Methods for enantioselective preparation of chiral tetraarylmethanes

1. 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;

Ar 1 is:

Ar 2 is:

X is NH;

Y is NH;

R 1′ is selected from the group consisting of —OR 3 , —OSi(R 3 ) 3 , —O(C═O)R 3 , —O(C═O)OR 3 , —N(R 4 ) 2 , —N(R 4 )(C═O)R 3 , —N(R 4 )(C═O)N(R 4 ) 2 , —N(R 4 )(C═O)OR 3 , —O(C═O)N(R 4 ) 2 , —SR 3 , —N(R 4 )SO 2 R 3 , —SeR 3 , —P(R 3 ) 3 , and —P(OR 3 ) 3 ;

R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, cyanide, nitro, azide, —OR 3 , —OSi(R 3 ) 3 , —O(C═O)R 3 , —(C═O)OR 3 , —O(C═O)OR 3 , —(C═O)R 3 , —N(R 4 ) 2 , —N(R 4 )(C═O)R 3 , —(C═O)N(R 4 ) 2 , —N(R 4 )(C═O)N(R 4 ) 2 , —N(R 4 )(C═O)OR 3 , —O(C═O)N(R 4 ) 2 , —SR 3 , —(S═O)R 3 , —SO 2 R 3 , —SO 2 N(R 4 ) 2 , —N(R 4 )SO 2 R 3 , —SeR 3 , —P(R 3 ) 3 , —P(OR 3 ) 3 , and —(P═O)(OR 3 ) 3 ; or two instances of R 1 taken together with the carbons to which they are attached form a 5-6 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two instances of R 2 taken together with the carbons to which they are attached form a 5-6 membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R 3 is selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, and heteroaryl; and

R 4 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 R 4 taken together with the nitrogen to which they are attached form a 3-6 membered heterocycloalkyl; or one instance of R 3 and one instance of R 4 taken together with the atoms to which they are attached form a 4-6 membered heterocycloalkyl;

each R 9 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, cyanide, nitro, azide, —OR 3 , —OSi(R 3 ) 3 , —O(C═O)R 3 , —(C═O)OR 3 , —O(C═O)OR 3 , —(C═O)R 3 , —N(R 4 ) 2 , —N(R 4 )(C═O)R 3 , —(C═O)N(R 4 ) 2 , —N(R 4 )(C═O)N(R 4 ) 2 , —N(R 4 )(C═O)OR 3 , —O(C═O)N(R 4 ) 2 , —SR 3 , —(S═O)R 3 , —SO 2 R 3 , —SO 2 N(R 4 ) 2 , —N(R 4 )SO 2 R 3 , —SeR 3 , —P(R 3 ) 3 , —P(OR 3 ) 3 , and —(P═O)(OR 3 ) 3 ;

R 9′ is —OH;

R 10 is selected from the group consisting of alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, and halide; and

each R 12 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, azide, —OR 3 , —OSi(R 3 ) 3 , —O(C═O)R 3 , —O(C═O)OR 3 , —N(R 4 ) 2 , —N(R 4 )(C═O)R 3 , —N(R 4 )(C═O)N(R 4 ) 2 , —N(R 4 )(C═O)OR 3 , —O(C═O)N(R 4 ) 2 , —SR 3 , —N(R 4 )SO 2 R 3 , —SeR 3 , —P(R 3 ) 3 , and —P(OR 3 ) 3 ; or two instances of R 12 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 Ar 1 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;

R 1′ is selected from the group consisting of —OR 3 , —OSi(R 3 ) 3 , —O(C═O)R 3 , —O(C═O)OR 3 , —N(R 4 ) 2 , —N(R 4 )(C═O)R 3 , —N(R 4 )(C═O)N(R 4 ) 2 , —N(R 4 )(C═O)OR 3 , —O(C═O)N(R 4 ) 2 , —SR 3 , —N(R 4 )SO 2 R 3 , —SeR 3 , —P(R 3 ) 3 , and —P(OR 3 ) 3 ;

each R 9 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, cyanide, nitro, azide, —OR 3 , —OSi(R 3 ) 3 , —O(C═O)R 3 , —(C═O)OR 3 , —O(C═O)OR 3 , —(C═O)R 3 , —N(R 4 ) 2 , —N(R 4 )(C═O)R 3 , —(C═O)N(R 4 ) 2 , —N(R 4 )(C═O)N(R 4 ) 2 , —N(R 4 )(C═O)OR 3 , —O(C═O)N(R 4 ) 2 , —SR 3 , —(S═O)R 3 , —SO 2 R 3 , —SO 2 N(R 4 ) 2 , —N(R 4 )SO 2 R 3 , —SeR 3 , —P(R 3 ) 3 , —P(OR 3 ) 3 , and —(P═O)(OR 3 ) 3 ;

R 9′ is —OH; and

R 10 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 R 12 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, azide, —OR 3 , —OSi(R 3 ) 3 , —O(C═O)R 3 , —O(C═O)OR 3 , —N(R 4 ) 2 , —N(R 4 )(C═O)R 3 , —N(R 4 )(C═O)N(R 4 ) 2 , —N(R 4 )(C═O)OR 3 , —O(C═O)N(R 4 ) 2 , —SR 3 , —N(R 4 )SO 2 R 3 , —SeR 3 , —P(R 3 ) 3 , and —P(OR 3 ) 3 ; or two instances of R 12 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 NSO 2 R 16 ;

Z is O, S, or Se;

each of R 5 and R 5′ is independently hydrogen, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or triarylsilane;

each of R 6 and R 6′ is independently hydrogen, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or trialkylsilane;

each of R 7 and R 7′ is independently alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or trialkylsilane; or R 6′ and R 7′ taken together with the carbons to which they are attached form 5-6 membered cycloalkyl or 6 membered aryl and R 6 and R 7 taken together with the carbons to which they are attached form 5-6 membered cycloalkyl or 6 membered aryl;

each of R 14 and R 14′ is independently hydrogen, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or trialkylsilane;

each of R 15 and R 15′ is independently hydrogen, alkyl, haloalkyl, perhaloalkyl, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, or trialkylsilane; and

R 16 is alkyl or aryl.

2. The method of claim 1 , wherein the chiral phosphoric acid is represented by the Formula IIIe:

wherein R 8 is alkyl, cycloalkyl, or aryl.

3. The method of claim 2 , wherein R 8 is isopropyl, cyclohexyl, or phenyl.

4. The method of claim 1 , wherein each R 12 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene, alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, azide, —OR 3 , —OSi(R 3 ) 3 , —O(C═O)R 3 , —O(C═O)OR 3 , —N(R 4 ) 2 , —N(R 4 )(C═O)R 3 , —N(R 4 )(C═O)N(R 4 ) 2 , —N(R 4 )(C═O)OR 3 , —O(C═O)N(R 4 ) 2 , —SR 3 , —N(R 4 )SO 2 R 3 , and —SeR 3 ; or two instances of R 12 taken together with the carbons to which they are attached form a 6 membered cycloalkyl or aryl.

5. The method of claim 1 , wherein m is 0 or 1; R 1′ is —OR 3 , —OSi(R 3 ) 3 , —O(C═O)R 3 , —O(C═O)OR 3 , or —O(C═O)N(R 4 ) 2 ,

and the heteroaromatic nucleophile is selected from:

wherein

t is 0 or 1; and

R 12 is selected from the group consisting of hydrogen, alkyl, haloalkyl, perhaloalkyl, alkene alkyne, cycloalkyl, heterocycloalkyl, aryl, araalkyl, heteroaryl, halide, azide, —OR 3 , —OSi(R 3 ) 3 , —O(C═O)R 3 , —O(C═O)OR 3 , —N(R 4 ) 2 , —N(R 4 )(C═O)R 3 , —N(R 4 )(C═O)N(R 4 ) 2 , —N(R 4 )(C═O)OR 3 , —O(C═O)N(R 4 ) 2 , —SR 3 , —N(R 4 )SO 2 R 3 , —SeR 3 , —P(R 3 ) 3 , and —P(OR 3 ) 3 .

6. The method of claim 5 , wherein the chiral Brønsted acid is represented by the Formula IIIf or Formula IIIg:

wherein each of R 5 and R 5′ is alkyl, aryl, or triarylsilane.

7. The method of claim 6 , wherein each of R 5 and R 5′ is 2,4,6-(iPr) 3 C 6 H 2 —, 2,4,6-Cy 3 C 6 H 2 —, 1-napthyl, 9-anthryl, 9-phenanthryl, or 1-pyrene.

8. The method of claim 1 , wherein the step of contacting the compound of Formula IIa with the heteroaromatic nucleophile in the presence of the chiral Brønsted acid occurs in a solvent selected from the group consisting of chlorobenzene, PhCF 3 , PhF, CCl 4 , CH 2 Cl 2 (DCM), CHCl 3 , PhMe, and ClCH 2 CH 2 Cl (DCE).

9. The method of claim 1 , wherein the chiral Brønsted acid is present at a mole concentration of between 0.1% and 25% relative to the compound of Formula IIa.

10. The method of claim 1 , wherein the step of contacting the compound of Formula IIa with the heteroaromatic nucleophile in the presence of the chiral Brønsted acid occurs at a temperature between −30° C. and 40° C.

11. The method of claim 1 , wherein the tetraarylmethane having Formula Ia is prepared with an enantiomeric excess (ee) between 40 to 99.9%.

12. The method of claim 4 , wherein the tetraarylmethane having Formula Ia is prepared with an ee of 80 to 97%.

13. The method of claim 1 , wherein the compound of Formula IIa is a racemic mixture.