Stereoselective ring opening reactions
AssigneePresident and Fellows of Harvard College
InventorsEric N. Jacobsen, James L. Leighton, Luis E. Martinez
Life of this patent
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Abstract
The present invention relates a process for stereoselective or regioselective chemical synthesis which generally comprises reacting a nucleophile and a chiral or prochiral cyclic substrate in the presence of a non-racemic chiral catalyst to produce a steroisomerically or regioselectively enriched product.
Claims82
A process of stereoselective chemical synthesis which comprises reacting a nucleophile and a chiral or prochiral cyclic substrate in the presence of a non-racemic chiral catalyst to produce a stereoisomerically enriched product, wherein said cyclic substrate comprises a carbocycle or heterocycle having a reactive center susceptible to nucleophilic attack by said nucleophile, and said chiral catalyst comprises an asymmetric tetradentate ligand complexed with a metal atom, which complex has a rectangular planar or rectangular pyrimidal geometry.
A process of stereoselective chemical synthesis which comprises reacting a nucleophile and a chiral or prochiral cyclic substrate in the presence of a non-racemic chiral catalyst to produce a stereoisomerically enriched product, wherein said cyclic substrate comprises a carbocycle or heterocycle having a reactive center susceptible to nucleophilic attack by said nucleophile, and said chiral catalyst comprises an asymmetric tridentate ligand complexed with a metal atom, which complex has a planar geometry.
A stereoselective ring opening process which comprises
- combining a nucleophilic reactant, a prochiral or chiral cyclic substrate, and a non-racemic chiral catalyst, wherein said cyclic substrate comprises a carbocycle or heterocycle having an electrophilic atom susceptible to attack by said nucleophile, and said chiral catalyst comprises a chiral ligand having at least one schiff base nitrogen complexed with a late-transition metal which is not in its highest state of oxidation;
- and
- maintaining the combination under conditions appropriate for said chiral catalyst to catalyze stereoselective opening of said cyclic substrate at said electrophilic atom by reaction with said nucleophilic reactant.
A method for catalyzing a stereoselective ring opening reaction which comprises
- combining a nucleophile, a prochiral or chiral cyclic substrate, and a non-racemic chiral catalyst, wherein said cyclic substrate comprises a carbocycle or heterocycle having an reactive center susceptible to attack by said nucleophile, and said chiral catalyst comprises a chiral tetradentate ligand complexed with a late-transition metal which is not in its highest state of oxidation;
- and
- maintaining the combination under conditions appropriate for said chiral catalyst to catalyze stereoselective opening of said cyclic substrate at said reactive center by nucleophilic attack by the said nucleophile.
A method for catalyzing a stereoselective ring opening reaction which comprises
- combining a nucleophile, a prochiral or chiral cyclic substrate, and a non-racemic chiral catalyst, wherein said cyclic substrate comprises a carbocycle or heterocycle having an reactive center susceptible to attack by said nucleophile, and said chiral catalyst comprises a chiral tridentate ligand complexed with a late-transition metal which is not in its highest state of oxidation;
- and
- maintaining the combination under conditions appropriate for said chiral catalyst to catalyze stereoselective opening of said cyclic substrate at said reactive center by nucleophilic attack by the said nucleophile.
A method for synthesis of enantiomerically enriched chiral compounds, comprising reacting a nucleophile with a prochiral or chiral cyclic substrate in the presence of a chiral catalyst, and under conditions which said chiral catalyst catalyzes enantioselective opening of said cyclic substrate by nucleophilic attack of the cyclic substrate by the nucleophile to produce a product which is enantiomerically enriched relative to a racemic mixture produced in the absence of said chiral catalyst, wherein the chiral cyclic substrate is represented by the general formula:
- ##STR83## in which Y represents O, S, N(R.sub.50), C(R.sub.52)(R.sub.54), or has the formula A--B--C;
- wherein R.sub.50 represents a hydrogen, an alkyl, a carbonyl-substituted alkyl, a carbonyl-substituted aryl, or a sulfonate, R.sub.52 and R.sub.54 each independently represent an electron-withdrawing group;
- A and C are independently absent, or represent a C.sub.1 -C.sub.5 alkyl, O, S, carbonyl, or N(R.sub.50);
- and B is a carbonyl, a thiocarbonyl, a phosphoryl, or a sulfonyl;
- and
- R.sub.30, R.sub.31, R.sub.32, and R.sub.33 represent organic or inorganic substituent which form a covalent bond with the C1 or C2 carbon atoms of 118, and which permit formation of a stable ring structure including Y;
- and
- the chiral catalyst is represented by the general formula:
- ##STR84## the substituents R.sub.1, R.sub.2, Y.sub.1, Y.sub.2, X.sub.1, X.sub.2, X.sub.3 and X.sub.4 each, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7,
- or any two or more of the substituents taken together form a carbocyle or heterocycle ring having from 4 to 8 atoms in the ring structure,
- with the proviso that at least one of R.sub.1, Y.sub.1, X.sub.1 and X.sub.2 is covalently bonded to at least one of R.sub.2, Y.sub.2, X.sub.3 and X.sub.4 to provide the .beta.-iminocarbonyls to which they are attached as a tetradentate ligand, and at least one of Y.sub.1 and Y.sub.2 is a hydrogen;
- R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
- m is zero or an integer in the range of 1 to 8;
- M represents the late transition metal;
- and
- A represents a counterion or a nucleophile,
- wherein each of of the substituents R.sub.1, R.sub.2, Y.sub.1, Y.sub.2, X.sub.1, X.sub.2, X.sub.3 and X.sub.4, are selected such that the catalyst is asymmetric.
A method of stereoselectively opening a ring of a cyclic compound of the general formula:
- ##STR86## in which Y represents O, S, N(R.sub.50), C(R.sub.52)(R.sub.54), or has the formula A--B--C;
- wherein R.sub.50 represents a hydrogen, an alkyl, a carbonyl-substituted alkyl, a carbonyl-substituted aryl, or a sulfonate, R.sub.52 and R.sub.54 each independently represent an electron-withdrawing group;
- A and C are independently absent, or represent a C.sub.1 -C.sub.5 alkyl, O, S, carbonyl, or N(R.sub.50);
- and B is a carbonyl, a thiocarbonyl, a phosphoryl, or a sulfonyl;
- and
- R.sub.30, R.sub.31, R.sub.32, and R.sub.33 represent organic or inorganic substituent which form a covalent bond with the C1 or C2 carbon atoms of 118, and which permit formation of a stable ring structure including Y;
- which method comprises reacting a nucleophile with said cyclic compound in the presence of at least a catalytic amount of a chira metallosalenate catalyst.
A method of resolving enantiomers from a racemic mixture of a chiral cyclic compound having the general form ##STR88## in which Y represents O, S, N(R.sub.50), C(R.sub.52)(R.sub.54), or has the formula A--B--C;
- wherein R.sub.50 represents a hydrogen, an alkyl, a carbonyl-substituted alkyl, a carbonyl-substituted aryl, or a sulfonate, R.sub.52 and R.sub.54 each independently represent an electron-withdrawing group;
- A and C are independently absent, or represent a C.sub.1 -C.sub.5 alkyl, O, S, carbonyl, or N(R.sub.50);
- and B is a carbonyl, a thiocarbonyl, a phosphoryl, or a sulfonyl;
- and
- R.sub.30, R.sub.31, R.sub.32, and R.sub.33 represent organic or inorganic substituent which form a covalent bond with the C1 or C2 carbon atoms of 118, and which permit formation of a stable ring structure including Y;
- the method comprising contacting a mixture of the compound and its enantiomer with a nucleophile able to react with the ring structure in the presence of a chiral catalyst having the form:
- ##STR89## in which Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 each represent a Lewis base;
- the C.sub.1 moiety, taken with Z.sub.1, Z.sub.3 and M, and the C.sub.2 moiety, taken with Z.sub.2, Z.sub.4 and M, each, independently, form a heterocycle;
- R.sub.1, R.sub.2, R'.sub.1 and R'.sub.2 each, independently, are absent or represent a covalent substitution with an organic or inorganic substituent permitted by valence requirements of the electron donor atom to which it is attached,
- R.sub.40 and R.sub.41 each independently are absent, or represent one or more covalent substitutions of C.sub.1 and C.sub.2 with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached,
- or any two or more of the R.sub.1, R.sub.2, R'.sub.1, R'.sub.2 R.sub.40 and R.sub.41 taken together form a bridging substituent;
- with the proviso that C.sub.1 is substituted at at least one site by R.sub.1, R'.sub.1 or R.sub.41, and C.sub.2 is substituted at at least one site by R.sub.2, R'.sub.2 or R.sub.40, and
- at least one of R.sub.1, R'.sub.1 and R.sub.41 is taken together with at least one of R.sub.2, R'.sub.2 and R.sub.40 to form a bridging substituent so as to provide Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 as a tetradentate;
- M represents the late transition metal;
- and
- A represents a counterion or a nucleophile,
- wherein each R.sub.1, R.sub.2, R'.sub.1, R'.sub.2 R.sub.40 and R.sub.41 are selected to provide at least one
- stereogenic center in said tetradentate ligand,
- under conditions wherein the ring of one enantiomer is selectively opened leaving the other enantiomer substantially unchanged.
A method of providing a chiral carbonate, comprising reacting a prochiral epoxide with carbon dioxide in the presence of a chiral catalyst and an auxiliary catalyst such that a chiral carbonate is formed, wherein the catalyst chiral catalyst comprises an asymmetric tetradentate ligand complexed with a metal atom, which complex has a rectangular planar or rectangular pyrimidal geometry.
A method of providing a chiral carbonate, comprising reacting a prochiral epoxide with carbon dioxide in the presence of a chiral catalyst and an auxiliary catalyst such that a chiral carbonate is formed, wherein the catalyst chiral catalyst comprises an asymmetric tridentate ligand complexed with a metal atom, which complex has a planar geometry.
A method of stereospecifically expanding a ring of a cyclic compound having the form:
- ##STR90## in which Y represents O, S, N(R.sub.50), C(R.sub.52)(R.sub.54), or has the formula A--B--C;
- wherein R.sub.50 represents a hydrogen, an alkyl, a carbonyl-substituted alkyl, a carbonyl-substituted aryl, or a sulfonate, R.sub.52 and R.sub.54 each independently represent an electron-withdrawing group;
- A and C are independently absent, or represent a C.sub.1 -C.sub.5 alkyl, O, S, carbonyl, or N(R.sub.50);
- and B is a carbonyl, a thiocarbonyl, a phosphoryl, or a sulfonyl;
- and
- R.sub.30, R.sub.31, R.sub.32, and R.sub.33 represent organic or inorganic substituent which form a covalent bond with the C1 or C2 carbon atoms of 118, and which permit formation of a stable ring structure including Y;
- the method comprising reacting a ring expansion agent with said cyclic compound in the presence of a chiral catalyst having the form ##STR91## in which Z.sub.1, Z.sub.2, Z.sub.3 and Z.sub.4 each represent a Lewis base;
- the C.sub.1 moiety, taken with Z.sub.1, Z.sub.3 and M, and the C.sub.2 moiety, taken with Z.sub.2, Z.sub.4 and M, each, independently, form a heterocycle;
- R.sub.1, R.sub.2, R'.sub.1 and R'.sub.2 each, independently, are absent or represent a covalent substitution with an organic or inorganic substituent permitted by valence requirements of the electron donor atom to which it is attached,
- R.sub.40 and R.sub.41 each independently are absent, or represent one or more covalent substitutions of C.sub.1 and C.sub.2 with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached,
- or any two or more of the R.sub.1, R.sub.2, R'.sub.1, R'.sub.2 R.sub.40 and R.sub.41 taken together form a bridging substituent;
- with the proviso that C.sub.1 is substituted at at least one site by R.sub.1, R'.sub.1 or R.sub.41, and C.sub.2 is substituted at at least one site by R.sub.2, R'.sub.2 or R.sub.40, and
- at least one of R.sub.1, R'.sub.1 and R.sub.41 is taken together with at least one of R.sub.2,
- R'.sub.2 and R.sub.40 to form a bridging substituent so as to provide Z.sub.1, Z.sub.2, Z.sub.3 and
- Z.sub.4 as a tetradentate;
- M represents the late transition metal;
- and
- A represents a counterion or a nucleophile,
- wherein each R.sub.1, R.sub.2, R'.sub.1, R'.sub.2 R.sub.40 and R.sub.41 are selected to provide at least one stereogenic center in said tetradentate ligand,
- under conditions wherein the ring of one enantiomer is selectively opened leaving the other enantiomer substantially unchanged,
- under conditions such that said ring of said cyclic compound is stereoselectively expanded.
A composition comprising an aged metallosalenate catalyst, which catalyst is represented by the general formula:
- ##STR92## in which each of the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, Y.sub.1, Y.sub.2, X.sub.1, X.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.6, X.sub.7, and X.sub.8, independently, represent hydrogen, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphoryls, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or --(CH.sub.2).sub.m --R.sub.7 ;
- or any two or more of the substituents taken together form a carbocycle or heterocycle having from 4 to 10 atoms in the ring structure;
- R.sub.7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
- m is zero or an integer in the range of 1 to 8;
- M represents a transition metal;
- and
- A represents a nucleophile;
- wherein
- if R.sub.5 is absent, at least one of R.sub.1 and R.sub.2 is taken together with at least one of R.sub.3 and R.sub.4 to form a bridging substituent, and each of of the substituents of 106 are selected such that the salenate is asymmetric.
Dependencies are inferred from the claim text.