when R¹ is hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl or substituted heteroatom-containing hydrocarbyl, and an C-,β-unsaturated aldehyde when R¹ is hydrido.

Examples of specific C.,β-unsaturated carbonyl compounds having the structure of formula (I) thus include, but are not limited to, the following:

The catalyst composition, as noted earlier herein, comprises a first catalyst precursor and a second catalyst precursor. The first catalyst precursor is a heteroatom- containing activator which in one embodiment is a chiral compound, i.e., a compound that is chiral with respect to an axis, plane or center of asymmetry. Preferably, the heteroatom of the heteroatom-containing activator is an element selected from Groups 15 and 16 of the periodic table. Such elements include nitrogen, oxygen, sulfur and phosphorus, and a preferred heteroatom is nitrogen. Oxygen-containing and sulfur-containing activators may be, for example, alcohols and thiols, respectively, while phosphorus-containing activators will generally be phosphines. Heteroatom-containing activators in which the heteroatom is a nitrogen atom may be primary amines, secondary amines or nitrogen-containing polymers. The primary and secondary amines will generally have the structure of formula (III)

F _^R⁶

(HI)

In formula (III), R⁵ is selected from the group consisting of hydrido, hydrocarbyl (e.g., alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), substituted hydrocarbyl (e.g., substituted alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), heteroatom-containing hydrocarbyl (e.g., heteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), and substituted heteroatom-containing hydrocarbyl (e.g., substituted heteroatom-containing alkyl,' alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), and R⁶ is selected from the group consisting of hydrocarbyl (e.g., alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), substituted hydrocarbyl (e.g., substituted alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), heteroatom-containing hydrocarbyl (e.g., heteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), and substituted heteroatom-containing hydrocarbyl (e.g., substituted heteroatom-containing alkyl, alkenyl, alkynyl, aryl, alkaryl, alkaryl, etc.), or R⁵ and R⁶ are joined together in a substituted or unsubstituted ring structure optionally containing a further heteroatom in addition to the nitrogen atom shown in formula (III). When R⁵ and R⁶ are linked, the ring formed may be, for example, a five- or six-membered alicyclic or aromatic group, e.g., R⁵ and R⁶ may together form substituted or unsubstituted cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, pyridinyl, pyrimidinyl, imidazolyl, or the like. Preferred compounds are secondary amines, i.e., compounds wherein R⁵ is other than hydrido, and particularly preferred compounds are those wherein R⁵ and R⁶ are independently selected from the group consisting of methyl, ethyl, propyl, butyl, cyclopentyl, cyclohexyl, cyclooctyl, phenyl, naphthyl, benzyl and trimethylsilyl, or are linked to form a 3- to 15-membered, optionally substituted cyclic moiety having the structure of formula (IV)

wherein n is 0 or 1, X is a moiety that contains up to 50 atoms and is selected from the group consisting of hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene and substituted heteroatom-containing hydrocarbylene, and X¹ and X² are independently substituted or unsubstituted methylene. Exemplary such secondary amines have the structure of formula (V)

wherein R⁷, R⁸, R⁹ and R¹⁰ are independently hydrido, hydroxyl, sulfhydryl, amino, substituted amino, carboxyl, alkyl, heteroalkyl, substituted alkyl, alkenyl, heteroalkenyl, substituted alkenyl, alkynyl, heteroalkynyl, substituted alkynyl, aryl, heteroaryl or substituted aryl, or R⁷ and R⁸ and/or R⁹ and R¹⁰ together form a carbonyl group =O. X may be, for example, -(CR^uR¹²)-(X³)_q-(CR¹³R¹⁴)_r, in which case the amine has the structure of formula (NI)

wherein X³ is O, S, NH, N(alkyl) or CR¹⁵R¹⁶, q is 0 or 1, t is 0 or 1, and R^π through R¹⁶ are defined as for R⁷ through R¹⁰.

Chiral amines are chiral with respect to an axis, plane or center of asymmetry, but are generally chiral with a center of asymmetry present. It will be appreciated by those skilled in the art that the various R groups discussed with respect to the foregoing amines can be selected to create the desired chirality. Numerous structures are shown below that those of skill in the art can use for guidance in selecting appropriate R groups to obtain a useful chiral molecule.

^•v _0₂Me o

TfOH HX •HX ■HX pTSA

o-CIC₆H₄C0₂H

HX = HBr

• HX •HX •HX HCI

HF

H₂S0₄

CH₃C0₂H

HX = . HBr . TfOH

• HX • HX •HX • HCI . HF

. H₂S0₄

• H₃P0₄

. C₆F₅0H

• o-02NC₆H₄C0₂H

•HX •HX •HX

HX = . HBr • TfOH

• H₂S0₄

• H₃P0₄

• o-CIC₆H₄C0₂H

. m-0₂NC₆H₄C0₂H p-0₂NC₆H₄C0₂H

•HX •HX •HX

HF

H₂S0₄

H3PO4

o-0₂NC₆H₄C0₂H m-0₂NC₆H₄C0₂H

When the heteroatom-containing activator is a nitrogenous polymer, the polymer may contain nitrogen in either the polymer backbone, pendant moieties, or both. For example, the polymer may be polyethylene imine, polyvinylpyridine, polyallylamine (including N-alkylated and N,N-dialkylated polyallylamines), polyimidazole, a polyfamino or alkylated amino)ethylene, or the like.

The heteroatom-containing activators can be obtained commercially or synthesized using routine methodology known to those skilled in the' art of synthetic organic chemistry and/or described in the pertinent texts and literature. For purposes of exemplification, a detailed description of an imidazolidinone activator ((5S)-5-benzyl-2,2,3- trimethylimidazolidin-4-one hydrochloride) is described in Example 1. Suitable nitrogen- containing polymers can be obtained commercially or can be obtained, for example, by reacting or anchoring a chiral or achiral amine to a support comprised of an organic polymeric material or an inorganic polymeric material or matrix.

The acid component of the catalyst system is believed to function to facilitate reaction of the heteroatom-containing activator with the first reactant, e.g., an 0_,β- unsaturated carbonyl compound. For example, with amine activators and carbonyl-containing reactants, the acid component provides a counterion for the iminium cation that serves as an intermediate, as will be discussed below. Suitable acids include both inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., as well as organic acids, e.g., acetic acid, benzoic acid, sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid, and the like. The acid component may also be a Lewis acid such as boron trifluoride, aluminum chloride, stannic chloride, zinc chloride or ferric chloride. A single acid may be used, or a combination of one or more acids or acid types may be employed. In a related embodiment, the catalyst composition comprises a single component, a salt of a heteroatom-containing activator, as described above, and an acid, e.g., an inorganic acid, an organic acid, a Lewis acid, combinations thereof, or the like. In such a case, the process of transforming the first reactant involves reaction with the second reactant in the presence of the aforementioned salt, and no added acid is required. The second reactant may be any compound that is capable of reacting with the first reactant by virtue of the lowered LUMO of the first reactant in the presence of the catalyst composition. The second reactant may or may not be covalently linked, directly or indirectly, to the first reactant, i.e., the reaction between the first and second reactants may be either intramolecular or intermolecular. Selection of the second reactant will depend on the reaction of interest; thus, for example, in a Diels-Alder reaction, the second reactant is a diene (while the first reactant is a dienophile such as an α,β-unsaturated carbonyl compound). Examples of various reactants and corresponding reaction types are discussed in further detail below.

In a preferred embodiment, the invention particularly provides a process for transforming an 0i,β-unsaturated carbonyl compound by reaction with a second reactant in the presence of a catalyst composition comprising an amine and an acid, wherein the α,β- unsaturated carbonyl compound has the structure of formula (II)

and the amine has the structure of formula (III)

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined previously. Without being bound by theory, this catalytic method appears to proceed by reaction of the α,β-unsaturated carbonyl compound with the amine component of the catalyst to form a positively charged iminium ion (i.e., a positively charged α,β-unsaturated imine) as an intermediate. The second reactant, e.g., a 1,3-diene in a Diels-Alder reaction, then reacts with the iminium ion- which is essentially an activated o-,β-unsaturated carbonyl compound—to produce the desired product and regenerate the amine. The amine acts to lower the LUMO of the α,β-unsaturated carbonyl compound and thus increase the compound's reactivity, e.g., with respect to its original state and generally with respect to the HOMO of the second reactant. With the CX,β- unsaturated carbonyl compound represented by formula (II) and the amine component of the catalyst system represented by formula (III), the positively charged iminium intermediate has the structure of formula (Nil)

where R¹ through R⁶ are as defined previously. Generally, since secondary amines are preferred, R⁵ and R⁶ are either independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl, or are linked together in a ring structure. This compound represents an additional embodiment of the invention. Particularly preferred such compounds are wherein R⁵ and R⁶ are joined together in a ring structure, typically a 3- to 15-membered, optionally substituted cyclic moiety, in which case the compound has the structure of formula

(vπi)

wherein R¹ through R⁴ are as defined above, n is 0 or 1, X is a moiety that contains up to 50 atoms and is selected from the group consisting of hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene and substituted heteroatom- containing hydrocarbylene, and X' and X² are independently substituted or unsubstituted methylene. For those compounds wherein X is -(CR¹¹R¹²)-(X³)_q-(CR¹³R¹⁴)_t-, the structure may be represented by formula (IX)

wherein X³ is O, S, NH, N(alkyl) or CR¹⁵R¹⁶, q is 0 or 1, t is 0 or 1, and Rⁿ through R¹⁶ are defined as for R⁷ through R¹⁰.

The foregoing discussion employs 0-,β -unsaturated carbonyl compounds as first reactants for simplicity; it will be appreciated that since FG can comprise moieties other than C=C bonds, the positively charged iminium ion intermediate may be more generally represented by structural formula (Vila)

wherein A, B and R¹ through R⁶ are defined earlier herein. Although other methods for lowering the LUMO of C-,β-unsaturated carbonyl compounds have been proposed, for example using Lewis acid catalysis, Bronsted acid catalysis and in situ generated dienophiles (see, e.g., International Patent Publication WO 92/02505, cited supra), the present process has not been disclosed previously. Relative to prior methods, the present invention is useful in conjunction with a wide variety of reactions, in turn enabling preparation of a host of reaction products.

The invention is useful, for example, in catalyzing cycloaddition reactions, 1,4- nucleophile conjugate addition reactions, 1,4 radical addition reactions, organometallic insertion reactions (including Heck reactions), ene reactions, and any combination thereof (including reactions occurring in tandem or cascade).

Cycloaddition reactions include, for example, [2+2] cycloaddition, [3+2] cycloaddition and [4+2] cycloaddition, with the latter reactions exemplified by Diels-Alder reactions, inverse demand Diels-Alder reactions, and hetero Diels-Alder reactions. An example of a Diels-Alder reaction catalyzed using a catalyst composition of the invention is illustrated in Figure 1, wherein the first and second reactants are acrolein and cyclopentadiene, respectively. An intramolecular [4+2] cycloaddition reaction of the invention is illustrated in Figure 4. A [3+2] cycloaddition reaction is illustrated in Figure 5. Other types of cycloaddition reactions that can be catalyzed using the. compositions and methods of the invention are described, for example, by Gothelf et al. (1998) Chem. Rev. 98:863-909.

1,4 Nucleophile conjugate addition reactions, include 1,4 carbon addition (e.g., cyclopropanation), 1,4 amine addition (e.g., aziridination), 1,4 oxygen addition (e.g., epoxidation), 1,4 sulfur addition, 1,4 hydride addition, and 1,4 organometallic addition. A cyclopropanation reaction of the invention is illustrated in Figure 2, while an epoxidation reaction of the invention is illustrated in Figure 3. Such reactions are examples of Michael additions, wherein the first reactant is an C-,β-unsaturated carbonyl compound (or an alternative compound encompassed by structural formula (I) and the second reactant is a nucleophile containing a π bond, a lone pair bearing heteroatom, or a negative charge, as illustrated in Figures 6 and 7 (Michael addition of furan and nitromethane, respectively). The foregoing list of possible reactions is intended to be illustrative and not in any way limiting of the reactions with which the present catalyst compositions and methods are useful.

In another embodiment, the invention is directed to the production of chiral molecules from starting materials that may or may not be chiral themselves, using a compound of structural formula (I) as a substrate or "first reactant" (e.g., an C.,β-unsaturated carbonyl compound) and a catalyst system comprised of a heteroatom-containing activator and an acid (or a salt of a heteroatom-containing activator and an acid). Preferably, the heteroatom-containing activator, e.g., a secondary amine, is chiral with respect to a center of asymmetry. Additionally, the heteroatom-containing activator is appropriately substituted so as to limit access to the activated double bond in the substrate (e.g., the C-,β-unsaturated carbonyl compound) and thus provide enantiofacial discrimination. That is, the heteroatom- containing activator can be selectively substituted in one or more regions of its molecular structure with a sterically bulky group which substantially prevents access to the activated double bond from one side of the molecule, but leaves the other side exposed and capable of reaction. By way of example, the Diels-Alder reaction between cyclopentadiene and an ,β- unsaturated carbonyl compound can result in either of two iminium ion intermediates, leading to two possible enantiomeric products, as illustrated in Figure 8. With an appropriately substituted chiral amine, as illustrated in Figure 9, one can achieve control of the iminium ion geometry and thus the enantioselectivity of the process. Methods known to those skilled in the art, e.g., MM2 and MM3 techniques, may be advantageously employed to assist in the selection and substitution of the heteroatom-containing activator to achieve the desired enantioselectivity .

Process conditions: The catalytic reactions of the invention are preferably although not necessarily carried out in water, organic solvents or ionic liquids, i.e., in any solvent that allows retention and regeneration of the catalyst composition and removal of the reaction product following completion of the reaction. The reactions may be carried out in batch, semi-continuously or continuously, in air or an inert atmosphere, at autogenous pressure or higher, depending, for example, on the nature of the catalyst composition and reactants used. The reaction temperature will generally be in the range of about -110°C to

200°C, preferably in the range of about -50°C to 100°C, most preferably in the range of about 0°C to 50°C. The amount of catalyst is generally in the range of 1 mole % to 1 stoichiometric equivalent, and the ratio of the first reactant to the second reactant (for Diels-Alder reactions, the ratio of the enone to the diene) is generally in the range of about 100:1 to 1:100, preferably in the range of about 10:1 to 1:10. Industrially, the reaction may be scaled up to 10,000 gallons or more. Catalysis may be heterogeneous or homogeneous. It will be appreciated by those skilled in the art of catalysis that the aforementioned process conditions may vary depending on the particular reaction, the desired product, the equipment used, and the like. Figure 10 illustrates, in detail, one possible manufacturing process. As shown in Figure 10, the purified product is obtained after completion of the reaction, wherein an optional extraction and/or catalyst recovery step and/or drying is followed by concentration or distillation to give the crude product and purification, e.g., by chromatography, sublimation, precipitation, extraction, crystallization with optional seeding and/or co-crystallization aids.

The present invention thus represents an important contribution to the field of catalysis by providing an entirely new method of catalyzing chemical reactions using nonmetallic, organic catalyst compositions. The present processes and compositions are useful in conjunction with an enormous variety of reactants and reaction types, and, importantly, can be used to prepare chiral compounds in enantiomerically pure form, from either chiral or achiral starting materials.

It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description above as well as the examples which follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.

EXPERIMENTAL:

In the following example, efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental error and deviation should be accounted for. Unless indicated otherwise, temperature is in degrees C and pressure is at or near atmospheric. All solvents were used as obtained from commercial suppliers unless otherwise indicated. Other commercial reagents were purified prior to use following the guidelines of Perrin and Armarego, Purification of Laboratory Chemicals, Fourth Edition (Oxford, Butterworth-Heinemann, 1996). Thin-layer chromatography (TLC) was performed on EM Reagents 0.25 mm silica gel 60-F plates. Visualization of the developed chromatogram was performed by fluorescence quenching, KMnO₄ stain or -anisaldehyde stain. Organic solutions were concentrated under reduced pressure on a Bϋchi rotary evaporator. Chromatographic purification of products was accomplished using forced-flow chromatography on ICN 60 32-64 mesh silica gel 63 according to the method of Still et al. (1978) J. Org. Chem. 43:2923.

Η and ¹³C NMR spectra were recorded on Bruker DRX-500 (500 MHz and 125 MHz, respectively), AM-400 (400 MHz and 100 MHz), or AMX-300 (300 MHz and 75 MHz) instruments, as noted, and are internally referenced to residual protio solvent signals. Data for *H NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (Hz), integration, and assignment. Data for ¹³C are reported in terms of chemical shift. IR spectra were recorded on an ASI React-IR 1000 spectrometer and are reported in terms of frequency of absorption (cm" '). Mass spectra were obtained from the University of California, Berkeley Mass Spectral facility. Gas chromatography was performed on Hewlett-Packard 5890A and 6890 Series gas chromatographs equipped with a split-mode capillary injection system and flame ionization detectors using the following columns: Bodman Chiraldex T-TA (30 m x 0.25 mm), Bodman Chiraldex β-PH (30 m x 0.25 mm), and C&C Column Technologies CC-1701 (30 m x 0.25 mm). HPLC analysis was performed on a Hewlett-Packard 1100 Series HPLC, UV detection monitored at 254 nm, using a Chiracel OD-H column (25 cm) and Chiralcel OD guard (5 . cm).

Progress of the Diels-Alder reaction was typically monitored by TLC analysis, or in cases where necessary, by ^]H NMR analysis of the reaction in situ in deuterated solvent or by GLC analysis of reaction aliquots. rø ^,-Pyrrolidine-2,5-dicarboxylic acid dimethyl ester hydrochloride ( 5) and bis-(l-methoxycarbonyl-2-phenylethyl amine) hydrochloride (6) were prepared as described by Effenbarger et al. (1986) Liebigs Ann. Chem. 334 and Ishihara et al. (1998) J Am. Chem. Soc. 120:6920. respectively.

Absolute configurations were determined by correlation to literature optical rotation values where indicated. Other absolute configurations were assigned by analogy.

General Procedure for Amine-Catalyzed Diels-Alder Reaction: To a solution of (55)-5-benzyl-2,2,3-trimethylimidazolidin-4-one hydrochloride (7) in CH₃OH/H₂O (95/5 v/v, 1.0 M) was added the ,β-unsaturated aldehyde. The solution was stirred for 1-2 minutes before addition of the appropriate diene. Upon consumption of the limiting reagent, the reaction mixture was diluted with Et₂O and washed successively with

H₂O and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated. Hydrolysis of the product dimethyl acetal was performed by stirring the crude product mixture in TFA:H₂O:CHCl₃ (1 : 1 :2) for 2 hr at room temperature, followed by neutralization with saturated aqueous NaHCO₃. Purification of the Diels-Alder adduct was accomplished by silica gel chromatography.

EXAMPLE 1

Preparation of (55)-5-benzyl-2,2,3-trimethylimidazolidin-4-one hydrochloride (7):

To a solution of ethanolic MeNH₂ (8.0 M, 60 mL) was added (5)-phenylalanine methyl ester hydrochloride (26.0 g, 121 mmol) and the resulting solution was stirred at room temperature until the amino ester was judged to be consumed as determined by TLC (20 hr). After removal of the organic solvents in vacuo, the residue was suspended. in Et₂O and then concentrated. This Et₂O addition-removal cycle was repeated several times (to remove excess MeNH₂) until (S)-phenylalanine N-methyl amide hydrochloride was obtained as a white solid. This amide hydrochloride was then treated with saturated aqueous NaHCO₃ (100 mL) and the free amine was extracted with CHC1₃ (100 x 3), dried (Na₂SO₄), filtered, and concentrated. To this residue was added MeOH (240 mL), acetone (45 mL, 605 mmol), and pTSA (230 mg, 1.2 mmol). The resulting solution was heated to reflux for 18 hr, cooled to room temperature, and then concentrated in vacuo. The residue was taken up in Et₂O, and a solution of HC1- dioxane (4.0 M) was added to precipitate compound (7). The precipitate was recrystallized from isopropanol to provide (5S)-5-benzyl-2,2,3-trimethylimidazolidin-4-one hydrochloride as colorless crystals in 59% overall yield from phenylalanine methyl ester hydrochloride (18.1 g, 71 mmol). IR (CH₂C1₂) 3366, 1722, 1644, 1397 cm^"1; Η NMR: (400 MHz, d₆-DMSO) δ 7.47-7.49 (d, J = 7.2 Hz, 2H, PhH), 7.32-7.36 (m, 2H, PhH), 7.25-7.29 (m, IH, PhH), 4.59-4.57 (br d, J = 7.6 Hz, IH, COCH), 3.35-3.42 (dd, J = 15.0, 10.2 Hz, IH,

PhCHH), 3.22-3.26 (dd, J = 15.0, 3.6 Hz, IH, PhCHH), 2.76 (s, 3H, NCH₃), 1.70 (s, 3H, CHCH₃CH₃), 1.50 (s, 3H, CHCH₃CH₃); ¹³C NMR (100 MHz, d₆-DMSO) δ 166.9, 136.8, 129.7, 128.8, 127.2, 77.1, 57.7, 33.2, 25.2, 23.9, 22.2;HRMS (Cl) exact mass calcd for C₁₃H₁₉N₂O) requires m/z 219.1497, found m/z 219.1387. The enantiopurity was confirmed (>99% ee) by HPLC analysis of the free amine using a Chiracel OD-H column (6% isopropanol in hexanes, 1 mL/min); (S)-enantiomer t_r = 14.1 min, (R)-enantiomer t_ — 16.6 min.

EXAMPLE 2 Preparation of (IS, 2S, 3S, 4R)-3-Phenylbicyclo[2.2.1]hex-5-ene-2-carboxaldehyde and

(IR, 2S, 3S, 4S)-3-Phenylbicyclo[2.2.1]hex-5-ene-2-carboxaIdehyde (Table 1, entry 5):

Prepared according to the general procedure with (E)-cinnamaldehyde (6.36 mL, 50.4 mmol), cyclopentadiene (12.5 mL, 151 mmol), and 7 (640 mg, 2.5 mmol) to afford the title compound as a colorless oil in 99% yield (12.2 g, 50.0 mmol) after silica gel chromatography (10% ΕtO Ac/hex); 1.0/1.3 endo:exo, endo 93% ee, exo 93% ee. Product ratios were determined by GLC (Bodman B-PH column, 60 °C, 1.5 °C/min gradient, 23 psi); endo isomers t_r = 53.1 min, 53.4 min, exo isomers t_r = 52.2 min, 52.7 min. 'H NMR, ¹³C NMR, and IR data were consistent with previously reported values (see Ishihara et al. (1998), supra). EXAMPLE 3

Preparation of (IS, 2R, 3S, 4R)-3-Methylbicyclo[2.2.1]hex-5-ene-2-carboxaldehyde and (IR, 2R, 3S, 4S)-3-Methylbicyclo[2.2.1]hex-5-ene-2-carboxaldehyde (Table 2, entry 1):

Prepared according to the general procedure with (E)-crotonaldehyde (871 μL, 10.0 mmol), cyclopentadiene (2.50 mL, 30.0 mmol), and 7 (109 mg, 0.50 mmol) to afford the title compound as a colorless oil in 75% yield (1.02 g, 7.5 mmol) after silica gel chromatography (3% ΕtO Ac/hex); 1.0/1.0 endo:exo, endo 90% ee, exo 86% ee. Product ratios were determined by GLC (Bodman T-TA column, 50 °C, 2 °C/min gradient, 23 psi); (IS, 2R, 3S, 4R) endo isomer t_r = 24.7 min, (IR, 2S, 3R, 45) endo isomer t_r = 25.0 min, exo isomers t_r = 22.4 min, 22.9 min. ^!H NMR, ¹³C NMR, and IR data for the endo isomer were consistent with previously reported values (see Ishihara et al. (1998) J Am. Chem. Soc. 120:6920-6930). The endo isomer was reduced to the corresponding alcohol (4 equiv NaBH₄ in MeOH (0.1 M)) and purified by silica gel chromatography for correlation of optical rotation with the literature value: [α_D]²⁰ = +73.6 (c = 0.92, 95% ΕtOH). Literature [α_D]²⁰ = +86.6 (c = 1.2, 95% ΕtOH) for (IR, 2R, 3S, 4S)-3-methylbicyclo[2.2. l]hex-5-ene-2- carboxaldehyde (see Sartor et al. (1990) S «/ett, pp. 197-198). Exo isomer: IR (CH₂C1₂) 2968, 1714 cm^"1; ^!H NMR (400 MHz, CDC1₃) δ 9.78-9.79 (d, j = 2.8 Hz, IH, CHO), 6.23-6.25 (dd, J = 5.7, 3.1 Hz, IH, CH=CH), 6.15-6.17 (dd, j = 5.7, 3.0 Hz, IH, CH-CH), 3.02 (br s, IH, CHCH-CH), 2.79 (br s, IH, CHCH=CH), 2.37-2.45 (m, IH, CHCHO), 1.70-1.73 (m, IH, CHCH₃), 1.44-1.48 (m, 2H, CHH), 0.89-0:91 (d, J = 6.9 Hz, CHCH₃); ¹³C

NMR (100 MHz, CDC1₃) δ 203.8, 136.3, 135.9, 60.0, 47.5, 47.4, 45.3, 35.7, 18.8; HRMS (ΕI) exact mass calcd for (C₉H₁₂O) requires m/z 136.0888, found m/z 136.0892; [α_D]²⁰ = +91 (c=0.81, CHCl₃).

EXAMPLE 4

Preparation of (IS, 2R, 3S, 4R)-3-Propyl-bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde and (IR, 2R, 3S, 4S)-3-Propyl-bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (Table 2, entry 2):

Prepared according to the general procedure with (E)-hex-2-enal (142 μL, 1.22 mmol), cyclopentadiene (302 μL, 3.66 mmol), and 7 (16 mg, 0.061 mmol) to provide the title compound as a colorless oil in 92% yield (184 mg, 1.12 mmol) after silica gel chromatography (10% EtO Ac/hex); 1.0:1.0 endo:exo; endo 90% ee; exo 86% ee. Product ratios were determined by GLC (Bodman ΪT-TA column, 100 °C isotherm, 23 psi); exo isomers t_r = 25.6 min and 26.7 min, endo isomers t_r = 30.2 min and 30.9 min. Η NMR, ¹³C NMR, and IR data for the endo isomer were consistent with previously reported values (Ishiara et al. (1998), supra). Exo isomer: IR (CH₂C1₂) 1719, 1466, 1456 cm^"1; ^]H NMR

(400 MHz, CDC1₃) δ 9.76 (d, J= 2.7 Hz, IH, CHO), 6.19 (dd, J= 5.6, 3.2 Hz, IH, CH=CH), 6.11 (dd, J= 5.6, 2.9 Hz, IH, CH=CH), 3.00 (br s, IH, CHCH=CH), 2.85 (br s, IH, CHCH-CH), 2.23-2.30 (m, IH, CHCH₂CH₂), 1.72-1.76 (m, IH, CHCHO), 1.00-1.47 (m, 6H, CHCH₂CH, CH₂CH₂CH₃), 0.86 (t, J= 7.2 Hz, 3H, CH₂CH₃); ¹³C NMR (100 MHz, CDC1₃) δ 203.9, 136.0, 135.9, 58.7, 47.0, 45.7, 44.8, 41.6, 36.4, 21.6, 14.1; HRMS (El) exact mass calcd for (C„H₁₆O) requires m/z 164.1201, found m/z 164.1200; [α]_D = +89.4 (c = 2.7, CHC1₃).

EXAMPLE 5 Preparation of (IS, 2S, 3S, 4R)-3-Isopropyl-bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde and (IR, 2S, 3S, 4S)-3-Isopropyl-bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (Table 2, entry 3):

Prepared according to the general procedure with (E)-4-methyl-pent-2-enal (142 μL, 1.22 mmol), cyclopentadiene (302 μL, 3.66 mmol), and 7 (16 mg, 0.061 mmol) to afford the title compound as a colorless oil in 81% yield (162 mg, 0.99 mmol) after silica gel chromatography (10% ΕtO Ac/hex); 1.0:1.3 endo:exo; endo 93% ee; exo 84% ee. Product ratios were determined by GLC (Bodman T-TA column, 100 °C isotherm, 23 psi); endo isomers t_r = 29.7 min and 30.5 min, exo isomers t. = 25.5 min and 27.2 min. Endo isomer: IR (CH₂C1₂) 1719, 1469, 1387, 1368, 1333 cm^"1; Η NMR (400 MHz, CDC1₃) δ 9.36 (d, J- 3.4 Hz, IH, CHO), 6.26 (dd, J- 5.7, 3.2 Hz, IH, CH=CH), 6.06 (dd, J= 5.7, 2.8 Hz, IH,

CH<Η), 3.11 (m, IH, CHCH=CH), 2.85 (m, IH, CHCH=CH), 2.49 (m, IH, CHCHO), 1.41-1.52 (m, 3H, CHCH(CH₃)₂, CHCH₂CH), 1.29-1.35 (m, IH, CH(CH₃)₂), 1.01 (d, J= 6.5 Hz, 3H, CHfCH^), 0.91 (d, J= 6.6 Hz, 3H, CH(CH₃)₂); ¹³C NMR (100 MHz, CDC1₃) δ 205.2, 138.9, 133.0, 58.6, 50.0, 46.5, 45.2, 45.1, 32.8, 21.9, 21.8; HRMS (ΕI) exact mass calcd for (C_nH₁₆O) requires m/z 164.1201, found m/z 164.1198; [α]_D = +44 (c = 0.47, CHCI₃). Exo isomer: IR (CH₂C1₂) 1719, 1465, 1368, 1336 cm^"1; Η NMR (400 MHz, CDC1₃) δ 9.78 (d, J= 2.6 Hz, IH, CHO), 6.19 (dd, J= 5.6, 3.1 Hz, IH, CH=CH), 6.15 (dd, J= 5.6, 2.8 Hz, IH, CH=CH), 3.02 (br s, IH, CHCH=CH), 2.96 (br s, IH, CHCH=CH), 1.84-1.92 (m, 2H, CHCHO, CHC(H)HCH), 1.38-1.47 (m, 2H, CHCH(CH₃)₂, CHC(H)HCH), 0.97-1.08 (m, IH, CH(CH₃)₂), 0.94 (d, J- 6.2 Hz, 3H, CT^CH^), 0.84 (d, J= 6.4 Hz, 3H, CH^I J,);

¹³C NMR (100 MHz, CDC1₃) δ 204.1, 136.2, 135.7, 57.9, 50.2, 46.9, 45.0, 44.9, 32.4, 22.0, 21.5; HRMS (El) exact mass calcd for (C„H₁₆O) requires m/z 164.1201, found m/z 164.1202; [α]_D = +82.8 (c = 1.7, CHC1₃).

EXAMPLE 6

Preparation of (IS, 2S, 3S, 4R)-3-Furan-2-yl-bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde and (IR, 2S, 3S, 4S)-3-Furan-2-yl-bicyclo[2.2.1]hept-5-ene-2-carboxaldehyde (Table 2, entry 5):

Prepared according to the general procedure with (E)-3-furyl-acrolein (166 mg, 1.36 mmol), cyclopentadiene (329 μL, 3.99 mmol) and 7 (34 mg, 0.13 mmol) to afford the title compound as a colorless oil as a mixture of acetal and aldehyde in 88% yield (5.7:1, 270 mg) after silica gel chromatography (10% ΕtO Ac/hex); 1.1:1.0 endo: exo; endo 93% ee; exo 91% ee. A small sample of the aldehyde was purified by prepatory HPLC for characterization purposes. Product ratios were determined by GLC (Bodman T-TA column, 70 °C, 5 °C/min gradient, 23 psi); exo isomers t_r = 17.4 min and 17.7 min, endo isomers t_ =

17.9 min and 18.1 min. Endo isomer: IR (CH₂C1₂) 1718, 1506, 1332cm^"1; Η NMR (500 MHz, CDC1₃) δ 9.56 (d, J= 1.9 Hz, IH, CHO), 7.32 (d, J= 1.0 Hz, IH, furyl), 6.35 (dd, J= 5.6, 3.1 Hz, IH, CH=CH), 6.30 (dd, J= 3.1, 1.9 Hz, IH, furyl), 6.13 (dd, J= 5.6, 2.7 Hz, IH, CH=CH), 6.07 (d, J= 3.2 Hz, IH, furyl), 3.33 (br s, IH), 3.13-3.09 (m, IH), 3.08-3.04 (m, 2H), 1.78 (br d, J= 8.7, IH), 1.59-1.53 (m, 2H); ¹³C NMR (125 MHz, CDC1₃) δ 202.5, 157.0, 141.3, 138.1, 133.7, 110.1, 105.0, 58.3, 48.5, 47.4, 44.6, 39.7; HRMS exact mass calcd for (C₁₂H₁₂O₂) requires m/z 188.0837, found m/z 188.0842; [α]_D = +157 (c = 0.28, CHC1₃). Exo isomer: IR (CH₂C1₂) 1717, 1506, 1334 cm^"1; ΗNMR (500 MHz, CDC1₃) δ 9.90 (d, J= 1.7 Hz, IH, CHO), 6.29 (dd, J= 5.6, 3.2 Hz, IH, CH=CH), 6.23 (dd, J= 3.1, 1.9 Hz, IH, furyl), 6.05 (dd, J= 5.6,2.9 Hz, IH, CH=CH), 5.89 (d, J= 3.2, IH, furyl), 3.70 (t, J= 4.3 Hz, IH), 3.26 (br s, IH, CHCH=CH), 3.20 (br s, IH, CHCH=CH), 2.50 (d, J= 5.1 Hz, IH, CHCHO), 1.57 (br s, IH), 1.55-1.48 (m, 2H); ^,3C NMR (125 MHz, CDC1₃) δ 201.9, 156.9, 141.1, 136.6, 136.2, 110.0, 105.0, 58.2, 46.9, 46.9, 44.9, 39.1; HRMS exact mass calcd for (C₁₂H₁₂O₂) requires m/z 188.0837, found m/z 188.0838; [α]_D = +210 (c = 0.53, CHC1₃).

EXAMPLE 7

Preparation of (IS, 8R, 9S, 10S)-l,8-Diphenyl-10-methyl-ll-oxa- tricyclo[6.2.1.0²'⁷]undeca-2(7),3,5-triene-9-carboxaldehyde (Table 3, entry 1):

To a 10 °C solution of 5 (13 mg, 0.058 mmol), 1,3-diphenylisobenzofuran (162 mg, 0.60 mmol), and MeOH (12 μL, 0.30 mmol) in DMF/H₂O (95/5 v/v, 1.0 M) was added (E)-crotonaldehyde (25 μL, 0.30 mmol). The solution was stirred at 10 °C for 24 h. The reaction mixture was then diluted with Εt₂O (10 mL) and washed with H₂O (10 mL). The aqueous layer was extracted with Et₂O (10 mL x 2) and the combined organics were dried (Na₂SO₄), and concentrated. Purification by silica gel chromatography (7% EtO Ac/hex) afforded the title compound as a yellow solid in 75% yield (76 mg, 0.22 mmol); 35:1 exo endo; 96% ee. Product ratios were determined, after reduction to the corresponding alcohol (4 eq NaBH₄, EtOH (0.1 M)), by HPLC (Chiralcel OD-H column, 3% EtOAc/hex, 1.0 mL/min) exo isomers t_r = 14.1 min and 15.3 min, endo isomers t_ = 16.5 min and 20.8. IR (CH₂C1₂) 3066, 3041, 2828, 2729, 1722, 1603, 1499, 1457, 1448, 1381, 1355, 1309 cm^"1; »H NMR (500 MHz, CDC1₃) δ 9.36 (d, J= 5.8 Hz, IH, CHO), 7.73-7.78 (m, 2H, ArH), 7.43- 7.57 (m, 7H, ArH), 7.35-7.40 (m, IH, ArH), 7.16-7.26 (m, 3H, ArH), 7.04-7.08 (m, IH, ArH), 3.08 (dq, J= 6.9, 4.1 Hz, IH, CHCH₃), 2.56 (dd, J= 5.8, 4.2 Hz, IH, CHCHO), 0.96 (d, J= 6.9 Hz, 3H, CH₃); ¹³C NMR (125 MHz) δ 201.9, 147.4, 145.0, 145.0, 136.6, 135.7, 135.5, 128.8, 128.6, 128.0, 127.4, 127.3, 127.0, 126.0, 125.5, 121.7, 118.5, 91.4, 89.2, 66.0, 43.0, 34.2, 30.3, 16.5; HRMS exact mass calcd for (C₂₄H₂₀O₂) requires m/z 341.1541, found m/z 341.1542; [α]_D = -82.4 (c = 1.0, CHC1₃). EXAMPLE 8

Preparation of (2R)-Bicyclo [2.2.2] oct-5-ene-2-carboxaldehyde (Table 3, entry 2):

To a solution of 7 (32 mg, 0.12 mmol) in CH₃CN/H₂O (95/5 v/v, 1.0 M) was added acrolein (501 μL, 7.5 mmol), and cyclohexadiene (238 μL, 2.5 mmol). The solution was stirred for 24 h, after which time the reaction mixture was diluted with Et₂O (10 mL) and washed with H₂O (10 mL). The aqueous layer was extracted with Et₂O (10 mL x 2) and the combined organics were dried (Na₂SO₄), and concentrated. Purification by silica gel chromatography (10% ether/pentane) afforded the title compound as a colorless oil in 82% yield (280 mg, 2.06 mmol); 14:1 endo:exo; 94% ee. Product ratios were determined by GLC (Bodman T-TA column, 75 °C isotherm, 23 psi) t_r = 51.0 min and 54.4 min. ^!H NMR, ¹³C

NMR, and IR data were consistent with previously reported values (Ishihara et al. (1998), supra).

EXAMPLE 9 Preparation of (lR)-4-methyl-3-cyclohexene-l-carboxaldehyde (Table 3, entry 3):

To a 0 °C solution of 7 (32 mg, 0.12 mmol) in CH₃NO₂/H₂O (95/5 v/v, 1.0 M) was added acrolein (1.0 mL, 15 mmol), and isoprene (0.50 mL, 5 mmol). The solution was stirred at 0 °C for 7 hr, then directly placed onto a silica gel column and eluted with 3% Et₂O/pentane, affording the title compound as a colorless oil in 84% yield (745 mg, 89% ee). Product ratios were determined by GLC (Bodman T-TA column, 35 °C, 0.25 °C/min gradient, 23 psi) t. = 84.1 min, 85.3 min. ^]H NMR, ¹³C NMR, and IR data were consistent with previously reported values (see Ishihara et al. (1998), supra). The absolute configuration was determined by oxidation to 4-methyl-3-cyclohexene-l -carboxylic acid and correlation of the optical rotation to the reported value; see Poll et al. (1985) Tetrahedron Lett. 26:3095-3098. To the aldehyde (255 mg, 2 mmol) was added a solution of isobutylene in THF (2.0 M, 30 mL) followed by tBuOH-H₂O (5/1, 20 mL), KH₂PO₄ (840 mg, 6 mmol), and NaClO₂ (540 mg, 6 mmol). The heterogenous mixture was stirred for 4 hr, then partitioned between EtOAc and H₂O. The organic extract was washed with brine, dried (MgSO₄), and concentrated. The white solid was purified by silica gel chromatography (20% EtOAc/hex): [α]_D ²⁰ = +89 (c = 4.0, 95% EtOH). Literature [α]_D ²⁰ = -107

(c = 4, 95% EtOH) for (S)-4-methyl-3-cyclohexene-l -carboxylic acid.

EXAMPLE 10 Preparation of (lR)-4-phenyl-3-cyclohexene-l-carboxaldehyde (Table 3, entry 4):

To a 0 °C solution of 2-pheny 1-1, 3 -butadiene (89 mg, 0.68 mmol) in CH₃NO₂/B₂O (95/5 v/v, 1.0 M) was added 7 (29.8 mg, 0.14 mmol) and acrolein (135 μL, 2.1 mmol). The solution was stirred at 0 °C for 7 hr, then directly placed onto a silica gel column and eluted with 5% EtOAc/hex affording the title compound as a cololess oil in 90% yield , (114 mg, 0.61 mmol, 83% ee). Product ratios were determined, after reduction to the corresponding alcohol (4 eq NaBH₄, MeOH (0.1 M)), by HPLC (Chiralcel OD-H column, 6% isopropanol in hexanes, 1 mL/min) t_r = 16.2 and 20.4, min. (lR)-4-phenyl-3-cyclohexene-l- carboxaldehyde: IR (CH₂C1₂) 2926, 2837, 2714, 1722, 1494, 1444 cm^"1; Η NMR (400 MHz, CDC1₃) δ 9.78 (s, IH, CHO), 7.40-7.23 (m, 5H, ArH), 6.16-6.12 (m, IH, PhC=CH), 2.64- 2.50 (m, 5H), 2.23-2.15 (m, IH), 1.90-1.79 (m, IH). ¹ C NMR (100 MHz, CDC1₃) δ 204.2,

141.6, 136.8, 128.2, 126.9, 125.0, 122.0, 45.7, 26.0, 25.0, 22.6; HRMS (Cl) exact mass calcd for (C₁₃H,₉N₂OCl) requires m/z 186.1045, found m/z 186.1041. (lR)-4-phenyl-3- cyclohexene-1-ol: IR (CH₂C1₂) 3374, 3289, 2918, 2860, 1444, 1034 cm^"1; Η NMR (500 MHz, CDC1₃) δ 7.41-7.39 (d, J= 7.6 Hz, 2H, o-PhH), 7.34-7.31 (t, J= 7.7 Hz, 2H, m-PhH), 7.26-7.22 (m, lH,^-PhH), 6.13 (br, IH, PhC=CH), 3.66-3.58 (m, 2H, CH₂OH), 2.58-2.41 (m,

2H), 2.40-2.31 (m, IH), 2.05-1.83 (m, 3H), 1.72-1.68 (s, IH), 1.50-1.41 (m, IH); ¹³C NMR (125 MHz, CDC1₃) δ 142.1, 136.5, 128,2, 126.6, 124.9, 123.3, 67.6, 35.9, 28.8, 26.8, 25.7; HRMS (Cl) exact mass calcd for (C₁₃H₁₉N₂OCl) requires m/z 188.1201, found m/z 188.1203.

EXAMPLE 11

Preparation of (IR, 2S)-2,4-Dimethyl-cyclohex-3-ene-l-carboxaldehyde (Table 3, entry

5):

To a -10 °C solution of 7 (27 mg, 0.11 mmol) in CH₃CN/H₂O (95/5 v/v, 1.0 M) was added acrolein (102 μL, 1.53 mmol), and 2-methyl-l,3-pentadiene (60 μL, 0.51 mmol). The solution was stirred for 31 h then filtered through a silica plug with CH₂C1₂. To the eluent was added (R,R)-2,4-pentanediol (160 mg, 1.54 mmol) and a single crystal of pTSA. The solution was allowed to stand 10 h before concentration and purification by silica gel chromatography (10% EtOAc/hex) affording the (R,R)-2,4-pentanediol acetal as a colorless oil in 75% yield (85 mg, 12 mmol); 5:1 endo: exo; 90% ee. Product ratios were determined by GLC (Bodman T-TA column, 70 °C initial temp, 3 °C/min gradient, 23 psi) t- = 24.0 min and 24.9 min. 'H NMR, ¹³C NMR, and IR data were consistent with previously published spectra (see Ishihara et al. (1998), supra).

EXAMPLE 12 Preparation of (IR, 2S)-Acetic acid 6-formy_-cyclohex-2-enyl ester (Table 3, entry 6):

To a solution of 7 (27 mg, 0.11 mmol) and 1 ,4-dimethoxybenzene (50 mg, 0.36 mmol) in CF₃OH/H₂O (95/5 v/v, 1.0 M) was added acrolein (214 μL, 3.21 mmol) followed by 1-acetoxybutadiene (127 μL, 1.07 mmol). The resulting solution was stirred until the diene was consumed (GLC analysis, CC-1701 column, 50 °C isotherm for 10 min, then 50 °C/min to 240 °C isotherm, 25 psi); cis- 1-acetoxybutadiene t_r = 4.5 min, trans-1- acetoxybutadiene t_ = 4.7 min, cyclohexa-l,3-dienecarbaldehyde t_r = 12.0 min, 1,4- dimethoxybenzene t_r = 13.0 min, trørø-acetic acid 6-formyl-cyclohex-2-enyl ester t_r = 13.7 min, cw-acetic acid 6-formyl-cyclohex-2-enyl ester t_r = 13.8 min. A GLC yield of 72% was determined by comparison of the peak areas of acetic acid 6-formyl-cyclohex-2-enyl ester and 1,4-dimethoxybenzene; 85% ee. ^]H NMR, ¹³C NMR, and IR data were consistent with previously reported value (Gouesnard et al. (1974) Tetrahedron 30:151. Enantiomeric excess was determined by GLC analysis using a Bodman T-TA column (100 °C, 1 mL/min) t. = 34.0 min and 47.9 min.

EXAMPLE 13

Enantioselectivity Studies:

The capacity of chiral amines to enantioselectively catalyze the Diels-Alder reaction bewteen α,β -unsaturated aldehydes and various dienes was evaluated. The proposed mechanism for the reaction is outlined in Scheme 1. As shown therein, the condensation of aldehyde (1) with an enantiopure amine results in the formation of activated iminium ion (2), which in turn engages a diene reaction partner. Accordingly, Diels-Alder cycloaddition would lead to the formation of an iminium ion (3), which upon hydrolysis would provide the enantio-enriched cycloaddition product (4) while reconstituting the chiral amine catalyst.

Scheme 1:

Catalysts:

The enantioselective catalytic Diels-Alder strategy was first evaluated using cyclopentadiene with (E)-cinnemaldehyde and a series of chiral secondary amine HCI salts. As revealed in

Table 1, this LUMO lowering strategy was successful using catalytic quantities (10 mol%) of both (S)-proline and (S)-aberine derived methyl esters providing the Diels-Alder adduct in excellent yield and moderate stereoselectivity (Table 1, entries 1 and 2, >80%, exo:endo 2.3-2.7: 1, 48-59% ee). In an effort to increase the enantiofacial discrimination of the cycloaddition step, catalysts were then designed in order to enforce high levels of stereocontrol in the formation of the iminium ion. With the C₂-symmetric amines 5 and 6, a significant increase in enantiocontrol was observed (entries 3 and 4, >82% yield, exo:endo 2.6-3.6:1, 57-74% ee). Iminium ion control through the use of steric constraints on the catalyst architecture was found to provided the highest levels of π-facial discrimination. High levels of enantioselectivity (92% ee) and catalyst efficiency (5 mol%) displayed by imidazolidinone 3 to provide the Diels-Alder adduct in 90% yield (entry 5) confirm the utility of such an amine salt as an optimal organic catalyst.

Table 1. Organocatalyzed Diels-Alder Reaction between Cinnemaldehyde and Cyclopentadiene

entry catalyst Time (h) % yield exo.endo exo ee (%)^a'

1 (_7)-Pro-OMeΗCl 27 81 2.7 1 48 (2R)

. 2 (5)-Abr-OMeΗCl 10 80 2.3 1 59 (2S)

3 5 23 92 2.6 1 57 (2Rf

4 6 84 82 3.6 1 74 (2R)

5 7 8 99 1.3 1 93(25)

Subsequent experiments that probed the scope of the dienophile reaction component are summarized in Table 2. Variation in the steric contribution of the olefm substituent (R, =

Me, Pr, -Pr entries 1-3) was found without loss in yield or enantioselectivity (>75% yield, endo ee >90%, exo ee >84%). The dienophile component was also tolerant of aromatic groups on the dienophile (entries 4-5, 89% yield, endo ee >93%, exo ee >91%). To confirm the preparative utility of the methodology, the addition of cyclopentadiene to cinnamaldehyde was performed on a 50-mmol scale utilizing catalyst 7. Table 2.

Organocatalyzed Diels-Alder Cycloadditions between Cyclopentadiene and Representative Dienophiles

entry R Time (h) % yield exo.endo^⁰ exo ee (%) endo ee (%)

1 Me 16 75 1:1 86 (25) 90 (25)

2 Pr 14 92 1: 1 86 (25) 90 (25)

3 /-Pr 14 81 1:1 84 (25) 93 (IS)

4 Ph 21 99 1.3:1 93 (25) 93 (25)

5 Furyl 24 89 1 : 1 91 (25) 93 (25)

This amine-catalyzed Diels-Alder cycloaddition was also general with respect to diene structure (Table 3). As revealed with 1 ,3-diρhenylisobenzofuran and cyclohexadiene

(entries 1 and 2), a range of diene structures could be used without loss in stereocontiol (entry 1, 75% yield, 35:1 exo:endo, 96% ee; entry 2, 82% yield, 1 :14 exo:endo, 94% ee). This methodology allows access to a number of cyclohexenyl building blocks tha tincorporate acetoxy, alkyl, formyl and aryl substituents with high levels of regio-, diastereo- and enantioselectivity (entries 3-6, 72-89% yield, 1:5-1 :11 exo:endo, 83-90% ee). It should also be noted that the reactions depicted in Tables 2 and 3 were performed under an aerobic atmosphere, using wet solvents and an inexpensive, bench-stable catalyst, further emphasizing the preparative advantages of the methods and compositions of the invention. Table 3.

Organocatalyzed Diels-Alder Cycloadditions between Acrolein or Crotonaldehyde and Representative Dienes

entry diene R product" yield exo.endo % ee a,b

Enantioselective formation of the (R)-formyl Diels-Alder adduct was observed in all cases involving the imidazolidinone catalyst 7, and was consistent with the calculated iminium ion model MM3-9 (a Monte-Carlo simulation using the MM3 force-field;

Macromodel V6.5). . Inspection of structure MM3-9 reveals two salient stereocontiol elements: (i) the enforced formation of the (E)-iminium isomer to avoid non-bonding interactions between the appendant olefin and the sterically encumbered dimethyl-bearing carbon and (ii) the bulky benzyl group on the catalyst framework which effectively shields the Re-face of the unsaturated iminium ion, leaving the Sz-face exposed to cycloaddition.

Claims (38)

1. A process for transforming an CC,β-unsaturated carbonyl compound by reaction with a second reactant, said process comprising: reacting an α,β-unsaturated carbonyl compound with the second reactant in the presence of a catalyst composition comprising a secondary amine and an acid selected from the group consisting of inorganic Bronsted acids, carboxylic acids, and mixtures thereof, wherein the 0C,β-unsaturated carbonyl compound has the structure of formula (II)

in which R¹ is hydrido, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl or silyl, and R², R³ and R⁴ are independently selected from the group consisting of hydrido, hydroxyl, sulfhydryl, amino, substituted amino, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, silyl and phosphino, or wherein two or more of R¹, R², R³ and R⁴ are joined together in a ring structure.

2. The process of claim 1, wherein the secondary amine has the structure of formula (III)

wherein R⁵ and R⁶ are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom- containing hydrocarbyl, or wherein R⁵ and R⁶ are joined together in a ring structure.

3. The process of claim 2, wherein R⁵ and R⁶ are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl.

4. The process of claim 2, wherein R⁵ and R⁶ are joined together in a ring structure.

5. The process of claim 2, wherein the ring is a 3- to 15-membered, optionally substituted cyclic moiety.

6. The process of claim 5, wherein the secondary amine has the structure of formula (IV)

wherein n is 0 or 1, X is a moiety that contains up to 50 atoms and is selected from the group consisting of hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene and substituted heteroatom-containing hydrocarbylene, and X¹ and X² are independently substituted or unsubstituted methylene.

7. The process of claim 6, wherein the secondary amine has the structure of ^' formula (V)

wherein R⁷, R⁸, R⁹ and R¹⁰ are independently hydrido, hydroxyl, sulfhydryl, amino, substituted amino, carboxyl, alkyl, heteroalkyl, substituted alkyl, alkenyl, heteroalkenyl, substituted alkenyl, alkynyl, heteroalkynyl, substituted alkynyl, aryl, heteroaryl or substituted aryl, or wherein R⁷ and R⁸ and/or R⁹ and R¹⁰ together form a carbonyl group =O.

8. The process of claim 7, wherein X is -(CRⁿR¹²)-(X³)_q-(CR¹³R¹⁴)_t- and the secondary amine therefore has the structure of formula (VI)

wherein X³ is O, S, NH, N(alkyl) or CR¹⁵R¹⁶, q is 0 or 1, t is 0 or 1, and R" through R¹⁶ are defined as for R⁷ through R¹⁰.

9. The process of claim 2, 6, 7, or 8, wherein the secondary amine is a chiral , compound.

10. The process of claim 9, wherein the secondary amine is chiral with respect to an axis, plane or center of asymmetry.

11. The process of claim 10, wherein the secondary amine is chiral with respect to a center of asymmetry.

12. The process of claim 1, wherein the acid is an inorganic Bronsted acid.

13. The process of claim 1, wherein the acid is a carboxylic acid.

14. The process of claim 1, wherein the second reactant is a 1,3-diene and the reaction is a Diels-Alder reaction.

15. The process of claim 1, wherein the second reactant is a nucleophile containing a π bond, a lone pair bearing heteroatom, or a negative charge, and the reaction is a Michael addition.

16. The process of claim 1, wherein the second reactant is a sulfur ylide and the reaction is a cyclopropanation.

17. The process of claim 1, wherein the second reactant is an organic peroxide and the reaction is an epoxidation.

18. The process of claim 1, wherein an intermediate is formed by reaction of the C6,β-unsaturated carbonyl compound with the amine, the intermediate comprising a positively charged C.,β-unsaturated imine.

19. A method for producing a chiral product from an achiral starting material, comprising:

(a) providing a substrate having the structural formula (I)

wherein FG comprises the functional group, R¹ is hydrido, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl or silyl and is optionally covalently bound, directly or indirectly, to FG, and Q¹ and Q² are independently selected from the group consisting of OR¹, SR¹, N(R^!)₂, NR^OR¹), NR^SR¹), and NR^NfR¹)^, or Q¹ and Q² together form =Q in which Q is O, S, NR¹, NfOR¹), N(SR¹), and N-N(R¹)₂;

(b) contacting the substrate with a catalyst composition comprising a first catalyst precursor and a second catalyst precursor, wherein the first catalyst precursor is a chiral heteroatom-containing activator and the second catalyst precursor is an acid selected from the group consisting of inorganic Bronsted acids, carboxylic acids, and mixtures thereof, to provide a chiral intermediate, with the proviso that when Q¹ and Q² together form =NR" or =N(OR'), then the heteroatom-containing activator is other than a secondary amine.

(c) reacting the achiral starting material with the chiral intermediate formed in step (b) so as to provide at least one newly formed covalent bonds within the functional group FG; and

(d) treating the product of step (c) with a reagent effective to regenerate the chiral heteroatom-containing activator and provide the desired chiral product in a form that is enantiomerically pure.

20. A method for preparing a chiral product from an achiral starting material, comprising:

(a) providing an achiral starting material having a molecular structure that enables reaction with an 0-,β-unsaturated carbonyl compound;

(b) reacting an 0-,β-unsaturated carbonyl compound with a chiral amine in the presence of an acid selected from the group consisting of inorganic Bronsted acids, carboxylic acids, and mixtures thereof to provide a positively charged, chiral o-,β-unsaturated iminium ion as an intermediate;

(c) reacting the achiral starting material with the α,β-unsaturated iminium ion so as to provide one or more newly formed covalent bonds therebetween; and (d) treating the product of step (c) with a reagent effective to regenerate the chiral amine and provide the desired chiral product in a form that is enantiomerically pure.

21. A process for catalytically transforming a compound containing a functional group to provide a product in which the functional group contains at least one newly formed covalent bond, comprising: reacting (a) a first reactant having the structural formula (I)

wherein FG comprises the functional group, R¹ is hydrido, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl or silyl and is optionally covalently bound, directly or indirectly, to FG, and Q¹ and Q² are independently selected from the group consisting of OR¹, SR¹, N(R¹)₂, NR^OR¹),

NR' SR¹), and NR¹-N(R¹)₂, or Q¹ and Q² together form =Q in which Q is O, S, NR¹, N(OR'), N(SR^!), and N-N(R¹)₂, with (b) a second reactant, in the presence of (c) a catalyst composition comprising a first catalyst precursor and a second catalyst precursor, wherein the first catalyst precursor is a heteroatom-containing activator and the second catalyst precursor is an acid selected from the group consisting of inorganic Bronsted acids, carboxylic acids, and mixtures thereof, with the proviso that when Q¹ and Q² together form =NR^] or =N(OR^!), then the heteroatom-containing activator is other than a secondary amine.

22. The process of claim 21, wherein FG contains a π bond between two atoms that are and β to the carbon atom bound to Q¹ and Q².

23. The process of claim 22, wherein FG comprises A=B or A≡B wherein A is C orN and B is N, C or O.

24. The process of claim 23, wherein FG comprises C=C, C=C=C, C=C, C=N, C≡N, C=O or C=S.

25. The process of claim 24, wherein FG is alkenyl and Q¹ and Q² together form =O, such that the first reactant is an 0C,β-unsaturated carbonyl compound.

26. The process of claim 25, wherein R¹ is other than hydrido, such that the first reactant is an C-,β-unsaturated ketone.

27. The process of claim 25, wherein R¹ is hydrido, such that the first reactant is an α,β-unsaturated aldehyde.

28. The process of claim 21, wherein the heteroatom of the heteroatom- containing activator is an element selected from Groups 15 and 16 of the periodic table.

29. The process of claim 28, wherein the heteroatom is selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus.

30. The process of claim 29, wherein the heteroatom is nitrogen.

31. The process of claim 30, wherein the heteroatom-containing activator is a primary amine, a secondary amine or a nitrogen-containing polymer.

32. The process of claim 21, wherein the heteroatom-containing activator is a chiral compound.

33. The process of claim 21, wherein the acid is an inorganic Bronsted acid.

34. The process of claim 21, wherein the acid is a carboxylic acid.

35. A process for catalytically transforming a compound containing a functional group to provide a product in which the functional group contains at least one newly formed covalent bond, comprising: reacting (a) a first reactant having the structural formula (I)

wherein FG comprises the functional group, R¹ is hydrido, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl or silyl and is optionally covalently bound, directly or indirectly, to FG, and Q¹ and Q² are independently selected from the group consisting of OR¹, SR¹, N(R^])₂, NR^OR¹), NR^SR¹), and NR¹-N(R¹)₂, or Q¹ and Q² together form =Q in which Q is O, S, NR¹, N(OR¹), N(SR^!), and N-N(R')₂, with (b) a second reactant, in the presence of (c) a catalyst comprising a salt of a heteroatom-containing activator and an acid selected from the group consisting of inorganic Bronsted acids, carboxylic acids, and mixtures thereof, with the proviso that when Q¹ and Q² together form =NR' or =N(OR¹), then the heteroatom-containing activator is other than a secondary amine.

36. A chemical reaction wherein a first reactant comprised of first reactant having the structural formula (I)

wherein FG comprises a functional group, R¹ is hydrido, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl or silyl and is optionally covalently bound, directly or indirectly, to FG, and Q¹ and Q² are independently selected from the group consisting of OR¹, SR¹, N(R¹)₂, NR^OR¹), NR'(SR'), and NR^!-N(R^!)₂, or Q¹ and Q² together form =Q in which Q is O, S, N(SR') or N- N(R¹)₂, is reacted with a second reactant in the presence of catalyst composition comprising a first catalyst precursor and a second catalyst precursor, wherein the first catalyst precursor is a heteroatom-containing activator in which the heteroatom is a Group 15 or Group 16 element, and the second catalyst precursor is an acid selected from the group consisting of inorganic Bronsted acids, carboxylic acids, and mixtures thereof, wherein the lowest unoccupied molecular orbital of the first reactant is lowered sufficiently to enable reaction with the second reactant relative to the energy state of the first reactant prior to contact with the catalyst composition.

37. A chemical reaction wherein a first reactant comprised of an α.,β-unsaturated carbonyl compound is reacted with a second reactant in the presence of a catalyst composition comprising a first catalyst precursor and a second catalyst precursor, wherein the first catalyst precursor is a heteroatom-containing activator in which the heteroatom is a Group 15 or Group 16 element, and the second catalyst precursor is an acid selected from the group consisting of inorganic Bronsted acids, carboxylic acids, and mixtures thereof, wherein the lowest unoccupied molecular orbital of the α,β-unsaturated carbonyl compound is lowered sufficiently to enable reaction with the second reactant relative to the energy state of the compound prior to contact with the catalyst composition.

38. The process of claim 35, wherein the catalyst comprises (5S)-5-benzyl-2,2,3- trimethylimidazolidin-4-one hydrochloride.