U.S. patent application number 16/166893 was filed with the patent office on 2019-02-21 for asymmetric catalytic decarboxylative alkyl alkylation using low catalyst concentrations and a robust precatalyst.
The applicant listed for this patent is California Institute of Technology. Invention is credited to Robert A. Craig, Douglas Duquette, Kelly E. Kim, Marc Liniger, Alexander N. Marziale, Yoshitaka Numajiri, Brian M. Stoltz.
Application Number | 20190055182 16/166893 |
Document ID | / |
Family ID | 56973955 |
Filed Date | 2019-02-21 |
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United States Patent
Application |
20190055182 |
Kind Code |
A1 |
Stoltz; Brian M. ; et
al. |
February 21, 2019 |
ASYMMETRIC CATALYTIC DECARBOXYLATIVE ALKYL ALKYLATION USING LOW
CATALYST CONCENTRATIONS AND A ROBUST PRECATALYST
Abstract
This invention provides efficient and scalable enantioselective
methods that yield 2-alkyl-2-allylcycloalkyanone compounds with
quaternary stereogenic centers. Methods include the method for the
preparation of a compound of formula (I): ##STR00001## comprising
treating a compound of formula (II) or (III): ##STR00002## with a
palladium (II) catalyst under alkylation conditions.
Inventors: |
Stoltz; Brian M.; (San
Marino, CA) ; Marziale; Alexander N.; (Binningen,
CH) ; Craig; Robert A.; (Stanford, CA) ;
Duquette; Douglas; (Los Angeles, CA) ; Kim; Kelly
E.; (Pasadena, CA) ; Liniger; Marc; (Baden,
CH) ; Numajiri; Yoshitaka; (Kamakura, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
California Institute of Technology |
Pasadena |
CA |
US |
|
|
Family ID: |
56973955 |
Appl. No.: |
16/166893 |
Filed: |
October 22, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15081157 |
Mar 25, 2016 |
10106479 |
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16166893 |
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62139522 |
Mar 27, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01J 2531/004 20130101;
C07C 2601/14 20170501; C07D 223/10 20130101; C07C 45/65 20130101;
B01J 31/04 20130101; B01J 2231/44 20130101; B01J 31/189 20130101;
C07D 317/72 20130101; C07C 2601/20 20170501; C07C 2602/10 20170501;
C07C 2601/18 20170501; C07D 211/94 20130101; B01J 2531/824
20130101; C07C 45/65 20130101; C07C 49/647 20130101; C07C 45/65
20130101; C07C 49/683 20130101 |
International
Class: |
C07C 45/65 20060101
C07C045/65; C07D 211/94 20060101 C07D211/94; C07D 223/10 20060101
C07D223/10; B01J 31/04 20060101 B01J031/04; C07D 317/72 20060101
C07D317/72; C07C 49/647 20060101 C07C049/647; C07C 49/683 20060101
C07C049/683 |
Goverment Interests
GOVERNMENT SUPPORT
[0002] This invention was made with government support under Grant
Number GM080269, awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1-40. (canceled)
41. A method for the preparation of a compound of formula (I):
##STR00063## the preparing comprising treating, with a Pd(II)
catalyst in an organic solvent, (i) a compound of formula (II) or
(III) or a salt thereof: ##STR00064## or (ii) a compound of formula
(IV) or (V) or a salt thereof: ##STR00065## and a compound of
formula (X): ##STR00066## wherein the Pd(II) catalyst is used in an
amount from about 0.01 mol % to about 3 mol % relative to the
compound of formula (II), (III), (IV), or (V), wherein, as valence
and stability permit, R.sup.1 represents hydrogen or substituted or
unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to
10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl,
(cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered
heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino,
or halo; R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.12, R.sup.13,
R.sup.14, and R.sup.15 are independently selected for each
occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl,
alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino,
alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl,
ether group, thioether group, ester group, amide, thioester group,
carbonate group, carbamate group, urea group, sulfonate group,
sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy,
acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl,
3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to
10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to
10-membered heterocyclyl)alkyl; W represents, as valence permits,
--O--, --S--, --NR.sup.6--, --CR.sup.7R.sup.8--, --C(O)--,
--CR.sup.7.dbd., or --N.dbd.; R.sup.6 represents hydrogen or
optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,
aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered
heteroaryl)alkyl, alkenyl, alkynyl, --C(O)alkyl, --C(O)aryl,
--C(O)aralkyl, --C(O) (5- to 10-membered heteroaryl), --C(O)-(5- to
10-membered heteroaryl)alkyl, --C(O)O(alkyl), --C(O)O(aryl),
--C(O)O(aralkyl), --C(O)O(5- to 10-membered heteroaryl),
--C(O)O-(5- to 10-membered heteroaryl)alkyl, --S(O).sub.2(aryl),
--S(O).sub.2(alkyl), --S(O).sub.2(haloalkyl), --OR.sup.10,
--SR.sup.10, or --NR.sup.10R.sup.11; R.sup.7 and R.sup.8 each
independently represent hydrogen, hydroxyl, halo, nitro, alkyl,
cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered
heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered
heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl,
alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy,
arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl,
aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group,
ester group, amido, thioester group, carbonate group, carbamate
group, urea group, sulfonate group, sulfone group, sulfoxide group,
sulfonamide group, acyl, acyloxy, or acylamino; or R.sup.6,
R.sup.7, and R.sup.8 taken together with a substituent on ring A
and the intervening atoms, form an optionally substituted aryl, 5-
to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to
10-membered heterocyclyl, or (5- to 10-membered
heterocyclyl)alkenyl; R.sup.10 and R.sup.11 are independently
selected for each occurrence from hydrogen or substituted or
unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered
heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl,
cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to
10-membered heterocyclyl, alkenyl, and alkynyl; and ring A
represents an optionally substituted cycloalkyl, 5- to 10-membered
heterocyclyl, cycloalkenyl, or (5- to 10-membered
heterocyclyl)alkenyl, wherein each heteroaryl or heterocyclyl
comprises 1 to 4 heteroatoms selected from N, O, and S; and wherein
substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl,
aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered
heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to
10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl,
alkoxy, or amino are selected from halo, hydroxyl, carboxyl,
alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group,
thioformate group, alkoxy, phosphate group, phosphonate group,
phosphinate, amino, amido, amidine group, imine group, cyano,
nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate
group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered
heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered
heteroaromatic group.
42. A method of preparing a pharmaceutical agent, comprising
preparing a compound of formula (I): ##STR00067## the preparing
comprising treating, with a Pd(II) catalyst in an organic solvent,
(i) a compound of formula (II) or (III) or a salt thereof:
##STR00068## or (ii) a compound of formula (IV) or (V) or a salt
thereof: ##STR00069## and a compound of formula (X): ##STR00070##
wherein the Pd(II) catalyst is used in an amount from about 0.01
mol % to about 3 mol % relative to the compound of formula (II),
(III), (IV), or (V), wherein, as valence and stability permit,
R.sup.1 represents hydrogen or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered
heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl,
cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to
10-membered heterocyclyl, alkoxy, amino, or halo; R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are
independently selected for each occurrence from hydrogen, hydroxyl,
halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate
group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl,
alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether
group, ester group, amide, thioester group, carbonate group,
carbamate group, urea group, sulfonate group, sulfone group,
sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl,
(5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered
heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered
heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered
heterocyclyl)alkyl; W represents, as valence permits, --O--, --S--,
--NR.sup.6--, --CR.sup.7R.sup.8--, --C(O)--, --CR.sup.7.dbd., or
--N.dbd.; R.sup.6 represents hydrogen or optionally substituted
alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to
10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl,
alkenyl, alkynyl, --C(O)alkyl, --C(O)aryl, --C(O)aralkyl, --C(O)
(5- to 10-membered heteroaryl), --C(O)-(5- to 10-membered
heteroaryl)alkyl, --C(O)O(alkyl), --C(O)O(aryl), --C(O)O(aralkyl),
--C(O)O(5- to 10-membered heteroaryl), --C(O)O-(5- to 10-membered
heteroaryl)alkyl, --S(O).sub.2(aryl), --S(O).sub.2(alkyl),
--S(O).sub.2(haloalkyl), --OR.sup.10, --SR.sup.10, or
--NR.sup.10R.sup.11; R.sup.7 and R.sup.8 each independently
represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl,
(cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5-
to 10-membered heteroaryl)alkyl, (5- to 10-membered
heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl,
alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy,
arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl,
aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group,
ester group, amido, thioester group, carbonate group, carbamate
group, urea group, sulfonate group, sulfone group, sulfoxide group,
sulfonamide group, acyl, acyloxy, or acylamino; or R.sup.6,
R.sup.7, and R.sup.8 taken together with a substituent on ring A
and the intervening atoms, form an optionally substituted aryl, 5-
to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to
10-membered heterocyclyl, or (5- to 10-membered
heterocyclyl)alkenyl; R.sup.10 and R.sup.11 are independently
selected for each occurrence from hydrogen or substituted or
unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered
heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl,
cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to
10-membered heterocyclyl, alkenyl, and alkynyl; and ring A
represents an optionally substituted cycloalkyl, 5- to 10-membered
heterocyclyl, cycloalkenyl, or (5- to 10-membered
heterocyclyl)alkenyl, wherein each heteroaryl or heterocyclyl
comprises 1 to 4 heteroatoms selected from N, O, and S; and wherein
substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl,
aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered
heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to
10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl,
alkoxy, or amino are selected from halo, hydroxyl, carboxyl,
alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group,
thioformate group, alkoxy, phosphate group, phosphonate group,
phosphinate, amino, amido, amidine group, imine group, cyano,
nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate
group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered
heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered
heteroaromatic group.
43. A method comprising (a) preparing a compound of formula (I):
##STR00071## the preparing comprising treating with a Pd(II)
catalyst in an organic solvent, (i) a compound of formula (II) or
(III) or a salt thereof: ##STR00072## or (ii) a compound of formula
(IV) or (V) or a salt thereof: ##STR00073## and a compound of
formula (X): ##STR00074## wherein the Pd(II) catalyst is used in an
amount from about 0.01 mol % to about 3 mol % relative to the
compound of formula (II), (III), (IV), or (V); and (b) synthesizing
a pharmaceutical agent from the compound of formula (I), wherein,
as valence and stability permit, R.sup.1 represents hydrogen or
substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl,
aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered
heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered
heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino,
or halo; R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.12, R.sup.13,
R.sup.14, and R.sup.15 are independently selected for each
occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl,
alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino,
alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl,
ether group, thioether group, ester group, amide, thioester group,
carbonate group, carbamate group, urea group, sulfonate group,
sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy,
acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl,
3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to
10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to
10-membered heterocyclyl)alkyl; W represents, as valence permits,
--O--, --S--, --NR.sup.6--, --CR.sup.7R.sup.8--, --C(O)--,
--CR.sup.7.dbd., or --N.dbd.; R.sup.6 represents hydrogen or
optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,
aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered
heteroaryl)alkyl, alkenyl, alkynyl, --C(O)alkyl, --C(O)aryl,
--C(O)aralkyl, --C(O) (5- to 10-membered heteroaryl), --C(O)-(5- to
10-membered heteroaryl)alkyl, --C(O)O(alkyl), --C(O)O(aryl),
--C(O)O(aralkyl), --C(O)O(5- to 10-membered heteroaryl),
--C(O)O-(5- to 10-membered heteroaryl)alkyl, --S(O).sub.2(aryl),
--S(O).sub.2(alkyl), --S(O).sub.2(haloalkyl), --OR.sup.10,
--SR.sup.10, or --NR.sup.10R.sup.11; R.sup.7 and R.sup.8 each
independently represent hydrogen, hydroxyl, halo, nitro, alkyl,
cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered
heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered
heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl,
alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy,
arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl,
aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group,
ester group, amido, thioester group, carbonate group, carbamate
group, urea group, sulfonate group, sulfone group, sulfoxide group,
sulfonamide group, acyl, acyloxy, or acylamino; or R.sup.6,
R.sup.7, and R.sup.8 taken together with a substituent on ring A
and the intervening atoms, form an optionally substituted aryl, 5-
to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to
10-membered heterocyclyl, or (5- to 10-membered
heterocyclyl)alkenyl; R.sup.10 and R.sup.11 are independently
selected for each occurrence from hydrogen or substituted or
unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered
heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl,
cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to
10-membered heterocyclyl, alkenyl, and alkynyl; and ring A
represents an optionally substituted cycloalkyl, 5- to 10-membered
heterocyclyl, cycloalkenyl, or (5- to 10-membered
heterocyclyl)alkenyl, wherein each heteroaryl or heterocyclyl
comprises 1 to 4 heteroatoms selected from N, O, and S; and wherein
substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl,
aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered
heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to
10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl,
alkoxy, or amino are selected from halo, hydroxyl, carboxyl,
alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group,
thioformate group, alkoxy, phosphate group, phosphonate group,
phosphinate, amino, amido, amidine group, imine group, cyano,
nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate
group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered
heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered
heteroaromatic group.
44. The method of claim 43, wherein the compound of formula (I) is
represented by formula (Ia): ##STR00075## and the compound of
formula (II) is represented by formula (IIa): ##STR00076## and the
compound of formula (III) is represented by formula (IIIa):
##STR00077## wherein: B, D, and E independently for each occurrence
represent, as valence permits, O, S, NR.sup.6, CR.sup.7R.sup.8,
C(O), CR.sup.7, or N; provided that no two adjacent occurrences of
W, B, D, and E are NR.sup.6, O, S, or N; or any two occurrences of
R.sup.6, R.sup.7, and R.sup.8 on adjacent W, B, D, or E groups,
taken together with the intervening atoms, form an optionally
substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl,
cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered
heterocyclyl)alkenyl; each occurrence of independently represents a
double bond or a single bond as permitted by valence; and m and n
are integers each independently selected from 0, 1, and 2.
45. The method of claim 44, wherein the sum of m and n is 0, 1, 2,
or 3.
46. The method of claim 44, wherein each occurrence of W, B, D, and
E is each independently --CR.sup.7R.sup.8--, or --CR.sup.7--, or
--C(O)--.
47. The method of claim 46, wherein one occurrence of W, B, D, and
E is --CR.sup.7R.sup.8-- or --C(O)--, and the remaining three are
--CR.sup.7R.sup.8--; optionally wherein R.sup.7 and R.sup.8,
independently for each occurrence, are selected from hydrogen,
hydroxyl, halo, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,
aralkyl, 5- to 10-membered heteroaryl, 5- to 10-membered
heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to
10-membered heterocyclyl, alkenyl, alkynyl, amino, alkoxy, aryloxy,
arylalkoxy, alkylamino, and amido.
48. The method of claim 44, wherein at least two adjacent
occurrences of W, B, D, and E are --CR.sup.7--.
49. The method of claim 48, wherein W and B are each --CR.sup.7--
and m is 1; optionally wherein R.sup.7 is independently selected
for each occurrence from hydrogen, hydroxyl, halo, alkyl,
cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered
heteroaryl heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to
10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl,
alkenyl, alkynyl, amino, alkoxy, aryloxy, alkylamino, amido, and
acylamino; or the occurrence of R.sup.7 on W and the occurrence of
R.sup.7 on B are taken together to form an optionally substituted
aryl, 5- to 10-membered heteroaryl, cycloalkenyl, or (5- to
10-membered heterocyclyl)alkenyl.
50. The method of claim 44, wherein at least one occurrence of W,
B, D, and E is --NR.sup.6--.
51. The method of claim 50, wherein W is --NR.sup.6--; optionally
wherein at least one occurrence of the remaining B, D, and E is
--NR.sup.6-- or O.
52. The method of claim 50, wherein R.sup.6 represents,
independently for each occurrence, hydrogen or optionally
substituted alkyl, aralkyl, (5- to 10-membered heteroaryl)alkyl,
--C(O)alkyl, --C(O)aryl, --C(O)aralkyl, --C(O)O(alkyl),
--C(O)O(aryl), --C(O)O(aralkyl), or --S(O).sub.2(aryl).
53. The method of claim 44, wherein at least one occurrence of W,
B, D, and E is --O--.
54. The method of claim 43, wherein W represents --O--, --S--,
--NR.sup.6--, --CR.sup.7R.sup.8--, or --CR.sup.7.dbd..
55. The method of claim 43, wherein R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each
hydrogen.
56. The method of claim 43, wherein R.sup.1 represents substituted
or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to
10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl,
(cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered
heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, or halo.
57. The method of claim 43, wherein the Pd(II) catalyst is selected
from Pd(OC(O)R).sub.2, Pd(OAc).sub.2, PdCl.sub.2,
Pd(PhCN).sub.2Cl.sub.2, Pd(CH.sub.3CN).sub.2Cl.sub.2, PdBr.sub.2,
Pd(acac).sub.2, [Pd(allyl)Cl].sub.2, Pd(TFA).sub.2, and pre-formed
Pd(II)-ligand complex; wherein R.sup.c is optionally substituted
alkyl, alkenyl, alkynyl, aryl, 5- to 10-membered heteroaryl,
aralkyl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 5- to
10-membered heterocyclyl, (cycloalkyl)alkyl, or (5- to 10-membered
heterocyclyl)alkyl.
58. The method of claim 43, wherein the Pd(II) catalyst is
Pd(OAc).sub.2.
59. The method of claim 43, wherein the Pd(II) catalyst is used in
an amount from about 0.02 mol % to about 2.5 mol % relative to the
compound of formula (II), (III), (IV), or (V).
60. The method of claim 43, wherein the Pd(II) catalyst further
comprises a chiral ligand.
61. The method of claim 60, wherein the chiral ligand is used in an
amount from about 0.1 mol % to about 100 mol % relative to the
compound of formula (II), (III), (IV), or (V).
62. The method of claim 43, wherein the organic solvent is selected
from methyl tert-butyl ether, toluene, and
2-methyltetrahydrofuran.
63. The method of claim 43, whereby the compound of formula (I) is
enantioenriched.
Description
RELATED APPLICATIONS
[0001] This Application claims the benefit of U.S. Provisional
Application 62/139,522, filed Mar. 27, 2015, the content of which
is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0003] The catalytic enantioselective construction of all-carbon
quaternary centers represents a considerable challenge in synthetic
organic chemistry..sup.[1,2] A new carbon-carbon bond must be
formed in the face of significant steric hindrance to accomplish
this goal.
[0004] Synthetic methods for the generation of quaternary
stereocenters are extremely desirable given their prevalence in a
broad variety of biologically active natural products..sup.[2]
Despite their importance, the number of highly enantioselective
transformations that construct quaternary stereocenters under mild
reaction conditions is limited. The palladium-catalyzed
decarboxylative asymmetric allylic alkylation is a powerful and
reliable approach to bridge this gap..sup.[3]
[0005] However, despite the importance of palladium-catalyzed
decarboxylative asymmetric alkylation in total synthesis, its
application on an industrial scale is often hampered by the need
for high catalyst loadings (5.0-10.0 mol %). The high cost of
palladium significantly increases the cost of each reaction.
Furthermore, high catalyst loadings also increase the risk of
poisoning downstream chemistry or contaminating active
pharmaceutical ingredients..sup.[4]
[0006] These drawbacks have discouraged application of the
enantioselective allylic alkylation on a larger scale. The
application of transition metal catalysis to industry-scale
synthesis requires transformations that are safe, robust,
cost-effective, and scalable..sup.[5] Consequently, there remains a
significant need to develop new reaction protocols that employ
lower catalyst concentrations and hence facilitate the scale-up of
such transformations.
SUMMARY OF THE INVENTION
[0007] The present invention provides methods for preparing a
compound of formula (I):
##STR00003##
comprising treating a compound of formula (II) or (III):
##STR00004##
or a salt thereof; [0008] with a Pd(II) catalyst under alkylation
conditions, wherein, as valence and stability permit, [0009]
R.sup.1 represents hydrogen or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl,
(cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,
heterocycloalkyl, alkoxy, amino, or halo; [0010] R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are
independently selected for each occurrence from hydrogen, hydroxyl,
halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate,
amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl,
aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester,
carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,
sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, arylalkoxy, heteroaralkyl,
(cycloalkyl)alkyl, and (heterocycloalkyl)alkyl; [0011] W
represents, as valence permits, --O--, --S--, --NR.sup.6--,
--CR.sup.7R.sup.8--, --C(O)--, --CR.sup.7.dbd., or --N.dbd.; [0012]
R.sup.6 represents hydrogen or optionally substituted alkyl,
cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl, alkenyl, alkynyl, --C(O)alkyl, --C(O)aryl,
--C(O)aralkyl, --C(O)heteroaryl, --C(O)heteroaralkyl,
--C(O)O(alkyl), --C(O)O(aryl), --C(O)O(aralkyl),
--C(O)O(heteroaryl), --C(O)O(heteroaralkyl), --S(O).sub.2(aryl),
--S(O).sub.2(alkyl), --S(O).sub.2(haloalkyl), --OR.sup.10,
--SR.sup.10, or --NR.sup.10R.sup.11; [0013] R.sup.7 and R.sup.8
each independently represent hydrogen, hydroxyl, halogen, nitro,
alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl,
alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy,
arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl,
aminoalkyl, thioalkyl, haloalkyl, ether, thioether, ester, amido,
thioester, carbonate, carbamate, urea, sulfonate, sulfone,
sulfoxide, sulfonamide, acyl, acyloxy, or acylamino; [0014] or
R.sup.6, R.sup.7, and R.sup.8 taken together with a substituent on
ring A and the intervening atoms, form an optionally substituted
aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl group; [0015] R.sup.10 and R.sup.11 are
independently selected for each occurrence from hydrogen or
substituted or unsubstituted alkyl, aralkyl, aryl, heteroaralkyl,
heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,
heterocycloalkyl, alkenyl, and alkynyl; and [0016] ring A
represents an optionally substituted cycloalkyl, heterocycloalkyl,
cycloalkenyl, or heterocycloalkenyl group.
[0017] The present invention further provides methods for preparing
a compound of formula (I):
##STR00005##
comprising treating a compound of formula (IV) or (V) or a salt
thereof:
##STR00006##
with a compound of formula (X):
##STR00007##
and [0018] a Pd(II) catalyst under alkylation conditions, wherein,
as valence and stability permit, [0019] R.sup.1 represents hydrogen
or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl,
aryl, heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,
(heterocycloalkyl)alkyl, heterocycloalkyl, alkoxy, amino, or halo;
[0020] R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.12, R.sup.13,
R.sup.14, and R.sup.15 are independently selected for each
occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl,
alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino,
alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether,
thioether, ester, amide, thioester, carbonate, carbamate, urea,
sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy,
acylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl,
arylalkoxy, heteroaralkyl, (cycloalkyl)alkyl, and
(heterocycloalkyl)alkyl; [0021] W represents, as valence permits,
--O--, --S--, --NR.sup.6--, --CR.sup.7R.sup.8--, --C(O)--,
--CR.sup.7.dbd., or --N.dbd.; [0022] R.sup.6 represents hydrogen or
optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,
aralkyl, heteroaryl, heteroaralkyl, alkenyl, alkynyl, --C(O)alkyl,
--C(O)aryl, --C(O)aralkyl, --C(O)heteroaryl, --C(O)heteroaralkyl,
--C(O)O(alkyl), --C(O)O(aryl), --C(O)O(aralkyl),
--C(O)O(heteroaryl), --C(O)O(heteroaralkyl), --S(O).sub.2(aryl),
--S(O).sub.2(alkyl), --S(O).sub.2(haloalkyl), --OR.sup.10,
--SR.sup.10, or --NR.sup.10R.sup.11; [0023] R.sup.7 and R.sup.8
each independently represent hydrogen, hydroxyl, halogen, nitro,
alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl,
alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy,
arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl,
aminoalkyl, thioalkyl, haloalkyl, ether, thioether, ester, amido,
thioester, carbonate, carbamate, urea, sulfonate, sulfone,
sulfoxide, sulfonamide, acyl, acyloxy, or acylamino; [0024] or
R.sup.6, R.sup.7, and R.sup.8 taken together with a substituent on
ring A and the intervening atoms, form an optionally substituted
aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl group; [0025] R.sup.10 and R.sup.11 are
independently selected for each occurrence from hydrogen or
substituted or unsubstituted alkyl, aralkyl, aryl, heteroaralkyl,
heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,
heterocycloalkyl, alkenyl, and alkynyl; [0026] ring A represents an
optionally substituted cycloalkyl, heterocycloalkyl, cycloalkenyl,
or heterocycloalkenyl group; [0027] R.sup.a represents optionally
substituted alkyl, aryl, or alkoxyl; and [0028] X represents a
halide, carbonate, sulfonate, acetate, or carboxylate.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0029] The definitions for the terms described below are applicable
to the use of the term by itself or in combination with another
term.
[0030] The term "acyl" is art-recognized and refers to a group
represented by the general formula hydrocarbyl-C(O)--, preferably
alkyl-C(O)--.
[0031] The term "acylamino" is art-recognized and refers to an
amino group substituted with an acyl group and may be represented,
for example, by the formula hydrocarbyl-C(O)NH--.
[0032] The term "acyloxy" is art-recognized and refers to a group
represented by the general formula hydrocarbylC(O)O--, preferably
alkylC(O)O--.
[0033] The term "alkoxy" refers to an alkyl group, preferably a
lower alkyl group, having an oxygen attached thereto.
Representative alkoxy groups include methoxy, ethoxy, propoxy,
tert-butoxy and the like.
[0034] The term "alkoxyalkyl" refers to an alkyl group substituted
with an alkoxy group and may be represented by the general formula
alkyl-O-alkyl.
[0035] The term "alkenyl", as used herein, refers to an aliphatic
group containing at least one double bond that is straight chained
or branched and has from 1 to about 20 carbon atoms, preferably
from 1 to about 10 unless otherwise defined. The term "alkenyl" is
intended to include both "unsubstituted alkenyls" and "substituted
alkenyls", the latter of which refers to alkenyl moieties having
substituents replacing a hydrogen on one or more carbons of the
alkenyl group. Such substituents may occur on one or more carbons
that are included or not included in one or more double bonds.
Moreover, such substituents include all those contemplated for
alkyl groups, as discussed below, except where stability is
prohibitive. For example, substitution of alkenyl groups by one or
more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups
is contemplated.
[0036] An "alkyl" group or "alkane" is a straight chained or
branched non-aromatic hydrocarbon which is completely saturated.
Typically, a straight chained or branched alkyl group has from 1 to
about 20 carbon atoms, preferably from 1 to about 10 unless
otherwise defined. Examples of straight chained and branched alkyl
groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A
C.sub.1-C.sub.6 straight chained or branched alkyl group is also
referred to as a "lower alkyl" group.
[0037] Moreover, the term "alkyl" (or "lower alkyl") as used
throughout the specification, examples, and claims is intended to
include both "unsubstituted alkyls" and "substituted alkyls", the
latter of which refers to alkyl moieties having substituents
replacing a hydrogen on one or more carbons of the hydrocarbon
backbone. Such substituents, if not otherwise specified, can
include, for example, a halogen, a hydroxyl, a carbonyl (such as a
carboxyl, an alkoxycarbonyl, a formyl, or an acyl such as an
alkylC(O)), a thiocarbonyl (such as a thioester, a thioacetate, or
a thioformate), an alkoxyl, a phosphoryl, a phosphate, a
phosphonate, a phosphinate, an amino, an amido, an amidine, an
imine, a cyano, a nitro, an azido, a silyl ether, a sulfhydryl, an
alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a
sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or
heteroaromatic moiety. It will be understood by those skilled in
the art that the moieties substituted on the hydrocarbon chain can
themselves be substituted, if appropriate. For instance, the
substituents of a substituted alkyl may include substituted and
unsubstituted forms of amino, azido, imino, amido, phosphoryl
(including phosphonate and phosphinate), sulfonyl (including
sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups,
as well as ethers, alkylthiols, carbonyls (including ketones,
aldehydes, carboxylates, and esters), --CF.sub.3, --CN and the
like. Exemplary substituted alkyls are described below. Cycloalkyls
can be further substituted with alkyls, alkenyls, alkoxys,
alkylthios, aminoalkyls, carbonyl-substituted alkyls, --CF.sub.3,
--CN, and the like.
[0038] The term "C.sub.x-y" when used in conjunction with a
chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl,
or alkoxy is meant to include groups that contain from x to y
carbons in the chain. For example, the term "C.sub.x-yalkyl" refers
to substituted or unsubstituted saturated hydrocarbon groups,
including straight-chain alkyl and branched-chain alkyl groups that
contain from x to y carbons in the chain, including haloalkyl
groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc.
C.sub.0 alkyl indicates a hydrogen where the group is in a terminal
position, a bond if internal. The terms "C.sub.2-yalkenyl" and
"C.sub.2-yalkynyl" refer to substituted or unsubstituted
unsaturated aliphatic groups analogous in length and possible
substitution to the alkyls described above, but that contain at
least one double or triple bond respectively.
[0039] The term "alkylamino", as used herein, refers to an amino
group substituted with at least one alkyl group.
[0040] The term "alkylthio", as used herein, refers to a thiol
group substituted with an alkyl group and may be represented by the
general formula alkyl-S--.
[0041] The term "alkynyl", as used herein, refers to an aliphatic
group containing at least one triple bond and is intended to
include both "unsubstituted alkynyls" and "substituted alkynyls",
the latter of which refers to alkynyl moieties having substituents
replacing a hydrogen on one or more carbons of the alkynyl group.
Such substituents may occur on one or more carbons that are
included or not included in one or more triple bonds. Moreover,
such substituents include all those contemplated for alkyl groups,
as discussed above, except where stability is prohibitive. For
example, substitution of alkynyl groups by one or more alkyl,
carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is
contemplated.
[0042] The term "amide", as used herein, refers to a group
##STR00008##
wherein each R.sup.10 independently represent a hydrogen or
hydrocarbyl group, or two R.sup.10 are taken together with the N
atom to which they are attached complete a heterocycle having from
4 to 8 atoms in the ring structure.
[0043] The terms "amine" and "amino" are art-recognized and refer
to both unsubstituted and substituted amines and salts thereof,
e.g., a moiety that can be represented by
##STR00009##
wherein each R.sup.10 independently represents a hydrogen or a
hydrocarbyl group, or two R.sup.10 are taken together with the N
atom to which they are attached complete a heterocycle having from
4 to 8 atoms in the ring structure.
[0044] The term "aminoalkyl", as used herein, refers to an alkyl
group substituted with an amino group.
[0045] The term "aralkyl", as used herein, refers to an alkyl group
substituted with an aryl group. An aralkyl group is connected to
the rest of the molecule through the alkyl component of the aralkyl
group.
[0046] The term "aryl" as used herein include substituted or
unsubstituted single-ring aromatic groups in which each atom of the
ring is carbon. Preferably the ring is a 5- to 10-membered ring,
more preferably a 6- to 10-membered ring or a 6-membered ring. The
term "aryl" also includes polycyclic ring systems having two or
more cyclic rings in which two or more carbons are common to two
adjoining rings wherein at least one of the rings is aromatic,
e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,
cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl
groups include benzene, naphthalene, phenanthrene, phenol, aniline,
and the like. Exemplary substitution on an aryl group can include,
for example, a halogen, a haloalkyl such as trifluoromethyl, a
hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a
formyl, or an acyl such as an alkylC(O)), a thiocarbonyl (such as a
thioester, a thioacetate, or a thioformate), an alkoxyl, a
phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an
amido, an amidine, an imine, a cyano, a nitro, an azido, a silyl
ether, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a
sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl,
or an aromatic or heteroaromatic moiety
[0047] The term "carbamate" is art-recognized and refers to a
group
##STR00010##
wherein R.sup.9 and R.sup.10 independently represent hydrogen or a
hydrocarbyl group, such as an alkyl group, or R.sup.9 and R.sup.10
taken together with the intervening atom(s) complete a heterocycle
having from 4 to 8 atoms in the ring structure.
[0048] The terms "carbocycle", and "carbocyclic", as used herein,
refers to a saturated or unsaturated ring in which each atom of the
ring is carbon. The term carbocycle includes both aromatic
carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles
include both cycloalkane rings, in which all carbon atoms are
saturated, and cycloalkene rings, which contain at least one double
bond. "Carbocycle" includes 5-7 membered monocyclic and 8-12
membered bicyclic rings. Each ring of a bicyclic carbocycle may be
selected from saturated, unsaturated and aromatic rings. Carbocycle
includes bicyclic molecules in which one, two or three or more
atoms are shared between the two rings. The term "fused carbocycle"
refers to a bicyclic carbocycle in which each of the rings shares
two adjacent atoms with the other ring. Each ring of a fused
carbocycle may be selected from saturated, unsaturated and aromatic
rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl,
may be fused to a saturated or unsaturated ring, e.g., cyclohexane,
cyclopentane, or cyclohexene. Any combination of saturated,
unsaturated and aromatic bicyclic rings, as valence permits, is
included in the definition of carbocyclic. Exemplary "carbocycles"
include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane,
1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene,
bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary
fused carbocycles include decalin, naphthalene,
1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane,
4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene.
"Carbocycles" may be substituted at any one or more positions
capable of bearing a hydrogen atom.
[0049] A "cycloalkyl" group is a cyclic hydrocarbon which is
completely saturated. "Cycloalkyl" includes monocyclic and bicyclic
rings. Typically, a monocyclic cycloalkyl group has from 3 to about
10 carbon atoms, more typically 3 to 8 carbon atoms unless
otherwise defined. The second ring of a bicyclic cycloalkyl may be
selected from saturated, unsaturated and aromatic rings. Cycloalkyl
includes bicyclic molecules in which one, two or three or more
atoms are shared between the two rings. The term "fused cycloalkyl"
refers to a bicyclic cycloalkyl in which each of the rings shares
two adjacent atoms with the other ring. The second ring of a fused
bicyclic cycloalkyl may be selected from saturated, unsaturated and
aromatic rings. A "cycloalkenyl" group is a cyclic hydrocarbon
containing one or more double bonds.
[0050] The term "cycloalkylalkyl", as used herein, refers to an
alkyl group substituted with a cycloalkyl group.
[0051] The term "carbonate" is art-recognized and refers to a group
--OCO2-R.sup.10, wherein R.sup.10 represents a hydrocarbyl
group.
[0052] The term "carboxyl", as used herein, refers to a group
represented by the formula --CO.sub.2H.
[0053] The term "ester", as used herein, refers to a group
--C(O)OR.sup.10 wherein R.sup.10 represents a hydrocarbyl
group.
[0054] The term "ether", as used herein, refers to a hydrocarbyl
group linked through an oxygen to another hydrocarbyl group.
Accordingly, an ether substituent of a hydrocarbyl group may be
hydrocarbyl-O--. Ethers may be either symmetrical or unsymmetrical.
Examples of ethers include, but are not limited to,
heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include
"alkoxyalkyl" groups, which may be represented by the general
formula alkyl-O-alkyl.
[0055] The terms "halo" and "halogen" as used herein means halogen
and includes chloro, fluoro, bromo, and iodo.
[0056] The terms "hetaralkyl" and "heteroaralkyl", as used herein,
refers to an alkyl group substituted with a heteroaryl group.
[0057] The term "heteroalkyl", as used herein, refers to a
saturated or unsaturated chain of carbon atoms and at least one
heteroatom, wherein no two heteroatoms are adjacent.
[0058] The terms "heteroaryl" and "hetaryl" include substituted or
unsubstituted aromatic single ring structures, preferably 5- to
7-membered rings, more preferably 5- to 6-membered rings, whose
ring structures include at least one heteroatom, preferably one to
four heteroatoms, more preferably one or two heteroatoms. The terms
"heteroaryl" and "hetaryl" also include polycyclic ring systems
having two or more cyclic rings in which two or more carbons are
common to two adjoining rings wherein at least one of the rings is
heteroaromatic, e.g., the other cyclic rings can be cycloalkyls,
cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or
heterocyclyls. Heteroaryl groups include 5- to 10-membered cyclic
or polycyclic ring systems, including, for example, pyrrole, furan,
thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine,
pyrazine, pyridazine, and pyrimidine, and the like. Exemplary
optional substituents on heteroaryl groups include those
substituents put forth as exemplary substituents on aryl groups,
above.
[0059] The term "heteroatom" as used herein means an atom of any
element other than carbon or hydrogen. Preferred heteroatoms are
nitrogen, oxygen, and sulfur.
[0060] The terms "heterocycloalkyl", "heterocycle", and
"heterocyclic" refer to substituted or unsubstituted non-aromatic
ring structures, preferably 3- to 10-membered rings, more
preferably 3- to 7-membered rings, whose ring structures include at
least one heteroatom, preferably one to four heteroatoms, more
preferably one or two heteroatoms. The terms "heterocycloalkyl" and
"heterocyclic" also include polycyclic ring systems having two or
more cyclic rings in which two or more carbons are common to two
adjoining rings wherein at least one of the rings is heterocyclic,
e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,
cycloalkynyls, aryls, heteroaryls, and/or heterocycloalkyls.
Heterocycloalkyl groups include, for example, piperidine,
piperazine, pyrrolidine, morpholine, lactones, lactams, and the
like.
[0061] The term "heterocycloalkylalkyl", as used herein, refers to
an alkyl group substituted with a heterocycle group.
[0062] The term "hydrocarbyl", as used herein, refers to a group
that is bonded through a carbon atom that does not have a .dbd.O or
.dbd.S substituent, and typically has at least one carbon-hydrogen
bond and a primarily carbon backbone, but may optionally include
heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and
trifluoromethyl are considered to be hydrocarbyl for the purposes
of this application, but substituents such as acetyl (which has a
.dbd.O substituent on the linking carbon) and ethoxy (which is
linked through oxygen, not carbon) are not. Hydrocarbyl groups
include, but are not limited to aryl, heteroaryl, carbocycle,
heterocyclyl, alkyl, alkenyl, alkynyl, and combinations
thereof.
[0063] The term "hydroxyalkyl", as used herein, refers to an alkyl
group substituted with a hydroxy group.
[0064] The term "lower" when used in conjunction with a chemical
moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy
is meant to include groups where there are ten or fewer
non-hydrogen atoms in the substituent, preferably six or fewer. A
"lower alkyl", for example, refers to an alkyl group that contains
ten or fewer carbon atoms, preferably six or fewer. In certain
embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy
substituents defined herein are respectively lower acyl, lower
acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower
alkoxy, whether they appear alone or in combination with other
substituents, such as in the recitations hydroxyalkyl and aralkyl
(in which case, for example, the atoms within the aryl group are
not counted when counting the carbon atoms in the alkyl
substituent).
[0065] The terms "polycyclyl", "polycycle", and "polycyclic" refer
to two or more rings (e.g., cycloalkyls, cycloalkenyls,
cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which
two or more atoms are common to two adjoining rings, e.g., the
rings are "fused rings". Each of the rings of the polycycle can be
substituted or unsubstituted. In certain embodiments, each ring of
the polycycle contains from 3 to 10 atoms in the ring, preferably
from 5 to 7.
[0066] The term "silyl" refers to a silicon moiety with three
hydrocarbyl moieties attached thereto. A "silyl ether" refers to a
silyl group linked through an oxygen to a hydrocarbyl group.
Exemplary silyl ethers include --OSi(CH.sub.3).sub.3 (--OTMS),
--OSi(CH.sub.3).sub.2t-Bu (--OTBS), --OSi(Ph).sub.2t-Bu (--OTBDPS),
and --OSi(iPr).sub.3 (--OTIPS).
[0067] The term "substituted" refers to moieties having
substituents replacing a hydrogen on one or more carbons of the
backbone. It will be understood that "substitution" or "substituted
with" includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., which does not spontaneously undergo transformation
such as by rearrangement, cyclization, elimination, etc. As used
herein, the term "substituted" is contemplated to include all
permissible substituents of organic compounds. In a broad aspect,
the permissible substituents include acyclic and cyclic, branched
and unbranched, carbocyclic and heterocyclic, aromatic and
non-aromatic substituents of organic compounds. The permissible
substituents can be one or more and the same or different for
appropriate organic compounds. For purposes of this invention, the
heteroatoms such as nitrogen may have hydrogen substituents and/or
any permissible substituents of organic compounds described herein
which satisfy the valences of the heteroatoms. Substituents can
include any substituents described herein, for example, a halogen,
a haloalkyl, a hydroxyl, a carbonyl (such as a carboxyl, an
alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a
thioester, a thioacetate, or a thioformate), an alkoxyl, a
phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an
amido, an amidine, an imine, a cyano, a nitro, an azido, a
sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a
sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic
or heteroaromatic moiety. It will be understood by those skilled in
the art that substituents can themselves be substituted, if
appropriate. Unless specifically stated as "unsubstituted,"
references to chemical moieties herein are understood to include
substituted variants. For example, reference to an "aryl" group or
moiety implicitly includes both substituted and unsubstituted
variants.
[0068] The term "sulfate" is art-recognized and refers to the group
--OSO3H, or a pharmaceutically acceptable salt thereof.
[0069] The term "sulfonamide" is art-recognized and refers to the
group represented by the general formulae
##STR00011##
wherein R.sup.9 and R.sup.10 independently represents hydrogen or
hydrocarbyl, such as alkyl, or R.sup.9 and R.sup.10 taken together
with the intervening atom(s) complete a heterocycle having from 4
to 8 atoms in the ring structure.
[0070] The term "sulfoxide" is art-recognized and refers to the
group --S(O)--R.sup.10, wherein R.sup.10 represents a
hydrocarbyl.
[0071] The term "sulfonate" is art-recognized and refers to the
group SO.sub.3H, or a pharmaceutically acceptable salt thereof. In
some embodiments, a sulfonate can mean an alkylated sulfonate of
the formula SO.sub.3(alkyl).
[0072] The term "sulfone" is art-recognized and refers to the group
--S(O).sub.2--R.sup.10, wherein R.sup.10 represents a
hydrocarbyl.
[0073] The term "thioalkyl", as used herein, refers to an alkyl
group substituted with a thiol group.
[0074] The term "thioester", as used herein, refers to a group
--C(O)SR.sup.10 or --SC(O)R.sup.10 wherein R.sup.10 represents a
hydrocarbyl.
[0075] The term "thioether", as used herein, is equivalent to an
ether, wherein the oxygen is replaced with a sulfur.
[0076] The term "urea" is art-recognized and may be represented by
the general formula
##STR00012##
wherein R.sup.9 and R.sup.10 independently represent hydrogen or a
hydrocarbyl, such as alkyl, or either occurrence of R.sup.9 taken
together with R.sup.10 and the intervening atom(s) complete a
heterocycle having from 4 to 8 atoms in the ring structure.
[0077] "Protecting group" refers to a group of atoms that, when
attached to a reactive functional group in a molecule, mask, reduce
or prevent the reactivity of the functional group. Typically, a
protecting group may be selectively removed as desired during the
course of a synthesis. Examples of protecting groups can be found
in Greene and Wuts, Protective Groups in Organic Chemistry,
3.sup.rdEd., 1999, John Wiley & Sons, NY and Harrison et al.,
Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John
Wiley & Sons, NY. Representative nitrogen protecting groups
include, but are not limited to, formyl, acetyl, trifluoroacetyl,
benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"),
trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"),
trityl and substituted trityl groups, allyloxycarbonyl,
9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl
("NVOC") and the like. Representative hydroxyl protecting groups
include, but are not limited to, those where the hydroxyl group is
either acylated (esterified) or alkylated such as benzyl and trityl
ethers, as well as alkyl ethers, tetrahydropyranyl ethers,
trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers,
such as ethylene glycol and propylene glycol derivatives and allyl
ethers.
II. Description of the Invention
[0078] This invention is based on the discovery of an efficient,
scalable catalytic decarboxylative allylic alkylation reaction that
generates cyclic cycloalkanone and lactam products having an
.alpha.-stereocenter, such as lactones, thiolactones,
cycloalkanones, and lactams. The decarboxylative allylic alkylation
reaction is catalyzed by a robust Pd(II) catalyst and a ligand,
preferably a chiral ligand, and the products can be quickly and
efficiently elaborated into complex products.
[0079] According to embodiments of the present invention, a wide
range of structurally-diverse, functionalized products are prepared
by a readily scalable stereoselective method of palladium-catalyzed
enantioselective enolate allylic alkylation. This chemistry is
useful in the synthesis of bioactive alkaloids, and for the
construction of novel building blocks for medicinal and polymer
chemistry.
[0080] Indeed, in some embodiments of the present invention, a
method of making a building block compound comprises reacting a
substrate compound with a ligand in the presence of a
palladium-based catalyst and a solvent. The palladium-based
catalysts, ligands and solvents useful in this reaction are
described in more detail below in Section III.
III. Methods of the Invention
[0081] In certain aspects, the present invention provides a method
for preparing a compound of formula (I):
##STR00013##
comprising treating a compound of formula (II) or (III):
##STR00014##
or a salt thereof; [0082] with a Pd(II) catalyst under alkylation
conditions, wherein, as valence and stability permit, [0083]
R.sup.1 represents hydrogen or substituted or unsubstituted alkyl,
alkenyl, alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl,
(cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,
heterocycloalkyl, alkoxy, amino, or halo; [0084] R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are
independently selected for each occurrence from hydrogen, hydroxyl,
halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate,
amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl,
aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester,
carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide,
sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, aralkyl, arylalkoxy, heteroaralkyl,
(cycloalkyl)alkyl, and (heterocycloalkyl)alkyl; [0085] W
represents, as valence permits, --O--, --S--, --NR.sup.6--,
--CR.sup.7R.sup.8--, --C(O)--, --CR.sup.7.dbd., or --N.dbd.; [0086]
R.sup.6 represents hydrogen or optionally substituted alkyl,
cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl, alkenyl, alkynyl, --C(O)alkyl, --C(O)aryl,
--C(O)aralkyl, --C(O)heteroaryl, --C(O)heteroaralkyl,
--C(O)O(alkyl), --C(O)O(aryl), --C(O)O(aralkyl),
--C(O)O(heteroaryl), --C(O)O(heteroaralkyl), --S(O).sub.2(aryl),
--S(O).sub.2(alkyl), --S(O).sub.2(haloalkyl), --OR.sup.10,
--SR.sup.10, or --NR.sup.10R.sup.11; [0087] R.sup.7 and R.sup.8
each independently represent hydrogen, hydroxyl, halogen, nitro,
alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl,
alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy,
arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl,
aminoalkyl, thioalkyl, haloalkyl, ether, thioether, ester, amido,
thioester, carbonate, carbamate, urea, sulfonate, sulfone,
sulfoxide, sulfonamide, acyl, acyloxy, or acylamino; [0088] or
R.sup.6, R.sup.7, and R.sup.8 taken together with a substituent on
ring A and the intervening atoms, form an optionally substituted
aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl group; [0089] R.sup.10 and R.sup.11 are
independently selected for each occurrence from hydrogen or
substituted or unsubstituted alkyl, aralkyl, aryl, heteroaralkyl,
heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,
heterocycloalkyl, alkenyl, and alkynyl; and [0090] ring A
represents an optionally substituted cycloalkyl, heterocycloalkyl,
cycloalkenyl, or heterocycloalkenyl group.
[0091] In certain embodiments, the compound of formula (I) is
represented by formula (Ia):
##STR00015##
and the compound of formula (II) is represented by formula
(IIa):
##STR00016##
and the compound of formula (III) is represented by formula
(IIIa):
##STR00017## [0092] In certain such embodiments, B, D, and E each
independently for each occurrence represent, as valence permits,
--O--, --S--, --NR.sup.6--, --CR.sup.7R.sup.8--, --C(O)--,
--CR.sup.7.dbd., or --N.dbd.; provided that no two adjacent
occurrences of W, B, D, and E are NR.sup.6, O, S, or N; [0093] or
any two occurrences of R.sup.6, R.sup.7, and R.sup.8 on adjacent W,
B, D, or E groups, taken together with the intervening atoms, form
an optionally substituted aryl, heteroaryl, cycloalkyl,
cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group; [0094]
each occurrence of independently represents a double bond or a
single bond as permitted by valence; and [0095] m and n are
integers each independently selected from 0, 1, and 2.
[0096] In certain embodiments, W represents --O--, --S--,
--NR.sup.6--, --CR.sup.7R.sup.8-- or --CR.sup.7.dbd..
[0097] In certain embodiments, the sum of m and n is 0, 1, 2, or 3;
that is, ring A is a 4-7 membered ring.
[0098] In certain embodiments, ring A is a carbocyclic ring.
[0099] In certain such embodiments, each occurrence of W, B, D, and
E is independently --CR.sup.7R.sup.8--, or --CR.sup.7--, or
--C(O)--. For example, one occurrence of W, B, D, and E may be
--CR.sup.7R.sup.8-- or --C(O)--, while the remaining three may be
--CR.sup.7R.sup.8--. In certain such embodiments, R.sup.7 and
R.sup.8, independently for each occurrence, are selected from
hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, (cycloalkyl)alkyl,
aryl, aralkyl, heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl,
heterocycloalkyl, alkenyl, alkynyl, amino, alkoxy, aryloxy,
arylalkoxy, alkylamino, and amido.
[0100] In certain embodiments, ring A contains one or more double
bonds, e.g., one or more carbon-carbon double bonds.
[0101] In certain such embodiments, at least two adjacent
occurrences of W, B, D, and E are --CR.sup.7--. For example, W and
B may each be --CR.sup.7-- while m is 1. In certain such
embodiments, R.sup.7 is independently selected for each occurrence
from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,
(cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,
(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino,
alkoxy, aryloxy, alkylamino, amido, and acylamino; or the
occurrence of R.sup.7 on W and the occurrence of R.sup.7 on B are
taken together to form an optionally substituted aryl, heteroaryl,
cycloalkenyl, or heterocycloalkenyl group. In further such
embodiments, the occurrence of R.sup.7 on W and the occurrence of
R.sup.7 on B are taken together to form an optionally substituted
aryl, heteroaryl, cycloalkenyl, or heterocycloalkenyl group,
preferably an optionally substituted aryl group. For example, ring
A may be a tetralone-derived substrate.
[0102] Alternatively, in certain embodiments in which W and B are
each --CR.sup.7--, the occurrence of R.sup.7 on W is selected from
amino, alkylamino, amido, acylamino, and N-bound
heterocycloalkyl.
[0103] In alternative embodiments, at least one occurrence of W, B,
D, and E is --NR.sup.6--. For example, W may be --NR.sup.6--. In
certain such embodiments, at least one occurrence of the remaining
B, D, and E is --NR.sup.6-- or --O--. In further such embodiments,
R.sup.6 represents, independently for each occurrence, hydrogen or
optionally substituted alkyl, aralkyl, heteroaralkyl, --C(O)alkyl,
--C(O)aryl, --C(O)aralkyl, --C(O)O(alkyl), --C(O)O(aryl),
--C(O)O(aralkyl), or --S(O).sub.2(aryl).
[0104] In certain embodiments, at least one occurrence of W, B, D,
and E is --O--.
[0105] In certain embodiments, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are each independently
selected for each occurrence from hydrogen, halogen, cyano, alkyl,
alkoxy, alkylthio, amide, amine, aryloxy, and arylalkoxy. For
example, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.12, R.sup.13,
R.sup.14, and R.sup.15 are each independently hydrogen or lower
alkyl. Preferably, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.12,
R.sup.13, R.sup.14, and R.sup.15 are each hydrogen.
[0106] In certain embodiments, R.sup.1 represents substituted or
unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl,
heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,
(heterocycloalkyl)alkyl, heterocycloalkyl, or halo.
[0107] In certain embodiments, R.sup.1 represents substituted or
unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl,
heteroaralkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl,
heterocycloalkyl, or halo. In certain such embodiments, R.sup.1 is
selected from optionally substituted alkyl, aryl, aralkyl,
haloalkyl, alkoxyalkyl, and hydroxyalkyl. For example, R.sup.1 may
be alkyl, optionally substituted with halo, hydroxy, alkoxy,
aryloxy, arylalkoxy, cyano, nitro, azido, --CO.sub.2H,
--C(O)O(alkyl), amino, alkylamino, arylamino, aralkylamino, and
amido.
[0108] In certain embodiments, the method for preparing a compound
of formula (I) comprises treating a compound of formula (II) with a
Pd(II) catalyst under alkylation conditions.
[0109] In certain embodiments, the method for preparing a compound
of formula (I) comprises treating a compound of formula (III) with
a Pd(II) catalyst under alkylation conditions.
[0110] In certain embodiments, the method yields a compound of
formula (I) that is enantioenriched.
[0111] In further aspects, the present invention provides a method
for preparing a compound of formula (I), described above,
comprising treating a compound of formula (IV) or (V) or a salt
thereof:
##STR00018## [0112] with a compound of formula (X):
##STR00019##
[0112] and [0113] a Pd(II) catalyst under alkylation conditions,
wherein, as valence and stability permit, [0114] W, R.sup.1,
R.sup.12, R.sup.13, R.sup.14, R.sup.15, and ring A are as defined
for formulae (I) and (II), above; and further wherein: [0115]
R.sup.a represents optionally substituted alkyl, aryl, or alkoxyl;
and [0116] X represents a halide, carbonate, sulfonate, acetate, or
carboxylate.
[0117] In certain embodiments, the compound of formula (I) is
represented by formula (Ia):
##STR00020##
and the compound of formula (IV) is represented by formula
(IVa):
##STR00021##
and the compound of formula (V) is represented by formula (Va):
##STR00022##
wherein substituents B, D, E, n, and m are defined above for
formulae (Ia), (IIa), and (IIIa).
[0118] In certain embodiments, the alkylation conditions under
which the compound of formula (IV) or (V) reacts to form a compound
of formula (I) further comprise a fluoride source, such as TBAT,
TBAF, LiBF.sub.4, or a tetraalkylammonium fluoride salt.
[0119] In certain embodiments, the method for preparing a compound
of formula (I) comprises treating a compound of formula (IV) with a
Pd(II) catalyst under alkylation conditions.
[0120] In certain embodiments, the method for preparing a compound
of formula (I) comprises treating a compound of formula (V) with a
Pd(II) catalyst under alkylation conditions.
Transition Metal Catalysts
[0121] Preferred transition metal catalysts of the invention are
complexes of palladium (II).
[0122] It should be appreciated that typical transition metal
catalysts having a low oxidation state (e.g., (0) or (I)) suffer
from air- and moisture-sensitivity, such that these complexes of
transition metals necessitate appropriate handling precautions.
This may include the following precautions without limitation:
minimizing exposure of the reactants to air and water prior to
reaction; maintaining an inert atmosphere within the reaction
vessel; properly purifying all reagents; and removing water from
reaction vessels prior to use.
[0123] Palladium (II) catalysts are typically robust, and are less
sensitive to air and moisture than their lower-oxidation state
counterparts.
[0124] Exemplary Pd (II) catalysts that may be used in the methods
of the invention include Pd(OC(O)R.sup.c).sub.2, wherein R.sup.c is
optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl,
aralkyl, heteroaralkyl, cycloalkyl, heterocycloalkyl,
(cycloalkyl)alkyl, or (heterocycloalkyl)alkyl. Further exemplary Pd
(II) catalysts include Pd(OC(O)R.sup.c).sub.2,
Pd(OC(.dbd.O)CH.sub.3).sub.2 (i.e., Pd(OAc).sub.2), Pd(TFA).sub.2,
Pd(acac).sub.2, PdCl.sub.2, PdBr.sub.2,
PdCl.sub.2(R.sup.23CN).sub.2 (e.g., Pd(PhCN).sub.2C.sub.12 and
Pd(CH.sub.3CN).sub.2Cl.sub.2),
PdCl.sub.2(PR.sup.24R.sup.25R.sup.26).sub.2,
[Pd(.eta..sup.3-allyl)Cl].sub.2, and pre-formed Pd(II)-ligand
complex, wherein R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are
independently selected from hydrocarbyl, substituted hydrocarbyl,
heteroatom-containing hydrocarbyl, and substituted
heteroatom-containing hydrocarbyl. In preferred embodiments, the
transition metal catalyst is Pd(OAc).sub.2. Alternatively, the
transition metal catalyst is Pd(OC(O)R.sup.c).sub.2, wherein
R.sup.c is defined above. For example, R.sup.c may be alkyl,
substituted by one or more halo or cyano groups.
[0125] To improve the effectiveness of the catalysts discussed
herein, additional reagents may be employed, including, without
limitation, salts, solvents, and other small molecules. Preferred
additives include AgBF.sub.4, AgOSO.sub.2CF.sub.3,
AgOC(.dbd.O)CH.sub.3, and bipyridine. These additives are
preferably used in an amount that is in the range of about 1
equivalent to about 5 equivalents relative to the amount of the
catalyst.
[0126] A low oxidation state of a transition metal, i.e., an
oxidation state sufficiently low to undergo oxidative addition, can
be obtained in situ, by the reduction of transition metal complexes
that have a high oxidation state. Reduction of the transition metal
complex can optionally be achieved by adding nucleophilic reagents
including, without limitation, tetrabutylammonium hydroxide,
tetrabutylammonium difluorotriphenylsilicate (TBAT),
tetrabutylammonium fluoride (TBAF), 4-dimethylaminopyridine (DMAP),
tetramethylammonium hydroxide (e.g., as the pentahydrate),
KOH/1,4,7,10,13,16-hexaoxacyclooctadecane, sodium ethoxide,
TBAT/trimethyl-(2-methyl-cyclohex-1-enyloxy)-silane, and
combinations thereof. When a nucleophilic reagent is needed for the
reduction of the metal complex, the nucleophilic reagent is used in
an amount in the range of about 1 mol % to about 20 mol % relative
to the reactant, more preferably in the range of about 1 mol % to
about 10 mol % relative to the substrate, and most preferably in
the range of about 5 mol % to about 8 mol % relative to the
substrate.
[0127] For example, a Pd(II) complex can be reduced in situ to form
a Pd(0) catalyst. Exemplary transition metal complexes that may be
reduced in situ, include, without limitation,
allylchloro[1,3-bis(2,6-di-iso-propylphenyl)imidazol-2-ylidene]palladium(-
II),
([2S,3S]-bis[diphenylphosphino]butane)(.eta..sup.3-allyl)palladium(II-
) perchlorate,
[S]-4-tert-butyl-2-(2-diphenylphosphanyl-phenyl)-4,5-dihydro-oxazole(.eta-
..sup.3-allyl)palladium(II) hexafluorophosphate (i.e.,
[Pd(S-tBu-PHOX)(allyl)]PF.sub.6), and
cyclopentadienyl(.eta..sup.3-allyl) palladium(II).
[0128] Accordingly, when describing the amount of transition metal
catalyst used in the methods of the invention, the following
terminology applies. The amount of transition metal catalyst
present in a reaction is alternatively referred to herein as
"catalyst loading". Catalyst loading may be expressed as a
percentage that is calculated by dividing the moles of catalyst
complex by the moles of the substrate present in a given reaction.
Catalyst loading is alternatively expressed as a percentage that is
calculated by dividing the moles of total transition metal (for
example, palladium) by the moles of the substrate present in a
given reaction.
[0129] In certain embodiments, the transition metal catalyst is
present under the conditions of the reaction from an amount of
about 0.01 mol % to about 10 mol % total palladium relative to the
substrate, which is the compound of formula (II), (III), (IV), or
(V). In certain embodiments, the catalyst loading is from about
0.05 mol % to about 5 mol % total palladium relative to the
substrate. In certain embodiments, the catalyst loading is from
about 0.05 mol % to about 2.5 mol %, about 0.05 mol % to about 2%,
about 0.05 mol % to about 1%, about 0.02 mol % to about 5 mol %,
about 0.02 mol % to about 2.5 mol %, about 0.02 mol % to about 1
mol %, about 0.1 mol % to about 5 mol %, about 0.1 mol % to about
2.5 mol %, or about 0.1 mol % to about 1 mol % total palladium
relative to the substrate. For example, in certain embodiments, the
catalyst loading is about 0.01 mol %, about 0.05 mol %, about 0.1
mol %, about 0.15 mol %, about 0.2 mol %, about 0.25 mol %, about
0.3 mol %, about 0.4 mol %, about 0.5 mol %, about 0.6 mol %, about
0.7 mol %, about 0.8 mol %, about 0.9 mol %, about 1 mol %, about
1.5 mol %, about 2 mol %, about 3 mol %, or about 5 mol % total
palladium.
Ligands
[0130] One aspect of the invention relates to the
enantioselectivity of the methods. Enantioselectivity results from
the use of chiral ligands during the allylic alkylation reaction.
Accordingly, in certain embodiments, the Pd (II) catalyst further
comprises a chiral ligand. Without being bound by theory, the
asymmetric environment that is created around the metal center by
the presence of chiral ligands produces an enantioselective
reaction. The chiral ligand forms a complex with the transition
metal (i.e., palladium), thereby occupying one or more of the
coordination sites on the metal and creating an asymmetric
environment around the metal center. This complexation may or may
not involve the displacement of achiral ligands already complexed
to the metal. When displacement of one or more achiral ligands
occurs, the displacement may proceed in a concerted fashion, i.e.,
with both the achiral ligand decomplexing from the metal and the
chiral ligand complexing to the metal in a single step.
Alternatively, the displacement may proceed in a stepwise fashion,
i.e., with decomplexing of the achiral ligand and complexing of the
chiral ligand occurring in distinct steps. Complexation of the
chiral ligand to the transition metal may be allowed to occur in
situ, i.e., by admixing the ligand and metal before adding the
substrate. Alternatively, the ligand-metal complex can be formed
separately, and the complex isolated before use in the alkylation
reactions of the present invention.
[0131] Once coordinated to the transition metal center, the chiral
ligand influences the orientation of other molecules as they
interact with the transition metal catalyst. Coordination of the
metal center with a .pi.-allyl group and reaction of the substrate
with the .pi.-allyl-metal complex are dictated by the presence of
the chiral ligand. The orientation of the reacting species
determines the stereochemistry of the products.
[0132] Chiral ligands of the invention may be bidentate or
monodentate or, alternatively, ligands with higher denticity (e.g.,
tridentate, tetradentate, etc.) can be used. Preferably, the ligand
will be substantially enantiopure. By "enantiopure" is meant that
only a single enantiomer is present. In many cases, substantially
enantiopure ligands (e.g., ee>99%, preferably >99.5%, even
more preferably >99.9%) can be purchased from commercial
sources, obtained by successive recrystallizations of an
enantioenriched substance, or by other suitable means for
separating enantiomers.
[0133] Exemplary chiral ligands may be found in U.S. Pat. No.
7,235,698, the entirety of which is incorporated herein by
reference. In certain embodiments, the chiral ligand is an
enantioenriched phosphine ligand. In certain embodiments, the
enantioenriched phosphine ligand is a P,N-ligand such as a
phosphinooxazoline (PHOX) ligand. Preferred chiral ligands of the
invention include the PHOX-type chiral ligands such as
(R)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline,
(R)-2-[2-(diphenylphosphino)phenyl]-4-phenyl-2-oxazoline,
(S)-2-[2-(diphenylphosphino)phenyl]-4-benzyl-2-oxazoline,
(S)-2-[2-(diphenylphosphino)phenyl]-4-tert-butyl-2-oxazoline
((S)-t-BuPHOX) and
(S)-2-(2-(bis(4-(Trifluoromethyl)phenyl)phosphino)-5-(trifluoromethyl)phe-
nyl)-4-(tert-butyl)-4,5-dihydrooxazole
((S)--(CF.sub.3).sub.3-t-BuPHOX). In preferred embodiments, the
PHOX type chiral ligand is selected from (S)-t-BuPHOX and
(S)--(CF.sub.3).sub.3-t-BuPHOX). The ligand structures are depicted
below.
##STR00023##
[0134] Generally, the chiral ligand is present in an amount in the
range of about 1 equivalents to about 20 equivalents relative to
the amount of total metal from the catalyst, preferably in the
range of about 5 to about 15 equivalents relative to the amount of
total metal from the catalyst, and most preferably in the range of
about 10 equivalents relative to the amount of total metal from the
catalyst. Alternatively, the amount of the chiral ligand can be
measured relative to the amount of the substrate.
[0135] In certain embodiments, the ligand is present under the
conditions of the reaction from an amount of about 0.1 mol % to
about 100 mol % relative to the substrate, which is the compound of
formula (II), (III), (IV), or (V). The amount of ligand present in
the reaction is alternatively referred to herein as "ligand
loading" and is expressed as a percentage that is calculated by
dividing the moles of ligand by the moles of the substrate present
in a given reaction. In certain embodiments, the ligand loading is
from about 0.5 mol % to about 50 mol %. For example, in certain
embodiments, the ligand loading is about about 1 mol %, about 1.5
mol %, about 2 mol %, about 2.5 mol %, about 3 mol %, about 4 mol
%, or about 5 mol %. In certain embodiments, the ligand is in
excess of the transition metal catalyst. In certain embodiments,
the ligand loading is about 10 times the transition metal catalyst
loading. Without being bound to theory, it is thought that the
ligand (e.g., the PHOX ligand) may act as the reductive agent that
generates Pd(0) in situ.
[0136] Where a chiral ligand is used, the reactions of the
invention may enrich the stereocenter bearing R.sup.1 in the
product relative to the enrichment at this center, if any, of the
starting material. In certain embodiments, the chiral ligand used
in the methods of the invention yields a compound of formula (I)
that is enantioenriched. The level of enantioenrichment of a
compound may be expressed as enantiomeric excess (ee). The ee of a
compound may be measured by dividing the difference in the
fractions of the enantiomers by the sum of the fractions of the
enantiomers. For example, if a compound is found to comprise 98%
(S)-enantiomer, and 2% (R) enantiomer, then the ee of the compound
is (98-2)/(98+2), or 96%. In certain embodiments, the compound of
formula (I) has about 30% ee or greater, 40% ee or greater, 50% ee
or greater, 60% ee or greater, 70% ee or greater, about 80% ee,
about 85% ee, about 88% ee, about 90% ee, about 91% ee, about 92%
ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about
97% ee, about 98% ee, about 99% ee, or above about 99% ee, even
where this % ee is greater than the % ee of the starting material,
such as 0%/a ee (racemic). In certain embodiments, the compound of
formula (I) is enantioenriched. In certain embodiments, the
compound of formula (I) is enantiopure. In embodiments where the
starting material has more than one stereocenter, reactions of the
invention may enrich the stereocenter bearing R.sup.1 relative to
the enrichment at this center, if any, of the starting material,
and substantially independently of the stereochemical
disposition/enrichment of any other stereocenters of the molecule.
For example, a product of the methods described herein may have 30%
de or greater, 40% de or greater, 50% de or greater, 60% de or
greater, 70% de or greater, 80% de or greater, 90% de or greater,
95% de or greater, or even 98% de or greater at the stereocenter of
the product bearing R.sup.1.
[0137] In certain embodiments, the invention also relates to
methods that utilize an achiral ligand. Exemplary achiral ligands
include triphenylphosphine, tricyclohexylphosphine,
tri-(ortho-tolyl)phosphine, trimethylphosphite, and
triphenylphosphite.
Alkylation Conditions
[0138] In certain embodiments, the methods of the invention include
treating a compound of formula (II), (III), (IV), or (V) with a Pd
(II) catalyst under alkylation conditions. In certain embodiments,
alkylation conditions of the reaction include one or more organic
solvents. In certain embodiments, organic solvents include aromatic
or non-aromatic hydrocarbons, ethers, alkylacetates, nitriles, or
combinations thereof. In certain embodiments, organic solvents
include hexane, pentane, benzene, toluene, xylene, cyclic ethers
such as optionally substituted tetrahydrofuran and dioxane, acyclic
ethers such as dimethoxyethane, diethyl ether, methyl tertbutyl
ether, and cyclopentyl methyl ether, acetonitrile, isobutyl
acetate, ethyl acetate, isopropyl acetate, or combinations thereof.
In certain preferred embodiments, the solvent is toluene, methyl
tertbutyl ether, or 2-methyltetrahydrofuran. In certain other
preferred embodiments, the solvent is methyl tertbutyl ether.
[0139] In certain embodiments, alkylation conditions of the
reaction include a reaction temperature. In certain embodiments,
the reaction temperature is ambient temperature (about 20.degree.
C. to about 26.degree. C.). In certain embodiments, the reaction
temperature is higher than ambient temperature, such as, for
example, about 30.degree. C., about 35.degree. C., about 40.degree.
C., about 45.degree. C., about 50.degree. C., about 55.degree. C.,
or about 60.degree. C. Reaction temperature may be optimized per
each substrate.
[0140] In certain embodiments, instruments such as a microwave
reactor may be used to accelerate the reaction time. Pressures
range from atmospheric to pressures typically used in conjunction
with supercritical fluids, with the preferred pressure being
atmospheric.
EXEMPLIFICATION
[0141] The invention described generally herein will be more
readily understood by reference to the following examples, which
are included merely for purposes of illustration of certain aspects
and embodiments of the present invention, and are not intended to
limit the invention.
Example 1. Exploration of Alternative Pd-Catalyst
[0142] Pd.sub.2(dba).sub.3 is known to be oxygen-sensitive. In
order to increase the scalability of the reaction, alternative
Pd-based catalysts were explored. The catalytic cycle of the
allylic alkylation operates starting from a zero valent palladium
source and is believed to involve a palladium (0/II) redox
cycle..sup.[6] While utilization of Pd.sub.2(dba).sub.3 renders in
situ reduction of the catalyst obsolete, its application is
hampered by increased sensitivity to oxygen. Furthermore, the
dibenzylideneacetone ligand is challenging to separate from
non-polar reaction products. Below is a survey of a variety of
Pd(II) sources in combination with the chiral phosphinooxazoline
ligands (S)-t-BuPHOX 3.sup.[7] and (S)--(CF.sub.3).sub.3-t-BuPHOX
4..sup.[8]
##STR00024##
TABLE-US-00001 TABLE 1 Comparison between palladium precursors in
different oxidation states. ##STR00025## ##STR00026## Ligand Pd
Entry [mmol] source [mol %] Pd Yield [%] .sup.a) ee [%] .sup.b) 1 3
10.0 Pd(OAc).sub.2 1.0 99 86 2 4 10.0 Pd(OAc).sub.2 1.0 99 82 3 3
10.0 Pd.sub.2(dba).sub.3 1.0 99 84 4 4 10.0 Pd.sub.2(dba).sub.3 1.0
90 82 5 3 1.0 Pd(OAc).sub.2 0.1 99 79 6 4 1.0 Pd(OAc).sub.2 0.1 99
83 7 3 1.0 Pd.sub.2(dba).sub.3 0.1 12 n.d. 8 4 1.0
Pd.sub.2(dba).sub.3 0.1 14 n.d. .sup.a) GC yield relative to an
internal standard (tridecane). .sup.b) Enantiomeric excess measured
by chiral GC.
[0143] When comparing Pd(OAc).sub.2 and Pd.sub.2(dba).sub.3 at 1.0
mol % palladium in combination with a tenfold excess of PHOX
ligands 3 or 4 respectively, in TBME at 80.degree. C. both
palladium sources exhibited comparable catalytic performance (Table
1, entries 1-4). At lower palladium concentrations, however,
Pd(OAc).sub.2 was clearly superior, delivering quantitative yields
and good enantioselectivity at only 0.10 mol % Pd (Table 1, entries
5 and 6). When 0.10 mol % Pd.sub.2(dba).sub.3 was used to form the
catalyst, a dramatic decrease in yields was observed (Table 1,
entries 7 and 8).
[0144] Other palladium(II) sources were then investigated to
determine whether the sources were equally suited to catalyze the
decarboxylative allylic alkylation. Consequently, a total of eight
different commercially available Pd(II) precursors were examined in
our model reaction in the presence of ligand 3 (Pd(OAc).sub.2,
PdCl.sub.2, Pd(PhCN).sub.2Cl.sub.2, Pd(CH.sub.3CN).sub.2Cl.sub.2,
PdBr.sub.2, Pd(acac).sub.2, [Pd(allyl)Cl].sub.2, Pd(TFA).sub.2).
Solubility of certain palladium salts in TBME can hinder
catalysis.
Example 2. Exploration of Catalyst Loading
[0145] Using Pd(OAc).sub.2 as the palladium catalyst precursor, we
turned our attention to minimizing the catalyst loading. A
screening of six different catalyst loadings, ranging from 0.05 mol
% to 1.0 mol %, was performed (Table 2). All reactions were
conducted in the presence of a tenfold excess of ligand with
respect to palladium, in TBME at 40.degree. C. The high-excess of
ligand was chosen to facilitate formation of the active catalyst
through in situ reduction of Pd(OAc).sub.2. We reasoned that the
PHOX ligand hereby acts as the reductive agent.
[0146] Under these reaction conditions, palladium loadings as low
as 0.10 mol % were sufficient to deliver the desired allylic
alkylation product in 90% yield and with high enantioselectivity
(Table 2, entry 5). To obtain a quantitative yield of ketone 2a,
the catalyst loading was increased to 0.15 mol % of Pd(OAc).sub.2
(Table 2, entry 4).
TABLE-US-00002 TABLE 2 Assessment of the Pd(OAc).sub.2 loading for
the decarboxylative allylic alkylation. ##STR00027## ##STR00028##
Entry Pd [mol %] 3 [mol %] Yield [%] .sup.a) ee [%] .sup.b) 1 1.00
10.0 99 90 2 0.50 5.0 99 90 3 0.25 2.50 99 90 4 0.15 1.50 99 89 5
0.10 1.0 90 89 6 0.05 0.50 10 89 .sup.a) GC yield relative to an
internal standard (tridecane). .sup.b) Enantiomeric excess measured
by chiral GC.
Example 3. Solvent Survey
[0147] Enantioselective allylic alkylation reactions are typically
performed in solvents such as THF, DCM, dioxane, or diethylether.
While these solvents are common for academic laboratory scale,
their use prohibits conducting the reaction in an industrial
setting. We sought to overcome this limitation and performed a
solvent survey with a total often different solvents that are
considered to be safe, sustainable and cost-efficient (Table
3)..sup.[9,10]
[0148] Conversion of allyl 1-methyl-2-oxocyclohexane-carboxylate
(1a) in TBME resulted in a high yield and good enantioselectivity
(Table 3, entry 1). When the reaction was performed in various
alkyl acetates the yields dropped dramatically, to 12%, 28% and 17%
respectively (Table 3, entries 2, 4 and 5). Similarly low yields
were observed for reactions performed in acetonitrile,
dimethylacetamide, 2-Me-THF, and acetone (Table 3, entries 3, 6, 8
and 10). Moderate conversion was found when the reaction was
performed in toluene (Table 3, entry 7). Consequently, all further
experiments were carried out in TBME.
TABLE-US-00003 TABLE 3 Assessment of the reaction medium.
##STR00029## ##STR00030## Entry solvent Yield [%] .sup.a) ee [%]
.sup.b) 1 TBME 88 89 2 EtOAc 12 .sup.c) 74 3 Acetonitrile trace --
4 Isopropyl acetate 28 64 5 Isobutyl acetate 17 -- 6
Dimethylacetamide trace -- 7 Toluene 52 80 8 2-Me--THF 21 89 9
t-AmylOH -- .sup.c) -- 10 Acetone 12 .sup.c) 47 .sup.a) GC yield
relative to an internal standard (tridecane). .sup.b) Enantiomeric
excess measured by chiral GC. .sup.c) Reaction performed at
60.degree. C.
Example 4. Temperature Survey
[0149] At this point, we considered that the palladium
concentration could be lowered further by performing the reaction
at higher temperatures, and we were interested in the influence of
increased reaction temperature on stereoselectivity. All
experiments were performed in TBME with a tenfold excess of ligand
3 (Table 4). A palladium loading as low as 0.075 mol % afforded
ketone 2a in 99% yield when the reaction was performed at
80.degree. C., which corresponds to a turnover number of 1320 for
the in situ formed catalyst. Nevertheless, a slightly lower
enantioselectivity of 84% was observed in this case (Table 4, entry
1). At 60 OC and 40.degree. C., palladium loadings of 0.10 and
0.125 mol % respectively were sufficient to deliver the desired
product in quantitative yield and retain high enantioselectivity
(Table 4, entries 2 and 3).
TABLE-US-00004 TABLE 4 Assessment of the palladium loading for the
decarboxylative allylic alkylation at various temperatures.
##STR00031## ##STR00032## Entry Pd [mol %] T [.degree. C.] Yield
[%] .sup.a) ee [%] .sup.b) 1 0.075 80 99 84 2 0.10 60 99 88 3 0.125
40 99 89 .sup.a) GC yield relative to an internal standard
(tridecane). .sup.b) Enantiomeric excess measured by chiral GC.
Example 5. Increasing Reaction Scale
[0150] We then applied the protocol to the 10 and 20 mmol scale
synthesis of alpha-quaternary ketones 2a and 2b (Table 5). Both
reactions were performed in TBME with a tenfold excess of ligand 3.
Cyclohexanone 1a was converted on a 10.0 mmol scale (1.96 g) in the
presence of 0.15 mol % (3.37 mg) of Pd(OAc).sub.2 at 60.degree. C.
The corresponding product 2a was isolated by distillation in
excellent yield and high enantioselectivity (Table 5, entry 1).
Similarly, tetralone substrate 1b was subjected to enantioselective
allylic alkylation conditions at 40.degree. C. on a 20 mmol scale
(4.89 g). The desired product 2b was purified by flash
chromatography and isolated in 95% yield and 88% ee (Table 5, entry
2).
TABLE-US-00005 TABLE 5 Scale-up experiments. ##STR00033##
##STR00034## Scale Pd Entry Substrate [mol] T [.degree. C.] [mol %]
Yield [%] ee [%] 1 Cyclo- 0.01 60 0.150 95 .sup.a) 89 .sup.c)
hexanone 1a 2 Tetralone 1b 0.02 40 0.125 95 .sup.b) 88.sup.d)
.sup.a) Isolated yield, purification by distillation. .sup.b)
Isolated yield, purification by flash chromatography. .sup.c)
Enantiomeric excess measured by chiral GC. .sup.d)Enantiomeric
excess measured by chiral SFC.
Example 6. Ligand Loading and Reaction Concentration
[0151] Six experiments were conducted, employing different
quantities of ligand, from 0.20 mol % to 1.0 mol %, in the presence
of 0.10 mol % Pd(OAc).sub.2 (Table 6). A ligand loading of 0.40 mol
%, which corresponds to a 4-fold excess of ligand with respect to
palladium, was sufficient to provide the desired product in
quantitative yield and high enantioselectivity (Table 6, entry 4).
Only at a loading of 0.20 mol % of ligand 3 a slight decrease in
enantioselectivity was observed (Table 6, entry 5).
TABLE-US-00006 TABLE 6 Assessment of the ligand loading for the
decarboxylative allylic alkylation. ##STR00035## ##STR00036## Entry
Ligand 3 [mol %] Yield [%] .sup.a) ee [%] .sup.b) 1 1.00 99 88 2
0.80 99 89 3 0.60 99 88 4 0.40 99 88 5 0.20 99 86 .sup.a) GC yield
relative to an internal standard (tridecane). .sup.b) Enantiomeric
excess measured by chiral GC.
[0152] Finally, we investigated the influence of concentration on
reactivity. A brief study across five different substrate
concentrations was executed (Table 7).
TABLE-US-00007 TABLE 7 Assessment of the reaction concentration.
##STR00037## ##STR00038## Entry concentration [M] Yield [%] .sup.a)
ee [%] .sup.b) 1 0.40 99 88 2 0.20 99 88 3 0.10 99 89 4 0.05 99 89
5 0.033 91 87 .sup.a) GC yield relative to an internal standard
(tridecane). .sup.b) Enantiomeric excess measured by chiral GC.
[0153] We were pleased to find that the decarboxylative alkylation
reaction could be performed in high concentrations of up to 0.40 M
without any negative impact on yield or enantiomeric excess (Table
7, entry 1). When the reaction was performed at higher dilution
(0.033 M) a slight decrease in yield and optical purity was
observed (Table 7, entry 5).
Example 7. Lactams as Substrates
[0154] The decarboxylative allylic alkylation of lactams is
particularly useful and important, given the prevalence of
quaternary N-heterocycles in biologically active alkaloids and
their potential importance in pharmaceutical agents..sup.[11]
Initial experiments suggested that higher palladium loadings were
required for the decarboxylative allylic alkylation of
piperidinones. Consequently, a brief study was performed to
determine the minimal palladium loading needed to efficiently
catalyze the reaction (Table 8). The electron-poor ligand
(S)--(CF.sub.3).sub.3-t-BuPHOX 4 was applied in the presence of
varying amounts of Pd(OAc).sub.2 in TBME at 60.degree. C.
TABLE-US-00008 TABLE 8 Assessment of the palladium loading for the
decarboxylative allylic alkylation of lactams. ##STR00039##
##STR00040## Entry Pd [mol %] 4 [mol %] Yield [%] .sup.a) ee [%]
.sup.b) 1 0.50 5.0 87 96 2 0.30 3.0 85 97 3 0.10 1.0 77 84 .sup.a)
GC yield relative to an internal standard (tridecane). .sup.b)
Enantiomeric excess measured by HPLC.
[0155] At 0.10 mol % of Pd(OAc).sub.2 the desired product was
obtained in only 77% yield and a reduced enantioselectivity of 84%
ee. (Table 8, entry 3) Nevertheless, a catalyst concentration of
only 0.30 mol % was sufficient to render the chiral lactam 6a in
85% yield and 97% ee (Table 8, entry 2). Compared to the original
report, in which 5.0 mol % of Pd.sub.2(dba).sub.3 were applied,
this constitutes a more than thirtyfold decrease in palladium
loading.
Example & Additional Substrate Studies
[0156] To demonstrate the broad applicability of this novel
protocol, a total often compounds were subjected to the improved
reaction parameters (Table 9). Asymmetric allylic alkylation to
generate products 2a, 2b and 6a was discussed previously in detail
(Table 9, entries 1-3). Allylmethylpiperidinone 6b and
allylfluoropiperidinone 6d were synthesized in a similar fashion.
Yields of 81% and 80% respectively, and enantioselectivities of up
to 99% could be obtained (Table 9, entry 4 and 6). In the latter
case, a catalyst loading as low as 0.125 mol % was sufficient to
yield the product in near to perfect enantioselectivity. Despite
the 80-fold reduction in palladium loading compared to the original
procedure, no erosion of enantioselectivity was observed (Table 9,
entry 6).
[0157] Gratifyingly, the novel allylic alkylation protocol could be
applied to seven-membered rings as well; however, despite a near
quantitative yield only reduced enantiomeric excess of 70% was
observed for ketone 2c (Table 9, entry 7). Nevertheless,
seven-membered caprolactam 6e was isolated in 95% yield and high
enantioselectivity (Table 9, entry 8). Notably, despite the
dilution, cyclohexylketal 2d was generated in 79% yield and good
enantioselectivity through intermolecular allylic alkylation of the
corresponding silyl enol ether and allyl methanesulfonate (Table 9,
entry 9).
[0158] Finally, cyclohexanedione 2e, which is a critical
intermediate in the synthesis of (-)-cyanthiwigin F,.sup.[12] could
be accessed through double enantioselective allylic alkylation of
the bis(.quadrature.-ketoester) 1e in excellent yield and near
perfect enantioselectivity using only 0.25 mol % palladium. This
corresponds to 5% of the palladium loading used in the original
protocol. Despite the considerable reduction in catalyst
concentration the yield for this reaction was improved to 97%
(Table 9, entry 10).
TABLE-US-00009 TABLE 9 Scope of the decarboxylative allylic
alkylation..sup.a) Entry Product Protocol Pd [mol %] Yield [%] ee
[%] 1 ##STR00041## old new 5.00 0.125 89 99 .sup.b) 88 89 2
##STR00042## old new 8.00 0.125 97 85 .sup.b) 92 89 3 ##STR00043##
old new 10.0 0.30 97 85 .sup.f) 99 97 4 ##STR00044## old new 10.0
0.50 85 81 .sup.f) 99 95 5 ##STR00045## old new 10.0 0.125 91 99
.sup.f) 94 88 6 ##STR00046## old new 10.0 0.125 89 80 .sup.f) 99 99
7 ##STR00047## old new 5.00 0.10 83 97 .sup.e), f) 87 70 8
##STR00048## old new 5.00 0.125 83 95 .sup.f) 93 90 9 ##STR00049##
old new -- 0.10 -- 79 .sup.c), e), f) -- 90 10 ##STR00050## old new
5.00 0.25 78 97 .sup.d), e), f), h) 99 99 .sup.g)
.sup.a)Conditions: Reactions were performed according to the
"general procedure" in TBME at 60.degree. C. with a tenfold excess
of ligand 3 with respect to Pd. b) Temperature: 40.degree. C. c)
Temperature: 32.degree. C. d) Temperature: 27.degree. C. e)
Reaction performed in toluene. f) Ligand 4 was used. g) Diketone 2e
was obtained in 4.85:1.00 d.r. h) Isolated yield. GC yield relative
to an internal standard (tridecane). Enantiomeric excess measured
by chiral GC, HPLC or SFC.
Example 9. Experimental Procedures
Low Pd-Loading Allylic Alkylation Reactions--General Method
[0159] In a nitrogen-filled glove box, Pd(OAc).sub.2 (1.1 mg, 4.9
.mu.mol) was weighed into a 20 mL scintillation vial and dissolved
in TBME (20 mL). In a separate 1-dram vial, (S)-t-BuPHOX (1.9 mg,
4.9 .mu.mol) was dissolved in TBME (1 mL). To a 2-dram vial
equipped with a magnetic stirbar, 1.02 mL of the Pd(OAc).sub.2
solution was added (56 .mu.g, 0.25 .mu.mol, 0.125 mol %) followed
by 0.51 mL of the (S)-t-BuPHOX solution (0.97 mg, 2.5 .mu.mol, 1.25
mol %). This mixture was stirred at ambient temperature (28.degree.
C.) in the glove box for 30-40 min. Substrate (0.20 mmol, 1.0
equiv) was taken up in TBME (0.5 mL) and added to the stirring
catalyst solution. For reactions analyzed by GC, tridecane (24
.mu.L, 0.1 mmol, 0.5 equiv) was added. The reaction was sealed with
a Teflon-lined cap, removed from the glove box and stirred at the
indicated temperature for the indicated period of time. At this
point, the reaction was analyzed by GC, or passed through a silica
plug, concentrated in vacuo, and purified by column
chromatography.
##STR00051##
(S)-2-allyl-2-methylcyclohexan-1-one (2a)
[0160] Synthesized according to the general method from
cyclohexanone 1a. The reaction was passed through a plug of
SiO.sub.2 and analyzed by GC (99% yield). The product could be
isolated by column chromatography (SiO.sub.2, 5% Et.sub.2O in
pentane) as a colorless oil and matched previously reported
characterization data.
##STR00052##
(S)-2-allyl-2-methyl-3,4-dihydronaphthalen-1(2H)-one (2b)
[0161] Synthesized according to the general method from tetralone
1b. Product was isolated by column chromatography (SiO.sub.2, 5-10%
Et.sub.2O in hexanes) as a pale yellow oil (85% yield) and matched
previously reported characterization data.
##STR00053##
(S)-2-allyl-2-methylcycloheptan-1-one (2c)
[0162] Synthesized according to the general method from
cycloheptanone 1c using 1.0 mol % (S)-t-BuPHOX and 0.10 mol %
Pd(OAc).sub.2 in toluene at 60.degree. C. for 10 h. Product was
isolated by column chromatography (SiO.sub.2, 3% Et.sub.2O in
pentane) as a colorless oil (97% yield) and matched previously
reported characterization data.
##STR00054##
(2R,5R)-2,5-diallyl-2,5-dimethylcyclohexane-1,4-dione (2e)
[0163] Synthesized according to the general method from diketone 1e
using 2.5 mol % (S)--(CF.sub.3).sub.3-t-BuPHOX and 0.25 mol %
Pd(OAc).sub.2 in toluene at 25.degree. C. for 19 h. Product was
isolated by column chromatography (SiO.sub.2, 3% EtOAc in hexanes)
as a colorless oil (97% yield) and matched previously reported
characterization data.
##STR00055##
(S)-3-allyl-1-benzoyl-3-ethylpiperidin-2-one (6a)
[0164] Synthesized according to the general method from lactam 5a
using 3.0 mol % (S)--(CF.sub.3).sub.3-t-BuPHOX and 0.30 mol %
Pd(OAc).sub.2. Product was isolated by column chromatography
(SiO.sub.2, 15-20% Et.sub.2O in hexanes) as a colorless oil (85%
yield) and matched previously reported characterization data.
##STR00056##
(S)-3-allyl-1-benzoyl-3-methylpiperidin-2-one (6b)
[0165] Synthesized according to the general method from lactam 5b
using 5.0 mol % (S)--(CF.sub.3).sub.3-t-BuPHOX and 0.50 mol %
Pd(OAc).sub.2. Product was isolated by column chromatography
(SiO.sub.2, 5-10% Et.sub.2O in hexanes) as a colorless oil (81%
yield) and matched previously reported characterization data.
##STR00057##
(S)-3-allyl-1-benzoyl-3-methylpiperidine-2,6-dione (6c)
[0166] Synthesized according to the general method from imide 5c
using 1.25 mol % (S)--(CF.sub.3).sub.3-t-BuPHOX and 0.125 mol %
Pd(OAc).sub.2. Product was isolated by column chromatography
(SiO.sub.2, 10-20% EtOAc in hexanes) as a colorless oil (99% yield)
and matched previously reported characterization data.
##STR00058##
(R)-3-allyl-1-benzoyl-3-fluoropiperidin-2-one (6d)
[0167] Synthesized according to the general method from lactam 5d
using 1.25 mol % (S)--(CF.sub.3).sub.3-t-BuPHOX and 0.125 mol %
Pd(OAc).sub.2. Product was isolated by column chromatography
(SiO.sub.2, 10-20% EtOAc in hexanes) as a colorless oil (80% yield)
and matched previously reported characterization data.
##STR00059##
(S)-3-allyl-1-(4-methoxybenzoyl)-3-methylazepan-2-one (6e)
[0168] Synthesized according to the general method from lactam 5e
using 1.25 mol % (S)--(CF.sub.3).sub.3-t-BuPHOX and 0.125 mol %
Pd(OAc).sub.2. Product was isolated by column chromatography
(SiO.sub.2, 10-20% EtOAc in hexanes) as a colorless oil (95% yield)
and matched previously reported characterization data.
##STR00060##
(S)-2-allyl-2-methyl-1,5-dioxaspiro[5.5]undecan-3-one (2d)
[0169] A 20 mL vial was soaked in a 20:1 isopropanol:toluene bath
saturated with potassium hydroxide for 12 h, rinsed with deionized
water, acetone, and dried in a 120.degree. C. oven overnight. The
hot vial was the cycled into a nitrogen-filled glovebox and allowed
to cool to ambient temperature. The vial was then charged
Bu.sub.4NPh.sub.3SiF.sub.2 (TBAT, 184 mg, 0.34 mmol, 1.00 equiv)
and toluene (12.0 mL, 0.033 M) with stirring, followed by
Pd(OAc).sub.2 (0.10 mg, 0.0004 mmol, 1.0 mg/mL in toluene, 0.00125
equiv) and (S)--(CF.sub.3).sub.3-t-BuPHOX (2.37 mg, 0.004 mmol, 10
mg/mL in toluene, 0.0125 equiv). The reaction vessel was
immediately introduced to a heat block at 32.degree. C. and allowed
to stir for 20 minutes. To the resulting tan solution was added
allylmesylate (57 mg, 0.42 mmol, 1.20 equiv) quickly dropwise.
After 3 minutes, silyl enol ether 1d (100 mg, 0.34 mmol, 1.00
equiv) was added quickly dropwise. Upon complete consumption of the
enol ether (as determined by TLC analysis, 24 h), the resultant tan
solution was removed from the heat block, allowed to cool to
ambient temperature, and removed from the glove box. The reaction
mixture was filtered through a pad of SiO.sub.2 using hexanes
eluent to remove toluene, followed by Et.sub.2O eluent to isolate
the volatile reaction products. The filtrate was concentrated in
vacuo to a brown oil which was subsequently purified by flash
chromatography (SiO.sub.2, 4% Et.sub.2O in hexanes) to afford
volatile allyl ketal 2d (60 mg, 79% yield) as a clear, colorless
oil: R.sub.f=0.35 (19:1 hexanes:Et.sub.2O); .sup.1H NMR (400 MHz,
CDCl.sub.3), 5.85 (ddt, J=17.4, 10.3, 7.2 Hz, 1H), 5.14-5.03 (m,
2H), 4.20 (d, J=1.0 Hz, 2H), 2.51 (ddt, J=14.0, 7.2, 1.2 Hz, 1H),
2.41 (ddt, J=14.0, 7.2, 1.2 Hz, 1H), 1.87-1.42 (m, 10H), 1.38 (s,
3H); .sup.13C NMR (101 MHz, CDCl.sub.3), 211.4, 132.7, 118.8,
100.0, 82.0, 66.6, 44.0, 35.8, 35.5, 25.4, 24.7, 23.1, 23.1; IR
(Neat Film, NaCl) 2938, 2860, 1742, 1446, 1365, 1259, 1159, 1112,
1056, 1000, 943, 916, 826 cm.sup.-1; HRMS (EI+) m/z calc'd for
C.sub.13H.sub.20O.sub.3 [M.cndot.].sup.+: 224.1412, found 224.1409;
[.alpha.].sub.D.sup.25.0-45.9.degree. (c 1.10, CHCl.sub.3, 90%
ee).
Scale Up Procedures
##STR00061##
[0170] (s)-2-allyl-2-methyl-cyclohexanone (2a)
[0171] An oven-dried 250 mL round-bottom flask equipped with a
magnetic stir bar was fitted with a rubber septum and cooled to
room temperature under an atmosphere of argon. To the flask were
added Pd(OAc).sub.2 (3.37 mg, 15 .mu.mol, 0.150 mol %) and
(S)-t-BuPHOX (58 mg, 150 .mu.mol, 1.50 mol %). The flask was
evacuated and backfilled with argon three times. TBME (90 mL) was
added to the flask and the mixture was stirred for 30 min in a
40.degree. C. oil bath. Substrate 1a (1.96 g, 10.0 mmol, 1.0 equiv)
was taken up in TBME (10 mL) and added to the stirring catalyst
solution. The reaction was stirred for 16 h at 60.degree. C., the
reaction mixture was passed through a pad of silica gel (2 cm
diameter.times.3 cm height) and rinsed with diethyl ether (50 mL).
The filtrate was concentrated in vacuo and the remaining oil was
distilled through a short path apparatus (bp. 91-93.degree. C./16
mmHg) into a receiving flask immersed in an ice water bath to yield
product 2a as a pale yellow oil (1.45 g, 9.50 mmol, 95% yield). The
product was determined to be in 89% ee by chiral GC and matched
previously reported characterization data.
##STR00062##
(S)-2-allyl-2-methyl-3,4-dihydronaphthalen-1(2H)-one (2b)
[0172] An oven-dried 500 mL round-bottom flask equipped with a
magnetic stir bar was fitted with a rubber septum and cooled to
room temperature under an atmosphere of argon. To the flask were
added Pd(OAc).sub.2 (5.6 mg, 25 .mu.mol, 0.125 mol %) and
(S)-t-BuPHOX (97 mg, 250 .mu.mol, 1.25 mol %). The flask was
evacuated and backfilled with argon three times. TBME (190 mL) was
added to the flask and the mixture was stirred for 30 min in a
40.degree. C. oil bath. Substrate 1b (4.89 g, 20.0 mmol, 1.0 equiv)
was taken up in TBME (10 mL) and added to the stirring catalyst
solution. The reaction was stirred for 16 h, concentrated in vacuo
and purified by column chromatography (SiO.sub.2, 5-10-20%
Et.sub.2O/hexanes) to yield product 2b as a pale yellow oil (3.81
g, 19.0 mmol, 95% yield). The product was determined to be in 88%
ee by chiral SFC and matched previously reported characterization
data.
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INCORPORATION BY REFERENCE
[0185] All publications and patents mentioned herein are hereby
incorporated by reference in their entirety as if each individual
publication or patent was specifically and individually indicated
to be incorporated by reference. In case of conflict, the present
application, including any definitions herein, will control.
EQUIVALENTS
[0186] While specific embodiments of the subject invention have
been discussed, the above specification is illustrative and not
restrictive. Many variations of the invention will become apparent
to those skilled in the art upon review of this specification and
the claims below. The full scope of the invention should be
determined by reference to the claims, along with their full scope
of equivalents, and the specification, along with such
variations.
* * * * *