Methods for enantioselective preparation of chiral tetraarylmethanes

An enantioselective method for preparing a tetraarylmethane, wherein the tetraarylmethane has Formula Ia:

• wherein
• m is 0, 1, 2, or 3;n is 1, 2, 3, or 4;
• p is 0, 1, 2, or 3;
• t is 0, 1, 2, or 3;
• Ar1 is:
• Ar2 is:
• X is NH;
• Y is NH;
• R1′ is selected from the group consisting of —OR3, —OSi(R3)3, —O(C═O)R3, —O(C═O)OR3, —N(R4)2, —N(R4)(C═O)R3, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —N(R4)SO2R3, —SeR3, —P(R3)3, and —P(OR3)3;
• R1 and R2 are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, cyanide, nitro, azide, —OR3, —OSi(R3)3, —O(C═O)R3, —(C═O)OR3, —O(C═O)OR3, —(C═O)R3, —N(R4)2, —N(R4)(C═O)R3, —(C═O)N(R4)2, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —(S═O)R3, —SO2R3, —SO2N(R4)2, —N(R4)SO2R3, —SeR3, —P(R3)3, —P(OR3)3, and —(P═O)(OR3)3;
• or two instances of R1 taken together with the carbons to which they are attached form a 5-6 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• or two instances of R2 taken together with the carbons to which they are attached form a 5-6 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• R3 is selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl;
• and
• R4 for each instance is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl;
• or two instances of R4 taken together with the nitrogen to which they are attached form a 3-6 membered heterocycloalkyl;
• or one instance of R3 and one instance of R4 taken together with the atoms to which they are attached form a 4-6 membered heterocycloalkyl;
• each R9 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, cyanide, nitro, azide, —OR3, —OSi(R3)3, —O(C═O)R3, —(C═O)OR3, —O(C═O)OR3, —(C═O)R3, —N(R4)2, —N(R4)(C═O)R3, —(C═O)N(R4)2, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —(S═O)R3, —SO2R3, —SO2N(R4)2, —N(R4)SO2R3, —SeR3, —P(R3)3, —P(OR3)3, and —(P═O)(OR3)3;
• R9′ is —OH;
• R10 is selected from the group consisting of alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, and halide;
• and
• each R12 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, azide, —OR3, —OSi(R3)3, —O(C═O)R3, —O(C═O)OR3, —N(R4)2, —N(R4)(C═O)R3, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —N(R4)SO2R3, —SeR3, —P(R3)3, and —P(OR3)3;
• or two instances of R12 taken together with the carbons to which they are attached form a 5-6 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• and the method comprises:
• contacting a compound of Formula IIa, wherein the compound of Formula IIa is
• wherein Ar1 is selected from the group consisting of:
• m is 0, 1, 2, or 3;
• n is 1, 2, 3, or 4;
• p is 0, 1, 2, or 3;
• X is NH;
• R1′ is selected from the group consisting of —OR3, —OSi(R3)3, —O(C═O)R3, —O(C═O)OR3, —N(R4)2, —N(R4)(C═O)R3, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —N(R4)SO2R3, —SeR3, —P(R3)3, and —P(OR3)3;
• each R9 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, cyanide, nitro, azide, —OR3, —OSi(R3)3, —O(C═O)R3, —(C═O)OR3, —O(C═O)OR3, —(C═O)R3, —N(R4)2, —N(R4)(C═O)R3, —(C═O)N(R4)2, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —(S═O)R3, —SO2R3, —SO2N(R4)2, —N(R4)SO2R3, —SeR3, —P(R3)3, —P(OR3)3, and —(P═O)(OR3)3;
• R9′ is —OH;
• and
• R10 is selected from the group consisting of alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, and halide;
• with a heteroaromatic nucleophile in the presence of a chiral Brønsted acid under conditions that facilitate an electrophilic aromatic substitution reaction thereby forming the compound of Formula Ia, wherein the heteroaromatic nucleophile is represented by the Formula IV:
• wherein
• t is 0, 1, 2, or 3;
• Y is NH;
• and
• each R12 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, azide, —OR3, —OSi(R3)3, —O(C═O)R3, —O(C═O)OR3, —N(R4)2, —N(R4)(C═O)R3, —N(R4)(C═O)N(R4)2, —N(R4)(C═O)OR3, —O(C═O)N(R4)2, —SR3, —N(R4)SO2R3, —SeR3, —P(R3)3, and —P(OR3)3;
• or two instances of R12 taken together with the carbons to which they are attached form a 5-6 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• and
• the chiral Brønsted acid is a chiral phosphoric acid represented by Formula IIIa, Formula IIIb, or Formula IIId:
• wherein
• Q is O, S, or NSO2R16;
• Z is O, S, or Se;
• each of R5 and R5′ is independently hydrogen, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or triarylsilane;
• each of R6 and R6′ is independently hydrogen, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or trialkylsilane;
• each of R7 and R7′ is independently alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or trialkylsilane;
• or R6′ and R7′ taken together with the carbons to which they are attached form 5-6 membered cycloalkyl or 6 membered aryl and R6 and R7 taken together with the carbons to which they are attached form 5-6 membered cycloalkyl or 6 membered aryl;
• each of R14 and R14′ is independently hydrogen, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or trialkylsilane;
• each of R15 and R15′ is independently hydrogen, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or trialkylsilane;
• and
• R16 is alkyl or aryl.