Method for synthesizing epothilones and epothilone analogs
A method for making epothilones and epothilone analogs is described, as are novel compounds made by the method. One embodiment of the method was used to synthesize epothilone B by a convergent approach that entailed Wittig coupling of an ylide derived from phosphonium bromide with an aldehyde. The former was prepared from propargyl alcohol by a nine-step pathway which installed both trisubstituted double bonds with clean Z configuration. Macrolactonization of a resulting seco acid provided the following intermediate diene epothilone analog. Selective saturation of the 9,10-olefin and subsequent epoxidation provided epothilone B.
1 . A method for making an epothilone or an epothilone analog, comprising:
providing a compound having Formula 1
where R substituents independently are H, lower alkyl, or a protecting group, R 1 is an aryl group, R 2 is H or lower alkyl, C 13 and C 12 are carbons bonded together by a single bond or a double bond, R 3 and R 4 independently are H, lower aliphatic groups, or are bonded to O in an epoxide or to N in an aziridine, C 10 and C 9 are carbons in a double bond or triple bond, and, where C 10 and C 9 are carbons in a double bond, the configuration of the double bond may be cis or trans or E or Z, R 5 and R 6 independently are H, or lower aliphatic, and R 7 substituents independently are selected from the group consisting of lower aliphatic groups; and
converting the compound into an epothilone or an epothilone analog.
2 . The method according to claim 1 where the compound has Formula 2
where R is H or a protecting group, R 1 is an aryl group, R 2 -R 5 substituents independently are selected from the group consisting of H and lower alkyl groups, and R 6 substituents independently are selected from the group consisting of lower alkyl groups.
3 . The method according to claim 1 where C 10 and C 9 are bonded together by a triple bond.
4 . The method according to claim 2 further comprising converting at least one double bond of the compound to an epoxide.
5 . The method according to claim 4 where the compound has formula where R is H or a protecting group and R 1 is an aryl group.
6 . The method according to claim 4 where the compound has a formula
where R is H or a protecting group and R 1 is an aryl group.
7 . The method according to claim 6 where R 1 has Formula 3
where X and Y independently are selected from the group consisting of heteroatoms.
8 . The method according to claim 7 where X and Y independently are selected from the group consisting of O, N and S.
9 . The method according to claim 7 where R 1 is an imidazole, a thiazole or an oxazole.
10 . The method according to claim 7 where R 1 is
11 . The method according to claim 4 where the compound has the formula
12 . The method according to claim 2 and further comprising converting double bonds of the compound to epoxides and/or aziridines.
13 . The method according to claim 12 where the compound has formula
14 . The method according to claim 13 where R 1 is
15 . The method according to claim 1 where R is H, and converting the compound involves forming an epoxide at C-12, C-13.
16 . The method according to claim 1 where R substituents are protecting groups, and converting the compound involves:
removing the protecting groups; and
forming an epoxide at C-12, C-13.
17 . The method according to claim 1 where providing the compound comprises:
making a precursor compound by coupling a first compound having Formula 4
where R is H or a protecting group and X is a functional group equivalent to a carbanion at a terminal carbon of the first compound, with a second compound having Formula 5
where R 2 is H or lower alkyl, R 3 is H or a protecting group, and Y is an electrophillic group capable of reacting with and coupling to the terminal carbon of the first compound; and
converting the precursor compound into the compound.
18 . The method according to claim 17 where X of Formula 4 is PPH 3 + .
19 . The method according to claim 17 where X of Formula 4 is a sulfone.
20 . The method according to claim 17 where Y of Formula 5 is CHO.
21 . The method according to claim 1 where the epothilone is selected from the group consisting of epothilone A, epothilone B, epothilone C, epothilone D, epothilone E and epothilone F.
22 . The method according to claim 2 where R 2 -R 5 independently are H or methyl.
23 . The method according to claim 2 where all R 6 substituents are methyl.
24 . The method according to claim 1 where providing the compound comprises:
making a precursor compound by coupling a first compound having Formula 6
where R is H or a protecting group and X is a halide, with a second compound having Formula 7
where R 1 is H or a protecting group and R 2 is H or lower alkyl; and
converting the precursor compound into the compound.
25 . The method according to claim 24 where R is a protecting group and X is bromine.
26 . The method according to claim 24 where R 1 is a protecting group and R 2 is lower alkyl.
27 . The method according to claim 26 where R 2 is methyl.
28 . The method according to claim 24 where the precursor compound is
where R 1 is a protecting group and R 2 is lower alkyl.
29 . The method according to claim 28 where R 2 is methyl.
30 . A method for making an epothilone or an epothilone analog, comprising:
forming a precursor compound having Formula 1
where R 1 is H or a protecting group, or Formula 2
where R 1 is H or a protecting group, R 2 is H or lower alkyl, and R 3 is H or a protecting group;
converting the compound having Formula 1 or 2 into a compound having a formula
where R substituents independently are H, lower alkyl, or a protecting group, R 1 is an aryl group, R 2 is H or lower alkyl, C 13 and C 12 are carbons bonded together by a single bond or a double bond, R 3 and R 4 independently are H, lower aliphatic groups, or are bonded to O in an epoxide or to N in an aziridine, C 10 and C 9 are carbons in a double bond or triple bond, and, where C 10 and C 9 are carbons in a double bond, R 5 and R 6 independently are H, or lower aliphatic, and R 7 substituents independently are selected from the group consisting of lower aliphatic groups; and
converting the compound having Formula 3 into an epothilone or an epothilone analog.
31 . The method according to claim 30 where the compound having Formula 1 is converted into the compound having Formula 2.
32 . The method according to claim 31 where the compound having Formula 2 is converted into the compound having Formula 3 by catalytic semi-hydrogenation.
33 . The method according to claim 32 where the catalytic semi-hydrogenation is accomplished using Lindlar's catalyst.
34 . A compound having according to the formula
where R substituents independently are H, lower alkyl, or a protecting group, R 1 is an aryl group, R 2 is H or lower alkyl, C 13 and C 12 are carbons bonded together by a single or double bond, R 3 and R 4 independently are H, lower aliphatic groups, or are bonded to O in an epoxide or to N in an aziridine, C 3 and C 4 are carbons in a double bond or triple bond, and where C 10 and C 9 are carbons in a double bond, R 5 and R 6 independently are H or lower aliphatic, and R 7 substituents independently are selected from the group consisting of lower aliphatic groups.
35 . The compound according to claim 34 where R 1 is
where X and Y independently are selected from the group consisting of heteroatoms.
36 . The compound according to claim 35 where X and Y independently are selected from the group consisting of O, N and S.
37 . The compound according to claim 36 where R 1 is an imidazole, a thiazole or an oxazole.
38 . The compound according to claim 34 where R 1 is
39 . The compound according to claim 34 where the compound is
40 . The compound according to claim 34 where the compound has the formula
41 . The compound according to claim 39 where C 13 and C 12 are carbons in a double bond, R 3 is H and R 4 is lower alkyl.
42 . The compound according to claim 39 where at least one of R 5 and R 6 are H.
43 . The compound according to claim 39 where R 5 and R 6 are H.
44 . The compound according to claim 39 where R 7 is lower alkyl.
45 . The compound according to claim 44 where R 7 is methyl.
46 . The compound according to 39 where C 13 and C 12 are bonded together by a single bond, and R 3 and R 4 are bonded to O in an epoxide.
47 . The compound according to claim 39 where C 10 and C 9 are bonded together by a double bond.
48 . The compound according to claim 39 where C 10 and C 9 are bonded together by a triple bond.
49 . A compound having a formula
where R 1 is H or a protecting group, and R 2 is H or lower alkyl.
50 . The method according to claim 49 where R 1 is a silyl protecting group.
51 . The method according to claim 50 where R 2 is lower alkyl.
52 . The compound according to claim 51 where R 2 is methyl.
53 . A compound having a formula
where R 1 is H or a protecting group and R 2 is H or lower alkyl.
54 . The compound according to claim 53 where R 1 is a silyl protecting group.
55 . The compound according to claim 54 where R 2 is lower alkyl.
56 . The compound according to claim 55 where R 2 is methyl.