Chiral synthesis of a tertiary alcohol
Disclosed herein are methods for preparing tertiary alcohols from an optionally substituted phenyl ketone or an optionally substituted pyridinyl ketone that includes the use of a chiral ligand and boron trifluoride diethyl etherate. Tertiary alcohols can be used to prepare synthetic versions of natural products and/or pharmaceuticals.
1. A method of preparing a tertiary alcohol, or a salt thereof, comprising combining:
an optionally substituted phenyl ketone or an optionally substituted pyridinyl ketone, or a salt of any of the foregoing, wherein when the phenyl ketone or pyridinyl ketone is substituted, the phenyl ketone and pyridinyl ketone is substituted with one or more substituents selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 alkoxy;
a zinc reagent selected from the group consisting of Et 2 Zn, Me 2 Zn and Ph 2 Zn;
a chiral ligand having the structure
wherein:
R 1 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 or —C(CH 3 ) 3 ;
R 2 is H; or
R 1 and R 2 are taken together along with the carbons to which each R 1 and R 2 are attached to form an unsubstituted cyclohexyl ring;
each Ar is independently an unsubstituted or a substituted phenyl or an unsubstituted or a substituted naphthyl, wherein when an Ar is a substituted phenyl or a substituted naphthyl, the phenyl or the naphthyl is substituted with one or more substituents independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 alkoxy; and
b is 1 or 2; and
BF 3 ·OEt 2 .
2. The method of claim 1 , wherein the optionally substituted phenyl ketone has a structure selected from the group consisting of:
wherein:
m1 is 0, 1, 2, 3 or 4;
n1 is 0, 1, 2, 3, 4 or 5;
m2 is 1 or 2;
X 1a is —CH 2 —;
X 2a is —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 — or O;
each R 1a and each R 1b are independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 alkoxy; and
R 2b is an unsubstituted C 1-4 alkyl.
3. The method of claim 2 , wherein the optionally substituted ketone is selected from the group consisting of:
4. The method of claim 1 , wherein the tertiary alcohol has a structure selected from the group consisting of:
wherein:
m3 is 0, 1, 2, 3 or 4;
n2 is 0, 1, 2, 3, 4 or 5;
m4 is 1 or 2;
X 3a is —CH 2 —;
X 4a is —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 — or O;
each R 2a and each R 3b are independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 alkoxy;
R 4b is an unsubstituted C 1-4 alkyl; and
R 3a and R 5b are independently —CH 3 , —CH 2 CH 3 or -Ph.
5. The method of claim 1 , wherein the optionally substituted pyridinyl ketone has a structure selected from the group consisting of:
wherein:
t1, u1 and v1 are independently 0, 1, 2 or 3;
w1, x1 and y1 are independently 0, 1, 2, 3 or 4;
t2, u2 and v2 are independently 1 or 2;
X 1g , X 1h and X 1j are each —CH 2 —;
X 2g , X 2h and X 2j are independently —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 — or O;
R 1g , R 1h , R 1j , R 1k , R 1l and R 1m are independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 alkoxy; and
R 2k , R 2l and R 2m are independently an unsubstituted C 1-4 alkyl.
6. The method of claim 5 , wherein the optionally substituted pyridinyl is selected from the group consisting of:
7. The method of claim 1 , wherein the tertiary alcohol has a structure selected from the group consisting of:
wherein:
t3, u3 and v3 are independently 0, 1, 2 or 3;
w2, x2 and y2 are independently 0, 1, 2, 3 or 4;
t4, u4 and v4 are independently 1 or 2;
X 3g , X 3h and X 3j are each —CH 2 —;
X 4g , X 4h and X 4j are independently —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 — or O;
R 2g , R 2h , R 2j , R 3k , R 3l and R 3m are independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 alkoxy;
R 4k , R 4l and R 4m are independently an unsubstituted C 1-4 alkyl; and
R 3g , R 3h , R 3j , R 5k , R 5l and R 5m are independently —CH 3 , —CH 2 CH 3 or -Ph.
8. The method of claim 1 , wherein the tertiary alcohol is obtained in enantiomeric purity of ≥50%.
9. The method of claim 1 , wherein the tertiary alcohol is obtained in enantiomeric purity of ≥90%.
10. The method of claim 1 , wherein the tertiary alcohol is obtained in enantiomeric purity of ≥95%.
11. The method of claim 1 , wherein the chiral ligand has the structure
wherein each Ar is an unsubstituted phenyl or a substituted phenyl substituted with one or more substituents independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 alkoxy.
12. The method of claim 1 , wherein the chiral ligand has the structure
wherein each Ar is an unsubstituted naphthyl.
13. The method of claim 1 , wherein the chiral ligand has the structure
wherein each Ar is a substituted naphthyl substituted with one or more substituents independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 alkoxy.
14. The method of claim 1 , wherein b is 1.
15. The method of claim 1 , wherein the chiral ligand has a structure selected from the group consisting of
16. The method of claim 1 , wherein the tertiary alcohol is selected from the group consisting of:
17. The method of claim 1 , wherein the tertiary alcohol obtained is selected from the group consisting of:
18. The method of claim 1 , wherein the method further comprises the use of NaHSO 3 on
wherein the use of NaHSO 3 increases the enantiomeric excess (ee %) of
compared to the ee % prior to the use of NaHSO 3 .
19. The method of claim 1 , wherein the method further comprises recrystallization of
wherein the recrystallization increases the enantiomeric excess (ee %) of
compared to the ee % prior to the recrystallization.