Asymmetric cycloaddition reactions
AssigneeHarvard University
InventorsEric N. Jacobsen, Scott E. Schaus, Alexander G. Dossetter, Timothy F. Jamison
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Abstract
The present invention relates to a process for stereoselective cycloaddition reactions which generally comprises a cycloaddition reaction between a pair of substrates, each either chiral or prochiral, that contain reactive π-systems, in the presence of a non-racemic chiral catalyst, to produce a stereoisomerically enriched product. The present invention also relates to novel asymmetric catalyst complexes comprising a metal and an asymmetric tridentate ligand.
Claims52
A process of stereoselective chemical synthesis, comprising the step of reacting a dienophile and a 1,3-diene in the presence of a non-racemic chiral catalyst to produce a stereoisomerically enriched product, wherein said product has an enantiomeric excess or diastereomeric excess of at least 60%;
- wherein said dienophile is represented by formula 119, said 1,3-diene is represented by formula 118, and said chiral catalyst consists of an asymmetric tridentate ligand, a metal atom, and a counterion, said catalyst having a trigonal planar or trigonal pyrimidal geometry:
- in which
- each occurrence of Z independently represents C(R50), Si(R50), N, or P, wherein R50 represents a hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- Y represents O, S, or N(R50);
- and
- R1, R2, R3, and R4 represent independentlv for each occurrence hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
- and
- m is zero or an integer in the range of 1 to 8.
A process for catalyzing a stereoselective cycloaddition reaction, comprising the steps of:
- combining a dienophile, a 1,3-diene, and a non-racemic chiral catalyst, wherein said dienophile is represented by formula 119, said 1,3-diene is represented by formula 118, and said chiral catalyst consists of an asymmetric tridentate ligand, a metal atom, and a counterion:
- in which
- each occurrence of Z independently represents C(R50), Si(R50), N, or P, wherein R50 represents a hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- Y represents O, S, or N(R50);
- and
- R1, R2, R3, and R4 represent independently for each occurrence hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
- and
- m is zero or an integer in the range of 1 to 8;
- and
- maintaining the combination under conditions whereby said chiral catalyst catalyzes a stereoselective cycloaddition reaction between said dienophile substrate and said 1,3-diene substrate to produce a stereoisomerically enriched product, wherein said product has an enantiomeric excess or diastereomeric excess of at least 60%.
A process of providing a non-racemic chiral dihydropyran, comprising the step of reacting an aldehyde represented by formula 119 with a 1,3-diene represeneted by formula 118 in the presence of a chiral, non-racemic catalyst to produce a non-racemic chiral dihydropyran, wherein said dihydropyran has an enantiomeric excess or diastereomeric excess of at least 60%, and wherein the chiral catalyst consists of an asymmetric tridentate ligand, a metal atom, and a counterion, said complex having a trigonal planar of trigonal pyrimidal geometry:
- in which
- each occurrence of Z independently represents C(R50), wherein R50 represents a hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- Y represents O;
- and
- R1, R2, R3, and R4 represent independently for each occurrence hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
- and
- m is zero or an integer in the range of 1 to 8.
A process of stereoselective chemical synthesis, comprising the step of reacting a dienophile and a 1,3-diene in the presence of a non-racemic chiral catalyst to produce a stereoisomerically enriched product, wherein said dienophile is represented by 119, and said 1,3-diene is reresented by 118:
- in which
- each occurrence of Z independently represents C(R50), Si(R50), N, or P, wherein R50 represents a hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- Y represents O, S, or N(R50);
- and
- R1, R2, R3, and R4 represent independently for each occurrence hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
- and
- m is zero or an integer in the range of 1 to 8;
- and
- said chiral catalyst consists of an asymmetric tridentate ligand, a metal atom, and a counterion, wherein said chiral tridentate ligand of said chiral catalyst is represented by formula 150:
- wherein
- R106 represents a hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- each of R112 and R′112 is absent or represent one or more covalent substitutions of the ring to which it is attached;
- R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
- and
- m is zero or an integer in the range of 1 to 8.
A process of stereoselective chemical synthesis, comprising the step of reacting a dienophile and a 1,3-diene in the presence of a non-racemic chiral catalyst to produce a stereoisomerically enriched product, wherein said dienophile is represeneted by 119, and said 1,3-diene is represented by 118:
- in which
- each occurrence of Z independently represents C(R50), Si(R50), N, or P, wherein R50 represents a hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- Y represents O, S, or N(R50);
- and
- R1, R2, R3, and R4 represent independently for each occurrence hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
- and
- m is zero or an integer in the range of 1 to 8;
- and
- said chiral catalyst is represented by structure 160:
- wherein
- Z represents N, P or As;
- X represents independently for each occurrence O, S, Se or ZR;
- M represents a metal ion and the requisite number of counterions;
- R represents independently for each occurrence hydrogen, alkyl, aryl, halo, acyl or aralkyl;
- or taken together any two instances of R on adjacent carbons may represent an optionally substituted ring consisting of 3-8 backbone atoms inclusive;
- said ring being saturated, unsaturated or aromatic;
- and said ring may be fused to another optionally substituted ring;
- R′ represents independently for each occurrence hydrogen, alkyl, aryl, halo, acyl or aralkyl;
- or taken together the two instances of R′ may represent an optionally substituted ring consisting of 3-8 backbone atoms inclusive;
- said ring being saturated, unsaturated or aromatic;
- and said ring may be fused to another optionally substituted ring;
- and
- one or both of the carbons bearing an instance of R′ may be asymmetric.
A process of stereoselective chemical synthesis, comprising the step of reacting a dienophile and a 1,3-diene in the presence of a non-racemic chiral catalyst to produce a stereoisomerically enriched product, wherein said dienophile is represented by 119, and said 1,3-diene is represented by 118:
- in which
- each occurrence of Z independently represents C(R50), Si(R50), N, or P, wherein R50 represents a hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- Y represents O, S, or N(R50);
- and
- R1, R2, R3, and R4 represent independently for each occurrence hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester, or —(CH2)m—R7;
- R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle;
- and
- m is zero or an integer in the range of 1 to 8;
- and
- said chiral catalyst is represented by structure 162:
- wherein
- X represents independently for each occurrence O, S, Se or ZR1;
- Z represents independently for each occurrence N, P or As;
- M represents a metal ion and the requisite number of counterions;
- R1 represents independently for each occurrence hydrogen, alkyl or aryl;
- R2 represents independently for each occurrence hydrogen, alkyl or aryl;
- and taken together the two instances of R2 may represent an optionally substituted ring consisting of 3-8 backbone atoms inclusive;
- said ring being saturated, unsaturated or aromatic;
- and said ring may be fused to another optionally substituted ring;
- R3 may be absent or present between one and four times inclusive;
- R3 represents independently for each occurrence alkyl, aryl, aralkyl, halo, acyl, sulfonyl, —(C(R1)2)mCOR1, —(C(R1)2)mCO2R1, —(C(R1)2)mNO2, —(C(R1)2)mS(O)nR1, —(C(R1)2)mOR1, —(C(R1)2)mN(R1)2;
- n represents independently for each occurrence an integer in the range 0-3 inclusive;
- m represents independently for each occurrence an integer in the range 0-8 inclusive;
- and
- one or both of the carbons bearing an instance of R2 may be asymmetric.
Dependencies are inferred from the claim text.